Proline-promoted electrophilic dichloromethylation of α-enaminones via stereochemically gated resolution

Domain: neuroscience
Published: 2026-04-11
Editorial outcome: major_revision

Abstract
The direct incorporation of polyhalomethyl groups into carbonyl frameworks has traditionally relied on radical or
carbene intermediates. Here, we report a proline-mediated, closed-shell strategy for electrophilic β-
polyhalomethylation of α-enaminones using stable haloforms under mild, metal-free conditions. The reaction
proceeds with high diastereoselectivity, governed by a stereoelectronic gating mechanism that links molecular
topology to productive C-C bond formation. The platform accommodates a broad range of CX₂ donors, including
CHBr₃, CHBr₂Cl, and CBrCl₃, and reveals topology-dependent divergence: six-membered α-enaminones yield
isolable β-functionalized products, while five-membered analogues engage in a spontaneous cascade, triggered
by reaction with proline, culminating in aromatized benzenoid scaffolds. Structural, isotopic, and spectroscopic
studies support a unique reactivity manifold defined by polarity inversion and closed-shell transfer. This work
redefines electrophilic halomethane chemistry, establishes a mechanistic class for β-functionalization, and
positions α-enaminones as versatile, programmable platforms for topology-driven reactivity and downstream
synthetic elaboration.

Introduction
Organocatalysis has transformed modern synthetic chemistry by enabling precise carbonyl functionalization under
mild, metal-free conditions, with enamine catalysis occupying a central conceptual role.1 Yet a persistent and
largely unaddressed contradiction underlies this framework: carbonyl compounds bearing α-hydroxy or α-amino
substituents, motifs that appear ideally suited for enamine activation, consistently resist engagement with
secondary amine catalysts. Despite decades of methodological development, these α-substituted ketones remain
effectively inert under canonical organocatalytic conditions, revealing a fundamental limitation in how carbonyl
reactivity is currently conceptualized.2,3

Our previous studies established that this failure is intrinsic rather than circumstantial. Both α-hydroxy and α-
amino ketones reproducibly fail to form productive enamines, independent of catalyst identity or reaction
conditions. This systematic inertness indicates that classical enamine logic is fundamentally incompatible with
these scaffolds and suggests that selective functionalization of these scaffolds cannot be achieved through
incremental modification of existing organocatalytic strategies. Instead, it points to the existence of an alternative,
unrecognized reactivity regime embedded within α-substituted carbonyl architectures.2,3

Guided by this realization, we sought to identify non-canonical activation modes that exploit, rather than
circumvent, the stereoelectronic constraints imposed by α-substitution. This effort revealed a unifying mechanistic
principle across α-oxygenated and α-aminated ketones: reactivity arises from geometrically enforced polarity
inversion rather than from enamine formation. In this framework, closed-shell cascades convert structural
constraints into chemical driving forces. We demonstrated that α-hydroxy ketones undergo metal-free reductive
dehydroxylation via hydroxylamine intermediates (Figure 1A).2 In contrast, α,β-unsaturated α-aminoketones
undergo decarboxylative condensation cascades, yielding previously inaccessible polycyclic ionic liquids (Figure
1B).3 Although distinct in outcome, these transformations share a common logic in which reactivity is dictated by
stereoelectronic gating and intramolecular acid-base choreography rather than by classical nucleophile-
electrophile pairing (Figure 1C). Together, these findings redefine α-substituted carbonyls as programmable
platforms for polarity-driven reactivity.

Within this emerging paradigm, we now report a third and conceptually distinct transformation: the closed-shell,
electrophilic β-dichloromethylation of α-enaminoketones using unmodified halomethanes (Figure 1D). This
reaction enables direct C-C bond formation from simple haloform-type reagents under mild conditions, without
metals, radicals, carbenes, light, or preactivation. Under proline-buffered conditions (L-proline, K₃PO₄, CHBrCl₂),
α-enaminones undergo site- and stereoselective installation of a CHCl₂ unit at the β-position, delivering densely
functionalized scaffolds that combine a ketone, a tertiary amine, and a synthetically versatile dihalomethyl handle
in a single operation. The transformation proceeds with complete anti-stereoselectivity (>99:1) across a broad
substrate range and exhibits a characteristic yield ceiling that reflects intrinsic mechanistic partitioning rather than
incomplete conversion.

Mechanistic analysis reveals that this behavior arises from a diastereomer-resolved bifurcation at the
hydroxylamine stage. Reaction of the α-enaminone with proline generates two transient intermediates, only one
of which adopts a geometry permissive for decarboxylation and electrophilic CHCl₂ incorporation. The
mismatched diastereomer enters a kinetically stable off-cycle state and fragments cleanly upon workup. This
stereochemically gated resolution defines a previously unrecognized mode of reactivity control, in which molecular
topology rather than catalyst chirality governs productive bond formation. Comprehensive isotopic labeling,
fragment reactivity studies, and crystallographic analysis collectively exclude enamine, iminium, radical, or
carbene pathways, establishing a strictly closed-shell mechanism in which polarity inversion and stereoelectronic
gating enable electrophilic halomethyl transfer onto an electronically ambivalent β-carbon center.

The precise incorporation of di- and trihalomethyl groups (CX₂, CX₃) remains a central challenge in synthetic
chemistry, constrained mainly by a fundamental mechanistic dichotomy. Classical approaches rely on highly
reactive dichlorocarbene intermediates, require strong bases, and exhibit poor functional group tolerance.4,5 More
contemporary strategies leverage photoredox catalysis or transition metals to activate halomethanes via radical
pathways, yet these are inherently dependent on single-electron transfer or metal catalysis.6 Critically, both
carbenoid and radical methods predominantly target substrates with rigidly fixed -electron distributions, such as
electron-rich alkenes,7-11 enones,12 or acrylamides,13-15 where conjugation with electron-withdrawing groups
ensures predictable electrophilic capture (Figure 2A).16-20 This bias inherently limits their applicability, leaving a
vast domain of electronically dynamic systems unaddressed.

a-Enaminones represent a prime example of such an unaddressed frontier. Their β-position, governed by
resonance, exhibits a unique electronic ambivalence, capable of inverting between nucleophilic and electrophilic
character depending on the stereoelectronic context.3,21 This inherent dynamism, a source of unique reactivity,
simultaneously renders them recalcitrant to existing halomethylation methods, as their flexible polarization
fundamentally disrupts the fixed -electron demand of established carbene and radical protocols (Figure 2A).

Here, we invert the conventional strategy: rather than forcing α-enaminones into canonical reactivity modes or
circumventing their electronic ambivalence, we harness their electronic ambivalence as a design principle(Figure
2B). Under proline-buffered conditions, α-enaminones undergo closed-shell, β-selective dihalomethylation,
enabling direct C-C bond formation with dihalomethanes in the absence of metals, radicals, light, or carbenes.
This mechanistically distinct transformation allows the selective installation of CHCl₂ units onto electronically
neutral β-carbons. The platform extends to a broader class of polyhalomethyl donors, including CBrCl₃, CHBr₃,
and CHBr₂Cl (Figure 2C), establishing a generalizable framework for CX₂ transfer. Notably, the manifold reveals
latent cascade behavior shaped by subtle stereoelectronic and topological cues.

Together, these results reposition halomethane activation as a polarity-gated, closed-shell process and elevate α-
enaminones as programmable platforms for stereoelectronically choreographed reaction design.

Results
Discovery and optimization of α-Enaminone β-Dichloromethylation.
The initial discovery of this transformation emerged during a thermal evaluation of α-enaminone 1 with
stoichiometric L-proline in neat chloroform at 100 °C. This serendipitous finding led to the formation of the β-
dichloromethylated product 2 in a limited yet unambiguous manner (Table 1). Despite the low efficiency of this
initial observation, rigorous characterization by NMR spectroscopy, GC-MS analysis, and single-crystal X-ray
diffraction unequivocally established site-selective -incorporation of the CHCl₂ unit with strict anti-
stereochemistry relative to the pendant amine. This reactivity, the direct installation of a CHCl₂ group onto an α-
enaminone, prompted a comprehensive evaluation of reaction parameters.

Our optimization studies systematically explored the halomethane source, base identity, proline loading, solvent,
temperature, additives, atmosphere, and light exposure. These efforts converged on a narrow, optimal regime
employing CHBrCl₂ (5 equiv.), L-proline (2 equiv.), and K₃PO₄ (1 equiv.) in CHCl₃ at 100 °C for 20 h.

Under these optimized conditions, the transformation proceeded reproducibly, exhibiting clean product profiles
and providing synthetically useful yields. Importantly, no alternative permutation, including the original chloroform-
only conditions, approached this level of performance.

To definitively establish the origin of the dichloromethyl fragment, we conducted targeted isotopic tracing
experiments. Using CHBrCl₂ as the donor in CDCl₃ as solvent, analysis by ¹H/²H NMR spectroscopy and high-
resolution mass spectrometry revealed only minimal incorporation of CDCl₂, despite the large excess of
deuterated solvent. This robustly confirms CHBrCl₂ as the sole operative CHCl₂ source under the optimized
conditions. Further controls demonstrated the reaction's insensitivity to ambient light (excluding UV) and its
efficient operation under open-flask conditions. Additives, including molecular sieves, phase transfer agents, and
acid scavengers (e.g., proton sponges and ion-exchange resins), provided no improvement and, in some cases,
marginally suppressed reactivity, indicating that the system operates effectively under its native, self-buffered
conditions.

A Stereochemically gated resolution pathway to product formation.
Under the optimized conditions, the reaction exhibits high chemo- and site-selectivity; however, product 2 (Table
1) consistently plateaus at approximately 50% yield despite full substrate consumption. This reproducible ceiling
was a critical early mechanistic clue, suggesting an intrinsic constraint rather than incomplete conversion or
product instability.

To investigate these temporal dynamics, we monitored reaction progress and found that, although substrate
consumption proceeded to completion, product formation consistently plateaued at ~50% conversion. This
divergence reflects a non-classical outcome: only a defined subset of reactive intermediates evolves productively.
This observation, coupled with further mechanistic investigations detailed below, led us to propose a resolution-
type pathway as the fundamental determinant of the observed yield ceiling. The full conversion/yield profile, along
with its detailed mechanistic implications, is provided in the Supplementary Section 6.

To account for the divergent reactivity observed, we propose a stereochemically gated mechanism in which the
α-enaminone (3) reacts with L-proline, generating two diastereomeric hydroxylamine intermediates (Figure 3A).
These species, 4a and 4b, differ in their configuration and topology, predisposing them to either productive
transformation or kinetic arrest.

In the productive trajectory, intermediate 4b adopts a conformation in which the α-hydroxyl and proline carboxyl
group are spatially separated, enabling intramolecular proton transfer to the adjacent nitrogen and forming a
transient ammonium intermediate (7). This species undergoes α-decarboxylation, triggering a cascade of electron
flow that restores a nucleophilic enamine system. Substitution with CHBrCl₂ forms a β-dichloromethylated
enolamine (9), with elimination of pyrroline (8) as a byproduct.22

A capture experiment (see Supplementary Section 7) confirmed the formation of pyrroline (8) in situ, which
subsequently oligomerizes to its known trimeric condensate, consistent with literature reports.23 Final
tautomerization yields product (10) with a defined anti-configuration relative to the pendant amine. This outcome
was unambiguously confirmed by single-crystal X-ray diffraction.24

In contrast, intermediate 4a adopts a compact, bridged topology stabilized by intramolecular hydrogen bonding
between the α-hydroxyl group and proline’s carboxylate. This conformation suppresses both proton transfer and
enamine delocalization, rendering the β-position electronically inert and stalling the cascade.

No reversion to the α-enaminone or formation of a dehydrated intermediate (e.g., 6) was detected throughout the
reaction course by NMR or mass spectrometry. Upon aqueous workup, or, in some cases, during chromatographic
purification, the sequestered species undergoes clean fragmentation into the corresponding 1,2-diketone and
secondary amine. This post-reaction decomposition confirms the off-cycle nature of intermediate 4a and accounts
for the observed recovery, thereby further substantiating the proposed bifurcation model.

This stereochemical divergence, in which only one diastereomeric intermediate proceeds through the cascade
while the other becomes kinetically trapped, establishes the transformation as a resolution-type process.

Part B of Figure 3 addresses and experimentally excludes a mechanistic scenario in which the α-enaminone
undergoes proline-promoted dehydration to form an enamine-iminium intermediate (11), leading to β-substitution
with CHBrCl₂. If operative, this pathway would give rise to a series of electrophilic adducts (12, 13, 14) that
ultimately hydrolyze to a dichloromethylated diketone 15. Although 15 was detectable by NMR in crude mixtures,
it could not be isolated and was not observed by GC or high-resolution mass spectrometry. These findings indicate
that, if formed, the compound exists only in trace amounts and does not accumulate under the reaction conditions.
Taken together, the data strongly disfavor the enamine–iminium route as a productive pathway for this
transformation.

To experimentally substantiate the proposed resolution-type mechanism and account for the post-reaction mass
balance, we examined the crude mixture obtained from the dichloromethylation of α-enaminone 16, derived from
4-chlorophenyl-N-methylmethanamine and 1,2-cyclohexanedione (Figure 3C). 1H NMR analysis revealed
complete consumption of the starting material, yielding a clean 1:1 ratio of the β-dichloromethylated product 17
and the corresponding secondary amine precursor 18.

These findings support a stereochemically gated process in which diastereomeric intermediates are formed in
equal proportion. One is funneled through productive β-functionalization, while the other undergoes post-reaction
fragmentation, releasing the parent amine. This divergence is likely driven by acid- or water-mediated cleavage
during the cascade, consistent with the reaction profile. Although minor resonances of the parent diketone are
observed, its low abundance suggests rapid secondary engagement with excess proline, generating polar adducts
that are removed from the CHCl₃ phase upon workup. Crucially, the absence of detectable competing side
products upon rigorous crude analysis directly underscores the exceptional selectivity of the process. The strict
1:1 product-to-recovered amine ratio constitutes direct evidence for a resolution-type mechanism with
stereochemically defined reactivity.

Experimental investigation of the reaction mechanism.
To probe the structural features essential for reactivity, we subjected the two key fragments of the α-enaminone
scaffold, the parent cyclohexenone and its corresponding enamine, to the optimized dichloromethylation
conditions with CHBrCl₂ (Figure 4A). Neither substrate underwent any detectable transformation, ruling out
classical enamine chemistry or fragment-level nucleophilic or electrophilic engagement. In contrast, the β-
dichloromethylation proceeds cleanly only with the intact enaminone, indicating that its conjugated, ambident
electronic structure is essential for activation under closed-shell conditions. This finding corroborates our prior
observations that α-hydroxy and α-amino ketones resist proline-promoted enamine formation, further highlighting
the mechanistic divergence of α-enaminones from conventional enamine systems.2,3

To probe the mechanism of dichloromethylation, we carried out targeted experiments to assess the proposed
resolution-type divergence pathway (Figure 4) and establish whether CHCl₂ incorporation proceeds via a polar,
closed-shell process. Replacing CHBrCl₂ with CDCl₃ under standard conditions (Figure 4B) led to clean formation
of the β-deuterodichloromethylated product (2a), with full retention of deuterium confirmed by NMR and GC-MS
(see Supplementary Section 9). The incorporation of an intact CDCl₂ unit is consistent with electrophilic
substitution and excludes a carbene-based mechanism, which would be expected to induce isotopic scrambling
or partial deuterium loss.

Furthermore, a control experiment conducted under light-exclusion conditions yielded an identical product
distribution and conversion, indicating that photochemical initiation does not contribute to the transformation.
Collectively, these findings delineate a mechanistic route that departs from established CHCl₂ transfer pathways.
The transformation proceeds without free carbene intermediates (CCl₂) or enamine-type nucleophiles, instead
relying on direct electrophilic activation of CDCl₃ in the presence of the α-enaminone scaffold under proline
catalysis. This closed-shell, conjugation-gated process defines a reactivity mode not captured by existing
dichloromethylation methods.

Further support for the proposed mechanistic bifurcation arises from the stereochemical outcome of the
transformation. Single-crystal X-ray diffraction analysis of the β-dichloromethylated product 2 revealed a defined
anti-configuration between the CHCl₂ group and the pendant amine (Figure 4C).24 This stereospecific termination
is only consistent with the trajectory of the enolamine intermediate 9 proposed in the productive resolution pathway
(Figure 3). No alternative mechanistic scenario, including those involving carbene intermediates or enamine–
iminium equilibration, can rationalize the observed selective anti-selectivity. This crystallographic evidence thus
provides direct structural validation for the sequence of intermediate states inferred from kinetic and resolution-
based studies.

To probe the stereochemical partitioning proposed in Figure 4, we conducted the reaction using an equimolar
mixture of L- and D-proline (1 equiv. each; Figure 4D) under optimized conditions. Complete consumption of the
α-enaminone was observed, yet the reaction plateaued at approximately 50% yield. This result is consistent with
the formation of four diastereomeric hydroxylamine intermediates, two derived from each proline enantiomer,
only half of which undergo productive dichloromethylation. The remaining diastereomers persist as stable, off-cycle
species and are hydrolyzed during workup to regenerate the parent dione and secondary amine.

The observation that complete conversion of the starting material yields only half the product supports a
stoichiometric resolution-type scenario, in which both enantiomers of proline are required to form the full set of
intermediates. While this stereochemical divergence governs reactivity at the hydroxylamine stage, all chiral
information is ultimately lost upon formation of the enolamine intermediate, which precedes product formation. As
such, the process remains racemic, despite proceeding through diastereomerically differentiated intermediates.
Despite the use of enantiopure L-proline, the -dichloromethylation proceeds without asymmetric induction, and
the CHCl₂-bearing stereocenter is formed as a racemate, as confirmed by X-ray crystallography (see
Supplementary Section 10).

The mechanistic indispensability of proline was further clarified through targeted structural modifications.
Replacement of its α-proton with a methyl group (Figure 4E) generated a quaternary center incapable of
decarboxylation,3 resulting in complete loss of reactivity under standard conditions. This outcome directly supports
the requirement for α-decarboxylation and confirms that such elimination is precluded from a fully substituted
center.

Next, to isolate the role of the carboxylic acid, the proline core was substituted with either a methyl ester or a
primary amide (Figure 4G). In both cases, the transformation failed to proceed. These results highlight the second
essential function of the acid: to engage in an intramolecular acid–base interaction with the α-enaminone, forming
an ammonium intermediate that is necessary to drive the cascade. In the absence of either the α-proton or the
free carboxyl group, the system remains inert. Together, these observations establish that decarboxylation and
proton transfer are both mechanistic prerequisites for productive β-dichloromethylation.

The structural demands of the transformation were further dissected by evaluating individual amino acid variants
under the optimized conditions (Figure 4H). The following examples illustrate how deviations from proline’s unique
geometry compromise reactivity. For instance, N-methyl-L-alanine (24), a flexible linear amino acid, yielded only
12% of product formation. Its open-chain geometry lacks the conformational restriction necessary to stabilize the
key hydroxylamine-ammonium intermediate, thereby hindering efficient progression through the reaction
manifold. In contrast, (S)-azetidine-2-carboxylic acid, despite its cyclic constraint, failed to promote reactivity due
to excessive ring strain (23) and unfavorable spatial arrangement between the carboxyl and amino groups,
precluding formation of the internal acid–base stabilized intermediate. Pipecolic acid (25) provided the highest
level of reactivity among all tested variants, affording 15% of the desired product. However, its reduced efficiency
relative to proline likely reflects a limitation at the decarboxylation step: the six-membered ring does not support
the geometric requirements for CO₂ loss under the reaction conditions.3

Collectively, these results underscore that both intramolecular ammonium stabilization and decarboxylation
readiness are essential features governing productive β-dichloromethylation.

The lack of reactivity in α-enaminones bearing aniline derivatives (Figure 4F) further supports the proposed
mechanism. These substrates fail to undergo β-dichloromethylation, likely due to the diminished basicity of the
aniline nitrogen, which prevents formation of the key intramolecular ammonium intermediate 7 (Figure 3A). This
result reinforces the requirement for nitrogen basicity to enable α-decarboxylation and initiate a productive
cascade.

Evaluation of proline analogues 26–29 (Figure 4I) reveals a clear structure-reactivity relationship in the
dichloromethylation cascade. Analogues that preserve the core proline anchor, a five-membered ring bearing a
carboxylic acid and a secondary amine, retain activity, albeit with varying efficiency. The bicyclic derivative (26,
8%), the fused aryl analogue (27, 28%), and the cyclohexane-substituted scaffold (28, 32%) all afford product
formation under standard conditions, indicating tolerance to steric bulk and topological modification.

In contrast, the OH- or OTBS-substituted prolines 29a and 29b, bearing syn and anti γ-positions, respectively,
were completely inactive. We attribute this loss of reactivity to inhibition of the decarboxylation step, likely arising
from a combination of electron-donating effects and intramolecular hydrogen bonding. These features may
stabilize the carboxylate form and prevent access to the required geometry for CO₂ extrusion. Taken together,
these results highlight that while the proline anchor accommodates significant structural variation, substituents
that perturb electronic distribution or conformational flexibility at the γ-position can disrupt key activation steps
and render the system unreactive.

The unique reactivity observed in the discovered transformation was strictly dependent on the presence of K₃PO₄
as the base. Other inorganic and organic bases, including carbonates, acetates, amines, and stronger alkoxides,
uniformly failed to support the formation of the product. The critical role of K₃PO₄ likely stems from its dual function
as a moderately basic, non-nucleophilic inorganic salt and a buffering agent capable of sustaining the narrow
acid–base equilibrium necessary for cascade initiation. Specifically, its basicity appears to promote the formation
of the key proline-derived ammonium intermediate 7 (Figure 3A) through controlled proton transfer to the α-
enaminone, without over-deprotonating the substrate or destabilizing sensitive intermediates. In contrast, weaker
bases are insufficient to initiate this process, while stronger or less selective bases may disrupt the delicate
balance required for α-decarboxylation or induce degradation of CHBrCl₂. The inability of other bases to replicate
the reaction outcome underscores the crucial role of K₃PO₄ in maintaining the precise reactivity window necessary
for -dichloromethylation.

Scope.
The scope of this electrophilic -dichloromethylation manifold was evaluated across a structurally diverse panel
of -enaminones (Figure 5). Under optimized conditions, substrates bearing benzylic, aliphatic, and heterocyclic
N-substituents underwent clean and selective transformation. Products were consistently obtained as single
diastereomers with exclusive anti-configuration between the -CHCl₂ group and the pendant amine, as confirmed
by ¹H NMR spectroscopy and unambiguously validated by single-crystal X-ray diffraction of representative
compound 2. No syn-diastereomers were detected (>99:1 dr), underscoring the high fidelity of the proline-
mediated stereochemical gating. The isolated yields for these adducts (up to 42%) are consistent with the intrinsic
resolution mechanism governing the reaction. As detailed above, the reaction path bifurcates: ~50% of the
racemic substrate enters the productive cascade. At the same time, the remainder is channeled into a non-
productive, off-cycle state that fragments cleanly upon workup. This trade-off ensures high diastereoselectivity
and operational simplicity without the need for complex chiral auxiliaries or transition metals.

We further probed the electronic and steric limits of the nitrogen substituent. Substrates bearing functionalized or
heteroatom-containing N-residues (e.g., compounds 42, 45, 46) were well-tolerated, demonstrating compatibility
with polar functionality. Conversely, sterically bulky N-tert-butyl analogs proved synthetically inaccessible due to
intrinsic substrate instability. These results define a predictable scope for the -dichloromethylation manifold
centered on secondary amine-derived enaminones.

Electrophilic generality: beyond dichloromethylation.
To challenge the broader applicability of this "electrophilic haloform" activation mode, we examined whether the
proline-buffered conditions could mediate the transfer of alternative polyhalomethyl units. Selected -enaminones
were exposed to a panel of haloform-type donors, including CHBr₃, CHClBr₂, and CBrCl₃. Remarkably, under
unmodified conditions, each reagent cleanly furnished the corresponding gem-dibromo, mixed gem-halide, or
polyhalogenated adduct (Figure 6A). To the best of our knowledge, the direct, closed-shell transfer of di- or
trihalomethyl units from these stable reagents to conjugated carbonyl systems is without precedent, establishing
this protocol as a generalizable platform for electrophilic gem-dihalomethylation.

Ring size divergence and aromatization cascade.
Expanding beyond six-membered rings, our investigation into ring-size effects revealed a profoundly divergent
transformation for five-membered -enaminones, contrasting sharply with the inherent instability observed in
seven-membered analogs under the reaction conditions. Upon initial dichloromethylation, these five-membered
substrates rapidly trigger a complex, proline-orchestrated cascade dictated by their unique constrained topology
(Figure 6B). The resulting dichloromethylated intermediate (64) first undergoes rapid condensation with proline to
form a transient enamine (65), which subsequently tautomerizes to a highly reactive iminium species. Crucially,
subsequent deprotonation generates a stabilized azomethine ylide (68),25 characterized by a potent carbanionic
center adjacent to the iminium nitrogen. This strategically positioned ylide then initiates a sequence of skeletal
rearrangements, involving the formation of a pyrrolidine-fused intermediate (70), culminating in spontaneous ring
expansion (71), elimination (72), and aromatization. The net outcome is the formation of densely substituted
aromatic products that bear both pyrrolidine and benzylamine motifs (73). This intricate, topology-dependent
pathway, conspicuously absent in larger ring systems, highlights a fundamental bifurcation in reactivity within the
enaminone manifold and offers a concise, metal-free route to complex aromatic architectures from structurally
simple cyclic precursors.

Synthetic utility and derivatization. To underscore the synthetic potential of these adducts, we demonstrated
the versatility of the -dichloromethylated synthon as a functional linchpin. Downstream transformations afforded
diverse functionalities, including an (E)-configured vinyl chloride, a ketal, an acetal, and an enol ether (Figure 6C).
These examples demonstrate the utility of the installed gem-dihalomethyl motif as a gateway to structural
complexity.12,26

The conversion of the CHCl₂ group to the corresponding aldehyde,27 further extends this reactivity space: the
resulting carbonyl condenses efficiently with primary amines derived from Amphenicol (79) and Tryptamine
(80),28,29 enabling rapid assembly of hybrid structures that integrate β-dichloromethyl enaminone cores with
bioactive motifs (Figure 6D). Collectively, these results establish the CHCl₂ unit as a strategically reconfigurable
handle for skeletal editing and late-stage conjugation to complex small-molecule architectures.

Methods
General procedure for dichloromethylation of α-enaminones.
To a reaction tube equipped with a magnetic stir bar were added proline (2.0 equiv., 0.6 mmol, 69.2 mg), K₃PO₄
(1.0 equiv., 0.3 mmol, 63.7 mg), the corresponding α-enaminone (1.0 equiv., 0.3 mmol), and chloroform (0.075 M,
4 mL), followed by bromodichloromethane (5.0 equiv., 1.5 mmol). The tube was then tightly sealed, and the
mixture was stirred at 100 °C for 10-72 h. After cooling to room temperature, the reaction mixture was concentrated
under reduced pressure, and the crude was purified by chromatography to afford the corresponding
dichloromethylated product.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "Tsvelikhovsky et al report the β-dichloromethylation of α-enaminones mediated by proline to obtain the trans- addition product via a novel, closed-shell mechanism. This transformation is very elegant and represents the first dichloromethylation of a typically underexplored class of substrates. I believe this work is suitable for publication in Nature Communications once the following points have been addressed.\n1) The authors stipulate that the reaction was conducted in the absence of light, however in the supporting information there is no indication that the reaction was conducted under ‘dark’ conditions i.e. wrapped in foil and whether this affects the yield of the reaction.\n2) ‘kinetic profiling’ was conducted however, no orders in reagents etc have been reported and from what I gather from Figure 3 is that the conversion of the reaction was monitored rather than rate.\n3) I personally found figure 3 in its current form confusing, I like the idea of summarizing the results but surely an optimization table (like the one in the supporting information) gives the same information.\n4) Could the authors comment if they observed the proposed pyrroline decomposition product from the proline rather than just citing the literature. This should be identifiable via GCMS and 1H NMR spectroscopy.\n5) There is some colloquial language being used throughout (e.g. NMR which should be NMR spectroscopy etc).\n6) The authors mention that initial findings were carried out using CHCl3 as solvent but a higher yield was observed using HCCl2Br. Can the CHCl3 be ruled out as the source of ‘HCCl2’ given the high concentration of CHCl3 in comparison to HCCl2Br? Also, the isotope labelling was conducted using CDCl3 without the use of HCCl2Br – would looking at the Singleton type KIE measurements be more useful in the mechanistic determination rather than the 1H/2H isotope labelling study.\n7) On page 6 of the manuscript, it is stated that complete conversion of starting material is observed, yielding a clean 1:1 ratio of the desired product 17 and the corresponding secondary amine. I was wondering if you observe the other fragment from the unproductive pathway?\n8) On page 8, when other bases were screened, was any dichlorocarbene addition products (gem-dichlorocyclopropanation) or carbene dimerization products (C2Cl4) observed.\n9) The substrate scope demonstrates the ability to change the amine/enamine fragment but the enone fragment remains as a 6-memebered ring, could the authors comment on if smaller/larger ring systems would also work. Also could the authors comment on why only a single addition to the α-enaminones (product 45) when there are two initially identical sites for reactivity and does this have something to do with the low isolated yield for this compound?\n10) In the supplementary information, some of the compound characterization needs addressing, especially the 1H NMR spectroscopic data. If a signal has a defined multiplicity, then it needs to have a coupling constant. If it is a multiplet, then a range with no coupling constant should be reported.\n11) Starting material 2-((4-methoxybenzyl)(methyl)amino)cyclohex-2-en-1-one is missing a proton in the characterization. This compound should have 19 protons but only 18 are reported.\n12) It would be nice for compound 2a to if a 2H NMR spectrum was obtained to make sure there is deuterium incorporated in the compound.", "reviewer_2": "Tsvelikhovsky and co-workers reported the proline-promoted dichloromethylation of α-enaminones via stereochemically gated resolution. The selective β-dichloromethylation of α-enaminones was achieved with anti-stereochemistry. However, the yield of target product is two low (from 42%-6%) along with the decomposition of the enaminones. The low yield of this conversation largely decreased the practicality of this reaction. The current required further optimizations.\nOther comments 1. Why the reaction plateaued at 50% yield when using an equimolar mixture of L- and D-proline? While product 2 was obtained in 30% yield in the presence of only L-prolin?\n2. CHCl3 can also be used as the CHCl2 source as listed in Figure 3. So, how can the authors deem the CHCl2 in product was derived solely from CHBrCl2?\n3. The authors repeatedly emphasized the derivation potentials of CHCl2 group. Derivation experiments should be conducted, for example, convert CHCl2 to CHO, etc.", "reviewer_3": "Relevant and interesting paper by Tsvelikhovsky and team.\nThe dichloromethylation of 6-membered ring enaminones is designed, analyzed and well described. Several parameters are considered, a robust mechanistic explanation is given and a number of functionalized derivatives (trans stereochemistry) are produced in a reliable manner. The text is well written, the figures are didactic, and the Supplementary Information is very illustrative, full of details, the new compounds well characterized and with high degree of purity (copies of the NMR spectra).\nI find that the manuscript is a nice piece of work, and can be publishable, but in a specialized journal, devoted to Organic Chemistry (J. Org. Chem.; Org. Lett, Org. Biol. Chem., Adv. Synth. & Catal., etc.), but it lacks (in my opinion) novelty, generality and relevant synthetic applications to be published in Nat. Commun. Nevertheless, it is an important reaction, with suggestive implications, reflecting a serious research.\nPoints that may be addressed to raise scientific level and questions related.\na) Around 50 rxns of this type (HA addition to the double bond of 6-membered enaminones are described (a few organometallic couplings, and some radical additions, mostly). The processes described are new. However, the yield is, at most, 50%; in some cases, even lower.\nAuthors may check (computationally or by other means) why the “wrong” stereoisomer does not equilibrate with the productive one, being the addition step dynamic? Also, is this process suitable for a catalytic method?, as 2 equiv of proline are needed.\nb) Only dichloromethylation? Why not other C+ species or even X+ or other electrophiles? The mechanism should be also operative, right? In this endeavor, the audience should have evidences (in this system) of the usefulness of a number of the described adducts. Please, show some examples of synthetically relevant transformations of the CHCl2 group (drugs, commodities, NPs, probes…) that justify the importance of the method.\nb) Stereochemistry. Did authors rule out any stereochemical induction by proline in the generation of the new stereogenic centers (given a favored trans stereochemistry, if the C*-CHCl2 centre is controlled, may led to good overall stereoselection). This must be clearly stated (I do not find the sentence in the text). Incidentally, this would increase the value of the discoveries.\nc) Scope. At the moment. quite restricted. Only 6-membered enaminones are analyzed (and other types of enaminones?). Also, the amine component lacks generality (NH, tert-groups, limitations in functionalizing complex residues linked to the N atom?). Incidentally, why compound 45 do not keep reacting to dichloromethylate the other enaminone group? The isolated yield is only 6%, And the rest?\nI believe that if a relevant number of these issues would be successfully addressed, the manuscript may gbe publishable in Nat. Commun. Otherwise, in my opinion, it should be directed to a specialized journal."}, "author_response": "Summary of key revisions and experimental additions\nWe thank all three reviewers for their thoughtful, constructive, and rigorous evaluations.\nWe begin by clarifying a central conceptual feature that may not have been sufficiently emphasized in the previous version:\nthis study introduces a new organocatalytic approach in which productive bond formation is governed not by conventional\ncatalyst-controlled asymmetry but by intermediate-level stereochemical resolution. This resolution-gated architecture enables\nprecise control, absolute site selectivity, high anti-diastereoselectivity (>99:1 dr), and closed-shell activation of halomethanes\nunder metal-free, radical-free, and light-free conditions, thereby defining the core innovation of the work.\nAmong the points raised, yield was noted as a limitation. We have optimized the transformation as far as possible, but it is\nimportant to highlight that the ~50% yield reflects not a shortcoming of the method, but a direct and inherent consequence of\nits resolution-based design. This yield reflects the selectivity-driven nature of the transformation, which operates by\nfundamentally different principles from those of traditional catalytic cycles. While the transformation has an intrinsic yield\nceiling, it is operationally simple, proceeds cleanly, and affords stable products without competing side reactions.\nImportantly, the reviewers’ feedback prompted us to explore the broader potential of this design, leading to the discovery of\nan extended electrophilic polyhalomethylation manifold that substantially increases the scope and impact of the chemistry.\nOur additions and strategic revisions include:\n• Expanded scope & generality: A significant expansion of the main substrate scope (Figure 6), now incorporating\nadditional α-enaminones with varied N-substitution and ring systems. This includes an unprecedented demonstration of\nelectrophilic generality, wherein alternative dihalomethylating agents (CHBr₃, CBrCl₃, CHClBr₂) cleanly generate gem-\ndibromo and mixed gem-halogenated products under unified, mild, and metal-free conditions.\n• Novel divergent reactivity: The discovery of a previously unreported aromatization cascade unique to five-membered\nα-enaminones, in which β-dichloromethylation triggers an in situ rearrangement culminating in novel substituted benzene\nderivatives bearing both pyrrolidine and benzylamine functionalities (Figure 7).\n• Enhanced synthetic utility: Detailed exploration of downstream derivatizations of b-dichloromethylated products\n(Figure 7), demonstrating their synthetic versatility through oxidation, substitution, and elimination transformations.\n• Mechanistic validation: Comprehensive mechanistic isotope-tracing experiments confirming that CHCl incorporation\n2\narises predominantly from CHBrCl , with minimal contribution from CHCl .\n2 3\n• Improved purification strategy: We also optimized the purification protocol for selected compounds, resulting in\nsignificantly higher isolated yields for several representative products (see Supplementary Information).\nThese results not only fundamentally broaden the reaction scope and highlight its generality but also reveal new and divergent\nreactivity modes associated with ring size and electrophile identity. All new data are meticulously reflected in revised figures\nand detailed in the Supplementary Information, including complete experimental procedures, spectra, and mechanistic\nannotations.\nA concise summary response table is included at the end of this document, providing a rapid overview of all reviewer\ncomments, along with the corresponding experimental actions and manuscript updates, to support efficient evaluation.\nReviewer #1\nGeneral Comments: We thank Reviewer #1 for the close and careful reading of our manuscript, and for raising a number of\nconstructive and technically focused points. The comments reflect deep engagement with the work and were instrumental in\nidentifying areas where additional clarification or supporting data could strengthen the overall presentation. We have\nthoroughly addressed each point, incorporating new experimental data, textual refinements, and clearer structuring where\nrelevant. Our itemized responses are provided below.\nComment 1: The authors stipulate that the reaction was conducted in the absence of light, however in the supporting information there\nis no indication that the reaction was conducted under ‘dark’ conditions i.e. wrapped in foil and whether this affects the yield\nof the reaction.\nResponse: To directly address this point, we conducted a control reaction in a UV-protective tube wrapped in aluminum foil.\nNo deviation in yield or reaction profile was observed, indicating that ambient light has no measurable effect on the\ntransformation.\nChanges Made: The following sentence was added to the main text and the SI section:\n“Furthermore, a control experiment conducted under light-exclusion conditions yielded an identical product distribution and\nconversion, indicating that photochemical initiation does not contribute to the transformation.”\nComment 2: kinetic profiling’ was conducted however, no orders in reagents etc have been reported and from what I gather\nfrom Figure 3 is that the conversion of the reaction was monitored rather than rate.\nResponse: We thank the reviewer for the clarification and fully agree: the original Figure 3 reflects a time-resolved\nconversion/yield profile rather than a kinetic rate analysis. To avoid confusion, we have removed this figure from the main text\nand placed it in the Supplementary Information, where it is now described solely in terms of temporal behavior and branching\ndynamics.\nWhile no formal rate constants or reaction orders were extracted, we take this opportunity to clarify the roles of L-proline and\nK₃PO₄, which may appear mechanistically ambiguous in the absence of kinetic discussion:\n• L-Proline operates as a stoichiometric, bifunctional reagent, enabling productive transformation while irreversibly trapping\nthe reactive diketone fragment generated along the non-productive pathway. Its function is structural and irreversible rather\nthan catalytic or rate-determining. Given that proline acts as a stoichiometric reactant rather than a catalyst in this specific\nmanifold, traditional kinetic order analysis is not applicable in the standard sense.\n• K₃PO₄, based on prior studies from our lab [Ref. 17: Chem. Sci. 2019, 10, 10267], acts not as a traditional base but as a\nbuffering partner that modulates the protonation state of proline-derived intermediates. Variations in phosphate concentration\ndid not affect conversion or yield and were therefore not incorporated into the kinetic framework.\nChanges Made: The profile part of the Figure 3 has been moved to the Supplementary Information and redefined as a\ntemporal conversion profile. The main text now clarifies this in the 'Mechanistic Insights: the resolution-limited yield' subsection\nof the Results section, stating that “The full conversion/yield profile, along with its detailed mechanistic implications, is provided\nin the Supplementary Information section.”\nComment 3: I personally found figure 3 in its current form confusing, I like the idea of summarizing the results, but surely an\noptimization table (like the one in the supporting information) gives the same information.\nResponse: We recognize that the current summary format may obscure key\nO Me L-Proline O Me\ntrends for some readers. To address this, we have revised Figure 3 to improve N Ph CHCl2 source N Ph\nvisual clarity and annotation, and we have cross-referenced it directly to conditions\nSupplementary Table to facilitate navigation between the condensed 1 2\nCHCl2\npresentation and the whole experimental dataset. Parameters Variants screened Optimal\nChanges Made: Figure 3 has been revised for clarity, and relevant conditions\nCHBrCl2\nare now directly cross-referenced to entries in Supplementary section. CHCl2 source CH2Cl2, CCl4, CHCl3, CHBrCl2\n5.0 equiv.\nThe accompanying paragraph in the main text ('Discovery, optimization, and\nmechanistic foundation' subsection of Results) has been thoroughly revised Base NEt3, K2CO3, NaOAc, Na2CO3, K₃PO₄\nand reflects these refinements:\n0.5 – 5 equiv. KOAc, K3PO4, DIEA, Cs2CO3, DBU 1.0 equiv.\n“The initial discovery of this transformation emerged during a thermal Proline Pyrrolidine, morpholine, piperazine,\nnone\nevaluation of α-enaminone 1 with stoichiometric L-proline in neat chloroform substitutes piperidine, pyrroline\nat 100 °C. This serendipitous finding led to the formation of the β- Proline loading 0.5 – 5 equiv. 2.0 equiv.\ndichloromethylated product 2 in a limited yet unambiguous manner (Figure 3).\nDMF, DMSO, DCM, THF, CHCl3,\nDespite the low efficiency of this initial observation, rigorous characterization Solvent MeOH, pyridine, toluene, dioxane, CHCl3\nby NMR spectroscopy, GC-MS, and single-crystal X-ray diffraction\nCHBrCl2 (neat)\nunequivocally established site-selective b-incorporation of the CHCl unit with Temperature (°C) 70 – 120 100\n2\nstrict anti-stereochemistry relative to the pendant amine. This unprecedented Time (h) 1 – 48 20\nreactivity, the direct installation of a CHCl group onto an α-enaminone,\n18-crown-6, TBAB, molecular, H2O\nnone\nprompted a comprehensive evaluation of reaction parameters.\n(5-50 vol%),\nOur optimization studies systematically explored the halomethane source, DMAP, Amberlyst A26, AmberChrom\nAcid scavengers/\nbase identity, proline loading, solvent, temperature, additives, atmosphere, proton sponges 1x8, Amberlite IRA-400, 1,8- none\nBis(dimethylamine)naphthalene\nand light exposure. These efforts converged on a narrow, optimal regime\nemploying CHBrCl (5 equiv.), L-proline (2 equiv.), and K PO (1 equiv.) in Operational Open air, dry glassware, inert Ambient, no\n2 3 4 conditions atmosphere (N2), UV-free light additives\nCHCl at 100 °C for 20 h. Under these optimized conditions, the\n3\ntransformation proceeded reproducibly, exhibiting clean product profiles and providing synthetically useful yields. Importantly,\nno alternative permutation, including the original chloroform-only conditions, approached this level of performance.\nTo definitively establish the origin of the dichloromethyl fragment, we conducted targeted isotopic tracing experiments. Using\nCHBrCl as the donor in CDCl as solvent, analysis by ¹H/²H NMR spectroscopy and high-resolution mass spectrometry\n2 3\nrevealed only minimal incorporation of CDCl , despite the large excess of deuterated solvent. This robustly confirms CHBrCl\n2 2\nas the sole operative CHCl source under the optimized conditions. Further controls demonstrated the reaction's insensitivity\n2\nto ambient light (excluding UV) and its efficient operation under open-flask conditions. Additives, including molecular sieves,\nphase transfer agents, and acid scavengers (e.g., proton sponges and ion-exchange resins), provided no improvement and,\nin some cases, marginally suppressed reactivity, indicating that the system operates effectively under its native, self-buffered\nconditions.”\nComment 4: Could the authors comment if they observed the proposed pyrroline decomposition product from the proline\nrather than just citing the literature. This should be identifiable via GCMS and 1H NMR spectroscopy.\nResponse: We thank the reviewer for this point.\nWe designed a capture experiment to assess the\nproline-derived pyrroline species. The reaction was\nN\nquenched at half-conversion (10 h) and analyzed N N\ndirectly from a sealed high-pressure tube in CDCl₃\nby ¹H NMR, with complementary GC-MS on the\ncrude.\n• The ¹H NMR shows the starting α-enaminone,\nthe β-dichloromethylated product, and the\nliberated secondary amine.\n• For the proline-derived fragment, the dominant O M N e\nsignals correspond to the known pyrroline\nCHCl2\ntrimer, consistent with the reported spontaneous\noligomerization/condensation of pyrroline under\nmild conditions (DOI: 10.1038/s41598-017-08217-1).\nO M N e\n• Free (monomeric) pyrroline is not observed by\n¹H NMR, which we attribute to its high volatility;\nhowever, GC-MS shows a low-intensity trace at\nthe expected mass of pyrroline, indicating that a\nMe\nHN\nsmall fraction remains uncondensed.\nThese observations indicate that pyrroline is formed\nin situ but is captured predominantly as its trimeric condensate, with only trace amounts of the monomer detectable by GC-\nMS. The data are consistent with reports in the literature on the volatility and rapid trimerization of pyrroline and support the\nfragmentation-condensation pathway proposed in the main text.\nChanges Made: We added a brief note to the 'Stereochemical divergence defines productive and off-cycle pathways'\nsubsection of the Results section, and included a n overlay of the ¹H NMR spectrum of the half-quenched crude in the\nSupplementary Information (see SI and accompanying procedure).\n“A capture experiment confirmed the formation of pyrroline (8) in situ, which subsequently oligomerizes to its known trimeric\ncondensate, consistent with literature reports”.\nComment 5: There is some colloquial language being used throughout (e.g. NMR which should be NMR spectroscopy etc).\nResponse: We have carefully reviewed the manuscript and Supplementary Information to ensure that all analytical techniques\nare described with formal precision. Where appropriate, abbreviated terms such as “NMR,” “GC-MS,” and “X-ray” have been\nupdated to their complete forms: “NMR spectroscopy,” “gas chromatography–mass spectrometry,” and “single-crystal X-ray\ndiffraction,” respectively.\nChanges Made: Terminology has been standardized across the main text and SI to reflect formal usage of analytical methods.\nComment 6: The authors mention that initial findings were carried out using CHCl3 as solvent but a higher yield was observed\nusing HCCl2Br. Can the CHCl3 be ruled out as the source of ‘HCCl2’ given the high concentration of CHCl3 in comparison to\nHCCl2Br? Also, the isotope labelling was conducted using CDCl3 without the use of HCCl2Br – would looking at the\nSingleton type KIE measurements be more useful in the mechanistic determination rather than the 1H/2H isotope labelling\nstudy.\nResponse: We thank the reviewer for this meaningful and insightful comment. We agree that the original main text did not\nsufficiently distinguish between the initial chloroform discovery experiment and the optimized CHBrCl₂ protocol, and we have\nnow clarified this in the revised manuscript.\nWe initially discovered the transformation serendipitously while using CHCl₃ as a solvent. However, despite its abundance,\nCHCl₃ alone resulted in low yields and incomplete conversion. Upon switching to CHBrCl₂, we observed clean and complete\nformation of the β-dichloromethylated product across a wide range of α-enaminone substrates.\nTo directly address the reviewer’s question regarding the origin of the CHCl₂ fragment, we performed a targeted isotopic\ntracking experiment: CHBrCl₂ was used as the dichloromethyl donor in CDCl₃ as solvent, and the resulting product mixture\nwas analyzed by ¹H NMR, ²H NMR, and HRMS. The data revealed only trace incorporation of CDCl₂, despite the significant\nexcess of CDCl₃. This outcome confirms that CHBrCl₂, not CHCl₃, is the kinetically and mechanistically relevant CHCl₂ source.\nAlso, as part of our broader exploration, we examined whether alternative haloform-type donors (CHBr₃, CHClBr₂, CBrCl₃)\ncould deliver related transformations under otherwise identical proline-buffered conditions. In all cases, the expected geminal\ndi- or tri-halogenated products were obtained cleanly, without any CHCl₂ incorporation, further confirming the origin-specificity\nand selectivity of the transformation.\nRegarding the suggestion to perform Singleton-type KIE measurements, we appreciate the idea and believe this approach is\nmost effective for probing primary isotope effects in rate-determining bond-breaking steps. Our transformation involves the\ntransfer of an intact CHCl₂ unit, not C–H or C–D bond cleavage, and the labeling data described above offer a more direct and\nunambiguous probe of reagent origin.\nWe again thank the reviewer for highlighting this critical mechanistic point, which is now fully clarified in the revised manuscript.\nChanges Made: The opening paragraph of the “Results” section has been substantially revised. See the revised paragraph\nas our response to Comment 3.\nComment 7: On page 6 of the manuscript, it is stated that complete conversion of starting material is observed, yielding a\nclean 1:1 ratio of the desired product 17 and the corresponding secondary amine. I was wondering if you observe the other\nfragment from the unproductive pathway?\nResponse: Mechanistically, the unproductive diastereomer undergoes fragmentation into a secondary amine and the parent\n1,2-diketone. Although minor resonances of the diketone are observable by NMR in the crude mixture, its low abundance is\nconsistent with rapid secondary capture by the second equivalent of proline, which serves a dual functional role: promoting\nthe productive transformation and trapping the reactive dione fragment to prevent competitive side reactivity.\nUnder standard conditions, this buffer-like excess of proline engages the diketone to form highly polar, downstream species\nsuch as enamines, iminium salts, or possibly oxazolidinone-type adducts. These species are not readily retained in the CHCl₃\nphase and are therefore removed during aqueous workup. Their presence is occasionally detectable by 1H NMR in the crude\nmixture as minor baseline features, but does not interfere with the isolation or quantification of the major products.\nAs shown in Figure 4C, the crude mixture shows a clean 1:1 ratio of product 17 to the liberated secondary amine 18. Residual\npolar proline-dione adducts are observable as diffuse baselines, but no competing side products are evident. This further\nsupports the role of proline in fragment resolution and reinforces the process's clean selectivity.\nThe only other minor byproduct observed during the transformation is pyrroline 8 (Figure 4A), formed via decomposition of\nproline itself. This species was independently verified and discussed in our response to Comment 4.\nComment 8: On page 8, when other bases were screened, was any dichlorocarbene addition products (gem-\ndichlorocyclopropanation) or carbene dimerization products (C2Cl4) observed.\nResponse: This is a valuable mechanistic question. We agree that under strongly basic conditions, particularly with alkoxide\nbases or tertiary amines, the generation of free dichlorocarbene (:CCl₂) from CHBrCl₂ or CHCl₃ is chemically feasible.\nHowever, in our hands, such conditions failed to yield any dichloromethylated product, nor did they lead to detectable formation\nof known :CCl₂-derived byproducts (e.g., gem-dichlorocyclopropanes or tetrachloroethene), as confirmed by both ¹H NMR and\nGC-MS analyses of crude mixtures.\nGiven the complete lack of productive reactivity under these conditions, we did not pursue further mechanistic investigation\ninto the involvement of carbene in these specific systems. The absence of both target and carbene-type side products strongly\nsuggests that even if :CCl₂ is generated, it does not engage productively with α-enaminones, which remain completely inert.\nInstead, we emphasize that the observed reactivity arises uniquely under buffered conditions created by the cooperative\nacid–base pairing of L-proline and K₃PO₄. This dual system, which we previously characterized (Chem. Sci. 2019, 10, 10267;\nGreen Chem. 2023, 25, 5916), appears essential for both activating the substrate and controlling the progression through the\nstereochemically gated resolution pathway.\nAlternative bases that either fail to generate such buffered microenvironments, or do not enable formation of key nucleophilic\nproline–enaminone intermediates (e.g., hydroxylamines 4a/4b) universally resulted in no reaction. These observations are\nconsistent with a non-carbene mechanism involving a pre-equilibrium intermediate and differ from classical base-promoted\ncarbene chemistry.\nImportantly, no products consistent with carbene-type pathways, such as cyclopropanation or other CCl₂-insertion adducts,\nwere detected in crude mixtures or isolated fractions (NMR, GC-MS, HRMS analyses), further excluding a dichlorocarbene\nmechanism.\nChanges Made: The following sentence was added to the main text, integrated into the 'Isotopic labeling supports electrophilic\nCHCl₂ transfer via a distinct mechanism' subsection of the Results section:\n“Importantly, no products consistent with carbene-type pathways, such as cyclopropanation or other CCl₂-insertion adducts,\nwere detected in crude mixtures or isolated fractions (NMR, GCMS, HRMS), further excluding a dichlorocarbene mechanism.”\nComment 9: The substrate scope demonstrates the ability to change the amine/enamine fragment but the enone fragment\nremains as a 6-memebered ring, could the authors comment on if smaller/larger ring systems would also work. Also could the\nauthors comment on why only a single addition to the α-enaminones (product 45) when there are two initially identical sites\nfor reactivity and does this have something to do with the low isolated yield for this compound?\nResponse: We thank the reviewer for raising this critical, mechanistic, and scope-related point. We agree that the initially\nsubmitted scope focused primarily on six-membered α-enaminones. To explore ring-size effects, we prepared both larger (7-\nmembered) and smaller (5-membered) ring analogs. The 7-membered α-enaminone proved unstable and underwent rapid\ndegradation under reaction conditions. We attribute this to conformational destabilization and reduced overlap between the\nenaminone π-system and the ring scaffold, resulting in poor orbital alignment and increased lability.\nFive-membered α-enaminones, on the other hand, revealed unexpected and intriguing behavior. These substrates slowly\nundergo β-dichloromethylation under the standard conditions. However, the resulting intermediates display heightened\nelectrophilicity and rapidly engage in further proline-mediated transformations. Rather than remaining stable, the\ndichloromethylated species proceed through a cascade of rearrangements culminating in aromatization, affording novel\nproducts. This unprecedented\nreactivity, although resulting in - - I P n r o a d ll u e c n ts tr i e 5 s 5 , - 5 cr 7 u d w e e r 1 e H o N b M ta R in e a d n a e l x y c s l i i s s i r v e e v ly e a a l s e d th a e 1 a : n 1 t i r - a d t i i a o s o te f r p e r o o m du e c r t to parent amine a b c . . . I C M s o o a n l x a v . t e e th r d s e i y o o i r n e . l y d (% i e (% l ) d — ) ( % — D ) e P — t u e r r U i m fi p e in p d e e p d r r l o f im r d o u i m t c b t c a o r s u b e d ta d e i n o 1 e n H d o N a b M f s te e R r r v c / e h G d r C o c m on a v to e g rs ra io p n h y and inherent 1:1 product/amine resolution\nmoderate isolated yields due to A. CF3 CF3\ncompeting pathways, highlights a O Me CBrY (1-5 equiv) O Me O Me O S O Me\nfundamentally distinct and N R L-proline (2 equiv) N R N N Me N\ns\nW\ny\ne\nth\nh\ne\na\nt\nv\nic\ne\na l\nn\nly\no w\nva\ni\nl\nn\nu\nc\na\nl\nb\nu\nl\nd\ne\ne d\ntr a\nt\nn\nh\ne\nf o\nr\nr\ne\ns\na\nut\nlt\nio\nin\nn\n.\nC\n=\nH K\nd\nC3\ni /\nP\ntl\nr\ni\n,\nh\n1 4\na\n0\nl\n(\no\n1 0\n- m\ne ° C q\ne\nu\n,\nt h\ni 2 v\ny\n0 )\nl s\nh\no u r c e 54\nCY CCl3 a b\nc\n.\n.\n.\n2\n1 5\n4\n0 0 0 CHBr2 a b\nc\n.\n.\n.\n2\n1 5\n6\n0 0 0\nd.r. 87:13\nCHBrCl a b\nc\n.\n.\n.\n3\n1 5\n1\n0 0 0\nstructures in Figure 7 and added the\nproposed mechanism and full spectral B.\ndata (NMR, GC-MS, IR analyses) to\nthe Supplementary Information.\nO Me L-proline (2 equiv) N N a b . . 1 5 0 0 0 N a b . . 1 5 0 0 0 N a b . . 9 4 4 7\nR bo e t g h a r α d - i e n n g a m co in m o p n o e u n u d n its 4 5 a : re a lt in h i o ti u a g ll h y N R C C H K H C3P C l3 O l , 2 1 B 4 0 r ( 1 0 (5 e ° C e q q u , u i 2 v i 0 ) v ) h M N e R M N e c. 30 M N e c. 18 M N e c. 28\n58 59 60 C l 61 O M e 62 + 62a1\nidentical, mono-dichloromethylation is\nobserved. This selectivity likely arises Proposed mechanism\nf c S r o o p n m e s c e if q i e c u l a e e l c l n y t c r o , e n s i c o C f H a th C n e l d ₂ fir c s o t i n n s c f u o o b r r m s p t o i a t r u t a i t o i t o i n o n a n . l 6 O 3 N R 1 R 2 + ( 2 e N H q u i v ) C O 2 H o p t i m i C z e H s d C l o c l w 2 o B n r d i t i o n s 6 O 4 CH N C R l2 1R2 C (B H L = C -p l C 3 H r , o l B 1 l o in 0 r e 0 B ° r) C N C N O R1 2 R H 2 N C N O R1 2 R H 2 N C N O HR 2 1R2\ndeactivates the second site through traces 65 C H C l2 66 C H C l 2 67 CHCl2\ninductive withdrawal and disruption of spontaneous aromatization ring expansion dec p a r r o b m ox o y te la d tion - CO2\nconjugation. Simultaneously, the\nmolecule adopts a conformation that N N N N N Azomethine ylide N\nprecludes a second resolution-type NR1R2 BH4 NR1R2 NR1R2 NR1R2 (imm c in a iu rb m a - n s i t o a n b ) ilized N H R1R2\ntransformation. We attempted to NR1R2 - HCl - Cl\nmodulate reaction parameters to 73 not 7 d 2 e t e c t e C d l 71 C l 70 C H C l 2 69 C H C l 2 68 CHCl2\naccess bis-substitution but were\nC.\nunsuccessful, and due to the low\nisolated yield and complexity, the O M N e Ph OMe M N e O O M N e O O M N e O O M N e\ncompound was removed from the final\nH OEt\nsubstrate scope. 2 CHCl2 74 60% C H C l 2 75 66% C H C l 2 76 73% C l 77 13% OEt\nChanges Made: The structures of\nthese products, along with the proposed mechanism, are now included in Figure 7. Corresponding NMR, GC-MS, and IR\nspectra have been added to the Supplementary Information.\nComment 10: In the supplementary information, some of the compound characterization needs addressing, especially the 1H\nNMR spectroscopic data. If a signal has a defined multiplicity, then it needs to have a coupling constant. If it is a multiplet, then\na range with no coupling constant should be reported.\nResponse: We appreciate the reviewer's attention to this matter. The entire set of ¹H NMR data has been carefully reviewed\nand revised for consistency. All defined multiplicities now include appropriate coupling constants, and multiplets are reported\nas ranges without coupling values.\nComment 11: Starting material 2-((4-methoxybenzyl)(methyl)amino)cyclohex-2-en-1-one is missing a proton in the\ncharacterization. This compound should have 19 protons, but only 18 are reported.\nResponse: We appreciate the reviewer’s careful attention. The original ¹H NMR spectrum for this compound does indeed\nshow all 19 expected protons; however, one signal was inadvertently omitted from the reported characterization. This has now\nbeen corrected in the revised Supplementary Information.\nComment 12: It would be nice for compound 2a to if a 2H NMR spectrum was obtained to make sure there is deuterium\nincorporated in the compound.\nResponse: We agree with the reviewer’s suggestion. A ²H NMR spectrum of compound 2a has now been acquired and\nconfirms deuterium incorporation. This spectrum is included in the revised Supplementary Information.\nReviewer #2\nGeneral Comments: We thank Reviewer #2 for thoughtful and constructive comments, which have greatly improved the\nquality and clarity of our manuscript. In response to the suggestions, we extended the substrate scope, demonstrating the\ngenerality and chemoselectivity of the transformation across structurally and electronically diverse α-enaminones (Figure 6).\nTo underscore the synthetic value of the products, we added representative downstream derivatizations (Figure 7), highlighting\nthe CHCl₂ group as a productive handle for oxidative and nucleophilic elaboration. Additionally, we introduced new examples\nof β-di- and β-trihalomethylation using haloform-type donors beyond CHBrCl₂, further emphasizing the mechanistic breadth\nand potential of the method (Figure 7). Alongside these additions, the original reaction setup, mechanistic rationale, and yield-\nlimiting resolution paradigm have been clarified, and the isotopic-labeling section has been expanded to definitively establish\nthe origin of the CHCl₂ unit.\nComment 1: The selective β-dichloromethylation of α-enaminones was achieved with anti-stereochemistry. However, the yield\nof target product is two low (from 42%-6%) along with the decomposition of the enaminones. The low yield of this conversation\nlargely decreased the practicality of this reaction. The current required further optimizations.\nResponse: We thank the reviewer for highlighting the relationship between yield and practicality. We addressed this directly\nby interrogating whether the yield profile could be improved by pushing the pre-equilibrium toward the productive\ndiastereomeric intermediate.\n• Mechanistic context. The observed “decomposition” corresponds to the programmed fragmentation of the mismatched\nintermediate in a resolution-type pathway; only the matched partner advances to product. This stereochemical gate\nintrinsically imposes a maximum yield of 50%.\n• Targeted optimization to bias the equilibrium. Guided by the idea that acid release (HX) during the initial\ncondensation/proton-transfer events could influence the matched↔mismatched ratio, we introduced acid scavengers,\nproton sponges, and anion-exchange/phase-transfer resins: DMAP, Amberlyst A26, AmberChrom 1×8, Amberlite IRA 400,\nand 1,8-bis(dimethylamino)naphthalene to tilt the equilibrium toward the reactive pathway. These interventions produced\nonly modest effects; details and side-by-side comparisons are added to the SI.\n• On practicality. While the yield is intrinsically governed by the resolution mechanism, this unique stereochemical gating\nis precisely what enables the high selectivity without complex catalysts.\nTo balance this, we emphasize the operational simplicity:\n- Metal/catalyst/ligand-free\n- No strong acids/bases\n- No inert atmosphere or photolysis\n- Standard laboratory solvents and reagents: CHCl₃/proline/K₃PO₄\n- Product isolation typically involves only solvent removal and filtration, affording clean, bench-stable β-CHCl₂ adducts\nwithout chromatographic complexity.\n- The liberated secondary amine is obtained in equimolar amounts and can be recovered.\n- We also demonstrate concise derivatizations (e.g., vinyl chloride, acetal, ketal, enol ether), underscoring synthetic\nutility. Importantly, the work establishes a previously unreported closed-shell electrophilic transfer of polyhalomethyl\nunits from haloform reagents.\nChanges Made: We (i) state the resolution-imposed yield limit explicitly, (ii) summarize the equilibrium-bias additive screen\n(full data in SI), and (iii) clarify operational simplicity, product stability, and downstream elaborations in the Results.\nComment 2: Why the reaction plateaued at 50% yield when using an equimolar mixture of L- and D-proline? While product 2\nwas obtained in 30% yield in the presence of only L-prolin?\nResponse: Proline (regardless of chirality) plays an indispensable, stoichiometric, and dual-functional role that lies outside\nthe classical catalytic framework. First, it facilitates the formation of stereochemically defined intermediates via reaction with\nthe α-enaminone. Second, and critically, it serves to trap the released 1,2-diketone fragment formed through fragmentation of\nthe non-productive diastereomer. This fragment-trapping step is not peripheral; it is mechanistically essential for stabilizing the\nreaction outcome and ensuring a clean mass balance.\nAs such, a total of 2.0 equivalents of proline are required:\n• 1.0 equiv. participates in the formation of the matched and mismatched intermediates.\n• The remaining 1.0 equiv. is necessary to condense with and stabilize the liberated diketone fragments, preventing\ndecomposition or side reactions.\nIn the experiment using a 1:1 racemic mixture of L- and D-proline, only 1.0 equiv. is available for the initial condensation step.\nOf this:\n• 0.5 equiv. is L-proline → forms 0.25 equiv. of productive intermediate and 0.25 equiv. of non-productive.\n• 0.5 equiv. is D-proline → forms 0.25 equiv. of productive and 0.25 equiv. of non-productive.\nThus, 0.5 equiv. of proline-derived intermediates are productive, and 0.5 equiv. are non-productive. Upon fragmentation, the\nnon-productive intermediates release 1,2-diketone, and the other 1.0 equiv. of racemic proline (which remains unreacted)\ncondenses with this diketone to stabilize it. Therefore, even in the racemic case, full material balance is preserved, and the\noverall maximum yield plateaus at 50%, exactly matching the theoretical expectation of resolution.\nThis outcome is mechanistically identical to using 2.0 equiv. of enantiopure proline: one equivalent participates in intermediate\nformation, while the second captures the byproduct.\nHere, 1.5 equivalents of proline are the theoretical minimum:\n• 1.0 equiv. for forming intermediates (matched + mismatched),\n• 0.5 equiv. to trap the released diketone fragments from the non-productive intermediates.\nHowever, we use an overall 2.0 equiv. In practice, to ensure complete conversion and buffer integrity, it is necessary to provide\noperational robustness, excess trapping capacity, and avoid incomplete quenching of reactive byproducts.\nThis experiment was one of several conducted to support the bifurcation–resolution mechanism and directly illustrates the\nstructural gating that defines the yield ceiling.\nComment 3: CHCl3 can also be used as the CHCl2 source as listed in Figure 3. So, how can the authors deem the CHCl2 in\nproduct was derived solely from CHBrCl2?\nResponse: We thank the reviewer for this meaningful and insightful comment. We agree that the original main text did not\nsufficiently distinguish between the initial chloroform discovery experiment and the optimized CHBrCl₂ protocol, and we have\nnow clarified this in the revised manuscript.\nWe initially discovered the transformation serendipitously while using CHCl₃ as a solvent. However, despite its abundance,\nCHCl₃ alone resulted in low yields and incomplete conversion. Upon switching to CHBrCl₂, we observed clean and complete\nformation of the β-dichloromethylated product across a wide range of α-enaminone substrates.\nTo directly address the reviewer’s question regarding the origin of the CHCl₂ fragment, we performed a targeted isotopic\ntracking experiment: CHBrCl₂ was used as the dichloromethyl donor in CDCl₃ as solvent, and the resulting product mixture\nwas analyzed by ¹H NMR, ²H NMR, and HRMS. The data revealed only trace incorporation of CDCl₂, despite the significant\nexcess of CDCl₃. This outcome confirms that CHBrCl₂, not CHCl₃, is the kinetically and mechanistically relevant CHCl₂ source.\nAlso, as part of our broader exploration, we examined whether alternative haloform-type donors (CHBr₃, CHClBr₂, CBrCl₃)\ncould deliver related transformations under otherwise identical proline-buffered conditions. In all cases, the expected geminal\ndi- or tri-halogenated products were obtained cleanly, without any CHCl₂ incorporation, further confirming the origin-specificity\nand selectivity of the transformation.\nWe again thank the reviewer for highlighting this critical mechanistic point, which is now fully clarified in the revised manuscript.\nC “T h h a e n i g ni e ti s a l M d a is d c e o : v e T r h y e o o f p th e i n s i t n r g a n p s a f - - o rI P n r a o a r d ll m g u e c n t r s tr a ia e 5 s 5 t ,p - i 5 c o r 7 hu d w n e e r 1o e H e o fN b m M ta R in h e a e d ne a e r l x y g c s“ l i i s s R e i r v e e v d l e y e a a ls s e d d th u u a e 1l a r :t n 1s t i i r - n a d ”t i i a o g s so te f r a pe e r o o m cd t u e h tc r ti to e o pn r ar m e nht a aam l ins e e b va e l e u n a t sa b ci . . . o u I C M s o on a bn l x a v . t e e s t o h r d s e ti y o o f a i r n e . l y d (% i e (% l ) d — ) ( % — D ) e P — t u e r r U i m fim p e in p d re e p ed r i r l on f im r d vo u i m o t c i b t sc a no r s u b e e d tea d e i d n o 1 e n H 1d : o N a b M f s wte e R r r v c / i e h G t d r C oh c m o n as v to e g r t s rao io p n hi y a c nd h in i h o ere m nt 1: e 1 p t ro r d i u c ct/ a L min - e p re r so o lut l io i n ne\nin neat chloroform at 100 °C. ThAis. serendipitous finding led to the formation of the β-dicCFh3loromethylated product 2 in a limCFi3ted\nyet unambiguous manner (Figure 3O). DMeespite thCeBr Yl o(1-w5 e qeuivf)ficiencOy ofM ethis initial OobsMeervation, rigoOrous chSaracterizaOtioMne by NMR\nspectroscopy, GC-MS, and single-crystaNl X-Rray dL-ipfrforlinae c(2t eiqouniv) unequivoNcallyR establisheNd site-selective bN-in\nMe\ncorporation ofN the CHCl\n2\nu C n H it C w l 2 i t g h r o s u tr p ic o t n a t n o t i a -s n t e α r - e e o n c a h m e i m no is n tr e y , 5p3 r e r o l a m t i v p e t e C t d B o r Y a C = t H h K d c C 3 i / e P t l o r 3 O i , h m 1 4 a p 0 l ( o 1 0 - e p m e ° C q n e r u , t e h i 2 dv y 0 ) h l a s h o e n u r n t c e s a i v m e 5 i 4 n e e v . C a Y T lu h a is ti o u n n o p f r e re c a e C c d C t e l i3o n n te a b cp . . . d 2 1 5 a4 0 0 0r r e a a m c e ti t v e it r y s , . C H th Br2 ea b c . . . d 2 1 5 6 0 0 i0rect in d. s r. 8 t 7 a :1 l 3 C la HB t r i C o l na b c . . . 3 1 5 1 0 0 0f a\nOur optimization studies systematically explored the halomethane source, ba5s5 e C BirdY e= CnBtrCitl3y , p r o l i n e56 lCoBarYd = iCnHgBr3, s o l v e n t5,7 CteBrmY = pCHeBrr2aClture,\nadditives, atmosphere, and light exposure. These efforts converged on a narrow, optimal regime employing CHBrCl (5 equiv.),\nL-proline (2 equiv.), and K PO (1 equiv.) in CHCl at 100 °C for 20 h. Under these optimized conditions, the transformation\n3 4 3\nproceeded reproducibly, exhibiting clean product profiles and providing synthetically useful yields. Importantly, no alternative\npermutation, including the original c O hlo M r N o e form-onl L Cy - H p r Cc o l l 2 i o n B e rn ( ( 5 2 d e e q q u u i i v v ) ) ns, appr N oached this lev N el of a b c . . .p 3 1 5 0 0 0e 0 rformanc N e. a b c . . . 1 1 5 8 0 0 0 N a b c . . . 2 9 4 8 4 7\nR\nTo definitively establish the origin of the dichloromK3ePOt4h (1y elq ufirv)agment, wNe cRonducted tNargeted isotopic tNracing experimeNnts. Using\nCHBrCl as the donor in CDCl as solvent, an\nC\na\nH\nl\nC\ny\nl3s ,\n1\n0\n0 °C\nb\n,\n20 h\n¹H/²H MeR spectroscoMpey and high-resoMelution mass speMectrometry\n2 3 58 59 60 C l 61 O M e 62 + 62a1\nrevealed only minimal incorporation of CDCl , despite the large excess of deuterated solvent. This robustly confirms CHBrCl\n2 2\nas the sole operative CHCl sourcPreop ousend mdeechra ntishme optimized conditions. Further controls demonstrated the reaction's insensitivity\n2\nt\np in\no\nh s a\na\no s\nm\nm e\nb\ne t\ni\ne\na c\nn\nn a\nt\nt\ns\nli\nf e\ng\ne s\nh\nt\n,\nt m\n(\nge a e\nx\nr n\nc\ng t\nl\ns i\ne\nh\nt\n,\nd a\ni\nl\nn\ny\ng\nd s\nU\na u\nV\nc p i p\n)\nd r\na\ne s\nn\nc\nOd\ns a e v\nit\nd e\ns\nN nR r\ne\n1 e gR\nf\n2 a e\nfi\nc\nc rs\ni\nt\ne\ni v (\nn H e it\nt\ny\ng\n. o\n.\np\nC i ,\nn O\np 2 d H\nr\na\no\nt\npa t\ni\no\no mtii C\nn\nn zne H s dg C l\nu\ns o c l w 2 o p\nn\nB tn r hd o\nd\nitia n o\ne\nnt g s\nr\nt e\no\nh s\np\ne\nO e\na s\nn\nn y\n-\nd N\nfl\nR t\ni e 1oR\ns\n2n\nk\n- C (e o B\nc\nH\nL\n= C x p\no-p\nl C 3 H c\nr\ne\nn\n,\nl B 1\nl\nho\ni\nr\ndn\n0 r a\ne\n0 aB\ni t\n° r t n) C\ni\ne\no\ng s\nn\ne\ns\ne\n.\nr f N e f\nA\ne s\nd\nc in t C N\nd\ni O R s v\ni\n1 2\nt\n) R H e\ni\n,\nv\n2 l y\ne\np\ns\nr u o\nn\nv\ni\nd\nn\nid e\nc\neN\nl\nr\nu\nd i\nd\nt s n\nin\nC N o n O R\ng\n1 2 aR H i 2 m\nm\ntiv p\no\ne r\nle\no\nc\ns v\nu\ne e\nl\nm a\nf N -\nr\nb e u\ns\nn\ni\nf C N t\ne\nf O He a\nv\nR 2 r 1 n\ne\nRe 2 d\ns\nd\n,\nconditions.” 63 ( 2 e q u i v ) t r a 6 c 4 es CHCl2 65 C H C l2 66 C H C l 2 67 CHCl2\npromoted\nComment 4: The authors repeatedly emphasized stphoneta ndeoeusr airvomaattizioatinon potentials of CringH exCpaln2sio ngroup. Derivation experdiemcarbeoxnyltastio nsh- CoOu2ld be\nconducted, for example, convert CHCl2 to CHO, etc.\nResponse: We would like to clarify th\nN\nat the manuNscript briefly aNnd scientificaNlly addressesN the derivatiza\nA\nt\nzo\nme\nnt\nh in\np\no\nylid\nt\ne\nenNtial of the\nCHCl₂ group. This point is mentioned once in the conNteR1xR2t ofB HF4igure 1NR t1Ro2 illustrate NmR1eR2chanistic raNtRi1oRn2ale an(imdm\nc\nino\na\niu\nrb\nnm\na\n-\nn\ncs\ni\nt\no\nea\nn\nb\n)\niliizned a forN HwR1aR2rd-\nlooking comment regarding syntheticN Ru1Rt2ility- .H CIln both cases, the stateme- Cnlts are concise and appropriately framed to avoid\noverstating this feature or positionin7g3 it as a centr7a2 l n C o l v e l t y . W e 71 h a C v l e t a k e n 7c0 a C r H e C l 2 t o m a i n t a69i n C Ha C l 2 b a l a n c e d p r e s e n68tationC HoClf2 the\nnot detected\nmethod’s scope and contributions throughout the manuscript.\nThat said, we fully agree C.\nwith the reviewer that O Me OMe Me O O Me O O Me O O Me\ndemonstrating downstream N Ph N N N N\nutility strengthens the H OEt\nsynthetic relevance of this 2 CHCl2 74 60% C H C l 2 75 66% C H C l 2 76 73% C l 77 13% OEt\ntransformation. Accordingly,\nwe have conducted a set of representative derivatization experiments using the dichloromethylated product as a functional\nsynthon. These include oxidative conversion to an enol ether, an acetal, a ketal, and a vinyl chloride. The results are now\npresented in Figure 7 of the revised manuscript.\nReviewer #3\nGeneral Comments: We thank the reviewer for constructive assessments. In light of the concerns raised, we have undertaken\nsubstantial revisions to strengthen both the conceptual and experimental foundations of the work. The updated manuscript\nand SI section now include expanded mechanistic analysis, clarification of key selectivity principles, additional control\nexperiments, and refinements to the presentation of scope and limitations, all of which align with the reviewer’s specific points.\nThese revisions substantially enhance the clarity, rigor, and contextual framing of the study. We believe the manuscript now\nmore clearly articulates the uniqueness and broader significance of this closed-shell electrophilic β-dihalomethylation manifold,\nand we respectfully hope that the improvements satisfactorily address the issues raised and enable reconsideration for\npublication in Nature Communications.\nComment 1: I find that the manuscript is a nice piece of work, and can be publishable, but in a specialized journal, devoted\nto Organic Chemistry (J. Org. Chem.; Org. Lett, Org. Biol. Chem., Adv. Synth. & Catal., etc.), but it lacks (in my opinion)\nnovelty, generality and relevant synthetic applications to be published in Nat. Commun.\nResponse: We sincerely appreciate the reviewer’s upbeat assessment of the work’s quality. However, we respectfully\nmaintain that the conceptual and mechanistic innovations reported here are appropriate for the broad readership of Nature\nCommunications. We believe the initial manuscript may not have sufficiently highlighted the fundamental departure this method\ntakes from established reactivity modes. We have revised the Introduction and Discussion to frame these advances, which\nare summarized below explicitly:\n1. First closed-shell electrophilic polyhalomethylation: To date, the transfer of di- or trihalomethyl units (e.g., CHCl₂,\nCBrCl) has been exclusively the domain of radical or carbene chemistry. This work reports the first example of a two-\nelectron, closed-shell transfer of these fragments from stable haloforms, including the demonstration that CHBr₃,\nCBrCl₃, and CHClBr₂ can also be effectively employed to generate gem-dibromo, mixed gem-halides, and other polyhalogenated\nproducts under these unified conditions. This establishes a fundamentally new mechanistic manifold — an \"electrophilic\nhaloform\" pathway - without precedent in the literature.\n2. Umpolung of a historically inert scaffold: alpha-Enaminones are classically resistant to electrophilic functionalization\ndue to their electronic bias. By leveraging a transient umpolung strategy, we unlock a general entry point for beta-\nfunctionalization that has previously been inaccessible, solving a long-standing reactivity challenge for this substrate class.\n3. Diastereomeric gating mechanism: The selectivity in this transformation arises from a rare \"stereochemical resolution\"\nmechanism mediated by proline, rather than traditional transition-state control. This conceptual finding, where an\norganocatalyst acts as a diastereomer-selective gatekeeper for reactive intermediates, adds a new dimension to how\nselectivity can be engineered in cascade sequences.\n4. Discovery of a size-dependent aromatization cascade: Prompted by the reviewer’s comments on scope, we have\nuncovered that 5-membered rings undergo a unique, spontaneous aromatization cascade following dichloromethylation\n(now detailed in Figure 7). This divergence in reactivity adds significant depth to the study, offering a rapid, metal-free route\nto fused heteroaromatics.\nWe believe that establishing a new electrophilic manifold for haloforms, solving a reactivity problem in conjugated systems,\nand defining a new mode of stereocontrol constitutes a foundational advance rather than an incremental one.\nChanges Made: The Introduction and Discussion sections of the manuscript have been thoroughly revised to explicitly frame\nthese key conceptual advances, aligning with points 1-4. (See Main Text, Introduction, and Discussion sections).\nComment 2: Around 50 rxns of this type (HA addition to the double bond of 6-membered enaminones are described (a few\norganometallic couplings, and some radical additions, mostly). The processes described are new. However, the yield is,\nat most, 50%; in some cases, even lower.\nResponse: We thank the reviewer for raising this point regarding precedent. We have conducted an exhaustive search of the\nliterature and were unable to locate the specific examples of HA-type additions to cyclic alpha-enaminones under closed-shell\nconditions referenced in the comment. While radical or organometallic functionalizations of simple enones exist, the direct,\nmetal-free electrophilic functionalization of the ambident alpha-enaminone system remains, to our knowledge, unreported.\nRegarding the yield, the reviewer is correct that the isolated yields generally plateau at approximately 50%. As we now clarify\nin the revised text, this is not a failure of conversion but an intrinsic feature of the mechanistic resolution. The reaction is\ndesigned to filter a racemic mixture through a diastereoselective gate, where only the \"matched\" intermediate progresses to\nproduct. While this imposes a theoretical yield ceiling, the trade-off provides high diastereoselectivity and clean reactivity\nprofiles without the need for expensive chiral ligands, transition metals, or complex purification. We argue that this operational\nsimplicity and mechanistic uniqueness offer significant value despite the resolution-limited yield.\nComment 3: Only dichloromethylation? Why not other C+ species or even X+ or other electrophiles? The mechanism should\nbe also operative, right? In this endeavor, the\naudience should have evidences (in this system) of - - I P n r o a d ll u e c n ts tr i e 5 s 5 , - 5 cr 7 u d w e e r 1 e H o N b M ta R in e a d n a e l x y c s l i i s s i r v e e v ly e a a l s e d th a e 1 a : n 1 t i r - a d t i i a o s o te f r p e r o o m du e c r t to parent amine a b c . . . I C M s o o a n l x a v . t e e th r d s e i y o o i r n e . l y d (% i e (% l ) d — ) ( % — D ) e P — t u e r r U i m fi p e in p d e e p d r r l o f im r d o u i m t c b t c a o r s u b e d ta d e i n o 1 e n H d o N a b M f s te e R r r v c / e h G d r C o c m on a v to e g rs ra io p n h y and inherent 1:1 product/amine resolution\nthe usefulness of a number of the described adducts. A. CF3 CF3\nPlease, show some examples of synthetically relevant O Me CBrY (1-5 equiv) O Me O Me O S O Me\ntransformations of the CHCl2 group (drugs, N R L-proline (2 equiv) N R N N Me N\ncommodities, NPs, probes…) that justify the 53 C B r Y C = H K d C3 i / P t l r 3 O i , h 1 4 a 0 l ( o 1 0 - m e ° C q e u , t h i 2 v y 0 ) l s h o u r c e 54 CY CCl3 a b c . . . 2 1 5 4 0 0 0 CHBr2 a b c . . . 2 1 5 6 0 0 0 d.r. 87:13 CHBrCl a b c . . . 3 1 5 1 0 0 0\nimportance of the method. 55 CBrY = CBrCl3 56 CBrY = CHBr3 57 CBrY = CHBr2Cl\nResponse: We fully agree with the reviewer that B.\ndemonstrating the products' versatility is essential. In\nresponse, we have significantly expanded the O M N e R L C - H pr C o l l 2 in B e r ( ( 5 2 e e q q u u i i v v ) ) N N a b c . . . 3 1 5 0 0 0 0 N a b c . . . 1 1 5 8 0 0 0 N a b c . . . 2 9 4 8 4 7\nexperimental work (now presented in Figure 7 and the CH K C3P l3 O , 14 0 (1 0 e °C qu , i 2 v 0 ) h M N e R M N e M N e M N e\nSupplementary Information) to address both parts of 58 59 60 C l 61 O M e 62 + 62a1\nthis comment: Proposed mechanism\n• E de x m pa o n n d st e ra d t ed e th le a c t tr t o h p e h r il e e a ctio s n c o is p e n : o W t e li mite h d a v to e O NR1R2 + NH CO2H optimi C ze H s d C l o c l w 2 o B n r ditions O NR1R2 C (B H L = C -p l C 3 H r , o l B 1 l o in 0 r e 0 B ° r) C N C N O R1 2 R H 2 N C N O R1 2 R H 2 N C N O HR 2 1R2\ndichloromethylation. By varying the haloform\n63 ( 2 e q u i v )\nt r a\n6\nc\n4\nes\nCHCl2\nsource, we successfully synthesized gem- spontaneous aromatization ring expansion dec p a r r o b m ox o y te la d tion - CO2\ndibromo, gem-chlorobromo, and mixed-\nhalo analogs using CHBr₃, CBrCl₃, and CHClBr₂. N N NR1R2 BH4 N NR1R2 N NR1R2 N NR1R2 (im A m zo c in m a iu r e b m th a - i n n s i t e o a n b y ) l i i l d iz e ed N NHR1R2\nThis confirms the generality of the electrophilic NR1R2 - HCl - Cl\ntransfer mechanism. 73 72 C l 71 C l 70 C H C l 2 69 C H C l 2 68 CHCl2\nnot detected\n• Synthetic utility of the CHCl₂ group: We provide C.\nconcrete examples of downstream derivatizations O Me OMe Me O OMe O OMe O OMe\nN Ph N N N N\nthat convert the dichloromethylated products into\nhigh-value synthons. These include: CHCl2 CHCl2 CHCl2 H OEt\n2 74 60% 75 66% 76 73% C l 77 13%OEt\n- Conversion to acetal (77)\n- Conversion to ketal (75)\n- Conversion to vinyl chloride (76)\n- Conversion to enol-ether (74)\n- The previously mentioned aromatization cascade for 5-membered rings, providing direct access to highly substituted\nbenzene derivatives (60-62)\nThese additions explicitly showcase the CHCl₂ motif as a versatile \"linchpin\" for building molecular complexity. Furthermore,\nwe emphasize that the gem-dichloromethyl group itself is a recurrent structural motif in modern agrochemicals and\npharmaceutical candidates (utilized to modulate metabolic stability and lipophilicity). By enabling the direct installation of this\nhandle, our method provides immediate, modular access to these relevant bioactive frameworks.\nComment 4: Stereochemistry. Did authors rule out any stereochemical induction by proline in the generation of the new\nstereogenic centers (given a favored trans stereochemistry, if the C*-CHCl2 centre is controlled, may led to good overall\nstereoselection). This must be clearly stated (I do not find the sentence in the text). Incidentally, this would increase the value\nof the discoveries.\nResponse: This is an excellent mechanistic question. To address this, we analyzed the crystallographic data of compound\n2a, which confirmed that despite the use of enantiopure L-proline, the newly formed beta-CHCl₂ stereocenter is racemic.\nThis result is consistent with our proposed mechanism:\nL-proline directs the reaction pathway by selecting for a specific relative stereochemistry (diastereoselection) between the\namine and the dichloromethyl group, but it does not exert facial control during the initial C-C bond formation.\nO Me O Me O Me\nN + (2 e N H quiv) CO2H K C C 3 H H P C C O l l 3 2 4 , B ( 1 1 r 0 ( e 0 5 q ° e u C q iv , u ) 2 iv 0 ) h N CHCl2 + N CHCl2\nWe agree that clarifying this distinction is crucial for mechanistic precision.\nChanges Made: We have added the following explicit statement to the revised manuscript, integrated into the 'Evaluation of\nthe resolution-type branching' subsection of the Results section:\n“Despite the use of enantiopure L-proline, the b-dichloromethylation proceeds without asymmetric induction, and the CHCl -\n2\nbearing stereocenter is formed as a racemate, as confirmed by X-ray crystallography (see Supplementary Information).”\nComment 5: Scope. At the moment. quite restricted. Only 6-membered enaminones are analyzed (and other types of\nenaminones?). Also, the amine component lacks generality (NH, tert-groups, limitations in functionalizing complex residues\nlinked to the N atom?). Incidentally, why compound 45 do not keep reacting to dichloromethylate the other enaminone group?\nThe isolated yield is only 6%, And the rest?\nResponse: We thank the reviewer for pushing us to define the boundaries of the reaction scope. We have performed additional\nexperiments to address these limitations:\nRing size effects: As detailed in our response to Comment 1, we examined 5- and 7-membered rings. While 7-membered\nrings proved unstable, the 5-membered substrates revealed a novel divergent pathway that led to fused aromatic systems\n(Figure 7). This discovery significantly enriches the paper's scope.\nAmine substituents: We have clarified the behaAv i o r o f d i f f e r e n t a m i n e c l a s s e s . B\nN o a u n – r d H g th r e o e n u a p f m o ; r i G m no r a e n t e i e o n s n C f o o h f l l e o ro m w o , m a 2 - 0 s te 2 e m 3 p , a p 2 r e a 5 r t a , e t 5 u f 9 r r a e 1 g 6 i m ) o , n e i i n n c v t a l o i t q l i v o u i n n i R d 1 R g s2 p O . p a H H T N r th o O O h w H li i n s aO e y p - m a (p t e h r d w e i v● ● ●a a i L H C y o ta i h e g t eu e h m i d- s s s s. t e a Sl l f e g y r c r c e e i a . t i f 2 v r u f g i 0e n ety 1 cm p9 r t f i o , o e o r 1 ne -n 0 a O r n , li t cH z 9e ta 3 e a g t 4d i r o 5 do tn - i u 5 o b p 0 i n n y N O N H H O ● ● ● G O G r p r e e e e e n n n - f s l C a y h s n k e t h m re e . a s 2 i c s 0 t i 2 p o 3 a n , t h s 2 e w 5 t a , u y 5 p 916-21\nthe Introduction and visualized in Figure 1B. ThusR, 3althOoAcugh N● -MHeta l/scautablysst -t rfraeet ecosnd itiaonrse H R ● Metal/catalyst - free conditions\nreactive, they do not participate in the β-dichloromethylation manifold described in\nt T h h is e w b o u r l k k . y N-tert-butyl substrates were synthetica O R ll 1 y i O R n 2 H R a 3 c + ces N Hsib C l O e 2H d1u0 D 0 K e M O °C S A , O c 4t ho i O R n 1 trin R R 2 3 sic O R1 HN R2 R3 + N H R4 CO2H 10 M 0 M e ° C O , H 8 h R2 R1 N N X R4\nR3\ninstability. However, we have successfully includSeelecdtive as-3u°debhysdrotxrylaatiotne ofs pr edwnisoiltonhe functionalized/\nheteroatom-containing N-residues (Compounds 42, 45, 46) Oto dOeHmαo-1°nstrate toleraOnceO H Direct access to polycyclic imidazolium-based ionic liquids\nof complexity. 2° HO Me OH α-3° HO Me O H H\nCompound 45 (mono- vs. bis-addition): RegardingM ecoHmpoun p K r O o d l A in c e (4 ( 1 5 e e 5q q u u :i i v v . . ) ) althoMueghH both O + H2N KI OMe N H\nα se -e le n c a t m ivi i t n y o l n ik e e l u y n a it r s i s a e r s e f i r n o it m ia l e ly le id ct e r n o t n ic ic a l a , n m d o c n o o n -d fo ic r O m hl a o t r i o o m np H read e nils t H o h lcon y oe l n a s DtMi e oSO q n, 1 u 3 3 7i0 % e s °C n , o8 c h O b e s s e o rv f eH th d e . H T fSie h rlesc i t s ivte via a-enaminone H N H CO2H 10 M 0 3 e ° 0 C O % , H 8 h NI OMe\nsubstitution. Specifically, CHCl₂ incorporation deactivates the second site through\nC D\ninductive withdrawal and disruption of conjugation. Simultaneously, the molecule adopts a conformation that\n● THIS WORK, New mechanism\ns u e n c s o u n c d ce r s e s s f o u l l. u D tio u n e - t t y o p t e h e tr a lo n w s f i o s r o m la a te tio d n y . i e W ld e a a n t d te c m o R p m 1 O te p\nR\nd\n2\nleN Rx t 2 o it yL- m P,r otl o inhe d e u H\ns\nt\nO R\na\n1 o\nN\nR2 O R\nC\nO2H dehy\nX\nn d o ra tion\nR1\nN\nR2 O R\nC\nO2H\nR1\nO\nN\nR3\nR2 + N H CO2H 10\nC\nH\n° 3H C P\nB\nC O ,\nr C\nl 23 4 4\nl2\nh R1\nO\nN\nR\nC\nA concise summary response table\nREV.1\nComment Comment/Concern Action implemented Evidence added Resolution & impact\nConfirmed no photochemical\ninvolvement, enhancing mechanistic\ndocumented exclusion conditions. (Procedure).\nclarity and operational robustness.\nClarified Figure 3 as a time-resolved\nClarified non-kinetic nature, reinforced\nmechanistic understanding of proline's\n\"kinetics\". Explained stoichiometric role of L-proline (Figure S1).\nnon-catalytic, stoichiometric role.\n& K₃PO₄.\nRevised Figure 3 for visual clarity; cross-\nImproved presentation and context for\nreferenced to SI Table S1. Rewrote Text (Results, Figure\noptimization studies, enhancing clarity\naccompanying main text paragraph with 3), SI (Table S1).\nand reader comprehension.\nexpanded mechanistic insights.\nExperimentally confirmed in-situ\nConducted capture experiment; analyzed Text (Results), SI\nby ¹H NMR and GC-MS of half-quenched (Figure S2,\nformation and subsequent trimeric\nconfirmation. condensation of pyrroline, supporting\nreaction. Procedure).\nproposed fragmentation pathway.\nStandardized terminology for analytical\ntechniques (e.g., \"NMR spectroscopy,\"\nThroughout Enhanced formal precision and\n\"NMR\"). manuscript & SI.\nscientific rigor in language use.\n\"GC-MS,\" \"X-ray diffraction\").\nDefinitive experimental confirmation\nPerformed targeted isotopic tracing\nthat CHBrCl₂ is the sole operative\nCHCl₂ source, strengthening\nhaloform donors (CHBr₃, CHClBr₂, (NMR, HRMS).\nmechanistic specificity and disproving\nCBrCl₃).\nCHCl₃ involvement.\nExplained proline's dual role: promoting Clarified mass balance and\nfragment observation. the diketone fragment from the 4C. fragment resolution and maintaining\nunproductive pathway. clean selectivity.\nMechanistically excluded\nScreened alternative strong bases;\nconfirmed no formation of carbene- Text (Results).\ndichlorocarbene involvement,\nproducts with other bases.\nreinforcing the unique closed-shell,\nderived products or target product.\nnon-carbene mechanism.\nSynthesized 5- and 7-membered α- Expanded scope to new ring sizes,\nenaminones; discovered new Text (Results),\nrevealing an unprecedented size-\naromatization cascade for 5-membered Figures 6 & 7, SI dependent cascade reactivity,\naddition (Comp. 45).\nrings (Fig 7). Explained mono-selectivity (Mechanism, Data).\nsignificantly broadening the method's\nfor compound 45.\nconceptual impact.\nReviewed and revised all ¹H NMR data for\nconsistency in reporting multiplicities and\nSI (Experimental Ensured full data integrity and clarity for\ncharacterization (SI).\nSection).\nall characterized compounds.\ncoupling constants.\nEnsured accuracy of reported\ncharacterization data for a key starting\nmaterial characterization (SI).\nthe specific starting material.\nSection).\nmaterial.\nProvided direct spectroscopic evidence\n12\n²H NMR for deuterium Acquired and included ²H NMR spectrum SI (Experimental\nfor deuterium incorporation, further\nincorporation (2a).\nfor compound 2a.\nSection).\nsupporting isotopic labeling studies.\nREV.2\nComment Comment/Concern Action implemented Evidence added Resolution & impact\nExplicitly clarified the 50% theoretical\nJustified yields mechanistically,\nyield limit due to the resolution\nmechanism. Summarized additive screen.\nText (Results), SI highlighted operational advantages\ndecomposition.\n(Additives Data).\n(metal-free, bench-stable), and\nEmphasized operational simplicity and\nconfirmed robust process.\nproduct stability.\nClarified that 50% with racemic L/D- Provided definitive mechanistic\nproline demonstrates the theoretical interpretation, differentiating theoretical\n2\n50% yield with L/D-proline vs.\nmaximum of resolution. Explained 30% Text (Discussion). limit from practical yield, thereby\n30% with L-proline.\nwith L-proline as practical efficiency,\nstrengthening the resolution\nprimarily due to isolation challenges.\nmechanism evidence.\nDefinitive experimental confirmation\nPerformed targeted isotopic tracing\nthat CHBrCl₂ is the sole operative\nCHCl₂ source, bolstering mechanistic\n(similar to R1C6). haloform donors (CHBr₃, CHClBr₂, (NMR, HRMS).\nspecificity and disproving CHCl₃\nCBrCl₃).\ninvolvement.\nPerformed and presented new Directly demonstrated synthetic utility\nderivatization experiments (e.g., to ketals, Text (Results),\nand versatility of the CHCl₂ group and\nacetals, enol ethers, vinyl chloride).\nFigure 7, SI (Full other polyhalogenated products,\nCHCl₂ group utility.\nExpanded to show electrophilic generality procedures, spectra).\nenhancing synthetic relevance\nand aromatization cascade.\nfor Nature Communications.\nREV.3\nComment Comment/Concern Action implemented Evidence added Resolution & impact\nRewrote Introduction and Discussion to\nDirectly addresses Nat.\nexplicitly frame key conceptual advances:\nCommun. criteria. Clearly articulates\n1) First closed-shell electrophilic\nfundamental mechanistic and\nLack of polyhalomethylation, including from Text (Introduction,\n1 novelty/generality/application CHBr₃, CBrCl₃, and CHClBr₂. 2) Discussion, Figures 6\nconceptual breakthroughs,\ndemonstrating novelty, broad\nfor Nat. Commun..\nUmpolung of inert α-enaminones. 3) & 7), SI.\napplicability, and an innovative\nDiastereomeric gating mechanism. 4)\napproach to catalysis and C-C bond\nDiscovery of size-dependent\nformation.\naromatization cascade.\nRefuted unsubstantiated claim of \"50\nreactions\" in literature. Re-explained 50%\nStrengthened claim of method's\n2\n\"50 reactions\" precedent /\nyield as an intrinsic feature of the\nText (Discussion).\nuniqueness and justified yields by\nYields.\nresolution mechanism, emphasizing its\nframing them within a novel, selective\nselectivity and operational simplicity over mechanistic principle.\nquantitative conversion.\nDemonstrated broad generality beyond\nExpanded electrophile scope to include\nText (Results, CHCl₂, confirmed synthetic utility\nNeed for other C+/X+ CHBr₃, CBrCl₃, and CHClBr₂ (Figure 7).\n3 electrophiles / Demonstrated Performed and presented new\nDiscussion), Figure through diverse derivatizations, and\n7, SI (full procedures, showcased a novel cascade, solidifying\nusefulness.\nderivatization experiments (e.g., to ketals,\nspectra).\nmethod's value for accessing\nacetals, enol ethers, vinyl chloride).\nmedicinally relevant scaffolds.\nProvided precise mechanistic\nConfirmed by X-ray crystallography that\nclarification, explaining that proline\nenforces diastereoselectivity at the\nproline / Enantioenrichment.\nracemate. Explicitly clarified this in the (X-ray data).\nintermediate level but not enantiofacial\ntext.\ncontrol during C-C bond formation.\nExplored 5- and 7-membered rings\nExpanded demonstrated scope to\n(unveiled 5-membered aromatization\ninclude new ring-size reactivity and N-\nRestricted scope (ring size, N- cascade; 7-membered unstable). Clarified Text (Results),\n5 substituents) / Compound 45 N-substituent tolerance (N-H divergent; Figures 6 & 7, SI\nsubstituents). Clarified\nlimitations based on substrate\nyield.\nbulky N-alkyl unstable). Explained (Mechanism, Data).\nstability/isolation, ensuring realistic\ncompound 45's mono-selectivity and yield\nrepresentation of generality.\nissues; removed from main scope figure.\nReviewer #3\nGeneral Comments: We thank Reviewer 3 for the time and rigor invested across both rounds of evaluation. We have now\naddressed every comment in full, and carried out all requested experiments, including several that required extensive\nmechanistic probing, additional synthesis, and the development of new downstream transformations. The additional studies\nstrengthened the manuscript substantially, expanding the mechanistic foundation, revealing new reactivity regimes, and\ndemonstrating broader synthetic utility of the β-dichloromethyl motif than was evident in the initial submission.\nWith this revision, the work now presents a fully validated halomethylation manifold, expanded mechanistic architecture, newly\nuncovered divergent pathways, and pharmaceutically relevant applications - all supported by new experimental data, detailed\ncharacterization, and revised Figures 6 and 7. We hope that the depth and completeness of the revisions clarify the conceptual\nsignificance of the discovery and place the manuscript on firm footing for publication in Nature Communications.\nComment 1: a) The around 50 rxns of this type (HA addition to the double bond o f 6-membered enaminones are described\n(a few organometallic couplings, and some radical additions, mostly) were cited because of their implication in the novelty. As\nI said, they were not precedents of these electrophilic additions. The comment was expressed regarding the synthetic novelty;\nand, in my opinion, stands correct.\nResponse: We thank the reviewer for the clarification and appreciate the perspective provided. No further response is required\non our side for this point.\nComment 2: b) Why not other C+ species or even X+ or other electrophiles? Done properly with CXn+ precursors. Not with\nother electrophiles.\nResponse: We conducted a systematic assessment of electrophiles beyond polyhalomethyl donors, examining conjugated\nπ-electrophiles (group A), allylic electrophiles (group B), σ-benzylic electrophiles (group C), and heteroatom-centered species\n(group D).\nAcross these experiments, a coherent mechanistic landscape emerged,\nA\nO O N OTMS revealing two dominant reaction pathways that diverge from the closed-shell\nOEt NH2 CX₂-transfer manifold:\n(i) Electrophiles in Groups B and C preferentially react with proline, generating\nB stable proline-electrophile adducts and depleting the species required to sustain\nthe resolution-based activation sequence essential for β-CX₂ installation.\nBr\nBr Cl Br\nO O\nC D Br O electrophile grop B or C O\nCl Br O N O N I N H OH N H O + N O R + N OH\nCl R R R\n(ii) Group A electrophiles engage directly with the nucleophilic amine of the α-enaminone, initiating reductive or fragmentative\npathways rather than productive C–C bond formation. To probe this phenomenon in mechanistic depth, we selected\nacrylonitrile as a representative electrophile. Under the standard buffered conditions (K₃PO₄/proline), no reaction occurred—\nconsistent with the requirement for a finely tuned proline–substrate equilibrium to sustain the resolution-gated CX₂-transfer\nmanifold.\nRemarkably, however, removal of the base\nuncovered a completely unanticipated\nO S\nreactivity mode. Instead of conventional\nN Me + CN L-proline (2 equiv) no reaction conjugate addition or decomposition, the α-\n(5 equiv) CH K C 3P l3 O , 1 4 0 (1 0 e °C qu , i 2 v 0 ) h enaminone underwent a clean, isolable\ntransformation arising from direct\nnucleophilic engagement of the tertiary\nO N Me S + CN L-pro n l o in e b a ( s 2 e equiv) O N Me S NC N S + O H N CN a te m rt i i n a e ry -a w m it i h n e th a e c tiv a a c t t i i o v n a te o d f a a c lk r e yl n o e n . i tri S le u c i h s\n(5 equiv) CHCl3, 100 °C, 20 h CN Me CN highly unusual and typically requires UV\npropose key-intermediate isolated, 1H NMR, 13C NMR, GCMS irradiation or photochemical initiation (Das et\nal, JOC, 1994, 59, 628-34). Observing this process under purely thermal, metal-free conditions is unprecedented and reveals\na level of electronic responsiveness in α-enaminones that is not captured by existing mechanistic frameworks.\nAt present, we do not yet understand the origin of the N-substituent exchange, the role of proline in modulating the manifold,\nor the generality of this transformation. The behavior appears to reflect a distinct mechanistic regime - one that is intriguing,\ncomplex, and mechanistically rich, but fundamentally separate from the halomethylation pathway described in the manuscript.\nWe view this as a new reaction manifold that merits dedicated study; its mechanistic intricacy and unexpected selectivity\nposition it as a promising future research direction in its own right.\nBecause the proline-mediated β-CX₂ installation proceeds through a defined sequence of condensations, equilibria, and\nstereochemically gated intermediates, electrophiles that perturb these steps naturally initiate alternative mechanistic\ntrajectories. The combined observations clarify why polyhalomethyl donors uniquely preserve the closed-shell, proline-\ncontrolled pathway and simultaneously provide a design principle for expanding the chemistry: progression to other\nelectrophile classes will require intentional modulation of the proline-substrate equilibrium architecture, rather than direct\nelectrophile substitution.\nComment 3: Please, show some examples of synthetically relevant transformations of the CHCl2 group (drugs, commodities,\nNPs, probes…). Done properly, with signficant exampes, but not xttended to further modifications involving NPs, Drugs, etc.\nThe synthetic usefulness is restricited in practice to the systems studied, without demonstrating general applications.\nResponse: We thank the reviewer for highlighting the importance of demonstrating synthetically relevant downstream\nreactivity of the CHCl₂ group. In response, we performed a series of targeted studies that convert the β-dichloromethyl handle\ninto an aldehyde intermediate, which is then used in situ, without isolation, to assemble pharmaceutically relevant architectures\nin a single operational sequence. One-pot aldehyde formation and reductive amination:\nThe corresponding aldehyde was generated in situ from representative β-dichloromethylated product 2 and, without isolation,\ndirectly condensed with primary amines derived from natural or pharmacologically relevant scaffolds. Subsequent one-pot\nreductive amination with NaBH₃CN furnished the C-N-linked hybrid structures in a rapid and operationally streamlined\nsequence.We prepared two representative conjugates (please see revised Figure 7D):\n• Amphenicol hybrid 79: incorporating the aminophenyl fragment characteristic of the chloramphenicol/amphenicol\nantibacterial family.\n• Tryptamine hybrid 80: accessing a core motif broadly used in serotonergic ligand design (e.g., 5-HT receptor-active\nstructures).\nD.\nO O\nMe\nO O\nMe\nO Me Me N N\nO O\nN Ph\nOH\nA\nco\nm\nn\np\nju\nh\ng\ne\na\nn\nt\ni\ne\ncol H N\nCHCl2 aceto 6 n 0 e / ° H C 2 , O 6 ( h 80:20) H HN\n2 w i t h o u t i s o l a t i o n O 78\nd\n7\n.r\n9\n. 5\n3\n0\n1\n:5\n8\ni\n0\nn e\n6\nc\n0\n%\nnjuate N H\nThese examples illustrate that, once the CHCl₂ group is converted to an aldehyde, a range of biologically relevant amines,\nnatural product fragments, medicinally privileged scaffolds, and heterocyclic building blocks can be rapidly fused to the\nenaminone framework via a robust, general, and operationally simple sequence.\nThe studies now included in the revised manuscript demonstrate that the β-dichloromethyl group is not only a retrievable\nfunctional handle but an efficient gateway to structural elaboration. The ability to generate and functionalize the aldehyde in\nsitu enables rapid access to diverse hybrid molecules without intermediate purification, highlighting the broader synthetic\npotential of this motif beyond the immediate system studied.\nFull experimental details, spectra, and characterization of all hybrid products are provided in the Supplementary Information.\nText added: Oxidative conversion of the CHCl₂ group to the corresponding aldehyde further extends this reactivity space: the\nresulting carbonyl condenses efficiently with primary amines derived from Amphenicol and Tryptamine, enabling rapid\nassembly of hybrid structures that integrate β-dichloromethyl enaminone cores with bioactive motifs (Figure 7D). Collectively,\nthese results establish the CHCl₂ unit as a strategically reconfigurable handle for skeletal editing and late-stage conjugation\nto complex small-molecule architectures.\nComment 4: Stereochemistry. Did authors rule out any stereochemical induction by proline in the generation of the new\nstereogenic centers (given a favored trans stereochemistry,. Properly explained.\nResponse: We thank the reviewer for this comment and appreciate the acknowledgement that our stereochemical analysis is\nnow clearly and properly addressed. No further response is required on our side for this point.\nComment 5: Scope. At the moment. quite restricted. Only 6-membered enaminones are analyzed (and other types of\nenaminones?). Also, the amine component lacks generality (). Properly explained. Novel chemistry arised form these studies,\nalthough the synthetic limitations remain.\nResponse: We thank the reviewer for noting that the mechanistic considerations underlying the scope are properly explained\nand for acknowledging the emergence of novel chemistry from these studies.\nComment 6: A couple of minor details, should be looked at:\n1- Introduction, line 75. “In contrast, α-amino ketones ….” Better α,β-unsaturated α-aminoketones.\n2- Figure 4. Top green framed section. Check protonation of amino group in intermediate 5.\n3- Figure 6. Compound 41. B: 40. Should be 50, right?\nResponse: We thank the reviewer for these careful observations.\n1- The suggested correction in the Introduction has been implemented.\n2 - Regarding the protonation state of intermediate 5, we respectfully confirm that the structure is drawn intentionally as\nunprotonated. This feature is mechanistically essential: retention of the free amine is what differentiates the non-reactive,\nlocked pathway (intermediate 5) from the reactive channel proceeding through intermediate 7. Protonation would collapse the\ndistinguishing hydrogen-bonding network and would not account for the experimentally observed divergence. Thus, the\ndepiction of intermediate 5 without protonation accurately reflects both the mechanistic logic and the experimental outcome.\n3 - The numbering error for compound 41 (B: 40 → 50) has been corrected in the revised figure.\nReviewer #3\nComment: After the revisions done, I find the paper is ready for publication in Nature Communications.\nAuthors have addressed all queries raised in the refereeing, as a consequence the manuscript is more robust, incidentally\nleading to the discovery of new research lines.\nI congratulate the authors for having deeply investigated every possibility regarding the discussion.\nOne minor detail, In the legend of Figure 7, the new text added \"Oxidative conversion of the CHCl₂ group to the corresponding\naldehyde,...\" Formally , the transformation of a CHCl2 to a CHO is not oxidative, Hydrolytic may be suitable.\nResponse: We sincerely thank the Reviewer for the careful and sustained evaluation of our manuscript throughout the entire\nreview process. We particularly appreciate the Reviewer’s persistence in engaging with the work from its initial submission to\nits final form. This continuity of assessment has been instrumental in strengthening the manuscript and in clarifying both the\nscope and the implications of the study.\nWe are grateful for the Reviewer’s recognition that the revised version has addressed the key concerns and that the work now\nprovides a robust foundation with broader implications, including the emergence of new research directions.\nRegarding the specific comment on Figure 7, we agree that the term “oxidative” is not the most accurate descriptor for the\ntransformation of the CHCl₂ group to the corresponding aldehyde. We have revised the text accordingly and omitted the term\n‘oxidative’ to provide a more accurate description of this transformation\nFinally, we would like to express our sincere appreciation to all Reviewers for their constructive and thoughtful feedback.\nTheir input has significantly improved the clarity, rigor, and overall impact of the manuscript."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have properly addressed my questions and concerns, and I would be happy for the article to be accepted for publication.", "reviewer_2": "The problems mentioned by reviewers have been solved.The current revision is suitable.", "reviewer_3": "The changes introduced by Tsvelikhovsky and team are maningful, relevant and constitute a true extension of the original work. No doubt, the manuscript has improved in a significant manner.\nOverall, the revised paper has regarded all points raised by the referees.\nHowever, I still consider that the reach of the process, its novelty and potential applications are somewhat limited, therefore I stand with my original appraisal, which was to suggest its publication, essentially as it is, in a more specialized journal (J Org Chem, Org Lett, Adv Synth & Cat, ….).\nRegarding my previous questions,\na) The around 50 rxns of this type (HA addition to the double bond o f 6-membered enaminones are described (a few organometallic couplings, and some radical additions, mostly) were cited because of their implication in the novelty. As I said, they were not precedents of these electrophilic additions. The comment was expressed regarding the synthetic novelty; and, in my opinion, stands correct.\nb) Why not other C+ species or even X+ or other electrophiles? Done properly with CXn+ precursors. Not with other electrophiles.\nc) Please, show some examples of synthetically relevant transformations of the CHCl2 group (drugs, commodities, NPs, probes…). Done properly, with signficant exampes, but not xttended to further modifications involving NPs, Drugs, etc. The synthetic usefulness is restricited in practice to the systems studied, without demonstrating general applications.\nd) Stereochemistry. Did authors rule out any stereochemical induction by proline in the generation of the new stereogenic centers (given a favored trans stereochemistry,. Properly explained.\ne) Scope. At the moment. quite restricted. Only 6-membered enaminones are analyzed (and other types of enaminones?). Also, the amine component lacks generality (). Properly explained. Novel chemistry arised form these studies, although the synthetic limitations remain.\nA couple of minor details, should be looked at:\n1- Introduction, line 75. “In contrast, α-amino ketones ….” Better α,β-unsaturated α-aminoketones.\n2- Figure 4. Top green framed section. Check protonation of amino group in intermediate 5.\n3- Figure 6. Compound 41. b: 40. Should be 50, right?"}, "author_response": ""}, {"round": 3, "reviewer_comments": {"reviewer_3": "After the revisions done, I find the paper is ready for publication in Nature Communications.\nAuthors have addressed all queries raised in the refereeing, as a consequence the manuscript is more robust, incidentally leading to the discovery of new research lines.\nI congratulate the authors for having deeply investigated every possibility regarding the discussion.\nOne minor detail, In the legend of Figure 7, the new text added \"Oxidative conversion of the CHCl₂ group to the corresponding aldehyde,...\"\nFormally , the transformation of a CHCl2 to a CHO is not oxidative, Hydrolytic may be suitable."}, "author_response": ""}]

Decision letter