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Convergent synthesis of thiodiazole dioxides from
simple ketones and amines through an unusual
nitrogen-migration mechanism†
Kunlayanee Punjajom, ‡a Paul P. Sinclair, ‡a Ishika Saha, b Mark Seierstad,bMichael K. Ameriks, b Pablo Garcı́a-Reynaga, *b Terry P. Lebold *b
and Richmond Sarpong *a
We report the modular preparation of dihydro-1,2,5-thiodiazole dioxide heterocycles starting frommethyl ketones and primary amines. This one-pot, three-component coupling employs 2,3dimethylimidazole-1-sulfonyl azide triﬂate as a coupling reagent and oxidant. The transformation isscalable and various ketones and amines can be used, yielding thiodiazole dioxide products in up to
89% yield. In addition, 15N- and 13C-labeling studies suggest a mechanism involving a 1,2-nitrogenmigration. Together with the mechanistic studies, DFT calculations provide insight into the reaction

Received 25th August 2023
Accepted 25th November 2023

pathway and set the stage for further exploration of the mechanistic nuances of reactions that use
sulfamoyl azides. In combination with the demonstrated modularity of the approach reported herein,

DOI: 10.1039/d3sc04478e

the derivatization of the thiodiazole dioxide products highlights the potential of this methodology to

rsc.li/chemical-science

rapidly access diverse chemical structures.

Introduction
Sulfamides and their derivatives, including the tetrahydro-1,2,5thiodiazole dioxide heterocycle, are well represented structural
motifs in pharmaceutical and other bioactive compounds (seeFig. 1A).1,2 These heterocycles are typically installed either byreaction of the corresponding diamine (II) with sulfamide (III)3
or by intramolecular C–H amination from the corresponding
sulfamoyl azide (IV)4 (Fig. 1B). While useful, these strategies do
not allow for late-stage diversication and in some cases rely on
starting materials with limited availability (e.g., diamines, II)—two factors which are oen important in medicinal chemistry
campaigns. To address these limitations, an alternate synthetic
entry to tetrahydro-1,2,5-thiodiazole dioxides through functionalization of the closely related dihydro-1,2,5-thiodiazole
dioxide (V) would be benecial. In general, the discovery of
direct, yet versatile, synthetic methods for the construction of
the dihydro-1,2,5-thiodiazole dioxide structural motif is of value
to synthetic and medicinal chemists. One of the most direct
approaches to V is the condensation of sulfamides ontoaDepartment of Chemistry, University of California, Berkeley, CA 94720, USA. E-mail:rsarpong@berkeley.edubJanssen Research and Development, San Diego, California 92121, USA. E-mail:pgarciar@its.jnj.com; terry.lebold@gmail.com† Electronic supplementary information (ESI) available. CCDC 2284144 for 3b. For
ESI and crystallographic data in CIF or other electronic format see DOI:
https://doi.org/10.1039/d3sc04478e‡ These authors contributed equally to this work.

328 | Chem. Sci., 2024, 15, 328–335

carbonyl compounds. The key challenge with this approach isthe need for a-oxidation of readily available ketones in order toinstall the C–N bond at the a-carbon. Historically, the requisite
oxidation pattern has been obtained by starting from aoxygenated ketones such as a-hydroxy ketones (VI)5 or 1,2
diketones (VII).6 However, there is limited commercial availability of these highly oxidized starting materials. A simple
method for the synthesis of the thiodiazole dioxide motif fromreadily available commercial materials (e.g., methyl ketones andaliphatic amines) could accelerate medicinal chemistry eﬀorts
to explore the function of diverse thiodiazole dioxides.
In the course of a recent collaborative study between the
Sarpong group and Janssen Research and Development to
prepare aza-bicyclohexanes and bicyclopentanes,7 we identied
3 as an unexpected product of the reaction between an imine
and 2,3-dimethylimidazole-1-sulfonyl azide triate (A, Fig. 1C).
We recognized that this transformation seemingly overcomes
the key challenge described above by obviating the need for preoxidation of the a-carbon of the ketone coupling partner enroute to the thiodiazole dioxide structural motif. This transformation represents a modular, three-component couplingthat allows for the rapid diversication of methyl ketones andprimary amines, two functional groups that are wellrepresented in pharmaceutical libraries.
In addition to the practical value of this discovery, we also
recognized an opportunity to explore the reactivity of 2,3dimethylimidazole-1-sulfonyl azide triate (A).8 Sulfamoyl
azides have been used in sulfonyl8 and diazo9 transfer reactions,
cycloadditions,10 and even nitrogen deletion reactions.11© 2024 The Author(s). Published by the Royal Society of ChemistryView Article Online

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Because of their diverse array of reactivity, the study of thesereagents with a variety of functional groups may give rise to newmechanistic insights and strategies for chemical diversication.

Results and discussion

Fig. 1 (A) Biologically active molecules containing the thiodiazole
dioxide motif. (B) Strategies for the preparation of thiodiazole dioxides.
(C) Unexpected formation of thiodiazole dioxide 3. PEP = paraethoxyphenyl HMDS: hexamethyldisilazide.

Table 1

We rst set out to optimize the yield of 3a (Table 1) by performing the reaction in two steps consisting of imine formationfrom 4-uoroacetophenone (1a) and allylamine (2a), followedby reaction of the imine with A. Initial conditions involved
stirring 1a and 2a in the presence of 3 Å molecular sieves atambient temperature in cyclohexane. Aer 24 h, the solvent wasremoved, the reaction vessel cooled to 0 °C, and a solution of
sulfonyl azide A in dry MeCN was slowly added. The reaction
mixture was then allowed to warm to room temperature yielding
the desired thiodiazole (3a) in 15% yield along with a 59% yieldof recovered ketone (entry 1). The large amount of remaining
starting ketone indicated to us that the condensation step (tomake the imine) did not reach completion. Increasing thetemperature for the imine formation to 60 °C led to a signicant
increase in overall yield (entry 2). However, running the reaction
at 80 °C resulted in mostly decomposition (entry 3). We also
speculated that a base additive could facilitate the conversion of
the initially formed imine to intermediates such as an enamine
en route to the product. Using 2,6-di-tert-butylpyridine as a baseled to a pronounced increase in the reaction yield (entry 4), with
2, 6-lutidine proving less eﬀective (entry 5). Lastly, we examinedother common solvents, including tetrahydrofuran (THF), anddichloromethane (DCM) (entries 6 and 7), which led todecreased yields of 3a. The optimized conditions (entry 4) also
proved viable without the need to remove the cyclohexane
solvent needed for imine formation, leading to an eﬃcient onepot reaction protocol.
With optimized conditions in hand, we next investigated thescope of the coupling partners (Scheme 1). Simple allylic
amines (see 3a–3b) perform well in this reaction, while

Optimization of reaction conditions

Entry

Temp

Solvent

Additive (1.0 equiv.)

Yielda (%)

RSM (%)

1
2
3
4
5
6
7

23 °C
60 °C
80 °C
60 °C
60 °C
60 °C
60 °C

MeCN
MeCN
MeCN
MeCN
MeCN
THF
DCM

—
—
—
Di-tert-butylpyridine
2,6-Lutidine
Di-tert-butylpyridine
Di-tert-butylpyridine

15
43
N/Ab
71c
48
61
38

59
26
N/A
18c
47
15
6

a
Yield was determined by 1H NMR with dimethyl sulfone as an internal standard. b Decomposition was observed. c Isolated yield. CyH =cyclohexane RSM: recovered starting material MS: molecular sieves.

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Substrate scope of amine. aReaction conditions: see Table 1, entry 4. bp-Fluoroacetophenone. c(E)-Cinnamylamine. Isolated yieldreported. Yield in parenthesis refer to recovered starting material. CyH: cyclohexane MS: molecular sieves.
Scheme 1

cinnamyl amine results in reduced yield of the product (3c).
Propargylic and homoallylic amines are also competent
coupling partners giving moderate yields of the desired products (3d and 3e, respectively). Diverse benzylic amines,
including those bearing electronically-disparate groups (see 3f–h) serve competently as coupling partners in the reaction,although a-substitution (see 3i) leads to decreased yields

330 | Chem. Sci., 2024, 15, 328–335

compared to other benzylic amines. Finally, aliphatic amines
can also be employed, giving the products (3j–3k) in moderate
to good yields. X-Ray crystallographic analysis of a single crystalof 3b provided support for the assigned structures. To further
establish the practicality of this approach, a gram-scale reaction
using 1a (1.00 g, 7.23 mmol) and 2a under the standard reaction
conditions proceeded without any loss in eﬃciency to give 3a in© 2024 The Author(s). Published by the Royal Society of ChemistryView Article Online

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70% yield along with 5% of recovered methyl ketone starting
material.
We then investigated the substrate scope of the ketone
coupling partner. Para- and meta-substitution is well tolerated
on the ketone coupling partner (see 3m–3n), while orthosubstitution signicantly reduces reaction eﬃciency (see 3o).
Electron-neutral and electron-poor ketones react well (see 3l–3q), whereas decreased yields are observed for an electron-rich
ketone (see 3p). Various heteroaryl substituted ketones arecompetent substrates and deliver the corresponding products(3r–3u) in up to 89% yield. A series of cyclic aromatic ketones,
including 5-uoro-1-indanone, a-tetralone, and b-tetralone
were successful substrates as well. Notably, a-tetralone and btetralone led to the same product (3w), presumably throughdiverging pathways (vide infra). Finally, vinyl and aliphatic
ketones were competent substrates, giving 3x and 3y–3ab,respectively. Ketones bearing a-branched, cyclic, groups aresuperior substrates, whereas linear substrates (e.g., 1aa) gave
lower yields of the desired products (e.g., 3aa).
There are also several limitations in the scope of this reaction. Specically, we found that ketones bearing a-substitution
were poor substrates. For example, 3ac was not formed from thecorresponding ketone even upon extended reaction times.
Amino acids and anilines also proved to be unsuccessful amine
coupling partners.
We hypothesized that ineﬃcient formation of the intermediate imine could account for the poor reaction outcomes
observed in several cases. To probe this possibility, we monitored the imine formation for one successful substrate (i.e., toform 3a) and two unsuccessful substrates (to form 3ac and 3ad)

(A) Ratios of 4 : 3 after 24 h (3 Å MS, CyH, 60 °C) andoutcome of subsequent reaction of A. (B) Success of reaction withpure 4o step 1: 3 Å MS, cyclohexane, 60 °C. Step 2: A, MeCN, dtbp, 0 °C
to r. t. dtbp: 2, 6-ditertbutylpyridine.

Scheme 2© 2024 The Author(s). Published by the Royal Society of Chemistry

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Scheme 3 (A) Outcome of reaction with 13C-acetophenone. (B)Outcome of reaction with 15N-allylamine for conditions see Table 1
entry 4.

as well as one low yielding product (3o). As shown in Scheme 2,for substrates that reacted poorly or unsuccessfully, only partial
conversion of the ketone to the imine was observed. When these
ketone/imine mixtures were treated with A, product was only
obtained from imines 4a and 4o. The mixtures containing
imines 4ac and 4ad returned only starting ketone aer treatment with A and workup. We then synthesized pure 4o andsubjected it to reaction with A. The product (3o) was isolated ina much improved 43% yield. From these experiments, weconclude that for some ketone substrates, low yields of the
product might result due to incomplete imine formation.
However, in some cases (e.g., 3ac), even substrates that form theimine intermediate eﬃciently can lead to low yields of the
products due to other incompatibility issues (e.g., diﬃculty withenamine formation).
To gain insight into the reaction mechanism, we chose to
conduct a series of studies with isotopically labeled substrates.
The use of a-13C acetophenone (13C-1l) provided thiodiazole
dioxide 13C-3l (Scheme 3A) bearing the 13C label at the imine
carbon, which suggests that the carbon chain remains intact(i.e., a phenyl migration does not occur). Next, we conducted thereaction with 15N labelled allyl amine, which gave 15N-3a(Scheme 3B) where the 15N label was incorporated only at theamine position and not at the imine nitrogen. This observation
indicates that the imine nitrogen in 4 undergoes a 1,2 migration
during the course of the reaction. Notably, the nitrogen also
migrates when an aliphatic ketone (1y) is used to give 15N-3y—
further evidence that the aromatic system is not involved or
critical to the rearrangement.
Nitrogen migrations of this type are known for enamine/azide cycloadditions.12 These cycloadditions can generateamino-triazolines which can in turn generate amino-aziridines(Fig. 2A). Each of these species can further transform in several
ways, including through C–C bond cleavage (Type I)13 andmigration of a carbon (Type II),13a–d,14 nitrogen (TypeIII),13e,14b,c,15b or hydride (Type IV)10,13e,14a,15 substituent (Fig. 2A).
Product mixtures are oen observed, and the selectivity is
dictated by the nature of the substituents on both the enamine

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Chemical ScienceFig. 2 (A) Rearrangements of amino-triazolines. (B) DFT investigation of possible reaction pathways (values given in kcal mol−1). (C) Reactivity oftetralone substrates (css: closed shell singlet. oss: open shell singlet. t: triplet).

and the azide components. Importantly, our system diﬀers fromthose described in the literature in several ways. Most notably,
our reaction proceeds through an imine formed from a primary

332 | Chem. Sci., 2024, 15, 328–335

amine (see Scheme 3A) rather than an enamine formed froma secondary amine (see ref. 12–15). Additionally, sulfamoyl
azide A is able to react with the imine at sulfur, to generate© 2024 The Author(s). Published by the Royal Society of ChemistryView Article Online

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a sulfamoyl enamine. These key diﬀerences, as well as thesuperb selectivity for the Type III nitrogen migration that we
observe, led us to further investigate the reaction pathway with
DFT. For ease of computation, calculations were performed
with a model enamine (5), where the N-allyl group is modied to
N-Me. Structure minima were generated with DFT or UDFT in
the gas phase in Jaguar (B3LYP-D3/6-31G+*). Transition structures were identied using coordinate scans, linear synchronous transit, quadratic synchronous transit, or a combination
thereof, at the same level of theory.
We considered two possible pathways to access the aminoaziridine precursor to the Type III product. Pathway 1
involving loss of nitrogen followed by (2 + 1) cycloaddition, andPathway 2 involving (3 + 2) cycloaddition followed by nitrogen
extrusion (Fig. 2B). To interrogate Pathway 1, we rst identieda transition state corresponding to loss of nitrogen from 5 (TS1)to form nitrene 6 in one of three spin states. At this stage, (2 + 1)
cycloaddition would generate aziridine 8 through the respective
transition structure, which subsequently undergoes exothermic
rearrangement via TS5 to give nal product 9. For Pathway 2, wewere able to identify a transition state for the intramolecular
cycloaddition of the azide and enamine (TS2) in 5, which resultsin the formation of triazoline 7. A transition structure for the
direct conversion of 7 to 9 by either a concerted or stepwise
mechanism could not be identied. However, TS4 was identied, corresponding to loss of nitrogen from triazoline 7 to give
8. Analogous to the rst pathway, 8 could undergo exothermic
rearrangement to give the nal product (9). The computationally computed barrier for the (3 + 2) cycloaddition at TS2 is
3.5 kcal mol−1 lower than the barrier for loss of nitrogen at TS1,
suggesting the former is the favored pathway. Consistent with
the isotope labelling experiments discussed above, one of the
C–N aziridine bonds is lengthened at TS5, and the imaginary
frequency at this transition structure corresponds to atomic
motion of the C and N atoms involved in the bondrearrangement.

Scheme 4

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We hypothesize that the preference for Type III reactivity
over either Type I or Type II arises from the sulfur dioxide groupconnecting the two nitrogens. This tether would make amidine
formation diﬃcult due to developing strain en route to a fourmembered heterocycle. Although we cannot rule out an intermolecular enamine/azide cycloaddition, the product selectivity
suggests that the S–N bond forms prior to rearrangement.
Additionally, we propose that the nitrogen rearrangement
accounts for the convergent reactivity of a- and b-tetralone. In
the case of a-tetralone, the expected Type III nitrogen migration
is observed (as conrmed by 15N NMR; see Fig. 2C). In the btetralone system, however, the nitrogen does not migrate.
Instead, the observed product results from Type IV hydridemigration (see Fig. 2A and C). We posit that in this case, thenitrogen shi is disfavored by developing “peri-strain” between
the ortho hydrogen on the aromatic ring and the N-allyl
substituent. In all other cases, the migrating group is moving
away from the aromatic ring, leading instead to a lessening of
any unfavorable interactions between the nitrogen substituent
and the aromatic protons. On the basis of this hypothesis, we
anticipated that a linear analog of b-tetralone (e.g., phenylacetone) should give only the expected nitrogen shi productbecause of the absence of “peri-strain” in this conformationallyexible system. Indeed, using 10 and 2a in the thiadiazole
dioxide forming reaction, we isolated only the two expected
products that involve a nitrogen shi (i.e., 11, arising from anintermediate benzylic enamine and 12, arising from a terminal
enamine intermediate). This observation supports our hypothesis that the conformational rigidity of the a-tetralone system
leads to the unique reactivity that is observed in that case.
With empirical and computational support for our proposedmechanism secured, we then set out to demonstrate thesynthetic utility of our dihydro-1,2,5-thiodiazole 1,1-dioxides(Scheme 4). For example, tetrahydro-1,2,5-thiodiazole dioxide
13 is obtained through either reduction with sodium borohydride or enantioselective transfer hydrogenation using

Synthetic transformations of dihydro-1,2,5-thiodiazole dioxide. FA/TEA: formic acid/triethylamine (∼5 : 2).

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ruthenium catalyst B to give 13 in high yield and, in the case of
the transfer hydrogenation, good enantiomeric excess (91%ee).6 In addition to hydrides, 3a is a competent electrophile forcarbon nucleophiles, exemplied by the addition of ethyl
magnesium bromide to form 14. The cyclic sulfamide moiety
can also be opened to 1,2 diamine 15 by heating with hydrazine.
This process allows for easy and modular access to diamines
which are precursors to a variety of biologically relevant structural motifs (imidazolidinones, etc.).16
Sulfonyl imines are well-established precursors to N-sulfonyloxaziridines, a very useful class of oxygen-transfer reagents.17
Accordingly, the dihydro-1,2,5-thiodiazole dioxide 3f was readily
converted to the corresponding oxaziridine (16) by oxidation
with meta-chloroperoxybenzoic acid (mCPBA). The modular
nature of our method should allow for the synthesis of a diverse
array of oxaziridines which could aid in the discovery of newreagents for oxygen transfer.

Conclusions
In conclusion, we have developed an eﬃcient method for theconversion of commercially available methyl ketones andprimary amines to dihydro-1,2,5-thiodiazole dioxides in a onepot protocol using 2,3-dimethylimidazole-1-sulfonyl azide. The
overall transformation constitutes a highly modular threecomponent coupling and provides a general and practical
approach to diversied drug-like thiodiazole dioxides. The
transformation displays a reasonably broad functional grouptolerance. A proposed reaction mechanism is supported byisotopic labelling of nitrogen and carbon atoms in the amineand ketone coupling partners, respectively. The subsequenttransformation of thiodiazole dioxides into other compounds of
medicinal relevance was also demonstrated.

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Acknowledgements
R. S. is grateful to Janssen Research and Development for
support (Agreement No. 1501907). Partial support of the work
conducted at Berkeley was supported by the NIGMS (R35
GM130345). K. P. was supported by a fellowship from the
National Research Council of Thailand (NRCT): NRCT5RGJ63023-175. We thank Dr Hasan Celik and UC Berkeley's
NMR facility in the College of Chemistry (CoC-NMR) for spectroscopic assistance. Instruments in CoC-NMR are supported inpart by NIH S10OD024998. We thank Dr Nicholas Settineri (UCBerkeley) for X-ray crystallographic studies of 3b. We thank Drs
Ulla Andersen and Zongrui Zhou at the UC Berkeley QB3 Mass
Spectrometry Facility for mass spectrometry analysis. Special
thanks to Deszra Shariﬀ, Dr Mona Sharar and Jonathan Malone
at Janssen Research and Development for NMR analysis andacquisition of HRMS. We thank Dr Michael Black (formerly
from the Sarpong Group), who was the rst to synthesize thethiodiazole dioxide product. We are grateful to Dr Ian Bakanas
for insightful discussions regarding the nitrogen migration
mechanism.

Notes and references

There are no conicts to declare.

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334 | Chem. Sci., 2024, 15, 328–335© 2024 The Author(s). Published by the Royal Society of Chemistry

Data availability
Data supporting the work in this publication are available via
the ESI and associated crystallographic data.†

Author contributions
This manuscript was written by P. S. and K. P. with input from I.
S., R. S., T. P. L., P. G. R. and M. A. P. P. G. R. rst characterized
the unexpected thiodiazole dioxide product. The majority of thesynthetic work was carried out by K. P. and P. S. Experiments
were designed by P. S. and R. S. with input from M. A., T. P. L.
and P. G. R. All calculations were carried out by I. S. under thesupervision of M. S., T. P. L, P. G. R., M. A., and R. S. supervised
the project.

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