Solvated Alkali and Calcium

2,2,6,6-Tetramethylpiperidides: Synthesis and Reactivity

Gabriel Duneş, Cléo Bastien, Savarithai Jenani Louis Anandaraj, Marie Cordier, Vincent Dorcet, Thierry Roisnel, William Erb, Florence Mongin, Yann Sarazin

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Gabriel Duneş, Cléo Bastien, Savarithai Jenani Louis Anandaraj, Marie Cordier, Vincent Dorcet, et al.. Solvated Alkali and Calcium 2,2,6,6-Tetramethylpiperidides: Synthesis and Reactivity. European Journal of Inorganic Chemistry, 2025, 10.1002/ejic.202500451. hal-05337295

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# Solvated Alkali and Calcium 2,2,6,6-Tetramethylpiperidides: Synthesis and Reactivity

Gabriel Duneş, Cléo Bastien, Savarithai Jenani Louis Anandaraj, Marie Cordier, Vincent Dorcet, Thierry Roisnel, William Erb, Florence Mongin, and Yann Sarazin*

Alkali 2,2,6,6-tetramethylpiperidides (TMP) are quintessential bases in organic chemistry. The syntheses and characterization of solvated lithium, potassium, and calcium tetramethylpiperidides are reported herein. The molecular solid-state structures of the homometallic salts [(TMP)Li(thp)]₂, [(TMP)Li(pmdta)], [(µ-TMP)K(pmdta)]₂, [(TMP)₂Ca(thp)₂], and [(TMP)₂Ca(thf)₂] are described (pmdta = N,N,N',N'',N''-pentamethyldiethylenetriamine; thp = tetrahydropyran). In addition, the structure of the heterobimetallic [K{pmdta}{µ³-NMe₂}{µ²-TMP}Li]₂, a compound obtained upon decomposition of pmdta in the presence of (TMP)Li and BuOK in petroleum ether, is also presented. These

six complexes complement the body of s-block metal tetramethylpiperidides that have been structurally authenticated, with, in particular, the addition of two new calcium-TMP complexes. To probe their reactivity, these bases have been used to mediate the deprotometallation of 1,3-dimethoxybenzene in thf, followed by quenching with iodine. While the calcium complexes show little efficacy, good to high yields are achieved with the different [(TMP)M]n (M = Li, K, Na) and (TMP)Li'BuOK alkali bases. The influence of temperature in this reaction is demonstrated, allowing for a better understanding of the overall behavior of the metal bases.

## 1. Introduction

Metallated secondary amides such as diisopropylamide, hexamethyldisilazide, and 2,2,6,6-tetramethylpiperidine (TMP) are polar metal reagents found in most synthetic chemistry laboratories. They are commercially available and safer to handle than metal alkyls and hydrides. Owing to the high basicity (Li-TMP, pKₐ = 36 in thf¹⁾) and poor nucleophilicity of the 2,2,6,6-tetramethylpiperidine anion, alkali TMP have been popular for a plethora of selective deprotometallation reactions, e.g., directed orthometallations, formation of enolates, and Wittig reactions.²⁻⁵⁾ The question of the structures of these salts in the solid state and in solution is of paramount importance. Collum and coworkers have dedicated considerable efforts to study the structures of lithium amides in solution, in particular through the use of ⁶Li and ¹⁵N multinuclear NMR.⁴,⁶⁻¹⁰⁾ Detailed structural information is essential to understand the reactivity of these species, and

solvation has been shown to impact their coordination chemistry. [(TMP)Li]n is an excellent showcase. Without coordinated Lewis base, two planar polymorphs are known, the tetramer [(TMP)Li]₄¹⁾ (A in Figure 1) and the trimer [(TMP)Li]₃ (B),¹²⁾ but in the presence of N,N,N',N''-tetramethylenediamine (tmeda) or thf, the open dimer [(TMP)Li(µ²-TMP)Li(tmeda)] (C) or the symmetrical dimer [(TMP)Li(thf)]₂ (D) are obtained, respectively.¹³,¹⁴⁾

Beyond these lithium compounds, occurrences of homometallic TMP-alkali metal complexes that have been authenticated by X-ray diffraction (XRD) analysis, such as the dimers [(TMP)Na(thf)]₂,¹⁴⁾ [(TMP)Na(tmeda)]₂,⁵⁾ and [(TMP)K(tmeda)]₂ (E–G),⁵⁾ are scarce. This is particularly true in comparison to the number of crystal structures that have been obtained for heterobimetallic TMP complexes that combine two alkali metals, either without Lewis base as [LiNa(µ²-TMP)]∞¹⁴⁾ or upon coordination of ligand(s) such as thf, tmeda, or N,N,N',N'',N''-pentamethyldiethylenetriamine (pmdta). Salient examples include [LiNa(µ²-TMP)₂(tmeda)], [LiK(µ²-TMP)₂(pmdta)] (H), and [NaK(µ²-TMP)₂(pmdta)],¹⁵⁾ or the open complexes [(TMP)Li(µ²-TMP)Na(tmeda)] and [(TMP)Li(µ²-TMP)K(tmeda)] structurally akin to C.¹⁵⁾ Other heterobimetallic combinations that involve different metals are reported, e.g., with coinage metals as in the planar [Li₂Cu₂(µ²-TMP)₄].¹⁶⁾

The heavy alkaline earths calcium, strontium, and barium are currently attracting major interest in molecular chemistry, organometallic chemistry, and catalysis science.¹⁷⁻²¹⁾ Yet, TMP complexes with these large metals are seldom. Reported examples only focus on calcium, the smallest of these elements (ionic radius r(Ca²⁺) = 1.00 Å²²⁾), and are limited to the monomeric [(TMP)₂Ca(tmeda)]²³⁾ and to the iodide-bridged dimer [Ca(µ-I)(TMP)(tmeda)]²⁴⁾ (respectively I and J in Figure 1). The utilization of these two complexes for catalysis or as reagents for organic

G. Duneş, C. Bastien, S. J. Louis Anandaraj, M. Cordier, V. Dorcet, T. Roisnel, W. Erb, F. Mongin, Y. Sarazin

Univ Rennes

CNRS

ISCR (Institut des Sciences Chimiques de Rennes)

UMR 6226

Université de Rennes

F-35000 Rennes, France

E-mail: yann.sarazin@univ-rennes.fr

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Supporting information for this article is available on the WWW under https://doi.org/10.1002/ejic.202500451

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© 2025 The Author(s). European Journal of Inorganic Chemistry published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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<figure><img src="image_7.png" /><figcaption>**Figure 1.** Examples of crystallographically characterized alkali and calcium tetramethylpiperidides.</figcaption></figure>

chemistry is as yet unreported. Moreover, although coordination of Lewis bases in Ca-silazides of the type [Ca{N(SiMe₃)₂}.(solvent)]ₓ has been abundantly covered,[21,25–27] it has not been extrapola- tated to Ca-TMP chemistry.

As part of our ongoing work toward the implementation of alkali and alkaline-earth strong bases in stoichiometric organic reactions,[28–30] we are reporting on the synthesis and structures of the alkali salts [(TMP)Li(thp)] (1; thp = tetrahydropyran), [(TMP) Li(pmdta)] (2), [(TMP)K(pmdta)] (3), and [K{pmdta}{µ³-NMe₂}{µ²-TMP]Li] (4) and of the calcium derivatives [(TMP)₂Ca(thp)₂] (5) and [(TMP)₂Ca(thf)₂] (6). Some aspects of their reactivity toward 1,3-dimethoxybenzene are presented and compared with per- taining literature precedents.

The widespread use of alkali-metal secondary amides in organic synthesis, and in particular of lithium diisopropylamide and tetramethylpiperidine, stems from their properties, which are both strongly basic and weakly nucleophilic, making them reagents of choice for many reactions where alkylmetal reagents cannot be employed.[3,15] Recently, sodium dialkylamides have emerged as promising reagents.[31] Herein, we also report on the reactivity of less studied Met-TMP bases (Met = K, Ca; pre- pared ex situ or in situ) in aromatic deprotometallations, in order to compare them with the much more common lithium–TMP analog.

## 2. Results and Discussion

### 2.1. Synthesis and Structural Characterization

The lithium salts [(TMP)Li(thp)]₂ (1₂) and [(TMP)Li(pmdta)] (2) were both isolated in moderate to good yields as colorless crys- tals upon deprotonation of TMP-H with stoichiometric amounts

of nBuLi in petroleum ether followed by treatment with an excess of the relevant Lewis base (Scheme 1). Note that thp was used on occasions instead of thf as the six-member cycle is less prone to deprotometallation in the presence of strong bases of early main group metals.[32] Moreover, we were also able to synthesize and crystallize the already reported [(TMP)Li(µ²-TMP)Li(tmeda)] (C).[13]

The identity of 1₂ and 2 was established by X-ray diffraction analysis. The NMR data recorded in benzene-d₆ were consistent with the proposed formulation, but the resonances were other- wise generally broad and difficult to assign, and in situ decom- position was always observed. This was also the case for all subsequent complexes presented herein. Attempts to record improved data with low-temperature NMR were unsuccessful. They were considerably complicated by the low solubility of the compounds in benzene-d₆, by the limited temperature range of this solvent, and by the high sensitivity and reactivity of the complexes toward moderately acidic deuterated solvents such as deuterated toluene or even thf. Because of the reactivity of the complexes and the difficulty in obtaining reliable NMR data, we have isolated and worked exclusively with X-ray quality single crystals. All yields provided herein for new compounds refer to nonoptimized yields of crystalline materials. The solvent-free [(TMP)K]ₙ was obtained in 82% following the reaction of TMP- H with nBuLi and tBuOK, involving removal of lithium by-products by thorough washing with petroleum ether (Scheme 1). Upon fur- ther treatment with pmdta, yellow single crystals of the dimeric [(µ-TMP)K(pmdta)]₂ (3₂) were isolated in 40% yield upon crystalli- zation from a solution of the neat triamine. Unexpectedly, if [(TMP)K]ₙ was not effectively separated from lithium by-products prior to the addition of pmdta, decomposition of the triamine was repeatedly observed. Hence, the reaction of fresh [(TMP)Li] with tBuOK reproducibly led to the isolation of colorless crystals (yield 20%–25%) of the heterobimetallic [K{pmdta}{µ³-NMe₂}
<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /><figcaption>**Scheme 1.** Synthesis of Li, K, and Ca complexes. Yields given for isolated XRD-quality crystals.</figcaption></figure>

The presence of NMe₂ anionic fragments in 4₂ evidently results from deprotonation and decomposition of pmdta in the presence of a very strong Li/K superbase, e.g., upon deprotometallation of the methylene moiety in α position to the central nitrogen atom followed by Me₂N-metal elimination (Scheme 2). Such type of decomposition pathway is already documented, e.g., in the case of 2-phenylethyldimethylamine that released NMe₂ moieties in the presence of the modified Lochmann–Schlosser 'BuLi-'BuOK superbase.[33] The 7Li NMR spectrum of complex 4 in benzene-d₆ exhibits a single resonance at δ₇Li 1.95 ppm. Finally, the monomeric calcium complexes [(TMP)₂Ca(thp)₂] (5) and [(TMP)₂Ca(thf)₂] (6) were obtained and crystallized as colorless single crystals by reaction of Cal₂ with freshly prepared [(TMP)K]ₙ, respectively, in a toluene/thp mixture and in thf (Scheme 1). The yields of isolated crystals were

relatively low (≈20%–35%) but reproducible. Note that 5 and 6 are pyrophoric and extremely reactive; they will also readily deprotonate ethereal solvents.

The structure of the dimer [(TMP)Li(thp)]₂ (1₂) is depicted in Figure 2. The geometry about each three-coordinated lithium atom is trigonal planar (Σ₀(Li1) = 359.84(10)° and Σ₀(Li2) = 359.94(10)°). The Li1-N and Li2-N interatomic distances, respectively, in the ranges 2.006(2)–2.108(2) and 2.022(2)–2.107(2), compare well with those in [(TMP)Li(thf)]₂ (2.012(3)–2.093(3) Å[14]). Likewise, the Li1-O11A (2.002(2) Å) and Li2-O31 (2.005(2) Å) distances in 1₂ match reasonably well those in Mulvey's analog (1.964(3) and 1.983(3) Å). Overall, the structures of the two complexes are very similar.

Whereas the open dimer [(TMP)Li(μ²-TMP)Li(tmeda)] (C) is obtained with the bidentate tmeda, the use of the tridentate

<figure><img src="image_10.png" /><figcaption>**Scheme 2.** Proposed decomposition of pmdta in the presence of (TMP)Li'BuOK.</figcaption></figure>
<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /><figcaption>**Figure 2.** ORTEP representation of the molecular solid-state structure of [(TMP)Li(thp)]<sub>2</sub> (1<sub>2</sub>). Ellipsoids at the 50% probability level. H atoms omitted for clarity. Only one of the two independent and identical molecules in the asymmetric unit and main component (85%) of the disordered thp molecule are depicted. Representative interatomic distances (Å) and angles (°): Li1-N1 = 2.006(2), Li1-N21 = 2.108(2), Li1-O11A = 2.002(2), Li2-N1 = 2.107(2), Li2-N21 = 2.022(2), and Li2-O31 = 2.005(2) and N1-Li1-N21 = 109.54(9), N1-Li1-O11A = 120.53(10), N21-Li1-O11A = 129.77(10), N1-Li2-N21 = 108.95(9), N1-Li2-O31 = 130.04(10), and N21-Li2-O31 = 120.95(10).</figcaption></figure>

<figure><img src="image_13.png" /><figcaption>**Figure 3.** ORTEP representation of the molecular solid-state structure of [(TMP)Li(pmdta)] (2). Ellipsoids at the 30% probability level. H atoms omitted for clarity. Representative interatomic distances (Å) and angles (°): Li1-N1 = 2.215(2), Li1-N6 = 2.472(3), Li1-N10 = 2.239(3), and Li1-N21 = 1.936(2) and N1-Li1-N6 = 78.28(8), N1-Li1-N10 = 119.83(11), N1-Li1-N21 = 116.99(11), N6-Li1-N21 = 145.41(12), N6-Li1-N10 = 76.54(8), and N10-Li1-N21 = 114.64(11).</figcaption></figure>

pmdta provided the monomeric, four-coordinated [(TMP)
Li(pmdta)] (2) (Figure 3). Complex 2 is to our knowledge the first
monometallic lithium–TMP compound that has been structurally
authenticated. The geometry around the lithium center forms a
highly distorted tetrahedron. The Li1-N21 interatomic distance to
the tetramethylpiperidide of 1.936(2) Å is noticeably shorter than
in the dimer 1₂ (in the range 2.006(2)–2.108(2) Å) and than in the
solvent-free aggregates A (1.981(3)–2.023(3) Å) and B (1.988(3)–
2.066(3) Å).<sup>[11,12]</sup> It compares better with the Li-N distances in
the open dimer C (1.885(5), 1.949(5), and 2.049(5) Å).<sup>[13]</sup> The three

Li1-N<sub>pmdta</sub> interatomic distances of 2.215(2), 2.239(3), and 2.472(3) Å are unremarkable; we note that the distance to the central nitrogen atom in the triamine (Li1-N6 = 2.472(3) Å) is much longer than the other two.

By contrast with the lithium complex 2 which forms a mono-
mer, the potassium congener crystallized as the TMP-bridged
dimer [(μ-TMP)K(pmdta)]<sub>2</sub> (3<sub>2</sub>; Figure 4). Each potassium is
five-coordinated with a highly distorted trigonal bipyramidal
environment (τ<sub>5</sub>(K1) = 0.65, τ<sub>5</sub>(K2) = 0.64),<sup>[34]</sup> and the K<sub>2</sub>N<sub>2</sub> central
core of the crystalline structure resembles that of the known
[(μ-TMP)K(tmeda)]<sub>2</sub> (G).<sup>[5]</sup> It is interesting to note that the isostruc-
tural heterobimetallic complexes [[(μ-TMP)KLi]<sub>2</sub>(pmdta)] and
[[[(μ-TMP)KNa]<sub>2</sub>(pmdta)] are also known,<sup>[15]</sup> but that only one
pmdta molecule is coordinated to the largest element, potassium,
in these two complexes, whereas the smaller Li or Na are devoid
of coordinated Lewis base. The much larger size of potassium
combined to its greater electropositivity and polarizability
allows for the coordination of pmdta where the smaller and
harder Li and Na do not. The K<sub>2</sub>N<sub>2</sub> core forms a rhomboid with
large discrepancies between the K-N interatomic distances, com-
pare K1-N1 (2.7896(10) Å) with K1-N2 (3.0042(11) Å), or K2-N1
(3.0049(11) Å) with K2-N2 (2.7848(10) Å). By contrast, the rhom-
boidal core in G is much more regular, with K-N interatomic dis-
tances in the range 2.744(2)–2.836(2) Å. Moreover, in opposition
to 2, the K-N interatomic distances to the central N atom of the
triamine ligand (K1-N4 = 3.0521(12) and K2-N7 = 3.0646(11) Å) is
now much shorter than the distances to the outer ones (K1-N3 =
3.2618(12) and K1-N5 = 3.1779(12) Å; K2-N6 = 3.2429(11) and
K2-N8 = 3.2021(12) Å). This presumably reflect the greater steric
constraint imposed to the metal centers by the presence of two
bulky bridging TMP units in 3<sub>2</sub>.

<figure><img src="image_14.png" /><figcaption>**Figure 4.** ORTEP representation of the molecular solid-state structure of [(μ-TMP)K(pmdta)]<sub>2</sub> (3<sub>2</sub>). Ellipsoids at the 30% probability level. H atoms omitted for clarity. Representative interatomic distances (Å) and angles (°): K1-N1 = 2.7896(10), K1-N2 = 3.0042(11), K1-N3 = 3.2618(12), K1-N4 = 3.0521(12), K1-N5 = 3.1779(12), K2-N1 = 3.0049(11), K2-N2 = 2.7848(10), K2-N6 = 3.2429(11), K2-N7 = 3.0646(11), and K2-N8 = 3.2021(12) and N1-K1-N2 = 97.68(3), N1-K1-N3 = 117.74(3), N1-K1-N4 = 105.38(3), N1-K1-N5 = 116.86(3), N2-K1-N3 = 108.24(3), N2-K1-N4 = 156.78(3), N2-K1-N5 = 112.97(3), N3-K1-N4 = 58.32(4), N3-K1-N5 = 103.39(3), N4-K1-N5 = 58.52(3), N1-K2-N2 = 97.76(3), N1-K2-N6 = 108.41(3), N1-K2-N7 = 157.58(3), N1-K2-N8 = 113.52(3), N2-K2-N6 = 118.89(3), N2-K2-N7 = 104.50(3), N2-K2-N8 = 116.43(3), N6-K2-N7 = 58.14(3), N6-K2-N8 = 102.10(3), and N7-K2-N8 = 58.29(3).</figcaption></figure>
<figure><img src="image_15.png" /></figure>

The heterobimetallic aggregate [K{pmdta}{µ³-NMe₂}{µ²-TMP}Li]₂ (4₂) presents a very unusual architecture, where two central three-coordinated Li atoms are connected to two capping, five-coordinated potassium ones through bridging tetramethylpiperidine and dimethylamide anions (Figure 5). The ten lithium, potassium, N_TMP, N_NMe₂, and central N_pmdta atoms are essentially coplanar, giving the overall construction a sheet-like architecture. The coordination around the lithium is perfectly trigonal planar (Σ₀(Li1) = 360.10(3)°), whereas the potassium center lies in a very distorted trigonal bipyramidal geometry (τ₅(K1) = 0.70).[34] The Li₂N₂ central core involving the N_NMe₂ atom forms a fairly regular rhomboid, compare Li1-N12 = 2.032(5) and Li1-N12' = 2.127(5) Å. The interatomic distance from Li1 to the N_TMP atom (Li1-N1 = 2.010(5) Å) falls within this same range. There is no example of pertaining terminal [Li]-NMe₂ species in the CCDC database. Relevant complexes include the homobimetallic dimer [Li(µ-NMe₂).(thf)₂]₂ featuring Li-N bond lengths of 1.996(4) and 2.007(4) Å,[35] and the heterobimetallic [tBu₂Zn(µ-NMe₂)Li(pmdta)] with a Li-N distance of 2.050(4) Å.[33] By contrast with 3₂, the central N_pmdta atom in 4₂ is located further from the potassium atom than the other two N_pmdta atoms (compare K1-N26 = 3.057(3) Å vs. K1-N21 = 2.927(3) and K1-N30 = 2.930(3) Å), suggesting lesser steric congestion around the large alkali metal in 4₂, in agreement with the small size of the NMe₂ fragment. With Li1-Li1' and Li1-K1 interatomic distances of 2.591(9) and 3.236(5) Å respectively, combined to the planarity of the compound and the small size of NMe₂ substituents, the three-coordinated Li centers are remarkably coordinatively unsheltered. A single example of similar geometry about lithium could be found in the CCDC database, for the heterobimetallic complex [(thf)Li(µ-TMP)(µ-NMe₂)Al'Bu₂] that exhibited comparable structural features, e.g., Li-N_TMP = 2.047(2) Å, Li-N_NMe₂ = 1.998(2) Å, Li-O_thf = 1.901(2) Å.[33]

<figure><img src="image_16.png" /><figcaption>**Figure 5.** ORTEP representation of the molecular solid-state structure of [K{pmdta}{µ³-NMe₂}{µ²-TMP}Li]₂ (4₂). Ellipsoids at the 30% probability level. H atoms omitted for clarity. Representative interatomic distances (Å) and angles (°): K1-N1 = 2.798(2), K1-N12 = 2.980(2), K1-N21 = 2.927(3), K1-N26 = 3.057(3), K1-N30 = 2.930(3), Li1-N1 = 2.010(5), Li1-N12 = 2.032(5), and Li1-N12' = 2.127(5) and N1-K1-N12 = 75.89(7), N1-K1-N21 = 120.93(9), N1-K1-N26 = 118.62(8), N1-K1-N30 = 123.15(8), N12-K1-N21 = 114.09(8), N12-K1-N26 = 165.36(8), N12-K1-N30 = 110.27(8), N21-K1-N26 = 61.55(8), N21-K1-N30 = 107.85(10), N26-K1-N30 = 61.29(8), N1-Li1-N12 = 123.20(3), N1-Li1-N12' = 133.90(3), and N12-Li1-N12' = 103.00(2). Symmetry operation used to generate equivalent atoms: 1-x, 1-y, and 1-z.</figcaption></figure>

<figure><img src="image_17.png" /><figcaption>**Figure 6.** ORTEP representation of the molecular solid-state structure of [(TMP)₂Ca(thp)₂] (5). Ellipsoids at the 50% probability level. H atoms omitted for clarity. Representative interatomic distances (Å) and angles (°): Ca1-N11 = 2.2894(12), Ca1-N11' = 2.2894(12), Ca1-O1 = 2.4065(11), and Ca1-O1' = 2.4065(11) and N11-Ca1-N11' = 125.43(6), N11-Ca1-O1 = 127.70(4), N11-Ca1-O1' = 95.06(4), N11'-Ca1-O1 = 95.06(4), N11'-Ca1-O1' = 127.70(4), and O1-Ca1-O1' = 80.52(6). Symmetry operation used to generate equivalent atoms: 1-x, y, and 1/2-z.</figcaption></figure>

The calcium center in the thp adduct 5 sits in a distorted tetrahedral arrangement (Figure 6), with τ₄ = 0.74.[36] The Ca-N_TMP interatomic distances in 5 (2.2894(12) Å) match those in the parent [(TMP)₂Ca(tmeda)] (I) (2.275(2) Å),[23] and the structures of the two compounds are, on the whole, very similar. The Ca-N distances in the related [Ca{N(SiMe₃)₂}₂.(thp)₂] are also similar (2.311(1) Å).[37] The O1-Ca1-O1' angle of 80.52(6)° in 5 is substantially larger than the corresponding N_tmeda-Ca-N'tmeda angle in I. The wider bite angle in 5 obviously results from the absence of chelating effect compared to the tmeda ligand and from increased steric repulsion between the two thp molecules. Indeed, the corresponding angle of 78.6(1)° in [Ca{N(SiMe₃)₂}.(thp)₂][37] matches well that in 5. The sum of angles around the N_TMP atoms (358.27(11)°) indicates a trigonal planar geometry with a minimal degree of pyramidalization. The molecular structure of the thf adduct [(TMP)₂Ca(thf)₂] (6) was also determined (Figure 7), and it resembles closely that of 5. The O1-Ca1-O1' angle of 83.1(2)° is even larger than in 5. The main metric parameters are otherwise very similar in the two complexes.

## 2.2. Reactivity Studies

The reactivity of different Met-TMP toward 1,3-dimethoxybenzene was studied. Through analysis of the ¹H NMR spectra of the crude mixtures, this substrate allows for easy determination of the ratios of the different products formed after deprotection-iodination. It is also particularly handy because its reactivity has already been assessed using bases such as monometallic n-butyllithium,[38,39] lithium-TMP,[4] and sodium diisopropylamide,[40] as well as aluminum[41] and copper[42] ate bases.
<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /><figcaption>**Figure 7.** ORTEP representation of the molecular solid-state structure of [(TMP)₂Ca(thf)₂] (6). Ellipsoids at the 50% probability level. H atoms omitted for clarity. Only the main components (site occupancy 86.5%) of the disordered thf molecules are depicted. Representative interatomic distances (Å) and angles (°): Ca1-N1 = 2.2628(12), Ca1-N1' = 2.2627(12), Ca1-O1 = 2.430(5), and Ca1-O1' = 2.430(5) and N1-Ca1-N1' = 117.20(6), N1-Ca1-O1 = 129.13(13), N1-Ca1-O1' = 98.55(12), N1'-Ca1-O1 = 98.55(12), N1'-Ca1-O1' = 129.13(13), and O1-Ca1-O1' = 83.1(2). Symmetry operation used to generate equivalent atoms: $-x, y, and 1/2 - z$.</figcaption></figure>

Yet, to our knowledge, no study that compares different Met-TMP bases has been conducted.

1,3-Dimethoxybenzene (7) has already been functionalized efficiently in thf using [(TMP)Li]ₙ (≈1 equiv), but in the presence of chlorotriethylgermane,[43] which facilitates the reaction by acting as an in-situ trap.[44] However, it is more difficult to accumulate 2,6-dimethoxyphenyllithium under these conditions. In particular, Kraus and coworkers observed a yield below 50% after consecutive treatment with 2 equiv of [(TMP)Li]ₙ at -80 °C for 3 h and benzaldehyde.[45] The partial conversion reported then was a convenient entry point, enabling us to compare the reactivity with different amides (Table 1).

In our hands, [(TMP)Li]ₙ (1 equiv; prepared freshly from TMP-H and n-butyllithium) in thf at -80 °C for 1 h was not able to fully deprotonate 7. After addition of iodine, the expected product 8 was obtained with a yield of only 53% (Table 1, entry 1). Increasing the temperature to -50 or -15 °C did not significantly improve this result, but adding an additional equivalent of base afforded conversions above 90% (entries 2 and 3).

We then interrogated the performance of the open dimer [(TMP)Li(µ²-TMP)Li(tmeda)] (C),[13] assuming that both amido groups in this compound were capable of deprotonation. However, by treating 7 with 0.5 equiv of C, the iodide 8 was formed in a low yield (20%, entry 4). This conversion was of the same magnitude as that obtained by using [(TMP)Li]ₙ (1 equiv) in the presence of 0.5 equiv of tmeda (entry 5),

<table><caption>**Table 1.** Deprotometallation of 1,3-dimethoxybenzene (7) using different Met-TMP bases in thf followed by interception with iodine.</caption><thead><tr><th>Entry</th><th>Base</th><th>n</th><th>Conditions</th><th>Yield of 8 [%]<sup>a)</sup></th></tr></thead><tbody><tr><td>1</td><td>[(TMP)Li]n</td><td>1</td><td>-80 °C, 1 h</td><td>53</td></tr><tr><td>2</td><td>[(TMP)Li]n</td><td>1 (2)</td><td>-50 °C, 1 h</td><td>69 (92)</td></tr><tr><td>3</td><td>[(TMP)Li]n</td><td>1 (2)</td><td>-15 °C, 1 h</td><td>57 (90)</td></tr><tr><td>4</td><td>[(Li-TMP)₂-tmeda] (C)</td><td>0.5</td><td>-15 °C, 1 h</td><td>20<sup>c)</sup></td></tr><tr><td>5<sup>b)</sup></td><td>[(TMP)Li]n</td><td>1</td><td>-15 °C, 1 h</td><td>35</td></tr><tr><td>6</td><td>[(TMP)K]n</td><td>1</td><td>-80 °C, 1 h</td><td>57</td></tr><tr><td>7</td><td>[(TMP)K]n</td><td>1 (2)</td><td>-50 °C, 1 h</td><td>30 (82)</td></tr><tr><td>8</td><td>[(TMP)K]n</td><td>1</td><td>-15 °C, 1 h</td><td>6</td></tr><tr><td>9</td><td>(TMP)Li'-BuOK</td><td>1</td><td>-50 °C, 1 h</td><td>43</td></tr><tr><td>10</td><td>(TMP)Li'-BuOK</td><td>1</td><td>-80 °C, 1 h</td><td>74</td></tr><tr><td>11</td><td>[(TMP)Na]n</td><td>1</td><td>-80 °C, 1 h</td><td>33</td></tr><tr><td>12</td><td>[(TMP)Na]n</td><td>1</td><td>-50 °C, 1 h</td><td>42</td></tr><tr><td>13</td><td>[(TMP)₂Ca(tmeda)] (I)</td><td>0.5</td><td>-80 °C, 1 h</td><td>Traces<sup>c)</sup></td></tr><tr><td>14</td><td>[(TMP)₂Ca(tmeda)] (I)</td><td>0.5</td><td>-50 °C, 1 h</td><td>Traces<sup>c)</sup></td></tr><tr><td>15</td><td>[(TMP)₂Ca(tmeda)] (I)</td><td>0.5</td><td>-15 °C, 1 h</td><td>29</td></tr></tbody></table>

<footnote>a) Determined by ¹H NMR; the rest is starting 7, except when degradation was also specified; b) In the presence of tmeda (0.5 equiv); c) Degradation was also noticed.</footnote>
<figure><img src="image_20.png" /></figure>

suggesting a deleterious effect of tmeda on the course of the reaction. Even if the reaction was carried out in bulk thf, it seems that the addition of tmeda changed the aggregation state of [[(TMP)Li]n, leading to a species less reactive than the thf-solvated monomer and dimer.[46]

Most of the deprotometallation reactions performed with [[(TMP)Li]n were repeated using the solvent-free [(TMP)K]n.[47] In thf at -80 °C for 1 h, the potassium base behaved in the same way as its lithium congener, delivering the iodide 8 in 57% yield (entry 6). However, by contrast with [(TMP)Li]n, the potassium amide afforded significantly lower yields as the temperature was increased, 30% at -50 °C (entry 7) and 6% at -15 °C (entry 8). At -50 °C, the use of 2 equiv of the potassium amide led to a high yield (82%, entry 7), suggesting that instability of the base is more likely than that of the arylmetal formed upon deprotometallation. This is consistent with the reputation of [(TMP)K]n for being highly pyrophoric and easily igniting on contact with low concentrations of oxygen or water.[47]

While [(TMP)K]n has never been involved in aromatic deprotometallation, the (TMP)Li·BuOK combination has been the subject of several studies.[48] It was therefore interesting to compare herein the behavior of these two bases on 1,3-dimethoxybenzene. Treated with (TMP)Li·BuOK at -50 and -80 °C, 7 was converted to 8 with respective yields of 43% and 74% (entries 9 and 10). A higher yield was therefore recorded by lowering the temperature, as observed for [(TMP)K]n, suggesting the in situ formation of this base. In these cases where the base is prepared in situ, the fact that there is no handling of the unstable [(TMP)K]n probably explains the better yields.

As [(TMP)Na]n has rarely been used in thf,[31] we also involved it in our reaction with 7 at -80 and -50 °C (entries 11 and 12); under these conditions, a reactivity lower than those of [(TMP)Li]n and [(TMP)K]n was noticed, as well as a stability higher than that of [(TMP)K]n.

We next turned our attention to the behavior of [(TMP)₂Ca(thf)₂] (6) in the reaction with 7. Unfortunately, the instability of the calcium complex led us to refrain from studying the reactivity of the complex formed ex situ.[47] We thus attempted an in-situ formation in thf by treatment of CaI₂ or its more soluble [CaI₂·(thf)₄] congener with [(TMP)K]n (2 equiv) at temperatures between -60 and -15 °C and with different contact times (from 2 to 6 h), with or without filtration of the KI formed, before carrying out the deprotometallation reaction. However, under these conditions, erratic yields in 8 (between 0% and 90%) were obtained. These results suggest that although a white precipitate assumed to be KI was always observed in these reactions, the formation of 6 by salt metathesis is too slow and/or the starting potassium amide [(TMP)K]n is too sensitive under these experimental conditions.

We therefore examined the behavior of the more stable [(TMP)₂Ca(tmeda)][23,24] (aka I; 0.5 equiv) in the reaction with 7 at the different temperatures. While no reaction took place at -80 °C (Table 1, entry 13) and at -50 °C (entry 14), a yield of 29% was recorded at -15 °C (entry 15); the calcium base is therefore less reactive toward 7 that the corresponding lithium- and

<table><caption>**Table 2.** Deprotometallation of 1,3-dimethoxybenzene (7) using different Met-TMP bases in hexane, at 0 °C, with or without an additive, followed by interception with iodine.</caption><thead><tr><th>Entry</th><th>Base</th><th>n</th><th>Additive [n']</th><th>Yield of 8 [%]<sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td>[(TMP)Li]<sub>n</sub></td><td>1</td><td>-</td><td>36</td></tr><tr><td>2</td><td>[(TMP)Li]<sub>n</sub></td><td>2</td><td>-</td><td>64</td></tr><tr><td>3</td><td>[(TMP)Li]<sub>n</sub></td><td>1</td><td>tmeda (1)</td><td>61</td></tr><tr><td>4</td><td>[(TMP)Li]<sub>n</sub></td><td>2</td><td>tmeda (2)</td><td>Quantitative</td></tr><tr><td>5</td><td>[(TMP)Li]<sub>n</sub></td><td>1</td><td>thp (1)</td><td>66</td></tr><tr><td>6</td><td>[(TMP)Li]<sub>n</sub></td><td>2</td><td>thp (2)</td><td>90</td></tr><tr><td>7</td><td>[(TMP)₂Ca(tmeda)] (I)</td><td>0.5</td><td>-</td><td>7<sup>b</sup></td></tr></tbody></table>

potassium-TMP dialkylamides, while also being less prone to degradation than the potassium compound.

As degradation in thf was noticed in some of the experiments above, hexane was also evaluated as a solvent (Table 2). However, in the case of a contact time between 7 and [(TMP)Li]n (1 or 2 equiv) of 1 h at 0 °C, the iodide 8 was obtained in respective yields of only 36% and 64% (Table 2, entries 1-2), i.e., lower than using bulk thf. Following an earlier contribution from Butler, who advantageously added tmeda to hexane in order to favor deprotolithiation,[49] we also probed the influence of two additives, tmeda (entries 3-4) and thp (entry 5-6) on the course of the reactions. As anticipated, the yields were substantially increased and were even higher than those recorded in thf, in particular when 2 equivalents of base were used to achieve near-quantitative yields. However, hexane was not a suitable solvent for the reaction using [(TMP)₂Ca(tmeda)] (I), resulting in low yield and degradation (entry 7).

### 3. Conclusion

In summary, we have prepared a number of solvated lithium, potassium, and calcium tetramethylpiperidides that were still missing from the set of existing metal bases in a field that has otherwise been particularly dynamic in the past three decades. Beyond the common thf, tetrahydropyran and N,N,N',N'',N''-pentamethyldiethylenetriamine have allowed for the crystallization and structural elucidation of the homometallic [(TMP)Li(thp)] (1), [(TMP)Li(pmdta)] (2), [(TMP)K(pmdta)] (3), and [K(pmdta){μ³-NMe₂}{μ²-TMP}Li] (4) and of the calcium derivatives [(TMP)₂Ca(thp)₂] (5) and [(TMP)₂Ca(thf)₂] (6). While the calcium complex we tested has shown little ability to mediate the deprotometallation of 1,3-dimethoxybenzene (7) in thf, we achieved the reaction by using the different [(TMP)M]n (M = Li, K, Na)

<footnote>a) Determined by ¹H NMR; the rest is starting 7, except when degradation was also specified; b) Degradation was also noticed.</footnote>
<figure><img src="image_21.png" /></figure>

and (TMP)Li·BuOK alkali bases. The tuning of temperature afforded for a better understanding of the behavior of these reagents in thf.

## 4. Experimental Section

All manipulations were performed under an inert atmosphere by using standard Schlenk techniques or in a dry, solvent-free glovebox (Jacomex; O₂ < 1 ppm, H₂O < 3 ppm). Tetrahydrofuran (thf) was distilled under argon from Na/benzophenone prior to use. Petroleum ether (45–65 °C), toluene, dichloromethane, and Et₂O were collected from MBraun SPS-800 purification alumina columns and degassed with argon before storage on 4 Å molecular sieves. Deuterated solvents (Eurisotop, France) were stored in sealed ampoules over activated 4 Å molecular sieves and degassed by freeze–thaw cycles. NMR spectra were recorded with Bruker AM-400 or AM-500 spectrometers. All chemical shifts (δ) [ppm] were determined relative to the residual signal of the deuterated solvent in benzene-d₆, chloroform-d and thf-d₈. Assignment of the resonances was assisted by 1D ('H, ¹³C) and 2D (COSY, HMBC, HMQC, and NOE) NMR experiments, 2,2,6,6-Tetramethylpiperidine (TMP-H), tetrahydropyran (thp), and N,N,N',N'',N'''-pentamethyldiethylenetriamine (pmdta) were dried over CaH₂ and distilled prior to use. The precursors [(TMP)Li]n, [11]([TMP]K)n, [5,47,50] and [(TMP)Na]n [51,52] were prepared according to literature procedures. Reliable and reproducible elemental analysis for the new complexes could not be obtained due to their high moisture-sensitivity.

### Synthesis of [(TMP)Li(thp)] (1)

⁷BuLi (2.0 mL, 1.6 M in hexanes, 3.2 mmol) was added to a stirring solution of TMP-H (0.54 mL, 3.2 mmol) in petroleum ether (5.0 mL) cooled to –40 °C. After 30 min, the colorless suspension was allowed to reach room temperature and thp (≈2 mL) was added dropwise until all solids dissolved, resulting in a clear pale orange solution. A crop of colorless crystals of [(TMP)Li(thp)]₂ (1₂) (0.57 g, 77%) formed upon storage of this solution in a freezer at –35 °C.

¹H NMR (500.13 MHz, 300 K, benzene-d₆): δ 3.49 (m, 4H, OCH₂), 1.78 (m, 2H, γ-CH₂ TMP), 1.38–1.34 (overlapping m, 16H, β-CH₂ TMP + CH₃), 1.31 (br, 6H, OCH₂CH₂ + OCH₂CH₂CH₂) ppm.

¹³C{¹H} NMR (125.77 MHz, 300 K, benzene-d₆): δ 68.70 (OCH₂), 52.47 (α-C(Me₂) TMP), 42.90 (β-CH₂ TMP), 37.03 (CH₃), 26.81 (OCH₂CH₂), 23.71 (OCH₂CH₂CH₂), 20.15 (γ-CH₂ TMP) ppm.

### Synthesis of [(TMP)Li(pmdta)] (2)

⁷BuLi (11.6 mL, 1.6 M in hexanes, 19 mmol) was added dropwise at –50 °C to a solution of TMP-H (3.0 mL, 17 mmol) in petroleum ether (60 mL). The mixture was slowly warmed to room temperature and then stirred overnight to 50 °C. The volatiles were then pumped off, and the residue was dissolved in excess pmdta (10.0 mL) to give a clear homogenous yellow solution. After storage for 3 days at –35 °C, the title compound was isolated as a large crop of colorless crystals. Nonoptimized yield 2.7 g (50%).

¹H NMR (400.16 MHz, 298 K, benzene-d₆): δ 2.49–1.80 (15 H, NCH₃), 1.71 (2 H, γ-CH₂ TMP), 1.45–1.20 (β-CH₂ TMP + NCH₂CH₂N + CH₃ TMP) ppm. Contamination by free TMP-H could not be avoided (e.g., sharp resonances at δ 1.71, 1.36, and 1.07 ppm). Besides, very broad resonances suggested high fluxionality or aggregated

structure(s). Low- or high-temperature NMR did not bring any improvement.

¹³C{¹H} NMR (125.77 MHz, 298 K, benzene-d₆): δ 57.44 (NCH₂ pmdta), 56.70 (NCH₂ pmdta), 52.67, 52.22 (α-C(Me₂) TMP), 45.74 (N(CH₃)₂ pmdta), 42.12 (NCH₃ pmdta), 36.63 (β-CH₂ TMP), 31.67 (CH₃ TMP), 20.67 (γ-CH₂ TMP) ppm. The quality of the spectrum was low due to gradual decomposition and could not be improved. In particular, contamination by free TMP-H could not be avoided (e.g., resonances at δ 52.67, 49.15, 38.27, and 18.48 ppm).

### Synthesis of [(TMP)K]n

⁷BuLi (13.0 mL of a 1.6 M solution) was added at –60 °C over 5 min to a solution of TMP-H (3.6 mL, 21 mmol) in petroleum ether (15 mL). Stirring was ensured for 30 min at this temperature. The solution was then warmed to room temperature and stirred for 1 h. Potassium tert-butoxide (3.5 g, 31.5 mmol) was added to the reacting mixture. Vigorous stirring for 15 h yielded a brown-colored precipitate of very reactive [(TMP)K]n that was isolated via cannula filtration and washed with petroleum ether (3 × 10 mL) and then dried under reduced pressure to constant weight. Yield: 2.5 g (17 mmol, 82%). The analytic data matched those reported earlier for this compound.

¹H NMR (thf-d₈, 400.13 MHz, 300 K): δ 1.68–1.56 (m, 2H, γ-CH₂), 1.31–1.27 (m, 4H, β-CH₂), 1.05 (s, 12H, CH₃) ppm.

### Synthesis of [(TMP)K(pmdta)] (3)

A Schlenk tube was loaded with lithium tetramethylpiperidine (1.0 g, 6.8 mmol) and freshly sublimed potassium tert-butoxide (0.76 g, 6.8 mmol). Petroleum ether (40 mL) was added and the mixture was stirred overnight, resulting in the formation of [(TMP)K]n as a precipitate.[5] The supernatant was filtered off, and the isolated solid was washed with petroleum ether (3 × 5.0 mL). It was then dissolved in pmdta (5.6 mL, 28 mmol), and stirring at room temperature yielded a brown solution that contained some insoluble material. After filtration, the solution was stored in a freezer at –35 °C. A crop of yellow crystals of [(μ-TMP)K(pmdta)]₂ (3₂) formed within 48 h and was isolated by filtration (0.95 g, 40%).

¹H NMR (500.13 MHz, 300 K, benzene-d₆): δ 3.30–3.08 (br m, 4H, TMP), 2.06 (m, 8H, NCH₂ pmdta), 2.03 (s, 12H, N(CH₃)₂ pmdta), 2.02 (s, 3H, NCH₃ pmdta), 1.82 (br, 4H, TMP), 1.50–1.30 (br m, 10H, TMP) ppm.

¹³C{¹H} NMR (125.77 MHz, 300 K, benzene-d₆): δ 57.89 (NCH₂ pmdta), 56.48 (NCH₂ pmdta), 50.12 (α-C(Me₂) TMP), 45.99 (N(CH₃)₂ pmdta), 42.05 (NCH₃ pmdta), 38.64 (β-CH₂ TMP), 32.25 (CH₃ TMP), 22.09 (γ-CH₂ TMP) ppm. A number of unidentified resonances could also be detected, and attributed to decomposition product(s) as gradual degradation of the sample in solution could be visually observed.

### Synthesis of [K{pmdta}{μ³-NMe₂}{μ²-TMP}Li] (4)

Freshly prepared lithium tetramethylpiperidine (1.0 g, 6.8 mmol) and sublimed potassium tert-butoxide (0.76 g, 6.8 mmol) were suspended in petroleum ether (40.0 mL) and stirred overnight. The solid was then isolated by filtration, and it was reacted with pmdta (5.6 mL, 27.0 mmol) in petroleum ether (15.0 mL), yielding a dark brown solution. A small crop of crystals of the title compound formed and was isolated after 2 days at room temperature (yield 0.64 g, 23%). Analysis by X-ray diffraction crystallography indicated the composition [K{pmdta}{μ³-NMe₂}{μ²-TMP}Li]₂ (4₂). ¹³C NMR spectroscopy data could not be recorded, as the product decomposed rapidly and
<figure><img src="image_22.png" /></figure>

systematically in all available deuterated solvents, including benzene-
d₆. Yet, reproducibility of the reaction, isolated yield, and formation of
X-ray quality crystals were overall very good.

¹H NMR (500.13 MHz, 300 K, benzene-d₆): δ 3.12 (br, 6H, 2.30-1.75 (br overlapping m, 30H), 1.55-1.30 (br overlapping m, 10H) ppm.

⁷Li NMR (155.52 MHz, 298 K, benzene-d₆): δ 1.95 ppm.

Synthesis of [(TMP)₂Ca(thp)₂] (5)

Freshly prepared [(TMP)K]n (0.50 g, 2.8 mmol) was suspended in tol-
uene (15.0 mL). The suspension was treated with excess thp (3.0 mL)
to give a dark red solution which was cooled to 0 °C. Anhydrous Cal₂
(458 mg, 1.56 mmol) was then added, and the resulting mixture was
then stirred for 5.5 h at 0 °C. The precipitate of KI was eliminated by
cannula filtration. The resulting solution was slowly concentrated
under reduced pressure to approximately half its initial volume,
and it was stored at -35 °C. After 2 days, a first crop of crystalline
highly air-sensitive [(TMP)₂Ca(thp)₂] was isolated as large blocks.
Another crop of crystals was obtained by reducing the volume of
the mother liquor by half and further storage at -35 °C. Yield
0.26 g, 34%.

¹H NMR (500.13 MHz, 300 K, benzene-d₆): δ 3.59 (br, 8H, OCH₂), 2.08 (m, 4H, γ-CH₂ TMP), 1.56 (m, 8H, β-CH₂ TMP), 1.53 (s, 24H, CH₃), 1.25 (br, 12H, thp OCH₂CH₂ + OCH₂CH₂CH₂) ppm.

¹³C[¹H] NMR (125.77 MHz, 300 K, benzene-d₆): δ 69.52 (OCH₂), 52.77 (α-C(Me₂) TMP), 40.92 (β-CH₂ TMP), 34.92 (CH₃), 26.47 (OCH₂CH₂), 23.29 (OCH₂CH₂CH₂), 21.13 (γ-CH₂ TMP) ppm.

Synthesis of [(TMP)₂Ca(thf)₂] (6)

Freshly prepared [(TMP)K]n (0.61 g, 3.42 mmol) was dissolved in thf (10.0 mL); then, the mixture was cooled to -40 °C. At this temperature, anhydrous Cal₂ (558 mg, 1.9 mmol) was added in portions, followed by subsequent stirring for 2 h. The precipitate of KI was eliminated by cannula filtration. During the slow evaporation of the volatile materials at -40 °C, brown crystals started to form. Resting this concentrated solution at -40 °C for another 30 min resulted in the further formation of a brown crystalline material, which was isolated by filtration and dried under reduced pressure to constant weight. Yield 0.22 g, 25%.

¹H NMR (500.13 MHz, 300 K, benzene-d₆): δ 3.69 (br, 8H, OCH₂), 2.09 (m, 4H, γ-CH₂ TMP), 1.58 (m, 8H, β-CH₂ TMP), 1.52 (s, 24H, CH₃), 1.40 (br, 8H, OCH₂CH₂) ppm.

¹³C[¹H] NMR (125.77 MHz, 300 K, benzene-d₆): δ 68.90 (OCH₂), 52.78 (α-C(Me₂) TMP), 41.29 (β-CH₂ TMP), 35.25 (CH₃ TMP), 25.52 (OCH₂CH₂), 21.22 (γ-CH₂ TMP) ppm.

Representative examples of the synthesis of 2-iodo-1,3-dimethoxy-
ybenzene (8) from 1,3-dimethoxybenzene (7)—see the Supporting
Information for the full data set.

With [(TMP)Li]n (2 Equiv) in thf at -50 °C Followed by
Interception with Iodine

"BuLi (1.3 M solution of in hexane, 1.5 mL, 2.0 mmol) was added drop-
wise to a stirred solution of TMP-H (0.36 mL, 2.0 mmol) in thf (2.0 mL)
at -50 °C. After 5 min, 1,3-dimethoxybenzene (7; 0.13 mL, 1.0 mmol)
was introduced, and the resulting mixture was stirred at -50 °C for
1 h. A solution of I₂ (0.53 g, 2.1 mmol) in thf (4.0 mL) was then added,

and the mixture was stirred for 1 h at -50 °C before quenching with a
saturated aqueous solution of Na₂S₂O₃ (5 mL). Extraction with
AcOEt (3 × 10.0 mL), drying over MgSO₄, and concentration under
reduced pressure led to the crude (94:6 ratio of 2-iodo-1,3-dimethox-
ybenzene (8) and starting 7), from which a 92% yield of 8 was
estimated by NMR.

Rf (98:2 petroleum ether-AcOEt) 0.7.

¹H NMR (300.16 MHz, 300 K, chloroform-d): δ 3.87 (s, 6H, OCH₃), 6.49 (d, 2H, ³JₗH = 8.3 Hz, H₄ and H₆), 7.24 (t, 1 H, ³JₗH = 8.3 Hz, H₅) ppm. These data matched those reported previously.[⁵³]

With [(TMP)K]n (2 Equiv) in thf at -50 °C Followed by
Interception with Iodine

A solution of 1,3-dimethoxybenzene (0.13 mL, 1.0 mmol) in thf (2.0 mL) was added dropwise to a stirred solution of [(TMP)K]n (0.36 g, 2.0 mmol) in thf (2.0 mL) at -50 °C, and the resulting mixture was stirred at -50 °C for 1 h. A solution of I₂ (0.51 g, 2.0 mmol) in thf (2.0 mL) was then added, and the mixture was stirred for 1 h at -50 °C before addition of a saturated aqueous solution of Na₂S₂O₃ (5.0 mL). Extraction with AcOEt (3 × 10.0 mL), drying over MgSO₄, and concentration under reduced pressure led to the crude which contains 2-iodo-1,3-dimethoxybenzene (8; yield estimated by NMR: 82%) and starting 7 in a 87:13 ratio.

With [(TMP)Li]n and 'BuOK (1 Equiv Each) in thf at -80 °C
Followed by Interception with Iodine

⁹BuLi (1.3 M solution in hexane, 0.75 mL, 1.0 mmol) was added drop-
wise to a stirred solution of TMP-H (0.18 mL, 1.0 mmol) and potassium
tert-butoxide (0.11 g, 1.0 mmol) in thf (3.0 mL) at -80 °C. After 1 h,
1,3-dimethoxybenzene (7; 0.13 mL, 1.0 mmol) was introduced, and
the resulting mixture was stirred at -80 °C for 1 h. A solution of I₂
(0.28 g, 1.1 mmol) in thf (2.0 mL) was then added, and the mixture
was stirred for 1 h at -80 °C before addition of a saturated aqueous
solution of Na₂S₂O₃ (5.0 mL). Extraction with AcOEt (3 × 10.0 mL), dry-
ing over MgSO₄, and concentration under reduced pressure led to
the crude (74:26 ratio of product 8 and starting material 7), from
which a 74% yield was estimated by NMR.

Using [(TMP)Li]n (2 Equiv) in Hexane at 0 °C Followed by
Interception with Iodine

"BuLi (1.3 M solution in hexane, 1.5 mL, 2.0 mmol) was added dropwise to stirred hexane (3.0 mL) and TMP-H (0.36 mL, 2.0 mmol) at 0 °C. After 15 min at this temperature, 1,3-dimethoxybenzene (7; 0.13 mL, 1.0 mmol) was introduced, and the resulting mixture was stirred at 0 °C for 1 h. A solution of I₂ (0.53 g, 2.1 mmol) in thf (2.0 mL) was then added, and the mixture was stirred for 1 h at 0 °C before addition of a saturated aqueous solution of Na₂S₂O₃ (5.0 mL). Extraction with AcOEt (3 × 10.0 mL), drying over MgSO₄ and concentration under reduced pressure led to the crude (36:64 ratio of product 8 and starting material 7), from which a 64% yield of 8 was estimated by NMR.

Acknowledgements

The authors thank the Agence Nationale de la Recherche for the
provision of a research grant (BiMeDep, ANR-21-CE07-0045).
<figure><img src="image_23.png" /></figure>

Conflict of Interest

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available in
the Supporting Information of this article.

Keywords: aromatic compounds · calcium · deprotometallation · lithium · potassium · tetramethylpiperidine

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Manuscript received: September 2, 2025

Revised manuscript received: September 29, 2025

Version of record online: