# Reactions of Tertiary Aliphatic Cations with Silylated Alkynes: Substitution, Cyclization and Unexpected C-H Activation Products

Paul Charki, Marie Cordier, Kai E. O. Ylijoki, Daniel S. Müller

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Paul Charki, Marie Cordier, Kai E. O. Ylijoki, Daniel S. Müller. Reactions of Tertiary Aliphatic Cations with Silylated Alkynes: Substitution, Cyclization and Unexpected C-H Activation Products. Chemistry - A European Journal, 2025, 31, pp.e202403979. 10.1002/chem.202403979. hal-04919761

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# Reactions of Tertiary Aliphatic Cations with Silylated Alkynes: Substitution, Cyclization and Unexpected C-H Activation Products

Paul Charki[a] Marie Cordier, Kai E. O. Ylijoki*[b], Daniel S. Müller*[a]

In memory of Giuseppe Capozzi

[a] P. Charki, M. Cordier, D. S. Müller
Univ Rennes, CNRS, ISCR (Institut des Sciences Chimiques de Rennes)-UMR6226, F-35000 Rennes, France
E-mail: daniel.muller@univ-rennes.fr

[b] Prof. Dr. K. E. O. Ylijoki
Department of Chemistry
Saint Mary's University
923 Robie St., Halifax, Nova Scotia, B3H 3C3, Canada

Supporting information for this article is given via a link at the end of the document.

**Abstract:** Capozzi's groundbreaking work in 1982 introduced a fascinating reaction involving highly reactive tertiary aliphatic cations and silylated alkynes. This reaction provided an innovative solution to the challenge of coupling a fully substituted tertiary aliphatic fragment with an alkyne moiety. Building upon Capozzi's pioneering efforts, we started an extensive exploration of reaction conditions to expand the initial scope of this reaction. Through meticulous control of the reaction parameters, we uncovered conditions capable of accommodating various functional groups, thereby enhancing the reaction's applicability. Intriguingly, our study revealed remarkably high diastereoselectivities for substrates with substitution in the α-position. Additionally, we made an unexpected discovery: an intriguing C-H activation of a cyclooctane ring furnishing a cyclooctane-fused cyclobutene. These findings not only extend the utility of Capozzi's original concept but also underscore the potential of highly reactive cations in modern organic C-H activation reactions.

## Introduction

The electrophilic substitution of metalated alkynes is mechanistically formally related to electrophilic aromatic substitution with carbenium ions, known as the Friedel-Crafts alkylation reaction.[1] The first step involves the reaction of an alkyne with the highly reactive carbenium ion to furnish a less reactive vinyl cation which with loss of a metal ion gives the corresponding alkyne product (Scheme 1). For the aromatic substitution the intermediate is an arenium ion, also known as Wheland-intermediate,[2] which with loss of a proton gives the corresponding substitution product. For carbenium ions with R¹, R² and R³ as alkyl substituents electrophilic alkyne substitution offers an efficient route to quaternary all-carbon centers bearing an alkyne substituent.[3] It should be noted that despite recent advances in radical,[4] enolate[5] and transition metal-catalyzed[6] coupling reactions, the synthesis of alkynyl-substituted all-carbon quaternary centers remains challenging, particularly for the synthesis of

quaternary centers beyond the well-established tert-butyl and adamantyl scaffolds.

<figure><img src="image_2.png" /><figcaption>**Scheme 1.** Comparison of electrophilic substitution of metalated alkynes and electrophilic aromatic substitutions.</figcaption></figure>

Few electrophilic alkyne substitutions with aliphatic carbenium ions and metalated alkynes were reported in the literature. Negishi, in 1975, was the first to report the substitution reaction of aluminumalkynes with tertiary aliphatic cations generated from the corresponding tertiary chlorides (Scheme 2a).[7] Subsequently, Sasaki[8] (Scheme 2b), Capozzi[9,10] (Scheme 2c), and Baba[11] (Scheme 2d) reported related studies with silylalkynes and tertiary chlorides. Maruoka[12] (Scheme 2e) and Young[13] (Scheme 2f) reported the coupling of aluminum or silyl alkynes with tertiary fluorides. Several details concerning the previously reported coupling reactions are noteworthy. In the work by Negishi (Scheme 2a) and Maruoka (Scheme 2e) the aluminum alkynes act as both
Lewis acids and nucleophiles at the same time. Negishi reported that the choice of the aluminum alkynyl species is very important.[7] He noted that diethyl aluminum alkynes and diisobutyl aluminum alkynes gave predominant elimination and undesired alkylation products with tertiary bromides, thus affording the desired coupling products in low yields. Trialkynyl aluminum reagents gave high yields for several tertiary aliphatic chlorides and adamantyl bromide. Maruoka reported that the corresponding chloride gave no reaction when exposed to dimethyl aluminum alkyne under conditions depicted in Scheme 2e.[12] Young reported a similar finding: when exchanging adamantyl fluoride with adamantyl bromide the yield of 6 dropped significantly (5%).[13] He also noted that compound 6 was observed in only 16% yield when phenyl acetylene was used instead of silyl alkyne 5. Notably, intramolecular reactions of silyl alkynes with tertiary aliphatic cations have previously been reported.[14] These findings indicate that the identification of an efficient combination of carbenium ion precursor (fluoride, chloride or bromide), Lewis acid, and alkyne is a non-trivial task and that the counteranion plays an important role in the reaction.

From a practical perspective, we found Capozzi's approach (Scheme 2c) particularly intriguing due to several reasons: a) numerous silylated alkynes are readily available either commercially or through synthesis;[15] b) unlike the alkynylalumnums used by Negishi, silylated alkynes are stable even in the presence of air and moisture; c) tertiary chlorides can be easily synthesized by substitution of tertiary alcohols or hydrochlorination of alkenes;[16] d) Capozzi used AlCl₃, an inexpensive and readily accessible bulk chemical. These facts suggest that the Capozzi reaction is highly underutilized, hence the objective of this work was to thoroughly study the Capozzi reaction and to better understand its potential and limitations. Additionally, we aimed to explore the diastereoselectivity of these reactions, a feature that has not yet been examined in previous cationic sp-sp³ coupling reactions. This report provides the full account of our previously published findings.[17]

## Results and discussion

### Optimization of reaction conditions

Extensive optimization of the reaction parameters (see supporting information, SI), including the evaluation of 24 Lewis acids (Table S2), revealed AlCl₃ and AlEt₃ as most effective. Consequently, we chose to focus further investigations on the cationic coupling reaction with these two Lewis acids. Temperature variation demonstrated that AlCl₃ afforded the product **15** in high yield at -78 °C (Table 1, Entry 4). A comparative study indicated that AlEt₃ was an equally efficient Lewis acid, which gave a slightly higher yield at 0 °C (Table 1, Entry 6).

**A. Negishi (1975)**

<figure><img src="image_3.png" /></figure>

**B. Sasaki (1980)**

<figure><img src="image_4.png" /></figure>

**C. Capozzi (1982, 1984)**

<figure><img src="image_5.png" /></figure>

**D. Baba (2009)**

<figure><img src="image_6.png" /></figure>

**E. Maruoka (1997)**

<figure><img src="image_7.png" /></figure>

**F. Young (2017)**

<figure><img src="image_8.png" /><figcaption>**Scheme 2.** Previously reported cationic sp³-sp coupling reactions.</figcaption></figure>
<table><caption>**Table 1.** Evaluation of various reaction temperatures<sup>[a]</sup></caption><thead><tr><th></th><th>Lewis acid</th><th>T (°C)</th><th>conv. 1<sup>[a]</sup></th><th>conv. 5<sup>[a]</sup></th><th>yield 15<sup>[a]</sup></th></tr></thead><tbody><tr><td>1</td><td>AlCl<sub>3</sub></td><td>20</td><td>100</td><td>100</td><td>14</td></tr><tr><td>2</td><td>AlCl<sub>3</sub></td><td>0</td><td>100</td><td>100</td><td>58</td></tr><tr><td>3</td><td>AlCl<sub>3</sub></td><td>-45</td><td>95</td><td>94</td><td>65</td></tr><tr><td>4</td><td>AlCl<sub>3</sub></td><td>-78</td><td>84</td><td>96</td><td>77</td></tr><tr><td>5</td><td>AlEt<sub>3</sub></td><td>20</td><td>100</td><td>98</td><td>56</td></tr><tr><td>6</td><td>AlEt<sub>3</sub></td><td>0</td><td>100</td><td>89</td><td>80</td></tr><tr><td>7</td><td>AlEt<sub>3</sub></td><td>-45</td><td>100</td><td>91</td><td>79</td></tr><tr><td>8</td><td>AlEt<sub>3</sub></td><td>-78</td><td>100</td><td>84</td><td>73</td></tr></tbody></table>

[a] Conversion and yield were determined by GC with n-decane as internal standard. Reactions were carried out on a 0.5 mmol scale and a 0.33 M dilution. LA = Lewis acid.

Next, we investigated the influence of catalyst loading (Table 2). AlCl₃ provided similar yields of **15** with 10 or 20 mol %, but almost no product was observed with 100 mol %, suggesting that the formed product engaged in oligo- or polymerization reactions. In fact, TLC analysis of the reaction carried out with 100 mol % of AlCl₃ (Table 2, Entry 3) revealed two major spots with an R<sub>f</sub> = 0.15 and R<sub>f</sub> = 0.34 in pentane (UV detection, 256 nm). The two spots were separated by column chromatography and analysed by NMR and SEC (Size exclusion chromatography). The ¹H and ¹³C NMR spectra showed broad signals (see SI). According to SEC analysis, both spots contain mixtures of several compounds with an estimated medium weight of 200-400 g/mol. Hence, no polymerization occurred under these conditions. In contrast, AlEt₃ gave no significant change in yield even in the presence of 100 mol % of Lewis acid (Table 2, Entry 6).

<table><caption>**Table 2.** Evaluation of catalyst loading<sup>[a]</sup>.</caption><thead><tr><th></th><th>Lewis acid</th><th>LA<br>(mol %)</th><th>conv.<br>1 (%)<sup>[a]</sup></th><th>conv.<br>5 (%)<sup>[a]</sup></th><th>yield<br>(%)<sup>[a]</sup></th></tr></thead><tbody><tr><td>1</td><td>AlCl<sub>3</sub></td><td>10</td><td>76</td><td>100</td><td>54</td></tr><tr><td>2</td><td>AlCl<sub>3</sub></td><td>20</td><td>100</td><td>100</td><td>58</td></tr><tr><td>3</td><td>AlCl<sub>3</sub></td><td>100</td><td>100</td><td>100</td><td>3</td></tr><tr><td>4</td><td>AlEt<sub>3</sub></td><td>10</td><td>100</td><td>84</td><td>72</td></tr><tr><td>5</td><td>AlEt<sub>3</sub></td><td>20</td><td>100</td><td>90</td><td>80</td></tr><tr><td>6</td><td>AlEt<sub>3</sub></td><td>100</td><td>100</td><td>92</td><td>77</td></tr></tbody></table>

[a] Conversion and yield were determined by GC with n-decane as internal standard. Reactions were carried out on a 0.5 mmol scale and a 0.33 M dilution.

To probe the influence of silicon substituents on the reaction outcome, we assessed whether varying the size of the silyl substituent would affect the yield (Table 3). We observed that larger groups such as DMPS (**16**) or TBDMS (**17**) resulted in lower yields of the desired product **15** (Table 3, Entries 3-6). Conversely, the very bulky TIPS group (**18**) proved to be completely inefficient, likely due to excessive shielding of the alkyne, hindering its approach to the tertiary carbenium ion.

<table><caption>**Table 3.** Variation of substitution of the silyl group<sup>[a]</sup></caption><thead><tr><th>Entry</th><th>Silyl alkyne</th><th>LA</th><th>conv.<br>1 (%)<sup>[a]</sup></th><th>conv.<br>Alkyne<br>(%)<sup>[a]</sup></th><th>yield<br>15 (%)<sup>[a]</sup></th></tr></thead><tbody><tr><td>1</td><td>Me<br>Me-Si-<br>Me</td><td>AlCl<sub>3</sub></td><td>100</td><td>100</td><td>58</td></tr><tr><td>2</td><td>5</td><td>AlEt<sub>3</sub></td><td>100</td><td>90</td><td>80</td></tr><tr><td>3</td><td>Me<br>Ph-Si-<br>Ph</td><td>AlCl<sub>3</sub></td><td>100</td><td>100</td><td>39</td></tr></tbody></table>
4 AlEt₃ 100 -- 43

5 Me₃ tBu-Si-Ph AlCl₃ 75 100 12

6 Me₃ 17 AlEt₃ 100 -- 17

7 AlCl₃ 50 -- 0

8 Me₃ Si-Ph AlEt₃ 100 -- 0

<figure><img src="image_9.png" /></figure>

[a] Conversion and yield were determined by GC with *n*-decane as internal standard. Reactions were carried out on a 0.5 mmol scale and a 0.33 M dilution.

adjustments were also necessary in several cases, with -45 °C proving more effective than 0 °C in several cases. Consequently, we tested all substrates under at least four conditions (0 °C and -45 °C) with both AlCl₃ and AlEt₃ using *n*-decane as internal standard. The reaction condition that produced the best product-to-*n*-decane ratio was then repeated and the product isolated. Employing this strategy, we successfully synthesized a significant number of products as depicted in Scheme 4.

We further confirmed the importance of steric hindrance by two competition reactions (Scheme 3). For both competition experiments, the more sterically hindered substrate reacts much slower compared to silylalkyne 5. Another piece of evidence for the steric dependence of the reaction, independent of electronic influences, is presented in Scheme 4. We observe a steady decrease in yield as the steric bulk of the alkyne substituent increases, progressing from *n*-butyl (3) to cyclopropyl (41) to tert-butyl (20).

A. competition experiment

<figure><img src="image_10.png" /></figure>

B. competition experiment

<figure><img src="image_11.png" /></figure>

**Scheme 3.** Competition experiments indicating the importance of steric hindrance in cationic coupling reactions. [a] Estimated by GC-analysis. [b] Determined by GC-analysis with *n*-decane as internal standard.

Scope of the cationic sp-sp³ coupling

Having optimized reaction yields for product 15, we sought to apply the best conditions (Table 1, Entry 6) to other substrates but quickly realized that a single set of conditions did not yield satisfactory results for many substrates. Furthermore, we observed that AlCl₃ was particularly effective for substrates bearing functional groups, however stoichiometric amounts were often required. Temperature
<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /><figcaption>**Scheme 4.** Explored alkyne scope. Yields refer to isolated material. [a] 5.0 equiv of bis(trimethylsilyl)acetylene (8) were used.</figcaption></figure>
Figure 1 illustrates two examples for the variation of conditions carried out for each substrate as illustrated. In the case of CF₃ containing product **24**, the lower yield at higher temperatures can be explained by competing chlorodefluorination[18] reactions (CCl₃ product observed by GC-MS, see SI for GC traces). Compound **30** shows that AlEt₃ is completely deactivated by a nitrile group, even when added in excess quantity. Fortunately, excess of AlCl₃ as Lewis acid allowed isolation of **30** in 67% yield. As previously observed with alkyne **5**, too high Lewis acid loadings can have deleterious effects (compare to Table 2, Entry 3). This shows that the careful fine-tuning of the reaction is very important in order to obtain useful yields.

<figure><img src="image_14.png" /><figcaption>B. Presence of coordinating functional group</figcaption></figure>

<figure><img src="image_15.png" /></figure>

**Figure 1.** Experiments carried out for each substrate according to the presence or absence of functional groups. [a] Yields determined by GC-analysis with *n*-decane as internal standard. [b] Yields in parentheses refer to isolated yields.

The scope displayed in Scheme 4 shows that not all functional groups strongly deactivate AlCl₃. For instance, anisole substrates (products **25** and **26**) were isolated in good yields with only 20 mol % of AlCl₃, indicating that even AlCl₃ when coordinated to anisole remains Lewis acidic enough to transform tertiary chlorides into corresponding carbenium ions. However, ester **28** and aldehyde **29** functionalities strongly diminish the Lewis acidity of AlCl₃, necessitating a significant excess of Lewis acid to counteract coordination effects. Interestingly, the pyridine functionality (product **32**) is much less tolerated compared to aniline **33**. The core of Capozzi's work centered on synthesizing 2,2,5,5-tetramethylhex-3-yne **9** (see Scheme 2c).[9] Recently, the Schrock group reported the synthesis of **9** according to the Cappozzi procedure (Scheme 2c), albeit with a significantly lower yield of 44%.[19] Despite significant

efforts to optimize the yields for related compound **21**, we did not obtain yields higher than 32%. In stark contrast, the adamantyl product **35** was obtained in 94% yield. Product **36**, which was detected only in trace amounts under standard reaction conditions, could be isolated in 44% yield by addition of five equivalents of bis(trimethylsilyl)acetylene **8**. While alkyl-substituted alkynes generally furnished substitution products in good yields (e.g. **3** and **39**), alkene-containing product **40** was only obtained in 16% yield.

Next, we explored the scope of the tertiary chloride reaction partner (Scheme 5). First, we varied the size of the cycloalkane and found satisfying yields for 5, 7, and 12-membered cycles (compounds **49**, **50** and **51**). We were delighted to observe high yields for sterically encumbered chloride (product **52**). Chloride substituted product **56** was isolated in only 44% yield, which is probably due to the formation of a chloronium ion intermediate that might lead to alternative reaction pathways. The corresponding homologue **57** did not suffer from this shortcoming. Aliphatic acetate **59** was isolated in 57% yield when stoichiometric amounts of AlCl₃ were used. We also investigated the possibility of tertiary aliphatic cations engaging in diastereoselective reactions. In our study we examined the impact of substituents at the 2, 3, and 4 positions of the parent cyclohexyl chloride. Notably, only the 2-position (compound **60**) exhibited high diastereoselectivity (95:5). The reaction likely proceeds via solvent-separated cations, as evidenced in compound **65**, where a ~50:50 mixture of unassigned diastereomers of chloride yielded >98:2 selectivity for the β-isomer **65**. Inspired by Shenvi's earlier findings,[20] we attempted reactions for products **60** and **65** in neat alkyne **5** (5 equiv) to promote contact ion pair formation, yet no change in diastereoselectivity was observed, suggesting the intermediacy of solvent-separated ion pairs. Our experiments align with Maruoka's[12] observations on related methylation reactions, indicating that the stereochemistry of the starting material did not impact the diastereoselectivity of the reaction. From our results (products **60**, **65** and **66**) we hypothesize that many cyclic substrates with substituents in the α-position yield high diastereoselectivities. The assignment of the relative stereochemistry of diastereomeric mixtures was based on the characteristic upfield ¹³C NMR shift of the axial quaternary methyl group (see SI for details).[21]
<figure><img src="image_16.png" /></figure>

molecular framework scope

<figure><img src="image_17.png" /></figure>

49

AICl₃ (20 mol %), -45 °C
44% yield

<figure><img src="image_18.png" /></figure>

50

AIEt₃ (20 mol %), -45 °C
64% yield

<figure><img src="image_19.png" /></figure>

51

AICl₃ (20 mol %), -45 °C
68% yield

<figure><img src="image_20.png" /></figure>

6

AICI₃ (20 mol %), 0 °C
76% yield

<figure><img src="image_21.png" /></figure>

52

AIEt₃ (20 mol %), -45 °C
70% yield

<figure><img src="image_22.png" /></figure>

53

AICl₃ (20 mol %), 0 °C
70% yield

<figure><img src="image_23.png" /></figure>

54

AIEt₃ (20 mol %), -45 °C
67% yield

<figure><img src="image_24.png" /></figure>

55

AIEt₃ (20 mol %), -45 °C
56% yield

<figure><img src="image_25.png" /></figure>

56

AICl₃ (20 mol %), -45 °C
44% yield

<figure><img src="image_26.png" /></figure>

57

AICl₃ (20 mol %), -45 °C
65% yield

<figure><img src="image_27.png" /></figure>

58

AIEt₃ (20 mol %), 0 °C
27% yield

<figure><img src="image_28.png" /></figure>

59

AICl₃ (120 mol %), -45 °C
57% yield

diastereoselective examples

<figure><img src="image_29.png" /></figure>

cis-60

trans-60

AIEt₃ (20 mol %), -45 °C
69% yield

cis/trans = 95:5
[cis/trans = 23:77]<sup>[a]</sup>

<figure><img src="image_30.png" /></figure>

cis-61

trans-61

AIEt₃ (20 mol %), -45 °C
75% yield

cis/trans = 39:61
[cis/trans = 70:30]<sup>[a]</sup>

<figure><img src="image_31.png" /></figure>

cis-62

trans-62

AIEt₃ (20 mol %), -45 °C
75% yield

cis/trans = 33:67
[cis/trans = 74:26]<sup>[a]</sup>

<figure><img src="image_32.png" /></figure>

cis-63

trans-63

AIEt₃ (20 mol %), -45 °C
64% yield

cis/trans = 32:68
[cis/trans = 20:80]<sup>[a]</sup>

<figure><img src="image_33.png" /></figure>

cis-64

trans-64

AIEt₃ (20 mol %), -45 °C
38% yield

cis/trans = 15:85
[cis/trans = 13:87]<sup>[a]</sup>

<figure><img src="image_34.png" /></figure>

α-65

<figure><img src="image_35.png" /></figure>

β-65

AIEt₃ (20 mol %), -45 °C
56% yield

α/β < 2:98
[α/β ~50:50]<sup>[a]</sup>

<figure><img src="image_36.png" /></figure>

α-66

AIEt₃ (20 mol %), -45 °C
32% yield

α/β > 2:98
[α/β < 83:17]<sup>[a]</sup>

inefficient coupling reactions<sup>[b]</sup>

<figure><img src="image_37.png" /></figure>

67

<figure><img src="image_38.png" /></figure>

68

<figure><img src="image_39.png" /></figure>

69

<figure><img src="image_40.png" /></figure>

70

<figure><img src="image_41.png" /></figure>

71

<figure><img src="image_42.png" /></figure>

72

<caption>**Scheme 5.** Molecular framework scope. [a] cis/trans with respect to the relative configuration of the methyl groups; cis/trans or α/β ratios in brackets [ ] refer to the corresponding tertiary chloride starting materials. See SI for the synthesis and relative configuration of tertiary chloride starting materials; [b] <10% yields observed for the reaction with the depicted alkyl chlorides.</caption>
# Competing side-reactions: Cyclization, Hydride shifts and C-H activation

## Intramolecular cyclization reactions

For certain substrates, we obtained products resulting from intramolecular Friedel-Crafts cyclization reactions (Figure 2). Specifically, with substrate **73**, we obtained products resulting from the intramolecular trapping of the intermediate vinylcation by the neighboring arene. The corresponding products **74** and **75** were notably low (Figure 2A), likely due to the oligo- or polymerization of styrene **76**, which might be formed under the reaction conditions from tertiary chloride **73** (Table S1). Interestingly, compound **75** was the sole compound in this study that retained its silyl group throughout the reaction process. The reaction with chloride **10** highlights the high reactivity of silyl alkynes towards tertiary aliphatic cations (Figure 2A). Despite a strongly favored intramolecular Friedel-Crafts cyclization (pathway A, Figure 2C), the competing intermolecular trapping of the tertiary aliphatic cation by silyl alkyne **5** is significantly faster. The intermediate vinyl cation appears to be relatively long-lived, allowing Friedel-Crafts arylation (pathway B) to occur before the silyl group is intercepted by AlCl₄⁻ (pathway C). It should be noted that Oestreich and co-workers recently reported the synthesis of related cycloheptenyl derivatives via the same silyl-stabilized vinyl cation intermediates.[22] We observed that the chemoselectivity of the reaction varies depending on the Lewis acid used: AlCl₃ showed a slight preference for compound **77** (product distribution of **11:77:78** = 31:58:11), whereas AlEt₃ favored the formation of the substitution product **11** (product distribution of **11:77:78** = 85:11:4). Interestingly, the groups of Baba and Maruoka (Scheme 2) do not mention the observation of side-products **77** and **78**.

## Intramolecular 1,5-hydride shift

When compound **78** was treated with catalytic amounts of AlEt₃ in the presence of silylalkyne **5**, we observed the formation of two products with identical R₁ values and nearly indistinguishable GC retention times (Figure 2D). HMBC analysis of the crude reaction mixture indicated that these products were indeed compounds **79** and **80**. The formation of these two species appears to arise from a 1,5-hydride shift, generating a slightly less hindered dimethyl alkyl cation, which subsequently reacts with **5** to yield compound **80**. Experimental observations of hydride shifts are well-documented in the context of vinyl cations.[23] Hydride shift between two sp³ configured C-H bonds was observed by NMR studies.[24] According to Saunders a 1,5-hydride shift is very rapid with an activation energy of only 6-7 kcal / mol.[24a] Interestingly, Baba reported the same cation reacting with allyl silane, though in their case, only the expected product was observed.[25]

## Intramolecular C-H activation

The reaction involving 1-chloro-1-methylcyclooctane **81** yielded an unexpected outcome (Figure 2E). Alongside the anticipated substitution product, a second compound was isolated. After careful analysis of the 2D-NMR spectra and NOE signals, we identified this second product as cyclobutene **82**. To confirm the structure, we conducted a reaction with bromo-substituted alkyne **84**, which produced solid cyclobutene **85**. Slow evaporation of a cyclohexane solution of **85** afforded colorless crystals, which were suitable for single-crystal X-ray diffraction, definitively confirming its structure.
<figure><img src="image_43.png" /><figcaption>**Figure 2.** Miscellaneous reactions and structure of 85 (ORTEP plot of molecule drawn at 50% probability level).</figcaption></figure>
Intrigued by this unexpected reaction divergence, we investigated the reaction mechanisms for the competing alkynylation and C-H activation pathways via density functional theory (DFT) studies at the B3LYP[26]/6-31G*[27] level of theory as implemented in the Spartan'20 software package.[28] Solvent corrections were applied via the conductor-like polarizable continuum (C-PCM) model (ε = 8.82).[29] Entropy corrections for solvated species were applied such that ΔG<sub>sol</sub> = ΔG<sub>gas</sub> - X, where X = 2.6 or 5.0 kcal/mol for bi- or trimolecular processes respectively.[30] 1-Chloro-1-methylcyclopentane was chosen as the initial model compound for computational investigation (INT 0 in Fig. 5A). The reaction begins through barrierless chloride abstraction to yield the thermodynamically favoured 3°-carbocation INT 1. Nucleophilic addition of phenyl trimethylsilylethyne 5 can then occur via TS 1-2, corresponding to a barrier of 18.7 kcal/mol, yielding the vinyl cationic INT 2. It is from INT 2 that the two possible reaction paths diverge. The experimentally observed reaction requires dissociation of trimethylsilyl cation to yield the alkyne product INT 6. Such a dissociation can be promoted by chloride transfer from AlCl<sub>4</sub><sup>-</sup> (TS 2-6) thereby producing TMSCl and regenerating the Lewis acid catalyst. Alternatively, the vinyl cation of INT 2 can activate the C-H bond of the proximal methylene group via TS 2-3 to yield the α-silyl cation INT 3.[31] As expected, the barrier leading to the experimentally observed INT 6 is lower than that leading to INT 3 (20.5 vs 22.7 kcal/mol). This 2.2 kcal/mol energy difference is quite small compared to the complete reaction selectivity experimentally observed, suggesting the difference is likely underestimated at this level of theory. From INT 3, carbocation rearrangement can occur through a 1,2-hydride shift via a very low energy barrier (0.5 kcal/mol, TS 3-4) to yield the thermodynamically favoured benzylic carbocation INT 4. Finally, silyl cation abstraction by chloride can occur via TS 4-5 in a fashion analogous to TS 2-6, yielding the cyclobutene INT 5, which is found to be thermodynamically favoured over the INT 6 alkyne product by 4.2 kcal/mol. With the kinetic preference of alkyne formation established for the five-membered ring case, we extended our investigation to rings of increasing size, with the expectation that the C-H activation barrier would decrease up to the eight-membered ring. Past this point, we expect the barrier to increase again, as seen for the twelve-membered ring case. When the data in Table 4, is examined, we see that this prediction holds true, with a general trend for decreasing energy of activation observed up to the eight-membered ring (19.3 kcal/mol; TS 2-3, n=4). The exception to the trend is the six-membered carbocycle (TS 2-3, n=2), which displays an even higher barrier to C-H activation than the five-membered system (26.5 vs 22.7 kcal/mol), which does fit with the lack of cyclobutene formation observed experimentally for the reaction with chloride 1. For the twelve-membered ring case, which we have demonstrated does not undergo the C-H activation pathway (compound 51, Scheme 5), we again see an elevated C-H activation barrier (27.2 kcal/mol; TS 2-3, n=8). We propose that the dependence of activation energy on the ring size arises from varying levels of carbocation stabilization at the TS due to

differences in the conformational flexibility of the ring. When TS 2-3 is examined for all ring sizes, it is evident that the C-H bond that is being activated is almost completely broken at the TS, with C-H bond distances ranging from 1.367 Å when n=4, to 1.491 Å when n=2, suggesting a high degree of carbocationic character in the vicinity of the activated C-H bond. Such a charge buildup is visualized in the electrostatic potential map (Figure 4). It is anticipated that this partial charge will be stabilized through hyperconjugation with the neighbouring methylene group. Figure 3B shows a series of Newman projections looking down the C-C bond between the neighbouring methylene and the carbon where the C-H bond activation is occurring for the various ring sizes. For the eight-membered ring (n=4), the Newman projection suggests this TS to have the most optimal balance of carbocation stabilization due to a low torsion angle between the electron donating C-H bond and the activated C-H bond (31°), and a large torsion angle between the carbon groups of the ring, thereby minimizing gauche-type strain. However, when the Newman projections for the n=4 and n=8 structures are compared, they are quite similar, therefore the large difference in the TS energies is slightly surprising. If the structures for INT 2 (n=8) and the corresponding TS are compared, it is evident that there is increased transannular strain at the TS, with the distances between hydrogens on opposite sides of the twelve-membered ring decreasing from 2.856 Å to 2.093 Å. Therefore, while the carbocation stabilization model provides a reasonable explanation for the observations, it is likely that the ring-size effects observed are a combination of multiple components and are not fully attributable to any one explanation.

<table><caption>Table 4. C-H activation energies vs. ring size</caption><thead><tr><th>entry</th><th>n</th><th>Activation Energy (kcal/mol)</th></tr></thead><tbody><tr><td>1</td><td>1</td><td>22.7</td></tr><tr><td>2</td><td>2</td><td>26.5</td></tr><tr><td>3</td><td>3</td><td>21.2</td></tr><tr><td>4</td><td>4</td><td>19.3</td></tr><tr><td>5</td><td>8</td><td>27.2</td></tr></tbody></table>
<figure><img src="image_44.png" /></figure>

B.

<figure><img src="image_45.png" /><figcaption>**Figure 3.** a) B3LYP/6-31G* potential energy surface for the reaction of 1-methylcyclopentane and TMS-phenylacetylene (Gibbs energy in kcal/mol). b) Newman projections looking down the C-C bond adjacent to the C-H activated centre for TS 2-3 (n = 1, 2, 3, 4, and 8).</figcaption></figure>

<figure><img src="image_46.png" /><figcaption>**Figure 4.** Electrostatic potential map of TS 2-3 (n=1) showing significant carbocationic character at the C-H activated carbon. Areas in blue correspond to higher positive charge density and red to areas of higher negative charge density.</figcaption></figure>

## Synthetic applications

The internal alkynes obtained via the cationic coupling process can be readily isomerized to terminal alkynes using the zipper-reaction (Scheme 6A).[32] We found the practical procedure reported by Hoye gave the desired product **87** in 94% yield.[33] The terminal alkyne can then participate in a variety of transformations (Scheme 6B), as demonstrated by the synthesis of triazole **88** via click-reaction, vinyl iodide **89** by hydroalumination followed by treatment of the vinyl alane with iodine,[34] or Sonogashira coupling to yield arylated-alkyne **90**. Hydroalumination of **15** under conditions reported by Eisch gave
styrene 91 after hydrolysis (Scheme 6C).[35] The intermediate vinyl
aluminum reagent can also be employed in Negishi coupling[36] to
access trisubstituted alkenes 92 (Scheme 6D).

<figure><img src="image_47.png" /><figcaption>B. Subsequent transformations of alkynes</figcaption></figure>

<figure><img src="image_48.png" /><figcaption>C. Hydroalumination followed by hydrolysis or Negishi coupling</figcaption></figure>

<figure><img src="image_49.png" /><figcaption>D. Hydroalumination followed by hydrolysis or Negishi coupling</figcaption></figure>

<figure><img src="image_50.png" /><figcaption>**Scheme 6.** Miscellaneous reactions.</figcaption></figure>

Proposed reaction mechanism

In accordance with DFT calculations (Figure 3a) and experimental
observations, we propose the catalytic cycle depicted in Scheme 7.
Initially, the Lewis acid (e.g. AlCl₃) abstracts a chloride from the
tertiary alkyl chloride **A**, resulting in the formation of the short-lived
and highly reactive cation **B**. This cation can engage in various
reactions, including side-reactions as discussed in this report (mainly
oligomerization and elimination). The productive reaction of **B** with
silylated alkyne **C** yields a stabilized vinyl-cation **D**. Silylated vinyl

cations of type **D** were prepared and analyzed by Siehl,[37] who
demonstrated through low-temperature ¹³C-NMR experiments that
the stabilization of a vinyl cation with a β-Si σ-bond is comparable to
the stabilization by a double bond (allenyl cation). Mass
spectroscopic studies by Brook indicate a stabilization of 43.5 kcal /
mol of a vinyl cation with a β-TMS group relative to hydrogen.[38]
Vinyl cations are kinetically stabilized as recently discussed by Mayr[39]
but will finally eliminate the TMS group by the reaction with
chloroaluminate (AlCl₄) to provide the desired product **E**.

<figure><img src="image_51.png" /><figcaption>**Scheme 7.** Proposed catalytic cycle.</figcaption></figure>

Conclusion

Approximately 40 years after Capozzi's initial report on the AlCl₃-
promoted coupling of silylalkynes and tertiary aliphatic chlorides,
we present a systematic study of this reaction. Through
meticulous optimization, we extended the original scope from 5
to over 40 examples, including several with functional groups.
For the first time the diastereoselectivity of this reaction was
investigated and we observed that cyclic substrates bearing a
substituent alpha to the tertiary cation gave coupling products
with excellent diastereoselectivities (>95:5). We also
investigated potential side reactions such as cyclization, hydride
transfer, and C-H activation reactions. DFT calculations support
the mechanism initially proposed by Capozzi[10] and rationalize
the formation of the C-H activation product for 8-membered rings.
The availability of many aliphatic chlorides and TMS-substituted
alkynes makes this methodology particularly useful. We
anticipate future applications in total synthesis, especially in
combination with the zipper-reaction, which enables the
traceless formation of quaternary centers while installing a highly
useful alkyne terminus.

**Supporting Information**

The authors have cited additional references within the
Supporting Information (SI).[40-94] The SI also includes
experimental data for this manuscript, copies of NMR spectra,
and computational data (coordinates). Crystallographic data for
compound 85 have been deposited with the CCDC under the
deposition number 2387813.
Acknowledgements

This work was supported by the Agence Nationale de la Recherche (ANR-21-CE07-0005-01 CatCoupling), the Centre National de la Recherche Scientifique (CNRS) and the Université de Rennes. We would also like to acknowledge Rennes Metropole for the AES grant and express our gratitude to the Langlois Foundation for their generous financial support.

**Keywords:** cations • alkyl chlorides • silylalkynes • quaternary centers • C-H activation • coupling reactions

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Entry for the Table of Contents

<figure><img src="image_52.png" /></figure>

* commercial or accessible starting materials

* inexpensive Lewis acid

* > 50 examples

* all-carbon quaternary centers

Capozzi's pioneering reaction involving tertiary aliphatic cations and silylated alkynes in 1982 laid the groundwork for an innovative solution to aliphatic-alkyne coupling. Building on this, our study systematically explored reaction conditions, broadening its applicability to diverse functional groups. Notably, we observed high diastereoselectivities and an unexpected C-H activation, yielding a cyclooctane-fused cyclobutene, further expanding the utility of this reaction.