Consecutive β,β′‐Selective C(sp3)−H Silylation of Tertiary Amines with Dihydrosilanes Catalyzed by B(C6F5)3

Abstract Tris(pentafluorophenyl)borane has been found to catalyze the two‐fold C(sp3)−H silylation of various trialkylamine derivatives with dihydrosilanes, furnishing the corresponding 4‐silapiperidines in decent yields. The multi‐step reaction cascade involves amine‐to‐enamine dehydrogenation at two alkyl residues and two electrophilic silylation reactions of those enamines, one inter‐ and one intramolecular.

Selective functionalization of C(sp 3 )ÀH bonds is an important goal in synthetic chemistry. [1] One way to achieve this is by transition-metal-catalyzed C(sp 3 ) À H silylation, [2,3] and recently selected boron Lewis acids also emerged as catalysts for this purpose. [4] For example, B(C 6 F 5 ) 3 has been shown to abstract hydride from a-C(sp 3 )ÀH bonds of amines to result in the formation of iminium ions and the borohydride; [5] that iminium ion is CÀH acidic and can be deprotonated by another molecule of the amine, affording the corresponding enamine along with the ammonium borohydride [6,7] (Scheme 1, gray box). The net reaction is a dehydrogenation that enables subsequent bond formation with electrophiles in the b-position to the nitrogen atom, thereby representing a formal activation of the b-C(sp 3 )ÀH bond. This process has already been employed for silylation, [8] alkylation, [9] deuteration, [10] and olefination [11] of the b-carbon atom of various (a)cyclic tertiary amines (Scheme 1, top). Of note, Park and Chang merged the C(sp 3 )ÀH silylation with a B(C 6 F 5 ) 3catalyzed intramolecular Friedel-Crafts-type silylation [12] for the synthesis of bridged silicon-containing nitrogen heterocycles starting from N-arylated piperidines. [8a] However, the undirected silylation of acyclic tertiary amines [3c] as well as their challenging two-fold C(sp 3 ) À H silylation are unprecedented. We disclose here a b,b'-selective C(sp 3 ) À H silylation of acyclic tertiary amines and dihydrosilanes catalyzed by B(C 6 F 5 ) 3 to directly arrive at sila analogues of piperidines (Scheme 1, bottom left). These are valuable building blocks in medicinal chemistry, [13] for example, for the dopamine receptor antagonist sila-haloperidol (Scheme 1, bottom right). [14] Different from our approach, established syntheses typically start from divinyl-substituted silanes employing a sequence of hydrobromination or hydroboration-oxidation-sulfonylation followed by dialkylation of a primary amine. [15] We began our investigation with optimizing the two-fold C(sp 3 ) À H silylation of benzyldiethylamine (1 a!3 aa; Table 1). Treatment of 1 a and Ph 2 SiH 2 (2 a, 2.0 equiv) with 20 mol % of B(C 6 F 5 ) 3 in p-xylene at 150 8C afforded 3 aa after 15 h in 56 % yield ( Table 1, entry 1). Previous reports had indicated that the use of a metal oxide [8a] or a silyl triflate [5c] as an additive could improve the reactivity. [16] However, substoichiometric amounts of CaO or SrO decreased the yield ( Table 1, entries 2 and 3). The addition of 40 mol % of a silyl triflate improved the reactivity ( Table 1, entries 4-6), and a 75 % yield of 3 aa was obtained with Me 3 SiOTf as the additive. That yield was somewhat lower when using less and more Me 3 SiOTf, respectively (Table 1, entries 7 and 8). The reaction was completed within 2 h while a further shortened Scheme 1. B(C 6 F 5 ) 3 -catalyzed b-C(sp 3 )ÀH functionalization of tertiary amines. R groups = various aryl and alkyl groups as well as H; Ar = aryl group. reaction time to 1 h resulted in a lower yield (Table 1, entries 9 and 10). Other arene solvents were tested but none provided a better outcome (Table 1, entries [11][12][13]. A control experiment verified that Me 3 SiOTf is unable to mediate the reaction in the absence of B(C 6 F 5 ) 3 (Table 1, entry 14). Less B(C 6 F 5 ) 3 or Ph 2 SiH 2 (2 a) as well as lowering the temperature to 120 8C led to a decreased reactivity (Table 1, entries 15-17). The volume of the reaction vessel was also examined, and the results indicate that vessels smaller than 10 mL are detrimental (Table 1, entries 18 and 19). We ascribe this to catalyst inhibition by dihydrogen at high pressure. [7] A good yield was restored on a 5.0 mmol scale when performing the two-fold C(sp 3 ) À H silylation in an open system with a continuous flow of nitrogen gas (Table 1, entry 20).
We continued exploring the scope under the optimized reaction setup (Scheme 2; cf. Table 1, entry 9). It must be noted that reductive C(sp 3 )ÀN bond cleavage [17] is competing in any of the reactions summarized in Scheme 2, and secondary amines are the major byproducts (not quantified because of their volatility). N-Benzylated diethylamine derivatives bearing various electron-donating or -withdrawing substituents on the aryl moiety reacted with Ph 2 SiH 2 (2 a) to furnish the corresponding 4-silapiperidines in moderate to good yields (1 b-l!3 ba-la; gray box). All halo groups (1 g-j) and a trifluoromethyl group (1 k) were compatible. Tertiary amine 1 l containing a methyl ether underwent demethylation/silylation, and the free phenol was isolated in 50 % yield after purification by flash chromatography on silica gel (1 l! 3 la). A lower yield was obtained for a naphth-2-ylmethyl instead of the benzyl group (1 m!3 ma). The bis(4-silapiperidine) 3 na was formed in 47 % yield by four-fold C(sp 3 )ÀH silylation of 1 n. Replacing the benzyl group by an alkyl group was feasible (1 o-q!3 oa-qa). Notably, the two-fold C(sp 3 )ÀH silylation of substrate 1 o bearing two ethyl groups and one cyclohexyl group proceeded chemoselectively at the ethyl groups to form 3 oa. Substituted 4-silapiperidine derivatives were obtained from tertiary amines with groups other than ethyl (1 r-t!3 ra-ta). As expected, 1 t gave 3 ta with essentially no diastereoselectivity (cis/trans = 58:42). Attempted but failed cyclizations included tertiary benzylamines as precursors having two isopropyl, cyclohexyl, isobutyl, or phenethyl groups as well as 1-benzylazepane (see the Supporting Information for details).
The benzyl group in 4-silapiperidines such as 3 aa serves as a linchpin for further manipulations (Scheme 4). Debenzylation was achieved by treatment with 1-chloroethyl chloroformate followed by the reaction of the resulting carbamate with MeOH (3 aa!6). The benzyl group can also be converted into a benzoyl group by oxidation with KMnO 4 in the presence of BnNEt 3 Cl (3 aa!7).
To gain insight into the reaction mechanism of this twofold C(sp 3 )ÀH silylation, deuterium-labeling experiments and stoichiometric experiments were performed (Scheme 5). The reaction of 1 a with Ph 2 SiD 2 (2 a-d 2 ) under standard conditions gave 3 aa-d 3 in the expected yield with 41 % deuterium incorporation in the benzylic position as well as at the a carbon atoms (Scheme 5, top). This result confirms the known reversible hydride abstraction from C(sp 3 )ÀH bonds a to an amine nitrogen atom. [6] Importantly, 6 % deuterium incorporation was also detected for the b carbon atoms, which is evidence for hydrogenation of the enamine intermediate. In the case of diethyl-substituted 1 a, silylation is faster than this backward reaction. Conversely, di-n-butyl-substituted 1 v shows a different outcome (Scheme 5, top). None of the hypothetical 4-silapiperidine 3 va-d 3 was found (not shown) but instead 1 v-d 3 with the usual deuteration in the apositions. However, the deuteration grade in the b-positions was 24 %, demonstrating that enamine hydrogenation is now a competitive if not the only reaction pathway for more hindered alkyl chains. To inspect the influence of the Me 3 SiOTf additive, we mixed 1 a and B(C 6 F 5 ) 3 in an equimolar ratio (Scheme 5,bottom). This known reaction [6] led to the formation of the three boron species 8 a-10 a in 52 %, 30 %, and 17 % yield, respectively, and this product distribution was not affected by the addition of 1.0 equiv of Me 3 SiOTf.
On the basis of the above experimental results and the literature precedent [6,8] as well as DFT calculations by Park and Dang, [8b] a plausible reaction mechanism is proposed (Scheme 6). B(C 6 F 5 ) 3 promotes hydride abstraction from the tertiary amine 1 a to generate the iminium borohydrides 11 a Scheme 3. Consecutive C(sp 3 )ÀH/C(sp 2 )ÀH silylation of an aniline derivative. and 11 a' in equilibrium. Their subsequent deprotonation by unreacted 1 a yields enamine 12 a and FLP-type dihydrogen adduct 8 a; these can regenerate the free amine 1 a and the catalyst B(C 6 F 5 ) 3 along with release of dihydrogen. [7,19] The thus-formed enamine 12 a then engages in the rate-determining B(C 6 F 5 ) 3 -catalyzed intermolecular hydrosilylation [8b] through the Piers mechanism [20] with 12 a as a carbon nucleophile (B(C 6 F 5 ) 3 !13 a!15 aa). Alternatively, B(C 6 F 5 ) 3 -activated hydrosilane 13 a can also react with the amine nitrogen nucleophile 1 a to equilibrate with silylammonium borohydride 14 aa, the resting species of the overall process. [8a,b] Initially formed 15 aa stands in equilibrium with regioisomeric 15 aa' and 15 aa'', and 15 aa'' can undergo another deprotonation affording enamine 16 aa. That enamine again enters the catalytic cycle of the B(C 6 F 5 ) 3 -promoted, now intramolecular hydrosilylation to eventually arrive at the title compound 3 aa.
In summary, we have developed a B(C 6 F 5 ) 3 -catalyzed twofold b,b'-selective (formal) C(sp 3 )ÀH silylation of acyclic tertiary amines with dihydrosilanes to construct 4-silapiperidines and its derivatives. The reaction involves two amine-toenamine dehydrogenation reactions each followed by an inter-and an intramolecular electrophilic enamine silylation, respectively.