Copper-catalyzed α-selective hydrostannylation of alkynes for the synthesis of branched alkenylstannanes

Abstract

A variety of branched alkenylstannanes can directly be synthesized with excellent α-selectivity by the copper-catalyzed hydrostannylation using a distannane or a silylstannane, irrespective of the electronic and steric characteristics of terminal alkynes employed. Synthetic utility of the resulting branched alkenylstannane has been demonstrated by the total synthesis of bexarotene.

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In view of the high synthetic versatility of alkenylstannanes, especially in carbon–carbon bond-forming processes via Migita–Kosugi–Stille coupling, tin–lithium exchange reaction, etc., the development of potent methods for making alkenylstannanes with defined structures in a regio- and stereoselective manner has continued to be a key subject in modern synthetic organic chemistry.¹ One of the most popular and straightforward routes to alkenylstannanes would be hydrostannylation of alkynes,² and three isomers, namely the α-adduct and the (E/Z)-β-adduct, can be generated in the case of terminal alkynes (eqn (1)).³ Hence the regio- and stereocontrol of hydrostannylation is a pivotal issue, and (Z)- or (E)-linear alkenylstannanes have successfully been synthesized with high β-selectivity under radical conditions,⁴ Lewis acid⁵ or transition metal catalysis.⁶ Although selective access to branched alkenylstannanes has also been achieved in some cases depending upon direct addition of a tin hydride^7–9 or a stannylmetallation–protonation sequence,¹⁰ the existing methods are still not versatile, owing to limited substrate scope of alkynes in every reaction and the use of an excess amount of a stannylmetal reagent in the latter case (Scheme 1). Therefore the development of a universal system for α-selective hydrostannylation of terminal alkynes, which gives direct and efficacious access to pharmacologically important 1,1-disubstituted alkenes such as bexarotene¹¹ and isocombretastatin A-4,¹² has been a long-awaited goal.

Scheme 1 Reported α-selective hydrostannylation of terminal alkynes.

We have recently riveted our attention on potential copper catalysis for metallation reactions of unsaturated carbon–carbon bonds, and have already disclosed that distannylation¹³ as well as various borylations¹⁴ of alkynes and alkenes facilely occur to afford organostannanes and -boranes with structural diversity by employing a distannane and a diboron as a metallating reagent. The distannylation of alkynes was found to proceed through intermediary formation of a β-stannylalkenylcopper species with enough nucleophilicity, which was finally converted into vic-distannylalkenes by capturing a tin electrophile. Therefore, we envisioned that a copper catalyst would also promote hydrostannylation of alkynes in the presence of a suitable protic reagent for trapping the β-stannylalkenylcopper intermediate.¹⁵ Herein we report that the hydrostannylation of terminal alkynes smoothly takes place under the copper catalysis by use of water as a protic reagent, and that the universal system allows a variety of branched alkenylstannanes to be synthesized with excellent α-selectivity, irrespective of the electronic and steric characteristics of terminal alkynes.

The α-selective hydrostannylation has proven to be feasible to provide a branched (2a) and a linear (2′a) alkenylstannane in 75% yield (2a : 2′a = 98 : 2), when we treated 1-tetradecyne (1a) with hexamethyldistannane and water in toluene at 110 °C in the presence of the Cu(OAc)₂–PtBu₃ catalyst (Table 1, entry 1).^16,17 The reaction was also applicable to 1-dodecyne (1b) and an imide-substituted alkyne (1c), giving 2b and 2c with high degrees of α-selectivity in excellent yield (entries 2 and 3), and furthermore functionalized aliphatic alkynes bearing an acetal (1d), a silyl ether (1e) or a benzyl ether (1f) smoothly underwent the α-selective hydrostannylation, leaving these reactive moieties intact (entries 4–6). The high functional group compatibility was also demonstrated by the reaction of a hydroxyl- (1g) or a bromo-substituted alkyne (1h), and propargyl-functionalized alkynes (1i and 1j), although the yields became moderate in some cases (entries 7–10). The regioselective installation of a stannyl group into an internal carbon of aromatic terminal alkynes was achieved under the present conditions as well, and thus pyridyl (1k), naphthyl (1l) and phenyl (1m and 1n) acetylenes were efficiently transformed into the respective branched alkenylstannanes (2k–2n) (entries 11–14). An internal alkyne, diphenylacetylene (1o), could participate in the reaction to furnish (E)-trimethylstannylstilbene (2o) as the sole product (eqn (2)), showing that hydrostannylation completely proceeds in a cis fashion.¹⁸

Table 1 Cu-catalyzed hydrostannylation with a distannane^a

Entry	R	Time (h)	Yield^b (%)	2 : 2′	Products
a General procedure: 1 (0.30 mmol, 1 equiv.), Me3Sn–SnMe3 (0.39 mmol, 1.3 equiv.), H2O (0.90 mmol, 3 equiv.), Cu(OAc)2 (0.015 μmol, 5 mol%), PtBu3 (0.053 mmol, 17.5 mol%), toluene (0.2 mL). b Isolated yield.
1	nC12H25 (1a)	1.5	75	98 : 2	2a,2′a
2	nC10H21 (1b)	2	89	97 : 3	2b,2′b
3		1.5	89	97 : 3	2c,2′c
4	THPO(CH2)4 (1d)	1	84	94 : 6	2d,2′d
5	TBSO(CH2)2 (1e)	1.5	85	96 : 4	2e,2′e
6	BnO(CH2)2 (1f)	1	76	97 : 3	2f,2′f
7	HO(CH2)8 (1g)	3	76	>99 : 1	2g
8	Br(CH2)8 (1h)	24	43	89 : 11	2h,2′h
9		8	63	>99 : 1	2i
10	BnOCH2 (1j)	6	37	92 : 8	2j,2′j
11	2-Pyridyl (1k)	5.5	68	>99 : 1	2k
12		6	68	86 : 14	2l,2′l
13	4-nBuC6H4 (1m)	24	61	>99 : 1	2m
14		2	80	>99 : 1	2n

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With the successful synthesis of diverse branched alkenylstannanes having a trimethylstannyl moiety, we next investigated α-selective installation of a tributylstannyl moiety. Although the reaction of 1-octyne (1p) with hexabutyldistannane in the presence of the Cu(OAc)₂–PCy₃ catalyst¹⁹ led to regioselective formation of a branched alkenylstannane (3p) in moderate yield (Table 2, entry 1), a silylstannane, tributyl(trimethylsilyl)stannane, turned out to serve as a more effective and reactive stannylating reagent to afford a 74% yield of 3p and 3′p (3p : 3′p = 86 : 14) (entry 2).¹⁷ It should be noted that a silyl moiety was not incorporated into an alkyne at all in the reaction with a silylstannane, which is in marked contrast to the copper-catalyzed selective silyl incorporation reactions into unsaturated hydrocarbons with a silylborane.²⁰ Hydrostannylation using a silylstannane also took place smoothly with 1-decyne (1q), 1-hexyne (1r) and branched aliphatic terminal alkynes (1s and 1t) to provide 3q–3t with high α-selectivity (entries 3–6), and furthermore functionalized terminal alkynes bearing a cyano (1u), a chloro (1v) or a benzyloxy moiety (1f), and 3-phenyl-1-propyne (1w) were transformed into the respective branched alkenylstannanes (entries 7–10).²¹

Table 2 Cu-catalyzed hydrostannylation with a silylstannane^a

Entry	R	Time (h)	Yield^b (%)	3 : 3′	Products
a General procedure: 1 (0.45 mmol, 1.5 equiv.), Me3Si–SnBu3 (0.30 mmol, 1 equiv.), H2O (0.45 mmol, 1.5 equiv.), Cu(OAc)2 (0.03 μmol, 10 mol%), PCy3 (0.11 mmol, 35 mol%), toluene (0.2 mL). b Isolated yield. c Bu3Sn–SnBu3 was used instead of Me3Si–SnBu3. H2O = 0.4 mL (74 equiv.). d NMR yield.
1^c	nC6H13 (1p)	43	43^d	>99 : 1	3p
2	nC6H13 (1p)	4	73	86 : 14	3p,3′p
3	nC8H17 (1q)	2	74	88 : 12	3q,3′q
4	nBu (1r)	2	74	85 : 15	3r,3′r
5	iAmyl (1s)	2	60	84 : 16	3s,3′s
6	iBu (1t)	2	48	92 : 8	3t,3′t
7	NC(CH2)3 (1u)	3	55	93 : 7	3u,3′u
8	Cl(CH2)3 (1v)	2	44	92 : 8	3v,3′v
9	BnO(CH2)2 (1f)	2	55	88 : 12	3f,3′f
10	Bn (1w)	2	46	93 : 7	3w,3′w

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Since water can serve as a proton source in hydrostannylation, we expected that the present system may be extended to deuteriostannylation by use of deuterium oxide. Surprisingly, the copper-catalyzed reaction of 1-tetradecyne (1a) with hexamethyldistannane in the presence of deuterium oxide produced a dideuteriostannylation product (2a-d₂) predominantly (2a-d₂ : 2a-d : 2a = 79 : 7 : 14, eqn (a), Scheme 2). The formation of 2a-d₂ can be rationalized by considering the deuteriostannylation of 1-tetradecyne-d (1a-d), which should be generated in situ prior to deuteriostannylation. Actually, hydrogen–deuterium exchange between 1a and deuterium oxide was demonstrated to occur smoothly under the copper catalysis (eqn (b), Scheme 2).

Scheme 2 Cu-catalyzed deuteriostannylation with deuterium oxide.

As depicted in Scheme 3, the branched alkenylstannane (2n) was found to be facilely converted into 1,1-diarylalkene 4 by the Migita–Kosugi–Stille coupling with ethyl 4-iodobenzoate. Hydrolysis of the ester moiety of 4 provided bexarotene 5 in 39% overall yield (3 steps, based on alkyne 1n), which is widely used in the treatment of cutaneous T-cell lymphoma,¹¹ demonstrating the synthetic significance of the present α-selective hydrostannylation.

Scheme 3 Total synthesis of bexarotene.

Formation of a stannylcopper species (6) via σ-bond metathesis between a distannane (or silylstannane) and Cu–OH would initiate hydrostannylation (Scheme 4).²² The resulting stannylcopper species (6) then adds across a carbon–carbon triple bond of a terminal alkyne (stannylcupration) to produce a β-stannylalkenylcopper species (7), which is finally transformed into a hydrostannylation product through protonation with water.²³ The formation of branched alkenylstannanes (2 and 3) with high α-selectivity should be attributed to the regioselective generation of 7, possessing the stannyl moiety at the internal carbon, in the stannylcupration step, which has already been well documented to be kinetically favored in a stoichiometric reaction of a stannylcopper species with a terminal alkyne.²⁴

Scheme 4 A plausible catalytic cycle for hydrostannylation.

In conclusion, we have developed a universal system for the α-selective hydrostannylation of terminal alkynes by using a distannane or a silylstannane as a stannylating reagent in the presence of a copper–trialkylphosphine catalyst, which leads to a convenient and straightforward method for synthesizing diverse branched alkenylstannanes, irrespective of the electronic and steric nature of terminal alkynes employed. The resulting branched alkenylstannane has been demonstrated to be facilely transformed into bexarotene of pharmacologically importance via the cross-coupling reaction. Further studies on copper-catalyzed stannylation reactions using a distannane or a silylstannane are in progress.

Notes and references

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17. For optimization of reaction conditions (ligand, protic reagent, solvent, etc.), see ESI†.
18. The reaction of 1-phenyl-1-butyne did not give a hydorostannylation product.
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21. The relatively low yields with TMSSnBu₃ compared with those with Me₃Sn–SnMe₃ are ascribed to the formation of Bu₃Sn–SnBu₃ as a by-product, which has been demonstrated to occur only in the presence of a Cu catalyst and a proton source. See ESI† for details.
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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and characterization data. See DOI: 10.1039/c5cc02720a

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