Synthesis of trisubstituted alkenylstannanes through copper-catalyzed three-component coupling of alkylboranes, alkynoates, and tributyltin methoxide

Article abstract of DOI:10.1002/anie.201305973

A versatile route to trisubstituted alkenylstannanes is presented. The alkyl and Sn moieties were introduced at the β and α carbon atoms of alkynoates, respectively, in a formal syn addition mode with complete regioselectivity (see scheme). A variety of functional groups were tolerated in the alkylboranes and alkynoates. Copyright

Full text of DOI:10.1002/anie.201305973

Angewandte
Chemie
DOI: 10.1002/anie.201305973
Synthetic Methods
Synthesis of Trisubstituted Alkenylstannanes through Copper-
Catalyzed Three-Component Coupling of Alkylboranes, Alkynoates,
and Tributyltin Methoxide**
Takamichi Wakamatsu, Kazunori Nagao, Hirohisa Ohmiya,* and Masaya Sawamura*
Alkenylstannanes are useful synthetic intermediates in
organic synthesis because of their applicability in various
transformations (e.g., Kosugi–Migita–Stille cross-coupling).[1]
In particular, trisubstituted alkenylstannanes should be useful
for the synthesis of various tetrasubstituted alkenes that are
found in many important pharmaceuticals and bioactive
natural products.[2] Among the routes to trisubstituted
alkenylstannanes, transition-metal-catalyzed stereoselective
carbostannylation of internal alkynes with organostannanes is
the most straightforward and attractive (Scheme 1a).[3–7] This
have not been used for the introduction of alkyl groups.[5]
Furthermore, the regioselectivity is not always reliable,
especially as the regiocontrol is generally difficult even with
alkynes that are desymmetrized by electronic effects.[3b]
Herein, we report a copper-catalyzed three-component
coupling of alkyl boranes (alkyl-9-BBN), alkynoates, and
tributyltin methoxide (Bu3SnOMe) as a versatile route to
trisubstituted alkenylstannanes (Scheme 1b).[8–10] The alkyl
and Sn moieties are introduced at the b and a carbon atoms of
the alkynoates, respectively, in a formal syn addition mode
with complete regioselectivity. A variety of functional groups
are tolerated in the alkylboranes and alkynoates. Although
the scope of the alkyne is limited to alkynoates, they are easily
accessible and the alkoxycarbonyl group in the coupling
products can be a point of diversification for synthesizing
tetrasubstituted alkenes. These points can be synthetic merits
of using alkynoates as substrates.
The reaction of alkylborane 2a (0.375 mmol), which was
prepared by hydroboration of styrene (1a) with 9-
borabicyclo[3.3.1]nonane (9-BBN-H) dimer, with ethyl 3-
phenylpropiolate (3a) and Bu3SnOMe in the presence of
CuOAc and tBuOK in 1,4-dioxane afforded trisubstituted
alkenylstannane 4aa in 74% yield with excellent syn/anti
selectivity [Eq. (1)]. An exogenous ligand for the copper ion
was not necessary. The three-component coupling was readily
scalable: a gram-scale reaction with 1.0 g (5.7 mmol) of 3a
afforded 4aa in 70% yield with also excellent stereoselectiv-
ity (syn/anti 97:3).
Scheme 1. Synthesis of trisubstituted alkenylstannanes.
À
catalytic method allows the simultaneous formation of C C
À
and C Sn bonds. Shirakawa, Hiyama, and co-workers devel-
oped the palladium- or nickel-catalyzed carbostannylation of
internal alkynes with allyl-, acyl-, and alkynylstannanes.[3]
These methods are useful for the preparation of trisubstituted
alkenylstannanes, but require tedious preparation of the
organostannane reagents. Additionally, sp3-alkylstannanes
[*] T. Wakamatsu, K. Nagao, Prof. Dr. H. Ohmiya,
Prof. Dr. M. Sawamura
The use of CuCl or Cu(OAc)2 instead of CuOAc resulted
in significantly reduced yields (20 and 45%, respectively).
When tBuOK was omitted, the trisubstituted alkenylstannane
product was not obtained at all. The corresponding amides or
ketones as well as nonpolar internal alkynes showed no
reactivity as alkyne substrates under similar conditions. Our
attempts to use phenyl-9-BBN, PhB(OH)2, phenylboronic
acid pinacolate ester, or vinylpinacolate ester instead of the
alkyl 9-BBN reagents were unsuccessful.
Department of Chemistry, Faculty of Science
Hokkaido University, Sapporo 060-0810 (Japan)
E-mail: ohmiya@sci.hokudai.ac.jp
sawamura@sci.hokudai.ac.jp
Homepage: http://wwwchem.sci.hokudai.ac.jp/~orgmet/
index.php
[**] This work was supported by Grants-in-Aid for Young Scientists (A)
and Challenging Exploratory Research, JSPS, to H.O. and by CREST
and ACT-C, JST, to M.S. K.N. thanks the JSPS for their scholarship
support.
This hydroboration/three-component coupling one-pot
method afforded a variety of trisubstituted alkenylstannanes
with high stereoselectivities (Table 1). The reaction tolerated
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305973.
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Table 1: Copper-catalyzed three-component coupling.[a]
functional groups such as methoxy,
ester, acetal, benzyl ether, phthal-
imide, bromoaryl, silyl ether, and
fluoroaryl moieties in the alkylbor-
ane and/or alkynoate (entries 1, 2,
5–7, 9–13).
The alkynoate scope is shown in
Table 1. Methoxy, ester, and fluoro
groups were tolerated at the para-
position of the b-aryl substituent
(entries 1, 2, 13). The alkynoate 3h,
bearing a 2-thienyl group at the b-
position, also underwent coupling
in 65% yield with 92:8 syn selectiv-
ity (entry 12). Alkyl groups were
acceptable as b-substituent of the
alkynoate (entries 4–7). The alky-
noate with a methyl group at the b-
position reacted with excellent syn
selectivity (> 99:1, entry 4). The
reactions of 3 f and 3g having
a THPOCH2 and BnOCH2 group,
respectively, at the b-position also
proceeded with > 99:1 syn selectiv-
ity (entries 5–7).
Entry Alkene
Alkynoate
Product
Yield [%][b] syn/anti[c]
1
1a
55
95:5
2
1a
1a
61
71
91:9
3[d]
>99:1
4[e]
5[e]
6[e]
7[e]
8
1a
1a
1a
49
88
74
74
75
>99:1
>99:1
>99:1
>99:1
93:7
The tolerance toward steric
demand in the alkylboranes 2 and
alkynoates
Table 1.
3
is also shown in
methyl group was
A
3g
3a
acceptable as an ortho-substituent
of the aromatic ring at the b-posi-
tion (entry 3). Also the sterically
more demanding alkylborane 2 f,
which was derived from a terminal
alkene (1 f) bearing a tertiary alkyl
substituent, afforded the corre-
sponding product (4 fa; 64% yield,
91:9 syn selectivity; entry 11). How-
ever, the use of secondary alkylbor-
ane reagents prepared from internal
alkenes resulted in no reaction
(data not shown).
Alkene hydroboration of 1i fol-
lowed by copper-catalyzed cycliza-
tion gave the corresponding five-
membered carbocycle 4i in 80%
yield with > 99:1 syn selectivity
[Eq. (2)].
9
3a
68
94:6
10
3a
3a
77
64
96:4
91:9
11
12
65
63
92:8
93:7
A possible catalytic cycle for
this copper-catalyzed transforma-
tion is shown in Figure 1. The reac-
tion of CuOAc and tBuOK forms
alkoxocopper(I) complex A. B–Cu
13
transmetalation between
A and
[a] The reaction was carried out with 3 (0.25 mmol), 2 (0.375 mmol), CuOAc (10 mol%), tBuOK
(10 mol%), and Bu3SnOMe (0.5 mmol) in dioxane (1 mL) at 608C for 12 h. Alkylborane 2 was prepared
in advance by hydroboration of 1 with the 9-BBN dimer at 608C for 1 h and used without purification.
THP: tetrahydropyranyl; TIPS: triisopropylsilyl. [b] Yield of isolated product. The isolated products were
contaminated with traces of unidentified materials (0.1–3%). [c] Determined by 1H NMR analysis of the
purified product. [d] 20 mol% of CuOAc/tBuOK were used. [e] The reaction was carried out with CuOAc
(20 mol%), tBuOK (20 mol%), and Bu3SnOMe (1.0 mmol) in dioxane (0.5 mL).
alkylborane 2 results in the alkyl-
copper(I) species B and an alkoxy-
borane (9-BBN-OtBu or 9-BBN-
OMe).[9,10] Species B then forms
a p-complex (C) with alkynoate 3.
2
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nitrobenzene to afford the corresponding tetrasubsti-
tuted alkene 5hi [Eq. (4)], stannane 4ae coupled with
methyl 2-(bromoethyl)acrylate to afford allylation
product 5ae [Eq. (5)], and the Kosugi–Migita–Stille
cross-coupling product 5af underwent a THP depro-
tection followed by cyclization to afford a,b-buteno-
lide 6af [Eq. (6)].
In summary, we have developed a new approach to
trisubstituted alkenylstannanes through copper-catalyzed
three-component coupling of alkylboranes, alkynoates, and
tributyltin methoxide, which proceeds with complete regio-
selectivity and high syn selectivity. A variety of functional
groups are tolerated in the alkylborane and the alkynoate.
Figure 1. Putative mechanism of our copper-catalyzed synthesis
of trisubstituted alkenylstannanes.
ꢀ
Syn carbocupration across the C C of C leads to
alkenylcopper intermediate D. Finally, stannylation by
Bu3SnOMe releases syn-4,[11] regenerating alkoxo-
copper(I) complex A for the next catalytic cycle. On
this pathway, the alkoxyborane may play a role in
activating the alkynoate through its Lewis-acidic
character.[9a,10c,d]
The occurrence of anti-stannylation as a side
reaction suggests the geometrical isomerization of
the alkenylcopper species (D/D’) through a copper(I)
allenoate complex (E in Scheme 2).[12,13] Stannylation
Thus, this copper-catalyzed procedure gives straightforward
access to functionalized, trisubstituted alkenylstannanes.
Experimental Section
Typical procedure [Eq. (1)]: Styrene (1a; 47.2 mL, 0.41 mmol) and (9-
BBN-H)2 (45.8 mg, 0.188 mmol) were placed in a vial containing
a magnetic stirring bar. The vial was sealed with a Teflon-coated
silicon rubber septum, evacuated, and filled with argon. 1,4-Dioxane
(0.4 mL) was added to the vial, and the mixture was stirred at 608C
for 1 h to prepare the alkylborane 2a. CuOAc (3.1 mg, 0.025 mmol)
and tBuOK (2.8 mg, 0.025 mmol) were placed in another vial. The vial
was also sealed with a Teflon-coated silicon rubber septum, evac-
uated, and filled with argon. After 1,4-dioxane (0.6 mL) was added,
the mixture was stirred at 258C for 1 h. Next, the alkyl borane
solution was transferred to the vial containing the CuI complex,
followed by addition of alkynoate 3a (43.6 mg, 0.25 mmol) and
Bu3SnOMe (160.5 mg, 0.5 mmol). After stirring for 12 h at 608C,
diethyl ether was added to the mixture. The mixture was filtered
through a short plug of Al2O3, which was then washed with diethyl
ether. After removing the solvent under reduced pressure, gel
Scheme 2. Isomerization of the alkenyl copper intermediate.
of this allenoate can result in the formation of syn-4 or anti-4
depending on the substituent effects of R1 and R2, while the
isomerized alkenyl copper(I) D’ should preferentially yield
the anti-stannylation product anti-4.
The trisubstituted alkenylstannanes obtained were used in
several syntheses:[14] Stannane 4aa was readily derivatized to
the trisubstituted alkenyl iodide 5aa [Eq. (3)], stannane 4hi
underwent Kosugi–Migita–Stille cross-coupling with 4-iodo-
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permeation chromatography (CHCl3) provided 4aa (105.3 mg,
0.185 mmol) in 74% yield with 97:3 syn/anti selectivity.
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Received: July 10, 2013
Published online: && &&, &&&&
Keywords: alkylboranes · copper · stannylation ·
.
trisubstituted alkenylstannanes
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G. Lalic, Org. Lett. 2011, 13, 362 – 365.
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[14] For Sn-to-Li transmetalation of multisubstituted alkenylstan-
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4
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Synthetic Methods
T. Wakamatsu, K. Nagao, H. Ohmiya,*
M. Sawamura*
&&&& — &&&&
Synthesis of Trisubstituted
Alkenylstannanes through Copper-
Catalyzed Three-Component Coupling of
Alkylboranes, Alkynoates, and Tributyltin
Methoxide
A versatile route to trisubstituted alke-
nylstannanes is presented. The alkyl and
Sn moieties were introduced at the b and
a carbon atoms of alkynoates, respec-
tively, in a formal syn addition mode with
complete regioselectivity (see scheme). A
variety of functional groups were toler-
ated in the alkylboranes and alkynoates.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!