Synthesis of tetrasubstituted alkenes by stereo- and regioselective stannyllithiation of diarylacetylenes

Article abstract of DOI:10.1021/ja1059119

Addition of trimethylstannyllithium to a diarylacetylene takes place exclusively in an anti-fashion to produce a lithio vinylstannane intermediate. The regioselectivity of the addition is controlled by the steric and electronic property of the acetylene and reaches up to >99:1. The two newly formed C-metal bonds can be sequentially and stereospecifically transformed into two new C-C bonds as illustrated by stereoselective synthesis of 4-hydroxytamoxifen and its regioisomer. A tetraarylethene bearing different aryl groups can be synthesized similarly and cyclized to a substituted dibenzo[g,p]chrysene derivative via a palladium-catalyzed arylation reaction.

Full text of DOI:10.1021/ja1059119

Published on Web 08/10/2010
Synthesis of Tetrasubstituted Alkenes by Stereo- and Regioselective
Stannyllithiation of Diarylacetylenes
Hayato Tsuji,* Yasuyuki Ueda, Laurean Ilies, and Eiichi Nakamura*
Department of Chemistry, School of Science, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received May 1, 2010; E-mail: tsuji@chem.s.u-tokyo.ac.jp; nakamura@chem.s.u-tokyo.ac.jp
Table 1. Synthesis of 1,2,2-Triorgano Stannylalkenes 4 and 5
Abstract: Addition of trimethylstannyllithium to a diarylacetylene
Isolated yield/%
(4:5 ratio)a
takes place exclusively in an anti-fashion to produce a lithio
vinylstannane intermediate. The regioselectivity of the addition is
controlled by the steric and electronic property of the acetylene and
reaches up to >99:1. The two newly formed C-metal bonds can
be sequentially and stereospecifically transformed into two new C-C
bonds as illustrated by stereoselective synthesis of 4-hydroxytamoxifen
and its regioisomer. A tetraarylethene bearing different aryl groups can
be synthesized similarly and cyclized to a substituted dibenzo[g,p]chry-
sene derivative via a palladium-catalyzed arylation reaction.
Entry
Ar1
Ar2
E1 (condition)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
EtI (a)
CH2dCHCH2Br (a)
PhCHO (a)
82 (-)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
62 (-)
80 (-)
Ph2CO (a)
88 (-)
p-MeO-C6H4-I (b)
3-pyridyl-I (b)
p-MeO-C6H4-I (b)
91 (-)
76 (-)
o-Tolb
86 (14:86)
87 (10:90)
75 (1:>99)
84 (91:9)
80 (34:66)
74 (36:64)
85 (>99:1)
84 (>99:1)
81 (>99:1)
o-MeO-C6H4 p-Tol-I (b)b
9
1-naphthyl
p-MeO-C6H4-I (b)
10
11
12
13
14
15
p-MeO-C6H4 p-Tol-I (b)b
p-F-C6H4
p-Cl-C6H4
p-MeO-C6H4-I (b)
p-MeO-C6H4-I (b)
o-Tolb p-MeO-C6H4 p-Tol-I (b)b
o-Tolb p-MeO-C6H4 p-CF3-C6H4-I (b)
o-Tolb p-MeO-C6H4 2-thienyl-I (b)
The chemistry of tetrasubstituted alkenes has been underrated
because of the paucity of synthetic access.1 Providing a potential route
to such alkenes by way of a dianion or dipolar synthon, the addition
of a bimetallic species to an internal acetylene is intriguing (eq 1) but
to date has not received proper attention because of selectivity
problems, in particular regioselectivity.2 We report herein that the
stannyllithiation of a simple diarylacetylene 1 proceeds with 100%
anti-selectivity to generate the Z dimetallic product 2 or 33 and that
the resulting C-Li and C-Sn bonds can be converted sequentially to
two C-C bonds, to selectively produce tetrasubstituted alkenes
possessing various functional groups (Scheme 1). The regioselectivity
of the addition is sensitive to the steric and electronic nature of the
two aryl groups and may reach 90-99% (Table 1), which is rather
remarkable in light of some previously reported examples.4,5 Notably,
the present reaction also provides a stereoselective entry to 1,1,2,2-
tetraarylethenes and chrysene derivatives (Scheme 3).
a Determined from the 1H NMR of isolated isomer mixture. b Tol ) tolyl.
According to a report in 1981, triethylstannyllithium in THF
adds to diphenylacetylene in only 2% yield,6,7 and in our case,
trimethylstannyllithium in THF afforded the Z-adduct 2 in 31%
yield. To our pleasant surprise, trimethylstannyllithium in hexane
at 0 °C afforded after D2O quenching (2-deuterio-1,2-diphenylethe-
nyl)stannane 4a in 97% yield with 100% Z selectivity (for all cases
shown in Table 1) and with 100% deuterium incorporation. The
reaction of tributyl- and triphenylstannyllithium took place similarly
but in lower yield (Scheme 1). Although this reaction can be applied
only to diarylacetylenes, it exhibits considerable synthetic utility
because of the versatility of the lithiated vinylstannane intermediate
and the regio- and stereoselectivity of the reaction.
We can trap the lithio intermediate 2 or 3 with a variety of
electrophiles to obtain 1,2,2-triorgano stannylalkenes (Scheme 1 and
Table 1; condition a; no catalyst). Trapping with ethyl iodide and allyl
bromide afforded the 2-ethylated and 2-allylated 1-stannylethene in
82% and 62% isolated yield, respectively (entries 1 and 2).8 The
reaction with benzaldehyde and benzophenone afforded the corre-
sponding secondary and tertiary allylic alcohols in 80% and 88% yield,
respectively (entries 3 and 4). After transmetalation from lithium to
zinc, Negishi coupling (condition b, with SPhos9 ligand) with p-anisyl
and 3-pyridyl iodides afforded 2-(p-anisyl)- and 2-(3-pyridyl)-1-
stannylalkene in 91% and 76% yield, respectively (entries 5 and 6).
The stannyl group remained intact during these transformations.
The regioselectivity of the stannylmetalation is critically impor-
tant for this reaction to be synthetically useful and was found to be
controlled by subtle steric and electronic effects (entries 7-15).
Steric hindrance caused by o-tolyl and o-anisyl groups puts the
stannyl group away from these groups and gave predominantly
isomer 5 (14:86 and 10:90, respectively) after trapping with an aryl
iodide under condition b (entries 7 and 8). The bulkier 1-naphthyl
group increased the regioselectivity to >99% (entry 9).
Scheme 1. Stannyllithiation Route to Tetrasubstituted Alkenesa
a Conditions. a: E1 (1.1 equiv), hexane, 0 °C to rt; b: ZnCl2 (1.1 equiv),
hexane/THF ) 2/1, 0 °C to rt, then E1 (1.1 equiv), Pd2(dba)3 ·CHCl3 (5
mol %), SPhos (20 mol %), rt.
Interestingly, the electronic properties of Ar1 and Ar2 control the
regioselectivity. An electron-rich aryl group places the stannyl group
9
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10.1021/ja1059119  2010 American Chemical Society

C O M M U N I C A T I O N S
onto the same carbon to which this aryl group is attached (entry 10 as
opposed to entry 8 where the steric effect of the o-anisyl group wins);
on the other hand, an electron-withdrawing aryl group puts the stannyl
group away from this aryl group (entries 11 and 12). With an added
steric factor (Ar1 ) o-Tol), the selectivity increases to >99:1 (entries
13-15). This electronic effect can be understood in terms of the
stabilization by the lithium atom of an anionic charge on the vinylic
carbon atom that develops during the course of the reaction.10
However, the reaction time was found to be insensitive to the electronic
properties of the p-substituent (entries 10-12), suggesting that the rate-
limiting step differs from the regioselectivity-determining step.
acetylene was stannyllithiated and then successively treated with
2-bromo-4-fluoro-1-iodobenzene and 2-bromo-1-iodo-4-nitrobenzene
to afford the tetraarylethene 12 in 77% yield with 100% stereoselec-
tivity (see Supporting Information). Palladium-catalyzed cyclization13
of 12 gave the dibenzochrysene derivative 13 in 89% yield.
In summary, we have developed the stannyllithiation of diarylacety-
lene, which proceeds in a 100% anti-addition fashion with a regiose-
lectivity up to >99:1, without the assistance of a catalyst or a directing
group. This reaction provides a versatile stereo- and regioselective
synthesis of multisubstituted alkenes via a dianion or dipolar alkene
synthon. Although the origin of the selectivity of the metallometalation
step is unclear at this time,10 the new method complements the previous
syntheses of this class of alkenes,1 such as the reaction of 1,1-
dihaloalkene14 and alkynylmetal species.15,16 The method also provides
a stereo- and regioselective synthesis of substituted dibenzo[g,p]chry-
senes that are expected to have good potential as organic semiconductor
materials.17 This dibenzochrysene synthesis is complementary to the
previously reported methods that can only be applied to the synthesis
of electron-rich derivatives.18
Scheme 2. Selective Synthesis of Two Regioisomers of
Hydroxytamoxifen
Acknowledgment. We thank MEXT (KAKENHI for E.N., No.
22000008, H.T., No. 20685005) and the Global COE Program for
Chemistry Innovation.
Supporting Information Available: Detailed experimental proce-
dures. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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We illustrate the synthetic utility of the reaction by a 1-g scale
synthesis of two different regioisomers, 4-hydroxytamoxifen 10 and
4′-hydroxytamoxifen 11 from the readily available compound 8
(Scheme 2). To obtain 10, the stannyllithiation of 8 generated the
vinyllithium intermediate 9, which was trapped in situ by EtI, and the
ethylated product was arylated with p-Me2NCH2CH2O-C6H4-I.11
Removal of the methoxymethyl (MOM) group gave 10 in 71% overall
yield in a 10:11 ratio of 95:5. To obtain the regioisomer 11, we
introduced the p-Me2NCH2CH2O-C6H4 group first. Thus, we trans-
metalated the vinyllithium intermediate 9 into the corresponding zinc
reagent and coupled it with the required aryl iodide. The vinylstannane
product was then converted to the corresponding iodide and coupled
with ethylzinc chloride under palladium catalysis. Removal of the
MOM group gave 11 in 71% overall yield in a 10:11 ratio of 7:93.
(8) Procedure for Table 1, entry 1: A THF solution of trimethylstannyllithium
was obtained from hexamethyldistannane (0.5 mol/L in THF, 3.5 mL, 1.75
mmol) and an excess amount of Li granules at 0 °C. 1.1 mL of this solution
was transferred with a gas-tight syringe to a Schlenk reaction vessel to
remove excess lithium, and the volatiles were removed in Vacuo. Hexane
(2 mL) and diphenylacetylene (178 mg, 1.0 mmol) were added, and the
mixture was stirred at 0 °C for 3 h. Iodoethane (166 mg, 1.1 mmol) was
added, and the mixture was stirred for another 3 h at room temperature.
Aqueous workup and silica gel column chromatography afforded the product
(303 mg, 82%).
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Scheme 3. Stereoselective Synthesis of a Dibenzo[g,p]chrysene
Derivative
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Second, we show a selective synthesis of an unsymmetrically
substituted dibenzo[g,p]chrysene derivative (Scheme 3).12 Diphenyl-
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