Synthesis of 1,1-diarylethylenes from an α-stannyl β-silylstyrene

Article abstract of DOI:10.1016/j.tetlet.2003.12.106

The synthesis of a family of 1,1-diarylethylenes from an α-stannyl β-silylstyrene through a combination of a Stille coupling and a protodesilylation reaction is described. This approach avoids the problematic cine-substitution, which is a well documented side reaction during the palladium-assisted elaboration of α-substituted vinylstannanes to 1,1-disubstituted ethylenes.

Full text of DOI:10.1016/j.tetlet.2003.12.106

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1693–1697
Synthesis of 1,1-diarylethylenes from an a-stannyl b-silylstyrene
Makonen Belema,* Van N. Nguyen and F. Christopher Zusi
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford,
CT 06492, USA
Received 23 November 2003; revised 8 December 2003; accepted 17 December 2003
Abstract—The synthesis of a family of 1,1-diarylethylenes from an a-stannyl b-silylstyrene through a combination of a Stille
coupling and a protodesilylation reaction is described. This approach avoids the problematic cine-substitution, which is a well
documented side reaction during the palladium-assisted elaboration of a-substituted vinylstannanes to 1,1-disubstituted ethylenes.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
R'
ArX
+
Ar
R3Sn
R'
Ar
R'
In one of our programs, we were interested in preparing
a family of diarylethylenes (1), in which the benzoate
moiety was kept constant (Fig. 1). One logical discon-
nection is at the aryl–alkene C–C bond, putatively
formed from vinylstannane 2 and an aryl halide or tri-
flate. A review of the literature however reveals that the
palladium-assisted coupling of vinylstannanes (3) with
electrophilic halides/triflates affords a mixture of ipso-
and cine-substituted products (Scheme 1).1;2 A number
of investigators have reported that for a given vinyl-
stannane, the ipso/cine ratio and the efficiency of the
reaction are influenced by the position of electron
withdrawing groups on the electrophilic halides and the
nature of the coupling conditions employed, among
other factors.3 It is not yet apparent how these factors
influence the ipso/cine selectivity based on the currently
accepted mechanism for the formation of the cine-
substituted products.4
"Pd"
3
5
4
Scheme 1. For example, R0 ¼ CO2Me, Ph; X ¼ Br, I.
Although optimizing Stille coupling conditions to min-
imize the formation of the cine-products from stannane
2 was considered, we elected instead to explore the
applicability of the readily accessible a-stannyl b-silyl-
styrenes (such as 8) in the preparation of the target
family of compounds. The seminal work of Mitchell
et al.5 and Chenard et al.6 has demonstrated that cis-a-
stannyl b-silylolefins can be prepared regio- and stereo-
selectively by the addition of R3SiSnR03 (e.g., R ¼ Me,
R0 ¼ n-Bu) to an alkyne, and that they would couple
with various electrophilic halides under Stille conditions.
There are reports on the further elaboration of the
resultant Stille products, that is, the 2,2-disubstituted
vinylsilanes,7 but to the best of our knowledge their
desilylation as an entry to 1,1-disubstituted ethylenes
has not been described. In this communication, we
report that 1,1-diarylethylenes can be synthesized from
an a-stannyl b-silylstyrene and aryl iodides or bromides,
in respectable yields, through a combination of Stille
coupling and protodesilylation protocols.
Ar
R3Sn
CO2Et
CO2Et
1
2
Figure 1.
2. Results and discussion
Keywords: 1,1-Diarylethylene; cine-Substitution; Stille coupling; Pro-
todesilylation.
Alkyne 7 was synthesized from iodide 6 under standard
conditions (Scheme 2). Addition of the commercially
* Corresponding author. Tel.: +1-203-677-6928; fax: +1-203-677-7702;
e-mail: makonen.belema@bms.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.106

1694
M. Belema et al. / Tetrahedron Letters 45 (2004) 1693–1697
TMS
TMS
I
(i)-(ii)
(95%)
(iii)
(iv)
(87%)
Bu3Sn
(91%)
CO2Et
CO2Et
CO2Et
CO2Et
7
9
6
8
Scheme 2. Reagents and conditions: (i) HCCTMS, Pd(Ph3P)4, CuI, Et3N, DMF, 25 °C; (ii) catalytic K2CO3, EtOH, 25 °C; (iii) n-Bu3SnTMS,
Pd(Ph3P)4, dioxane, D; (iv) 1% TFA/CH2Cl2.
available n-Bu3SnTMS across the alkyne bond of 7
afforded silylstannane 8 in a high yield. The regio- and
stereochemical assignments, which were based on the
works of Mitchell et al. and Chenard et al.,5;6 have been
confirmed by chemical and spectroscopic means. 1H
NMR revealed Sn/vinyl hydrogen J-couplings of 154
and 161 Hz, which are consistent with their trans-dis-
position.8 In addition, the treatment of silylstannane 8
with 1% TFA/CH2Cl2 afforded trans-silylstyrene 9,
which confirmed the regiochemical assignment.
For example, the desilylation of 11 was complete in
about 0.5 h, but required 22 h for 17. This is consistent
with the desilylation step involving a benzylic carbo-
cation, vide infra. Interestingly, when the incoming aryl
moiety was more electron rich, as was the case for
vinylsilane 20, the desilylation was complete in less than
10 min and the product (20a) began to pseudo-dimerize
(Scheme 4).12 The pseudo-dimer was assigned structure
24 based on HRMS and NMR studies, and the stereo-
chemistry of the olefin was not determined. Pseudo-
dimerization was not observed for the other aryl halides,
and it is believed that the electron-donating ability of the
p-methoxyphenyl group is responsible for such a reac-
tion. Milder acidic conditions (AcOH/50 °C/40 h) did
effect the desilylation of 20 cleanly, albeit slowly, with-
out any noticeable pseudo-dimerization. The desilyl-
ation of 21 was also conducted under similar conditions
and it was complete in about 22 h.
In a typical reaction, silylstannane 8 was coupled with
iodide 10 under palladium catalysis to afford vinylsilane
11 (Scheme 3).9;10 Although the stereochemical outcome
of this reaction was inconsequential for the next step,
NOE studies indicated that the coupling was stereo-
specific. However, vinylsilane 11 was susceptible to cis/
trans-isomerization when exposed to traces of acid (such
as the DCl present in CDCl3). The protodesilylation of
vinylsilane 11 with 10% TFA/CH2Cl2 afforded the
desired product (12) in a 73% overall yield.
Not surprisingly, the TFA/CH2Cl2 desilylation failed
when a pyridine moiety was present (see entry 10).
Vinylsilane 22 was stable to 10% TFA/CH2Cl2, and only
a minor amount of the desired product (22a) was
detected after 40 h of reaction time. Increasing the TFA
content from 10% to 20% made no significant difference.
It is believed that the protonation of the pyridine moiety
prevented the formation of the carbocation intermediate
(25) (Scheme 5). After several attempts, the desilylation
was cleanly effected under a microwave condition
(170 °C, AcOH, 6 h). The absence of the ester group
allows desilylation under milder and nonacidic condi-
tions. For example, vinylsilane 28, readily synthesized
from the commercially available alkyne 26, was desilyl-
ated cleanly with TBAF/THF (Scheme 6). Interestingly,
the same yield was obtained when the microwave pro-
cedure was applied to substrate 28. As noted above, the
overall yield of ethylene 29 reflects the efficiency of the
Stille coupling, and no attempt has been made to opti-
mize this step for substrate 27.
The two-step procedure described for iodide 10 was
applied to a set of aryl iodides (see entries 1–8 and 10 in
Table 1) and the following observations were made. For
entries 1–7, LC/MS analysis of the crude reaction mix-
ture indicated that, in general, the desilylation step
proceeded cleanly. Thus, the overall yield for the two-
step process reflects the efficiency of the Stille coupling
step. It is apparent that the coupling step tolerated a
number of functional groups, and that the yield eroded
noticeably in one case (entry 3) due to the steric inter-
ference of the ortho-carboxylate group. The main side
product from the Stille coupling was vinylsilane 9.11 It
was isolated in about 10% yield for entry 9, and in this
case we believe that the relatively acidic phenol-OH may
have helped the destannylation of silylstannane 8.
During the TFA/CH2Cl2 desilylation studies of the
various vinylsilane intermediates (11, 13–20, 22), it was
observed that the reaction time was inversely related to
the Ôelectron richnessÕ of the incoming aryl substrate.
The Stille condition employed for the aryl iodides
(Pd2dba3/CuI/Ph3As/DMF) failed for the corresponding
NOE
TMS
H
H
I
(i)
(ii)
(89%)
(82%)
CO2Et
CO2Et
10
11
12
Scheme 3. Reagents and conditions: (i) silylstannane 8, Pd2dba3, CuI, Ph3As, DMF, 50 °C; (ii) 10% TFA/CH2Cl2.

M. Belema et al. / Tetrahedron Letters 45 (2004) 1693–1697
Table 1. Conditions and yields for the synthesis of 1,1-diarylethylenes
1695
TMS
TMS
Ar
ArX
H
Ar
Bu3Sn
CO2Et
8
CO2Et
Xa
CO2Et
Diarylvinylsilane
Entry
ArX
Desilylationc
conditions
Final product
Yieldd
O
X
1
I
13
(i)
13a
66
2
3
PhX
I/Br
Ib
14
15
(i)
(i)
14a
15a
77/80
88
X
I
56
CO2Me
X
4
I
Br
16
(i)
16a
72
89
MeO2C
F3C
X
5
6
I
I
17
18
(i)
(i)
17a
18a
77
68
CF3
H
N
X
O
NC
X
7
8
I
Br
19
20
(i)
19a
20a
71
83
X
I
I
I
(ii)
72
64
73
O
HO
N
X
9
21
22
(ii)
21a
22a
X
10
(iii)
a For the Stille coupling of ArI and ArBr, [Pd2dba3, Ph3As, CuI, DMF, 50 °C] and [Pd(Ph3P)4, CuI, LiCl, DMF, 70 °C] were employed, respectively.
b The Stille coupling step was carried out under [Pd(Ph3P)4, CuI, LiCl, DMF, 70 °C].
c Desilylating conditions: (i) 10% TFA/CH2Cl2; (ii) AcOH, 50 °C, 24–40 h; (iii) AcOH, microwave at 170 °C for 6 h.
d Combined isolated yields for the Stille coupling and desilylation steps.
aryl bromides. After a careful study of catalysts/addi-
tives/solvents on a bromobenzene/silylstannane 8 sys-
tem, it was observed that the coupling could be effected
readily with Pd(Ph3P)4/CuI/LiCl/DMF (see entries 2, 4,
and 7). Compared to the aryl iodides, the aryl bromides
reacted cleanly under the new condition, and there was a
noticeable improvement in yields for entries 4 and 7.
Interestingly, when the new coupling condition was
applied to iodobenzene, the overall yield increased to
88% (see entry 2), suggesting a more effective catalyst
system.
In conclusion, we have devised a two-step protocol that
readily elaborates an a-stannyl b-silylstyrene to a family

1696
M. Belema et al. / Tetrahedron Letters 45 (2004) 1693–1697
observed with JSn–H ¼ 153.8 and 160.8), 4.37 (q, J ¼ 7.1,
R1
R2
2H), 1.57–1.37 (m, 9H), 1.29–1.22 (m, 6H), 0.92–0.83
(m, 15H), 0.18 (s, 9H). 13C NMR (125.8 MHz, CDCl3,
d ¼ 77.0): 166.8, 165.4, 156.8, 149.5, 129.4, 127.4, 125.8
H
R1
24
R2
H
H
- H+
TFA
Me
R1
(JSn–C ¼ 14.0), 60.8, 29.0 (JSn–C ¼ 19.7), 27.3 (JSn–C
¼
R1
R2
20a
R1
R2
60.4), 14.4, 13.6, 12.0 (JSn–C ¼ 330.3, 315.7), 0.12. MS
(CI) (M+H)þ ¼ 539.25. Anal. Calcd for C26H46O2SiSn:
C, 58.11; H, 8.63. Found: C, 58.46; H, 8.64.
R2
23
Scheme 4. R1 ¼ p-MeOPh; R2 ¼ p-EtO2CPh.
Vinylsilane 13:
A mixture of Pd2dba3 (15.9 mg,
0.017 mmol), Ph3As (20.0 mg, 0.065 mmol), and CuI
(11.0 mg, 0.058 mmol) was added to a DMF (4.0 mL)
solution of silylstannane 8 (300 mg, 0.558 mmol) and
7-iodo-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one
(195.2 mg, 0.650 mmol). After N2 was bubbled through
the reaction mixture for 2 min, it was stirred at room
temperature for 5 min and at 50 °C for 6 h. The volatile
components were removed in vacuo, and the residue was
submitted to flash chromatography (5% EtOAc/hex-
anes) to afford the desired compound (13) along with
minor impurities. Rechromatographing (20% CH2Cl2/
hexanes) afforded clean 13 as a viscous colorless oil
(162 mg, 69%). 1H NMR (500.1 MHz, CDCl3, d ¼ 7.26):
7.93 (d, J ¼ 8.5, 2H), 7.89 (d, J ¼ 2.0, 1H), 7.41 (d,
J ¼ 8.0, 1H), 7.32–7.30 (m, 3H), 6.39 (s, 1H), 4.36 (q,
J ¼ 7.0, 2H), 2.76 (t, J ¼ 6.8, 2H), 2.07 (t, J ¼ 6.8, 2H),
1.43 (s, 6H), 1.38 (t, J ¼ 7.0, 3H), 0.12 (s, 9H). 13C NMR
(125.8 MHz, CDCl3, d ¼ 77.0): 198.2, 166.4, 155.1,
151.9, 147.1, 140.1, 134.8, 133.4, 130.7, 129.5, 129.4,
128.3, 127.2, 125.6, 60.9, 37.1, 35.2, 33.9, 29.8, 14.3,
)0.1. MS (EI) (M+H)þ ¼ 421.2. Anal. calcd for
C26H32O3Si: C, 74.24; H, 7.67. Found: C, 73.96; H, 7.62.
H
TMS
H
TFA
22
-TMS
22a/H+
N
H
CO2Et
25
Scheme 5.
of 1,1-diarylethylenes. In order to expand the substrate
scope, a number of complementary Stille coupling and
desilylation protocols have been developed. Considering
the ease of synthesis of a-stannyl b-silylstyrenes and the
ipso/cine-substitution complications associated with the
Stille coupling, the approach communicated in this
manuscript should prove valuable in the synthesis of
1,1-diarylethylenes.
3. Representative procedures
Diarylethylene 13a: 10% TFA/CH2Cl2 (2.0 mL) was
added to vinylsilane 13 (140 mg, 0.333 mmol). The
resulting reaction mixture was stirred at room temper-
ature for 105 min and the volatile components were
removed in vacuo. The residue was submitted to flash
chromatography (10% EtOAc/hexanes) to afford
Final products were fully characterized with 1H/13C
NMR, MS, and either elemental analysis or HRMS.
The molecular ion of silylstannane 27 was not observed
1
in MS analysis, albeit the sample gave satisfactory H/
1
13C NMR and elemental analysis. Except for 11 and 13,
the vinylsilane intermediates were not characterized; for
these intermediates, only LC/MS data was obtained.
diarylethylene 13a as a viscous oil (110 mg, 95%). H
NMR (500.1 MHz, CDCl3, d ¼ 7.26): 8.02–8.00 (m, 3H),
7.44–7.36 (m, 4H), 5.58 (s, 1H), 5.55 (s, 1H), 4.39 (q,
J ¼ 7.1, 2H), 2.75 (app t, J ¼ 6.8, 2H), 2.04 (app t,
J ¼ 6.8, 2H), 1.41 (s, 6H), 1.40 (t, J ¼ 7.1, 3H). 13C
NMR (125.8 MHz, CDCl3, d ¼ 77.0): 198.3, 166.4,
152.0, 148.3, 145.6, 138.9, 133.5, 131.2, 129.9, 129.6,
128.1, 126.8, 126.0, 116.4, 61.0, 37.0, 35.2, 33.9, 29.7,
Silylstannane 8: Pd(Ph3P)4 (855 mg, 0.740 mmol) was
added to a 1,4-dioxane (90 mL) solution of alkyne 7
(8.32 g, 47.76 mmol) and n-Bu3SnTMS (19.95 g,
54.92 mmol), and the reaction mixture was refluxed for
35 min. The volatile components were removed in vacuo
and the residue was submitted to flash chromatography
(2.5% EtOAc/hexanes) to afford silylstannane 8 as a
colorless viscous oil (23.47 g, 91%). 1H NMR
(500.1 MHz, CDCl3, d ¼ 7.26): 7.94 (d, J ¼ 8.3, 2H), 7.02
(d, J ¼ 8.2, 2H), 6.56 (s, 1H; two satellite peaks were
14.4.
HRMS
(CI)
calcd
for
C23H25O3
(M+H)þ ¼ 349.1804, found 349.1793.
A general Stille coupling condition for aryl bromides:
LiCl (101 mg, 2.38 mmol) followed by a mixture of
Pd(Ph3P)4 (57.1 mg, 0.0494 mmol) and CuI (29.8 mg,
TMS
TMS
(iii) or (iv)
Ph
(i)
(ii)
Ph
Ph
Ph
SnBu3
27
(95%)
53% from 27
N
N
29
28
26
Scheme 6. Reagents and conditions: (i) n-Bu3SnTMS, Pd(Ph3P)4, dioxane, D; (ii) 3-iodopyridine, Pd2dba3, CuI, Ph3As, DMF, 50 °C; (iii) AcOH,
microwave at 170 °C, 5 h; (iv) TBAF/THF, 50 °C, <26 h.

M. Belema et al. / Tetrahedron Letters 45 (2004) 1693–1697
1697
Lett. 1996, 37, 6997–7000; (c) Fillion, E.; Taylor, N. J. J.
Am. Chem. Soc. 2003, 125, 12700–12701; (d) For an
alternative mechanism, see Ref. 2a.
0.156 mmol) were added to a DMF (6.0 mL) solution of
silylstannane 8 (534.2 mg, 0.994 mmol) and the aryl
bromide (1.23 mmol). N2 was bubbled through the
reaction mixture for 2 min, and it was heated at 70 °C
until the stannane was consumed as determined by TLC
and/or LC/MS. The product was isolated by employing
standard chromatographic techniques. The resultant
vinylsilane was submitted to the corresponding desilyl-
ation protocol described in Table 1, and the final product
was purified by a standard flash chromatography.
5. Mitchell, T. N.; Wickenkamp, R.; Amamria, A.; Dicke,
R.; Schneider, U. J. Org. Chem. 1987, 52, 4868–4874.
6. (a) Chenard, B. L.; Van Zyl, C. M.; Sanderson, D. R.
Tetrahedron Lett. 1986, 27, 2801–2804; (b) Chenard, B. L.;
Van Zyl, C. M. J. Org. Chem. 1986, 51, 3561–3566.
7. (a) Timbart, L.; Cintrat, J.-C. Chem. Eur. J. 2002, 8, 1637–
1640; (b) See also Refs. 5,6.
8. Tin has two NMR active isotopes, 117Sn and 119Sn, with a
natural abundance of 7.7% and 8.7%, respectively, and a
spin of 1/2: (a) Jackman, L. M.; Sternhell, S. In Applica-
tions of Nuclear Magnetic Resonance Spectroscopy in
Organic Chemistry. 2nd ed.; Pergamon: New York, NY,
1993; pp 354–356; (b) Leusink, A. J.; Budding, H. A.;
Marsman, J. W. J. Organomet. Chem. 1967, 9, 285–
294.
Acknowledgements
We thank Dr. Stella Huang and Dr. Daniel Schroeder
for conducting a number of NMR studies.
9. (a) Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113,
9585–9595; (b) Farina, V.; Kapadia, S.; Krishnan, B.;
Wang, C.; Liebeskind, L. S. J. Org. Chem. 1994, 59, 5905–
5911; (c) Ciattini, P. G.; Morera, E.; Ortar, G. Synth.
Commun. 1995, 25, 2883–2894; (d) The Stille coupling
failed when CuI was omitted, and everything else was kept
the same.
10. It was convenient to prepare and use a stock sample of a
Ôpre-mixedÕ catalyst by grinding together Pd2dba3/CuI/
Ph3As in the ratio indicated in the experimental section.
Such a mixture kept its catalytic activity for at least eight
weeks, when stored at ambient temperature.
References and notes
1. For cine-substitution in the coupling of vinylstannanes
with aryl halides, or arylstannanes with vinyl triflates, see:
(a) Stork, G.; Isaacs, R. C. A. J. Am. Chem. Soc. 1990,
112, 7399–7400; (b) Levin, J. I. Tetrahedron Lett. 1993, 34,
6211–6214; (c) Chen, S. Tetrahedron Lett. 1997, 38, 4741–
4744; (d) Quayle, P.; Wang, J.; Xu, J. Tetrahedron Lett.
1998, 39, 489–492; (e) Flohr, A. Tetrahedron Lett. 1998,
39, 5177–5180.
11. Although the presence of traces of acid may contribute to
protodestannylation, one study indicates that the interplay
of steric/electronic factors may also be important: Keay,
B. A.; Bontront, J.-L. J. Can. J. Chem. 1991, 69, 1326–
1330.
12. According to LC/MS monitoring of the desilylation step,
the following HPLC ratios of desired product 20a to
pseudo-dimer 24 were observed: 15.1/1.0 (at 10 min) and
1.0/2.4 (at 26.5 h). The LC/MS was conducted at 220 nm
wavelength.
2. For cine-substitution in the coupling of vinylstannanes
with diazonium salts, and a vinyl bromide with organozinc
reagents, see: (a) Kikukawa, K.; Umekawa, H.; Matsuda,
T. J. Organomet. Chem. 1986, 311, C44–C46; (b) Ennis, D.
S.; Gilchrist, T. L. Tetrahedron Lett. 1989, 30, 3735–3736.
3. (a) See Refs. 1b,c,e. (b) Han, X.; Stoltz, B. M.; Corey, E. J.
J. Am. Chem. Soc. 1999, 121, 7600–7605.
4. (a) Busacca, C. A.; Swestock, J.; Johnson, R. E.; Bailey,
T. R.; Musza, L.; Rodger, C. A. J. Org. Chem. 1994, 59,
7553–7556; (b) Farina, V.; Hossain, M. A. Tetrahedron