Suzuki arylation of 1,1-Dibromo-1-alkenes: Synthesis of tetra-substituted alkenes

Article abstract of DOI:10.1055/s-2001-10776

1,1-Dibromo-1-alkenes were coupled with a variety of aryl boronic acids using Suzuki conditions (PdCl₂(PPh₃)₂/Na₂CO₃/T HF-H₂O or DME-H₂O/65-90 °C). The 1,1-dibromo-1-alkenes were prepared from ketones, and thus, the overall process furnished tetra-substituted alkenes in a very efficient manner.

Full text of DOI:10.1055/s-2001-10776

254
LETTER
Suzuki Arylation of 1,1-Dibromo-1-alkenes: Synthesis of Tetra-substituted
Alkenes
Annette Bauer, Michael W. Miller,* Susan F. Vice, Stuart W. McCombie
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Rd., Kenilworth, New Jersey 07033-1300,
USA
Fax (908) 740-7441; E-mail: michael.miller@spcorp.com
Received 25 November 2000
R
Br
Br
R
Ph
Ph
4-6 eq.
PhB(OH)2
Abstract: 1,1-Dibromo-1-alkenes were coupled with a variety of
aryl boronic acids using Suzuki conditions (PdCl2(PPh3)2/Na2CO3/
THF-H2O or DME-H2O/65-90 °C). The 1,1-dibromo-1-alkenes
were prepared from ketones, and thus, the overall process furnished
tetra-substituted alkenes in a very efficient manner.
PdCl2(PPh3)2
Na2CO3
THF/H2O
70 °C
MeO2C
MeO2C
Key words: Suzuki reaction, cross-coupling, arylations, palladium,
alkenes
2a R = Me
R = H
1
3
R = Me
R = H
4
Scheme 1
1,1-Dibromo-1-alkenes have been utilized in various syn-
thetic transformations. Historically, they have been valu-
able intermediates for the synthesis of acetylenes from
aldehydes and ketones.1 More recently, 1,1-dihalo-1-alk-
enes have been used as electrophiles in palladium cata-
lyzed coupling reactions.2,3 In particular, most palladium
mediated reactions of 1,1-dihalo-1-alkenes, where one or
both electrophilic centers participate in the palladium cat-
alyzed step, produce functionalized, tri-substituted alk-
enes.4
yields of coupled products arising from acyclic dibromo-
alkenes II. The ester substituted derivative 1 was the ex-
ception which gave high yields of coupled product using
Method A.
Substitution on the aryl boronic acid was well tolerated.
Para- and meta-substituted aryl boronic acids gave higher
yields than ortho-substituted acids, presumably due to
steric crowding in the 1,1-bis-aryl alkenes formed. Elec-
tron donating (e.g. 4-CH3O) and electron withdrawing
(e.g. 4-F and 4-CF3) groups were tolerated in the aryl bo-
ronic acid. Hetero-aryl boronic acids also participated in
the reaction. Reactions with 4-pyridyl boronic acid were
somewhat sluggish and required the use of Pd(PPh3)4 in
DME/H2O (4/1) at 90 °C (Method B).10
In light of Shen’s recent reports on the Suzuki and Stille
arylation of 1,1-dibromo alkenes, derived from alde-
hydes,3a-c we wish to report our studies for the synthesis of
tetra-substituted alkenes utilizing a tandem dibromo-
olefination5/Suzuki arylation6 sequence. The 1,1-dibro-
mo-alkene 1, derived from the corresponding ketone, was
reacted with phenyl boronic acid (4-6 eq.) under Suzuki
arylation conditions (cat. PdCl2(PPh3)2/3 eq. Na2CO3/
THF-H2O) which furnished the tetra-substituted alkene 2a
in 95% yield.7 In related work, Shen and Wang described
the bis-arylation of the aldehyde derived 1,1-dibromo-alk-
ene 3, under Stille conditions, to give the tri-substituted
alkene 4 in quantitative yield.3b Treatment of 1,1-dibro-
mo-alkene 3 under the above mentioned Suzuki arylation
conditions gave a mixture of the tri-substituted alkene 4
and the arylated alkyne.8 We wished to explore the scope
of the bis-arylation of 1,1-dibromo-alkenes derived from
ketones under Suzuki arylation conditions.
R1
R2
Br
Br
R1
R2
Ar
Ar
R1
R2
Suzuki
dibromo-
O
Method
A or B
olefination
I
II
III
Method A: 4-6 eq. ArB(OH)2, PdCl2(PPh3)2, THF/H2O (4/1), 65 °C
Method B: 4-6 eq. ArB(OH)2, Pd(PPh3)4, DME/H2O (4/1), 90 °C
Scheme 2
The 1,1-dibromo-1-alkenes9 were coupled to various aryl
boronic acids under typical conditions for Suzuki cross
coupling (Table). The tetra-substituted alkenes III were
formed in moderate to excellent yields (24-95%). Acyclic
and cyclic 1,1-dibromo-1-alkenes II participated in the re-
action. In general, 1,1-dibromo-1-alkenes II derived from
cyclic ketones I underwent coupling more efficiently than
acyclic derivatives. The use of higher temperature and
Pd(PPh3)4 (Method B) was needed to afford reasonable
The Suzuki arylation of 1,1-dibromo-1-alkenes was toler-
ant of a variety of functional groups present in the alkene.
Methyl ester 1, ketal 13, ketone 15, oxime 17, and amide
19 underwent very efficient coupling with diverse boronic
acids (75-97%).
With reduced amounts (down to 1 eq.) of aryl boronic acid
under a variety of conditions (solvent/catalyst), tetrasub-
stituted olefin plus starting material were obtained.11 This
Synlett 2001, No. 2, 254–256 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Suzuki Arylation of 1,1-Dibromo-1-alkenes
255
Table
a Satisfactory spectra (1H and 13C NMR, HRMS) were obtained for the coupled products. Yields refer to isolated
yields (flash chromatography and/or preparative thin-layer chromatography).
Synlett 2001, No. 2, 254–256 ISSN 0936-5214 © Thieme Stuttgart · New York

256
A. Bauer et al.
LETTER
(5) Ramirez, F.; Desai, N.B.; McKelvie, N. J. Am. Chem. Soc.
indicates the mono-arylated intermediate is more suscep-
tible than the dibromo compound towards oxidative addi-
tion to Pd(0) and subsequent coupling to form the tetra-
substituted product. We continue to explore this and relat-
ed reactions for the synthesis of derivatives containing
two different aryl rings.
1962, 84, 1745.
(6) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Suzuki, A. J. Organomet. Chem. 1999, 576, 147.
(7) Representative example: A solution of dibromo-alkene 13
(100 mg, 0.32 mmol), PhB(OH)2 (137 mg, 1.1 mmol),
PdCl2(PPh3)2 (22 mg, 0.032 mmol), and Na2CO3 (102 mg,
0.96 mmol) were taken up in THF/H2O (4/1, 4 mL) and stirred
at 70 °C under N2 (17 h). The mixture was partitioned between
EtOAc and H2O. The aqueous layer was extracted with
EtOAc. The combined organic layers were washed with brine
and dried (Na2SO4). Filtration and concentration gave the
crude product. Purification via flash chromatography (9/1 to
4/1 hexanes/Et2O, SiO2) gave 87 mg (89%) of 14a as a
colorless solid. mp = 124 128 °C. 1H NMR (300 MHz,
CDCl3) 1.75 (t, 4 H, J = 6.6 Hz), 2.42 (t, 4 H, J = 6.0 Hz),
3.99 (s, 4 H), 7.12 7.32 (m, 10 H). 13C NMR (75.5 MHz,
CDCl3) 28.98, 36.27, 64.44, 108.85, 126.38, 128.06, 129.75,
136.16, 136.34, 142.85. HRMS (FAB) calcd for C21H22O2
(M+): 306.1620; Found: 306.1625. Note: No coupled product
was obtained in the absence of palladium.
In summary, this report describes the bis-Suzuki arylation
of 1,1-dibromo-1-alkenes derived from ketones. This
overall process results in a concise and efficient synthesis
of tetra-substituted alkenes. Further applications of this
methodology to both drug discovery and organic synthe-
sis are under investigation.
References and Notes
(1) For a recent review of synthesis/applications of 1,1-dihalo-
alkenes see: Eymery, F.; Iorga, B.; Savignac, P. Synthesis
2000, 185.
(2) Suzuki coupling: (a) Roush, W.R.; Moriarty, K.J.; Brown,
B.B. Tetrahedron Lett. 1990, 31, 6509. (b) Soderquist, J.A.;
Leon, G.; Colberg, J.C.; Martinez, I. Tetrahedron Lett. 1995,
36, 3119. (c) Baldwin, J.E.; Chesworth, R.; Parker, J.S.;
Russell, A.T. Tetrahedron Lett. 1995, 36, 9951. (d) Hanisch,
I.; Brückner, R. Synlett 2000, 374. Coupling with tin, zinc,
magnesium, and zirconium species: (e) Minato, A.; Suzuki,
K.; Tamao, K. J. Am. Chem. Soc. 1987, 109, 1257. (f) Minato,
A J. Org. Chem. 1991, 56, 4052. (f) Panek, J.S.; Hu, T. J. Org.
Chem. 1997, 62, 4912. (g) Xu, C.; Negishi, E. Tetrahedron
Lett. 1999, 40, 431. Sonogashira coupling with terminal
alkynes: (h) Ratovelomanana, V.; Hammoud, A.;
Linstrumelle, G. Tetrahedron Lett. 1987, 28, 1649. (i) Torii,
S.; Okumoto, H.; Tadokoro, T.; Nishimura, A.; Rashid, A.
Tetrahedron Lett. 1993, 34, 2139. (j) Neidlein, R.; Winter, M.
Synthesis 1998, 1362.
(3) (a) Shen, W. Synlett 2000, 737. (b) Shen, W.; Wang, L. J. Org.
Chem. 1999, 64, 8873. (c) Shen, W.; Thomas, S. Poster 212,
Division of Organic Chemistry Abstracts; 219 th ACS
National Meeting; San Francisco, CA; March 2000. For a
related Pd functionalization of 1,1-dibromo-alkenes into
isocoumarins by the same authors see: (d) Wang, L.; Shen, W.
Tetrahedron Lett. 1998, 39, 7625.
(8) Shen and Wang also describe the exclusive formation of
arylated acetylenes from 3 using amine bases during the Stille
coupling step (ref. 3b). Near the completion of our studies,
Shen reported the Suzuki mono-arylation of 1,1-dibromo-1-
alkenes, derived from aldehydes, which furnished tri-
substituted alkenes (ref. 3a).
(9) 1,1-Dibromo alkenes 1, 11, and 13 were prepared according
the standard methods (ketone/CBr4/PPh3) in ref. 5 and (a)
Corey, E.J.; Fuchs, P.L. Tetrahedron Lett. 1972, 3769. 1,1-
Dibromo alkenes 5, 7, and 9 were prepared by the method of
Savignac and Coutrot: (b) Savignac, P.; Coutrot, P. Synthesis
1976, 197. The dibromo alkene 15 was obtained by
deprotection (PPTS) of the corresponding ethylene ketal:
(c) Lambert, J.B.; Ciro, S.M. J. Org. Chem. 1996, 61, 1940.
(10) During our studies, it was noted that use of Method A for the
coupling of 4-pyridyl boronic acids with 1,1-dibromo-1-
alkenes resulted in little or no coupled product. This could be
due to the reluctance of the electron-poor pyridyl boronic acid
to undergo homocoupling with the Pd(II) species. This
process is essential for generating the Pd(0) species required
for coupling.
(11) Selective palladium catalyzed coupling of the (E)-bromide in
1,1-dibromo alkenes derived from aldehydes has been well
documented (see refs. 2a,c-g and 3a,b).
(4) Sonogashira coupling of 1,1-dibromo-1-alkenes derived from
cyclic ketones with terminal alkynes, which furnish tetra-
substituted alkenes, has been reported by Neidlein and Winter
(ref. 2j).
Article Identifier:
1437-2096,E;2001,0,02,0254,0256,ftx,en;S03500ST.pdf
Synlett 2001, No. 2, 254–256 ISSN 0936-5214 © Thieme Stuttgart · New York