Widely applicable Pd-catalyzed trans-selective monoalkylation of unactivated 1,1-dichloro-1-alkenes and Pd-catalyzed second substitution for the selective synthesis of E or Z trisubstituted alkenes

Article abstract of DOI:10.1002/anie.200503519

(Chemical Equation Presented) Double substitution: The first selective and widely applicable method for a step-wise alkylation of 1,1-dichloro-1-alkenes involving a cross-coupling double substitution using Pd-catalysis has been developed. This method provides an efficient and highly selective route for the synthesis of E or Z trisubstituted alkenes. dpephos = bis(o- diphenylphosphanylphenylether).

Full text of DOI:10.1002/anie.200503519

Communications
Cross-Coupling
DOI: 10.1002/anie.200503519
Widely Applicable Pd-Catalyzed trans-Selective
Monoalkylation of Unactivated 1,1-Dichloro-1-
alkenes and Pd-Catalyzed Second Substitution for
the Selective Synthesis of E or Z Trisubstituted
Alkenes**
Ze Tan and Ei-ichi Negishi*
Dedicated to Professor P. L. Fuchs
on the occasion of his 60th birthday
Since the discovery of the Pd-catalyzed highly trans-selective
monosubstitution of 1,1-dihalo-1-alkenes and the subsequent
second substitution to produce trisubstituted alkenes
[Eq. (1)],[1] its development as a method for not only the
selective synthesis of monosubstitution products[2] but also for
disubstitution products[1,2c,e,3–5] has attracted considerable
attention from synthetic chemists.
Although the development of the monosubstitution
reaction with aryl,[3] alkenyl,[4] and alkynyl metals[5] and
related nucleophiles has been reasonably successful, the Pd-
or Ni-catalyzed monoalkylation has not been,[6] except in one
isolated example, which consists of the Pd-catalyzed stepwise
double alkylation of b,b-dichlorostyrene with nBuZnCl (81%
yield) and then nHexMgBr (77% yield).[1] These results were
reproducible in our hands but could not be extended to a
similar stepwise dialkylation of alkyl-substituted 1,1-dichloro-
1-alkenes, such as 1,1-dichloro-1-octene. Under the influence
of 5 mol% of [PdCl2(dppb)] (dppb = 1,4-bis(diphenylphos-
phino)butane), its reaction with nOctZnBr produced only a
trace amount, if any, of (Z)-8-chloro-7-hexadecene, with (Z)-
8-(n-octyl)-7-hexadecene as practically the only product. The
tendency to produce dialkylation products is even more
pronounced in the corresponding reactions of 1,1-dibromo-1-
alkenes. Thus, even b,b-dibromostyrenes would produce only
[*] Dr. Z. Tan, Prof. E.-i. Negishi
Herbert C. Brown Laboratories of Chemistry
Purdue University, 560 Oval Drive
West Lafayette, IN 47907-2084 (USA)
Fax: (+1)765-494-0239
E-mail: negishi@purdue.edu
[**] We thank the National Science Foundation (grant CHE-0309613),
the National Institutes of Heath (grant GM36792), and Purdue
University for support of this research.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
762
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 762 –765

Angewandte
Chemie
their dialkylation products. Despite these disap-
pointing results, a systematic screening of Pd
catalysts, additives, and solvents was conducted,
which led to an optimized set of conditions that
involve 5 mol% of [PdCl2(dpephos)] (dpephos =
bis(o-diphenylphosphanylphenylether))[7]
and
dimethylformamide (DMF). In some cases, the
use of one molar equivalent of N-methylimidazole
(NMI)[8] relative to an alkyl zinc reagent has been
shown to further improve the yields. The results of
the trans-selective monoalkylation are summar-
ized in Table 1.
Scheme 1. Putative mechanistic scheme for the competitive formation of the mono- and
dialkylation products.
Although the intricate mechanistic details remain unclear,
the following features are worth mentioning: First, as long as
the combination of [PdCl2(dpephos)] and DMF, along with
one molar equivalent of NMI for some cases of monomethy-
lation, is used, various types of 1,1-dichloro-1-alkenes that
contain alkyl, aryl, alkenyl, and alkynyl groups as the R1
group can be satisfactorily monoalkylated for the first time
with alkyl zinc compounds containing Me, Et, and higher
linear and b-branched primary alkyl groups. Second, the
difference between dppb and dpephos ligands in the selective
monoalkylation of alkyl-substituted 1,1-dichloro-1-alkenes is
striking, and it is clear that competitive formation of the
disubstitution products is the major side reaction to be
minimized. This goal may be attained by suppressing the
second substitution through promotion of catalyst dissocia-
tion from the putative monosubstituted alkene–Pd p-complex
1 (Scheme 1).[9] The success observed with 1,1-dichloro-1-
alkenes but not with 1,1-dibromo-1-alkenes can also be
readily understood in these terms. Third, although unwanted,
the formation of the disubstitution product must undoubtedly
be responsible for the high stereoselectivity (ꢀ 98–99%)
attainable by Pd-catalyzed trans-selective monosubstitution
through kinetic resolution in the second stage of disubstitu-
tion, in which the undesired cis-monosubstituted isomer of 1
must be significantly more reactive than 1 itself. In this sense,
the observed formation of the disubstitution products must be
a blessing in disguise to a certain extent.
With the development of a widely applicable and sat-
isfactory protocol for the trans-selective monoalkylation of
1,1-dichloro-1-alkenes, the second substitution of relatively
unreactive internal Z chloroalkenes was investigated. In the
only reported case of a stepwise dialkylation using b,b-
dichlorostyrene,[1] the second alkylation was achieved by
using nHexMgBr and 1 mol% [NiCl2(dppp)] (dppp = 1,3-
bis(diphenylphosphino)propane). This procedure was very
satisfactory for the methylation of (Z)-2-chloro-1-phenyl-1-
decene with MeMgBr, thus provid-
ing the desired methylation product
Table 1: Pd-catalyzed trans-selective monoalkylation of 1,1-dichloro-1-alkenes with alkyl zinc compounds
in almost quantitative yield and
with > 98% stereoisomeric purity.
Its application to the methylation of
(Z)-8-chloro-7-hexadecene was also
high yielding, but the product was
essentially a 1:1 mixture of the E
and Z isomers (Scheme 2).[10] The
use of some other chelating ligands
containing the diphenylphosphino
group, such as dppf and dpephos,
did improve the stereoisomeric
ratio, but the highest E/Z ratio
never exceeded 6:1 (Scheme 2).
Fortunately, a recent development
of satisfactory procedures for the
Pd-catalyzed cross-coupling of
organochlorides through the use of
bulky trialkylphosphines[8,11] and
dialkylarylphosphines[12] came to
the rescue. Thus, when (7Z)-8-
chloro-7-hexadecene was treated
with MeMgBr in the presence of
5 mol% [Pd(tBu3P)2] at 508C for
6 h, the desired product of (7E)-8-
methyl-7-hexadecene was obtained
in 90% yield and with high stereo-
selectivity (E/Z = 97:3). Under the
and a catalytic amount of [PdCl2(dpephos)].
Entry R1
R2ZnX[a] (additive)
Conditions
T [8C]
Conditions
t [h]
Yield[b] [%]
Mono[c]
Di
50
15
13
<3
25
1
2
3
nHex
nHex
nHex
Me2Zn
70
55
50
23
16
10
6
20
20
6
50
75
76
85
70
76
85
80
85
83
90
Me2Zn–NMI[d]
Et2Zn
4
nHex
nOctZnBr
5
6
7
8
nHex
nOctCH(Me)CH2ZnBr 50
TBSOCH2CHMe
TBSOCH2CHMe
TBDPSO(CH2)2
Me2Zn–NMI[d]
Et2Zn
60
23
50
65
50
65
15
6
5[e]
nOctZnBr
20
16
24
7
12
12
10
5
9
TBSOCH(Me)CH2 Me2Zn–NMI[d]
10
11
TBSO(CH2)3
nOctZnBr
Me2Zn
12
Me2Zn
65
5
82
15
13
14
PhMe
Ph
2Zn
nOctZnBr
70
50
5
12
80
90
10
3
[a] Me2Zn and Et2Zn were purchased from Aldrich, R2ZnBr were prepared from R2I by lithiation with
tBuLi (2 equiv) and zincation withdry ZnBr . [b] Determined by GLC withan internal standard. [c] All
2
monoalkylated products were >98–99% isomerically pure, and their configurations were determined
by a combination of NMR techniques, including NOE interaction studies and chemical-shift analysis.
[d] NMI (1 equiv relative to Me2Zn) was added. [e] In addition to the disubstitution product, another by-
product identified as the dechlorinated monosubstitution product was produced in 8% yield.
Angew. Chem. Int. Ed. 2006, 45, 762 –765
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
763

Communications
same conditions, (3Z)-1-tert-butyldiphenylsilyloxy-4-chloro-
3-dodecene gave the desired methylation product in quanti-
tative yield as a 96:4 mixture of the E and Z isomers
(Scheme 2).
Even with the use of [Pd(tBu3P)2], however, Z chloro-
alkenes could not be alkylated in useful yields with higher
alkyl magnesium halides, such as nOctMgBr, with b-dehy-
drometallation and hydrogenolysis of the Z chloroalkenes as
the major side reactions. On the other hand, the use of Cy3P or
Cyp3P as ligands (Cy = cyclohexyl and Cyp = cyclopentyl,
respectively)[8,11] led to the formation of the desired alkylation
products in high yields (Scheme 3). Satisfactory results were
also observed with the use of [Fe(acac)3] (acac = acetylacet-
onate)[13] as a catalyst. As indicated by the results summarized
in Scheme 3, Pd complexes with Cy3P and Cyp3P appear to be
generally satisfactory catalysts for the second substitution
with Grignard reagents containing alkyl, aryl, alkenyl, and
allyl groups. In some favorable cases, even organozinc
reagents, such as PhZnBr, can successfully couple with the
Z chloroalkenes in the presence of a
Scheme 2. [Pd(tBu3P)2]-catalyzed cross-coupling of Z chloroalkenes with MeMgBr
for the synthesis of trans-trisubstituted alkenes.
Pd–Cyp3P complex. Despite all these
favorable results, the reaction of (Z)-
=
TBSOCH(Me)CH2CH C(Cl)Me
(TBS = tert-butyldimethylsilyl) with
ꢁ
nHexC CMgBr in the presence of
5 mol% of Pd(Cy3P)2 failed to pro-
duce the desired alkynylation prod-
ꢁ
uct. However, the use of Et3SiC CH
ꢁ
or iPr3SiC CH in MeCN in the pres-
ence of 2-dicyclohexylphosphino-
2’,4’,6’-triisopropyl-1,1’-biphenyl[12g]
(2; X-PHOS; purchased from Strem
Chemicals) proved to be reasonably
satisfactory.
Thus, for the first time, a selective
and widely applicable method for the
stepwise double substitution of 1,1-
dichloro-1-alkenes involving the first
trans-selective alkylation followed by
a second substitution with alkyl-, aryl-
, alkenyl-, allyl-, and alkynyl metal
compounds has been developed.
Although this protocol has not yet
been applied to the synthesis of
natural products, it promises to be
applicable to the synthesis of natural
products containing Z trisubstituted
alkenes, such as hennoxazole A,[14]
discodermolide,[15] and ratjadone.[16]
Experimental Section
General procedure for monoalkylation: A
flame-dried 25-mL round-bottomed flask
under argon was charged with 1,1-
dichloro-1-alkene
(1 mmol),
DMF
(3 mL), and [PdCl2(dpephos)] (35 mg,
0.05 mmol, 5 mol%). After the addition
of the organozinc reagent (1.2 mmol), the
reaction mixture was stirred at the appro-
Scheme 3. Cross-coupling of internal Z chloroalkenes with Grignard reagents or terminal alkynes in the
presence of Pd catalysts containing bulky trialkylphosphines or 2.
764
www.angewandte.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2006, 45, 762 –765

Angewandte
Chemie
priate temperature until gas–liquid chromatographic (GLC) analysis
indicated the disappearance of the starting material. The reaction
mixture was then quenched with diluted HCl. After extraction with
diethyl ether, the combined organic layers were washed with brine,
dried over MgSO4, filtered, and concentrated. The residue was
purified by flash column chromatography on silica gel to give the
desired product.
General procedure for the cross-coupling of the Z chloroalkenes
with Grignard reagents: A flame-dried 25-mL three-neck round-
bottomed flask under argon was charged with Pd(OAc)2 (11 mg,
0.05 mmol, 5 mol%), Cyp3P (24 mg, 0.1 mmol, 10 mol%), and THF
(2 mL). The mixture was stirred at 238C for 10 min and a Z
chloroalkene (1 mmol) was added followed by the Grignard reagent
(1.5 mmol). The flask was stirred at the appropriate temperature until
GLC analysis indicated the consumption of the starting material. The
mixture was allowed to cool to room temperature, quenched with
saturated NH4Cl, and extracted with diethyl ether. The combined
organic layers were washed with brine, dried over MgSO4, filtered,
and concentrated. The residue was purified by flash column
chromatography on silica gel to give the desired product.
General procedure for the cross-coupling of the Z chloroalkenes
with terminal alkynes: A flame-dried 25-mL three-neck round-
bottomed flask with a reflux condenser under argon was charged with
[PdCl2(MeCN)2] (8 mg, 0.03 mmol, 3 mol%), 2 (43 mg, 0.09 mmol,
9 mol%), and Cs2CO3 (812 mg, 2.5 mmol), followed by anhydrous
acetonitrile (3 mL) and the appropriate Z chloroalkene (1 mmol).
The slightly yellow suspension was stirred at 238C for 25 min. The
alkyne (1.5 mmol) was added by syringe, and the reaction mixture was
stirred in a heating bath at the desired temperature for the indicated
time. The mixture was allowed to cool to room temperature,
quenched with saturated NH4Cl, and extracted with diethyl ether.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel to give the desired product.
[10] The high stereoselectivity observed with b-chlorostyrenes could
be because of stabilization of the putative alkenyl nickel
intermediate through chelation by the phenyl group, which is
absent in the case of alkyl-substituted chloroalkenes.
[11] a) C. Dai, G. C. Fu, J. Am. Chem. Soc. 2001, 123, 2719; b) M. R.
Netherton, C. Dai, K. Neuschütz, G. C. Fu, J. Am. Chem. Soc.
2001, 123, 10099; c) J. H. Kirchhoff, C. Dai, G. C. Fu, Angew.
Chem. 2002, 114, 2025; Angew. Chem. Int. Ed. 2002, 41, 1945;
d) M. R. Netherton, G. C. Fu, Angew. Chem. 2002, 114, 4066;
Angew. Chem. Int. Ed. 2002, 41, 3910; e) J. H. Kirchhoff, M. R.
Netherton, I. D. Hills, G. C. Fu, J. Am. Chem. Soc. 2002, 124,
13662; f) A. F. Littke, G. C. Fu, Angew. Chem. 2002, 114, 4350;
Angew. Chem. Int. Ed. 2002, 41, 4176; g) K. Meuzel, G. C. Fu, J.
Am. Chem. Soc. 2003, 125, 3718; h) J. Y. Lee, G. C. Fu, J. Am.
Chem. Soc. 2003, 125, 5616; i) M. Eckhardt, G. C. Fu, J. Am.
Chem. Soc. 2003, 125, 13642; j) J. Zhou, G. C. Fu, J. Am. Chem.
Soc. 2003, 125, 14726.
[12] a) D. W. Old, J. P. Wolfe, S. L. Buchwald, J. Am. Chem. Soc.
1998, 120, 9722; b) J. P. Wolfe, R. A. Singer, B. H. Yang, S. L.
Buchwald, J. Am. Chem. Soc. 1999, 121, 9550; c) A. Aranyos,
D. W. Old, A. Kiyomori, J. P. Wolfe, J. P. Sadighi, S. L. Buchwald,
J. Am. Chem. Soc. 1999, 121, 4369; d) J. Yin, M. P. Rainka, X.
Zhang, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 1162;
e) H. N. Nguyen, X. Huang, S. L. Buchwald, J. Am. Chem. Soc.
2003, 125, 11818; f) D. Gelman, S. L. Buchwald, Angew. Chem.
2003, 115, 6175; Angew. Chem. Int. Ed. 2003, 42, 5993; g) J. E.
Milne, S. L. Buchwald, J. Am. Chem. Soc. 2004, 126, 13028.
[13] a) A. Fürstner, A. Leitner, M. Mendez, H. Krause, J. Am. Chem.
Soc. 2002, 124, 13856; b) A. Fürstner, M. MØndez, Angew.
Chem. 2003, 115, 5513; Angew. Chem. Int. Ed. 2003, 42, 5355;
c) M. Nakamura, K. Matsuo, S. Ito, E. Nakamura, J. Am. Chem.
Soc. 2004, 126, 3686; d) for Fe-catalyzed dialkylation and
reductive monoalkylation of 1,1-dichloro-1-alkenes, see: M.
Dos Santos, X. Franck, R. Hocquemiller, B. Figad›re, J. F.
Peyrat, O. Provot, J. D. Brion, M. Alami, Synlett 2004, 2697.
[14] a) T. Ichiba, W. Y. Yoshida, P. J. Scheuer, T. Higa, J. Am. Chem.
Soc. 1991, 113, 3173; b) P. Wipf, S. Lim, J. Am. Chem. Soc. 1995,
117, 558; c) D. R. Williams, D. A. Brooks, M. A. Berliner, J. Am.
Chem. Soc. 1999, 121, 4924; d) F. Yokokawa, T. Asano, T. Shiori,
Org. Lett. 2000, 2, 4169.
[15] a) S. P. Gunasekera, M. Gunasekera, R. E. Longley, G. K.
Schulte, J. Org. Chem. 1990, 55, 4912; b) J. B. Nerenberg, D. T.
Hung, P. K. Sommers, S. L. Schreiber, J. Am. Chem. Soc. 1993,
115, 12621; c) S. S. Harried, G. Yang, M. A. Strawn, D. C. Myles,
J. Org. Chem. 1997, 62, 6098; d) J. A. Marshall, B. A. Johns, J.
Org. Chem. 1998, 63, 7885; e) A. B. Smith, T. J. Beauchamp,
M. J. LaMarche, M. D. Kaufmann, Y. Qui, H. Arimoto, D. R.
Jones, K. Kobayashi, J. Am. Chem. Soc. 2000, 122, 8654; f) I.
Paterson, G. J. Florence, K. Gerlach, J. P. Scott, Angew. Chem.
2000, 112, 385; Angew. Chem. Int. Ed. 2000, 39, 377; g) A.
Arefolov, J. S. Panek, J. Am. Chem. Soc. 2005, 127, 5596.
[16] a) D. Schummer, K. Gerth, H. Reichenbach, G. Höfle, Liebigs
Ann. 1995, 685; b) U. Bhatt, M. Christmann, M. Quitschalle, E.
Claus, M. Kalesse, J. Org. Chem. 2001, 66, 1885; c) D. R.
Williams, D. C. Ihle, S. V. Plummer, Org. Lett. 2001, 3, 1383.
Received: October 5, 2005
Published online: December 20, 2005
Keywords: cross-coupling · Grignard reagents ·
.
homogeneous catalysis · organozinc reagents · phosphanes
[1] A. Minato, K. Suzuki, K. Tamao, J. Am. Chem. Soc. 1987, 109,
1257.
[2] a) W. R. Roush, K. J. Moriarty, B. B. Brown, Tetrahedron Lett.
1990, 31, 6509; b) W. R. Roush, K. Koyama, M. L. Martine, K. J.
Moriarty, J. Am. Chem. Soc. 1996, 118, 7502; c) A. Minato, J.
Org. Chem. 1991, 56, 4052; d) C. Xu, E. Negishi, Tetrahedron
Lett. 1999, 40, 431; e) W. Shen, L. Wang, J. Org. Chem. 1999, 64,
8873; f) M. Ogasawara, H. Ikeda, T. Hayshi, Angew. Chem. 2000,
112, 1084; Angew. Chem. Int. Ed. 2000, 39, 1042; g) M.
Ogasawara, H. Ikeda, T. Hayashi, Chem. Lett. 2000, 776; h) J.
Uenishi, K. Matsui, Tetrahedron Lett. 2001, 42, 4353; i) J.
Uenishi, K. Matsui, H. Ohmiya, J. Organomet. Chem. 2002,
653,141.
[3] J. Shi, E. Negishi, J. Organomet. Chem. 2003, 687, 518.
[4] a) X. Zeng, Q. Hu, M. Qian, E. Negishi, J. Am. Chem. Soc. 2003,
125, 13636; b) X. Zeng, M. Qian, Q. Hu, E. Negishi, Angew.
Chem. 2004, 116, 2309; Angew. Chem. Int. Ed. 2004, 43, 2259.
[5] J. Shi, X. Zeng, E. Negishi, Org. Lett. 2003, 5, 1825.
[6] J. S. Panek, T. Hu, J. Org. Chem. 1997, 62, 4914.
[7] P. W. N. M. van Leeuwen, P. C. J. Kamer, J. N. H. Reek, P.
Dierkes, Chem. Rev. 2000, 100, 2741.
[8] J. Zhou, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 12527.
[9] It is possible that the ethereal oxygen atom of dpephos may exert
a chelation effect to facilitate the dissociation of alkenes.
Angew. Chem. Int. Ed. 2006, 45, 762 –765
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
765