Palladium-catalyzed highly regio- and stereoselective synthesis of (1E)- or (1Z)-1,2-dihalo-1,4-dienes via haloallylation of alkynyl halides

Article abstract of DOI:10.1039/c0cc04879h

A highly efficient and selective synthesis of (1E)- or (1Z)-1,2-dihalo-1,4- dienes via Pd-catalyzed coupling of haloalkynes and allylic halides is described. The (1E)-1,2-dihalo-1,4-dienes were generated in good yields with excellent stereoselectivities (1E/1Z up to >98/2), while (1Z)-1,2-dihalo-1,4- dienes were produced in excellent yields and stereoselectivities (1Z/1E up to >98/2) by simply adding stoichiometric lithium halides.

Full text of DOI:10.1039/c0cc04879h

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COMMUNICATION
Palladium-catalyzed highly regio- and stereoselective synthesis of (1E)-
or (1Z)-1,2-dihalo-1,4-dienes via haloallylation of alkynyl halidesw
Xiaoyi Chen, Wei Kong, Haiting Cai, Lichun Kong and Gangguo Zhu*
Received 9th November 2010, Accepted 10th December 2010
DOI: 10.1039/c0cc04879h
A highly efficient and selective synthesis of (1E)- or (1Z)-1,2-
dihalo-1,4-dienes via Pd-catalyzed coupling of haloalkynes and
allylic halides is described. The (1E)-1,2-dihalo-1,4-dienes were
generated in good yields with excellent stereoselectivities (1E/1Z
up to >98/2), while (1Z)-1,2-dihalo-1,4-dienes were produced in
excellent yields and stereoselectivities (1Z/1E up to >98/2) by
simply adding stoichiometric lithium halides.
Table 1 Optimization of the reaction conditions for the haloallyla-
tion of phenylethynyl bromidea
Entry PdX2
Solvent
LiBr/equiv. Yieldb (%) E/Zc
1
2
3
4
5
6
7
8
Pd(OAc)2 THF
/
/
/
/
/
/
/
1.0
1.0
1.0
2.0
5.0
76
70
60
84
85
79
82
86
60
73
80
74
98/2
Transition-metal-catalyzed carbon–carbon or carbon–heteroatom
bond formation is a central theme in organic synthesis.1 In
particular, the halopalladation reaction of acetylenes has
attracted dramatic interests in the past decades, since it has
proven to be a powerful method for the highly efficient and
atom-economic formation of carbon–carbon and carbon–
halide bonds in a single step.2 Despite the great success
achieved along the line with halopalladation of electronic- or
steric-unbalanced acetylenes, such as terminal alkynes,3 the
alkynes containing electron-withdrawing3a–f or coordination
groups,4,5 the halopalladation of unsymmetrical internal
alkynes remains to be challenging. In our efforts to develop
new reactions involving the halopalladation process,6 we report
herein the first palladium-catalyzed haloallylation7 reaction of
alkynyl halides, in which regio- and stereodefined 1,2-dihalo-
1,4-dienes were efficiently synthesized.
Pd(OAc)2 DMF
Pd(OAc)2 MeCN
Pd(OAc)2 Toluene
Pd(OAc)2 CH2Cl2
23/77
42/58
>98/2
>98/2
>98/2
>98/2
97/3
PdCl2
PdBr2
CH2Cl2
CH2Cl2
Pd(OAc)2 CH2Cl2
Pd(OAc)2 DMF
Pd(OAc)2 HOAc
Pd(OAc)2 HOAc
Pd(OAc)2 HOAc
9
16/84
5/95
10
11
12
o3/97
o2/98
a
Reaction conditions: 1a (0.5 mmol), 2a (0.75 mmol) and Pd
b
catalyst (0.025 mmol) in 2 mL of solvent at 23 1C. Isolated yields.
Determined by GC.
c
stereoselectivities (entries 4 and 5, Table 1). CH2Cl2 was then
chosen as the solvent and other palladium reagents, such as
PdBr2 and PdCl2, were tested as the catalyst, unfortunately,
the products were produced in lower yields (entries 5 and 6,
Table 1). Therefore, we selected 5 mol% of Pd(OAc)2 as the
catalyst and CH2Cl2 as the solvent as the optimized condition
A for the cis-haloallylation reaction of haloalkynes.
To explore the haloallylation reaction of haloalkynes,
phenylethynyl bromide (1a) and allyl bromide (2a) were
chosen for the initial screening. In the presence of 5 mol%
of Pd(OAc)2 as a catalyst, the starting materials were
completely consumed within 30 min at room temperature in
THF, providing 3aa in 76% yield with a high E-stereoselectivity
(E/Z = 98/2 by GC). Encouraged by this result, we looked
further into the reaction conditions and the results are
summarized in Table 1.
While now we have the condition A for the efficient and
selective synthesis of (E)-3aa, we wish to obtain (Z)-3aa
through introducing additional halide sources, since it is
known that the halopalladation reaction may undergo trans-
addition in the presence of halides, in sharp contrast to the
well-documented cis-insertion in the absence or at low concen-
trations of halides.8 As such, the reactions were performed in
the presence of halides, and as expected, the addition of 1.0
equiv. of LiBr increased the selectivity of the (Z)-isomer from
77% to 84% in DMF (entries 2 vs. 9, Table 1). The use of
HOAc as the solvent further raised the selectivity of (Z)-3aa to
95% (entry 10, Table 1). Increasing the amount of LiBr did
improve the selectivity; however, a relatively lower yield was
observed using 5.0 equiv. of LiBr as an additive, due to the
generation of the homocoupling product of 1a (entries 11
and 12, Table 1). The stereochemistry of the haloallylation
We first checked the solvents for this reaction. Polar
solvents such as acetonitrile and N,N-dimethylformamide
(DMF) favored the formation of the Z-isomer (entries 2 and
3, Table 1), whereas non-coordinating solvents, such as
toluene and CH2Cl2, significantly increased the yields and
Department of Chemistry, Zhejiang Normal University, 688 Yingbing
Road, Jinhua 321004, PR China. E-mail: gangguo@zjnu.cn;
Fax: +86 579-82282610; Tel: +86 579-82283702
w Electronic supplementary information (ESI) available: Experimental
details and characterization of new compounds. See DOI: 10.1039/
c0cc04879h
c
2164 Chem. Commun., 2011, 47, 2164–2166
This journal is The Royal Society of Chemistry 2011

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Table 2 Pd-catalyzed haloallylation of haloalkynes with 2aa
Table 3 Pd-catalyzed haloallylation of haloalkynes with various
allylic chloridesa
Entry
1
R
X
Cond.
3
Yieldb (%) E/Zc
Entry
1
1
2
Cond. Product
A
Yield/%b
1
2
3
4
5
6
1a Ph
1a Ph
1b Ph
1b Ph
1c TBSO(CH2)2
1c TBSO(CH2)2
1d TBSO(CH2)2
1d TBSO(CH2)2
1e CH2OAc
1f C9H19
Br
Br
Cl
Cl
Br
Br
Cl
Cl
Br
Br
A
B
A
B
A
B
A
B
A
A
A
A
A
(E)-3aa 85
(Z)-3aa 80
(E)-3ba 83
(Z)-3ba 81
(E)-3ca 65
(Z)-3ca 62
(E)-3da 84
(Z)-3da 68
(E)-3ea 62
(E)-3fa 86
(E)-3ga 66
(E)-3ha 78
(E)-3ia 76
>98/2
o3/97
>98/2
o2/98
>98/2
o2/98
>98/2
o2/98
>98/2
>98/2
>98/2
>98/2
>98/2
1a 2b
1a 2b
1b 2b
1b 2b
(E)-3ab 85 (>98/2)c
2
3
4
B
A
B
(Z)-3ab 80 (11/89)c
(E)-3bb 89 (>98/2)c
(Z)-3bb 83 (o2/98)c
7
8c
9
10
11
12
13
1g 1-Cyclohexenyl Br
1h p-OMe–C6H4
1i p-Cl–C6H4
Br
Br
14
1j
Br
A
(E)-3ja 91
>98/2
5
6
7
1c 2b
1c 2b
1i 2b
A
B
(E)-3cb 81 (>98/2)c
(Z)-3cb 72 (o2/98)c
(E)-3ib 90 (>98/2)c
a
Cond.
A = 1 (0.5 mmol), 2a (0.75 mmol) and Pd(OAc)2
(0.025 mmol) in 2 mL of CH2Cl2 at 23 1C; cond. B = 1 (0.5 mmol),
2a (0.75 mmol), Pd(OAc)2 (0.025 mmol) and LiBr (1.0 mmol) in 2 mL
b
c
of HOAc at 23 1C. Isolated yields. Determined by GC.
A
products (E)-3aa and (Z)-3aa was established by NOE
measurements and consistent with the related literature report.9
Thus, for the trans-haloallylation products, we chose 5 mol% of
Pd(OAc)2 as the catalyst, 2.0 equiv. of lithium halides as the
additives and HOAc as the solvent for the standard condition B.
With the optimized reaction conditions A and B in hand, we
next turned our attention to the scope of the haloallylation
reaction. As shown in Table 2, both bromoalkynes and chloro-
alkynes are good coupling partners for this Pd-catalyzed
bromoallylation transformation. For example, phenylethynyl
chloride (1b) reacted with 2a in the same fashion as 1a, and
afforded the cis-allylation product (E)-3ba in 83% yield with
excellent stereoselectivity (E/Z > 98/2) under the optimized
condition A, or furnished the trans-allylation adduct (Z)-3ba in
81% yield and with Z/E > 98/2 selectivity if the optimized
condition B was employed (entries 3 and 4, Table 2). The
conventional protecting groups, such as tert-butyldimethylsilyl
(TBS) and acetyl (Ac), could be well tolerated under the reaction
conditions (entries 5À9, Table 2). Aliphatic haloalkynes also
participated well in this reaction. Both the primary and secondary
alkyl substituted bromoalkynes 1f and 1g could undergo the same
reaction to give (E)-3fa and (E)-3ga in 86 and 66% yields,
respectively (entries 10 and 11, Table 2). We also examined the
electronic effects on the aromatic rings and found that both
electron-rich and electron-deficient aromatic haloalkynes were
smoothly converted into the desired products in good yields and
excellent stereoselectivities (entries 12À14, Table 2).
8
1f 2b
1f 2c
1b 2c
A
A
B
(E)-3fb 81 (>98/2)c
(E)-3bc 83 (>98/2)c
(Z)-3bc 72 (o2/98)c
9
10
11
1b 2d
1a 2e
A
A
(E)-3bd 39 (>98/2)c
12
3ae
67 (50/50)d
a
Cond. A = 1 (0.5 mmol), Pd(OAc)2 (0.025 mmol) and 2 (0.75 mmol)
in 2 mL of CH2Cl2 at 23 1C; cond. B = 1 (0.5 mmol), Pd(OAc)2
(0.025 mmol), 2 (0.75 mmol) and LiBr or LiCl (1.0 mmol) in 2 mL of
b
c
d
HOAc at 23 1C. Isolated yields. The ratio of 1E/1Z. The ratio of
4E/4Z.
2-chloro-substituted allyl chloride (2d) afforded (E)-3bd in only
39% yield (entry 11, Table 3). The sharp contrast suggested great
electronic effect on the electrophiles: the more electron-rich allyl
halides are, the better reactivity they exhibited towards the
halopalladation reaction. As for the secondary allylic chloride,
3-chloro-1-heptene (2e), for example, provided the bromo-
allylation product 3ae in 67% yield with 50 : 50 mixture of
Z : E isomers (entry 12, Table 3). Allyl halides having an internal
CÀC double bond, such as crotyl bromide 2f and cinnamyl
bromide 2g, failed to give the desired products.
The versatility of this protocol was further demonstrated by the
reactions of various allylic halides (Table 3). Allyl chloride (2b)
reacted smoothly with numerous alkynyl halides to give the
corresponding 1,2-dihalo-1,4-diene products in good yields (entries
1À8, Table 3). While 2-methyl-substituted allyl chloride (2c)
afforded the desired (E)-3bc and (Z)-3bc in 83 and 72%
yields, respectively (entries 9 and 10, Table 3), interestingly,
Therefore, we have been able to develop a rather practical,
efficient, and most importantly, highly versatile method for the
c
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Chem. Commun., 2011, 47, 2164–2166 2165

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with palladium-catalyzed haloallylation of alkynyl halides as
the key step. This procedure is a significant advance in
the halopalladation reaction because it represents the first
regio- and stereoselective halopalladation process of the
electron-rich internal alkynes. Further investigation of the
reaction mechanism, as well as the synthetic applications of
this protocol for the establishment of tetrasubstituted alkenes
are currently in progress.
Scheme 1 Two possible pathways for 1,2-dihaloalkenes.
We thank the National Natural Science Foundation of China
(No. 20902084), Qianjiang Talents Project of the Science and
Technology Office in Zhejiang Province (2010R10016) and
Zhejiang Normal University for their financial support.
Notes and references
1 (a) A. de Meijere and F. Diederich, Metal-Catalyzed Cross-
Coupling Reactions, Wiley-VCH, Weinheim, Germany, 2004, vol.
1; (b) J. F. Hartwig, Acc. Chem. Res., 2008, 41, 1534; (c) G. C. Fu,
Acc. Chem. Res., 2008, 41, 1555.
Scheme 2 Proposed mechanism for the haloallylation of alkynyl
halides.
2 For halopalladation reviews, see: (a) J. Tsuji, Palladium Reagents
in Organic Synthesis, Academic Press, New York, 1985; (b) X. Lu,
Handbook of Organopalladium Chemistry for Organic Synthesis, ed.
E.-I. Negishi, John Wiley & Sons, Hoboken, NJ, 2002, vol. 2,
p. 2267 and references therein.
3 (a) K. Kaneda, F. Kawamoto, Y. Fujiwara, T. Imanaka and
S. Teranishi, Tetrahedron Lett., 1974, 15, 1067; (b) K. Kaneda,
T. Uchiyama, Y. Fujiwara, T. Imanaka and S. Teranishi, J. Org.
Chem., 1979, 44, 55; (c) A. N. Thadani and V. H. Rawal, Org.
Lett., 2002, 4, 4317; (d) A. N. Thadani and V. H. Rawal, Org.
Lett., 2002, 4, 4321; (e) J. Huang, L. Zhou and H. Jiang, Angew.
Chem., Int. Ed., 2006, 45, 1945; (f) H. Jiang, X. Liu and L. Zhou,
Chem.–Eur. J., 2008, 14, 11305; (g) H. Jiang, C. Qiao and W. Liu,
Chem.–Eur. J., 2010, 16, 10968.
synthesis of 1,2-dihalogenated (E)- or (Z)-1,4-dienes, depending
on the condition A or B employed. Even though 1,2-dihaloalkenes
are valuable synthetic building blocks in organic synthesis,
there are not too many methods available for their synthesis.
Considering the relatively easy preparation of trans-1,2-
dihaloalkenes from the electrophilic halogenation of alkynes,10
there are rather limited examples for the synthesis of cis-1,2-
dihaloalkenes,11 especially the differentially halogenated ones
(Scheme 1). However, with the optimized conditions A and B
presented here, we can easily synthesize both trans- and cis-
1,2-dihalo-1,4-dienes in a highly regio- and stereoselective
fashion. In addition, the resulting 1,2-dihalo-1,4-dienes could
serve as useful intermediates for the rapid synthesis of
stereodefined tetrasubstituted alkenes,12 which represent
another challenging targets in organic synthesis. Further
development of our methods towards the synthesis of these
targets is on the way.
4 (a) S. Ma, B. Wu and S. Zhao, Org. Lett., 2003, 5, 4429; (b) S. Ma,
B. Wu and X. Jiang, J. Org. Chem., 2005, 70, 2588.
5 For intramolecular halopalladation processes, see: (a) S. Ma and
X. Lu, J. Chem. Soc., Chem. Commun., 1990, 733; (b) S. Ma and
X. Lu, J. Org. Chem., 1991, 56, 5120; (c) S. Ma, G. Zhu and X. Lu,
J. Org. Chem., 1993, 58, 3692; (d) S. Tang, Q.-F. Yu, P. Peng, J.-H. Li,
P. Zhong and R.-Y. Tang, Org. Lett., 2007, 9, 3413; (e) X.-C. Huang,
F. Wang, Y. Liang and J.-H. Li, Org. Lett., 2009, 11, 1139; (f) G. Yin
and G. Liu, Angew. Chem., Int. Ed., 2008, 47, 5442; (g) T. R. Hoye and
J. Wang, J. Am. Chem. Soc., 2005, 127, 6950.
The possible mechanism for this Pd-catalyzed haloallylation
of alkynyl halides is proposed in Scheme 2. The dichotomy of
this process originates from the observation that halopalladation
can undergo a cis- or trans-pathway under different reaction
conditions.
6 G. Zhu and Z. Zhang, J. Org. Chem., 2005, 70, 3339.
7 For a radical-mediated haloallylation of acetylenes, see: T. Kippo,
T. Fukuyama and I. Ryu, Org. Lett., 2010, 12, 4006.
8 (a) S. Ma and X. Lu, J. Org. Chem., 1993, 58, 1245;
(b) J.-E. Backvall, Y. I. M. Nilsson and R. G. P. Gatti, Organo-
¨
metallics, 1995, 14, 4242; (c) Q. Zhang, W. Xu and X. Lu, J. Org.
Chem., 2005, 70, 1505.
In the absence of halides, haloalkyne 1 reacted with the
Pd–X bond in a cis-insertion pathway to give an alkenyl
palladium intermediate IA. The excellent regioselectivity in
this step may come from the relatively small steric hindrance
of the halogen atom compared with the carbon chain or
aromatic ring.13 Then, IA underwent carbopalladation with
allylic halides to afford alkyl palladium intermediate IIA,
followed by the b-heteroatom elimination to furnish the cis-
haloallylation product (E)-3 and to regenerate the palladium
catalyst (path A, Scheme 2).
9 It is worth mentioning that the chemical shifts for the methylene
protons of the allyl groups in cis-1,2-dihaloalkene products are
shifted upfield when compared to that of the trans-isomer, which is
consistent with the corresponding analogues, see: R. Bianchini,
C. Chiappe, G. Lo Moro, D. Lenoir, P. Lemmen and N. Goldberg,
Chem.–Eur. J., 1999, 5, 1570.
10 (a) A. B. Lemay, K. S. Vulic and W. W. Ogilvie, J. Org. Chem., 2006,
71, 3615; (b) K. Schuh and F. Glorius, Synthesis, 2007, 2297;
(c) U. Nubbemeyer, Sci. Synth., 2008, 32, 57 and references therein.
11 N. Henaff and A. Whiting, J. Chem. Soc., Perkin Trans. 1, 2000, 395.
´
12 For reviews of tetrasubstituted alkenes, see: (a) A. B. Flynn and
W. W. Ogilvie, Chem. Rev., 2007, 107, 4698; (b) E.-I. Negishi,
Z. Huang, G. Wang, S. Mohan, C. Wang and H. Hattori, Acc.
Chem. Res., 2008, 41, 1474. For the preparation of tetrasubstituted
alkenes from 1,2-dihaloalkenes, see: (c) R. Rathore,
M. I. Deselnicu and C. L. Burns, J. Am. Chem. Soc., 2002, 124,
14832; (d) M. G. Organ, H. Ghasemi and C. Valente, Tetrahedron,
2004, 60, 9453; (e) J. Simard-Mercier, A. B. Flynn and
W. W. Ogilvie, Tetrahedron, 2008, 64, 5472; (f) C.-G. Dong,
T.-P. Liu and Q.-S. Hu, Synthesis, 2008, 2650.
On the other hand, the present excess halides could undergo
SN2-like reaction to attack Pd(II)-activated alkynyl halides in
polar solvents and resulted in the trans-halopalladation adduct
IB. Then, the same carbopalladation-b-heteroatom elimination
sequence gave the trans-haloallylation product (Z)-3 (path B,
Scheme 2).
In summary, we have developed an efficient and practical
procedure for the synthesis of (1E)- or (1Z)-1,2-dihalo-1,4-dienes
13 G. Zweifel and H. Arzoumanian, J. Am. Chem. Soc., 1967, 89, 5086.
c
2166 Chem. Commun., 2011, 47, 2164–2166
This journal is The Royal Society of Chemistry 2011