Palladium-catalyzed cross-coupling of alkynylzincs with allylic electrophiles: An efficient and selective synthesis of stereo- and regio-defined 1,4-enynes

Article abstract of DOI:10.1055/s-2005-871560

Clean and high-yielding cross-coupling of alkynylzincs with allylic chlorides, bromides, or acetates exhibiting ≥ 98% regio-and stereoselectivity can be achieved by using 1 mol% of Pd(DPEphos)Cl₂ and either 1:1 THF-DMF or pure DMF. This reaction provides a satisfactory route to 1,4-enynes via Pd-catalyzed alkynyl-allyl coupling. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871560

CLUSTER
1789
Palladium-Catalyzed Cross-Coupling of Alkynylzincs with Allylic
Electrophiles: An Efficient and Selective Synthesis of Stereo- and
Regio-Defined 1,4-Enynes
P
d-Catalyze
d
Cross-Co
i
upling
n
of
A
lkynylz
g
incs with A
l
x
i
hile
s
ng Qian, Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907-2084, USA
E-mail: negishi@purdue.edu
Received 24 February 2005
Abstract: Clean and high-yielding cross-coupling of alkynylzincs
with allylic chlorides, bromides, or acetates exhibiting ≥ 98% regio-
and stereoselectivity can be achieved by using 1 mol% of
Pd(DPEphos)Cl2 and either 1:1 THF–DMF or pure DMF. This re-
action provides a satisfactory route to 1,4-enynes via Pd-catalyzed
alkynyl-allyl coupling.
X
1% Pd(DPEphos)Cl2
70 °C
R
Product
Yield (%)
Me3Si
91
Solvent
E (%)
X
R
98.5
98
Cl
OAc
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
Me3Si 93
Key words: Pd-catalyzed alkynyl-allyl coupling, 1,4-enynes, alky-
nylzincs, allylic electrophiles, Pd(DPEphos)Cl2
OAc Ph
90
99
R
ZnBr
X
Despite the broad scope and wide synthetic applicability
of the Pd-catalyzed cross-coupling,1 the Pd-catalyzed
reaction of alkynylmetals with allylic electrophiles have
remained largely undeveloped.2,3 To the best of our
knowledge, only a couple of papers reporting low-yield-
ing and/or non-regioselective reactions of alkynylmetals
containing Mg3a or Sn3b with allylic halides catalyzed by
Pd complexes have been documented, although some
related alkynyl–allyl coupling reactions involving other
transition metals, such as Ni,3 Cu,4 and Zr,5 are also
known. Recent development of previously unknown,
clean, and high-yielding Pd-catalyzed alkynyl–benzyl
coupling reaction6,7 prompted us to develop related Pd-
catalyzed alkynyl–allyl coupling procedures.
1% Pd(DPEphos)Cl2
70 °C
R
Product
Yield (%)
Solvent
Z (%)
X
R
OAc
1:1 THF–DMF
DMF only
Me3Si 89
98
97
93
OAc Ph
Scheme 1
the presence of 5 mol% of Pd(PPh3)4 or Pd(PPh3)2Cl2 even
at 23 °C (entries 5 and 6). The use of only 1 mol% of
Pd(DPEphos)Cl2 in conjunction with a 1:1 THF–DMF at
23 °C improved the yield of 1 to 89% yield (entry 7). Even
though the corresponding reaction of allyl chloride at
23 °C was very sluggish (entry 8), heating the mixture to
70 °C gave 1 in 87% yield in 10 hours (entry 9). Under the
same conditions, the use of 5 mol% each of Pd(dppf)Cl2,
Pd(PPh3)2Cl2, Pd(t-Bu3P)2, and Pd(TFP)2Cl2, where TFP
is tris(o-furyl)phosphine, produced 1 in 72%, 56%, 46%,
and 14% yields, respectively. These and other related
results are summarized in Table 1.
We now report a high-yielding and highly regio- and
stereoselective method for Pd-catalyzed cross-coupling of
alkynylmetals with allylic electrophiles exemplified by
the results shown in Scheme 1. In addition to the use of
Zn1,2,7 and In6 as countercations, that of chelating
phosphines,8 such as DPEphos9 [bis(2-diphenylphos-
phinophenyl) ether] and dppf10 [1,1¢-bis(diphenylphos-
phino)ferrocene], as well as of DMF as a solvent or co-
solvent has proved to be crucial to the development of
satisfactory procedures.
Comparison of several other metal countercations under
the conditions optimized above was also made. The re-
sults summarized in Table 2 indicate that In is nearly as
satisfactory as Zn (entries 1 and 2). However, no satisfac-
tory results were obtained by using Mg3a (entry 3), Sn3b
(entry 4), and B (entry 5). Also unsatisfactory was the use
of PhC≡CH in the presence of 10 mol% of CuI and
various basic additives (entries 6–11).
The reaction of phenylethynylzinc bromide generated in
situ by treating PhC≡CLi with ZnBr2 (1 equiv) with allyl
bromide in THF in the presence of 5 mol% of Pd(PPh3)4
or Pd(DPEphos)Cl2 did not produce any detectable
amount of the desired product (1), i.e., PhC≡CCH2CH=
CH2, even at the refluxing temperature of THF (entry 4).
The use of a 1:1 mixture of THF–DMF as the solvent,
however, led to the formation of 1 in about 60% yield in
On the basis of the results presented above, treatment of
alkynylzinc bromides with allylic bromides, chlorides, or
acetates in the presence of 1 mol% of Pd(DPEphos)Cl2 in
1:1 THF–DMF at either 23 °C or 70 °C was chosen as a
satisfactory set of reaction conditions, and its synthetic
scope as a method for Pd-catalyzed alkynyl–allyl cou-
pling was investigated. As indicated by the results sum-
SYNLETT 2005, No. 11, pp 1789–1793
0
7
.0
7
.2
0
0
5
Advanced online publication: 27.06.2005
DOI: 10.1055/s-2005-871560; Art ID: Y00105ST
© Georg Thieme Verlag Stuttgart · New York

1790
M. Qian, E.-i. Negishi
CLUSTER
Table 1
Optimization of Reaction Conditions for Pd-Catalyzed Cross-Coupling of PhC≡CZnBr with XCH2CH=CH2
cat. PdLn
PhC CMLn
1.2 equiv
+ XCH2CH CH2
PhC CCH2CH CH2
solvent
Entry
1
X
PdLn
Solvent
Temp (°C)
Time (h)
Product yield (%)
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
5% Pd(PPh3)4
THF
23
70
23
70
23
23
23
23
70
70
70
70
70
4
10
4
<1
<1
<1
<1
60
61
89
<1
87
72
56
46a
14b
2
5% Pd(PPh3)4
THF
3
5% Pd(DPEphos)Cl2
5% Pd(DPEphos)Cl2
5% Pd(PPh3)4
THF
4
THF
10
10
10
4
5
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
6
5% Pd(PPh3)2Cl2
1% Pd(DPEphos)Cl2
1% Pd(DPEphos)Cl2
1% Pd(DPEphos)Cl2
5% Pd(dppf)Cl2
5% Pd(PPh3)2Cl2
5% Pd(t-Bu3P)2
7
8
4
9
10
10
16
16
16
10
11
12
13
5% Pd(TFP)2Cl2
a (PhC≡C)2 was formed in 55% yield.
b PhC≡CH was fully consumed.
Table 2 Effect of Metal Countercations on the Reactions of
PhC≡CMLn with XCH2CH=CH2 in the Presence of Pd(DPEphos)Cl2
marized in Table 3, this procedure is not only widely
applicable but also regio- and stereoselective. The follow-
ing points are noteworthy.
5 mol%
Pd(DPEphos)Cl2
PhC CMLn
1.2 equiv
+ XCH2CH CH2
PhC CCH2CH CH2
(i) Terminal alkynes containing various types of substitu-
ents including n-Hex, Ph, TBSOCH2, and Me3Si have
been satisfactorily allylated.
1:1 THF–DMF
Entry PhC≡CMLn
X
Temp Time Product
(°C)
70
70
70
70
70
70
70
70
70
70
70
(h)
10
10
10
10
10
10
10
10
10
24
24
yield (%)
(ii) Synthetically important g,g-disubstituted allyl deriva-
tives can be satisfactorily alkynylated (entries 8, 10, 12,
15, and 16). Thus, both geranyl and neryl chlorides and
acetates can be incorporated into the desired 1,4-enynes in
excellent yields with ≥ 97–98% retention of their regio-
chemical and stereochemical identities (Scheme 1). How-
ever, some puzzling exceptions also exist. For example,
the reaction of TBSOCH2C≡CZnBr with neryl chloride
did not proceed even in DMF at 70–150 °C (entry 20).
Fortunately, the corresponding reaction of neryl acetate in
DMF at 70 °C provided the desired product in 85% yield
by GLC (75% isolated) as a 92:8 mixture of the Z and E
isomers (entry 18), and the corresponding products
obtained with geranyl chloride and acetate are ≥ 97% E
(entries 15 and 16).
1
2
(PhC≡C)3In
(PhC≡C)3In
PhC≡CMgBr
PhC≡CSnBu3
Cl
Cl
Cl
Cl
Cl
78
76a
32
3
4
3
b
5
PhC≡CBLn
<1
6
PhC≡CH + 10% CuIc Cl
PhC≡CH + 10% CuIc OAc
PhC≡CH + 10% CuId Cl
PhC≡CH + 10% CuId OAc
PhC≡CH + 10% CuIe Cl
PhC≡CH + 10% CuIe OAc
<1
7
<1
8
<1
9
<1
10
11
32
(iii) (E)-Crotyl chloride and bromide purchased from a
commercial source were 95% and 85% regioisomerically
pure, respectively. Their alkynylation with PhC≡CZnBr
gave 93:7 and 83:17 regioisomeric mixtures, respectively,
of the linear and branched 1,4-enynes in good yields (en-
tries 5 and 6). The major product obtained from (E)-crotyl
chloride did not contain a detectable amount of the Z-iso-
mer. As promising as these results are, further clarifi-
12
a 1 mol% of Pd(DPEphos)Cl2 was used.
b Ln = B-MeO-9-BBN.
c Et2NH used as solvent.
d Piperidine used as an additive.
e Cs2CO3 used as an additive.
Synlett 2005, No. 11, 1789–1793 © Thieme Stuttgart · New York

CLUSTER
Pd-Catalyzed Cross-Coupling of Alkynylzincs with Allylic Electrophiles
1791
cation of the regio- and stereochemical details, especially 19 with entries 5, 12, 16, and 18, respectively, indicate
with isomerically pure (E)- and (Z)-crotyl derivatives, that, under comparable conditions, the reactions of alky-
e.g., acetates, is desirable.
nylindium derivatives are somewhat but unmistakably
less selective.
(iv) In a few cases (entries 5, 13, 17, and 19), tris(alky-
nyl)indiums were used in place of the corresponding alky-
nylzinc bromides. Comparisons of entries 7, 13, 17, and
Table 3 Scope of Allylation of Alkynylzinc Bromides and its Comparison with Tris(alkynyl)indiums in the Presence of 1 mol%
Pd(DPEphos)Cl2
1 mol% Pd(DPEphos)Cl2
+
XR2
R1C CMLn
1.2 equiv
R1C CR2
solvent
Entry
R1C≡CMLn
XR2
Solvent
Temp (°C)
Time (h)
R1C≡CR2 (%)a
87 (80)
89
1
2
3
4
5
6
7
8
PhC≡CZnBr
PhC≡CZnBr
n-HexC≡CZnBr
TMSC≡CZnBr
PhC≡CZnBr
PhC≡CZnBr
(PhC≡C)3In
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
70
23
23
23
70
23
70
70
10
4
Cl
Br
Br
Br
Cl
Br
Cl
4
80 (76)
84 (79)
84 (74)b
86 (79)c
75 (70)d
94 (87)e
4
10
4
10
10
PhC≡CZnBr
Cl
9
10
11
PhC≡CZnBr
PhC≡CZnBr
PhC≡CZnBr
1:1 THF–DMF
1:1 THF–DMF
1:1 THF–DMF
23
70
70
10
4
57e
90e
88f
Br
AcO
4
AcO
AcO
12
13
PhC≡CZnBr
(PhC≡C)3In
Pure DMF
Pure DMF
70
70
4
4
93 (89)g
89h
AcO
Cl
14
15
16
17
18
1:1 THF–DMF
Pure DMF
Pure DMF
Pure DMF
Pure DMF
70
70
70
70
70
10
4
62i
TBSO
TBSO
TBSO
TBSO
TBSO
CZnBr
95 (86)i
93i
CZnBr
CZnBr
Cl
4
AcO
AcO
4
88j
C
3In
4
85 (75)k
CZnBr
AcO
AcO
19
Pure DMF
70
4
81l
TBSO
C
3In
Synlett 2005, No. 11, 1789–1793 © Thieme Stuttgart · New York

1792
M. Qian, E.-i. Negishi
CLUSTER
Table 3 Scope of Allylation of Alkynylzinc Bromides and its Comparison with Tris(alkynyl)indiums in the Presence of 1 mol%
Pd(DPEphos)Cl2 (continued)
1 mol% Pd(DPEphos)Cl2
+
XR2
R1C CMLn
1.2 equiv
R1C CR2
solvent
Entry
20
R1C≡CMLn
XR2
Solvent
Temp (°C)
Time (h)
R1C≡CR2 (%)a
Pure DMF
Pure DMF
70
150
4
4
<1
<1
TBSO
CZnBr
Cl
a GLC yield. The number in parentheses is the isolated yield.
b (4E)-1-Phenyl-4-hexen-1-yne(A):3-methyl-5-phenyl-1-penten-4-yne(B) = 93:7. No Z-isomer of A detectable by NMR spectroscopy.
c A:B = 83:17.
d (4E)-1-Phenyl-4-hexen-1-yne:(4Z)-1-phenyl-4-hexen-1-yne = 75:25. No branched regioisomer detectable by NMR spectroscopy.
e E isomer ≥ 98%.
f Z:E = 81:19.
g Z:E = 97:3.
h Z:E = 94:6.
i E:Z = 97:3.
j E:Z = 89:11.
k Z:E = 92:8.
l Z:E = 89:11.
Finally, it has been observed that, even with a given set of with neryl acetate. It should also be noted that the use of
starting compounds, catalysts, and solvents, stereoselec- (Me3SiC≡C)3In leads to lower stereoselectivity figures
tivity can be significantly affected by catalyst loading. As than those observed with Me3SiC≡CZnBr.
the results summarized in Table 4 indicate, the high stere-
Representative Procedure
oselectivity level (≥ 98%) can be attained in the reaction
of Me3SiC≡CZnBr with geranyl and neryl electrophiles in
the presence of 1 mol% of Pd(DPEphos)Cl2. On the other
hand, the use of 0.1 mol% of Pd(DPEphos)Cl2 resulted in
significantly lower selectivity levels of 85–88% for the
reactions with geranyl electrophiles and only 72% for that
(4E)-1-Trimethylsilyl-5,9-dimethyl-4,8-decadien-1-yne.
To trimethylsilylacetylene (118 mg, 1.2 mmol) in THF (2 mL)
cooled to –78 °C was added n-BuLi (0.48 mL, 2.5 M in hexane, 1.2
mmol). The resultant solution was stirred for 30 min at –78 °C, fol-
lowed by addition of a solution of dry ZnBr2 (270 mg, 1.2 mmol) in
Table 4 Effects of Palladium Catalyst Loading on the Stereoselectivity of the Reaction of Me3SiC≡CMLn with Geranyl and Neryl Electro-
philes in the Presence of Pd(DPEphos)Cl2
cat. Pd(DPEphos)Cl2
1:1 THF-DMF, 70 °C
R1
R1
R2
+
MLn
Me3Si
R2
Me3Si
Time (h)
4
X
a
XCH2CH=CR1R2
Catalyst loading (mol%)
1.0
MLn
Yield of E and Z (%)b E:Z
ZnBr
In( SiMe3)2
91
90
98.5:1.5
97:3
Cl
0.1
1.0
0.1
1.0
24
4
86
80
85:15
80:20
ZnBr
In( SiMe3)2
Cl
93
93
98:2
94:6
ZnBr
In( SiMe3)2
AcO
AcO
24
4
90
80
88:12
86:14
ZnBr
In( SiMe3)2
89
88
2:98
8:92
ZnBr
In( SiMe3)2
AcO
AcO
0.1
24
89
80
28:72
33:64
ZnBr
In( SiMe3)2
a 1.2 molar equiv of Me3SiC≡CZnBr or 0.4 molar equiv of (Me3SiC≡C)3In was used.
b Yield by GLC.
Synlett 2005, No. 11, 1789–1793 © Thieme Stuttgart · New York

CLUSTER
Pd-Catalyzed Cross-Coupling of Alkynylzincs with Allylic Electrophiles
1793
THF (1 mL). After the mixture thus obtained had been stirred for 5
min at –78 °C and warmed to 0 °C over 25 min, geranyl chloride
(173 mg, 1.0 mmol), Pd(DPEphos)Cl2 (7.2 mg, 0.01 mmol), and
DMF (3 mL) were added at 23 °C. The resultant mixture was stirred
at 70 °C and monitored by GLC analysis. After 4 h, GLC analysis
indicated that the starting material had been completely consumed
and that the title compound was formed in 91% yield by GLC as a
98.5:1.5 mixture of the E and Z isomers. The reaction mixture was
quenched with 1 M HCl, extracted with Et2O, washed with aq
NaHCO3, dried over MgSO4, filtered, and concentrated. Flash chro-
matography (silica gel, hexane) afforded 204 mg (87%) of the title
compound. 1H NMR (300 MHz, CDCl3): d = 0.15 (s, 9 H), 1.61 (s,
6 H), 1.68 (s, 3 H), 2.00–2.10 (m, 4 H), 2.95 (d, J = 7.0 Hz, 2 H),
5.11 (t, J = 7.0 Hz, 1 H), 5.20 (t, J = 6.4 Hz, 1 H). 13C NMR (75
MHz, CDCl3): d = 0.12 (3 C), 16.06, 17.65, 19.01, 25.66, 26.42,
39.40, 83.64, 105.99, 118.67, 124.02, 131.49, 137.25. Anal. Calcd
for C15H26Si: C, 76.84; H, 11.18. Found: C, 76.66; H, 11.24.
References
(1) For extensive reviews of Pd-catalyzed cross-coupling, see
(a) Handbook of Organopalladium Chemistry for Organic
Synthesis, Vols. 1 and 2, Part III; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002, 215–1119. (b) Metal-
Catalyzed Cross-Coupling Reactions, Vols. 1 and 2; de
Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004.
(2) For a recent review on Pd-catalyzed alkynylation, see,
Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
(3) (a) Florio, S.; Ronzini, L.; Sgarra, R. Gazz. Chim. Ital. 1994,
124, 77. (b) Cui, D.-M.; Hashimoto, N.; Ikeda, S.; Sato, Y.
J. Org. Chem. 1995, 60, 5752.
(4) (a) Danheiser, R. L.; Gee, S. K. J. Org. Chem. 1984, 49,
1672. (b) Negishi, E.; Zhang, Y.; Cederbaum, F. E.; Webb,
M. B. J. Org. Chem. 1986, 51, 4080. (c) Jeffery, T.
Tetrahedron Lett. 1989, 30, 2225. (d) Matucera, E. D.; Erin,
A. S.; Kung, A. L. Russ. J. Org. Chem. 1997, 33, 1061.
(5) Yamanoi, S.; Imai, T.; Matsumoto, T.; Suzuki, K.
Tetrahedron Lett. 1997, 38, 3031.
(6) (a) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett. 1999,
1, 1267. (b) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am.
Chem. Soc. 2001, 123, 4155.
(4Z)-1-Trimethylsilyl-5,9-dimethyl-4,8-decadien-1-yne.
The title compound was prepared according to the Representative
Procedure except that neryl acetate was used in place of geranyl
acetate. The title compound was formed in 93% yield by GLC as a
98:2 mixture of the Z and E isomers.
(7) Qian, M.; Negishi, E. Tetrahedron Lett. 2005, 46, 2927.
(8) For recent papers from the authors’ group reporting
favorable effects of chelating phosphines in Pd-catalyzed
cross-coupling, see: (a) Shi, J.; Zeng, X.; Negishi, E. Org.
Lett. 2003, 5, 1825. (b) Zeng, X.; Hu, Q.; Qian, M.; Negishi,
E. J. Am. Chem. Soc. 2003, 125, 13636. (c) Shi, J.; Negishi,
E. J. Organomet. Chem. 2003, 687, 518. (d)Zeng, X.;Qian,
M.; Hu, Q.; Negishi, E. Angew. Chem. Int. Ed. 2004, 43,
2259. (e) Tan, Z.; Negishi, E. Angew. Chem. Int. Ed. 2004,
43, 2911. (f) Qian, M.; Huang, Z.; Negishi, E. Org. Lett.
2004, 6, 1531. (g) Novak, T.; Tan, Z.; Liang, B.; Negishi, E.
J. Am. Chem. Soc. 2005, 127, 2838. (h) Huang, Z.; Qian,
M.; Babinski, D. T.; Negishi, E. Organometallics 2005, 24,
475.
(4Z)-1-Phenyl-5,9-dimethyl-4,8-decadien-1-yne.
The title compound was prepared according to the Representative
Procedure except that phenylacetylene (122 mg, 1.2 mmol), neryl
acetate (196 mg, 1.0 mmol), and pure DMF were used. The title
compound was formed in 93% yield by GLC as a 97:3 mixture of
the Z- and E-isomers. The reaction mixture was quenched with 1 M
HCl, extracted with Et2O, washed with aq NaHCO3, dried over
MgSO4, filtered and concentrated. Flash chromatography (silica
gel, hexane) afforded 212 mg (89%) of the title compound. 1H NMR
(300 MHz, CDCl3): d = 1.61 (s, 3 H), 1.68 (s, 3 H), 1.73 (s, 3 H),
2.05–2.2 (m, 4 H), 3.12 (d, J = 7.0 Hz, 2 H), 5.14 (s, 1 H), 5.31 (t,
J = 5.90 Hz, 1 H), 7.20–7.45 (m, 5 H). 13C NMR (75 MHz, CDCl3):
d = 17.60, 18.33, 23.45, 25.66, 26.29, 31.91, 79.97, 88.97, 119.46,
123.91, 123.97, 127.43, 128.06 (2 C), 131.51 (2 C), 131.83, 137.53.
Anal. Calcd for C18H22: C, 90.70; H, 9.30. Found: C, 90.71; H, 9.27.
(9) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.;
van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J.
Organometallics 1995, 14, 3081.
(10) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi,
T.; Hirotsu, K. J. Am. Chem. Soc. 1984, 106, 158.
Acknowledgment
We thank the National Institutes of Health (GM 36792) and Purdue
University for support of this research.
Synlett 2005, No. 11, 1789–1793 © Thieme Stuttgart · New York