Palladium-catalyzed cross-coupling reaction of alkynylzincs with benzylic electrophiles

Article abstract of DOI:10.1016/j.tetlet.2005.02.137

The reaction of alkynylzinc bromides with benzyl bromides or chlorides in the presence of a catalytic amount of Pd(DPEphos)Cl₂ in THF at 23°C cleanly produces the corresponding benzylated alkynes in 73-97% yields. With 10^-3 mol % of Pd(DPEphos)Cl₂, the maximum turnover number of 7.1 × 10⁴ has been observed for the formation of PhCCCH₂Ph.

Full text of DOI:10.1016/j.tetlet.2005.02.137

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2927–2930
Palladium-catalyzed cross-coupling reaction of alkynylzincs
with benzylic electrophiles
Mingxing Qian and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907-2084, USA
Received 26 October 2004; accepted 14 February 2005
This paper is dedicated to Professor Iwao Ojima of State University of New York at Stony Brook on the occasion of his 60th birthday
Abstract—The reaction of alkynylzinc bromides with benzyl bromides or chlorides in the presence of a catalytic amount of Pd(DPE-
ꢀ
3
phos)Cl
phos)Cl
2
2
in THF at 23 ꢀC cleanly produces the corresponding benzylated alkynes in 73–97% yields. With 10 mol% of Pd(DPE-
4
, the maximum turnover number of 7.1 · 10 has been observed for the formation of PhC„CCH
2
Ph.
ꢁ
2005 Published by Elsevier Ltd.
1. Introduction
2. Results and discussion
Despite the well-known facts that benzyl halides readily
1
As the results summarized in Table 1 indicate, the use of
10
undergo oxidative addition to Pd and that the resultant
benzylpalladium derivatives participate in cross-cou-
Pd(DPEphos)Cl2 and Pd(dppf)Cl has led to the for-
2
mation of PhC„CCH Ph in excellent yields (entries
2
2
–5
2,6,7
pling reactions with aryl- and alkenylmetals
con-
9,10,15,16). In particular, the reaction in the presence
of 5 mol% of Pd(DPEphos)Cl was complete in 4 h at
3
4
5,6
7
taining various metals, such as Zn, B, Sn, and Al,
the corresponding reaction of alkynylmetals with ben-
zylic electrophiles had remained virtually unknown until
2
23 ꢀC to produce PhC„CCH Ph in 97% yield (entry
2
9). The reaction in the presence of 5 mol% of
Pd(dppf)Cl2 hardly proceeded (<1%) within 4 h at
23 ꢀC (entry 14). In refluxing THF, however,
8
Sarandeses and his co-workers reported the reaction of
(
ducing the corresponding benzylated alkynes in excel-
PhC„C) In and (TMSC„C) In with PhCH Br pro-
3
3
2
PhC„CCH Ph was obtained in 96% yield in 10 h (entry
2
9
lent yields in the presence of 1 mol% of Pd(dppf)Cl2.
Earlier attempts in the authorsÕ group to achieve cross-
15).
coupling of PhC„CZnBr with PhCH Br in THF in
The superiority of Pd(DPEphos)Cl as compared with
2
Pd(dppf)Cl was magnified, when the turnover numbers
2
2
the presence 5 mol% of Pd(PPh ) Cl or Pd(PPh ) led
only to very low yields of 1,3-diphenylpropyne. Reinves-
tigation of the reaction in light of the favorable results
3
2
2
3 4
(TONs) of the reaction run in the presence of these two
catalysts were compared. The maximum TON of
8
4
reported by Sarandeses and co-workers improved the
7.1 · 10 accompanied by a P70% yield of PhC„
ꢀ
3
CCH Ph was observed with 10 mol% of Pd(DPE-
product yield to 43% by refluxing the reaction mixture
at ca. 70 ꢀC. However, bibenzyl was also produced in
up to 47% yield. A more systematic optimization includ-
ing ligand screening was thus conducted.
2
phos)Cl (entry 12), whereas the use of Pd(dppf)Cl at
2
2
ꢀ
3
the same 10 mol% catalyst loading level yielded
PhC„CCH Ph only in 17% yield (entry 17). Since none
2
of the catalysts containing monodentate phosphines,
that is, PPh , (2-furyl) P, and Bu P, was satisfactory
t
3
3
3
(entries 1–8), the use of bidentate ligands may be consid-
ered to be critically important under the conditions
used. A couple of Ni catalysts, that is, Ni(PPh ) Cl
2
3
2
Keywords: Palladium-catalyzed cross-coupling; Alkynylzincs; Benzylic
and Ni(dppf)Cl , were also tested. However, neither
2
electrophiles; Benzylated alkynes; Pd(DPEphos)Cl
*
2
.
Corresponding author. Tel.: +1 765 494 5301; fax: +1 765 496
380; e-mail: negishi@purdue.edu
proved to be satisfactory, the yield of PhC„CCH Ph
2
3
being ca. 30%.
0
040-4039/$ - see front matter ꢁ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.02.137

2928
M. Qian, E. Negishi / Tetrahedron Letters 46 (2005) 2927–2930
Table 1. Screening of catalysts for the reaction of PhC„CZnBr with PhCH
2
Br in THF
cat. PdLn
THF
PhC CZnBr + BrCH
Ph
2
PhC CCH Ph+ PhCH
2
2
2
3
1
2
Entry
PdL
n
Mol%
Temp (ꢀC)
Time (h)
1 (%)
2 (%)
3 (%)
1
2
3
4
5
6
7
8
9
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
3
)
)
)
)
4
4
2
2
5
5
5
5
5
5
5
5
5
23
Reflux
23
4
10
4
2
43
1
<1
47
<1
41
3
96
<1
96
<1
76
<1
30
13
<1
<1
82
24
40
97
<1
14
80
Cl
Cl
2
2
Reflux
23
10
4
38
5
a
Pd(TFP)
2
Cl
Cl
2
Pd(TFP)
2
2
Reflux
23
10
4
18
40
46
97
8
t
Pd( Bu
3
P)
P)
2
18
21
1
t
Pd( Bu
3
2
Reflux
23
10
4
a
Pd(DPEphos)Cl
Pd(DPEphos)Cl
Pd(DPEphos)Cl
Pd(DPEphos)Cl
2
2
2
2
2
ꢀ
ꢀ
ꢀ
ꢀ
1
3
3
4
b
10
11
12
13
14
15
16
17
10
10
10
10
5
23
23
8
98
17
<1
<1
<1
<1
<1
<1
<1
<1
10
24
24
4
c
Reflux
Reflux
23
71
Pd(DPEphos)Cl
53
<1
96
a
Pd(dppf)Cl
Pd(dppf)Cl
Pd(dppf)Cl
Pd(dppf)Cl
2
2
2
2
5
Reflux
Reflux
Reflux
10
24
24
ꢀ1
3
d
10
10
80
17
ꢀ
a
b
c
0
TFP = tris(2-furyl)phosphine. DPEphos = bis(o-diphenylphosphinophenyl) ether, dppf = 1,1 -bis(diphenylphosphino)ferrocene.
2
TON = 9.8 · 10 .
4
TON = 7.1 · 10 .
d
2
TON = 8.0 · 10 .
In order to find the optimal countercations for the Pd-
catalyzed alkynyl–benzylic coupling, several metals, that
is, Mg, Zn, In, and Sn as well as Cu us ed in a catalytic
(PhC„C) In and accompanied by a P65–70% yield was
4 4
3
6.9 · 10 (entry 3), which is comparable with 7.1 · 10
observed with PhC„CZnBr (Table 1, entry 12), that ob-
served with the corresponding borate under the condi-
1
1b
amount (Sonogashira alkynylation) were screened for
the reaction of phenylethynylmetals with benzyl bro-
4
tions employed was less than 3.2 · 10 , the maximum
1
1
mide in the presence of Pd(DPEphos)Cl2 in THF.
The results with PhC„CZnBr are summarized in Table
(entries 9–13). In addition to Zn, two other metals,
TON accompanied by a P65–70% product yield being
2
8.3 · 10 .
1
that is, B and In, can also serve as satisfactory metal
countercations (Table 2, entries 1–3, 5, and 6). On the
other hand, the product yields observed with Mg
(42%), Sn (57%), and Cu(32%) were low, as indicated
in parentheses. While the maximum TON observed with
As zinc salts are significantly less expensive than the cor-
responding indium salts on either per mole or equivalent
basis, zinc was chosen for exploring the scope of the
Pd-catalyzed alkynyl–benzyl coupling. As the results
summarized in Table 3 indicate, various alkynylzinc
1
2
a
n 2 2
Table 2. Effect of metal countercations on the reaction of PhC„CML with PhCH Br in the presence of Pd(DPEphos)Cl in THF
Pd(DPEphos)Cl2
THF
PhC CML + BrCH
Ph
2
PhC CCH Ph + PhCH
n
2
2 2
3
1
2
1 (%)
Entry
PhC„CML
n
Mol%
5
Temp (ꢀC)
Time (h)
2 (%)
3 (%)
1
2
3
4
5
6
7
8
(PhC„C)
(PhC„C)
(PhC„C)
(PhC„C)
PhC„CBL
PhC„CBL
PhC„CBL
PhC„CMgBr
PhC„CMgBr
PhC„CMgBr
PhC„CSnBu
PhC„CSnBu
3
3
3
3
ln
23
23
4
16
24
24
10
16
24
4
96
95
69
49
90
83
31
20
42
2
<1
<1
<1
<1
2
<1
<1
27
50
3
ꢀ1
ꢀ3
ꢀ4
ln
ln
ln
10
10
10
Reflux
Reflux
23
b
n
n
n
5
ꢀ
3
1
10
10
Reflux
Reflux
23
<1
<1
6
9
ꢀ
62
69
27
39
94
<1
90
18
5
5
0
5
5
5
5
Reflux
Reflux
23
24
24
4
23
35
<1
<1
1
9
1
0
3
<1
57
2
3
Reflux
23
24
4
c
11
PhC„CH+Culc
PhC„CH+Cul
Reflux
24
32
14
a
b
c
All reactions were run with 1.2 equiv of alkynylmetals.
BL = B-MeO-9-BBN.
CO used as an additive.
n
K
2
3

M. Qian, E. Negishi / Tetrahedron Letters 46 (2005) 2927–2930
Table 3. Scope of benzylation of alkynylzinc bromides in the presence
2929
PhC CCH3
. nBuLi
2. ZnBr2
CH2 ZnBr
PhI
a
2
of 1 mol% of Pd(DPEphos)Cl in THF
1
1
% Pd(DPEphos)Cl
2
o
THF, 23 C, 10 h
PhC
C
1
1
R C CZnBr + ArCH Br(or Cl)
R C CCH Ar
2
2
PhI
5
% Pd(PPh3)4
cf. ref. 13
5% Pd(DPEphos)Cl2
1
R
b
Yield (%) of
Entry
ArCH
2
Br(or Cl)
o
o
1
23 C, 16 h
2
3 C, 20 h
2
R C„CCH Ar
1
2
3
4
5
6
7
Ph
Ph
PhCH
PhCH
PhCH
PhCH
2
2
2
2
Br
Cl
Br
Br
96 (91)
89
Ph C
C
1%
+
CH2 Ph C
C
CH2
2
2
8
3%
p-Tol
p-FC
94 (89)
97 (92)
+
6
H
4
PhC CCH Ph
n
c
2
PhC CCH2Ph
36%
Hex
Hex
p-TolCH
m-PyCH
2
Br
81 (77)
80 (76)
5
%
n
d
2
Br
e
HOCH
2
CH
2
PhCH
2
Br
73 (70)
Scheme 2. Effects of Pd–phosphine catalysts on the propargyl–aryl
coupling.
8
PhCH
2
Br
94 (90)
9
PhC„C
HexC„C
PhCH
PhCH
PhCH
PhCH
2
2
2
2
Br
Br
Br
Br
96 (93)
95 (89)
95 (91)
92 (88)
n
of organozincs with BuLi and ZnBr with PhI, which
n
1
1
1
0
1
2
2
1
3
H
produced 1,1-diphenylallene, it became interesting to
see if the cross-coupling regiochemistry could be
switched from allene formation to benzylated alkyne
formation. The reaction of c-phenylpropargylzinc bro-
mide with PhI in the presence of Pd(PPh ) produced
3
Me Si
a
All reactions were run with 1.2 equiv of alkynylzinc derivatives gen-
erated in situby treating alkynyllithiums with 1.2 equiv of dry ZnBr
By GLC. The numbers in parentheses are isolated yields.
p-TolCH2 2 was produced in 14% yield.
Py = pyridyl.
10% of PhCH
2
.
b
c
3
4
1,1-diphenylallene and 1,3-diphenylpropyne in 81%
and 5% yields, respectively, confirming in the main the
d
e
13
Br remained.
previously reported results. On the other hand, the
use of Pd(DPEphos)Cl2 led to a mixture containing
2
3
6–39% of 1,3-diphenylpropyne and only 3% of 1,1-
bromides containing aryl (entries 1–4), alkyl (entries 5–
diphenylallene (Scheme 2). Although significant
amounts of the starting materials appeared to remain
unreacted, the product yields could not be further
improved at temperatures varying from 23 to 150 ꢀC.
The use of Pd(dppf)Cl also produced predominantly
1
of 1,1-diphenylallene being 1–2%. Unless further devel-
oped, the Pd-catalyzed propargyl–aryl coupling does
not appear promising as a route to benzylated alkynes.
The Pd-catalyzed reaction of PhZnBr with 3-bromo-1-
phenylpropyne was not investigated.
7
1
), alkenyl (entry 8), alkynyl (entries 9 and 10), H (entry
1), and Me Si (entry 12) can produce the correspond-
3
ing benzylated alkynes in P70% isolated yields.
Although the survey of scope with respect to benzyl ha-
lides has been limited, the use of PhCH Cl (entry 2) indi-
2
cates that benzyl chloride may be satisfactory, while
entry 6 represents a successful use of a heteroaryl-con-
taining benzylic halide.
2
,3-diphenylpropyne, but its yield was 616%, the yield
In principle, the synthesis of benzylated alkynes via Pd-
catalyzed cross-coupling can be achieved in several dif-
ferent manners, as shown in Scheme 1.
3
. Summary
The results presented above pertain to the Pd-catalyzed
alkynyl–benzyl coupling route (Eq. 1). The synthesis of
In summary, this investigation, following a seminal but
8
very brief investigation by Sarandeses and co-workers,
has established that the Pd-catalyzed alkynyl–benzyl
coupling provides a long-sought, highly satisfactory,
and widely applicable method for the synthesis of benzy-
lated alkynes, the use of Zn and In as the countercations
3
-phenylpropyne (entry 11 in Table 3) has also made
the alkynylation route shown in Eq. 5 attractive and
eminently feasible. On the other hand, the benzyl–alkyn-
yl route (Eq. 2) and that via 1-halo-3-arylpropyne
(
Eq. 6) requiring in each case the preparation of 1-halo-
alkynes do not appear to be attractive. In the view of
recent studies on the reaction of a regioisomeric mixture
in alkynylmetals and Pd(DPEphos)Cl as a catalyst has
2
been demonstrated to be advantageous. Several other
alternative Pd-catalyzed cross-coupling routes either
appear to be unattractive or remain undeveloped, except
that the Pd-catalyzed cross-coupling of 3-aryl-1-propy-
nylmetals (Eq. 5 of Scheme 1) promises to provide a
general and satisfactory route to benzylated alkynes.
alkynyl-benzyl coupling
benzyl-alkynyl coupling
Ar
Ar
R
M +
X
(1)
R
R
R
X + M
(2)
(3)
(4)
(5)
propargyl-aryl coupling
aryl-propargyl coupling
via 3-arylpropynylmetals
Ar
+
XAr
MAr
M
R
+
X
M
Ar
Ar
RX
+
4. Representative procedures
via 1-halo-3-arylpropynes
RM +
X
(6)
Representative procedure A. 1,3-Diphenylpropyne: To
phenylacetylene (123 mg, 1.2 mmol) in THF (3 mL)
Scheme 1. Various cross-coupling routes to benzylated alkynes.

2930
M. Qian, E. Negishi / Tetrahedron Letters 46 (2005) 2927–2930
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, followed by addition of a solution
References and notes
1. Stille, J. K.; Lau, K. S. Y. Acc. Chem. Res. 1977, 10, 434,
and reference therein.
. For a review on Pd-catalyzed benzylation, see: Negishi, E.;
Liu, F. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley: New York,
002, pp 551–589, Chapter III. 2.9.
. (a) Ennis, D. S.; Gilchrist, T. L. Tetrahedron 1990, 46,
623; (b) Fisher, L. E.; Labadie, S. S.; Reuter, D. C.;
Clark, R. D. J. Org. Chem. 1995, 60, 6224; (c) de Lang, R.
J.; van Hooijdonk, M. J. C. M.; Brandsma, L.; Kramer,
H.; Seinen, W. Tetrahedron 1998, 54, 2953; For Pd-
catalyzed benzyl–aryl coupling, see: (d) Negishi, E.; King,
A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821.
of dry ZnBr (270 mg, 1.2 mmol) in THF (1 mL). After
2
2
the mixture thus obtained had been stirred for 5 min at
ꢀ
78 ꢀC and warmed to 0 ꢀC over 25 min, benzyl bro-
mide (171 mg, 1.0 mmol) and Pd(DPEphos)Cl
(
2
2
7.2 mg, 0.01 mmol) were added at 23 ꢀC. The resultant
3
mixture was stirred at 23 ꢀ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 97% GLC yield.
The reaction mixture was quenched with 1 M HCl, ex-
2
tracted with ether, washed with aqueous NaHCO , dried
3
over MgSO , filtered, and concentrated. Flash chroma-
4
tography (silica gel, hexane) afforded 175 mg (91%) of
the title compound.
4
5
6
7
. Song, Z. Z.; Wong, H. N. C. J. Org. Chem. 1994, 59,
3
. Kuribayashi, T.; Gohya, S.; Mizuno, Y.; Satoh, S. J.
Carbohydr. Chem. 1999, 18, 393.
. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101,
3.
Representative procedure B. 1,5-Diphenyl-1,3-pentadiyne:
4
992.
To
.4 mmol) in 4 mL of THF was added n-BuLi
0.96 mL of 2.5 M solution in hexane, 2.4 mmol) at
a solution of N,N-diisopropylamine (243 mg,
. Negishi, E.; Matsushita, H.; Okukado, N. Tetrahedron
Lett. 1981, 22, 2715.
8. (a) P e´ rez, I.; Sestelo, J. P.; Sarandeses, L. A. Org. Lett.
1999, 1, 1267; (b) P e´ rez, I.; Sestelo, J. P.; Sarandeses, L. A.
J. Am. Chem. Soc. 2001, 123, 4155.
2
(
0
3
1
ꢀC in a flame-dried flask under Ar atmosphere. After
14
0 min, 2-chloro-4-phenyl-1-buten-3-yne
(195 mg,
.2 mmol) in 1 mL THF was added to the LDA solution
9
. Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.;
Higuchi, T.; Hirotsu, K. Z. J. Am. Chem. Soc. 1984, 106,
prepared above by cannula at ꢀ78 ꢀC. The reaction mix-
1
58.
ture was stirred first at ꢀ78 ꢀC for 30 min and then at
1
1
0. 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.
ꢀ
30 ꢀC for 30 min, and treated with a solution of anhy-
drous ZnBr (270 mg, 1.2 mmol) in THF (1 mL), and
warmed to 0 ꢀC over 30 min. Benzyl bromide (171 mg,
2
1. (a) For the use of metal counteractions in the Pd-catalyzed
alkynylation, see: Negishi, E.; Anastasia, L. Chem. Rev.
2003, 103, 1979; (b) Sonogashira, K. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negi-
shi, E., Ed.; Wiley: New York, 2002, pp 493–529, Chapter
III. 2.8.1; (c) Negishi, E.; Xu, C. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negi-
shi, E., Ed.; Wiley: New York, 2002, pp 531–549, Chapter
III. 2.8.2.
1
.0 mmol) and Pd(DPEphos)Cl2 (7.2 mg, 0.01 mmol)
were added to the reaction mixture at 0 ꢀC, which was
then stirred at 23 ꢀC for 3 h. The reaction mixture was
diluted with Et O, washed with aqueous NH Cl and
2
4
then with aqueous NaHCO , dried over MgSO , fil-
4
3
tered, and concentrated. Chromatography on silica gel
hexane) gave 191 mg (93%) of the title compound as a
light yellow oil.
(
1
2. The prices of ZnBr
(
2
and InCl
2003–2004) are as follows: ZnBr (98+% pure) $129.70/
3
in the Aldrich catalogue
2
5
$
3
00 g or $58.41/mol; InCl (98% pure) $171.40/50 g or
212.23/0.33 mol.
Acknowledgements
1
3. (a) Ma, S.; Zhang, A. J. Org. Chem. 1998, 63, 9601; (b)
Ma, S.; Zhang, A. J. Org. Chem. 2002, 67, 2287.
14. Qian, M.; Negishi, E. Org. Process Res. Dev. 2003, 7,
The authors thank the National Institutes of Health
GM 36792) and Purdue University for support of this
research.
(
412.