Palladium-catalyzed Heck alkynylation of benzyl chlorides

Article abstract of DOI:10.1055/s-2006-949625

An efficient and general protocol for the palladium-catalyzed Heck alkynylation of benzyl chlorides was developed. A catalyst system comprised of PdCl₂(CH₃CN)₂ and 2-dicyclohexylphosphino- 2′,4′,6′-triisopropylbiphenyl (XPhos), with Cs ₂CO₃ as the base, efficiently couples a wide range of functionalized terminal alkynes and substituted benzyl chlorides at 65 °C. We have also demonstrated that the corresponding aryl allene product can be selected for using an excess amount of base and higher reaction temperatures (80 °C) in a one-pot procedure. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-949625

LETTER
2941
Palladium-Catalyzed Heck Alkynylation of Benzyl Chlorides
P
alladium-Cataly
a
ze
d
H
eck A
t
lkynyl
h
a
tion of Ben
a
zyl Chlorid
r
e
s
ine H. Larsen, Kevin W. Anderson, Rachel E. Tundel, Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Fax +1(617)2533297; E-mail: sbuchwal@mit.edu
Received 17 April 2006
This article is dedicated to Richard F. Heck in honor of his seminal contributions to organic and organometallic chemistry.
the transmetallating agent.2,9 A system using catalytic pal-
ladium can also be used with alkynyl zinc reagents to cou-
ple simple benzyl bromides.10 Interestingly, a reported
attempt to couple benzyl halides with terminal alkynes us-
Abstract: An efficient and general protocol for the palladium-cata-
lyzed Heck alkynylation of benzyl chlorides was developed. A
catalyst system comprised of PdCl2(CH3CN)2 and 2-dicyclohexyl-
phosphino-2¢,4¢,6¢-triisopropylbiphenyl (XPhos), with Cs2CO3 as
the base, efficiently couples a wide range of functionalized terminal ing a PdCl2(PPh3)2/CuCl catalyst only provides small
alkynes and substituted benzyl chlorides at 65 °C. We have also
amounts of the desired benzyl-substituted alkyne. Instead,
demonstrated that the corresponding aryl allene product can be
highly substituted enynes are produced via a tandem So-
selected for using an excess amount of base and higher reaction
nogashira–carbopalladation–Sonogashira sequence.11
temperatures (80 °C) in a one-pot procedure.
We postulated that the use of an electron-rich bulky ligand
(XPhos, 1) would suppress formation of the proposed Pd-
bound benzyl alkynyl species and prevent formation of
Key words: palladium, alkynes, Heck alkynylation, benzyl chlo-
rides, allene
the
enyne
product.
Indeed,
using
catalytic
PdCl2(CH3CN)2/1 and 2.5 equivalents Cs2CO3 as the base
in acetonitrile (MeCN), benzyl chloride and 1-decyne
were efficiently combined providing the benzyl alkyne in
96% yield (Equation 1). Note that this transformation pro-
ceeds in the absence of a copper co-catalyst and without
isomerization to the undesired allene. In fact, the addition
of 4 mol% CuI inhibited the desired alkynylation while
forming multiple side products. Exploration of these ini-
tial catalytic conditions revealed that while KOAc pro-
vides a faster initial reaction rate than Cs2CO3, it also
consumes the terminal alkyne leaving significant amounts
of unreacted benzyl chloride. The use of most other bases
is unproductive, but NaOAc and K3PO4·H2O do provide
50% conversion to product in the same time frame in
which the reaction with Cs2CO3 is complete. While the
process is water-tolerant, if it is not carried out under an
inert atmosphere, the rate is 4–5 times slower. Utilization
of Pd(OAc)2 as the precatalyst is just as efficacious as
PdCl2(CH3CN)2 with either MeCN or THF as the solvent.
Over the past 30 years, transition-metal-catalyzed cross-
coupling methodology to form carbon–carbon bonds has
become a staple of modern synthesis.1 The preeminent
method for the incorporation of an alkynyl moiety in or-
ganic compounds is the palladium-catalyzed cross-cou-
pling reaction of terminal alkynes and organic
electrophiles.1,2 The most widely used of these is a cross
between the Cu-promoted Castro–Stephens reaction3 and
the Heck alkynylation,4 known as the Sonogashira reac-
tion.5 While significant advances in palladium-based sys-
tems to catalyze the reaction of aryl halides and terminal
alkynes have been made through the development of more
sterically hindered/electron-rich phosphine ligands, very
few reports for the coupling of alkyl or benzyl halides
have been reported.6 For example, the report of Fu and co-
workers that a catalyst system derived from [PdCl(p-al-
lyl)]2/CuI and 1,3-bis(1-adamantyl)imidazolium chloride
allowed the coupling of unactivated alkyl bromides and
iodides and terminal alkynes represents the most general
method for coupling these difficult electrophiles.7
We had previously disclosed that a catalyst system based
on PdCl2(CH3CN)2/2-dicyclohexylphosphino-2¢,4¢,6¢-tri-
isopropylbiphenyl (XPhos, 1) provided excellent reactiv-
ity in the Heck alkynylation (copper-free Sonogashira
coupling) of aryl chlorides/tosylates and terminal
alkynes.8 We were interested in expanding the substrate
scope of this catalyst system to include readily available
benzyl chlorides as coupling partners. To our knowledge,
only one protocol is operative with substoichiometric
metal, in which the alkynylation of benzyl bromide is ac-
complished using palladium and tris(alkynyl)indiums as
C8H17
PCy2
PdCl2(CH3CN)2
(2.5 mol%)
i-Pr
i-Pr
Cl
C8H17
Ligand 1
(7.5 mol%)
Cs2CO3, MeCN
96%
R
1, R = i-Pr
2, R = SO3Na
65 °C, 8 h
Equation 1
Unfortunately, when the conditions in Equation 1 were
applied to the coupling of 4-fluorobenzyl chloride and 4-
cyano-1-butyne, an inseparable mixture of alkyne and al-
lene products were formed, with the allene predominat-
ing. Lowering the stoichiometry of base to 1.5 equivalents
gave a 1:2 ratio of alkyne to allene and to 1.1 equivalents
SYNLETT 2006, No. 18, pp 2941–2946
0
3
.1
1
.2
0
0
6
Advanced online publication: 14.08.2006
DOI: 10.1055/s-2006-949625; Art ID: S08106ST
© Georg Thieme Verlag Stuttgart · New York

2942
C. H. Larsen et al.
LETTER
finally provided a majority of the desired alkyne product ed to the fact that oxidative addition to benzyl chloride oc-
in a 5:1 ratio. Switching the solvent to THF, toluene, or di- curs much faster than non-productive alkyne
oxane is the key to obtaining solely the alkynyl Heck polymerization. However, it should be noted that the reac-
product for this more highly functionalized set of sub- tion of 3-ethynylthiophene must be halted after two hours
strates, with the reactions in both THF and dioxane pro- as the alkynyl product begins to isomerize to the allene
ceeding to completion. If the alkynyl Heck product is not upon consumption of the benzyl chloride starting materi-
prone to isomerization to the allene, then the original con- al. Interestingly, the water-soluble sodium sulfonate ver-
ditions in acetonitrile also cleanly provide the coupled sion of XPhos (2) in biphasic mixture of H2O–MeCN is
product.
proficient in the coupling of benzyl chloride with both
phenylacetylene and the water-soluble terminal alkyne, 5-
hexynoic acid, where 94% and 81% of the disubstituted
alkynes are obtained, respectively (Table 1, entries 4, 5).12
Phthalimide-protected 5-aminohexyne is smoothly cou-
pled with benzyl chloride in THF (Table 1, entry 6). Ter-
As is illustrated in Table 1, a wide variety of terminal
alkynes can be successfully coupled with benzyl chloride
using this catalyst system derived from PdCl2(CH3CN)2
and XPhos (1). Aryl and heteroaryl alkynes are effective
coupling partners as shown with 3-ethynylthiophene and
2-ethynyl-6-methoxynaphthalene where, in contrast to the
Heck alkynylation of aryl chlorides using this same cata-
lyst system, slow addition of the aryl/heteroaryl alkyne is
not necessary (Table 1, entries 2, 3). This may be attribut-
minal
aliphatic
alkynes
possessing
either
tetrahydropyran- or tosyl-protected alcohols are well tol-
erated and provide the corresponding benzyl alkynes in
82% and 95% yield, respectively (Table 1, entries 8, 9).
Table 1 Palladium-Catalyzed Coupling of Benzyl Chloride and Terminal Alkynesa
PdCl2(CH3CN)2 (1.0–2.5 mol%)
Cl
Ligand 1 or 2 (3.0–7.5 mol%)
+
R
R
Cs2CO3, MeCN or THF, 65 °C
Entry
1
Alkyne
Product
Time (h)
8
Yield (%)b
96c
C8H17
C8H17
2
3
2
88c
96c
S
S
1.5
OMe
OMe
4
10
94d
5
6
10
17
81d,e
94
CO2H
CO2Me
O
O
N
O
N
O
7
1.5
91
8
9
4
82
95
OTHP
OTs
OTHP
OTs
12
aReaction conditions: 1.0 equiv benzyl chloride, 1.3–1.5 equiv alkyne, 1.05 equiv Cs2CO3, THF (2.5 mL/mmol), PdCl2(CH3CN)2 (2.0 mol%),
ligand 1 (6.0 mol%), 65 °C.
b Yield of isolated product (average of 2 runs).
c MeCN was used as the solvent.
d Ligand 2 and a H2O–MeCN solvent system were used.
e To ease in purification, the product was converted to the methyl ester using trimethylsilyldiazomethane.
Synlett 2006, No. 18, 2941–2946 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Heck Alkynylation of Benzyl Chlorides
2943
PdCl2(MeCN)2
(2.5 mol%)
The substrate scope was expanded further by varying the
type and position of substituents on the benzyl halide. As
shown in Table 2, electron-rich 4-methoxybenzyl chlo-
ride and triethylsilyl-protected acetylene react to form the
corresponding benzyl alkyne in nearly quantitative yield
(Table 2, entry 1). Electron-deficient 3-trifluoromethyl-
benzyl chloride is combined with 1-ethynylcyclohexene
with high fidelity (Table 2, entry 2). Complete selectivity
of a benzyl chloride over an aryl chloride is achieved
when coupling both 4-chloro and 2-chloro benzyl chloride
with terminal alkynes (Table 2, entries 3, 4). The coupling
products of 4-fluorobenzyl chloride and either tetrahydro-
pyran-protected propynol or 3-chlorophenylacetylene are
also produced in good yields (Table 2, entry 5, 6). While
primary benzyl chlorides were suitable coupling partners
using this catalyst system, reactions conducted with sec-
ondary benzyl chlorides resulted in significant amounts of
styrene (presumably formed via b-hydride elimination).13
Cl
C8H17
+
C8H17
Ligand 1
(7.5 mol%)
Cs2CO3, MeCN
68%
90 °C, 12 h
Equation 2
alkyne product from Table 1, entry 1 to 2.5 equivalents
Cs2CO3 in MeCN at 90 °C for 10 hours. Under these con-
ditions, the product is completely converted to the corre-
sponding aryl allene, confirming the role of the base in
this reaction. As is seen in Table 3, by changing the
amount of base used, as well as the solvent, and tempera-
ture, one can predictably convert benzyl chlorides to ei-
ther the benzyl alkyne (65 °C, 1.05 equiv Cs2CO3) or the
aryl allene (>80 °C, 2.50 equiv Cs2CO3) in a one-pot pro-
tocol. For substrates in which the reaction in MeCN gives
a mixture of alkyne and allene even at 65 °C with only
1.05 equivalents of base, switching the solvent to THF
provides solely the alkyne product.
In the initial optimization studies, we found that if we
heated the reaction to greater than 65 °C for the simple
combination of benzyl chloride and 1-decyne, instead of
only forming the desired benzyl alkyne, a significant
amount of aryl allene is produced. In fact, heating the re-
action at 90 °C for 12 hours with excess Cs2CO3 (2.5
equiv) produced aryl allene in a modest 68% yield
(Equation 2).
In summary, we have developed an efficient procedure for
the direct coupling of benzyl chlorides and terminal
alkynes using a catalyst comprised of PdCl2(CH3CN)2 and
ligands 1 or 2, which provide benzyl alkynes in good to
excellent yields. We also found that by using this same
catalyst, an excess of base and more forcing reaction con-
ditions, the coupling of benzyl chlorides and terminal
To determine whether the isomerization was mediated by
the metal or by the base, we subjected the octyl-benzyl
Table 2 Palladium-Catalyzed Coupling of Substituted Benzyl Chlorides and Terminal Alkynesa
PdCl2(CH3CN)2 (1.0–2.5 mol%)
Ligand 1 (3.0–7.5 mol%)
Cl
R1
+
R1
R2
R2
Cs2CO3, MeCN or THF
65 °C
Entry
1
Benzyl chloride
Alkyne
Product
Time (h)
16
Yield (%)b
99c
Cl
SiEt3
SiEt3
MeO
MeO
2
4
97
Cl
CF3
CF3
3
4
5
24
22
2
82
Cl
SiMe3
C8H17
SiMe3
Cl
Cl
71c
91c
Cl
C8H17
Cl
Cl
Cl
Cl
Cl
F
F
F
F
6
6
94
Cl
OTHP
OTHP
a Reaction conditions: 1.0 equiv benzyl chloride, 1.3–1.5 equiv alkyne, 1.05 equiv Cs2CO3, THF (2.5 mL/mmol), PdCl2(CH3CN)2 (2.0 mol%),
ligand 1 (6.0 mol%), 65 °C.
b Yield of isolated product (average of 2 runs).
c MeCN used as the solvent.
Synlett 2006, No. 18, 2941–2946 © Thieme Stuttgart · New York

2944
C. H. Larsen et al.
LETTER
Table 3 Palladium-Catalyzed Coupling of Benzyl Chlorides with Terminal Alkynes to Form Benzyl Alkynes or Aryl Allenesa
Conditions A
Cs2CO3 (1.05 equiv)
THF
R1
Cl
R1
R2
R2
65 °C
PdCl2(CH3CN)2
+
Conditions B
Cs2CO3 (2.50 equiv)
Ligand 1
R2
R1
MeCN, >80 °C
Entry
1
Benzyl chloride
Alkyne
Condition
Product
Time (h)
8
Yield (%)b
A
96
Cl
C8H17
C8H17
C8H17
2
3
B
A
16
25
68
93
Cl
C8H17
C8H17
Cl
C8H17
C8H17
CF3
CF3
4
B
12
72
Cl
C8H17
CF3
CF3
5
6
A
B
6
91c
70
Cl
CN
CN
CN
CN
F
F
F
12
Cl
F
a Reaction conditions: 1.0 equiv benzyl chloride, 1.3–1.5 equiv alkyne, PdCl2(CH3CN)2 (2.0 mol%), ligand 1 (6.0 mol%). Conditions A: 1.05
equiv Cs2CO3, THF (2.5 mL/mmol), 65 °C, 4–25 h. Conditions B: 2.50 equiv Cs2CO3, MeCN (2.5 mL/mmol), 80–90 °C, 12 h.
b Yield of isolated product (average of 2 runs).
c 1,4-Dioxane was used as the solvent.
2-Undecynylbenzene (Table 1, Entry 1; Table 3, Entry 1;
Equation 1)14
alkynes produces aryl allenes via a base-catalyzed isomer-
ization of the resultant benzyl alkyne. Further investiga-
tion of the scope and potential applications of this
methodology are underway in our laboratories.
The title compound was obtained as a clear oil (220 mg, 96%). 1H
NMR (400 MHz, CDCl3): d = 7.33 (d, J = 7.2 Hz, 2 H), 7.28 (t,
J = 7.2 Hz, 2 H), 7.17 (t, J = 6.8 Hz, 1 H), 3.56 (br t, J = 2.4 Hz, 2
H), 2.20 (tt, J = 4.8, 2.4 Hz, 2 H), 1.52 (m, 2 H), 1.28–1.42 (m, 10
H), 0.88 (t, J = 6.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d =
137.8, 128.5, 128.0, 126.5, 82.9, 77.7, 32.0, 29.5, 29.4, 29.2, 29.1,
25.3, 22.9, 19.0, 14.3.
General Procedure for Heck Alkynylation of Benzyl Chlorides
to Form Benzyl Alkynes (Table 1 and Table 2)
A disposable tube equipped with a screw cap, Teflon septum and
stir bar was charged with PdCl2(CH3CN)2 (5.2 mg, 0.020 mmol,
3-(3-Phenyl-1-propynyl)thiophene (Table 1, Entry 2)
The title compound was obtained as a brown oil (174 mg, 88%). 1H
NMR (400 MHz, CDCl3): d = 7.42 (m, 3 H), 7.36 (t, J = 7.5 Hz, 2
2
mol%), 2-dicyclohexylphosphino-2¢,4¢,6¢-triisopropylbiphenyl
(28.6 mg, 0.060 mmol, 6 mol%), and Cs2CO3 (342 mg, 1.05 mmol).
If the benzyl chloride or terminal alkyne was a solid, it was also add-
ed at this time. The tube was evacuated and back-filled with argon
three times. The solvent/solvents and benzyl chloride (1.00 mmol,
liquid) were added. The terminal alkyne (1.30 mmol, liquid) was
then added and the solution was heated to the noted temperature un-
til the reaction was complete as judged by GC analysis. After cool-
ing to r.t., the products were extracted from the water layer with
Et2O and dried over MgSO4 or with hexane–EtOAc, filtered
through Celite®, and concentrated to dryness. Purification by col-
umn chromatography on silica gel provided the benzyl alkyne prod-
ucts (Note: many of these alkynes are unstable upon purification
and concentration. It is recommended that they be stored at –20 °C
or lower in solution).
H), 7.26 (m, 2 H), 7.14 (dd, J = 5.0, 1.0 Hz, 1 H), 3.83 (s, 2 H). 13
NMR (100 MHz, CDCl3): d = 136.9, 130.2, 128.8, 128.25, 128.16,
126.9, 125.3, 122.8, 87.3, 77.9. IR (neat): 3107, 3029, 1601, 1521,
1493, 1453, 1357, 1178, 1076, 859, 780, 695, 626 cm–1.
C
2-Methoxy-6-(3-phenyl-1-propynyl)naphthalene (Table 1,
Entry 3)
The title compound was obtained as a white solid (261 mg, 96%,
mp: 101–102 °C). 1H NMR (400 MHz, CDCl3): d = 7.94 (s, 1 H),
7.71 (t, J = 8.1 Hz, 2 H), 7.52 (m, 3 H), 7.41 (m, 2 H), 7.32 (m, 1
H), 7.19 (dd, J = 8.9, 2.5 Hz, 1 H), 7.14 (d, J = 2.5 Hz, 1 H), 3.95 (s,
3 H), 3.93 (s, 2 H). 13C NMR (100 MHz, CDCl3): d = 158.2, 137.0,
134.0, 131.2, 129.4, 129.3, 128.7, 128.6, 128.1, 126.9, 126.8, 119.4,
118.7, 105.8, 87.3, 83.3, 55.4, 26.0. IR (neat): 3060, 3029, 2938,
1625, 1599, 1493, 1241, 1162, 1027, 896, 857, 818, 697 cm–1.
Synlett 2006, No. 18, 2941–2946 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Heck Alkynylation of Benzyl Chlorides
2945
1,3-Diphenyl-1-propyne (Table 1, Entry 4)10
1-(3-Cyclohex-1-enylprop-2-ynyl)-3-trifluoromethylbenzene
(Table 2, Entry 2)
1
The title compound was obtained as a clear oil (92 mg, 94%). H
NMR (400 MHz, CDCl3): d = 7.40–7.46 (m, 4 H), 7.33 (t, J = 7.2
Hz, 2 H), 7.22–7.30 (m, 4 H), 3.82 (s, 2 H). 13C NMR (100 MHz,
CDCl3): d = 136.9, 131.8, 128.7, 128.4, 128.2, 128.0, 126.8, 123.8,
87.7, 82.8, 25.9.
The title compound was obtained as a clear oil (256 mg, 97%). 1H
NMR (400 MHz, CDCl3): d = 7.65 (s, 1 H), 7.44–7.29 (m, 3 H), 5.98
(m, 1 H), 3.64 (s, 2 H), 2.05–1.96 (m, 4 H), 1.55–1.43 (m, 4 H). 13
C
NMR (100 MHz, CDCl3): d = 136.4, 134.6, 131.5, 129.1, 124.9 (q,
J = 3.9 Hz), 123.6 (q, J = 3.9 Hz), 120.8, 85.4, 83.5, 29.6, 25.8,
25.7, 22.5, 21.7. IR (neat): 3067, 3024, 2939, 2862, 2212, 2185,
1708, 1676, 1653, 1616, 1450, 1327, 1257, 1124, 1070, 918, 795,
702, 660 cm–1.
7-Phenyl-5-heptynoic Acid Methyl Ester (Table 1, Entry 5)15
The title compound was obtained as a clear oil (108 mg, 81%). 1H
NMR (400 MHz, CDCl3): d = 7.19–7.36 (m, 5 H), 3.66 (s, 3 H), 3.56
(t, J = 2.4 Hz, 2 H), 2.45 (t, J = 7.2 Hz, 2 H), 2.29 (tt, J = 6.8, 2.4
Hz, 2 H), 1.85 (p, J = 7.2 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
d = 173.8, 137.5, 128.7, 128.6, 127.9, 126.6, 81.3, 78.7, 51.7, 33.0,
25.2, 24.3, 18.5.
[3-(4-Chlorophenyl)prop-1-ynyl]trimethylsilane (Table 2,
Entry 3)
The title compound was obtained as clear oil (183 mg, 82%). H
1
NMR (400 MHz, CDCl3): d = 7.29 (m, 4 H), 3.63 (s, 2 H), 0.20 (s,
9 H). 13C NMR (100 MHz, CDCl3): d = 135.0, 132.6, 129.4, 128.8,
103.8, 87.6, 25.8, 0.3. IR (neat): 3041, 3031, 2960, 2899, 2361,
2340, 1492, 1417, 1250, 1091, 1030, 1017, 844, 797, 760, 644 cm–1.
N-(3-Phenyl-1-propynyl)pthalimide (Table 1, Entry 6)
The title compound was obtained as an off-white oil (284 mg, 94%).
1H NMR (400 MHz, CDCl3): d = 7.85 (m, 2 H), 7.71 (m, 2 H), 7.30
(m, 4 H), 7.22 (m, 1 H), 3.82 (m, 2 H), 3.45 (m, 2 H), 2.26–2.35 (m,
2 H), 1.99 (m, 2 H).13C NMR (100 MHz, CDCl3): d = 168.5, 137.3,
134.0, 132.3, 128.5, 127.9, 126.5, 123.3, 81.2, 78.5, 37.5, 27.7,
25.1, 16.9. IR (neat): 3462, 3289, 3059, 3025, 2936, 2190, 1773,
1709, 1614, 1493, 1438, 1396, 1373, 1116, 1027, 887, 722 cm–1.
1-Chloro-2-undec-2-ynylbenzene (Table 2, Entry 4)
The title compound was obtained as a light-yellow oil (259 mg,
99%). 1H NMR (400 MHz, CDCl3): d = 7.69 (d, J = 7.6 Hz, 1 H),
7.37 (dd, J = 1.6, 8.0 Hz, 1 H), 7.30 (td, J = 1.6, 5.6 Hz, 1 H), 7.21
(td, J = 2.0, 6.0 Hz, 1 H), 3.71 (t, J = 2.4 Hz, 2 H), 2.30 (tt, J = 2.4,
4.8 Hz, 2 H), 1.52 (q, J = 2.4 Hz, 2 H), 1.51–1.35 (m, 10 H), 0.95 (t,
J = 6.8 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 135.4, 133.6,
129.7, 129.2, 127.9, 126.9, 83.9, 76.2, 32.1, 29.5, 29.4, 29.2, 29.1,
23.5, 22.9, 19.0, 14.3. IR (neat): 2955, 2927, 2855, 1705, 1593,
1573, 1468, 1444, 1322, 1050, 1038, 748 cm–1.
(3-Cyclo-1-hexenyl-2-propynyl)benzene (Table 1, Entry 7)10
The title compound was obtained as a light-yellow oil (179 mg,
91%). This compound decomposes significantly when concentrated
and stored at –20 °C for 8 d (only trace decomposition of the same
sample stored in CDCl3 was observed). 1H NMR (400 MHz,
CDCl3): d = 7.39–7.31 (m, 4 H), 7.26 (t, J = 7.1 Hz, 1 H), 6.10 (m,
1 H), 3.74 (s, 2 H), 2.16 (m, 2 H), 2.10 (m, 2 H), 1.67–1.58 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 137.4, 134.0, 128.6, 128.1, 126.6,
121.0, 84.7, 29.7, 25.8, 25.7, 22.6, 21.8.
1-(m-Chlorophenyl)-3-(p-fluorobenzyl)-1-propyne (Table 2,
Entry 5)
The title compound was obtained as a yellow oil (221 mg, 90%). 1H
NMR (400 MHz, CDCl3): d = 7.48–7.49 (m, 1 H), 7.24–7.41 (m, 5
H), 7.06–7.10 (m, 2 H), 3.83 (s, 2 H). 13C NMR (100 MHz, CDCl3):
d = 161.9 (163.2, 160.7, d, J = 244.4 Hz), 134.3, 132.2 (132.20,
132.16, d, J = 3.2 Hz), 131.7, 129.9, 129.6 (129.67, 129.61, d,
J = 5.1 Hz), 129.5, 128.4, 125.4, 115.5 (115.69, 115.48, d, J = 21.4
Hz), 88.9, 81.7, 25.1. IR (neat): 3069, 2893, 2226, 2205, 1700,
1593, 1561, 1509, 1475, 1418, 1225, 1158, 1095, 1016, 882, 818,
785, 682 cm–1.
2-(5-Phenyl-3-pentynyloxy)tetrahydropyran (Table 1, Entry 8)
The title compound was obtained as a pale-yellow oil (299 mg,
1
95%). H NMR (400 MHz, CDCl3): d = 7.37–7.30 (m, 4 H), 7.25
(m, 1 H), 4.67 (t, J = 3.5 Hz, 1 H), 3.87 (m, 2 H), 3.61–3.48 (m, 3
H), 2.55 (tt, J = 7.1, 2.4 Hz, 2 H), 1.83 (m, 1 H), 1.72 (m, 2 H), 1.62–
1.51 (m, 4 H). 13C NMR (100 MHz, CDCl3): d = 137.5, 128.6,
128.0, 126.6, 98.9, 79.5, 78.9, 66.2, 62.3, 30.8, 25.6, 25.3, 20.5,
19.6. IR (neat): 3291, 3063, 3030, 2943, 2874, 2237, 2207, 1734,
1704, 1454, 1353, 1263, 1201, 1137, 1121, 1072, 1034, 980, 699
cm–1.
2-[4-(4-Fluorophenyl)-2-butynyloxy]tetrahydropyran (Table 2,
Entry 6)
The title compound was obtained as a clear oil (233 mg, 94%) and
decomposes quickly upon concentration. 1H NMR (400 MHz,
CDCl3): d = 7.28 (m, 2 H), 6.99 (m, 2 H), 4.83 (t, J = 3.3 Hz, 1 H),
4.31 (qt, J = 15.0, 2.2 Hz, 2 H), 3.85 (m, 1 H), 3.61 (s, 2 H), 3.53
(m, 1 H), 1.88–1.50 (m, 6 H). 13C NMR (100 MHz, CDCl3): d =
161.8 (163.0, 160.6, d, J = 244.4 Hz), 132.3 (132.30, 132.27, d,
J = 3.2 Hz), 129.5 (129.50, 129.43, d, J = 7.8 Hz), 115.5, 115.3,
96.9, 83.9, 78.4, 62.1, 54.7, 30.4, 25.5, 24.6, 19.2. IR (neat): 3070,
3043, 2944, 2871, 2854, 2359, 2340, 1604, 1509, 1454, 1223, 1132,
1117, 1025, 905, 816 cm–1.
Toluene-4-sulfonic Acid 5-Phenyl-3-pentynyl Ester (Table 1,
Entry 9)
The title compound was obtained as a yellow oil (299 mg, 95%). 1H
NMR (400 MHz, CDCl3): d = 7.81 (d, J = 8.3 Hz, 2 H), 7.31 (m, 6
H), 7.25 (m, 1 H), 4.13, (t, J = 7.0 Hz, 2 H), 3.53 (s, 2 H), 2.61 (tt,
J = 7.0, 2.3 Hz, 2 H), 2.44 (s, 3 H). 13C NMR (100 MHz, CDCl3):
d = 14.0, 136.8, 133.0, 128.6, 128.0, 127.9, 126.7, 80.4, 76.5, 68.2,
25.1, 21.7, 19.9. IR (neat): 3061, 3030, 2958, 2919, 2236, 2201,
1700, 1598, 1495, 1454, 1361, 1176, 1097, 987, 902, 816, 770, 725,
664 cm–1.
1-Trifluoromethyl-2-undec-2-ynylbenzene (Table 3, Entry 3)
The title compound was obtained as a clear oil (270 mg, 91%). 1H
NMR (400 MHz, CDCl3): d = 7.84 (d, J = 7.8 Hz, 1 H), 7.62 (d,
J = 7.8 Hz, 1 H), 7.54 (t, J = 7.6 Hz, 1 H), 7.34 (t, J = 7.6 Hz, 1 H),
3.80 (s, 2 H), 2.25 (tt, J = 7.1, 2.4 Hz, 2 H), 1.54 (m, 2 H), 1.41 (m,
2 H), 1.30, (m, 10 H), 0.89 (t, J = 6.8 Hz, 3 H). 13C NMR (100 MHz,
CDCl3): d = 136.2, 132.2, 130.3, 126.7, 125.9 (q, J = 5.7 Hz), 84.2,
76.3, 32.1, 29.5, 29.4, 29.1, 22.9, 22.33 (q, J = 3.2 Hz). IR (neat):
3074, 2929, 2855, 2361, 2334, 1710, 1457, 1315, 1158, 1124, 1060,
1037, 768 cm–1.
Triethyl[3-(4-methoxyphenyl)-1-propynyl]silane (Table 2,
Entry 1)
The title compound was obtained as a clear oil (259 mg, 99%). 1H
NMR (400 MHz, CDCl3): d = 7.32 (d, J = 8.4 Hz, 2 H), 6.90 (d,
J = 8.4 Hz, 2 H), 3.84 (s, 3 H), 3.67 (s, 2 H), 1.06 (t, J = 8.0 Hz, 9
H), 0.68 (q, J = 8.0 Hz, 6 H). 13C NMR (100 MHz, CDCl3): d =
158.4, 128.9, 128.7, 113.9, 105.9, 83.9, 55.4, 25.5, 7.7, 4.7. IR
(neat): 2955, 2911, 2874, 2174, 1612, 1586, 1512, 1462, 1417,
1333, 1302, 1247, 1175, 1039, 1020, 815, 807, 726 cm–1.
Synlett 2006, No. 18, 2941–2946 © Thieme Stuttgart · New York

2946
C. H. Larsen et al.
LETTER
6-(4-Fluorophenyl)-hex-4-ynenitrile (Table 3, Entry 5)
160.9, d, J = 246.4 Hz), 129.6 (129.77, 129.73, d, J = 4.0 Hz), 128.4
(128.45, 128.38, d, J = 7.0 Hz), 119.3, 115.6 (115.8, 115.5, d,
J = 21.9 Hz), 96.2, 92.4, 24.7, 16.6. IR (neat): 2927, 2246, 1951,
1603, 1507, 1224, 1156, 879, 838 cm–1.
The title compound was obtained as a clear oil (170 mg, 91%). 1H
NMR (400 MHz, CDCl3): d = 7.30 (m, 2 H), 7.01 (m, 2 H), 3.57 (m,
2 H), 2.60 (m, 4 H). 13C NMR (100 MHz, CDCl3): d = 161.8 (163.0,
160.5, d, J = 244.4 Hz), 132.4 (132.39, 132.36, d, J = 3.1 Hz), 129.4
(129.45, 129.37, d, J = 8.0 Hz), 118.7, 115.5, 115.3, 80.8, 78.3,
24.3, 17.2, 16.3. IR (neat): 3075, 2928, 2854, 2248, 2208, 1722,
1648, 1599, 1508, 1424, 1269, 1225, 1157, 853 cm–1.
Acknowledgment
We thank the National Institutes of Health (GM 46059) and the Na-
tional Cancer Institute (Cancer Training Grant GM 5-T32-
CAO9112-30) for support of this work. The Bruker Advance-400
MHz instrument used in this work was purchased with funding from
the National Institutes of Health (GM 1S10RR13886-01). We are
grateful to Merck and Amgen for additional support.
General Procedure for Heck Alkynylation of Benzyl Chlorides
To Form Benzyl Allenes (Table 3)
A disposable tube with a screw cap, Teflon septum and stir bar
was charged with PdCl2(CH3CN)2 (5.2 mg, 0.02 mmol, 2.0 mol%),
2-dicyclohexylphosphino-2¢,4¢,6¢-triisopropylbiphenyl (1, 28.6 mg,
0.06 mmol, 6.0 mol%) and Cs2CO3 (2.5 equiv). The tube was evac-
uated and back-filled with argon three times. The benzyl chloride
(1.00 mmol) and solvent was added and the reaction mixture was al-
lowed to stir at r.t. for 3 min. The terminal alkyne (1.30 mmol) was
added all at once and the solution was heated to the noted tempera-
ture until the reaction was complete as judged by GC analysis. After
cooling to r.t., the products were extracted from the water layer with
Et2O or EtOAc, dried over MgSO4, filtered through Celite® and
concentrated to dryness and purified by column chromatography on
silica gel.
References and Notes
(1) Metal-Catalyzed Cross-Coupling Reactions, Vol. 2; de
Meijere, A.; Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004.
(2) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
(3) Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163.
(4) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93,
259.
(5) (a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(b) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.;
Hagihara, N. Synthesis 1980, 627.
(6) (a) Bohm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem.
2000, 22, 3679. (b) Hundertmark, T.; Littke, A. F.;
Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729.
(c) Kollhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem.
Int. Ed. 2003, 125, 13642.
Undeca-1,2-dienylbenzene (Table 3, Entry 2/Equation 2)16
The title compound was obtained as a clear oil (130 mg, 60%). 1H
NMR (400 MHz, CDCl3): d = 7.25–7.32 (m, 4 H), 7.14–7.19 (m, 1
H), 6.11 (m, 1 H), 5.55 (q, J = 3.2 Hz, 1 H), 2.11 (qd, J = 3.2, 7.2
Hz, 2 H), 1.25–1.51 (m, 15 H), 0.87 (t, J = 6.8 Hz, 3 H). 13C NMR
(100 MHz, CDCl3): d = 205.3, 135.4, 128.7, 126.79, 126.77, 95.3,
94.7, 32.0, 29.6, 29.5, 29.4, 29.3, 28.9, 22.9, 14.3.
(7) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642.
(8) Gelman, D.; Buchwald, S. L. Angew. Chem. Int. Ed. 2003,
42, 5993.
(9) Perez, I.; Sestelo, J. P.; Sarandeses, L. A. J. Am. Chem. Soc.
2001, 123, 4155.
(10) Qian, M.; Negishi, E. Tetrahedron Lett. 2005, 46, 2927.
(11) Pottier, L. R.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Synlett
2004, 1503.
(12) For the preparation and use of ligand 2, see: Anderson, K.
W.; Buchwald, S. L. Angew. Chem. Int. Ed. 2005, 44, 6173.
(13) Reaction of (1-chloroethyl)benzene and 1-decyne resulted in
a reproducible yield of 54%; however, the product was
unstable and decomposed rapidly.
1-Trifluoromethyl-2-undeca-1,2-dienylbenzene (Table 3, Entry
4)
The title compound was obtained as a clear oil (214 mg, 72%). 1H
NMR (400 MHz, CDCl3): d = 7.52 (t, J = 8.0 Hz, 2 H), 7.36 (t,
J = 7.6 Hz, 1 H), 7.15 (t, J = 7.6 Hz, 1 H), 6.41 (m, 1 H), 5.52 (q,
J = 6.8 Hz, 1 H), 2.06 (qd, J = 2.8, 7.6 Hz, 2 H), 1.39 (m, 2 H), 1.10–
1.28 (m, 10 H), 0.79 (m, 3 H). 13C NMR (100 MHz, CDCl3): d =
206.7, 134.1, 131.8, 128.7, 126.7 (q, J = 30.1 Hz), 126.5, 126.0 (q,
J = 26.7 Hz), 123.3, 120.6, 32.1, 29.6, 29.5, 29.4, 29.3, 28.7, 22.9,
14.3. IR (neat): 2927, 2856, 1950, 1605, 1579, 1493, 1455, 1316,
1159, 1124, 1035, 763 cm–1.
(14) Kunishima, M.; Nakata, D.; Tanaka, S.; Hioki, K.; Tani, S.
Tetrahedron 2000, 56, 9927.
(15) Friary, R.; Seidl, V. J. Org. Chem. 1986, 51, 3214.
(16) Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726.
6-(4-Fluorophenyl)hexa-4,5-dienenitrile (Table 3, Entry 6)
The title compound was obtained as a yellow oil (130 mg, 70%). 1H
NMR (400 MHz, CDCl3): d = 7.17 (q, J = 5.6 Hz, 2 H), 6.90 (t,
J = 8.4 Hz, 2 H), 6.17 (m, 1 H), 5.54 (q, J = 6.0 Hz, 1 H), 2.32–3.47
(m, 4 H). 13C NMR (100 MHz, CDCl3): d = 204.9, 162.1 (163.3,
Synlett 2006, No. 18, 2941–2946 © Thieme Stuttgart · New York