Alkylation of terminal alkynes with transient σ-alkylpalladium(II) Complexes: A carboalkynylation route to alkyl-substituted alkynes

Article abstract of DOI:10.1002/chem.201303879

A mild and general alkylation of terminal alkynes with transient σ-alkylpalladium(II) complexes for assembling alkyl-substituted alkynes is described. This method represents a new way to the use of transient σ-alkylpalladium(II) complexes in organic synthesis through 1,2-carboalkynylation of alkenes.

Full text of DOI:10.1002/chem.201303879

DOI: 10.1002/chem.201303879
Communication
&
Triple Bond Chemistry
Alkylation of Terminal Alkynes with Transient s-Alkylpalladium(II)
Complexes: A Carboalkynylation Route to Alkyl-Substituted
Alkynes
Ming-Bo Zhou, Xiao-Cheng Huang, Yan-Yun Liu, Ren-Jie Song, and Jin-Heng Li*[a]
Abstract: A mild and general alkylation of terminal al-
kynes with transient s-alkylpalladium(II) complexes for as-
sembling alkyl-substituted alkynes is described. This
method represents a new way to the use of transient s-al-
kylpalladium(II) complexes in organic synthesis through
1,2-carboalkynylation of alkenes.
Alkynes are important structural motifs in a broad range of
natural products, bioactive compounds and materials, that dis-
play valuable utility as building blocks in organic synthesis.[1]
The development of new methods for the synthesis of alkynes
is therefore an important subject of current research.[2–5] De-
spite significant advances in the field, direct introduction of an
alkyl group into a carbon-carbon triple bond for the assembly
of alkyl-substituted alkynes remains a challenge.[3–5] Traditional-
ly, uncatalyzed nucleophilic alkylation of alkali metal acetylides
with alkyl halides is employed for the synthesis of alkyl-substi-
tuted alkynes.[1] However, the procedure is carried out in liquid
Scheme 1. Synthesis of alkyl-substituted alkynes.
ammonia and/or hexamethylphosphoramide at rather low
temperatures (often À788C); moreover, its substrate scope is
metal alkyl intermediates and oxidative dimerization of the
unsatisfactory due to both the strongly basic conditions and
the limited solubility of acetylides in liquid ammonia. The ap-
plications of this method in organic synthesis are, therefore,
limited. Alternatively, transition metal-catalyzed cross-coupling
reactions afford an efficient and direct synthetic approach to
diversified alkyl-substituted alkynes. To date, three elegant
types of transformation have been reported (Scheme 1a),[3–5]
including the Sonogashira-type cross-coupling of alkyl halides
and their derivatives with terminal alkynes,[3] cross-coupling
with organometallic reagents,[4] and cross-coupling of terminal
alkynes with N-tosylhydrazones by a migratory alkynyl inser-
tion of copper into a carbene.[5] However, the transition metal-
catalyzed synthesis of alkyl-substituted alkynes has not re-
ceived much attention and remains challenging because of the
potential for an undesired b-hydride elimination from the
metal alkynyl moieties during the cross-coupling process. Thus,
the development of conceptually novel cross-coupling routes
to alkyl-substituted internal alkynes is thus particularly impor-
tant and urgent.
Among these examples of transition metal-catalyzed cross-
coupling, in situ generation of the metal alkyl intermediates is
the key driving force.[3–5] Inspired by these, we reason that the
metal alkyl intermediates from other transition metal-catalyzed
processes, such as carbopalladation of alkenes (intermediate B;
Scheme 1b),[6] may be enough stable to be trapped by termi-
nal alkynes leading to alkyl-substituted alkynes. Herein, we
report
a new, highly selective palladium-catalyzed cross-
coupling of a transient s-alkylpalladium(II) complex B, generat-
ed in situ from 4-(o-haloaryl)alkenes and a Pd0 precursor[7] with
a terminal alkyne as a concise and convenient means of ac-
cessing diverse alkyl-substituted alkynes (Scheme 1b). Impor-
tantly, these alkyl-substituted alkyne derivatives containing
heterocyclic rings make this methodology more useful in or-
ganic synthesis because heterocyclic rings, such as oxindoles
and indolines, are important skeletal units that found in nu-
merous natural products and pharmaceutical compounds.[8]
Our work began with extensive screening of Pd catalysts, Cu
catalysts, bases and solvents, and the optimization data are
[a] M.-B. Zhou, X.-C. Huang, Y.-Y. Liu, Dr. R.-J. Song, Prof. Dr. J.-H. Li
State Key Laboratory of Chemo/Biosensing and Chemometrics
College of Chemistry and Chemical Engineering
Hunan University, Changsha 410082 (China)
Fax: (+86)731-8871-3642
E-mail: jhli@hnu.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201303879.
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Communication
Table 1. Screening optimal conditions.[a]
Table 2. Scope of alkynes (2)[a]
Entry [Pd] ([mol%])
[Cu] Base ([equiv]) t [h]
Isolated yield [%]
1
2
3
4
5
6
7
8
PdCl2(PPh3)2 (5) CuI
PdCl2(PPh3)2 (5) CuI
Et3N (24)
Et3N (48)
Et3N (48)
Et3N (48)
Et3N (48)
Et3N (48)
Et3N (6)
THF
–
–
–
–
–
toluene
toluene
toluene
toluene
toluene
85
93
0
PdCl2(PPh3)2 (5)
–
Pd(OAc)2 (5)
Pd(PPh3)4 (5)
–
CuI
CuI
CuI
0
74
83
88
82
64
98
99
PdCl2(PPh3)2 (5) CuI
PdCl2(PPh3)2 (5) CuI
Et3N (4)
9
PdCl2(PPh3)2 (5) CuBr Et3N (6)
PdCl2(PPh3)2 (5) CuCl Et3N (6)
PdCl2(PPh3)2 (1) CuCl Et3N (6)
PdCl2(PPh3)2 (1) CuCl pyridine (6)
PdCl2(PPh3)2 (1) CuCl K2CO3 (6)
10
11
12
13
toluene trace
toluene
toluene
toluene
95
47
97
14[b] PdCl2(PPh3)2 (1) CuCl Et3N (6)
15[c]
PdCl2(PPh3)2 (1) CuCl Et3N (6)
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), [Pd], [Cu]
(4 mol%), base, and solvent (1 mL) at room temperature under argon at-
mosphere for 24 h. [b] Under air atmosphere. [c] 1a (4 mmol, 1.204 g)
and 2a (4.8 mmol).
[a] Reaction conditions: 1a (0.3 mmol),
2
(0.36 mmol), PdCl2(PPh3)2
summarized in Table 1. Interestingly, treatment of N-(2-iodo-
phenyl)-N-methylmethacrylamide (1a) with phenylacetylene
(2a) Pd(PPh3)2Cl2, CuI and Et3N in THF at room temperature
under argon atmosphere furnished the desired product, 1,3-di-
methyl-3-(3-phenylprop-2-ynyl)indolin-2-one (3aa), in 85%
yield (Table 1, entry 1). With Et3N as the base and medium, the
yield of 3aa was increased to 93% (Table 1, entry 2). However,
substrate 1a is sluggish without either Pd or Cu catalysts
(Table 1, entries 3 and 4). Screening revealed that other Pd cat-
alysts, Pd(OAc)2 and Pd(PPh3)4, were less efficient than Pd-
(PPh3)2Cl2 (Table 1, entry 2 vs. Table 1, entries 5–6). We were
pleased to find that an excellent yield was still obtained when
the reaction was carried out with six equivalents of Et3N in tol-
uene (Table 1, entry 7); however, the yield was lowered to 82%
in the presence of four equivalents of Et3N (Table 1, entry 8).
Among the Cu catalysts examined, it turned out that CuCl was
the most effective: CuCl (98% yield)>CuI (88% yield)>CuBr
(64% yield) (Table 1, entries 7, 9 and 10). Notably, the current
reaction could successfully be carried out at 1 mol% Pd, lead-
ing to product 3aa in quantitative yield (Table 1, entry 11). In
the presence of 1 mol% Pd, two bases, pyridine and K2CO3,
were examined (Table 1, entries 12 and 13): whereas the reac-
tion with pyridine resulted in no conversion of substrate 1a,
excellent yield was achieved in the presence of K2CO3. It is
noteworthy that the presence of air does not favor the reac-
tion because homocoupling of alkyne 2a readily takes place
(Table 1, entry 14). Gratifyingly, on a 4 mmol scale with sub-
strate 1a the reaction also takes place smoothly to furnish
product 3aa in excellent yield (Table 1, entry 15).
(1 mol%), CuCl (4 mol%), Et3N (6 equiv), and toluene (1 mL) at room tem-
perature under argon atmosphere for 24 h. [b] At 508C. [c] 1a (0.5 mmol)
and 2p (0.2 mmol).
conditions can be applied to a wide range of terminal alkynes,
such as aryl alkynes, aliphatic alkynes and alkynes with func-
tional groups including olefins, SiMe3 and unprotected alco-
hols. Initially, a variety of aryl alkynes 2b–2i were investigated
in the presence of N-(2-iodophenyl)-N-methylmethacrylamide
(1a), Pd(PPh3)2Cl2, CuCl and Et3N (Products 3ab–3ai). Either
electron-rich or electron-deficient aryl alkynes reacted, but the
reactivity of the former is lower than that of the latter. For ex-
ample, 4-methyl- or 4-methoxy-substituted aryl alkynes 2b and
2c reacted smoothly to afford 3-alkynylindolin-2-ons 3ab and
3ac in 86% and 87% yields, respectively. Gratifyingly, the 4-
nitro-susbtitued alkyne 2 f furnished product 3af in 93% yield.
It was noted that a Cl group in the para- or ortho-position
could be tolerated, thereby facilitating additional modifications
at the halogenated position (Products 3ad and 3ae). Hetero-
aryl alkyes 5-ethynylpyrimidine (2g), 2-ethynylthiophene (2h),
particularly ethynylferrocene (2i), were found to be compatible
with the optimized conditions, providing the corresponding 3-
alkynylindolin-2-ons 3ag–3ai in excellent yields. For the ali-
phatic dec-1-yne (2l), a good yield was still achieved, although
higher temperature (508C) was required to improve the con-
version (Product 3al). Several functional groups including ole-
fins, SiMe3 and unprotected alcohols, at the terminal alkynes
were tolerated, making this method useful for the preparation
of pharmaceuticals and natural products (Products 3aj, 3ak,
3am and 3an). Notably, product 3ao contains two bioactive
With the optimized conditions in hand, we set out to probe
the scope of the reaction with both 4-arylalkenes (1) and al-
kynes (2; Tables 2 and 3). As shown in Table 2, the optimized
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Table 3. Scope of 4-(o-haloaryl)-1-alkenes (1).[a]
Scheme 2. Reactions of other 4-(o-haloaryl)-1-alkenes (1).
loxy)-2-(phenylethynyl)benzene (4na), in 79% total yield with
1:2 ratio.
As shown in Scheme 2, three other 4-(o-iodophenyl)alkenes
1o–q were tested with respect to phenylacetylene (2a) under
the optimal conditions. The results demonstrated the chemo-
selectivity of the cross-coupling reaction based on the struc-
ture of the substrates of type 1. For example, the internal
alkene 1o gave a Heck-type product 5o, exclusively, in good
yields [Eq. (1)]. However, 2-iodophenyl methacrylate (1p), an
ester, only afforded a Sonogashira-type product 4pa [Eq. (2)].
With S-2-iodophenyl 2-methylprop-2-enethioate (1q), only So-
nogashira-type product 4qa was observed in a low yield.
Interestingly, product 3aa could be readily converted into
2a,3-dihydrobenzo[cd]indol-2(1H)-one 6aa in moderate yield
through the palladium-catalyzed hydroarylation process along
with a hydration by-product 7aa in low yield [Eq. (3)].[9]
[a] Reaction conditions: 1a (0.3 mmol),
2 (0.36 mmol), PdCl2(PPh3)2
(1 mol%), CuCl (4 mol%), Et3N (6 equiv) and toluene (1 mL) at room tem-
perature under argon atmosphere for 24 h. Unless specified otherwise,
X=I. [b] At 808C. [c] At 508C.
molecule frameworks, indolin-2-one and testosterone, that
may elevate its pharmacokinetic properties. With 1,4-diethynyl-
benzene (2p), a symmetric bis(alkynyl)bis(indolin-2-
one) 3ap was assembled in 83% yield.
The scope of 4-arylalkenes 1 in the presence of
phenylacetylene (2a) or dec-1-yne (2l), Pd(PPh3)2Cl2,
CuCl and Et3N (Table 3) was investigated. Gratifyingly,
N-(2-bromophenyl)-N-methylmethacrylamide
(1b)
was a viable substrate for the tandem reaction with
alkyne 2a leading to product 3aa in 86% yield. Un-
fortunately, N-phenyl-N-methylmethacrylamide (1c)
was inert under the optimized conditions. Use of the
analogous amide with the N-methyl group replaced by
a benzyl or an acetyl group also resulted in good yields (Prod-
ucts 3ea and 3 fa), but substitution by a hydrogen atom was
sluggish (Product 3da). Substituents, such as Me, Cl or CF3, on
the aromatic ring of the N-aryl moiety were examined: they
were well-tolerated, although slight alterations to the condi-
tions (temperature) for reacting with aliphatic alkynes 2l (Prod-
ucts 3ha–3ja and 3hl–3jl) are necessary. For substrates 1k
and 1l with a functional group, Ph or CH2OAc, at the 2-posi-
tion of acrylamide, good yields were still obtained (Products
3ka and 3la). This process was successfully performed for the
cyclization of 2-iodo-N-(2-methylallyl)aniline 1m, an amine, in
high yields (Product 3ma). Interestingly, 1-iodo-2-(2-methylally-
loxy)benzene (1n), an ether, was suitable for the tandem cycli-
zation reaction, affording the desired product 3na together
with a Sonogashira cross-coupled product, 1-(2-methylally-
In summary, we have developed a novel direct and mild pro-
tocol for the synthesis of diverse alkyl-substituted alkynes by
palladium-catalyzed alkylation of terminal alkynes with transi-
ent s-alkylpalladium(II) complexes. This cross-coupling method
is achieved through a carbopalladation-alkynylation tandem
process, and has a broad substrate scope with respect to both
4-(o-haloaryl)alkenes and alkynes. Studies of the mechanism
and applications of this transient s-alkylpalladium(II) complex
in organic synthesis are currently underway in our laboratory.
Experimental Section
Typical experimental procedure for palladium-catalyzed synthe-
sis of alkyl-substituted alkynes: To a Schlenk tube were added 4-
(o-haloaryl)alkenes 1 (0.3 mmol), alkynes 2 (0.36 mmol), PdCl2-
(PPh3)2 (1 mol%), CuCl (4 mol%), Et3N (6 equiv) and toluene (2 mL).
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Acknowledgements
We thank the Specialized Research Fund for the Doctoral Pro-
gram of Higher Education (No. 20120161110041), Hunan Pro-
vincial Natural Science Foundation of China (No. 13JJ2018),
and Natural Science Foundation of China (No. 21172060) for fi-
nancial support.
1
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Keywords: 4-(o-haloaryl)alkenes
carboalkynylation · palladium
·
alkylation
·
alkynes
·
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Received: October 3, 2013
Revised: November 1, 2013
Published online on January 21, 2014
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