Palladium-catalyzed methylation of alkynyl C(sp)-H bonds with dimethyl sulfonium ylides

Article abstract of DOI:10.1021/jo401851m

A novel palladium-catalyzed methylation protocol for the synthesis of methyl-functionalized internal alkynes has been established. This methylation method is achieved through a C(sp)-C(sp³) bond formation process and represents a new synthetic application of sulfonium ylides.

Full text of DOI:10.1021/jo401851m

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Article
Palladium-Catalyzed Methylation of Alkynyl
C(sp)-H Bond with Dimethyl Sulfonium Ylides
Yan-Yun Liu, Xu-Heng Yang, Xiao-Cheng Huang, Wen-Ting Wei, Ren-Jie Song, and Jin-Heng Li
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 23 Sep 2013
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The Journal of Organic Chemistry
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Palladium-Catalyzed Methylation of Alkynyl C(sp)-
H Bond with Dimethyl Sulfonium Ylides
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Yan-Yun Liu,a Xu-Heng Yang,a Xiao-Cheng Huang,a,b Wen-Ting Wei,a Ren-Jie Song,a and Jin-Heng
Li*a
a State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha 410082, China
b
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of
Education), Hunan Normal University, Changsha 410081, China
jhli@hnu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
Abstract
Pd(MeCN)2Cl2
-Bu-xantphos
t
CH3
R2
S
R1
H
R1
+
R2
S
CH3
+
CsF/K2CO3
toluene, 100 oC, Ar 29 examples
up to 93% yield
A novel palladium-catalyzed methylation protocol is established for the synthesis of methyl-
functionalized internal alkynes. This methylation method is achieved through a C(sp)-C(sp3) bond
formation process and represents a new synthetic application of sulfonium ylides.
Introduction
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Alkynes, particularly functionalized internal alkynes, are important unsaturated organic compounds that
found in a wide range of natural products, bioactive compounds and materials, as well as are significant
as synthetic intermediates in organic synthesis.1 As a consequence, the development of new chemical
methodologies using alkynes as the synthetic targets remains an active area all the while.1-7 In this
content, the classical Sonogashira cross-coupling reaction represents one of the most powerful methods
for the functionalized internal alkyne synthesis wherein aryl or vinyl halides and pseudohalides are
generally employed to react with terminal alkynes in the presence of a palladium catalyst and a copper
co-catalyst.2-5 Despite impressive advances in the Sonogashira cross-coupling field, examples of
transition metal-catalyzed Sonogashira cross-coupling of an alkyl electrophile with a terminal alkyne are
quite rare (Scheme 1a).3-5 Fu group has firstly established the Pd/N-heterocyclic carbene catalytic system
for the Sonogashira coupling of primary alkyl iodides and bromides.3 Subsequently, Glorius group4 has
reported another Pd/N-heterocyclic carbene catalytic system, extending the scope to secondary alkyl
bromides. Recently, Hu group illustrated that the NiII pincer complex was an efficient catalyst for the
Sonogashira coupling with alkyl halides, even primary alkyl chlorides.5 In these cases, however, Cu co-
catalyst was still necessary to trigger these transformations by the in-situ generation of copper acetylides
and phosphine ligands were ineffective. Moreover, the synthesis of methyl-functionalized internal
alkynes through this C(sp)-C(sp3) bond formation strategy has not been reported.3-5 Thus, the
development of conceptually novel Cu-free cross-coupling methods involving the use of new alkyl
electrophiles and/or new metal catalytic systems for preparing alkyl-substituted internal alkynes is thus
particularly important and urgent.6,7
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Sulfonium ylides are dipolarophiles and widely serve as versatile synthetic blocks in organic synthesis
because of their high reactivity and useful functionality.8 Generally, sulfonium ylides are utilized as
nucleophiles to construct the carbon-carbon bonds. To our knowledge, however, it is reasonable to
expect that sulfonium ylides as electrophiles for the cross coupling reaction should provide a convenient
method for the synthesis of functionalized internal alkynes. More recently, Maulide and co-workers
developed a transformation that the C-S linkage of a diphenyl sulfonium ylide was cleaved using
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Pd(OAc)2 and silane.9 Herein, we report a novel, copper-free cross-coupling route to selectively
synthesizing methyl-functionalized internal alkynes via PdCl2(MeCN)2/t-Bu-xantphos-catalyzed
methylation of alkynyl C(sp)-H bond with dimethyl sulfonium ylides, wherein dimethyl sulfonium
ylides are used as methyl electrophile (Scheme 1b).
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a) The reported Sonogashira cross-coupling process (refs. 3-5)
R'
R'
Pd or Ni
R
H + X
R
CuI, base
R''
R''
b) This work
Pd(MeCN)2Cl2
CH3
-Bu-xantphos
t
R2
S
R2
S
R1
H
+
R1
+
CH3
CsF/K2CO3
toluene, 100 oC, Ar
3
1
4
2
Scheme 1. Alkylation of Alkynyl C(sp)-H Bond.
Results and discussion
We began with our evaluation on the reaction between 1-ethynyl-4-methoxybenzene (1a) and
dimethyl (2-oxo-2-phenylethyl)sulfonium ylide (2a) (Table 1).10 Unfortunately, treatment of alkyne 1a
t
with ylide 2a, PdCl2(MeCN)2 and BuOLi only afforded a trace of 1-methoxy-4-(prop-1-ynyl)benzene
(3aa) (entry 1). The reported literatures suggested that the presence of ligands can improve the
Sonogashira coupling reaction with alkyl electrophiles. As expected, a series of ligands L1-L7,
including the reported efficient N-heterocyclic carbene ligand L13 and other phosphine ligands L2-L7,
were found to effect the reaction (entries 2-8), and the phosphine ligand L2 were the most efficient
(entry 3). In light of these, three other Pd catalysts, PdCl2, Pd(OAc)2 and Pd(dba)2 were subsequently
tested, and they displayed less catalytic activity (entries 9-11). Extensive screening revealed that bases
t
played an important role in the reaction (entries 12-18). While both BuONa and K2CO3 suppressed the
reaction (entries 12 and 13), both Cs2CO3 and CsF favored the reaction (entries 14 and 15). Notably, the
amount of base affected the reaction: product 3aa was obtained in 65% yield at 2 equiv CsF (entry 15),
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and increased to 70% yield at 1 equiv CsF (entry 16). We were delighted to discover that the use of
mixed bases could increase the yield (entries 17 and 18). For example, the yield of product 3aa was
enhanced to 81% using 1 equiv CsF combined with 2 equiv K2CO3 (entry 18). Among the reaction
temperature examined, it turned out that the reaction at 100 oC gave the best results (entries 18-20). It is
noteworthy that the reaction can not take place without Pd catalysts (entry 21).
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Table 1. Screening Optimal Conditionsa
MeO
Ph
L
[Pd],
3aa
S
+
MeO
+
base
O
Ph
S
2a
1a
O
4aa
PCy3
L5
tBu
P(tBu)2
O
P(tBu)2
PPh2
PPh2
N
O
Cl
P(tBu)2
PPh3
L6
N
tBu
L1
dppp
L7
L4
L2
L3
Entry
[Pd]
Ligand
Base (equiv)
T (oC)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18b
19
20
21
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2
tBuOLi (2)
tBuOLi (2)
tBuOLi (2)
tBuOLi (2)
tBuOLi (2)
tBuOLi (2)
tBuOLi (2)
tBuOLi (2)
tBuOLi (2)
tBuOLi (2)
tBuOLi (2)
tBuONa (2)
K2CO3 (2)
Cs2CO3 (2)
CsF (2)
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
trace
16
46
15
30
26
10
32
40
23
35
42
9
60
65
70
76
81
58
66
0

L1
L2
L3
L4
L5
L6
L7
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
Pd(OAc)2
Pd(dba)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2

CsF (1)
CsF (1)/Cs2CO3 (2) 100
CsF (1)/K2CO3 (2) 100
CsF (1)/K2CO3 (2) 120
CsF (1)/K2CO3 (2) 80
CsF (1)/K2CO3 (2) 100
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a Reaction conditions: 1a (0.5 mmol), 2a (1.2 equiv), [Pd] (5 mol %), Ligand (10
1
2
3
o
b
mol %), base and toluene (2 mL) at 100 C under argon atmosphere for 20 h.
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5
6
Product 4aa was isolated in 90% yield.
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As shown in Scheme 2, we next turned our attention to exploit the viable sulfonium ylides for the
alkylation reaction in the presence of PdCl2(MeCN)2, L2, CsF and K2CO3. The results indicated that the
substitution effect had a fundamental influence on the reaction. Ylides 2b, 2c and 2e with an electron-
rich aryl groups were still found to be efficient methylation reagents, albeit with lower yields than ylide
2a. However, ylide 2d with an electron-deficient aryl groups was ineffective. The other two sulfonium
ylides, dimethyl (2-ethoxy-2-oxoethyl)sulfonium ylide (2f) and dimethyl benzylsulfonium ylide (2g),
were examined, and both were unsuitable methylation reagents. Unfortunately, the other ylides,
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including
diethyl
(2-oxo-2-phenylethyl)sulfonium
ylide
(2ha),
di(n-butyl)
(2-oxo-2-
phenylethyl)sulfonium ylide (2ia) and diphenyl (2-oxo-2-phenylethyl)sulfonium ylide (2ja), could not
react with alkyne 1a under the optimal conditions, although decomposition of ylides took place.
Interestingly, methyl phenyl (2-oxo-2-phenylethyl)sulfonium ylide (2ka) selectively gave 1-methoxy-4-
(prop-1-ynyl)benzene (3aa) alone in 68% yield.
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Pd(MeCN)2Cl2
1
2
3
4
5
6
7
8
-Bu-xantphos
t
R2
S
MeO
MeO
+
CsF/K2CO3
toluene, 100 oC
Ar, 20 h
2
1a
O
3aa
S
O
S
O
R
9
Ph
2g
S
R = Me, 2b, 73%
R = MeO, , 67%
Et
S
2c
2d
O
10
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2f
, trace
2e
, 57%
, 9%
R = NO2, , <5%
O
R3
S
R4
2
Ph
Pd(MeCN)2Cl2
-Bu-xantphos
O
t
MeO
S
MeO
R3
+
R4
Ph
CsF/K2CO3, toluene
100 oC, Ar, 20 h
1a
4
3
3
4
2h
3ah
)
4ah
R = R = Et (
)
0% (
0% (3ai)
3aj
95% (
92% (4ai)
4aj
51% ( )
)
R3 = R4 = -Bu (2i)
n
3
4
2j
R = R = Ph ( )
0% (
)
R3 = Me, R4 = Ph (2k) 68% (3aa), 0% (3aj) 75% (4aj)
Scheme 2. Scope of Sulfonium Ylides (2).
With the optimal reaction conditions in hand, we set out to examine the scope of this new
methylation protocol (Table 2). Gratifyingly, this methylation protocol was general to a wide range of
terminal alkynes. Initially, a variety of arylalkynes 1b-1q were employed to react with dimethyl (2-oxo-
2-phenylethyl)sulfonium ylide (2a) in the presence of PdCl2(MeCN)2, L2, CsF and K2CO3 (Products
3ba-qa). The results showed that several substituents, such as Me, t-Bu, Br, Cl, F, CN, COCH3 or MeO,
on the aryl ring were well-tolerated, and the order of the reactivity was para>meta>ortho (Products 3ba-
na). Phenylacetylene (1b), for example, was successfully treated with ylide 2a, providing the expected
alkyne 3ba in 80% yield. Me- or even bulky t-Bu-substituted aryl alkynes 2c and 2d were also viable for
the methylation reaction (Products 3ca and 3da). Importantly, substituents, Br, Cl and F, on the aryl ring
were compatible with the optimal conditions, thereby easily facilitating additional modifications at the
halogenated positions (Products 3ea-ga). Using electron-deficient aryl alkynes, good yields were still
achieved (Products 3ha and 3ia). While 3-MeO- or 2,4-diMeO-substituted aryl alkynes offered the
corresponding products 3ja and 3ma in 76% and 77% yields, respectively, 2-MeO-substituted aryl
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alkyne resulted in product 3ka in 69% yield. We were pleased to find that the optimal conditions could
be applied to access 1-(prop-1-ynyl)naphthalene (3la) and bulky 1,3,5-trimethyl-2-(prop-1-ynyl)benzene
(3na). Interestingly, 1,4-diethynylbenzene 1o successfully underwent double methylation reactions,
providing a dimethylation product, 1,4-di(prop-1-ynyl)benzene (3oa), in good yield. Using heteroaryl
alkynes 1p and 1q, moderate yields were still achieved (Products 3pa and 3qa). Extensive screening
revealed that both vinyl alkyne 1r and aliphatic alkyne 1s were viable to react with ylide 2a leading to
the corresponding products 3ra and 3sa in high yields. Notably, oxygen-, nitrogen-, silicon- and iron-
functionalized alkynes 1t-1w were consistent with the optimal conditions, which made this methodology
more useful in organic synthesis (Products 3ta-wa).
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Table 2. Scope of Alkynesa
Pd(MeCN)2Cl2
Ph
-Bu-xantphos
t
R1
+
S
R1
CsF/K2CO3
toluene, 100 oC, Ar
1
O
3
2a
R
3ba
R = H,
, 80%
MeO
OMe
R = Me, 3ca, 82%
3ja
, 76%
3ka
, 69%
b
3da
, 75%
R = -Bu,
t
OMe
R = Br, 3ea, 73%
3fa
R = Cl,
, 93%
R = F, 3ga, 63%
3ha
MeO
R = CN,
R = COCH3, 3ia, 77%
, 71%
3la, 85%
3ma
, 77%
N
b
3oa
c
, 79%
3pa
, 48%
3na, 61%
C H
n-
N
8
17
c
3sa
, 75%
3ra
, 76%
N
Ph
3qa, 63%
O
3ua
(iPr)3Si
3va, 62%c
, 60%
Fe
Ph N
3ta, 76%
3wa
, 57%
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a
Reaction conditions: 1 (0.5 mmol), 2a (1.2 equiv), PdCl2(MeCN)2 (5
1
2
t
mol %), Bu-xantphos (10 mol %), CsF (1 equiv), K2CO3 (2 equiv) and
toluene (2 mL) at 100 oC under argon atmosphere for 20 h. 2a (2.4 equiv). c
b
3
4
5
For 48 h.
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7
8
9
An intermolecular deuterium-labeled experiment was carried out to understand the mechanism
(Scheme 3). The results demonstrated that the ratio of 3aa and 3aa-D3 was 1.2:1, suggesting that the
methyl group is really from dimethyl sulfonium ylide, and the cleavage of the S-CH3 bond is superior to
the cleavage of the S-CD3.
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OMe
OMe
Ph
Ph
CH3
OMe
S
O
O
CH3
Pd(MeCN)2Cl2
2a
+
-Bu-xantphos
t
+
+
CsF/K2CO3
toluene, 100 oC
Ar, 20 h
CD3
S
CH3
3aa
CD3
3aa-D3
80% (1.2:1)
CD3
1a
2a-D6
Scheme 3. Control Experiments.
Consequently, possible mechanisms as outlined in Scheme 4 were proposed on the present results.2-
5,8,9
Initially, oxidative addition of the active Pd0Ln species to the S-CH3 bond takes place to yield
intermediate B. Subsequently, intermediate B undergoes the reaction with alkyne 1 to afford
intermediate C and 2-(methylthio)-1-phenylethanone 4aa. Finally, reductive elimination of intermediate
C affords the desired methyl-functionalized internal alkyne 3 and the active Pd0Ln species. Notably,
another possible mechanism including Pd carbene intermediate E can be ruled out according to the
deuterium-labeled experiment (Scheme 3).
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Ph
Ph
1
2
3
4
5
6
7
S
S
S
Pd0Ln
O
O
O
A
2a
R1
Ln
Pd
Ph
S
Ph
O
B
8
9
3
R1
S
D
1
Pd0Ln
10
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Ln
Pd
Ph
PdLn
R1
O
C
4aa
E
Scheme 4. Possible mechanisms.
Conclusions
In summary, we have illustrated a conceptually novel Cu-free cross-coupling route to methyl-
functionalized internal alkynes through a C(sp)-C(sp3) bond formation process. This new methylation
method has a high alkyne compatibility and represents the first example of preparing alkyl-substituted
internal alkynes via the cross-coupling of terminal alkynes using sulfonium ylides as alkyl electrophiles.
Experimental Section
General Considerations:
The 1H and 13C NMR spectra were recorded in CDCl3 solvent on a NMR spectrometer using TMS as
internal standard. LRMS was performed on a GC-MS instrument and HRMS was measured on an
electrospray ionization (ESI) apparatus using time-of-flight (TOF) mass spectrometry. Melting points
are uncorrected.
Preparation of Terminal Alkynes:
Alkynes 1a-1c, 1g-1i, 1r, 1s, 1v and 1w were purchased from commercial sources and were used as
received. Alkynes 1t11, 1u12 and the other terminal alkynes 1d-1f and 1j-1q13 were prepared according
to literature procedures.
Preparation of Sulfur Ylides:
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Sulfide ylides 2a-2g were prepared according to the known procedures.14 2a-D was prepared by the
reaction of dimethyl-d6 sulfide15 with 2-bromo-1-phenylethanone.14
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3
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5
6
Typical Experimental Procedure for the Pd-Catalyzed Methylation Reaction:
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To a Schlenk tube were added alkyne 1 (0.5 mmol) and sulfonium ylide 2 (1.2 mmol),
PdCl2(MeCN)2 (5 mol %), tBu-xantphos (L1, 10 mol %), CsF (1 equiv), K2CO3 (2 equiv) and toluene (2
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mL). Then the tube was charged with argon, and was stirred at 100 C (oil bath temperature) for the
indicated time until complete consumption of starting material as monitored by TLC and GC-MS
analysis. After the reaction was finished, the reaction mixture was washed with brine. The aqueous
phase was re-extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4,
concentrated in vacuum, and the resulting residue was purified by silica gel column chromatography
(only hexane) to afford the desired product 3.
1-methoxy-4-(prop-1-ynyl)benzene (3aa):16 59 mg, 81%; Colorless oil; H NMR (500 MHz, CDCl3)
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δ: 7.32 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H), 2.02 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ: 159.0, 132.8, 116.2, 113.8, 84.1, 79.4, 55.2, 4.2; LRMS (EI, 70 eV) m/z (%): 147 (M++1, 19),
146 (M+, 100), 131 (47), 103 (75).
prop-1-ynylbenzene (3ba):17 46 mg, 80%; Colorless oil; 1H NMR (500 MHz, CDCl3) δ: 7.39-7.38 (m,
2H), 7.29-7.25 (m, 3H), 2.04 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 131.5, 128.2, 127.5, 124.0, 85.8,
79.7, 4.3; LRMS (EI, 70 eV) m/z (%): 117 (M++1, 7), 116 (M+, 77), 115 (100), 89 (12).
1-methyl-4-(prop-1-ynyl)benzene (3ca):16 53 mg, 82%; Colorless liquid; H NMR (500 MHz, CDCl3)
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δ: 7.27 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 2.32 (s, 3H), 2.03 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ: 137.4, 131.3, 128.9, 120.9, 84.9, 79.7, 21.3, 4.3; LRMS (EI, 70 eV) m/z (%): 131 (M++1, 13),
130 (M+, 100), 115 (70), 102 (6).
1-tert-butyl-4-(prop-1-ynyl)benzene (3da):18 65 mg, 75%; White solid, mp 66.7-67.8 oC (uncorrected);
1H NMR (500 MHz, CDCl3) δ: 7.33-7.28 (m, 4H), 2.04 (s, 3H), 1.30 (s, 9H); 13C NMR (125 MHz,
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CDCl3) δ: 150.6, 131.2, 125.2, 121.0, 84.9, 79.7, 34.6, 31.2, 4.3; LRMS (EI, 70 eV) m/z (%): 173
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(M++1, 5), 172 (M+, 38), 157 (100), 129 (27).
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1-bromo-4-(prop-1-ynyl)benzene (3ea):16 71 mg, 73%; Colorless oil; H NMR (500 MHz, CDCl3) δ:
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7.40 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 2.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 132.9,
131.4, 123.0, 121.6, 87.1, 78.7, 4.3; LRMS (EI, 70 eV) m/z (%): 194 (M++1, 4), 193 (M+, 40), 115 (100),
89 (16).
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1-chloro-4-(prop-1-ynyl)benzene (3fa):19 70 mg, 93%; Colorless oil; H NMR (500 MHz, CDCl3) δ:
7.30 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.5 Hz, 2H), 2.03 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 133.4,
132.7, 128.5, 122.5, 86.9, 78.7, 4.3; LRMS (EI, 70 eV) m/z (%): 152 (M++2, 20), 150 (M+, 63), 115
(100), 89 (10).
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1-fluoro-4-(prop-1-ynyl)benzene (3ga):19 42 mg, 63%; Colorless oil; H NMR (500 MHz, CDCl3) δ:
7.37-7.33 (m, 2H), 6.98-6.94 (m, 2H), 2.02 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 162.0 (d, J = 246.5
Hz), 133.2 (d, J = 8.1 Hz), 120.1 (d, J = 3.6 Hz), 115.3 (d, J = 21.8 Hz), 85.3, 78.6, 4.1; LRMS (EI, 70
eV) m/z (%): 135 (M++1, 3), 134 (M+, 77), 133 (100), 107 (10).
4-(prop-1-ynyl)benzonitrile (3ha):16 50 mg, 71%; Light yellow solid, mp 104.5-105.9 oC (uncorrected);
1H NMR (500 MHz, CDCl3) δ: 7.56 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 2.08 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ: 132.0, 131.9, 129.0, 118.6, 110.8, 91.1, 78.6, 4.4; LRMS (EI, 70 eV) m/z
(%): 142 (M++1, 10), 141 (M+, 99), 140 (100), 114 (43).
o
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1-(4-(prop-1-ynyl)phenyl)ethanone (3ia):20 61 mg, 77%; White solid, 50.3-51.6 C (uncorrected); H
NMR (500 MHz, CDCl3) δ: 7.86 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 2.57 (s, 3H), 2.07 (s, 3H);
13C NMR (125 MHz, CDCl3) δ: 197.2, 135.7, 131.5, 129.0, 128.1, 89.6, 79.2, 26.4, 4.3; LRMS (EI, 70
eV) m/z (%): 159 (M++1, 6), 158 (M+, 55), 143 (100), 115 (71).
1-methoxy-3-(prop-1-ynyl)benzene (3ja):16 55 mg, 76%; Colorless oil; 1H NMR (500 MHz, CDCl3) δ:
7.18 (t, J = 8.0 Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.93-6.92 (m, 1H), 6.83-6.81 (m, 1H), 3.78 (s, 3H),
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2.04 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 159.3, 129.2, 125.1, 124.0, 116.4, 114.1, 85.7, 79.7, 55.2,
4.2; LRMS (EI, 70 eV) m/z (%): 147 (M++1, 11), 146 (M+, 100), 131 (13), 115 (36).
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1-methoxy-2-(prop-1-ynyl)benzene (3ka):16 50 mg, 69%; Colorless oil; H NMR (500 MHz, CDCl3)
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δ: 7.38-7.36 (m, 1H), 7.24-7.21 (m, 1H), 6.89-6.83 (m, 2H), 3.86 (s, 3H), 2.10 (s, 3H); 13C NMR (125
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MHz, CDCl3) δ: 159.8, 133.5, 128.8, 120.3, 113.0, 110.4, 89.9, 75.8, 55.7, 4.6; LRMS (EI, 70 eV) m/z
(%): 147 (M++1, 11), 146 (M+, 100), 131 (66), 115 (30).
1-(prop-1-ynyl)naphthalene (3la):16 71 mg, 85%; Colorless oil; 1H NMR (500 MHz, CDCl3) δ: 8.35 (d,
J = 8.5 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.61(d, J = 7.0 Hz, 1H), 7.55-7.52 (m,
1H), 7.50-7.47(m, 1H), 7.38 (t, J = 8.0 Hz, 1H), 2.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 133.5,
133.2, 129.9, 128.1, 127.9, 126.4, 126.3, 126.2, 125.2, 121.7, 90.8, 77.7, 4.6; LRMS (EI, 70 eV) m/z
(%): 167 (M++1, 12), 166 (M+, 88), 165 (100), 139 (7).
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2,4-dimethoxy-1-(prop-1-ynyl)benzene (3ma):21 68 mg, 77%; Colorless oil; H NMR (500 MHz,
CDCl3) δ: 7.30-7.27 (m, 1H), 6.43-6.41 (m, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 2.10 (s, 3H); 13C NMR (125
MHz, CDCl3) δ: 160.9, 160.5, 134.2, 105.6, 104.6, 98.3, 88.2, 75.5, 55.8, 55.3, 4.7; LRMS (EI, 70 eV)
m/z (%): 177 (M++1, 12), 176 (M+, 100), 161 (28), 133 (19).
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1,3,5-trimethyl-2-(prop-1-ynyl)benzene (3na):22 48 mg, 61%; Colorless oil; H NMR (500 MHz,
CDCl3) δ: 6.83 (s, 2H), 2.37 (s, 6H), 2.25 (s, 3H), 2.12 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 139.9,
136.6, 127.6, 127.4, 120.7, 93.0, 21.2, 20.9, 4.5; LRMS (EI, 70 eV) m/z (%): 159 (M++1, 14), 158 (M+,
100), 143 (63), 128 (73).
o
1,4-di(prop-1-ynyl)benzene (3oa):23 61 mg, 79%; White solid, 104.3-105.5 C (uncorrected); 1H NMR
(500 MHz, CDCl3) δ: 7.37 (s, 4H), 2.12 (s, 6H); 13C NMR (125 MHz, CDCl3) δ: 131.3, 123.2, 87.3,
79.5, 4.3; LRMS (EI, 70 eV) m/z (%): 155 (M++1, 13), 154 (M+, 100), 139 (8), 115 (19).
2-(prop-1-ynyl)pyridine (3pa):24 28 mg, 48%; Light yellow oil; 1H NMR (500 MHz, CDCl3) δ: 8.54 (d,
J = 4.5 Hz, 1H), 7.62-7.59 (m, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.19-7.17 (m, 1H), 2.08 (s, 3H); 13C NMR
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(125 MHz, CDCl3) δ: 149.8, 143.9, 136.0, 126.6, 122.3, 86.6, 79.6, 4.3; LRMS (EI, 70 eV) m/z (%): 118
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(M++1, 10), 117 (M+, 100), 89 (54), 78 (11).
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5-(prop-1-ynyl)pyrimidine (3qa): 37 mg, 63%; Light yellow oil; H NMR (500 MHz, CDCl3) δ: 9.12
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(s, 1H), 8.75 (s, 2H), 7.36 (d, J = 7.5 Hz, 1H), 7.19-7.17 (m, 1H), 2.08 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ: 158.7, 156.2, 120.5, 93.7, 73.2, 4.5; LRMS (EI, 70 eV) m/z (%): 119 (M++1, 9), 118 (M+,
100), 91 (39), 64 (80); HRMS m/z (ESI) calcd for C7H7N2 (M+H)+ 119.0609, found 119.0606.
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1-(prop-1-ynyl)cyclohex-1-ene (3ra):25 46 mg, 76%; Colorless oil; H NMR (500 MHz, CDCl3) δ:
5.99 (t, J = 4.0 Hz, 1H), 2.10-2.06 (m, 4H), 1.92 (s, 3H), 1.64-1.54 (m, 4H); 13C NMR (125 MHz,
CDCl3) δ: 133.0, 120.9, 82.5, 81.4, 29.4, 25.4, 22.3, 21.5, 4.0; LRMS (EI, 70 eV) m/z (%): 121 (M++1,
9), 120 (M+, 90), 105 (100), 91 (95).
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undec-2-yne (3sa):7f 57 mg, 75%; Colorless oil; H NMR (500 MHz, CDCl3) δ: 2.13-2.09 (m, 2H),
1.77 (t, J = 3.0 Hz, 3H), 1.50-1.44 (m, 2H), 1.39-1.28 (m, 10H), 0.88 (t, J = 7.0 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ: 79.4, 75.2, 31.9, 29.2 (2C), 29.1, 28.9, 22.7, 18.7, 14.0, 3.4; LRMS (EI, 70 eV) m/z
(%): 152 (M+, 0.22), 109 (29), 95 (100), 81 (80), 67 (91).
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N-(but-2-ynyl)-N-methylaniline (3ta): 60 mg, 76%; Light yellow oil; H NMR (500 MHz, CDCl3) δ:
7.27-7.23 (m, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.78 (t, J = 7.5 Hz, 1H), 3.98-3.97 (m, 2H), 2.94 (s, 3H),
1.76 (t, J = 2.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ: 149.3, 129.0, 117.8, 114.0, 79.6, 74.5, 42.6,
38.5, 3.5; LRMS (EI, 70 eV) m/z (%): 160 (M++1, 12), 159 (M+, 100), 144 (30), 104 (18); HRMS m/z
(ESI) calcd for C11H14N (M+H)+ 160.1126, found 160.1122.
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((but-2-ynyloxy)methyl)benzene (3ua):26 48 mg, 60%; Colorless oil; H NMR (500 MHz, CDCl3) δ:
7.36-7.33 (m, 4H), 7.29-7.26 (m, 1H), 4.57 (s, 2H), 4.13-4.12 (m, 2H), 1.86 (t, J = 2.5 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ: 137.5, 128.3, 128.0, 127.7, 82.6, 75.0, 71.4, 57.6, 3.5; LRMS (EI, 70 eV)
m/z (%): 160 (M++1, 3), 159 (M+, 18), 145 (22), 105 (85), 91 (100).
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triisopropyl(prop-1-ynyl)silane (3va):27 61 mg, 62%; Colorless oil; H NMR (500 MHz, CDCl3) δ:
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1.91 (s, 3H), 1.08-1.05 (m, 21H); 13C NMR (125 MHz, CDCl3) δ: 104.3, 79.4, 18.6, 11.3, 4.8; LRMS
(EI, 70 eV) m/z (%): 197 (M++1, 2), 196 (M+, 8), 153 (100), 125 (48), 97 (80).
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prop-1-ynylferrocene (3wa): 64 mg, 57%; Brown solid, mp 89.7-91.2 oC (uncorrected); 1H NMR (500
MHz, CDCl3) δ: 7.34 (t, J = 2.0 Hz, 2H), 4.19 (s, 5H), 4.12 (t, J = 2.0 Hz, 2H), 1.93 (s, 3H); 13C NMR
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(125 MHz, CDCl3) δ: 81.7, 77.3, 71.0, 69.7, 68.0, 66.5, 4.4; LRMS (EI, 70 eV) m/z (%): 225 (M++1, 2),
224 (M+, 17), 223 (100), 157 (24), 120 (18); HRMS m/z (ESI) calcd for C13H13Fe (M+H)+ 225.0367,
found 225.0361.
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2-(methylthio)-1-phenylethanone (4aa):28 75 mg, 90%; Yellow oil; H NMR (500 MHz, CDCl3) δ:
7.98-7.97 (m, 2H), 7.57 (t, J = 7.5 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 3.76 (s, 2H), 2.13 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ: 193.9, 135.1, 133.2, 128.6, 128.5, 38.9, 15.7; LRMS (EI, 70 eV) m/z (%): 167
(M++1, 3), 166 (M+, 28), 120 (7), 105 (100).
2-(ethylthio)-1-phenylethanone (4ah):29 86 mg, 95%; Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 7.90
(d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 3.72 (s, 2H), 2.54-2.48 (m, 2H),
1.18 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 194.5, 135.1, 133.2, 128.7, 128.6, 36.7, 26.2,
14.1; LRMS (EI, 70 eV) m/z (%): 181 (M++1, 6), 180 (M+, 44), 120 (87), 105 (100).
2-(butylthio)-1-phenylethanone (4ai):30 96 mg, 92%; Yellow oil; 1H NMR (400 MHz, CDCl3) δ: 7.90
(d, J = 8.0 Hz, 2H), 7.49 (t, J = 7..2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 3.70 (s, 2H), 2.48 (t, J = 7.6 Hz,
2H ), 1.53-1.46 (m, 2H), 1.35-1.26 (m, 2H), 0.82 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
194.5, 135.2, 133.2, 128.7, 128.6, 37.0, 32.0, 30.9, 21.8, 13.6; LRMS (EI, 70 eV) m/z (%): 209 (M++1,
2), 208 (M+, 13), 120 (42), 105 (100).
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1-phenyl-2-(phenylthio)ethanone (4aj):31 86 mg, 75%; Yellow oil; H NMR (500 MHz, CDCl3) δ:
7.94-7.92 (m, 2H), 7.58-7.55 (m, 1H), 7.46-7.43 (m, 2H), 7.39-7.37 (m, 2H), 7.28-7.24 (m, 2H), 7.23-
7.19 (m, 1H), 4.27 (s, 2H); 13C NMR (125 MHz, CDCl3) δ: 194.0, 135.3, 134.7, 133.4, 130.4, 129.0,
128.6, 127.0, 41.1; LRMS (EI, 70 eV) m/z (%): 229 (M++1, 3), 228 (M+, 20), 123 (7), 105 (100).
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2a-D6: 1H NMR (500 MHz, CDCl3) δ: 7.79-7.77 (m, 2H), 7.35-7.33 (m, 3H), 4.34 (s, 1H); 13C NMR
(125 MHz, CDCl3) δ: 183.0, 140.8, 129.4, 127.8, 126.2, 50.8 (the deuterated carbon).
3aa and 3aa-D3: 1H NMR (500 MHz, CDCl3) δ: 7.33-7.30 (m, 2H), 6.82-6.79 (m, 2H), 3.78 (s, 3H),
2.02 (s, 1.6H); 13C NMR (125 MHz, CDCl3) δ: 159.0, 132.8, 116.2, 113.8, 84.1, 84.0, 79.4 (2C), 55.2,
4.2.
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Acknowledgments. We thank the Natural Science Foundation of China (No. 21172060), Specialized
Research Fund for the Doctoral Program of Higher Education (No. 20120161110041), and Hunan
Provincial Natural Science Foundation of China (No. 13JJ2018) for financial support. Dr. X.-C. Huang
also thank the Hunan Provincial Innovation Foundation For Postgraduate (CX2010B219).
Supporting Information Available: (1) Copies of spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
References and notes
(1) (a) The Chemistry of Triple-Bonded Functional Groups; Patai, S. Ed.; Wiley: New York, 1994. (b)
Modern Acetylene Chemistry; Stang, P. J.; Diederich, F. Eds.; VCH: Weinheim, 1995.
(2) For special reviews: (a) Sonogashira, K. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E. Ed.; Wiley-Interscience: New York, 2002, pp 493-529. (b) Negishi, E.;
Anastasia, L. Chem. Rev. 2003, 103, 1979. (c) Tykwinski, R. R. Angew. Chem. Int. Ed. 2003, 42,
1566. (d) Plenio, H. Angew. Chem. Int. Ed. 2008, 47, 6954. (e) Cross-coupling Reactions: A
Practical Guide; Miyaura, N. Ed.; Springer: Berlin, 2002. (f) de Meijere, A.; Diederich, F. Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH: Weinheim, 2004.
(3) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642.
(4) Altenhoff, G.; Wurtz, S.; Glorius, F. Tetrahedron Lett. 2006, 47, 2925.
(5) Vechorkin, O.; Barmaz, D.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 12078.
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(6) Cu-catalyzed cross-coupling of N-tosylhydrazones with trialkylsilylethynes through the C(sp)-
C(sp3) bond formation process: Ye, F.; Ma, X.; Xiao, Q.; Li, H.; Zhang, Y.; Wang, J. J. Am. Chem.
Soc. 2012, 134, 5742.
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(7) For selected papers on the other methods for the synthesis of alkyl-substituted internal alkynes
through the C(sp)-C(sp3) bond formation process via the cross-coupling with organometallic
reagents: (a) Yang, L.; Huang, L.; Luh, T. Org. Lett. 2004, 6, 1461. (b) Ohmiya, H.; Yorimitsu, H.;
Oshima, K. Org. Lett. 2006, 8, 3093. (c) Zhao, Y.; Wang, H.; Hou, X.; Lei, A.; Zhang, H.; Zhu, L. J.
Am. Chem. Soc. 2006, 128, 15048. (d) Cahiez, G.; Gager, O.; Buendia, J. Angew. Chem. Int. Ed.
2010, 49, 1278. (e) Chen, M.; Zheng, X.; Li, W.; He, J.; Lei, A. J. Am. Chem. Soc. 2010, 132, 4101.
(f) Vechorkin, O.; Godinat, A.; Scopelliti, R.; Hu, X. Angew. Chem. Int. Ed. 2011, 50, 11777. (g)
Hatakeyama, T.; Okada, Y.; Yoshimoto, Y.; Nakamura, M. Angew. Chem. Int. Ed. 2011, 49, 10793.
via the decarboxylative cross-coupling: (h) Rayabarapu, D.; Tunge, J. A. J. Am. Chem. Soc. 2005,
127, 13510. (i) Torregrosa, R. R. P.; Ariyarathna, Y.; Chattopadhyay, K.; Tunge, J. A. J. Am. Chem.
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Soc. 2010, 132, 9280 (j) Bi, H.; Zhao, L.; Liang, Y.; Li, C. Angew. Chem. Int. Ed. 2009, 48, 792. (k)
.
Zhang, W.-W.; Zhang, X.-G.; Li, J.-H. J. Org. Chem. 2010, 75, 5259.
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