Copper-free sonogashira cross-coupling of ynamides: Easy access to various substituted ynamides from nonsubstituted ynamides

Article abstract of DOI:10.1055/s-0030-1258023

It is demonstrated herein that palladium-catalyzed Sonogashira cross-coupling of ynamides can be accomplished with moderate to good yields of substituted ynamides in the absence of copper salt, and NaOAc plays an important role in this reaction as an addi

Full text of DOI:10.1055/s-0030-1258023

2322
LETTER
Copper-Free Sonogashira Cross-Coupling of Ynamides: Easy Access to
Various Substituted Ynamides from Nonsubstituted Ynamides
C
opper-Free Sono
i
gashira
d
Cross-Coup
e
ling of
Y
na
a
mides ki Wakamatsu,* Mitsuhiro Takeshita
Department of Organic Reaction Chemistry, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan
E-mail: hiwaka@tohoku-pharm.ac.jp
Received 21 May 2010
copper iodide was added after mixing an ynamide, aryl
Abstract: It is demonstrated herein that palladium-catalyzed Sono-
halide, and palladium complex in a solvent. The synthesis
of 2-aminoindole derivatives, which was accomplished by
gashira cross-coupling of ynamides can be accomplished with mod-
erate to good yields of substituted ynamides in the absence of
the Sonogashira coupling of ynamides followed by hy-
droamination, was reported by Skrydstrup and co-
workers8 simultaneously with the finding of our result in
Scheme 1. Unfortunately, the isolation of coupling prod-
ucts was not completed, although their synthesis should
be achieved via a Sonogashira cross-coupling reaction. So
we decided to examine the details of our coupling reaction
of ynamides, because we were interested in this simple
handling reaction that proceeded without a catalytic
amount of copper salt to provide coupling product 39 in
good yield.
copper salt, and NaOAc plays an important role in this reaction as
an additive.
Key words: carboxylate anion, copper-free, cross-coupling, palla-
dium, ynamide
Ynamides should exhibit attractive reactivity because of
their differences in p-orbital electron density compared to
usual carbon–carbon triple bonds and should be useful
synthons in synthetic organic chemistry.1 Recently, sever-
al kinds of novel catalytic reactions of ynamides with
transition-metal complexes have been reported.2 We have
studied the ring-closing metathesis of ynamides, which
can be applied to useful synthetic methods for a wide
range of heterocycles.3 Encouraged by the success of our
results, we have continued to try to develop a new transi-
tion-metal-catalyzed reaction of ynamides. Herein, we de-
scribe efficient copper-free Sonogashira cross-coupling4,5
of ynamides, which provide substituted ynamides from
nonsubstituted ones.
At first, several kinds of additives were examined and are
shown in Table 1. When the reaction was carried out in
the presence of ammonium acetate, a similar yield was ob-
tained (Table 1, entry 2). An ammonium cation was not
required for unimpeded coupling and excellent yield was
obtained, when sodium acetate and potassium acetate
were used (entry 3, 4). Although the organic base could be
used for this reaction, the similar yield was obtained (en-
try 5). Furthermore, it is thought that the effective chemi-
cal species for this reaction is not the carbonate anion, as
concluded from the lower yield observed using potassium
carbonate and sodium hydrogen carbonate (entry 6, 7). It
is suggested that the presence of the carboxylate anion and
their basicity play the key roles from these results.
Bn
Ts
Bn
Ts
a
+
N
N
CO2Et
I
CO2Et
1
2
3
Scheme 1 Sonogashira cross-coupling of ynamide 1 catalyzed by
palladium acetate. Reagents and conditions: a) Pd(OAc)2 (5 mol%),
Ph3P (10 mol%), HCO2NH4 (1.5 equiv), DMF, 80 °C, 1 h, 74%.
The effect of sodium acetate was examined (Table 2).
When the reaction was carried out in the absence of sodi-
um acetate, coupling product 3 was not obtained at all (en-
try 1). Enhancement of the yield of 3 was observed in the
presence of 0.5 equivalent of the additive (entry 2), and a
60% yield of 3 was achieved by using a 1.0 equivalent of
sodium acetate (entry 3). When 2.0 equivalents of sodium
acetate were used, the yield resulted in a slight reduction
relative to using 1.5 equivalents of the additive (entry 5).
When a reaction of ynamide 1 with aryl iodide 2 in the
presence of 5 mol% of palladium acetate was carried out
at 80 °C for one hour in DMF, Sonogashira cross-
coupling proceeded smoothly to provide substituted
ynamide 3 in 74% yield (Scheme 1).
It is well known that a dimerized product of ynamide is
mainly obtained when an ynamide is exposed to a general
Sonogashira cross-coupling conditions.6 On the other
hand, the Sonogashira cross-coupling of ynamides was re-
ported by Hsung and co-workers.7 This first Sonogashira
coupling was achieved by a two-step procedure in which
The results of temperature effects are shown in Table 3.
The yield was slightly reduced by decreasing the reaction
temperature to 50 °C (entry 2). When the reaction was car-
ried out at room temperature, the prolonged reaction time
was required to provide the coupling product 3 in 76%
yield (entry 3).
On the basis of these results, the optimum reaction condi-
tions was defined as follows: Ynamide (1.0 equiv), aryl
halide (1.2 equiv), Pd(OAc)2 (5 mol%), Ph3P (10 mol%),
NaOAc (1.5 equiv), DMF, 80 °C, 1 h.
SYNLETT 2010, No. 15, pp 2322–2324
Advanced online publication: 09.08.2010
DOI: 10.1055/s-0030-1258023; Art ID: U04010ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
0

LETTER
Copper-Free Sonogashira Cross-Coupling of Ynamides
2323
Table 1 Screening of Additivesa
Table 3 Effects of Temperaturea
Bn
N
Bn
N
Ts
Ts
Pd(OAc)2, Ph3P
NaOAc, DMF
Pd(OAc)2, Ph3P
additive, DMF
+
1
1
Bn
Ts
Bn
Ts
+
N
CO2Et
N
CO2Et
3
3
I
CO2Et
I
CO2Et
2
2
Entry
Additive (1.5 equiv)
Yield of 3 (%)b
Entry
Temp (°C)
Time (h)
Yield of 3 (%)b
1
2
3
4
5
6
7
HCO2NH4
NH4OAc
NaOAc
KOAc
74
74
75
74
71
43
21
1
2
3
80
50
r.t.
1
2
5
75
71
76
a Reaction conditions: 1 (1.0 equiv), 2 (1.2 equiv), Pd(OAc)2 (5
mol%), Ph3P (10 mol%), NaOAc (1.5 equiv), DMF.
b Isolated yield.
Et3N
K2CO3
effect of an electron-withdrawing group were verified,
and the yields of product were satisfactory (entry 6, 7).
NaHCO3
a Reaction conditions: 1 (1.0 equiv), 2 (1.2 equiv), Pd(OAc)2 (5
mol%), Ph3P (10 mol%), DMF, 80 °C, 1 h.
b Isolated yield.
Table 4 Sonogashira Cross-Coupling of Ynamide 1 with Various
Aryl Halidesa
Bn
N
Table 2 Effect of the Amount of NaOAca
Ts
Bn
N
Pd(OAc)2, Ph3P
NaOAc, DMF
1
Bn
+
Ts
N
Pd(OAc)2, Ph3P
1
X
Ts
Bn
DMF
I
3, 10–15
+
N
CO2Et
X
Ts
2, 4–9
3
I
CO2Et
Entry Aryl halides (X)
Products (X)
3 (4-EtO2C)
10 (H)
Yield (%)b
2
Entry
NaOAc (equiv)
Yield of 3 (%)b
1
2
3
4
5
6
7
2 (4-EtO2C)
4 (H)
75
68
32
71
36
72
65
1
2
3
4
5
0
0
5 (4-OMe)
6 (2-Me)
11 (4-MeO)
12 (2-Me)
0.5
1.0
1.5
2.0
26
60
75
66
7 (2,6-di-Me)
8 (4-F3C)
9 (4-NC)
13 (2,6-di-Me)
14 (4-F3C)
a Reaction conditions: 1 (1.0 equiv), 2 (1.2 equiv), Pd(OAc)2 (5
mol%), Ph3P (10 mol%), DMF, 80 °C, 1 h.
b Isolated yield.
15 (4-NC)
a Reaction conditions: 1 (1.0 equiv), ArX (1.2 equiv), Pd(OAc)2 (5
mol%), Ph3P (10 mol%), NaOAc (1.5 equiv), DMF, 80 °C, 1 h.
b Isolated yield.
The reactions of ynamide 1 with various aryl halides (4–
9) were examined and are shown in Table 4. Good con-
version and good product yield of 10 was obtained in the
reaction of ynamide 1 with iodobenzene 4 (entry 2). The
product yield decreased in the case of iodomethoxyben-
zene 5 which has an electron-donating group (entry 3).
The reaction of 6, having an ortho substituent, proceeded
to provide 12 in 71% yield (entry 4), although using
ortho-disubstituted aryl iodide 7 as a coupling partner fur-
nished a 36% yield (entry 5). Further examinations of the
Given the success of the copper-free Sonogashira cross-
coupling of ynamide 1, we tried to use not only sulfonyl
ynamide 1 as the substrate but also urethane ynamide 16
for the Sonogashira coupling. When a reaction of 16 with
2 was carried out under identical conditions, substituted
ynamide 17 was afforded in 77% yield (Table 5, entry 1).
A comparable yield was obtained in the reaction with
iodobenzene 4 (entry 2). The electron-donating group and
Synlett 2010, No. 15, 2322–2324 © Thieme Stuttgart · New York

2324
H. Wakamatsu, M. Takeshita
LETTER
(2) For recent examples of transition-metal-catalyzed reaction
of ynamides, see: (a) Oppenheimer, J.; Johnson, W. L.;
Figueroa, R.; Hayashi, R.; Hsung, R. P. Tetrahedron 2009,
65, 5001. (b) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.;
Rottlander, M.; Skrydstrup, T. Org. Lett. 2009, 11, 4208.
(c) Li, H.; Hsung, R. P. Org. Lett. 2009, 11, 4462.
(d) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009, 131,
3802. (e) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang,
Y.-S.; Huang, J.; Hsung, R. P. Org. Lett. 2009, 11, 899.
(f) Garcia, P.; Moulin, S.; Miclo, Y.; Leboeuf, D.; Gandon,
V.; Aubert, C.; Malacria, M. Chem. Eur. J. 2009, 15, 2129.
(3) Mori, M.; Wakamatsu, H.; Saito, N.; Sato, Y.; Narita, R.;
Sato, Y.; Fujita, R. Tetrahedron 2006, 62, 3872.
the ortho disubstituent reduced the yield of coupling prod-
ucts 19 and 21 (entry 3, 5). The reaction of 16 with o-
iodotoluene 6 succeeded, and 20 was provided in 63%
yield (entry 4). We had certainty about the possitive effect
of electron-withdrawing group for copper-free Sonogash-
ira coupling of ynamides, because p-trifluoromethyl and
p-nitrile substituents led to good product yields (entry 6,
7).
Table 5 Sonogashira Cross-Coupling of Ynamide 16 with Aryl
Halidesa
Ph
(4) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467. (b) Chinchilla, R.; Nájera, C. Chem.
Rev. 2007, 107, 874.
O
N
(5) For recent examples of copper-free Sonogashira cross-
coupling, see: (a) Suzuka, T.; Okada, Y.; Ooshiro, K.;
Uozumi, Y. Tetrahedron 2010, 66, 1064. (b) John, A.;
Shaikh, M. M.; Ghosh, P. Dalton Trans. 2009, 10581.
(c) Blaszczyk, I.; Trzeciak, A. M.; Ziolkowski, J. J. Catal.
Lett. 2009, 133, 262. (d) Finke, A. D.; Elleby, E. C.; Boyd,
M. J.; Weissman, H.; Moore, J. S. J. Org. Chem. 2009, 74,
8897. (e) Gracia, S.; Metay, E.; Pellet-Rostaing, S.; Lemaire,
M. Synlett 2009, 2617. (f) Bakherad, M.; Keivanloo, A.;
Bahramian, B.; Mihanparast, S. Tetrahedron Lett. 2009, 50,
6418. (g) Wang, X.; Qin, W.; Kakusawa, N.; Yasuike, S.;
Kurita, J. Tetrahedron Lett. 2009, 50, 6293. (h) Mao, J.;
Wu, M.; Xie, G.; Ji, S. Adv. Synth. Catal. 2009, 351, 2101.
(i) Samantaray, M. K.; Shaikh, M. M.; Ghosh, P. J.
Organomet. Chem. 2009, 694, 3477. (j) Luo, Y.; Wu, J.
Tetrahedron 2009, 65, 6810. (k) Zhang, B.-S.; Wang, C.;
Gong, J.-F.; Song, M.-P. J. Organomet. Chem. 2009, 694,
2555. (l) Chandra, A.; Singh, B.; Khanna, R. S.; Singh, R.
M. J. Org. Chem. 2009, 74, 5664. (m) Kuang, Y.-Y.; Chen,
F.-E. Helv. Chim. Acta 2009, 92, 897. (n) Pschierer, J.;
Plenio, H. Org. Lett. 2009, 11, 2551. (o) Dash, C.; Shaikh,
M. M.; Ghosh, P. Eur. J. Inorg. Chem. 2009, 1608.
(p) Ngassa, F. N.; Lindsey, E. A.; Haines, B. E. Tetrahedron
2009, 65, 4085. (q) Bakherad, M.; Keivanloo, A.;
Ph
O
Pd(OAc)2, PPh3
NaOAc, DMF
16
+
O
N
X
O
I
17–23
X
2, 4–9
Entry
Aryl halides (X)
2 (4-EtO2C)
4 (H)
Products (X)
17 (4-EtO2C)
18 (H)
Yield (%)b
1
2
3
4
5
6
7
77
62
37
63
35
81
87
5 (4-MeO)
6 (2-Me)
19 (4-MeO)
20 (2-Me)
7 (2,6-di-Me)
8 (4-F3C)
21 (2,6-di-Me)
22 (4-F3C)
9 (4-NC)
23 (4-NC)
a Reaction conditions: 16 (1.0 equiv), ArX (1.2 equiv), Pd(OAc)2 (5
mol%), Ph3P (10 mol%), NaOAc (1.5 equiv), DMF, 80 °C, 1 h.
b Isolated yield.
Bahramian, B.; Hashemi, M. Tetrahedron Lett. 2009, 50,
1557. (r) Gu, S.; Chen, W. Organometallics 2009, 28, 909.
(s) Lu, N.; Chen, Y.-C.; Chen, W.-S.; Chen, T.-L.; Wu, S.-J.
J. Organomet. Chem. 2009, 694, 278. (t) Carpita, A.;
Ribecai, A. Tetrahedron Lett. 2009, 50, 204.
In conclusion, we have studied the palladium-catalyzed
copper-free Sonogashira cross-coupling of ynamides. The
presence of a small excess of the carboxylate anion, and
the absence of copper play an important role in this reac-
tion. The dimerization of ynamide was not observed, and
moderate to good yields of the coupling products were ob-
tained. Many different kinds of syntheses of ynamides
have now become possible, although it was recognized
that the transformation of nonsubstituted ynamides to sub-
stituted ynamides by Sonogashira cross-coupling was
limited, except for Hsung’s report.7 Further studies of this
reaction and the possibility of ynamides for transition-
metal-catalyzed reactions are now in progress in our lab-
oratory.
(6) Rodríguez, D.; Castedo, L.; Saá, C. Synlett 2004, 783.
(7) Tracey, M. R.; Zhang, Y.; Frederick, M. O.; Mulder, J. A.;
Hsung, R. P. Org. Lett. 2004, 6, 2209.
(8) Dooleweerdt, K.; Ruhland, T.; Skrydstrup, T. Org. Lett.
2009, 11, 221.
(9) Typical Procedure for Sonogashira Cross-Coupling
Reaction of Ynamide 1 Promoted by Palladium Acetate
To a solution of ynamide 1 (53.7 mg, 0.19 mmol), Pd(OAc)2
(2.1 mg, 9.41 mmol, 5 mol%), Ph3P (4.9 mg, 18.82 mmol, 10
mol%), and NaOAc (23.2 mg, 0.28 mmol, 1.5 equiv) in
DMF (6 mL) was added methyl 4-iodobenzoate 2 (0.04 mL,
0.23 mmol, 1.2 equiv) at 0 °C under argon atmosphere. The
reaction mixture was stirred at 80 °C for 1 h. After the
consumption of starting ynamide 1 was confirmed by TLC
analysis, the resulting mixture was cooled to 0 °C. H2O (12
mL) was added to the mixture, which was extracted with
Et2O (3 × 50 mL). The organic phase was washed with brine
and dried under MgSO4. The volatiles were removed under
reduce pressure. The residue was separated by column
chromatography on silica gel (hexane–EtOAc, 10:1) to
afford 3 (61.0 mg, 75%).
References and Notes
(1) For recent reviews on the chemistry of ynamines and
ynamides, see: (a) Zificsak, C. A.; Mulder, J. A.; Hsung,
R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57,
7575. (b) Brückner, D. Tetrahedron 2006, 62, 3809; and
references cited therein.
Synlett 2010, No. 15, 2322–2324 © Thieme Stuttgart · New York

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