Palladium-Catalyzed Regioselective Hydroarylation of Ynamides with Aryl Iodides: Easy Synthesis of Various Substituted Enamides Containing Stilbene Derivatives

Article abstract of DOI:10.1055/s-0036-1588874

Palladium-catalyzed hydroarylation of ynamides has been developed. The desired coupling products were obtained in good yields and with high regioselectivities. Various aryl iodides can be used in this reaction, permitting the syntheses of many different k

Full text of DOI:10.1055/s-0036-1588874

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
letter
A
en
H. Wakamatsu et al.
Letter
Synlett
Palladium-Catalyzed Regioselective Hydroarylation of Ynamides
with Aryl Iodides: Easy Synthesis of Various Substituted Enamides
Containing Stilbene Derivatives
Hideaki Wakamatsu*
Ar
H
Rika Yanagisawa
Sho Kimura
Ar
N
H
R
Pd(OAc)2, DPPF
DMF, 100 °C, 18 h
Alkyl
N
R
Nao Osawa
Alkyl
EWG
EWG
Yoshihiro Natori
Yuichi Yoshimura*
R ≠ H
= alkyl chain
= aromatic ring
14 examples
up to 91% yield
Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical
University, Komatsushima 4-4-1, Aoba-ku, Sendai 981-8558, Japan
hiwaka@tohoku-mpu.ac.jp
yoshimura@tohoku-mpu.ac.jp
Received: 20.04.2017
Accepted after revision: 19.05.2017
Published online: 06.07.2017
hours, the desired coupling product 3a was obtained in 10%
yield, together with recovered 1a in 44% yield (Table 1, en-
try 1). Several phosphine ligands were tested for this reac-
tion (entries 2–5). Tricyclohexylphosphine did not work,
and 1a was recovered in 59% yield (entry 2). When 1,2-
bis(diphenylphosphino)ethane (DPPE), a typical bidentate
ligand, was used, a similar result was obtained to that with
Ph3P (entry 3). The use of 1,4-bis(diphenylphosphino)bu-
tane (DPPB) slightly improved the chemical yield of 3a (en-
try 4), but the best result was obtained when 1,1′-bis(di-
phenylphosphino)ferrocene (DPPF) was used (entry 5).
The stereochemistry of the enamide 3a was determined
by an NOE experiment, as shown in Figure 1.
DOI: 10.1055/s-0036-1588874; Art ID: st-2017-u0276-l
Abstract Palladium-catalyzed hydroarylation of ynamides has been
developed. The desired coupling products were obtained in good yields
and with high regioselectivities. Various aryl iodides can be used in this
reaction, permitting the syntheses of many different kinds of enamides
from ynamides.
Key words ynamides, hydroarylation, palladium catalysis, cross-cou-
pling, enamides, arylation
Over the past 20 years, the ynamide group has begun to
be recognized as a functional group that participates in a
new C–C bond-forming reaction.1 The useful C–C bond-
forming reaction of ynamides has been reported by several
research groups, who described the different π-orbital elec-
tron density in these compounds compared with that in
other C≡C triple bonds.2 We have also become interested in
the reactions of ynamides with transition-metal complexes.
A ring-closing metathesis (RCM) of ene–ynamides3 and a
copper-free Sonogashira coupling of unsubstituted
ynamides4 have already been reported by our research
group. Our continuing interests have focused on developing
additional transition-metal-catalyzed C–C bond-formation
reactions of ynamides. The hydroarylation of C≡C triple
bonds is known to be a useful method for the construction
of carbon frameworks.5–7 These reactions have been suc-
cessfully used for the synthesis of heterocycles.8 Here, we
describe a palladium-catalyzed regioselective hydroaryla-
tion reaction of substituted ynamides.
Table 1 Palladium-Catalyzed Hydroarylation of Ynamide 1a and
Screening of Ligandsa
EtO2C
Bn
Ts
N
n-Hex
5 mol% Pd(OAc)2, Ligand
1a
2a
HCO2NH4 (1.2 equiv)
DMF, 80 °C
Bn
N
n-Hex
I
CO2Et
Ts
3a
Entry
Ligand
Ph3Pb
Time (h)
Yield (%) of 3a Recovery (%) of 1a
1
2
3
4
5
20
18
18
18
18
10
–
44
59
63
30
45
b
PCy3
DPPE
DPPB
DPPF
12
23
24
When the reaction of ynamide 1a9 and aryl iodide 2a in
the presence of a catalytic amount of Pd(OAc)2 and Ph3P in
the presence of HCO2NH4 as a reducing agent was per-
formed in N,N-dimethylformamide (DMF) at 80 °C for 20
a Reaction conditions: 2a (1.2 equiv), ligand (5 mol%), HCO2NH4 (1.2
equiv).
b 10 mol% of the ligand was used.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
H. Wakamatsu et al.
Letter
Synlett
tively (Table 3, entries 1 and 2). 4-Iodobenzonitrile (2d),
which contains an additional electron-withdrawing group,
gave a satisfactory yield (entry 3). The C–C bond-forming
reaction proceeded smoothly to introduce the aryl substit-
uent at the α-position of the ynamide in the case of iodide
2e, which has a p-methoxy substituent as an electron-do-
nating group (entry 4). Aryl iodide 2f, with a methoxycar-
bonyl group in the ortho position, did not give a satisfactory
reaction (entry 5).
EtO2C
8.1%
Ts
N
6.3%
3.7%
Figure 1 NOE experiment for enamide product 3a
When the reaction of 1a with three equivalents each of
2a and HCO2NH4 was carried out at 80 °C for 18 hours, the
yield of the coupling product 3a increased to 56% (Table 2,
entry 1). At this point, we recovered 2a together with a de-
iodination product. Hydroarylation was restricted by the
reduction of 2a, as in the case shown in Table 1, entry 5. En-
couraged by these results, we decided to examine the reac-
tions of various aryl iodides. However, this required further
optimization of the reaction conditions, because decreased
coupling product yields were obtained in the cases of 1-flu-
oro-4-iodobenzene (2b) and 1-iodo-4-(trifluorometh-
yl)benzene (2c) (entries 2 and 3). The yields were slightly
improved on prolonging the reaction time (entry 4). Finally,
a satisfactory result in terms of regioselectivity was ob-
tained when the reaction was carried out at 100 °C; the ma-
jor isomer 3a was obtained in 76% yield together with a 15%
yield of 4a (entry 5).10
Table 3 Reactivity of Various Aryl Iodides to Hydroarylation of
Ynamide 1a
Ar
Bn
N
n-Hex
Bn
Bn
N
n-Hex
Ts
Ts
5 mol% Pd(OAc)2
5 mol% DPPF
1a
3
+
+
HCO2NH4 (3.0 equiv)
DMF, 100 °C, 18 h
Ar
I
Ar
(3.0 equiv)
N
n-Hex
Ts
4
Entry
Substrate Ar
Yield (%)
of 3
Yield (%) Recovery
of 4
(%) of 1a
1
2
3
4
5
2b
2c
2d
2e
2f
4-FC6H4
73
59
57
77
10
12
2
3
–
2
–
–
4-F3CC6H4
4-NCC6H4
13
5
4-MeOC6H4
2-MeO2CC6H4
Next, we examined the reactions of various aryl iodides
with ynamide 1a (Table 3). When the reactions of 2b and 2c
were repeated, the yields increased to 73% and 59%, respec-
9
At this point, we designed new substrates with the aim
of improving the regioselectivity. We surmised that if a
functional group was introduced onto the carbon substitu-
ent of the ynamide, it might coordinate with the palladium
to provide the palladacycle intermediate III, with suppres-
sion of the intermediate IV. Consequently, we predicted
that the yield of product V might be improved (Scheme 1).
When the reaction of ynamide 1b, having a benzoyl-
oxymethyl group at the terminal position of the alkyne, was
performed under the standard conditions, the desired
product was not obtained (Table 4, entry 1), and a complex
mixture was obtained on introduction of an ethoxycarbonyl
group (entry 2). When ynamide 1d, in which a siloxy group
was introduced at the end of the carbon chain, was exposed
to the standard reaction conditions, a good yield and high
regioselectivity were obtained (entry 3). Unfortunately, the
regioselectivity completely disappeared when the carboxy
amide 1e was used (entry 4). These results showed that an
improvement in the regioselectivity was difficult to achieve
through coordination of the functional group to the palladi-
um metal. Because the regioselectivity disappeared on
changing the 4-toluenesulfonamide group on the alkyne to
a carboxy amide group, the reaction of 1 should proceed re-
Table 2 Optimization of the Reaction Temperature and Time
Bn
N
n-Hex
Ts
5 mol% Pd(OAc)2
5 mol% DPPF
1a
+
HCO2NH4 (3.0 equiv)
DMF, 80 °C, 18 h
I
R
R
R
2a: R = CO2Et
2b: R = F
2c: R = CF3
+
(3.0 equiv)
Bn
N
n-Hex Bn
N
n-Hex
Ts
Ts
3
4
Entry
2
Yield (%) of 3 Yield (%) of 4 Recovery (%) of 1a
1
2a
2b
2c
2a
2a
56
30
38
59
76
7
–
22
48
52
18
4
2
3
4
4a
5b
9
15
a Reaction was carried out for 24 h.
b At 100 °C.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
H. Wakamatsu et al.
Letter
Synlett
Ar "Pd"
Y
Ar
H
Bn
N
Bn
Bn
N
n
n
Bn
Ts
Ts
Ts
Y
Y
N
V
Pd
intermediate III
"Pd" Ar
Bn
Ts
n
I
Y
H
N
Ar
+
I
Ar II
N
n
n
Ts
Y
Y = functional group
VI
intermediate IV
Scheme 1 Our hypothesis for the improvement of the regioselectivity
Next, we attempted to synthesize various stilbene de-
rivatives by introducing a phenyl group onto the terminal
carbon atom of the alkyne part of the ynamide (Table 5).
Under the optimized conditions, the reaction of ynamide
1f, substituted by a methyl group on the nitrogen atom and
a phenyl group on the terminal carbon of the alkyne, gave
the desired enamide 7f in 43% yield, together with a 25% re-
covery of substrate 1f (entry 1). An improved chemical yield
of 7g compared with that of 7f was observed on changing
the phenyl group to an electron-donating anisyl group (en-
try 2). The alkyl substituent on the nitrogen did not appear
to affect the product yield when the N-benzyl ynamide 1h
was used as a substrate (entry 3). However, we found that
the benzyl group had a slightly positive effect on the prod-
uct yield compared with that of the methyl group, and im-
proved yields were obtained when an anisyl group was
present on the terminal carbon atom of the alkyne (entry
4).
Table 4 Hydroarylation of Various Ynamides
R1
N
R2
EWG
5 mol% Pd(OAc)2
5 mol% DPPF
1
+
HCO2NH4 (3.0 equiv)
DMF, 100 °C, Time
I
CO2Et
2a (3.0 equiv)
EtO2C
CO2Et
+
R1
N
R2 R1
N
R2
EWG
EWG
5
6
Entry
1
Ynamide
Time
(h)
Yield (%) Yield (%)
of 5
of 6
Ts
N
N
N
18
18
24
–
–
Table 5 Synthesis of Stilbene Derivatives 7
Bn
O
O
1b
R1
EtO2C
Ts
O
N
Ts
R2
2
3
–
–
1
Bn
OEt
5 mol% Pd(OAc)2
5 mol% DPPF
+
1c
R2
R1
N
HCO2NH4 (3.0 equiv)
DMF, 100 °C, 18 h
I
CO2Et
2a (3.0 equiv)
Ts
Ts
7
57
13
Bn
OTBS
1d
Entry
Substrate R1
R2
Yield (%) of 7 Recovery (%) of 1
a
1
2
3
4
1f
Me
Me
Bn
H
43
55
40
71
25
–
Ph
1g
1h
1i
4-MeO
H
4
18
30
31
O
N
n-Hex
48
15
Bn
4-MeO
O
1e
a n-Hex = (CH2)5Me.
In conclusion, we have studied the palladium-catalyzed
hydroarylation of ynamides to establish a new method for
constructing C–C bonds. When ynamides were exposed to a
catalytic amount of Pd(OAc)2 and DPPF in the presence of
3.0 equivalents of an aryl iodide and HCO2NH4 in DMF at
100 °C, the reactions proceeded smoothly to provide the
desired products in good yields. Regioselective C–C bond
gioselectively to provide compound 5 through steric repul-
sion between the N-benzyl-N-(4-toluene)sulfonamide
group and the palladium metal.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
H. Wakamatsu et al.
Letter
Synlett
formation on a carbon atom neighboring a nitrogen atom
was achieved by using various ynamides containing a tosyl
group as an electron-withdrawing group; however, the re-
gioselectivity was not satisfactory by using ynamides con-
taining a carboxy group as an electron-withdrawing group.
Various aryl iodides can be used in this reaction, and many
different kinds of enamide can now be synthesized from
ynamides. Further studies on this type of reaction and on
the possibility of using ynamides for transition-metal-cata-
lyzed reactions are now in progress in our laboratory.
(6) (a) Zhang, Y.; Negishi, E. J. Am. Chem. Soc. 1989, 111, 3454. For
reviews on the reactions of transition metals with alkynes, see:
(b) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079. (c) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874.
(d) Schore, N. E. Chem. Rev. 1988, 88, 1081. (e) Fürstner, A.;
Davies, P. W. Chem. Commun. (Cambridge) 2005, 2307.
(7) Bates, R. Organic Synthesis using Transition Metals, 2nd ed.;
Wiley: Chichester, 2012.
(8) For a recent review on the synthesis of heterocycles by hydroa-
rylation of C≡C triple bonds, see: Yamamoto, Y. Chem. Soc. Rev.
2014, 43, 1575.
(9) (a) Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011.
(b) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6,
727. (c) Zhang, Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.;
Vera, E. L. Org. Lett. 2004, 6, 1151.
Supporting Information
(10) Ethyl 4-[(1Z)-1-{Benzyl[(4-tolyl)sulfonyl]amino}oct-1-en-1-
yl]benzoate (3a) and Ethyl 4-[(E)-2-{Benzyl[(4-tolyl)sulfo-
nyl]amino}-1-hexylvinyl]benzoate (4a); Typical Procedure
Ethyl 4-iodobenzoate (2a; 0.21 mL, 1.23 mmol, 3.0 equiv) was
added a solution of ynamide 1a (150.0 mg, 0.41 mmol),
Pd(OAc)2 (4.6 mg, 20.5 μmol, 5 mol%), DPPF (11.4 mg, 20.5 μmol,
5 mol%), and HCO2NH4 (77.6 mg, 1.23 mmol, 3.0 equiv) in DMF
(20 mL) at 0 °C under argon. The mixture was stirred at 100 °C
for 18 h and then cooled to 0 °C. H2O (22 mL) was added, and the
aqueous phase was extracted with Et2O (3 × 50 mL). The organic
phases were combined, washed with brine (1 × 50 mL), and
dried (Na2SO4). The volatiles were removed under reduce pres-
sure, and the residue was purified by column chromatography
[silica gel, hexane–Et2O (20:1) to hexane–EtOAc (10:1)] to
afford 3a, 4a, and recovered 1a (6.0 mg; 4%).
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588874.
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References and Notes
(1) For recent reviews on the chemistry of ynamines and ynamides,
see: (a) Nayak, S.; Prabagar, B.; Sahoo, A. K. Org. Biomol. Chem.
2016, 14, 803. (b) Wang, X.-N.; Yeom, H.-S.; Fang, L.-C.; He, S.;
Ma, Z.-X.; Kedrowski, B. L.; Hsung, R. P. Acc. Chem. Res. 2014, 47,
560. (c) Evano, G.; Jouvin, K.; Coste, A. Synthesis 2013, 45, 17.
(d) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064. (e) Evano, G.; Coste,
A.; Jouvin, K. Angew. Chem. Int. Ed. 2010, 49, 2840.
(2) For recent examples of transition-metal-catalyzed reactions of
ynamide, see: (a) Chen, M.; Sun, N.; Chen, H.; Liu, Y. Chem.
Commun. (Cambridge) 2016, 52, 6324. (b) He, G.; Qiu, S.; Huang,
H.; Zhu, G.; Zhang, D.; Zhang, R.; Zhu, H. Org. Lett. 2016, 18,
1856. (c) Liu, H.; Yang, Y.; Wu, J.; Wang, X.-N.; Chang, J. Chem.
Commun. (Cambridge) 2016, 52, 6801. (d) Singh, R. R.; Liu, R.-S.
Adv. Synth. Catal. 2016, 358, 1421. (e) Chen, Y.-L.; Sharma, P.;
Liu, R.-S. Chem. Commun. (Cambridge) 2016, 52, 3187. (f) Jadhav,
A. M.; Huple, D. B.; Singh, R. R.; Liu, R. S. Adv. Synth. Catal. 2016,
358, 1017. (g) Nonaka, S.; Sugimoto, K.; Ueda, H.; Tokuyama, H.
Adv. Synth. Catal. 2016, 358, 380. (h) Gillie, A. D.; Reddy, R. J.;
Davies, P. W. Adv. Synth. Catal. 2016, 358, 226. (i) Reddy, A. S.;
Kumari, A. L. S.; Saha, S.; Swamy, K. C. K. Adv. Synth. Catal. 2016,
358, 1625. (j) Straker, R. N.; Peng, Q.; Mekareeya, A.; Paton, R. S.;
Anderson, E. A. Nat. Commun. 2016, 7, 10109. (k) Lin, W.-J.; Shia,
K.-S.; Song, J.-S.; Wu, M.-H.; Li, W.-T. Org. Biomol. Chem. 2016,
14, 220. (l) Zheng, N.; Chang, Y.-Y.; Zhang, L.-J.; Gong, J.-X.; Yang,
Z. Chem. Asian J. 2016, 11, 371.
3a: off-white solid; yield: 161.1 mg (76%); mp 71 °C. IR (KBr):
3059, 2921, 1705, 1605 cm–1 1H NMR (400 MHz, CDCl3): δ =
.
0.88 (t, J = 7.2 Hz, 3 H), 1.04–1.28 (m, 8 H), 1.38 (t, J = 7.2 Hz, 3
H), 1.92 (br s, 2 H), 2.48 (s, 3 H), 4.14 (br s, 1 H), 4.36 (q, J = 7.2
Hz, 2 H), 4.71 (br s, 1 H), 6.11 (t, J = 7.4 Hz, 1 H), 7.06–7.12 (m, 4
H), 7.21–7.23 (m, 3 H), 7.35 (d, J = 7.6 Hz, 2 H), 7.81–7.85 (m, 4
H). 13C NMR (100 MHz, CDCl3): δ = 14.0, 14.3, 21.5, 22.5, 28.7,
29.1, 29.9, 31.6, 52.4, 60.9, 126.4, 127.6, 128.0, 128.2, 129.3,
129.5, 129.5, 129.7, 134.6, 135.5, 137.3, 137.9, 141.7, 143.6,
166.2. EI-LRMS: m/z = 519 [M+], 364, 155, 91. EI-HRMS; m/z [M+]
calcd for C31H37NO4S: 519.2443; found: 519.2442.
4a: off-white solid; yield: 31.9 mg (15%); mp 73–74 °C. IR (KBr):
2929, 1716, 1607 cm–1 1H NMR (400 MHz, CDCl3): δ = 0.65–
.
0.75 (m, 2 H), 0.81 (t, J = 7.2 Hz, 3 H), 0.97–1.05 (m, 4 H), 1.10–
1.18 (m, 2 H), 1.38 (t, J = 7.2 Hz, 3 H), 2.42–2.49 (m, 2 H), 2.44 (s,
3 H), 4.25 (s, 2 H), 4.36 (q, J = 7.2 Hz, 2 H), 5.32 (s, 1 H), 7.17 (d, J
= 8.2 Hz, 2 H), 7.26–7.35 (m, 7 H), 7.70 (d, J = 8.2 Hz, 2 H), 7.95
(d, J = 8.2 Hz, 2 H). 13C NMR (100 MHz, CDCl3): δ = 14.0, 14.3,
21.5, 22.5, 27.2, 29.3, 29.8, 31.5, 55.2, 60.9, 123.7, 126.8, 127.6,
127.9, 128.4, 129.3, 129.5, 129.7, 129.7, 134.7, 135.5, 143.7,
144.0, 149.2, 166.3. EI-LRMS: m/z: 519 [M+], 364, 155, 91. EI-
HRMS: m/z [M+] calcd for C31H37NO4S: 519.2443; found:
519.2423.
(3) (a) Mori, M.; Wakamatsu, H.; Saito, N.; Sato, Y.; Narita, R.; Sato,
Y.; Fujita, R. Tetrahedron 2006, 62, 3872. (b) Wakamatsu, H.;
Sakagami, M.; Hanata, M.; Takeshita, M.; Mori, M. Macromol.
Symp. 2010, 293, 5.
(4) Wakamatsu, H.; Takeshita, M. Synlett 2010, 2322.
(5) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44,
581. (b) Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320. For
recent reviews, see: (c) Beletskaya, I. P.; Cheprakov, A. V. Chem.
Rev. 2000, 100, 3009. (d) Felpin, F.-X.; Nassar-Hardy, L.; Le Cal-
lonnec, F.; Fouquet, E. Tetrahedron 2011, 67, 2815.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D