Palladium-catalyzed Suzuki-Miyaura coupling reactions involving β,β-dihaloenamides: Application to the synthesis of disubstituted ynamides

Article abstract of DOI:10.1055/s-2005-864821

β,β-Dihaloenamides can be successfully involved in palladium-catalyzed Suzuki-Miyaura coupling reactions. Whereas the resulting tri substituted (Z)-β-bromoenamides could participate in a second cross-coupling leading to β,β-disubstituted enamides, the (Z)-β-chloroenamides have been converted to disubstituted ynamides by an E₂ elimination.

Full text of DOI:10.1055/s-2005-864821

LETTER
905
Palladium-Catalyzed Suzuki–Miyaura Coupling Reactions Involving
b,b-Dihaloenamides: Application to the Synthesis of Disubstituted Ynamides
P
alladium-Cat
y
alyze
d
Suzuk
l
i–Miy
v
a
ura
C
ouplin
a
g Reaction
i
s
Invol
n
ving
b
,
b
-Dihaloena
C
mides outy, Marion Barbazanges, Christophe Meyer, Janine Cossy*
Laboratoire de Chimie Organique, associé au CNRS, ESPCI, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Fax +33(1)407946.60; E-mail: janine.cossy@espci.fr
Received 22 December 2004
R
R"B(OH)2
cat. Pd(0)
Abstract: b,b-Dihaloenamides can be successfully involved in
palladium-catalyzed Suzuki–Miyaura coupling reactions. Whereas
the resulting trisubstituted (Z)-b-bromoenamides could participate
in a second cross-coupling leading to b,b-disubstituted enamides,
the (Z)-b-chloroenamides have been converted to disubstituted
ynamides by an E2 elimination.
EWG
N
R"
R'
X = Br
EWG
R
R
C
EWG
N
X
X
N
X
R'B(OH)2
cat. Pd(0)
A
B
R
R'
N
R'
X = Cl, Br
EWG = SO2Ar, COAr
X = Cl
base
Key words: cross-coupling, palladium, enamides, eliminations,
ynamides
EWG
D
Scheme 1
Transition metal-catalyzed cross-coupling reactions of
1,1-dihalo-1-alkenes with various organometallic re-
agents provide a convenient and straightforward strategy
for the stereoselective synthesis of trisubstituted al-
kenes.1–6 Due to steric reasons, the oxidative addition of
the metal preferentially occurs at the less hindered trans
carbon–halogen bond, resulting in the differentiation of
the two halogen atoms.1–7 For similar reasons, a second
cross-coupling reaction of the resulting trisubstituted
haloalkene is much more difficult to achieve.1–6 However,
similar cross-couplings with heterosubstituted b,b-di-
haloalkenes have received much less attention in organic
synthesis. Whereas some palladium- and nickel-catalyzed
reactions of Grignard reagents with b,b-dibromoenol
ethers have been described,8 related cross-coupling reac-
tions of b,b-dihaloenamine derivatives have not been re-
ported to our knowledge, although alternative procedures
enable the substitution of one halogen on heterosubstitut-
ed gem-dihaloalkenes.9
or LiHMDS followed by addition of N-formylbenzotriaz-
ole (conditions I) to afford the corresponding formamides
2a (82%), 2b (94%) and 2d (95%), respectively.11 By con-
trast, the sulfonanilide 1c could be converted to the forma-
mide 2c (94%) by condensation with formic acid in the
presence of DCC (conditions II).11 Slow addition of CCl4
to a solution of formamides 2a–d in THF at reflux afford-
ed the gem-dichloroenamides 3a (92%), 3b (91%), 3c
(81%) and 3d (90%), respectively (Scheme 2, Table 1).11
R
R
H
R
EWG
N
Cl
Cl
PPh3, CCl4
THF, reflux
Conditions
EWG
N
EWG
N
I or II
CHO
1a–d
2a–d
3a–d
Scheme 2 Conditions I: n-BuLi or LiHMDS, THF, 0 °C then
N-formylbenzotriazole. Conditions II: HCO2H, DCC, CH2Cl2, r.t.
The feasibility of Suzuki–Miyaura reactions involving
b,b-dichloroenamides of type A and boronic acids was
first investigated with substrate 3a. Thus, the gem-dichlo-
roenamide 3a underwent successful cross-coupling with
benzeneboronic acid or 2-methoxybenzeneboronic acid in
the presence of a catalytic amount of Pd(PPh3)4 (5 mol%)
and Ba(OH)2 as the base5g–5i in a THF–MeOH–H2O mix-
ture (4:1:1) at reflux (conditions III, Table 2) to afford the
corresponding b-chloroenamides 4 (76%) and 5 (81%),
respectively. It was noticed that such a Suzuki–Miyaura
coupling could be also efficiently run using a 1 M aqueous
solution of NaOH as the base (3 equiv) in refluxing THF.
Under these latter conditions (conditions IV, Table 2),12
the gem-dichloroenamide 3a could be coupled with 4-fluo-
robenzeneboronic acid and the corresponding b-chloro-
enamide 6 was obtained in 89% yield (Table 2).
Herein, we would like to report that b,b-dihaloenamides
of type A can be successfully involved in Suzuki–Miyaura
coupling reactions with boronic acids to afford (Z)-b-ha-
loenamides of type B. For b-bromoenamides of type B
(X = Br), a second cross-coupling, under similar condi-
tions, led to b,b-disubstituted enamides of type C. The
synthetic utility of the less reactive (Z)-b-chloro-enamides
of type B (X = Cl) was highlighted by their ability to
undergo a base-induced dehydrochlorination to produce
disubstituted ynamides of type D (Scheme 1).
Several b,b-dichloroenamides of type A (3a–d) were syn-
thesized from the readily available sulfonamides 1a,b,c
and the benzamide 1d.10 Formylation of 1a, 1b and 1d
could be accomplished by metalation with n-butyllithium
These results were extended to the other gem-dichloro-
enamides 3b–d. Compound 3b underwent successful
Suzuki–Miyaura coupling with benzene-, 2-methoxy-
benzene- and 3,4-dichlorobenzene-boronic acids to afford
SYNLETT 2005, No. 6, pp 0905–0910
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864821; Art ID: G48504ST
© Georg Thieme Verlag Stuttgart · New York
0
6.
0
4.
2
0
0
5

906
S. Couty et al.
LETTER
Table 1 Synthesis of b,b-Dichloroenamides of Type A (3a–d)a
Compound
EWG
Conditions
Product
2a
Yield (%)
Product
3a
Yield (%)
1a
1b
1c
1d
(CH2)2CH=CH2
Bn
I
I
82
94
94
95
92
91
81
90
2b
3b
PMP
I
2c
3c
CH2CH(OMe)2
II
2d
3d
a Bn = CH2Ph, PMP = (p-MeO)Ph, Bz = COPh.
the corresponding b-chloroenamides 7 (98%), 8 (91%) As the same reaction conditions turned out to be satisfac-
and 9 (88%), respectively, in excellent yields. The gem- tory to achieve, with similar efficiency, the two consecu-
dichloroenamide 3b could be also coupled with an alke- tive Suzuki–Miyaura couplings, it was envisaged to
nylboronic acid such as (E)-hex-1-enylboronic acid and advantageously combine them in a one-pot transforma-
the corresponding b-chlorodienylenamide 10 was ob- tion. Thus, the gem-dibromoenamide 13 was first coupled
tained in satisfactory yield (65%), provided that an excess with 4-fluorobenzeneboronic acid (1 equiv) and upon
of organoboron reagent (3 equiv) was used. Finally, the completion of the reaction, 3,4-(methylenedioxy)ben-
gem-dichloroenamide 3c derived from p-anisidine and the zeneboronic acid was added to the reaction mixture as a
gem-dichloroenamide 3d in which the nitrogen is partner for the second cross-coupling. Under these condi-
substituted by an amide group, were both coupled with tions, the b,b-diarylenamide 17 was isolated in 70% yield
benzeneboronic acid to afford the corresponding b-chlo- (Scheme 3).
roenamides 11 (94%) and 12 (73%), respectively
(Table 2).
F
In all the Suzuki–Miyaura cross-coupling reactions in-
Bn
volving the b,b-dichloroenamides of type A, the resulting
Ts
N
b-chloroenamides of type B were obtained as single geo-
metric isomers.13 A (Z)-olefinic configuration could be
reasonably assigned to these compounds as the oxidative
addition of palladium should occur preferentially at the
less hindered trans carbon–chlorine bond.1–6,14,15 Under
these conditions, no subsequent cross-coupling was
observed at the second carbon–chlorine bond.
(HO)2B
F
MeO
Pd(PPh3)4 (5 mol%)
aq NaOH, THF, reflux
80%
16
B(OH)2
Bn
Bn
MeO
Ts
(1.05 equiv)
N
Br Ts
N
OMe
Bn
By contrast, the gem-dibromoenamide 13 (prepared from
the formamide 2b by treatment with PPh3/CBr4 in THF,
71%) exhibited a much higher reactivity in palladium-cat-
alyzed reactions compared to its dichloro counterpart. In-
deed, when the b,b-dibromoenamide 13 was subjected to
a Suzuki–Miyaura coupling with 2-methoxybenzene-
boronic acid (1.6 equiv) under standard conditions, a
mixture of the (Z)-b-bromoenamide 14 and the b,b-di-
arylenamide 15, arising from a double cross-coupling,
was produced in a 40:60 ratio (85%). By reducing the
amount of boronic acid used (1.05 equiv), the (Z)-b-bro-
moenamide 14 could be isolated in 74% yield and only
traces of the bis-coupled product 15 were detected (4%)
(Scheme 3).
Ts
N
Br
Br
Pd(PPh3)4 (5 mol%)
+
MeO
MeO
aq NaOH, THF
reflux
15 (4%)
13
14 (74%)
O
(HO)2B
F
1)
O
Bn
Ts
N
Pd(PPh3)4 (5 mol%)
aq NaOH, THF, reflux
17
(HO)2B
2)
O
70%
O
F
Scheme 3
The relative ease with which compound 14 underwent a
subsequent Suzuki–Miyaura coupling led us to investi-
gate the possibility of carrying out consecutive cross-cou-
plings with two different boronic acids. Indeed, the
previously synthesized (Z)-b-bromoenamide 14 could be
effectively coupled with 4-fluorobenzeneboronic acid in
the presence of a catalytic amount of Pd(PPh3)4 (5 mol%)
and aqueous NaOH as a base in THF at reflux to afford the
b,b-diarylenamide 16 in 80% yield (Scheme 3).
Obviously, the second Suzuki–Miyaura cross-coupling
was not feasible with (Z)-b-chloroenamides of type B
(X = Cl), at least under the standard conditions used
above. These compounds, however, turned out to be per-
fectly suitable for another application. Due to the anti
stereochemical relationship between the hydrogen and
the chlorine atom, it was envisaged to carry out an E2
elimination by treatment with an appropriate base in order
to generate the corresponding disubstituted ynamides of
type D (Scheme 1).16 As these stable electron-deficient
Synlett 2005, No. 6, 905–910 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Suzuki–Miyaura Coupling Reactions Involving b,b-Dihaloenamides
907
Table 2 Suzuki–Miyaura Cross-Coupling Reactions Involving the b,b-Dichloroenamides of Type Aa
R
R
R'B(OH)2
EWG
N
Cl
Cl
EWG
N
Cl
R'
Pd(PPh3)4 (5 mol%), base
solvent, reflux
B
A
Dichloroenamide
Boronic acid
Product
Conditions
Yield (%)
R¢B(OH)2
Ts
N
N
N
Cl
R'
Ts
N
Cl
Cl
3a
3a
3a
R¢ = Ph
4
5
6
III
III
IV
76
81
89
R¢ = (2-MeO)C6H4
R¢ = (4-F)C6H4
R¢B(OH)2
Bn
Bn
Ts
Cl
R'
Ts
N
Cl
Cl
3b
3b
3b
R¢ = Ph
7
8
9
IV
IV
IV
98
91
88
R¢ = (2-MeO)C6H4
R¢ = (3,4-Cl2)C6H3
Bn
Ts
Cl
(HO)2B
3b
IV
IV
IV
65
94
73
Bu
Bu
10
OMe
OMe
PhB(OH)2
Ts
N
Cl
Cl
Ts
N
Cl
Ph
3c
11
OMe
OMe
OMe
Cl
OMe
Cl
Bz
N
Bz
N
PhB(OH)2
Cl
Ph
3d
12
a Conditions III: Pd(PPh3)4 (5 mol%), Ba(OH)2·8H2O, THF–MeOH–H2O (4:1:1). Conditions IV: Pd(PPh3)4 (5 mol%), 1 M aq NaOH, THF.
variants of ynamines have attracted considerable attention material was observed in the case of the b-chloroenamide
in organic synthesis in recent years,17 this process would 7 (Table 3).
offer an interesting entry to disubstituted ynamides com-
Due to this result, alternative conditions were developed
relying on the use of concentrated NaOH as a convenient
plementary to the presently existing methods.11,18–21
Initially, the use of LiHMDS as a base in THF was con- base in a reaction carried out under phase-transfer cataly-
sidered to achieve the dehydrochlorination of the (Z)-b- sis. Under these conditions (50% aqueous NaOH–toluene,
chloroenamides of type B (conditions V). Indeed, the (Z)- 10–20 mol% n-Bu4NHSO4; conditions VI),22 several b-
b-chloroenamide 4 could be cleanly converted to the di- chloro-N-tosylenamides 5–8, 10, 11 underwent dehydro-
substituted ynamide 18 (56%) under these conditions but, chlorination to the corresponding ynamides 19–24 (54–
in sharp contrast, only decomposition of the starting 89%) (Table 3).
Synlett 2005, No. 6, 905–910 © Thieme Stuttgart · New York

908
S. Couty et al.
LETTER
Table 3 Reaction of b-Chloroenamides under Various Conditions (V–VII)a
R
R
EWG
N
Cl
R'
conditions
N
R'
EWG
V, VI or VII
B
D
b-Chloroenamides
Ynamides
Conditions
Yield (%)
Ts
N
Cl
N
Ph
Ph
Ts
4
18
V
56
84
Ts
N
Cl
OMe
MeO
N
Ts
5
19
VI
Ts
N
Cl
N
F
F
Ts
6
20
VI
89
Bn
Bn
Ts
N
N
Cl
Bn
N
Ph
Ph
Ts
V
VI
Degradation
81
7
21
Ts
Cl
OMe
MeO
Bn
N
N
Ts
8
22
VI
VI
65
65
Bn
Ts
N
Cl
Bn
Bu
Bu
Ts
10
23
OMe
MeO
Ts
N
Cl
N
N
Ph
Ph
Ts
Bz
11
24
VII
54
OMe
MeO
MeO
25
OMe
Cl
Bz
N
Ph
Ph
V
VI
50
12
No reaction
a Conditions V: LiHMDS, THF, 0 °C to r.t. Conditions VI: 50% aq NaOH, n-Bu4NHSO4 (10–20 mol%), toluene, r.t. Conditions VII: same as
conditions VI, at 50 °C instead of r.t.
Synlett 2005, No. 6, 905–910 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Suzuki–Miyaura Coupling Reactions Involving b,b-Dihaloenamides
909
Synlett 2001, 254. For the use of Ba(OH)2 as the base, see:
(g) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992,
207. (h) Baldwin, J. E.; Chesworth, R.; Parker, J. S.; Russell,
A. T. Tetrahedron Lett. 1995, 36, 9551. (i) Wong, L. S.-M.;
Sharp, L. A.; Xavier, N. M. C.; Turner, P.; Sherburn, M. S.
Org. Lett. 2002, 4, 1955.
It is worth mentioning that in the case of the b-chloro-N-
tosylanilide derivative 11, the temperature of the reaction
mixture had to be raised to 50 °C in order for the elimina-
tion to proceed at an appreciable rate (conditions VII).
However, the dehydrochlorination of the b-chloroena-
mide 12 in which the nitrogen is substituted by an amide
group could only be achieved by treatment with LiHMDS
in THF to produce the disubstituted ynamide 25 (50%).
(6) Cross-coupling reactions with alkynylcopper reagents:
(a) Ratovelomanana, V.; Hammoud, A.; Linstrumelle, G.
Tetrahedron Lett. 1987, 28, 1649. (b) Bryant-Friedrich, A.;
Neidlein, R. Synthesis 1995, 1506. (c) Shen, W.; Thomas, S.
A. Org. Lett. 2000, 2, 2857. (d) Myers, A. G.; Goldberg, S.
D. Angew. Chem. Int. Ed. 2000, 39, 2732. (e) Uenishi, J.;
Matsui, K. Tetrahedron Lett. 2001, 42, 4353. (f)Uenishi,J.;
Matsui, K.; Ohmiya, H. J. Organomet. Chem. 2002, 653,
141.
(7) Exceptions to this trend appear restricted to particular
classes of substrates. 1-Chloro-1-iodo-alkenes having the
more reactive carbon-iodine bond [towards oxidative
addition of Pd(0) complexes] at the cis position: (a) Alami,
M.; Crousse, B.; Linstrumelle, G. Tetrahedron Lett. 1995,
36, 3687. 1,1-Dibromoalkenes bearing a suitably located
carbon–carbon triple bond in the side chain undergo
oxidative addition of Pd(0) complexes at the cis carbon–
bromine leading to the alkyne carbopalladation followed by
cross-coupling: (b) Torii, S.; Okumoto, H.; Tadokoro, T.;
Nishimura, A.; Rashid, M. A. Tetrahedron Lett. 1993, 34,
2139. (c) Nuss, J. M.; Rennels, R. A.; Levine, B. H. J. Am.
Chem. Soc. 1993, 115, 6991. (d) McAlonan, H.;
In conclusion, we have reported that a variety of gem-di-
haloenamides of type A underwent efficient Suzuki–
Miyaura cross-coupling reactions with aryl- or alkenyl-
boronic acids to afford (Z)-b-haloenamides of type B in
satisfactory yields. Whereas the resulting (Z)-b-bromo-
enamides could participate in a subsequent Suzuki–
Miyaura coupling with another boronic acid to afford b,b-
disubstituted enamides of type C, the (Z)-b-chloroen-
amides of type B could be converted to disubstituted yn-
amides of type D by treatment with LiHMDS in THF or
concentrated NaOH under phase-transfer catalysis. Other
applications of the (Z)-b-haloenamides of type B are
currently being examined with the aim of synthesizing
heterocyclic compounds.
Acknowledgment
Montgomery, D.; Stevenson, P. J. Tetrahedron Lett. 1996,
37, 7151.
Financial support from Johnson & Johnson is gratefully acknowled-
(8) (a) Glazunova, E. Y.; Lutsenko, S. V.; Efimova, I. V.;
Trostyanskaya, I. G.; Kazankova, M. A.; Beletskaya, I. P.
Russ. J. Org. Chem. 1998, 34, 1104. (b) Kazankova, M. A.;
Trostyanskaya, I. G.; Lutsenko, S. V.; Efimova, I. V.;
Beletskaya, I. P. Russ. J. Org. Chem. 1999, 35, 1273.
(9) (a) Smithers, R. H. J. Org. Chem. 1983, 48, 2095.
(b) Barluenga, J.; Rodriguez, M. A.; Campos, P. J.; Asensio,
G. J. Am. Chem. Soc. 1988, 110, 5567. (c) Percy, J. M.;
Wilkes, R. D. Tetrahedron 1997, 53, 14749. (d) Uneyama,
K.; Kato, T. Tetrahedron Lett. 1998, 39, 587. (e) Fujiwara,
M.; Ichikawa, J.; Okauchi, T.; Minami, T. Tetrahedron Lett.
1999, 40, 7261.
(10) Tosylation of but-3-enylamine hydrochloride, benzylamine
and p-anisidine (TsCl, Et3N, CH2Cl2, 0 °C to r.t.) afforded
the corresponding sulfonamides 1a (58%), 1b (77%) and 1c
(84%), respectively. Benzoylation of aminoacetaldehyde
dimethylacetal (BzCl, Et3N, cat. DMAP, CH2Cl2, 0 °C)
provided the benzamide 1d (87%).
ged (Focus Giving Award to J. C.).
References
(1) Pd- and Ni-catalyzed cross-coupling reactions with Grignard
reagents: (a) Minato, A.; Suzuki, K.; Tamao, K. J. Am.
Chem. Soc. 1987, 109, 1257. (b) Braun, M.; Rahematpura,
J.; Bühne, C.; Paulitz, T. C. Synlett 2000, 1070. (c)Uenishi,
J.; Ohmi, M. Heterocycles 2003, 61, 365. (d) Braun, M.;
Hohmann, A.; Rahematpura, J.; Bühne, C.; Grimme, S.
Chem. Eur. J. 2004, 10, 4584.
(2) Iron-catalyzed coupling reactions between 1,1-dichloro-1-
alkenes and Grignard reagents have been recently reported,
see: Dos Santos, M.; Franck, X.; Hocquemiller, R.; Figadère,
B.; Peyrat, J.-F.; Provot, O.; Brion, J.-D.; Alami, M. Synlett
2004, 2697.
(3) Cross-coupling reactions with organozinc reagents:
(a) Minato, A. J. Org. Chem. 1991, 56, 4052. (b) Panek, J.
S.; Hu, T. J. Org. Chem. 1997, 62, 4912. (c) Xu, C.;
Negishi, E.-I. Tetrahedron Lett. 1999, 40, 431.
(11) Brückner, D. Synlett 2000, 1402.
(12) Representative Procedure: N-Benzyl-N-[(Z)-2-chloro-2-
phenylvinyl]-4-methylbenzenesulfonamide (7).
To a solution of the gem-dichloroenamide 3b (178 mg, 0.500
mmol) in THF (10 mL) were successively added
(d) Ogasawara, M.; Ikeda, H.; Ohtsuki, K.; Hayashi, T.
Chem. Lett. 2000, 776. (e) Ogasawara, M.; Ikeda, H.;
Hayashi, T. Angew. Chem. Int. Ed. 2000, 39, 1042. (f) Shi,
J.-C.; Zeng, X.; Negishi, E.-I. Org. Lett. 2003, 5, 1825.
(g) Zeng, X.; Hu, Q.; Qian, M.; Negishi, E.-I. J. Am. Chem.
Soc. 2003, 125, 13636. (h) Shi, J.-C.; Negishi, E.-I. J.
Organomet. Chem. 2003, 687, 518.
benzeneboronic acid (98 mg, 0.80 mmol, 1.6 equiv), a 1 M
aq solution of NaOH (1.50 mL, 1.50 mmol, 3 equiv) and
Pd(PPh3)4 (29 mg, 0.025 mmol, 0.05 equiv). After 3 h at
reflux, the reaction mixture was cooled to r.t., filtered
through a pad of Celite (EtOAc) and the filtrate was
evaporated under reduced pressure. The crude material was
purified by flash chomatography (petroleum ether–EtOAc,
90:10) to afford 195 mg (98%) of 7 as a white solid; mp
124 °C. IR: 1595, 1490, 1445, 1345, 1160, 1090, 1030, 915,
815, 780, 760, 740 cm–1. 1H NMR (300 MHz, CDCl3): d =
7.76 (d, J = 8.3 Hz, 2 H), 7.37–7.24 (m, 12 H), 6.53 (s, 1 H),
4.81 (s, 2 H), 2.43 (s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 143.8 (s), 136.7 (s), 136.05 (s), 136.0 (s), 132.9 (s), 129.7
(d, 2 C), 129.4 (d), 128.49 (d, 3 C or 2 C), 128.47 (d, 2 C or
(4) Cross-coupling reactions with organostannanes: Shen, W.;
Wang, L. J. Org. Chem. 1999, 64, 8873.
(5) Cross-coupling reactions with organoboranes: (a) Roush,
W. R.; Riva, R. J. Org. Chem. 1988, 53, 710. (b) Roush, W.
R.; Brown, B. B.; Drozda, S. E. Tetrahedron Lett. 1988, 29,
3541. (c) Roush, W. R.; Moriarty, K. J.; Brown, B. B.
Tetrahedron Lett. 1990, 31, 6509. (d) Roush, W. R.;
Koyama, K.; Curtin, M. L.; Moriarty, K. J. J. Am. Chem.
Soc. 1996, 118, 7502. (e) Shen, W. Synlett 2000, 737.
(f) Bauer, A.; Miller, M. W.; Vice, S. F.; McCombie, S. W.
Synlett 2005, No. 6, 905–910 © Thieme Stuttgart · New York

910
S. Couty et al.
LETTER
3 C), 128.4 (d), 127.8 (d), 127.3 (d, 2 C), 126.9 (d, 2 C),
122.9 (d), 52.2 (t), 21.6 (q). MS (EI, 70 eV): m/z (%) = 400
(1) [M(37Cl) + H+], 399 (3) [M(37Cl)+], 398 (2) [M(35Cl) +
H+], 397 (9) [M(35Cl)+], 362 (1) [M – Cl+], 242 (4) [M – Ts+],
206 (5), 178 (2), 155 (2), 92 (8), 91 (100), 89 (4), 65 (7).
Anal. Calcd for C22H20ClNO2S: C, 66.40; H, 5.07; N, 3.52.
Found: C, 66.47; H, 4.99; N, 3.48.
(16) Some chiral disubstituted ynamides have been synthesized
from enamides by bromination (Br2 or NBS) leading to
stereomeric mixtures of b-bromoenamides, in which the (Z)
isomer was selectively converted to the desired disubstituted
ynamide by treatment with a base (t-BuOK, THF) whereas
the (E) isomer did not react; see: Wei, L.-L.; Mulder, J. A.;
Xiong, H.; Zificsak, C. A.; Douglas, C. J.; Hsung, R. P.
Tetrahedron 2001, 57, 459.
(17) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar,
C.; Wei, L.-L. Tetrahedron 2001, 57, 7575; and references
therein.
(18) Witulski, B.; Gößmann, M. Synlett 2000, 1793.
(19) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P. Synlett 2003,
1379; and references therein.
(20) (a) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R.
P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J.
Am. Chem. Soc. 2003, 125, 2368. (b) Dunetz, J. R.;
Danheiser, R. L. Org. Lett. 2003, 5, 4011. (c) Zhang, Y.;
Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L.
Org. Lett. 2004, 6, 1151.
(13) In all the cross-couplings investigated, GC-MS and NMR
analyses of the crude b-haloenamides indicate a
stereoisomeric ratio > 95:5.
(14) The Pd-catalyzed hydrogenolysis of the gem-dibromo-
enamide 13 with n-Bu3SnH led to the (Z)-b-bromoenamide
26 (55%), whose configuration was readily assigned by 1H
NMR, and to the fully reduced enamide 27 (15%) as a by-
product. However, no trace of the (E) geometrical isomer of
compound 26 could be detected. A similar hydrogenolysis of
the gem-dichloroenamides could not be achieved
(Scheme 4).
Bn
n-Bu3SnH
Bn
Bn
(21) (a) Rodríguez, D.; Castedo, L.; Saá, C. Synlett 2004, 377.
(b) Rodríguez, D.; Castedo, L.; Saá, C. Synlett 2004, 783.
(c) Tracey, M. R.; Zhang, Y.; Frederick, M. O.; Mulder, J.
A.; Hsung, R. P. Org. Lett. 2004, 6, 2209.
Ts
N
Br cat. Pd(PPh3)4
Ts
N
Br Ts
+
N
H
H
THF, r.t.
Br
H
13
26 (55%)
27 (15%)
(22) Representative Procedure: N-Benzyl-N-(2-
phenylethynyl)-4-methylbenzenesulfonamide (21).
To a solution of b-chloroenamide 7 (100 mg, 0.251 mmol) in
toluene (10 mL) were successively added 50% aq NaOH (10
mL) and tetrabutylammonium hydrogensulfate (17 mg,
0.050 mmol, 0.2 equiv) and the resulting mixture was
vigorously stirred at r.t. After 7 h, the reaction mixture was
cooled to 5 °C, and diluted with H2O and Et2O. The layers
were separated and the aqueous phase was extracted with
Et2O. The combined extracts were washed with a sat. aq
solution of NH4Cl, brine, dried over MgSO4, filtered and
concentrated under reduced pressure. The residue was
purified by flash chromatography (petroleum ether–EtOAc,
95:5) to afford 74 mg (81%) of 21 as a pale yellow waxy
solid. IR: 3060, 3030, 2235, 1595, 1490, 1445, 1420, 1355,
1160, 1050, 1030, 940, 815, 765, 690, 655 cm–1. 1H NMR
(300 MHz, CDCl3): d = 7.77 (d, J = 8.3 Hz, 2 H), 7.30–7.14
(m, 12 H), 4.55 (s, 2 H), 2.40 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 144.7 (s), 134.7 (s), 134.5 (s), 131.1 (d, 2 C),
129.8 (d, 2 C), 128.9 (d, 2 C or 3 C), 128.6 (d, 2 C), 128.2 (d,
3 C), 127.7 (d, 3 C or 2 C), 122.8 (s), 82.7 (s), 71.4 (s), 55.7
(t), 21.7 (q). MS (EI, 70 eV): m/z (%) = 361 (21) [M+], 207
(9), 206 (45) [M – Ts+], 205 (6), 179 (26), 178 (11), 165 (3),
155 (3), 105 (6), 92 (8), 91 (100), 65 (13).
Scheme 4
This result confirms that in b,b-dihaloenamides of type A,
the oxidative addition of Pd(0) complexes occurs at the less-
hindered carbon-halogen bond, as in the non-hetero-
substituted series. For the Pd-catalyzed hydrogenolysis of
1,1-dibromoalkenes, see: (a) Uenishi, J.; Kawahama, R.;
Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1996, 61, 5716.
(b) Uenishi, J.; Kawahama, R.; Shiga, Y.; Yonemitsu, O.;
Tsuji, J. Tetrahedron Lett. 1996, 37, 6759. (c) Uenishi, J.;
Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem. 1998,
63, 8965. (d) Uenishi, J.; Kawahama, R.; Izaki, Y.;
Yonemitsu, O. Tetrahedron 2000, 56, 3493.
(15) The (Z)-olefinic configuration of the b-chloroenamides of
type B was further confirmed by their ability to undergo
dehydrochlorination (E2 anti-elimination) by treatment with
a base, whereas the (E) geometrical isomers would not react
under these conditions, see ref. 16.
Synlett 2005, No. 6, 905–910 © Thieme Stuttgart · New York