Cupric chloride promoted regioselective C-allylation of enaminones

Article abstract of DOI:10.1016/j.tetlet.2008.04.093

Regioselective allylation of enaminones using CuCl₂ as the catalyst to give C-allylated products is reported for the first time. The C-allylated products undergo hydrolysis followed by a rearrangement yielding β-keto allyl enamides in excellent yields.

Full text of DOI:10.1016/j.tetlet.2008.04.093

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3991–3994
Cupric chloride promoted regioselective C-allylation of enaminones
Sarangthem Joychandra Singh, Okram Mukherjee Singh *
Department of Chemistry, Manipur University, Canchipur, 795 003 Manipur, India
Received 8 October 2007; revised 8 April 2008; accepted 16 April 2008
Available online 20 April 2008
Abstract
Regioselective allylation of enaminones using CuCl2 as the catalyst to give C-allylated products is reported for the first time. The
C-allylated products undergo hydrolysis followed by a rearrangement yielding b-keto allyl enamides in excellent yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Allylation; Enaminone; b-Keto allyl enamides; Ketene N,S-acetal
Cuprous and cupric salts are used as effective catalysts in
several oxidative ring cyclization reactions,1 and in the
presence of oxygen and pyridine or amino ligands, they
are considered as useful oxidizing systems for cleavage of
hydrazides.2 Another interesting application of copper salts
is in the addition reaction of allylmetals to C@Z bonds
(Z = O or NR), which has emerged as a very useful
carbon–carbon bond-forming reaction.3 Metal-catalyzed
allylic substitution is a useful process in organic synthesis
for C–C and C–heteroatom bond forming reactions.4 How-
ever, these approaches are still extremely limited in scope
and functional group compatibility. Moreover, despite
the potential utility of allylated b-keto amides as synthetic
intermediates, their synthesis using copper salts as catalyst
has been rarely studied.5
We reported some years ago the synthesis of biologically
important 2,3-functionalized imidazo[1,2-a]pyridines via
an unprecedented CuCl2-induced oxidative ring closure of
certain a-oxoketene N,S-, N,O- and N,N-acetal interme-
dia-tes.6 Ketene N,S-acetals are highly versatile enamines
widely used in the synthesis of heterocycles.7 Junjappa
and co-workers have recently reported the synthesis of
substituted quinolines and quinoxalines via cyclization of
ketene N,S-acetals under Vilsmeier–Haack conditions.8
We now report a facile synthesis of b-keto allyl enamides
via regioselective allylation of N,S-acetals using cupric
chloride as the catalyst.
Ketene N,S-acetals were prepared starting from ketene
dithioacetals by displacement of the thiomethyl groups by
the respective amines either in refluxing ethanol or in tetra-
hydrofuran.9 Our various trial experiments to prepare
either the C- or the N-allylated products of the ketene
N,S-acetals, by treating 1a–l with allyl bromide without
using any catalyst in various solvents, resulted in failure.
Thus refluxing N,S-acetals 1a–l and allyl bromide in sol-
vents such as ethanol, acetonitrile and tetrahydrofuran
gave no significant results. Surprisingly, we observed the
formation of b-keto enamides 2a–l in excellent yields by
treating the N,S-acetals and allyl bromide directly in the
presence of cupric chloride and refluxing in THF for
2–3 h (Scheme 1).10
Ar
Ar
O
O
H
O
CuCl2
THF
Br
+
N
R
SMe
NH
R
1a-l
2a-l
*
Corresponding author.
Scheme 1.
E-mail address: ok_mukherjee@yahoo.co.in (O. M. Singh).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.093

3992
S. J. Singh, O. M. Singh / Tetrahedron Letters 49 (2008) 3991–3994
Table 2
In order to evaluate the scope of this catalytic system,
b-Keto allyl enamides 2a–l produced via C-allylation of ketene N,S-acetals
the range of metal salts was extended to various metal
halides and acetates as shown in Table 1, guided by the
template reaction between ketene N,S-acetal 1a and allyl
bromide. The CuCl2/THF combination was found to be
the best affording the highest yield of 90% after refluxing
for 3 h. Screening of different solvents revealed that THF
was the most suitable. It was also observed that ZnCl2
and SnCl2 gave good yields of the product, while MgCl2,
AlCl3, FeCl3, BiCl3 and LaCl3 gave poor yields of the
desired products (Table 1). Moreover, it is noteworthy to
mention that no C-allylation occurred in the absence of
catalyst (Table 1, entry 15).
After optimizing the reaction conditions, we investi-
gated the generality of this process. As can be seen from
Table 2, various ketene N,S-acetals 1a–l were C-allylated
with allyl bromide to give the corresponding products in
good to excellent yields.
1a–la
R1
R1
O
O
H
Br
CuCl2
THF
+
O
NH
R2
N
SMe
R2
1a-l
2a-l
Entry
R1
R2
Product
Yield (%)
Mp (°C)
1
2
3
4
5
6
7
8
9
10
11
12
a
C6H5
C6H5
C6H5
C6H5
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
CH3
C2H5
C3H7
CH2C6H5
CH3
C2H5
C3H7
CH2C6H5
CH3
C2H5
C3H7
2a
2b
2c
2d
2e
2f
90
92
86
85
90
92
90
80
91
92
92
90
103
120
105
120
122
113
107
125
125
94
2g
2h
2i
We wanted to confirm that the reaction pathway
occurred via C-allylation rather than N-allylation. For this
study, we required N-allylated ketene N,S-acetals 3a–l
(Scheme 2) and it was anticipated that N-allylated adducts
3a–l might undergo a 3-aza-Claisen rearrangement to give
2j
2k
2l
122
92
CH3
Reaction conditions: N,S-acetal (5.0 mmol), allyl bromide (5.0 mmol),
CuCl2 (5.0 mmol), THF (30 mL), 3 h, reflux.
C-allylated products.11 Recently, Oshima et al. reported12
a
facile method of synthesizing 2,2-disubstituted-4-pentene-
nitriles via aza-Claisen rearrangement of N-allyl-N-(phen-
ylethynyl)arenesulfonamides. Thus, as shown in Scheme
2, we treated N,S-acetals 1a–l with allyl bromide at 0 °C
to 25 °C in the presence of 2 equiv of sodium hydride in
R1
R1
O
O
H
Br
NaH
THF
+
MeS
N
N
SMe
R2
Table 1
R2
1a-l
3a-l
Optimization of the reaction conditions for the C-allylation of 1a with
allyl bromidea
Scheme 2.
Ph
Ph
tetrahydrofuran and generated N,S-acetals 3a–l in very
low yields (10–15%).13
O
H
O
Br
Catalyst
+
During optimization of the reaction conditions, the
effect of a number of factors was investigated, including
the nature of the base, solvent, the temperature (ranging
from 0 °C to reflux), substrate concentration and reaction
time. The best yields were obtained using NaH/THF at
25 °C under N2 and stirring for 10 h giving a 15% yield
(Table 3).
Subsequently, N,S-acetals 3a–l were submitted to possi-
ble intramolecular rearrangements in the presence of cupric
chloride and Lewis acids (AlCl3, ZnCl2, EtO–BF3). How-
ever, under these conditions, only inseparable by-products
were formed and none of the reactions yielded the b-keto
enamides 2a–l (Scheme 3). Thus the possible mechanism
for the formation of the C-allylated products from N-ally-
lated adducts 3a–l via a 3-aza-Cope rearrangement was
ruled out. This implied that C-allylation rather than N-
allylation was highly favourable in presence of the metal
halide and Lewis acid catalytic conditions.
solvent, reflux
N
SMe
O
NH
Me
Me
1a
2a
Entry
Catalyst
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
a
CuCl2
CuCl2
CuCl2
CuCl2
CuBr2
CuI2
Cu(OAc)2
MgCl2
AlCl3
FeCl3
BiCl3
DMF
6
10
5
3
6
65
60
60
90
60
45
45
10
20
35
15
10
50
50
0
Benzene
Toluene
THF
THF
THF
6
5
THF
Toluene
Toluene
Toluene
Toluene
Toluene
THF
12
12
10
10
8
6
6
24
LaCl3
ZnCl2
SnCl2
None
THF
THF
Compounds 2 existed as enamides as evident from their
spectral data.14 Compounds 2 exhibited ethylenic proton
N,S-Acetal (5.0 mmol), allyl bromide (5.1 mmol), catalyst (5.0 mmol),
solvent (20–30 mL).

S. J. Singh, O. M. Singh / Tetrahedron Letters 49 (2008) 3991–3994
3993
Table 3
SAIF, NEHU for some of the NMR recordings. OMS
thanks Anil Saikia of IIT Guwahati for his helpful sugges-
tions in analyzing some of the NMR spectra.
Base catalyzed synthesis of N-allylated ketene N,S-acetals 3a–la,b
R1
R1
O
Supplementary data
O
H
Basea,b
THF
Br
+
Detailed synthetic and isolation procedures and full
spectral identifications of the reported compounds 2a–l
and 3a are provided. All known N,S-acetals 1a–l were pre-
pared by earlier reported procedures.7a,9 Supplementary
data associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2008.04.093.
MeS
N
N
SMe
R2
R2
1a-l
3a-l
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
a
C6H5
C6H5
C6H5
C6H5
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
CH3
C2H5
C3H7
CH2C6H5
CH3
C2H5
C3H7
CH2C6H5
CH3
C2H5
C3H7
3a
3b
3c
3d
3e
3f
15
10
10
5
10
10
10
0
References and notes
1. (a) Bluhm, M. E.; Ciesielski, M.; Gorls, H.; Doring, M. Angew.
Chem., Int. Ed. 2002, 4, 2962–2965; (b) Bluhm, M. E.; Ciesielski, M.;
Gorls, H.; Doring, M. Angew. Chem., Int. Ed. 2002, 114, 3104–3107;
(c) Martin, R.; Rodriguez Rivero, M.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2006, 45, 7079–7082.
2. (a) Corey, E. J.; Knapp, S. Tetrahedron Lett. 1976, 3667–3668; (b)
Tsuji, J.; Nagashima, T.; Qui, N. T.; Takayanagi, H. Tetrahedron
1980, 36, 1311–1315; (c) Rodriguez Rivero, M.; Buchwald, S. L. Org.
Lett. 2007, 9, 973–976.
3g
3h
3i
15
5
5
3j
3k
3l
CH3
15
Reaction condition: N,S-acetal (5.0 mmol), allyl bromide (5.1 mmol),
NaH (5.5 mmol), THF (30 mL), stirring 10 h 0 °C to rt.
b
The use of Et3N/THF instead of NaH resulted in no product.
3. (a) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207; (b) Denmark,
S. E.; Fu, J. Chem. Rev. 2003, 103, 2763; (c) Kennedy, J. W. J.; Hall,
D. G. Angew. Chem., Int. Ed. 2003, 42, 4732–4739.
R1
R1
4. Tsuji, J. In Transition Metal Reagents and Catalysts. Innovations in
Organic Synthesis; Wiley: Chichester, 2000; p 109.
5. (a) Neo, A. G.; Delgado, J.; Polo, C.; Marcaccinib, S.; Marcosa, C. F.
Tetrahedron Lett. 2005, 46, 23–26; (b) Xu, F.; Armstrong, J. D., III;
Zhou, G. X.; Simmons, B.; Hughes, D.; Ge, Z.; Grabowski, E. J. J. J.
Am. Chem. Soc. 2004, 126, 13002–13009; (c) Zhang, X.; Houk, K. N.;
Lin, S.; Danishefsky, S. J. J. Am. Chem. Soc. 2003, 125, 5111–5114;
(d) Kamei, T.; Fujita, K.; Itami, K.; Yoshida, J. Org. Lett. 2005, 7,
4725–4728; (e) Ikeuchi, Y.; Taguchi, T.; Hanzawa, Y. J. Org. Chem.
2005, 70, 756–759.
O
O
CuCl2
O
NH
R2
MeS
N
R2
3a-l
2a-l
6. Barun, O.; Ila, H.; Junjappa, H.; Singh, O. M. J. Org. Chem. 2000, 65,
1583–1587.
Scheme 3.
7. (a) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423–
5506; (b) Ila, H.; Junjappa, H.; Mohanta, P. K. In Progress in
Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.;
Pergamon: New York, 2001; Vol. 13, Chapter 1; pp 1–24.
8. (a) Mahata, P. K.; Venkatesh, C.; Syamkumar, U. K.; Ila, H.;
Junjappa, H. J. Org. Chem. 2003, 68, 3966–3975; (b) Venkatesh, C.;
Singh, B.; Mahata, P. K.; Ila, H.; Junjappa, H. Org. Lett. 2005, 7,
2169–2172.
signals as multiplets at 4.98–5.10 ppm in the 1H NMR
spectra and two carbonyl signals at 167–170 (amide) and
197.5–198.8 (benzoyl) ppm in the 13C NMR spectra. The
IR spectra clearly showed the presence of two strong car-
bonyl peaks. In the case of 2a, the disappearance of the
vinylic proton and the observation of allylic methylene pro-
9. Singh, O. M.; Junjappa, H.; Ila, H. J. Chem. Soc., Perkin Trans. 1
1997, 3561–3565.
I
tons at d 2.60–2.70 ppm as a multiplet in the H NMR
10. General procedure for the preparation of 2a–l: An equimolar mixture
of N,S-acetal 1, allyl bromide (5 mmol) and CuCl2 (0.67 g, 5 mmol) in
THF (30 mL) was refluxed for 3 h with stirring (monitored by TLC).
Then, the mixture was brought to room temperature and CuCl2 was
filtered through a sintered funnel. The filtrate was concentrated under
reduced pressure and poured into water and extracted with chloro-
form (3 Â 50 mL). The combined organics were washed with H2O
(2 Â 50 mL) and dried over Na2SO4. The solvent was evaporated
under vacuum to give compounds 2, which were purified by column
chromatography over silica gel using hexane/EtOAc (10:1) as eluent.
Compound 2a: Mp 103 °C; IR (KBr): 1556, 1633, 1681, 2917,
spectra indicated C-allylation rather than N-allylation.
In conclusion, we have successfully demonstrated the
metal catalyzed C-allylation of enaminones yielding b-keto
enamides in excellent yields. The best yields were obtained
using CuCl2 as the catalyst and refluxing the enaminones
with allyl bromide in tetrahydrofuran. Further studies on
the mechanism and the role of CuCl2 are being investigated
in our laboratory.
3303 cmÀ1 1H NMR (CDCl3, 400 MHz): d 2.60–2.75 (m, 2H), 2.75
;
Acknowledgments
(d, J = 5 Hz, 3H), 4.44 (t, J = 9 Hz, 1H), 4.98–5.10 (m, 2H), 5.60–5.80
(m, 1H), 6.50 (br s, 1H), 7.45–7.50 (m, 2H), 7.57–7.62 (m, 1H), 7.99–
8.02 (m, 2H); 13C NMR (CDCl3, 100 MHz): 26.5, 28.0, 54.1, 115.5,
128.1, 128.8, 132.2, 137.9, 168.9, 197.8; m/z: (M+, %): 217 (M+, 10),
Financial assistance under CSIR Project (No. 01(2135)/
07/EMR-II) is acknowledged. The authors are grateful to

3994
S. J. Singh, O. M. Singh / Tetrahedron Letters 49 (2008) 3991–3994
216 (20), 202, 189, 105 (100); Anal. Calcd for C13H15NO2: C, 71.87;
H, 6.96; N, 6.45. Found: C, 71.78; H, 6.90; N, 6.51.
added and stirring was continued for 2 h at the same temperature. The
reaction mixture was brought to room temperature and stirring was
continued for 10 h (monitored by TLC). The reaction mixture was
poured into crushed ice and extracted with chloroform (3 Â 50 mL).
The combined organic layers were washed with H2O (2 Â 50 mL),
dried over Na2SO4, concentrated and purified by column chromato-
graphy over silica gel using hexane/EtOAc as eluent to yield 3a–l
Compound 2e: Mp 122 °C; IR (KBr): 1184, 1546, 1639, 1678,
3288 cmÀ1; 1H NMR (CDCl3, 400 MHz): d 2.41 (s, 3H), 2.63–2.71 (m,
2H), 2.75 (d, J = 5 Hz, 3H), 4.41 (t, J = 9 Hz, 1H), 4.97–5.07 (m, 2H),
5.66–5.76 (m, 1H), 6.50 (br s, 1H), 7.24 (d, J = 9 Hz, 2H), 7.88 (d,
J = 9 Hz, 2H); 13C (CDCl3, 100 MHz): 21.5, 26.5, 33.9, 55.3, 117.5,
128.1, 129.5, 134.0, 134.9, 145.0, 168.3, 198.8; m/z: (M+, %): 231 (M+,
8), 216 (10), 140, 119 (100); Anal. Calcd for C14H17NO2: C, 72.70; H,
7.41; N, 6.06. Found: C, 72.73; H, 7.48; N, 6.01.
Compound 3a: Viscous oil; IR (KBr): 1250, 1655, 2910, 3309 cmÀ1
;
1H NMR (CDCl3, 400 MHz): d 2.50 (s, 3H), 2.81 (d, J = 5 Hz, 2H),
2.96 (s, 3H), 4.98–5.25 (m, 2H), 5.80 (s, 1H), 5.85–5.95 (m, 1H), 7.45–
7.50 (m, 2H), 7.56–7.62 (m, 1H), 7.86–7.97 (m, 2H); 13C (CDCl3,
100 MHz): 20.1, 38.0, 54.1, 95.5, 118.2, 128.1, 128.8, 132.2, 137.9,
165.1, 187.8; m/z: (M+, %): 247 (M+,5), 216 (20), 105 (100); Anal.
Calcd for C14H17NOS: C, 67.98; H, 6.93; N, 5.66. Found: C, 67.92; H,
6.90; N, 5.31.
11. Castro, A. M. M. Chem. Rev. 2004, 104, 2939–3002.
12. Yasui, H.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2007, 36, 32–34.
13. General procedure for the preparation of 3a–l: NaH (5.5 mmol) was
added slowly to a solution of the ketene N,S-acetal 1a–l (5 mmol) in
dry THF (30 mL) under a nitrogen atmosphere. The reaction mixture
was stirred at 0 °C for 20 min, then allyl bromide (5.2 mmol) was
14. All the products were characterized from spectral and analytical data.