Pyridine-mediated, one-pot, stereoselective synthesis of acyclic enaminones

Article abstract of DOI:10.1016/j.tetlet.2011.05.112

A new one-pot, three-component reaction of phenacyl pyridinium bromides, various primary aromatic amines, and phenyl glyoxal or ethyl glyoxalate for the stereoselective synthesis of acylic enaminones in good chemical yields is described.

Full text of DOI:10.1016/j.tetlet.2011.05.112

Tetrahedron Letters 52 (2011) 4005–4007
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Pyridine-mediated, one-pot, stereoselective synthesis of acyclic enaminones
⇑
Mehdi Ghandi , Amir Hossein Jameà
School of Chemistry, College of Science, University of Tehran, PO Box 14155 6455, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A new one-pot, three-component reaction of phenacyl pyridinium bromides, various primary aromatic
amines, and phenyl glyoxal or ethyl glyoxalate for the stereoselective synthesis of acylic enaminones
in good chemical yields is described.
Received 25 March 2011
Revised 15 May 2011
Accepted 24 May 2011
Available online 1 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Acyclic enaminones
Phenyl glyoxal
Ethyl glyoxalate
b-Acyl enamines or enaminones are important intermediates in
organic synthesis.1 Their reactivity and stability are much different
to those of conventional enamines.2 Enaminones with the com-
bined nucleophilicity of an enamine and electrophilicity of an en-
one can be considered as versatile intermediates in chemical
research.3 As a consequence, enaminones have been used widely
for the preparation of heterocycles.3 Even though the development
of synthetic methods to cyclic enaminones cannot be overlooked,4
the investigation of new routes to acyclic enaminones, other than
the traditional condensation of amines and 1,3-dicarbonyl com-
pounds,5 and addition of amines to acetylenic ketones6 became
the impetus for this work. A few procedures for the preparation
of enaminones using imines have been reported previously. Reac-
phenacyl pyridinium bromide, 4-chloroaniline and a base afforded
acyclic enaminone 1 in varying yields depending on the base and
solvent (Table 1). The best result in terms of the yield was obtained
when phenacyl pyridinium bromide, ethyl glyoxalate and
4-chloroaniline were treated with NaOMe in toluene at reflux for
12 h (Table 1, entry 3).10 Based on the analytical and spectroscopic
data, the structure of 1 was in agreement with the proposed
structure.11
We next explored the substrate scope by reacting a variety of
phenacyl pyridinium bromides, amines, ethyl glyoxalate, and
NaOMe in toluene at reflux (Scheme 1 and Table 2). All analytical
data including IR, 1H and 13C NMR spectra of the products 1–10
were in agreement with the proposed structures.12 Inspection of
the results revealed that substrates with electron-donating and
electron-withdrawing groups were tolerated.
Utilization of various phenyl glyoxals in reactions with phena-
cyl pyridinium bromides and amines afforded the corresponding
enaminones 11–16 (Scheme 2, Table 3).13 In contrast to ethyl gly-
oxalate which afforded the corresponding enaminones 1–10 in
moderate yields (Table 2), reactions with substituted phenyl
glyoxals gave the desired enaminones 11–16 in higher yields
(Table 3).
Based on the postulated mechanism depicted in Scheme 3, con-
densation of the aldehyde with the amine initially affords the cor-
responding imine. Subsequent nucleophilic attack of ylide I,
generated in situ via deprotonation of the phenacyl pyridinium bro-
mide on the imine gives intermediate II. The enaminone is finally
obtained via a 1,2-H shift followed by elimination of pyridine
(Scheme 3). Phenyl glyoxal imine containing the more electron-
attracting Ph-CO group favors addition of ylide I by enhancing the
electrophilicity of the imine group in comparison to that of ethyl
tions of a
-metalated imines with esters7 and imine acylation with
benzotriazole8 are such examples. We hypothesized that acyclic
enaminones could be derived from condensation of phenacyl
pyridinium bromides with imines. Herein, we describe a one-pot,
three-component synthesis of acyclic enaminones via reaction of
phenacyl pyridinium bromides, various primary aromatic amines,
and phenyl glyoxal or ethyl glyoxalate.
Reaction of phenacyl pyridinium bromide9 with benzaldehyde,
4-chloroaniline and various bases, such as pyridine, triethylamine,
and sodium hydroxide in EtOH, CH2Cl2, THF or DMSO failed to
show any progress based on TLC results. The low electron-defi-
ciency of the imines generated in situ seemed to be responsible
for this lack of reactivity. Utilization of tosylimines gave the
desired enaminones in poor yields. Gratifyingly, condensation of
an electron-deficient aldehyde such as ethyl glyoxalate with
⇑
Corresponding author. Tel.: +98 21 61112250; fax: +98 21 66495291.
E-mail address: ghandi@khayam.ut.ac.ir (M. Ghandi).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.112

4006
M. Ghandi, A. H. Jameà / Tetrahedron Letters 52 (2011) 4005–4007
Table 1
Results obtained for the conversion of phenacyl pyridinium bromide into enaminone 1 using ethyl glyoxalate and p-
chloroaniline in the presence of a base
Cl
NH2
O
O
HN
Conditionsa
N
OEt
EtO CCHO +
+
2
H
O
Br
Cl
1
Entry
Base
Solvent
Isolated yield (%)
1
2
3
4
5
6
7
8
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
Et3M
H2O
Trace
10
68
35
15
58
60
40
CH2Cl2
PhMe
THF
EtOH
PhMe
PhMe
PhMe
Na2CO3
NaOH
aConditions: Phenacyl pyridinium bromide (1.0 equiv), ethyl glyoxalate (1.0 equiv), p-chloroaniline (1.0 equiv), base
(1.0 equiv), solvent (25 mL), 1 h at room temperature, then 12 h at reflux.
Ar
O
HN
O
NaOMe
OEt
+
EtO2CCHO + Ar-NH2
N
toluene
reflux, 12 h
H
O
Br
R1
R1
1-10
Scheme 1. Synthesis of enaminones 1–10.
Table 2
Yields of enaminones 1–10 obtained from reaction of phenacyl pyridinium bromides,
ethyl glyoxalate, various amines, and sodium methoxide in toluene at reflux
Table 3
Yields of enaminones 11–16 obtained from reaction of phenacyl pyridinium
bromides, phenyl glyoxals, various amines, and sodium methoxide in toluene at
reflux
Entry
R1
Ar
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
H–
4-Cl-C6H4–
4-Cl-C6H4–
4-Cl-C6H4–
3-Me-C6H4–
3,4-Me2-C6H3–
3,4-Me2-C6H3–
3,4-Me2-C6H3–
4-Me-C6H4–
4-Me-C6H4–
4-Me-C6H4–
1
2
3
4
5
6
7
8
68
72
60
58
60
62
42
63
45
57
4-Me–
4-Br–
4-Me–
4-Me–
4-Br–
4-Cl–
4-Me–
4-Cl–
4-Br–
Entry
R1
R2
Ar
Product
Yield (%)
1
2
3
4
5
6
4-Me–
4-Br–
4-Me–
4-Br–
4-Cl-
C6H5-CO–
4-Me-C6H4–
3,4-Me2-C6H3–
4-Me-C6H4–
4-Me-C6H4–
3,4-Me2-C6H3–
3,4-Me2-C6H3–
11
12
13
14
15
16
85
72
75
81
74
62
4-Cl-C6H4–CO-
4-Cl-C6H4-CO–
4-Me-C6H4-CO–
4-Me-C6H4-CO–
4-Me-C6H4-CO–
9
10
4-Br-
glyoxalate imine containing the less electron-attracting EtOCO
group. Enaminones 1–16 were obtained diastereomerically pure
since stabilization through hydrogen bonding of the N–H and
C@O groups as depicted in Scheme 3 blocks formation of the other
stereoisomer.
In conclusion, enaminones 1–16 were prepared via a new pyri-
dine-mediated method using phenacyl pyridinium bromides, vari-
ous primary aromatic amines, and phenyl glyoxals or ethyl
glyoxalate in moderate to good yields.
Ar
O
HN
O
NaOMe
R2-CHO + Ar-NH2
R2
+
N
toluene
reflux, 12 h
H
Br
R1
R1
11-16
Scheme 2. Synthesis of enaminones 11–16.

M. Ghandi, A. H. Jameà / Tetrahedron Letters 52 (2011) 4005–4007
4007
R2-CHO + Ar-NH2
R2-CH=NAr
O
Ar
H
O
N
O
R2
N
Br
R1
N
N
R1
R1
I
II
H
Ar
Ar
O
N
O
HN
R2
R2
+
N
N
R1
R1
1-16
Scheme 3. Postulated mechanism for the formation of enaminones 1–16.
in toluene) was stirred at room temperature for 1 h. The solution was then
heated at reflux for 12 h. The solvent was evaporated under reduced pressure
and the residue purified by column chromatography over silica gel (eluent:
hexane–EtOAc, 10:1) to afford 1.
Acknowledgment
The authors acknowledge the University of Tehran for financial
support of this research.
11. (Z)-ethyl 2-[(4-chlorophenyl)amino]-4-oxo-4-phenylbut-2-enoate (1). Yellow
solid, mp: 80–81 °C; 1H NMR (500 MHz, CDCl3)
d 1.19 (t, J = 7.1 Hz, 3H,
Me), 4.25 (q, J = 7.1 Hz, 2H, CH2), 6.49 (s, 1H, CH@C), 7.01–8.00 (m, 9H, Ar),
12.00 (s, 1H, NH); 13C NMR (125 MHz, CDCl3) d 14.4 (Me), 62.7 (CH2), 97.9
(CH@C), 123.4 (C@CH), 128.1, 129.6, 129.7, 130.7, 136.4, 139.0, 143.5, 149.6
References and notes
(Ar), 164.8 (C@O), 191.6 (C@O); IR (KBr) m: 3060 (CH), 1728 (OC@O), 1670
1. (a) Alizadeh, A.; Babaki, M.; Zohreh, N. Synthesis 2008, 3295–3298; (b)
Fernanda, R. A.; Pablo, M.; Marcelo, R.; Pâmela, V. S.; Helio, B. G.; Nilo, Z.;
Marcos, M. A. P. Synlett 2007, 3165–3171; (c) Ge, H.; Niphakis, M. J.; Georg, G. I.
J. Am. Chem. Soc. 2008, 130, 3708–3709; (d) Singh, V.; Saxena, R.; Batra, S. J. Org.
Chem. 2005, 70, 353–356; (e) Zhang, R.; Zhang, D.; Guo, Y.; Zhou, G.; Jiang, Z.;
Dong, D. J. Org. Chem. 2008, 73, 9504–9507.
2. (a) Michael, J. P.; De Koning, C. B.; Gravestock, D.; Hosken, G. D.; Howard, A. S.;
Jungmann, C. M.; Krause, R. W. M.; Parsons, A. S.; Pelly, S. C.; Stanbury, T. V.
Pure Appl. Chem. 1999, 71, 979–988; (b) Elassar, A. A.; El-Khair, A. A. Tetrahedron
2003, 59, 8463–8480.
(PhC@O) cmÀ1; MS (EI, 70 eV) m/z 329 (M+, 91), 256 (100), 105 (84), 77
(35%); Anal. Calcd for C18H16ClNO3: C, 65.56; H, 4.89; N, 4.25. Found: C,
65.58; H, 4.90; N, 4.23.
12. (Z)-ethyl 2-[(3,4-dimethylphenyl)amino]-4-oxo-4-p-tolylbut-2-enoate (5). Yellow
solid, mp: 83–84 °C; 1H NMR (500 MHz, CDCl3) d 1.17 (t, J = 7.1 Hz, 3H, Me),
2.21 (s, 6H, 2 Me), 2.44 (s, 3H, Me), 4.24 (q, J = 7.1 Hz, 2H, CH2), 6.37 (s, 1H,
CH@C), 6.79–7.91 (m, 7H, Ar), 12.09 (s, 1H, NH); 13C NMR (125 MHz, CDCl3): d
14.1 (Me), 19.6 (Me), 20.2 (Me), 22.0 (Me), 62.6 (CH2), 96.1 (CH@C), 116.6
(C@CH), 123.6,127.9, 129.6, 130.5, 134.0, 136.8, 137.7, 137.8, 143.0, 150.7 (Ar),
165.2 (C@O), 190.2 (C@O); IR (KBr) m: 2925 (CH), 1728 (OC@O), 1660 (PhC@O)
3. (a) Venkov, A. P.; Angelov, P. A. Synthesis 2003, 2221–2225; (b) Brandt, C. A.; da
Silva, A. C. M. P.; Pancote, C. G.; Brito, C. L.; da Silveira, M. A. B. Synthesis 2004,
1557–1559.
cmÀ1; MS (EI, 70 eV) m/z 337 (M+, 59), 264 (100), 119 (75), 91 (35), 77 (20%);
Anal. Calcd. for C21H23NO3: C, 74.75; H, 6.87; N, 4.15. Found: C, 74.70; H, 6.89;
N, 4.1713.
4. (a) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277–294; (b) Lue, P.; Greenhill, J. V.
Adv. Heterocycl. Chem. 1996, 67, 207–215; (c) Katritzky, A. R.; Barcock, R. A.;
Long, Q. H.; Balasubramanian, M.; Malhotra, N.; Greenhill, J. V. Synthesis 1993,
233–236; (d) Michael, J. P.; De Koning, C. B.; Gravestock, D.; Hosken, G. D.;
Howard, A. S.; Jungmann, C. M.; Krause, R. W. M.; Parsons, A. S.; Pelly, S. C.;
Stanbury, T. V. Pure Appl. Chem. 1999, 71, 979–988; (e) Turunen, B. J.; Georg, G.
I. J. Am. Chem. Soc. 2006, 128, 8702–8703; (f) Seki, H.; Georg, G. I. J. Am. Chem.
Soc. 2010, 132, 15512–15513.
5. Stefani, H. A.; Costa, I. M.; de O Silva, D. Synthesis 2000, 1526–1528.
6. Hendricks, J. B.; Rees, R. J. Am. Chem. Soc. 1961, 83, 1251–1252.
7. Bartoli, G.; Cimarelli, C.; Palmieri, G.; Bosco, M.; Dalpozzo, R. Synthesis 1990,
895–897.
13. (a)(Z)-4-(4-bromophenyl)-1-(4-chlorophenyl)-2-[(3,4-dimethylphenyl)amino]but
-2-ene-1,4-dione (12). Yellow solid, mp: 143–144 °C; 1H NMR (500 MHz, CDCl3)
d 2.24 (s, 3H, Me), 2.43 (s, 3H, Me), 6.09 (s, 1H), 6.87–7.94 (m, 11H), 12.51(s,
1H); 13C NMR (125 MHz, CDCl3): 21.2 (Me), 22.0 (Me), 95.1 (CH@C), 122.2
(C@CH), 127.9, 129.5, 129.7, 130.3, 131.4, 133.6, 135.5, 136.6, 136.7, 141.3,
143.1, 156.7 (Ar), 191.2 (C@O), 191.7 (C@O); IR (KBr) m: 2921 (CH), 1666 (C@O)
cmÀ1; MS (EI, 70 eV) m/z 467 (M+, 2), 250 (100), 119 (53), 91 (3), 77 (5%); Anal.
Calcd. for C24H19BrClNO2: C, 61.49; H, 4.09; N, 2.99. Found: C, 61.40; H, 4.06; N,
2.94; (b) (Z)-4-(4-chlorophenyl)-2-[(3,4-dimethylphenyl)amino]-1-p-tolylbut-2-
ene-1,4-dione (15). Yellow solid, mp: 108–109 °C; 1H NMR (500 MHz, CDCl3): d
2.14 (s, 6H, 2Me), 2.41 (s, 3H, Me), 6.08 (s,1H, CH@C), 6.70–7.94 (m, 11H, Ar),
12.48 (s,1H, NH); 13C NMR (125 MHz,CDCl3) d 19.2 (Me), 20.2 (Me), 22.0 (Me),
94.9 (CH@C), 119.5 (C@CH), 123.5, 127.7, 128.7, 129.0, 129.6, 129.7, 130.5,
130.7, 131.2, 131.4,133.6, 134.2, 136.7, 136.8, 138.2, 141.1, 143.0, 156.6 (Ar),
8. Katritzky, A. R.; Fang, Y.; Donkor, A.; Xu, J. Synthesis 2000, 2029–2032.
9.
A solution of pyridine (158 mg, 2 mmol) and phenacyl bromide (398 mg,
2 mmol) in EtOAc (5 mL) was stirred at room temperature for 24 h. The
resulting white salt was filtered and washed with EtOAc (5 mL) to afford
phenacyl pyridinium bromide as a white solid (526 mg, 95%).
191.1 (C@O), 191.8 (C@O); IR (KBr) m
: 2923 (CH), 1670 (C@O), cmÀ1; MS (EI,
70 eV) m/z 403 (M+, 20), 264 (100), 119 (70), 91 (51), 77 (36%); Anal.
Calcd. for C25H22ClNO2: C, 74.34; H, 5.49; N, 3.47. Found C, 74.30; H, 5.42; N,
3.49.
10.
A
mixture of phenacyl pyridinium bromide (556 mg, 2.0 mmol), p-
chloroaniline (254 mg, 2 mmol), and ethyl glyoxalate (2 mmol, 50% solution