Solvent-free stereoselective synthesis of β-aryl-β-amino acid esters by the Rodionov reaction using microwave irradiation

Article abstract of DOI:10.1070/MC2001v011n01ABEH001360

A rapid method for the title synthesis of β-aryl-β-amino acid esters was developed, and the absolute configurations of newly formed C-3 chiral centres in the major and minor diastereomers of the resulting ethyl N-[(S)-α-methylbenzyl]-β-amino-β-phenyl-propionate were determined.

Full text of DOI:10.1070/MC2001v011n01ABEH001360

, 2001, 11(1), 26–27
Solvent-free stereoselective synthesis of β-aryl-β-amino acid esters by the Rodionov
reaction using microwave irradiation
Nelly N. Romanova,* Alexander G. Gravis, Pavel V. Kudan and Yuri G. Bundel’
Department of Chemistry, M. V. Lomonosov Moscow State University, 119899 Moscow, Russian Federation.
Fax: +7 095 932 8846; e-mail: rom@org.chem.msu.su
10.1070/MC2001v011n01ABEH001360
A rapid method for the title synthesis of β-aryl-β-amino acid esters was developed, and the absolute configurations of newly
formed C-3 chiral centres in the major and minor diastereomers of the resulting ethyl N-[(S)-α-methylbenzyl]-β-amino-β-phenyl-
propionate were determined.
Table 1 Chemical and optical yields of ternary Rodionov condensation.a
ArCHO + RNH2·MeCOOH + HOOCCH2COOEt
The stereoselective synthesis of β-lactams, which are structure
constituents of many natural compounds and pharmaceuticals,
is of considerable importance. Homochiral β-lactams can be
prepared by cyclisation of enantiomeric esters of β-amino acids
that should be stereoselectively synthesised. The preparation of
β-amino acid esters by the Michael reaction is performed under
severe conditions and does not always result in adequate
yields.1 Previously,2 it was proposed to activate the Michael
reaction using microwave irradiation. This technique made it
possible to obtain esters of some β-amino acids in good yields
for several minutes. Note that ethyl cinnamate reacted only with
morpholine under these conditions.
As an extension of our studies on the rapid synthesis of
β-amino acid esters, we examined the effect of microwave
irradiation on the chemical yield and stereoselectivity of the
Rodionov reaction.3 This reaction is primarily used for the syn-
thesis of β-amino acids (R = H);4 however, it was found5 that
β-amino acid esters (R = Et) can also be obtained by this reaction:
ArCH(NHR)CH2COOEt + ArCH=CHCOOEt
I
II
Reaction Yield
Yield
of II
(%)
d.e. I
(%)
Entry Ar
R
t/min condi- of I
tions
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Ph
Ph
Ph
Ph
Ph
Ph
PhCH2
(S)-PhCHMe 10 MW
(S)-PhCHMe 720
(S)-PhCHMe 10 MWc
10 MW
18
19
2
17
4
—
35
36
40
32
51
53
14
—
27
—
—
—
80
67
95
74
92
68
85
72
68
72
87
28
34
b
—
b,c
(S)-PhCHMe 600
—
(S)-PhCHMe 14 MWd,e 17
(S)-PhCHMe 14 MWd,f
8
21
23
27
0
o-O2NC6H4 (S)-PhCHMe
p-O2NC6H4 PhCH2
p-O2NC6H4 (S)-PhCHMe 14 MW
p-Me2NC6H4 (S)-PhCHMe 20 MW
p-Me2NC6H4 (S)-PhCHMe 16 MWc
p-MeOC6H4 (S)-PhCHMe 15 MW
8
MW
10 MW
COOH
COOR
R3
R1
0
0
R1CHO
R2NH2
R3
*
*
R2HN
COOR
aMicrowave experiments (MW) were performed at a power of 170 W. The
chemical yields are given for chromatographically pure compounds. The
structures of the compounds were supported by IR and 1H NMR spectro-
scopy and GC–MS. The diastereomeric composition was determined from
1H NMR spectra (400 MHz). bBoiling in ethanol. cAn azomethine was used
in the reaction. dα-Methylbenzylamine was used in the reaction. eThe initial
amounts of the reactants were 1 mmol. f The initial amounts of the reactants
were 5 mmol.
R = H, Et
Scheme 1
The synthesis of β-amino esters was performed on long heating
of the reactants in alcohol; however only ammonia was intro-
duced into condensation with monoethyl malonate and substi-
tuted benzaldehydes. In this case, substituted cinnamates were
always formed in considerable amounts in addition to β-amino
esters.
In this study, monoethyl malonate, its C-alkyl derivatives,
aromatic aldehydes, benzylamine, (S)-α-methylbenzylamine and
the acetates and Schiff bases of these amines were used as
substrates.
The conditions of the Rodionov reaction under microwave
irradiation were optimised for the synthesis of ethyl N-[(S)-
α-methylbenzyl]-β-amino-β-phenylpropionate. The procedure
developed† was used for the syntheses of other esters (Table 1).
Microwave irradiation provides some advantages in the syn-
thesis of β-aminoesters by the Rodionov reaction. Thus, when
the synthesis of ethyl N-[(S)-α-methylbenzyl]-β-amino-β-phenyl-
propionate was performed under conventional conditions of
the Rodionov reaction (on boiling the reactants in ethanol for
10–12 h), only insignificant amounts of the ethyl ester were
isolated (Table 1, entries 3 and 5). However, this ester can be
obtained in a moderate yield at a similar stereoselectivity under
conditions of microwave irradiation in a matter of minutes
(Table 1, entry 2).
On the other hand, malonic acid and monoethyl esters of
C-alkyl substituted malonic acids cannot be introduced into
the reaction under typical conditions, whereas ethyl malonate
underwent almost quantitative conversion.
Note that the replacement of benzylamine with α-methyl-
benzylamine did almost not decrease the chemical yields of
β-amino esters (Table 1, entries 1 and 2 or 9 and 10). At the
same time, substituents at the aromatic nucleus of benzaldehyde
considerably affected the course of the Rodionov reaction. Elec-
tron-donating substituents in the para-position of the phenyl
ring resulted in that ethyl β-amino-β-arylpropionate was not
Ph
HN
Ph
Ph
HN
Ph
3
3
1
1
EtMgBr
55%
COOEt
COOEt
3''
3''
3R, 3''S
3S, 3''S
2.6 : 1
Ph
Ph
†
4
4
An equimolar mixture of an aldehyde, an amine acetate, and a malonic
acid derivative (without a solvent) was irradiated in an open glass vessel
in a microwave oven (Funai MO785VT, 170 W) for several minutes
(until the release of CO2 was complete). The reaction was monitored by
TLC. The reaction products were separated by column chromatography
on silica gel with a benzene–ethyl acetate eluent (2:1). Note that an
increase in the microwave power up to 350 W resulted in a decrease in
the yield of the target amino ester.
N
N
Ph
Ph
O
O
1'
1'
1' S, 4R
1' S, 4S
2.1 : 1
Scheme 2
– 26 –

, 2001, 11(1), 26–27
formed at all under microwave conditions (Table 1, entries 11–
13). In contrast, the electron-acceptor nitro group in the ortho-
or para-position increased the chemical yields of corresponding
β-amino esters with respect to unsubstituted benzaldehyde
(Table 1, entries 8 and 2, 9 and 1, 10 and 2).
Thus, microwave activation can be successfully used for the
stereoselective synthesis of β-amino acid esters by the Rodionov
reaction without solvent. The procedure is easy to perform, and
the esters can be obtained in moderate chemical and optical
yields in 10–14 min.
It should be emphasised that the Rodionov reaction was
stereoselective with the use of the above substrates. Thus, for
benzaldehyde and α-methylbenzylamine acetate under optimum
conditions, d.e. was 35% (Table 1, entry 2). The presence of a
nitro group at the para-position of an aromatic nucleus of
benzaldehyde decreased the stereoselectivity (d.e. is as low as
27%, Table 1, entry 10). It is likely that the electron-acceptor
nitro group decreases the activation energy of the addition
of monoethyl malonate to an azomethine, and steric factors
become less significant. The nitro group at the ortho-position
results in a more dramatic decrease in the stereoselectivity
(Table 1, entries 8 and 10).
References
1 N. N. Romanova, A. G. Gravis and Yu. G. Bundel’, Usp. Khim., 1996,
65, 1170 (Russ. Chem. Rev., 1996, 65, 1083).
2 (a) N. N. Romanova, A. G. Gravis, G. M. Shaidullina, I. F. Leshcheva
and Yu. G. Bundel’, Mendeleev Commun., 1997, 235; (b) N. N.
Romanova, A. G. Gravis, I. F. Leshcheva and Yu. G. Bundel’, Mendeleev
Commun., 1998, 147.
3 K. V. Vatsuro and G. L. Mishchenko, Imennye reaktsii v organicheskoi
khimii (Named Reactions in Organic Chemistry), Khimiya, Moscow,
1976, p. 361 (in Russian).
4 (a) V. M. Rodionov and A. M. Fedorova, Ber. Dtsch. Chem. Ges., 1927,
60, 804; (b) T. Johnson and J. Evans, J. Am. Chem. Soc., 1930, 52, 4993;
(c) V. M. Rodionov and N. G. Yartseva, Izv. Akad. Nauk SSSR, Otdel.
Khim. Nauk, 1952, 103 (in Russian); (d) V. M. Rodionov and E. V.
Yavorskaya, Zh. Org. Khim., 1953, 23, 983 (in Russian); (e) V. M.
Rodionov and K. P. Preobrazhenskaya, Zh. Org. Khim., 1954, 24, 1971
(in Russian); ( f ) V. P. Mamaev, N. N. Suvorov and E. M. Rokhlin, Dokl.
Akad. Nauk SSSR, 1955, 101, 269 (in Russian).
5 V. M. Rodionov and N. N. Bezinger, Izv. Akad. Nauk SSSR, Otdel. Khim.
Nauk, 1952, 696 (in Russian).
6 (a) M. Furukawa, T. Okawara and Y. Terawaki, Chem. Pharm. Bull.,
1977, 25, 1319; (b) N. Asao, T. Shimada, T. Sudo, N. Tsukada, K. Yazawa,
Y. S. Gyoung, T. Uyehara and Y. Yamamoto, J. Org. Chem., 1997, 62,
6374.
To study the stereochemistry of the synthesis of β-aryl-β-
aminopropionates by the Rodionov reaction under microwave
irradiation, we chemically determined6 the absolute configura-
tions of the newly formed C-3 chiral centre for the major and
minor diastereomers of ethyl N-[(S)-α-methylbenzyl]-β-amino-
β-phenylpropionate. A mixture of the diastereomers was sub-
jected to cyclisation to form a mixture of the corresponding
diastereomers of N-[(S)-α-methylbenzyl]-4-phenylazetidin-2-one,
the 1H NMR spectra of which were published.7
1
A comparison between the H NMR spectral data of the
prepared β-lactam diastereomers‡ with published data7 allowed
us to conclude that the major and minor diastereomers of ethyl
N-[(S)-α-methylbenzyl]-β-amino-β-phenylpropionate exhibit 3R-
and 3S-configurations, respectively.§
7 E. Rogalska and C. Belzecki, J. Org. Chem., 1984, 49, 1397.
‡
The NMR spectra were recorded on a VXR-400 Varian spectrometer
(400 MHz) in a CDCl3 solution at 28 °C using TMS as an internal
standard. Protons in the 1H NMR spectra are numbered as follows:
Received: 13th July 2000; Com. 00/1686
§
Ha
H
Ph
Hb
3
4
H
6
2
N
Me
Ph
1
Me
O
5
Ph H
NH
O
2
4
1
3
1H NMR, d: major isomer: 1.76 (d, 3H, Me, JMe,H-1 7.30 Hz), 2.78 (dd,
1H, Ha-3, JH -3,H -3 14.61 Hz, JH -3,H-4 2.56 Hz), 3.24 (dd, 1H, Hb-3,
Ph
O
Me
a
b
a
JH -3,H -3 14.61 Hz, JH -3,H-4 5.23 Hz), 4.26 (q, 1H, H-1, JH-1,Me 7.30 Hz),
1H NMR, d: major diastereomer: 1.16 (t, 3H, Me-1, JMe-1,C(2)H 7.14 Hz),
4.33 (add, 1H, H-4, JHb -4,H -3 2.56 Hz, JH-4,H -3 5.23 Hz); minor isomer:
1.25 (d, 3H, Me-6, JMe-6,H-5 6.71 Hz), 1.94 (s, 1H, NH), 2.51 (dd, 1H,
Ha-3, JH -3,H -3 15.03 Hz, JH -3,H-4 5.14 Hz), 2.61 (dd, 1H, Hb-3, JH -3,H -3
b
2
a
b
1.28 (d, 3H, Me, JMe,H-1 7.25 Hz), 2.79 (dd, 1H, Ha-3, JH -3,H -3 14.77 Hz,
JH -3,H-4 5.26 Hz), 3.20 (dd, 1H, Hb-3, JH -3,H -3 14.77 Hz, JaH -3,H-4 2.58 Hz),
15.03 Hz, JHb -3,H-4 9.04 Hz)a, 3.48 (q, 1H, H-5, JH-5,Me-6 6.71 Hz), 3.80
b
a
b
a
a
b
a
b
4.28 (dd, 1H, H-4, JH-4,H -3 5.26 Hz, JH-4,H -3 2.58 Hz), 5.01 (q, 1H, H-1,
(dd, 1H, H-4b, JH-4,H -3 5.14 Hz, JH-4,H -3 9.04 Hz), 4.06 [q, 2H, C(2)H2,
a
b
b
JH-1,Me 7.25 Hz).
J
C(2)H ,Me-1 7.14 Hz],a7.15–7.35 (m, 10H, Ph). 13C NMR, d: 14.12 (Me-6),
2
1H NMR spectra for the major and minor diastereomers correspond to
those reported7 for (1'S,4R)- and (1'S,4S)-isomers, respectively.
25.05 (Me-1), 43.55 (C-3), 55.03 and 56.82 (C-4 and C-5 or reverse),
60.33 (C-2), 126.79–128.49 (Ph-4 and Ph-5), 171.57 (C=O).
– 27 –