1,3-dipolar cycloaddition of schriff bases and electron-deficient alkenes, catalyzed by α-Amino acids

Article abstract of DOI:10.1007/s11178-008-3012-5

L-α-Amino acids catalyze 1,3-dipolar cycloaddition of methyl α-benzylideneamino acids to electron-deficient olefins in different solvents at room temperature. L-α-Amino acids ensure stereoselective formation of the corresponding syn,syn-azomethine ylides. The subsequent reaction with an active dipolarophile is stereospecific; it occurs as endo-cycloaddition with low asymmetric induction (up to ee 12%.). 3,4-Substituted 5-arylprolines were obtained in preparative yields using L-pyroglutamic acid or L-proline as catalyst.

Full text of DOI:10.1007/s11178-008-3012-5

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 3, pp. 378–387. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © K.V. Kudryavtsev, A.A. Zagulyaeva, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 3, pp. 384–393.
1,3-Dipolar Cycloaddition of Schiff Bases and Electron-Deficient
Alkenes, Catalyzed by α-Amino Acids
K. V. Kudryavtsev and A. A. Zagulyaeva
Faculty of Chemistry, Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
e-mail: kudr@org.chem.msu.ru
Received April 6, 2007
Abstract—L-α-Amino acids catalyze 1,3-dipolar cycloaddition of methyl α-benzylideneamino acids to elec-
tron-deficient olefins in different solvents at room temperature. L-α-Amino acids ensure stereoselective forma-
tion of the corresponding syn,syn-azomethine ylides. The subsequent reaction with an active dipolarophile is
stereospecific; it occurs as endo-cycloaddition with low asymmetric induction (up to ee 12%.). 3,4-Substituted
5-arylprolines were obtained in preparative yields using L-pyroglutamic acid or L-proline as catalyst.
DOI: 10.1134/S1070428008030123
[3+2]-Cycloaddition reactions provide an effective
and extensively used method for the synthesis of
proline derivatives I which are widespread in nature
[1] and are physiologically active toward some biolog-
ical targets [2]. As a rule, this procedure utilizes Schiff
bases II as synthetic precursors of compounds I. Com-
pounds II are readily available from the corresponding
aldehydes and α-amino acid esters having a primary
amino group (Scheme 1). Prototropic tautomerization
catalyzed by Brønsted or Lewis acids gives rise to
a 1,3-dipole, azomethine ylide A, which possesses
4π-electron system; it reacts with electron-deficient
alkenes R3CH=CHR4 with formation of pyrrolidine
ring [3, 4]. Each elementary step of the process shown
in Scheme 1 is characterized by high stereo- and regio-
selectivity, and this procedure was used by us previ-
ously to synthesize new functional derivatives of
pyrrolidine-2-carboxylic acids [5, 6]. Dipole A
(Scheme 1) has syn,syn configuration due to coordina-
tion of the carbonyl oxygen atom with acid; the latter
in turn interacts with lone electron pair on the azo-
methine nitrogen atom; cis arrangement of the ester
group in position 2 and substituent in position 5 of the
pyrrolidine ring in molecule I is also favored by steric
factors. Cycloaddition of unsymmetrical alkenes
R3CH=CHR4 (R3 ≠ R4) to dipole A occurs with a good
regioselectivity and with endo- [7] or exo-stereoselec-
tivity [8], depending on the reaction conditions. The
use of Co(II), Mn(II), Ag(I), Cu(II), and Zn(II) salts as
Lewis acids to generate metal-containing dipole A
(where M is a metal) and of chiral ligands ensures
asymmetric synthesis of pyrrolidines I with an optical
purity reaching 99% [9, 10].
Scheme 1.
1,3-Dipolar cycloaddition of alkenes to azomethine
ylides in the presence of Brønsted acids has been
studied to a lesser extent. The main reasons are
a limited set of dipolarophiles capable of reacting in
the presence of a protic acid and poor stereoselectivity
of the process. For example, methyl (benzylidene-
amino)acetate (III) reacted with N-methylmaleimide in
acetonitrile in the presence of 10 mol % of acetic acid
to give a mixture of isomeric cycloadducts IV and V at
a ratio of 1:2 in quantitative yield (Scheme 2) [11].
The temperature conditions given in [11] in the text
and Experimental section are contradictory; therefore,
the reaction conditions remain unclear.
R4
R3
R2
OR1
R2
R5
N
R5
O
N
O
H
R1O
R3
I
II
MX
R4
R2
R2
OR1
OR1
R5
N
R5
N
+
HX
M
O
XM
O
Generation of 1,3-dipole from imino esters VI and
the subsequent cycloaddition of N-phenylmaleimide
A
378

1,3-DIPOLAR CYCLOADDITION OF SCHIFF BASES
379
Scheme 2.
A
O
O
OMe
OMe
O
O
OMe
MeCN, AcOH
+
Ph
N
+
Me
N
NH
Me
N
NH
O
O
N
O
Me
III
O
Ph
O
Ph
( )-IV, 33%
( )-V, 67%
occur in a stereoselective fashion in the presence of
Brønsted acids on heating or in acetic anhydride con-
taining 6% of acetic acid at room temperature; as a re-
sult, bicyclic compounds VII are formed (Scheme 3)
[12]. Maleic anhydride was also brought into analo-
gous reaction as dipolarophile, whereas dimethyl male-
ate and dimethyl fumarate failed to react, presumably
due to their lower reactivity [12].
gen atom (Scheme 4). Hydrogen bond in azomethine
ylide A derived from Schiff bases II (R2 = H) and
III, which contain no substituent in the α-position, is
a weak stabilizing factor, and dipole B becomes
thermodynamically more stable (Scheme 4). As a re-
sult, the stereoselectivity of cycloaddition decreases
[11]. Electrostatic and other interactions between the
conjugate base of enantiomerically pure Brønsted acid
and azomethine ylide A could give rise to asymmetric
induction in the subsequent 1,3-dipolar cycloaddition.
Zwitterionic form of enantiomerically pure α-amino
acid is a bidentate chiral ligand which is capable of
reacting with azomethine ylide A to give hydrogen
bond-stabilized associate C, providing additional
activation and stabilization of syn,syn-dipole A
(Scheme 4).
As noted above, the use of transition metal salts in
combination with enantiomerically pure phosphine and
nitrogen-containing ligands makes it possible to ac-
complish a catalytic version of asymmetric 1,3-dipolar
cycloaddition of azomethines with high enantioselec-
tivity [9, 10, 13]. Chiral Brønsted acids were not
reported as catalysts in such reactions. In the present
work we were the first to examine L-α-amino acids as
catalysts in asymmetric 1,3-dipolar cycloaddition of
imino esters II to dipolarophiles. Catalysis by sub-
stoichiometric amounts of organic compounds having
a low molecular weight (so-called organocatalysis) is
widely used to perform various asymmetric organic
reactions (for review, see [14]). Asymmetric organo-
catalytic 1,3-dipolar cycloaddition of azomethine ylides
was not reported previously.
As model process we examined the reaction of
methyl (benzylideneamino)acetate (III) with N-meth-
ylmaleimide in various solvents at room temperature in
the presence of L-proline (L-Pro, 20 mol %; Scheme 5;
Table 1, run nos. 1–6). Proline is a cyclic amino acid
having a secondary amino group; it effectively cata-
lyzes reactions involving iminium and enamine inter-
mediates and is an effective organocatalyst in various
processes [15]. In our case, the acidity of amino acids
and their subsequent association with 1,3-dipole are
important.
α-Amino acids are cheap difunctional compounds
containing amino and carboxy groups and are available
as two individual enantiomers. Both these functional
groups are amphotheric. Reaction of an α-amino acid
with Schiff base III could initiate the following trans-
formation sequence generating azomethine ylide:
(1) protonation of the imino nitrogen atom and (2) de-
protonation at the α-position with respect to the nitro-
L-Proline was added to a mixture of the reactants
in appropriate solvent, and the mixture was stirred at
room temperature over a period indicated in Table 1.
The reaction mixtures were generally heterogeneous
(run nos. 1, 2, 4–6); an exception was the reaction in
Scheme 3.
R
O
COOMe
NH
R
Ph
N
R'
Bronsted acid, toluene, 105°C
/
or Ac2O, AcOH, 20°C
OMe
N
+
O
O
N
O
R'
O
Ph
( )-VI
( )-VII, 62–88%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

KUDRYAVTSEV, ZAGULYAEVA
380
Scheme 4.
OMe
Ph
N
H
R
O
OMe
Y
O–
Ph
N
H
A
N
O
H2
HB
OMe
O
Ph
N
O–
H
N
O
Y
III
O
O
OMe
H
R
C
Ph
N
H
B
aqueous acetonitrile (run no. 3). In all cases, the con-
version of the initial reactants was not complete. All
reactions performed in the presence of L-proline,
except for the process in water, gave the corresponding
cycloaddition products. The structure of the major
product was determined by comparing its physical
constants and spectral parameters with those reported
in the literature [8, 11, 13]; it was identified as cyclo-
adduct IV formed via endo-addition of N-methylmale-
imide to syn,syn-dipole A (Scheme 5). The minor prod-
uct was assigned structure V on the basis of its IR and
NMR spectral parameters and those given in [11].
Taking into account that the NMR spectra of isomeric
exo-addition product formed through intermediate
syn,syn dipole A differ only slightly from the corre-
sponding parameters of endo-adduct IV [8], the struc-
ture of racemate IV was finally proved by X-ray anal-
ysis (Fig. 1, Table 2). A unit cell of compound IV in
crystal includes two enantiomeric molecules linked by
two hydrogen bonds (Fig. 2). The asymmetric induc-
tion in reactions catalyzed by L-proline was low (run
nos. 1–5, Table 1). The optical purity of pyrrolidine IV
was determined by comparing its specific rotation with
published data [8, 13]. The highest optical purity of
compound IV was 12% (Table 1, run no. 5), when the
reaction was carried out in THF. The major enantiomer
IV is characterized by a positive optical rotation; in
keeping with published data, its absolute configuration
corresponds to that shown in Scheme 5. Imide VIII
was the only product in the reaction performed in
Scheme 5.
OMe
Ph
N
+
O
O
N
O
Me
III
OMe
O
O
COOMe
NH
O
Me
N
N
Me
N
Ph
H
Ph
O
O
O
A
IV
L
-Amino acid, 10–40 mol %, 20°C
O
COOMe
NH
MeO
Me
N
N
Me
O
N
H
Ph
O
O
Ph
B
V
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

1,3-DIPOLAR CYCLOADDITION OF SCHIFF BASES
381
Table 1. Reaction of methyl (benzylideneamino)acetate (III) with N-methylmaleimide in the presence of amino acids
Amino acid,
mol %
Reaction time,
day
Optical purity
Other products,
Run no.
Solvent
CH2Cl2
Yield of IV, %
of IV,a %
yield, %
01
02
03
04
05
06
07
08
09
10
11
12
13
14
15
16
17
18
19
20
21
22
L-Pro, 20
L-Pro, 20
L-Pro, 20b
L-Pro, 20
L-Pro, 20
L-Pro, 20
L-Pro, 40c
L-Pro, 40c
L-Glu, 20
L-Trp, 20
L-Hyp, 20
L-Pyr, 20
β-Ala
3
3
46
30
07
24
15
00
62
26
17
23
20
63
24
33
18
45
48
11
68
60
70
53
<1
06
<1
<1
12
–
–
V, 4
–
MeCN
MeCN/ H2O
MeOH
THF
3
3
–
3
–
H2O
1
VIII, 21
V, 3
–
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
MeCN
THF
4
03
–
4
4
–
V, 3
V, 3
V, 5
V, 4
V, 3
V, 2
–
4
–
4
–
1
<1
–
3
GlyGly, 20
L-Pyr, 20
L-Pyr, 20
L-Pyr, 20
L-Pyr, 20b
L-Pyr, 30
L-Pyr, 40c
L-Pyr, 40c, argon
L-Pyr, 40c
3
–
1
<1
<1
<1
–
.01.5
3
V, 21
–
MeCN/ H2O
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
3
–
2
05
<1
03
–
V, 8
V, 3
V, 4
V, 20
4
4
4
a
b
c
Calculated from the optical rotation of the isolated product and published data for compound IV with known optical purity [8, 13].
The amino acid was added as an aqueous solution to a solution of Schiff base III and N-methylmaleimide in acetonitrile.
The amino acid was added in portions (4×10 mol %) at 24-h intervals.
water (Table 1, run no. 6); compound VIII was formed
via Michael addition of glycine methyl ester to
N-methylmaleimide. Presumably, glycine methyl ester
appeared in the reaction mixture as a result of hydrol-
ysis of Schiff base III.
of cycloadduct IV were higher; these findings may
be regarded as an indirect support for the above as-
sumptions.
We also examined how the structure of amino acid
affects the enantioselectivity of 1,3-dipolar cycloaddi-
tion and the yields of products. For this purpose, we
performed 1,3-dipolar cycloadditions of Schiff base III
to N-methylmaleimide using 20 mol % of L-glutamic
acid (L-Glu), L-tryptophane (L-Trp), trans-4-hydroxy-
L-proline (L-Hyp), L-pyroglutamic acid (L-Pyr), β-ala-
nine (β-Ala), and glycylglycine (GlyGly) as catalyst
(Scheme 5; Table 1, run nos. 9–14). The reactions were
carried out in methylene chloride, taking into account
that the maximal yields of the target products in the
reactions catalyzed by L-proline were obtained just in
that solvent. In all cases, except for L-Pyr, the yields of
cycloadduct IV were poor, and the isolated product
Probable factors responsible for incomplete con-
version of the reactants in run nos. 1–5 (Table 1) are
the following: (1) conjugate addition of L-proline to
N-methylmaleimide and (2) accumulation in the reac-
tion medium of a mixture of pyrrolidines IV and V
which are likely to be stronger bases than Schiff base
III and are capable of competing with the latter for
proton. In order to maintain a required amount of the
amino acid catalyst in the reaction mixture, L-proline
was added in portions (10 mol % each) every 24 h (run
nos. 7, 8; Table 1). In the reaction performed in meth-
ylene chloride (run no. 7) the yield and optical purity
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

KUDRYAVTSEV, ZAGULYAEVA
the presence of acetic acid, where intermediate azo-
382
C1
N2
methine ylide preferentially adopts conformation B
(Scheme 4) [11]. The reaction catalyzed by L-Pyr oc-
curred at a higher rate, and the yield of diazabicyclo-
octane IV was greater. No appreciable increase in the
yield and enantioselectivity was observed when the
reactions catalyzed by L-Pyr were carried out in other
solvents (Table 1, run nos. 15–18). Raising the amount
of L-Pyr to 30 mol % increased the yield of cyclo-
adduct IV to 68% and the optical purity to 5% (solvent
CH2Cl2). The addition of L-Pyr in 10-mol % portions
at 24-h intervals did not affect the yield and asym-
metric induction to a considerable extent. These pa-
rameters were improved by carrying out the process in
an inert atmosphere with gradual addition of L-Pyr; on
the other hand, they did not exceed those obtained
upon addition of a smaller amount of the amino acid
catalyst in one portion.
O1
C2
C14
O2
C3
C13
C15
C12
C5
C4
O3
C10
C11
C6
N1
C7 H1
O4
C9
C8
F i g . 1 . St r u c t u r e o f t h e m o l e c u l e o f m e t h y l
(1S*,3R*,3aS*,6aR*)-5-methyl-4,6-dioxo-3-phenylocta-
hydropyrrolo[3,4-c]pyrrole-1-carboxylate (IV) according to
the X-ray diffraction data.
O2
O4
Dimethyl fumarate and dimethyl maleate also re-
acted with Schiff base III in the presence of L-Pro or
L-Pyr in CH2Cl2 at room temperature. However, the
stereoselectivity was poor. The cycloaddition of di-
methyl fumarate to Schiff base III catalyzed by L-Pro
gave a mixture of approximately equimolar amounts of
three isomeric pyrrolidinetricarboxylic esters IX–XI
(Scheme 6). In the presence of L-Pyr as catalyst, the
yield of isomer IX (product of endo-addition of di-
methyl fumarate to syn,syn-dipole A) increased almost
twofold, while the amount of pyrrolidine XI (endo-ad-
dition to syn,anti-dipole B) decreased (Schemes 5, 6).
The yields of compounds IX–XI were calculated from
N2
O3
H1D
N1A
N1
O1
O1A
H1
O3A
N2A
O4A
O2A
1
Fig. 2. Intermolecular interactions in crystal of methyl
(1S*,3R*,3aS*,6aR*)-5-methyl-4,6-dioxo-3-phenylocta-
hydropyrrolo[3,4-c]pyrrole-1-carboxylate (IV) according to
the X-ray diffraction data: N1–H1 0.92(2), H1–O3A 2.24(2),
N1–O3A 3.122(2) Å; N1H1O3A 159.9(19)°.
the H NMR spectra of fractions containing the corre-
sponding isomers; we failed to separate the isomers
completely because of their similar chromatographic
mobilities.
The structures of pyrrolidines IX and X were as-
signed by comparing their spectral parameters with
those given in [7, 8] for individual stereoisomers. The
cis arrangement of the methoxycarbonyl group in posi-
tion 4 of the pyrrolidine ring and phenyl substituent on
C5 in XI follows from the observed shielding of the
methoxy protons due to magnetically anisotropic prop-
erties of the aromatic ring, which is typical of pyrroli-
contained an impurity of isomer V; therefore, it was
sometimes impossible to determine the optical purity
of individual stereoisomers. Cycloadduct V is formed
via 1,3-dipolar cycloaddition of N-methylmaleimide to
syn,anti-azomethine ylide B (Scheme 5). In all the
examined reactions pyrrolidine V was formed as minor
product, while the reaction in acetonitrile in the pres-
ence of acetic acid gave compound V as the major
product [11] (Scheme 2). Samples of V isolated in the
present work were optically inactive. Thus the pres-
ence of an α-amino acid in the reaction mixture stabi-
lizes conformation A of azomethine ylide derived from
Schiff base III; as a result, the observed stereoselec-
tivity is the reversed as compared to 1,3-dipolar cyclo-
addition of III to N-methylmaleimide on heating or in
1
dines [6, 7]. In the H NMR spectra of XI and IX,
protons of the 4-COOMe group give signals at δ 3.17
and 3.21 ppm, respectively, while signals from the
other ester moieties in molecules XI and IX, as well as
analogous signals in the spectrum of stereoisomer X,
appear as singlets in the δ range 3.65–3.85 ppm. In-
sofar as the dipolarophile structure implies trans orien-
tation of the methoxycarbonyl groups on C3 and C4,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

1,3-DIPOLAR CYCLOADDITION OF SCHIFF BASES
383
Scheme 6.
O
OMe
OMe
+
MeO
Ph
N
O
O
III
L
-Amino acid, 40 mol %
MeOCO
Ph
COOMe
MeOCO
Ph
COOMe
MeOCO
Ph
COOMe
CH2Cl2, 20°C
+
+
COOMe
COOMe
COOMe
N
N
N
H
H
H
IX
X
XI
L-Pro:
L-Pyr:
26%
45%
22%
26%
23%
11%
Scheme 7.
R
O
R
COOMe
NH
L
-Amino acid, 20 mol %
CH2Cl2, 20°C
OMe
1
3
6a
Ph
N
+
Me
N
O
O
3a
N
O
Me
Ph
O
XIIa, XIIb
XIIIa, XIIIb
R = Me (a), Et (b).
compound XI should have a structure shown in
Scheme 6, which corresponds to endo-addition of di-
methyl fumarate to syn,anti-dipole B, in keeping with
the results of the reaction of Schiff base III with
N-methylmaleimide (Scheme 5). Isolated samples of
individual stereoisomers X and XI were optically in-
active. Dimethyl maleate reacted with compound III in
the presence of L-Pro or L-Pyr to give more than four
stereoisomers. Presumably, the process is accompanied
by isomerization of the dipolarophile into thermody-
namically more stable dimethyl fumarate.
dition. Schiff bases XIIa and XIIb obtained from race-
mic α-alanine methyl ester and methyl 2-aminobutano-
ate reacted with N-methylmaleimide and maleic anhy-
dride in methylene chloride in the presence of amino
acids to give the corresponding pyrrolidines XIII and
XIV with high stereoselectivity (Schemes 7, 8).
In the reaction with maleic anhydride, catalyzed by
L-proline, the amino acid quickly dissolves in methyl-
ene chloride, presumably due to formation of com-
pound XV which is the true catalyst in these reactions
(Scheme 8). Despite relatively small size, the methyl
or ethyl group in the α-position with respect to the
ester group in molecules XIIa and XIIb effectively
Introduction of a substituent into the α-position of
Schiff base improves the stereoselectivity of cycload-
Table 2. Selected bond lengths and bond angles in the molecule of methyl (1S*,3R*,3aS*,6aR*)-5-methyl-4,6-dioxo-3-
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (IV)
Bond
d, Å
Bond
d, Å
Angle
ω, deg
Angle
ω, deg
N1–C7
N1–C6
N1–H1
N2–C3
N2–C2
N2–C1
O1–C2
O2–C3
O3–C8
1.452(2)
1.473(2)
0.92(2)0
1.374(2)
1.396(2)
1.458(3)
1.205(2)
1.213(2)
1.196(2)
O4–C8
O4–C9
C2–C5
C3–C4
C4–C5
C4–C7
C5–C6
C6–C10
C7–C8
1.336(2)
1.447(2)
1.507(3)
1.507(3)
1.536(3)
1.539(3)
1.562(3)
1.509(3)
1.508(3)
C7N1C6
C3N2C2
C3N2C1
C2N2C1
O1C2C5
N2C2C5
O2C3N2
O2C3C4
N2C3C4
103.21(15)
112.64(18)
123.34(18)
124.00(19)
128.9(2)00
108.26(17)
123.8(2)00
127.12(19)
109.06(16)
C3C4C5
C3C4C7
C5C4C7
C2C5C4
C2C5C6
C4C5C6
C10C6C5
N1C7C4
C8C7C4
104.31(16)
111.76(16)
103.99(15)
104.69(16)
115.08(18)
104.03(15)
118.50(18)
100.77(16)
116.14(16)
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

KUDRYAVTSEV, ZAGULYAEVA
384
Scheme 8.
R
O
R
COOMe
NH
L
-Amino acid, 20 mol %
CH2Cl2, 20°C
OMe
4
6
3a
Ph
N
+
O
O
O
6a
O
O
Ph
O
XIIa, XIIb
XIVa, XIVb
R = Me (a), Et (b).
O
OH
N
OH
O
O
XV
hinders intramolecular rotation in intermediate syn,syn-
dipole like A. This factor together with endo-cycload-
dition of active dipolarophiles ensures stereoselectivity
of the process on the whole. Under analogous condi-
tions Schiff base III reacts with maleic anhydride to
produce a complex mixture of products.
EXPERIMENTAL
The H and 13C NMR spectra were recorded at
1
293 K from solutions in CDCl3 or DMSO-d6 on
1
a Bruker DRX-400 instrument at 400 MHz for H and
100 MHz for 13C; the chemical shifts were measured
relative to the residual solvent signals. The optical
rotations were determined on a VNIEKIProdmash
EPO 1A polarimeter using 10-cm cells. The optical
purities were calculated as described in [17]. The X-ray
diffraction data for a single crystal of compound IV
were acquired on an Enraf–Nonius CAD-4 diffractom-
eter at 293 K.
1
The H NMR spectra of methyl-substituted cyclo-
adducts XIIIa and XIVa were consistent with pub-
lished data [7, 16]. Bicyclic compounds IV, XIII, and
XIV are characterized by comparable chemical shifts
and coupling constants of protons in the pyrrolidine
ring, which confirm their steric structure shown in
Schemes 7 and 8. On the other hand, asymmetric in-
duction in the reactions catalyzed by L-Pro or L-Pyr
remains fairly poor: all the isolated samples of XIII
and XIV had optical rotations comparable in absolute
values with those found for cycloadduct IV. As fol-
lows from published data on the optical rotations of
structurally related diazabicycloctanes, introduction of
an alkyl group into the 2-position of the pyrrolidine
fragment does not affect [α]D to an appreciable extent
[8]. Development of a chromatographic procedure for
the determination of optical purity of compounds XIII
and XIV is now in progress.
To conclude, we were the first to propose a proce-
dure for asymmetric organocatalytic 1,3-dipolar cyclo-
addition of azomethine ylides using chiral Brønsted
acids as catalysts and to examine the catalytic activity
of some L-α-amino acids in this process. Despite low
asymmetric induction, L-pyroglutamic acid and L-pro-
line ensure stereoselective syntheses of functionalized
pyrrolidines with preparative yields under mild condi-
tions. Modification of the catalyst structure and reac-
tion conditions with a view to improve the optical
purity of the products and their analogs is the subject
of our current studies.
α-(Benzylideneamino) acid methyl esters III,
XIIa, and XIIb (general procedure). Triethylamine,
8.5 ml (61 mmol), was added to a suspension of
70.5 mmol of the corresponding α-amino acid methyl
ester hydrochloride and 11.28 g (94 mmol) of anhy-
drous MgSO4 in 150 ml of methylene chloride. The
mixture was stirred for 1 h at room temperature in
an inert atmosphere, 4.8 ml (47 mmol) of benzalde-
hyde was added, and the mixture was stirred for 24 h.
Water, 150 ml, was then added, the mixture was stirred
for 30 min, and the organic phase was separated,
washed in succession with a saturated solution of
NaHCO3, water, and a saturated solution of NaCl,
dried over Na2SO4, and evaporated. The product was
brought into further syntheses without additional
purification.
Methyl (benzylideneamino)acetate (III) was syn-
thesized from glycine methyl ester hydrochloride.
Yield 86%, oily substance. 1H NMR spectrum (CDCl3),
δ, ppm: 3.79 s (3H, OCH3), 4.43 s (2H, CH2), 7.41–
7.46 m (3H, Harom), 7.79 d.d (2H, Harom, J = 7.6,
1.8 Hz), 8.31 s (1H, CH=).
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1,3-DIPOLAR CYCLOADDITION OF SCHIFF BASES
385
Methyl 2-(benzylideneamino)propionate (XIIa)
2723 of which were independent (Rint = 0.0526), were
measured by ω-scanning in the range 4.10 < θ < 70.89°
(–7 ≤ h ≤ 7, –12 ≤ k ≤ 12, –4 ≤ l ≤ 13). The structure
was solved by the direct method [18]. All non-hydro-
gen atoms were refined in full-matrix anisotropic ap-
proximation with respect to F2 using SHELXL-97
program [19]. The final divergence factors were R1 =
0.0344, wR2 = 0.0836 [for 1263 reflections with I >
2σ(I)]. The complete set of crystallographic data for
compound IV is available from the authors.
was synthesized from DL-alanine methyl ester hydro-
1
chloride. Yield 92%, oily substance. H NMR spec-
trum (CDCl3), δ, ppm: 1.54 d (3H, CH3, J = 6.8 Hz),
3.75 s (3H, OCH3), 4.17 q (1H, CH, J = 6.8 Hz), 7.40–
7.45 m (3H, Harom), 7.79 d.d (2H, Harom, J = 7.6,
1.8 Hz), 8.32 s (1H, CH=).
Methyl 2-(benzylideneamino)butanoate (XIIb)
was synthesized from DL-α-aminobutanoic acid
methyl ester hydrochloride. Yield 97%, oily substance.
1H NMR spectrum (CDCl3), δ, ppm: 0.94 t (3H,
CH2CH3, J = 7.6 Hz), 1.87–1.98 m (1H, CH2CH3),
2.01–2.12 m (1H, CH2CH3), 3.76 s (3H, OCH3),
3.91 d.d (1H, CH, J = 8.0, 5.6 Hz), 7.39–7.46 m (3H,
Harom), 7.80 d.d (2H, Harom, J = 7.6, 1.8 Hz), 8.29 s
(1H, CH=).
Methyl (1R*,3R*,3aS*,6aR*)-5-methyl-4,6-di-
oxo-3-phenyloctahydropyrrolo[3,4-c]pyrrole-1-car-
boxylate (V). Colorless crystals, mp 141–143°C [11].
1H NMR spectrum (CDCl3), δ, ppm: 2.61 br.s (1H,
NH), 2.92 s (3H, NCH3), 3.38 d.d (1H, 3a-H, J = 8.6,
7.8 Hz), 3.69 d (1H, 6a-H, J = 7.8 Hz), 3.84 s (3H,
OCH3), 4.42 s (1H, 1-H), 4.63 d (1H, 3-H, J = 8.6 Hz),
Reaction of Schiff bases III, XIIa, and XIIb
with electron-deficient olefins in the presence of
L-α-amino acids (general procedure). The corre-
sponding dipolarophile, 1 equiv, was added at room
temperature to a solution of 500 mg of Schiff base III,
XIIa, or XIIb in 5 ml of a solvent indicated in Table 1,
and 0.2–0.4 equiv of L-α-amino acid was added. The
mixture was stirred at room temperature until the
initial reactants no longer changed, the precipitate was
filtered off, and the products were separated from the
amino acid by repeated washing of the precipitate with
methylene chloride and/or isolated from the filtrate by
chromatography on silica gel.
13
7.29–7.37 m (5H, Harom). C NMR spectrum (CDCl3),
δC, ppm: 25.11, 48.48, 48.68, 52.74, 61.51, 63.13,
127.08 (2C), 128.23, 128.36 (2C), 137.56, 172.95,
175.05, 177.48.
Methyl (1-methyl-2,5-dioxopyrrolidin-3-yl-
1
amino)acetate (VIII). Oily substance. H NMR spec-
trum (CDCl3), δ, ppm: 2.41 d.d (1H, CH2, J = 17.7,
4.6 Hz), 2.80 s (3H, NCH3), 2.87 d.d (1H, CH2, J =
17.7, 8.5 Hz), 3.49–3.59 m (2H, CH2COOCH3), 3.63 s
(3H, OCH3), 3.75 d.d (1H, CH, J = 8.5, 4.6 Hz). Mass
spectrum, m/z: 200 [M]+, 112, 88, 56.
Trimethyl (2S*,3R*,4R*,5R*)-5-phenylpyrroli-
dine-2,3,4-tricarboxylate (X). Colorless crystals,
Methyl (1S,3R,3aS,6aR)-5-methyl-4,6-dioxo-3-
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carbox-
ylate (IV). Colorless crystals, mp 216–218°C; pub-
lished data [11]: mp 215–216°C; [α]D20 = +16.7° (c =
0.42, CH2Cl2), optical purity 12%; published data [8]:
[α]D20 = +34.3° (c = 0.45, CH2Cl2), optical purity 25%.
1H NMR spectrum (CDCl3), δ, ppm: 2.44 br.s (1H,
NH), 2.88 s (3H, NCH3), 3.44 d.d (1H, 3a-H, J = 8.4,
8.0 Hz), 3.58 d.d (1H, 6a-H, J = 8.0, 6.8 Hz), 3.89 s
(3H, OCH3), 4.07 d (1H, 1-H, J = 6.8 Hz), 4.51 d (1H,
3-H, J = 8.4 Hz), 7.30–7.40 m (5H, Harom). 13C NMR
spectrum (DMSO-d6), δC, ppm: 24.35, 47.78, 48.89,
51.34, 60.86, 62.78, 127.14, 127.24 (2C), 127.70 (2C),
138.52, 170.24, 175.05, 176.40. Found, %: C 62.75;
H 5.66; N 9.58. C15H16N2O4. Calculated, %: C 62.49;
H 5.59; N 9.72. X-Ray diffraction data: triclinic crys-
tals, racemate, C15H16N2O4, M 288.31, space group
P-1; unit cell parameters: a = 6.382(1), b = 10.583(1),
c = 11.064(2) Å; α = 88.13(1), β = 76.89(1), γ =
76.57(1)°; V = 707.7(2) Å3; Z = 2; dcalc = 1.353 g/cm3;
CuKα-irradiation (λ = 1.54178 Å, graphite monochro-
mator), F(000) = 304. Intensities of 4027 reflections,
1
mp 95–97°C. H NMR spectrum (CDCl3), δ, ppm:
2.57 br.s (1H, NH), 3.43 d.d (1H, 4-H, J = 8.8, 8.4 Hz),
3.66 s (3H, OCH3), 3.72 s (3H, OCH3), 3.77 s (3H,
OCH3), 3.79 d (1H, 3-H, J = 8.4 Hz), 4.24 d (1H, 2-H,
J = 8.4 Hz), 4.34 d (1H, 5-H, J = 8.8 Hz), 7.30–7.39 m
(3H, Harom), 7.46–7.48 m (2H, Harom). Found, %:
C 60.00; H 5.94; N 4.59. C16H19NO6. Calculated, %:
C 59.81; H 5.96; N 4.36.
Trimethyl (2R*,3S*,4S*,5R*)-5-phenylpyrroli-
dine-2,3,4-tricarboxylate (XI). Colorless crystals,
1
mp 105–107°C. H NMR spectrum (CDCl3), δ, ppm:
2.53 br.s (1H, NH), 3.17 s (3H, 4-COOCH3), 3.71 s
(3H, OCH3), 3.74 s (3H, OCH3), 3.79 t (1H, 4-H, J =
9.2 Hz), 3.91 d.d (1H, 3-H, J = 9.2, 7.6 Hz), 4.51 d
(1H, 2-H, J = 7.6 Hz), 4.97 d (1H, 5-H, J = 9.2 Hz),
7.23–7.26 m (1H, Harom), 7.28–7.32 m (4H, Harom).
Found, %: C 59.93; H 5.99; N 4.49. C16H19NO6. Cal-
culated, %: C 59.81; H 5.96; N 4.36.
Methyl (1S,3R,3aS,6aR)-1,5-dimethyl-4,6-dioxo-
3-phenyloctahydropyrrolo[3,4-c]pyrrole-1-carbox-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

KUDRYAVTSEV, ZAGULYAEVA
386
ylate (XIIIa). Yield 83% (catalyst L-Pyr). Colorless
NH, J = 4.0 Hz), 3.69 d (1H, 3a-H, J = 8.0 Hz), 3.73 s
(3H, OCH3), 3.89 d.d (1H, 6a-H, J = 9.2, 8.0 Hz),
4.65 d.d (1H, 6-H, J = 9.2, 4.0 Hz), 7.26–7.28 m (1H,
Harom), 7.32–7.39 m (4H, Harom). 13C NMR spectrum
(DMSO-d6), δC, ppm: 8.11, 27.32, 50.55, 52.35, 55.69,
60.45, 71.54, 127.66 (2C), 128.18, 128.52 (2C),
139.10, 170.32, 171.68, 172.23. Found, %: C 63.28;
H 5.66; N 4.84. C16H17NO5. Calculated, %: C 63.36;
H 5.65; N 4.62.
crystals, mp 217–218°C; published data [20]: mp 217–
219°C; [α]D20 = +3° (c = 0.57, CH2Cl2). H NMR spec-
1
trum (CDCl3), δ, ppm: 1.63 s (3H, CH3), 2.57 br.s (1H,
NH), 2.83 s (3H, NCH3), 3.30 d (1H, 6a-H, J =
7.2 Hz), 3.56 d.d (1H, 3a-H, J = 9.2, 7.2 Hz), 3.90 s
(3H, COOCH3), 4.79 d (1H, 3-H, J = 9.2 Hz), 7.29–
7.39 m (5H, Harom). 13C NMR spectrum (CDCl3), δC,
ppm: 23.77, 24.84, 50.36, 52.65, 55.69, 62.13, 67.27,
126.96 (2C), 128.33, 128.46 (2C), 136.96, 172.78,
174.64, 175.79. Found, %: C 63.45; H 6.13; N 9.24.
C16H18N2O4. Calculated, %: C 63.57; H 6.00; N 9.27.
In the presence of L-Pro as catalyst, racemic prod-
uct with the same spectral parameters was obtained in
75% yield.
In the presence of L-Pro as catalyst, racemic prod-
uct with the same spectral parameters was obtained in
75% yield.
REFERENCES
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1-carboxylate (XIIIb). Yield 32 (L-Pro), 79% (L-Pyr).
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1
Colorless crystals, mp 170°C. H NMR spectrum
(CDCl3), δ, ppm: 0.90 t (3H, CH2CH3, J = 7.6 Hz),
1.79–1.89 m (1H, CH2CH3), 2.08–2.18 m (1H,
CH2CH3), 2.65 br.s (1H, NH), 2.82 s (3H, NCH3),
3.28 d (1H, 6a-H, J = 7.2 Hz), 3.50 d.d (1H, 3a-H, J =
9.2, 7.2 Hz), 3.90 s (3H, OCH3), 4.63 d (1H, 3-H, J =
9.2 Hz), 7.31–7.38 m (5H, Harom). 13C NMR spectrum
(CDCl3), δC, ppm: 7.94, 24.80, 27.91, 50.29, 52.48,
55.31, 61.40, 71.20, 126.99 (2C), 128.37, 128.48 (2C),
137.26, 172.03, 174.81, 175.87. Found, %: C 64.63;
H 6.48; N 8.93. C17H20N2O4. Calculated, %: C 64.54;
H 6.37; N 8.85.
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phenylhexahydrofuro[3,4-c]pyrrole-4-carboxylate
(XIVa). L-Pro: yield 48%, [α]D20 = –4.0° (c = 0.56,
CH2Cl2); L-Pyr: yield 42%, [α]D20 = –7.0° (c = 0.52,
1
CH2Cl2). Colorless crystals, mp 183–185°C. H NMR
spectrum (DMSO-d6), δ, ppm: 1.50 s (3H, CH3),
3.48 br.s (1H, NH), 3.65 d (1H, 3a-H, J = 8.0 Hz),
3.71 s (3H, OCH3), 3.92 d.d (1H, 6a-H, J = 8.8,
8.0 Hz), 4.78 d (1H, 6-H, J = 8.8 Hz), 7.23–7.28 m
(1H, Harom), 7.31–7.38 m (4H, Harom). 13C NMR spec-
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61.10, 67.47, 127.65 (2C), 128.14, 128.51 (2C),
139.07, 170.29, 172.17, 172.68. Found, %: C 62.00;
H 5.34; N 4.99. C15H15NO5. Calculated, %: C 62.28;
H 5.23; N 4.84.
Methyl (3aR,4S,6R,6aS)-4-ethyl-1,3-dioxo-6-
phenylhexahydrofuro[3,4-c]pyrrole-4-carboxylate
(XIVb). Yield 79% (L-Pyr), [α]D20 = +3.0° (c = 0.50,
CH2Cl2). Colorless crystals, mp 164°C. 1H NMR spec-
trum (DMSO-d6), δ, ppm: 0.79 t (3H, CH2CH3, J =
7.2 Hz), 1.88 q (2H, CH2CH3, J = 7.2 Hz), 3.58 d (1H,
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