Structure and properties of 4-amino derivatives of 5-oxoproline

Article abstract of DOI:10.1002/ejoc.200701154

On the basis of the results obtained from NMR spectroscopy, X-ray analysis and chemical transformations, it was established that acidic hydrolysis of (2S,4S)-4-arylaminoglutamates results in the formation of lactams in which ring closure occurs with the p

Full text of DOI:10.1002/ejoc.200701154

FULL PAPER
DOI: 10.1002/ejoc.200701154
Structure and Properties of 4-Amino Derivatives of 5-Oxoproline
Victor P. Krasnov,*[a] Irina A. Nizova,[a] Alexey Yu. Vigorov,[a] Tatyana V. Matveeva,[a]
Galina L. Levit,[a] Pavel A. Slepukhin,[a] Marina A. Ezhikova,[a] and Mikhail I. Kodess[a]
Keywords: Amino acids / Lactams / Cyclization / NMR spectroscopy / Structure elucidation
On the basis of the results obtained from NMR spectroscopy,
of the α-amino and γ-COOH groups are not formed. Isomeric
X-ray analysis and chemical transformations, it was estab- lactams, that is, (2S,4S)-4-arylamino-5-oxoprolines, can be
lished that acidic hydrolysis of (2S,4S)-4-arylaminoglutam-
ates results in the formation of lactams in which ring closure
occurs with the participation of the γ-amino and α-COOH
groups; but isomeric lactams resulting from the participation
easily converted in acidic medium into more stable 4-amino-
1-aryl-5-oxoprolines.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
The exceptionally important biological role of both glu-
tamic acid and the product of its cyclization, 5-oxoproline
(pyroglutamic acid), in metabolic processes[1] on the one
hand, and the wide use of 5-oxoproline as a chiral building
block on the other hand,[2] is reason for interest in the
modification of these compounds by introducing various
substituents into glutamic and pyroglutamic acids.
One of the most important chemical properties of glu-
tamic acid and its C derivatives is the ability to form lac-
tams, which are derivatives of pyroglutamic acid. Glutamic
acid in aqueous solutions with pH values close to neutral
is converted into pyroglutamic acid.[3] The derivatives of
glutamic acid with 4-substituents, such as amino,[4]
phenyl,[5] arylamino,[6] thiopyridinyl[7] and others,[8] are able
to form lactams in acidic and neutral media. It should be
noted that the amount of lactam formed increases when the
glutamic acid contains aromatic and heterocyclic substitu-
ents. Acidic hydrolysis of dimethyl (2S,4S)-4-arylamino-N-
phthaloylglutamates obtained from (2S,4RS)-4-bromoglu-
tamate derivative 1 (Scheme 1) resulted in lactams (4-substi-
tuted 5-oxoprolines) as the only reaction products.[6] When
the substituent is a fragment of a primary amine, in particu-
lar arylamine, both γ- and α-carboxylic groups can partici-
pate in the lactam-formation process to give A and B pyrog-
lutamic acids, respectively (Scheme 1).
Scheme 1.
thesis of 4-arylaminoglutamate derivatives with a tertiary
amino group,[8b] made it necessary to critically examine that
data. The purpose of the present work was the synthesis
and study of the structure of lactams derived from 4-aryl-
aminoglutamates.
Results and Discussion
At first, we studied the hydrolysis of dimethyl (2S,4S)-4-
phenylamino- (2) and (2S,4S)-4-(4-methoxyphenyl)amino-
N-phthaloylglutamates (3) obtained according to the de-
scribed method.[9] It was established that heating of com-
pounds 2 or 3 in 10  HCl for 1 h at 70 °C resulted in the
selective hydrolysis of ester groups with the formation of
compounds 4 and 5, respectively (Scheme 2). Acids 4 and
5, which were isolated from the reaction mixture, contained
crystallized water that was removed while heating under re-
duced pressure. Comparison of the 1H NMR spectra of the
reaction products with those of the dehydrated products at-
Earlier, we assigned a structure of type A to these formed
lactams;[6] this assignment did not contradict the available
data regarding the properties of these compounds. How-
ever, the results obtained recently, in particular on the syn-
[a] I. Ya. Postovsky Institute of Organic Synthesis of RAS (Ural
Division)
22/20, S. Kovalevskoy/Akademicheskaya St., 620041 Ekaterin-
burg, Russian Federation
Fax: +7-343-3741189
E-mail: ca@ios.uran.ru
1802
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1802–1810

Structure and Properties of 4-Amino Derivatives of 5-Oxoproline
Scheme 2.
tested to the fact that the cyclization reaction resulting in tives. However, because both ring opening and repeated clo-
the formation of 5-oxoproline derivatives has already oc- sure are possible during the hydrolysis of the lactam, the
curred at the stage of hydrolysis (Scheme 2).
reaction products could have a structure of type A or B
1
The structure of compound 4 was determined by both (Scheme 1) and their H NMR spectra are essentially iden-
X-ray crystallography and NMR spectroscopy. Single crys- tical.
tals of compound 4 were obtained by crystallization from
MeOH. It was established that the monoclinic unit cell (P21
space group, chiral) is formed by two crystallographic inde-
pendent molecules of compound 4 together with two mole-
cules of MeOH. In this case, MeOH molecules in the crystal
fill the channels between the piles of compound 4. They
form pairs of hydrogen bonds and are the acceptors of
bonds for carboxylic groups and the donors of bonds for
the carbonyl groups of the lactam and phthalimide. X-ray
data (Figure 1) and NMR spectra confirm the cis arrange-
ment of the protected amino and carboxylic groups in this
compound. In the 2D NOESY spectra of acid 4, the cross
peaks between 3A-H and both 2-H and 4-H, and also be-
tween 2-H and 4-H, were observed. Similar conclusions on
the structure of compound 5 were made on the basis of its
NMR spectra.
We established that the hydrolysis of compounds 4 and
5, as well as the hydrolysis of compounds 2 and 3, under
the conditions of prolonged (12–14 h) refluxing in 6  HCl
leads to compounds 6 and 7, which possess the B-type
structure. The lactams thus formed resulted from the
formation of a bond between the carbon atom of the α-
carboxy group and the nitrogen atom of the arylamino
group.
1
Because the H and 13C NMR spectra of compounds 6
and 7 in D2O and [D6]DMSO are inconclusive with regard
to the cyclization direction of the lactam ring (decision be-
tween A or B structures), to solve this problem we specially
synthesized acid 6* starting from 15N-glutamic acid. In the
15N NMR spectrum of compound 6*, only one signal at δ
= 40.85 ppm, undoubtedly related to the NH2 group, was
observed, which testifies to the formation of a lactam of
type B.
The next step in our investigation was the NMR study
of N-tert-butyloxycarbonyl (compounds 8 and 9) and N-
tosyl (compounds 10 and 11) derivatives of lactams 6 and
1
7. In the H NMR spectra of compounds 8–11, the signals
of the methylene protons of the pyrrolidone cycle were ob-
served in the range δ = 2.5–2.7 (3A-H) and 1.6–1.9 (3B–H)
ppm as a doublet of doublets of doublets with a geminal
2
coupling constant J3A,3B = 11–12 Hz and a vicinal con-
stant J = 7–10 Hz due to the spin–spin coupling of the 2-
H and 4-H protons. The 2-H and 4-H protons resonated in
the range δ = 4–5 ppm, and each of them are coupled to
the nonequivalent protons at C-3. Moreover, the higher-
field CH (δ = 4.2–4.4 ppm) was additionally split into the
Figure 1. X-ray structure of compound 4.
Acidic hydrolysis of compounds 4 and 5 under refluxing
in 6  HCl for 12 h led to the removal of the phthaloyl doublet owing to the coupling with the NH proton,
group and to the formation of pyroglutamic acid deriva- 3JCH,NH = 8.5–9.2 Hz. However, this multiplicity pattern is
Eur. J. Org. Chem. 2008, 1802–1810
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V. P. Krasnov et al.
FULL PAPER
possible in both A and B structures (Scheme 1), which
It was found that acyl chlorides obtained from N-tosyl
served as the reason for the erroneous interpretation of the pyroglutamic acids 10 and 11 undergo intramolecular cycli-
data in the previous work.[10]
zation in the presence of tertiary amines, which results in
The 13C NMR spectroscopic data for compounds 8–11, bicyclic compounds 12 and 13 (Scheme 2); however, this cy-
obtained in the present work, also provide evidence for al- clization is only possible if the molecule contains a Ts-NH
ternative assignments of the signals as a result of the close- group. The structure of compound 12 was confirmed by X-
ness of the chemical shifts of the C-2 and C-4 carbon atoms, ray analysis (Figure 3).
and the C-5 and COOH carbonyl carbon atoms; therefore,
the data supports the hypothesis that both A and B struc-
tures are possible.
In order to unambiguously determine the direction of the
formation of the pyrrolidone cycle and to prove the struc-
ture of the final products, we carried out extensive multinu-
clear NMR (1H, 13C and 15N) spectroscopic studies of com-
pounds 8–11, including 2D homo- and heteronuclear ex-
periments.
1
In the H coupled 13C NMR spectrum of compound 8,
the signal of the Boc carbonyl carbon atom (δ =
155.48 ppm) was a doublet with a coupling constant J =
1
4.9 Hz. In the 2D H–13C HMBC spectra of compounds 8
and 9, the cross peak between the signal of the Boc car-
bonyl carbon atom and the upfield signal of the CH proton
of pyrrolidone was observed; the latter in turn was coupled
with the NH proton. Consequently, the upfield proton and
Figure 3. X-ray structure of compound 12.
1
the connected upfield carbon atom (according to 2D H–
Removal of the phthaloyl group in compounds 4 and 5
13C HSQC experiments) are related to C-4–H of oxoproline. by hydrazinolysis under mild conditions resulted in com-
Such a combination of homo- and heteronuclear spin–spin pounds 6 and 7; their formation can be taken as additional
couplings is possible only for the B-type structure evidence that 6 and 7 have the B-type structure.
(Scheme 1).
Thus, it was established that acidic hydrolysis of pro-
Analysis of the 2D HMBC spectra made it possible to tected 4-arylaminoglutamates in acidic and neutral media
unambiguously assign the signals of the COOH group and resulted in stable lactams formed as a result of the interac-
the C-5 carbon atom by considering the corresponding tion between the α-COOH and γ-NH groups.
cross peaks with the 2-H and 4-H protons. Additional con-
Synthesis of 4-substituted pyroglutamic acids 16 and 17
firmation of the assignment of the cyclic carbon atoms and (Scheme 2) having the alternative type A structure was the
1
determination of the JC,C coupling constants were ob- final accent in the determination of the structure of the pyr-
tained from 1D INADEQUATE experiments. The follow- oglutamic acid derivatives obtained from arylamino glu-
ing values of coupling constants were measured for com- tamic acids. Thus, hydrazinolysis of compounds 2 and 3
1
1
pound 8: JC2,COOH = 61.6 Hz, 1JC2,C3 = 45.1 Hz, JC3,C4
=
yielded dimethyl 4-aminosubstituted glutamates, which
were already partially converted into methyl 4-aminosubsti-
1
45.5 Hz, JC4,C5 = 61.6 Hz.
In the 15N NMR spectra of compounds 8 and 10, the tuted pyroglutamates 14 and 15 in the course of the reac-
chemical shifts of N-1 had almost similar values (δ = tion; the complete ring closure occurred under heating at
135 ppm), whereas the chemical shift of the NH nitrogen 70 °C in vacuo. The structures of compounds 14 and 15
atom changed from δ = 88 ppm (compound 8) to δ = were confirmed by H and 13C NMR spectroscopy, includ-
1
103 ppm (compound 10). X-ray crystallography data also ing 2D NOESY, HSQC and HMBC experiments. The char-
1
confirmed the structure of compound 10 (Figure 2).
acteristic feature of the H NMR spectra was the presence
of two signals for the NH protons, that is, a singlet at δ =
8.3 ppm (N-1–H) and a doublet at δ = 5–6 ppm (C-4–NH).
The cross peaks observed in the 2D HMBC spectrum be-
tween the pairs of signals (4-H, Ci), (NH, Co) and (NH, C-
5) unambiguously proved a type A structure (Scheme 1).
The structure of compound 14 was also established on the
basis of the X-ray data (Figure 4).
Hydrolysis of the ester group in compounds 14 and 15
by 1  NaOH in acetone yielded pyroglutamic acids 16 and
17. The pyrrolidone ring was not affected in this case, which
was confirmed by 1H and 13C NMR spectra. In the 1H
NMR spectra of compounds 16 and 17, the signals of both
the NH groups had approximately the same chemical shifts
Figure 2. X-ray structure of compound 10.
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Eur. J. Org. Chem. 2008, 1802–1810

Structure and Properties of 4-Amino Derivatives of 5-Oxoproline
5-oxo-1-phenyl-3-pyrazoline) (Scheme 3) resulted in a mix-
ture of diastereoisomers 18 that was enriched with the
(2S,4S)-isomer (according to HPLC data); the latter was
isolated from the product mixture by repeated precipitation.
The structure of compound 18 was confirmed by 1H NMR
spectroscopic data and X-ray crystallography (Figure 5).
(2S,4S)-4-Amino-1-(2,3-dimethyl-5-oxo-1-phenyl-3-pyraz-
Figure 4. X-ray structure of compound 14.
as in esters 14 and 15; moreover, the signal of the C-4–NH
proton was considerably broadened due to the chemical ex-
change with the protons of COOH and solvent water.
The pyrrolidone rings of cis-4-arylamino and cis-1-aryl-
4-amino pyroglutamates (A and B types, respectively) had
different hydrolytic stabilities. Thus, heating of compounds
16 and 17 in 6  DCl at 108 °C for 30 min resulted in com-
plete conversion into acids 6 and 7, whereas the latter did
not undergo any transformation under those conditions.
Thus, having compounds of both A and B types at hand
1
we carried out a comparative analysis of their H and 13C
NMR spectra. The spectral parameters (δ and J) of cyclic
carbon atoms and protons do not have characteristic differ-
ences that make it possible to differentiate A or B structures
(Table 1). At the same time, chemical shifts of the protons
of the aryl moiety markedly differ in complete accordance
with the known regularities. In the 1H NMR spectra of the
4-arylamino derivatives, the aromatic protons were shifted
upfield by 0.5–0.9 ppm (similar to aniline) relative to those
of the 1-aryl-4-amino derivatives (similar to acetanilide).
Scheme 3.
1
Another characteristic feature of the H NMR spectra of
4-arylamino derivatives is the presence of two signals for
the NH protons in aprotic solvents.
It was also found that some other 4-aminosubstituted
glutamic acids tend to form lactams with a B-type structure,
in which the nitrogen atom of the pyrrolidone ring is substi-
tuted, and these compounds are stable in acidic and neutral
media.
In particular, we observed the formation of similar pyro-
glutamic acids under hydrolysis of dimethyl (2S,4S)-4-(2,3-
dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)amino-N-phthal-
oylglutamate (18). Nucleophilic substitution of bromine in
compound 1 by 4-aminoantipyrine (4-amino-2,3-dimethyl- Figure 5. X-ray structure of compound 18.
Table 1. Selected 1H and 13C NMR spectroscopic data for A (compounds 6 and 7) and B structures (compounds 16 and 17) in [D6]-
DMSO.
Compound
1H chemical shifts (δ, ppm) and coupling constants (J, Hz)
13C chemical shifts (δ, ppm)[a]
2-H
4-H
ortho–H
C-2
C-4
C-o
6
4.38
J = 7.9, 2.9
4.31
J = 7.9, 3.0
3.82
J = 9.2, 6.9
4.10
3.92
J = 8.1, 3.2
3.87
J = 7.9, 3.4
3.95
J = 9.9, 7.9
3.95
7.63
60.92
50.19
121.74
7
6.94
6.65
6.61
61.57
53.95
51.70
49.97
54.14
54.02
123.84
112.73
114.45
16
17
J = 9.0, 7.3
J = 9.5, 8.2
[a] 13C chemical shifts for compounds 6 and 7 were measured in D2O.
Eur. J. Org. Chem. 2008, 1802–1810
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V. P. Krasnov et al.
FULL PAPER
3
3
3J2,3B = 9.5 Hz, J2,3A = 7.3 Hz, 1 H, 2-H), 5.24 (dd, J4,3B
=
olin-4-yl)-5-oxoproline (19) and its Boc derivative 20 exhib-
ited the same features in their 1D and 2D NMR spectra as
did compounds 8 and 9.
11.0 Hz, J4,3A = 9.4 Hz, 1 H, 4-H), 7.21 (tt, 3J = 7.1 Hz, 4J =
1.4 Hz, 1 H, p-H), 7.38–7.46 (m, 4 H, Ph), 7.92 (m, AAЈBBЈ, 4 H,
Phth), 13.13 (br. s, 1 H, CO2H) ppm. 13C NMR (100 MHz, [D6]-
DMSO): δ = 26.92 (C-3), 49.70 (C-4), 57.13 (C-2), 121.53 (C-o),
123.37 (C-3Ј, C-6Ј), 125.21 (C-p), 128.57 (C-m), 131.24 (C-4Ј, C-
5Ј), 134.86 (C-2Јa, C-6Јa), 138.39 (C-i), 167.03 (C-2Ј, C-7Ј), 169.02
(C-5), 171.57 (COOH) ppm. C19H14N2O5 (350.33): calcd. C 65.14,
H 4.03, N 8.00; found C 65.10, H 3.96, N 7.84.
3
Conclusions
On the basis of the results of NMR spectroscopy, X-ray
analysis and chemical transformation, it was established
(2S,4S)-1-(4-Methoxyphenyl)-5-oxo-4-phthalimidoproline (5): Ac-
that lactams of type B (ring closure occurs with the partici- cording to the above procedure and starting from compound 3,
compound 5 (64% yield) was obtained as a white solid. M.p. 276–
282 °C. [α]D = +45.8 (c = 0.3, MeOH). H NMR (400 MHz, [D6]-
pation of the γ-amino and α-COOH groups) are formed
during the deprotection of α-amino and carboxylic groups
in (2S,4S)-4-aminoglutamate derivatives (compounds 2, 3,
and 18) by heating in 6  HCl. Lactams of type A, which
result from the participation of the α-amino and γ-COOH
groups are not formed, as it was considered earlier.[6,10] Iso-
meric lactams, that is, 4-arylamino-5-oxoprolines 16 and 17,
were easily converted in acidic medium into more stable
compounds 6 and 7.
1
2
3
3
DMSO): δ = 2.46 (ddd, J3B,3A = 12.0 Hz, J3B,4 = 11.0 Hz, J3B,2
= 9.5 Hz, 1 H, 3B-H), 2.80 (ddd, 2J3A,3B = 12.0 Hz, 3J3A,4 = 9.3 Hz,
3J3A,2 = 7.3 Hz, 1 H, 3A-H), 3.75 (s, 3 H, OCH3), 5.01 (dd, J2,3B
3
3
3
= 9.5 Hz, J2,3A = 7.3 Hz, 1 H, 2-H), 5.24 (dd, J4,3B = 11.0 Hz,
3J4,3A = 9.3 Hz, 1 H, 4-H), 6.97 (d, 3J = 9.2 Hz, 2 H, m-H), 7.34
(d, 3J = 9.2 Hz, 2 H, o-H), 7.92 (m, AAЈBBЈ, 4 H, Phth), 13.08 (br.
s, 1 H, CO2H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 27.02
(C-3), 49.54 (C-4), 55.22 (OCH3), 57.60 (C-2), 113.80 (C-m), 123.35
Thus, it was established that 4-aminoglutamic acid deriv- (C-3Ј, C-6Ј), 123.79 (C-o), 131.24 (C-4Ј, C-5Ј), 131.27 (C-i), 134.86
(C-2Јa, C-6Јa), 156.85 (C-p), 167.05 (C-2Ј, C-7Ј), 168.93 (C-5),
171.65 (CO2H) ppm. C20H16N2O6 (380.36): calcd. C 63.16, H 4.24,
N 7.36; found C 63.06, H 3.99, N 7.15.
atives in acidic and neutral solutions exist solely as lactams,
and the closure into the lactam occurs with the participa-
tion of the α-COOH and γ-amino groups.
(2S,4S)-4-Amino-5-oxo-1-phenylproline (6)
Procedure A: A mixture of compound 2 (4.7 g, 11.86 mmol) and
HCl (6 , 50 mL) was heated at reflux for 14 h and then cooled.
The precipitate of phthalic acid was filtered off; the filtrate was
evaporated to dryness under reduced pressure. The residue was dis-
solved in EtOH (30 mL) and pyridine (1.2 mL) was added to the
solution. The reaction mixture was kept for 3 h at –10 °C. The pre-
cipitate was filtered off and dried in vacuo to give compound 6
(2.45 g, 90%) as a white solid.
Experimental Section
General: Dimethyl (2S,4RS)-4-bromo-N-phthaloylglutamate (1),[11]
dimethyl (2S,4S)-4-phenylamino-N-phthaloylglutamate (2) and di-
methyl (2S,4S)-4-(4-methoxyphenyl)amino-N-phthaloylglutamate
(3)[9] were prepared according to literature procedures. All other
reagents were of commercial quality. Solvents were dried and puri-
fied by standard methods. Routine monitoring of reaction mixtures
was carried out by using Sorbfil UV 254 (Russia) TLC aluminium-
plated silica gel. Silica gel 60 (230–400 mesh) was used for flash
chromatography. Analytical HPLC was performed with a LiChro-
sorb Si-60 (4ϫ250 mm, 5 µm) column, with a flow rate of
Procedure B: To a suspension of compound 4 (0.995 g, 2.84 mmol)
in MeOH (10 mL) was added an aqueous solution of hydrazine
hydrate (64%, 0.9 mL, 11.5 mmol). The reaction mixture was
heated at reflux for 15 min and then concentrated HCl was added
up to pH 3–4. The precipitate was filtered off. The filtrate was
evaporated to dryness, and the residue was dried in vacuo, dis-
solved in EtOH (5 mL) and then cooled to –10 °C. The precipitate
of hydrazinium chloride was filtered off. Pyridine was added to the
filtrate up to pH 6. The reaction mixture was kept at –10 °C over-
night. The precipitate was filtered off and dried in vacuo to give
compound 6 (0.357 g, 55%) as a white solid. M.p. 224–227 °C (de-
1 mLmin–1 and by using a tunable UV detector set at 230 nm. H
1
and 13C NMR spectra were recorded at 400 and 100 MHz, respec-
tively, by using TMS or DSS as references. 15N NMR spectra were
recorded at 40.6 MHz by using liquid ammonia as external stan-
dard. Assignment of the δ values was based on standard 2D NMR
techniques (1H–13C HSQC and HMBC, H–1H NOESY). Optical
1
1
rotation values were measured with a Perkin–Elmer M 341 polari-
meter. All optical rotations were obtained at room temperature.
MS data were obtained by using a quadrupole Shimadzu LCMS-
2010 system in negative mode with an APCI probe installed with
CH3CN as the solvent. Quadrupole array and curved desolvation
line (CDL) were used in scan-mode according to the parameters
stored in the auto-tune file. The probe voltage was set to 4.5 kV,
and the APCI probe temperature was set to 400 °C. The CDL and
block heater were set at 250 °C and 200 °C, respectively.
comp.). [α]D = –39.4 (c = 1.0, H2O). H NMR (400 MHz, D2O): δ
2
3
3
= 2.11 (ddd, J3B,3A = 13.1 Hz, J3B,4 = 9.3 Hz, J3B,2 = 8.3 Hz, 1
2
3
3
H, 3B-H), 3.05 (ddd, J3A,3B = 13.1 Hz, J3A,4 = 9.3 Hz, J3A,2
7.1 Hz, 1 H, 3A-H), 4.33 (t, J4,3B
4.44 (dd, J2,3B = 8.3 Hz, J2,3A = 7.1 Hz, 1 H, 2-H), 7.35 (tt, J =
=
=
3J4,3A = 9.3 Hz, 1 H, 4-H),
3
3
3
3
4
3
4
7.1 Hz, J = 1.4 Hz, 1 H, p-H), 7.43 (dd, J = 8.7 Hz, J = 1.4 Hz,
2 H, o-H), 7.49 (dd, 3J = 8.7 Hz, J = 7.1 Hz, 2 H, m-H) ppm. 13
C
3
NMR (100 MHz, D2O): δ = 27.33 (C-3), 50.19 (C-4), 60.92 (C-2),
121.74 (C-o), 126.30 (C-p), 128.44 (C-m), 135.77 (C-i), 169.08 (C-
5), 175.85 (CO2H) ppm. C11H12N2O3·0.5H2O (229.24): calcd. C
57.63, H 5.72, N 12.22; found C 57.65, H 5.62, N 12.34.
(2S,4S)-5-Oxo-1-phenyl-4-phthalimidoproline (4):
A solution of
compound 2 (2.00 g, 5.05 mmol) in HCl (10 , 10 mL) was stirred
at 70 °C for 1 h. The precipitate was filtered off, washed with water
and dried in vacuo at 70 °C to give compound 4 (1.06 g, 60%) as
a white solid. M.p. 229–231 °C. [α]D = +49.1 (c = 0.45, MeOH).
1H NMR (400 MHz, [D6]DMSO): δ = 2.47 (ddd, 2J3B,3A = 12.0 Hz,
(2S,4S)-4-Amino-1-(4-methoxyphenyl)-5-oxoproline (7): According
to the above Procedure A and starting from compound 3, com-
pound 7 (89% yield) was obtained as a white solid. According to
the above Procedure B and starting from compound 5, compound
7 (75% yield) was obtained as a white solid. M.p. 229–231 °C (de-
comp.) (H2O/EtOH). [α]D = –19.8 (c = 1.0, H2O). 1H NMR
3
2
3J3B,4 = 11.0 Hz, J3B,2 = 9.5 Hz, 1 H, 3B-H), 2.82 (ddd, J3A,3B
=
3
3
12.0 Hz, J3A,4 = 9.4 Hz, J3A,2 = 7.3 Hz, 1 H, 3A-H), 5.01 (dd,
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Structure and Properties of 4-Amino Derivatives of 5-Oxoproline
2
3
3
(400 MHz, D2O): δ = 2.13 (ddd, 2J3B,3A = 13.2 Hz, 3J3B,4 = 9.1 Hz,
= 1.70 (ddd, J3B,3A = 12.0 Hz, J3B,4 = 10.4 Hz, J3B,2 = 9.4 Hz, 1
2
3
2
3
3J3B,2 = 7.8 Hz, 1 H, 3B-H), 3.04 (ddd, J3A,3B = 13.2 Hz, J3A,4
=
H, 3B-H), 2.37 (s, 3 H, CH3), 2.47 (ddd, J3A,3B = 12.0 Hz, J3A,4
3
3
3
9.1 Hz, J3A,2 = 7.3 Hz, 1 H, 3A-H), 3.83 (s, 3 H, OCH3), 4.33 (t,
= 8.8 Hz, J3A,2 = 7.0 Hz, 1 H, 3A-H), 4.29 (dt, J4,3B = 10.4 Hz,
3J4,3B = 3J4,3A = 9.1 Hz, 1 H, 4-H), 4.70 (dd, 3J2,3B = 7.8 Hz, 3J2,3A
3J4,3A = 3J4,NH = 8.8 Hz, 1 H, 4-H), 4.76 (dd, 3J2,3B = 9.4 Hz, 3J2,3A
3
3
3
4
= 7.3 Hz, 1 H, 2-H), 7.05 (d, J = 9.0 Hz, 2 H, m-H), 7.36 (d, J = = 7.0 Hz, 1 H, 2-H), 7.16 (tt, J = 6.4 Hz, J = 2.0 Hz, 1 H, p-H),
9.0 Hz, 2 H, o-H) ppm. 13C NMR (100 MHz, D2O): δ = 27.21 (C- 7.33–7.39 (m, 6 H, m-H Ph, o-H Ph, m-H Ts), 7.78 (d, 3J = 8.2 Hz,
3
3), 49.97 (C-4), 54.67 (OCH3), 61.57 (C-2), 113.73 (C-m), 123.84
2 H, o-H Ts), 8.34 (d, JNH,4 = 8.8 Hz, 1 H, NH), 13.20 (br. s, 1
(C-o), 128.91 (C-i), 156.81 (C-p), 169.14 (C-5), 175.99 (CO2H) ppm. H, CO2H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 21.02
C12H14N2O4 (250.26): calcd. C 57.60, H 5.64, N 11.19; found C
57.57, H 5.72, N 11.36.
(CH3), 30.59 (C-3), 53.62 (C-4), 56.81 (C-2), 121.40 (C-o Ph),
125.20 (C-p), 126.60 (C-o Ts), 128.62 (C-m Ph), 129.58 (C-m Ts),
138.37, 138.86 (C-i Ph, C-i Ts), 142.73 (C-p Ts), 170.39 (C-5),
171.92 (CO2H) ppm. 15N NMR (40.6 MHz, [D6]DMSO): δ =
103.29 (NH–C-4), 135.31 (N-1) ppm. C18H18N2O5S (374.42): calcd.
C 57.74, H 4.84, N 7.48, S 8.56; found C 57.90, H 4.85, N 7.49, S
8.42.
(2S,4S)-4-(tert-Butyloxycarbonyl)amino-5-oxo-1-phenylproline (8):
To a stirred solution of 6 (5.0 g, 22.7 mmol) and K2CO3 (3.41 g,
24.7 mmol) in water (22 mL) was added a solution of Boc2O
(6.27 g, 22.8 mmol) in iPrOH (9 mL), and the reaction mixture was
stirred at 40 °C for 3 h. The reaction mixture was diluted with water
and extracted with hexane (2ϫ15 mL). The aqueous layer was
acidified with citric acid to pH 4. The precipitate was filtered off
and recrystallized from EtOH to give compound 8 as a white solid
(5.24 g, 72%). M.p. 220–222 °C (decomp.). [α]D = –29.5 (c = 1.0,
(2S,4S)-1-(4-Methoxyphenyl)-4-[(4-methylbenzenesulfonyl)amino]-5-
oxoproline (11): According to the procedure outlined for 10 and
starting from compound 7, compound 11 (87% yield) was obtained
as a pale-yellow solid. M.p. 219–222 °C (acetone/hexane). [α]D
=
–5.7 (c = 1.0, acetone). 1H NMR (400 MHz, [D6]DMSO): δ = 1.66
1
acetone). H NMR (400 MHz, [D6]DMSO): δ = 1.41 (s, 9 H, CH3
2
3
3
2
3
3
(ddd, J3B,3A = 12.0 Hz, J3B,4 = 10.4 Hz, J3B,2 = 9.3 Hz, 1 H, 3B-
Boc), 1.91 (ddd, J3B,3A = 11.7 Hz, J3B,4 = 11.0 Hz, J3B,2
=
2
3
2
3
H), 2.38 (s, 3 H, CH3), 2.43 (ddd, J3A,3B = 12.0 Hz, J3A,4
=
9.6 Hz, 1 H, 3B-H), 2.70 (ddd, J3A,3B = 11.7 Hz, J3A,4 = 8.9 Hz,
8.7 Hz, 3J3A,2 = 7.0 Hz, 1 H, 3A-H), 3.73 (s, 3 H, OCH3), 4.24 (dt,
3J3A,2 = 7.0 Hz, 1 H, 3A-H), 4.42 (dt, J4,3B = 11.0 Hz, J4,3A
=
=
3
3
3J4,3B = 10.4 Hz, J4,3A
=
3J4,NH = 8.7 Hz, 1 H, 4-H), 4.64 (dd,
3
3J4,NH = 8.9 Hz, 1 H, 4-H), 4.83 (dd, J2,3B = 9.6 Hz, J2,3A
3
3
3J2,3B = 9.3 Hz, J2,3A = 7.0 Hz, 1 H, 2-H), 6.93 (d, J = 9.0 Hz, 2
3
3
7.0 Hz, 1 H, 2-H), 7.16 (tt, 3J = 7.0 Hz, 4J = 1.6 Hz, 1 H, p-H),
H, m-H Ts), 7.25 (d, 3J = 9.0 Hz, 2 H, o-H Ts), 7.40 (d, 3J = 8.0 Hz,
7.32 (d, JNH,4 = 8.9 Hz, 1 H, NH), 7.37 (dd, 3J = 8.9 Hz, 3J =
3
3
3
3
4
2 H, m-H Ph), 7.76 (d, J = 8.0 Hz, 2 H, o-H Ph), 8.27 (d, JNH,4
= 8.7 Hz, 1 H, NH), 13.06 (br. s, 1 H, CO2H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 20.96 (CH3), 30.68 (C-3), 53.35 (C-4),
55.20 (OCH3), 57.20 (C-2), 113.81 (C-m Ph), 123.60 (C-o Ph),
126.54 (C-o Ts), 129.51 (C-m Ts), 131.18 (C-i Ph), 138.80 (C-i Ts),
142.65 (C-p Ts), 156.80 (C-p Ph), 170.21 (C-5), 171.97 (CO2H)
ppm. C19H20N2O6S (404.45): calcd. C 56.43, H 4.98, N 6.93, S
7.93; found C 56.08, H 4.90, N 6.95, S 7.59.
7.0 Hz, 2 H, m-H), 7.41 (dd, J = 8.9 Hz, J = 1.6 Hz, 2 H, o-H),
13.05 (br. s, 1 H, CO2H) ppm. 13C NMR (100 MHz, [D6]DMSO):
δ = 28.32 (CH3 Boc), 29.63 (C-3), 51.52 (C-4), 56.70 (C-2), 78.40
(C Boc), 121.19 (C-o), 124.94 (C-p), 128.63 (C-m), 138.83 (C-i),
155.48 (CO Boc), 171.86 (C-5), 172.30 (CO2H) ppm. 15N NMR
(40.6 MHz, [D6]DMSO): δ = 88.22 (NH–C-4), 135.08 (N-1) ppm.
C16H20N2O5 (320.34): calcd. C 59.99, H 6.29, N 8.74; found C
60.17, H 6.27, N 8.45.
(1S,4S)-2-(4-Methylbenzenesulfonyl)-5-phenyl-2,5-diazabicyclo[2.2.1]-
heptane-3,6-dione (12): SOCl2 (1 mL) was added to a solution of
compound 10 (0.5 g, 1.33 mmol) in dry benzene (2 mL). The reac-
tion mixture was heated at reflux for 3 h and then evaporated to
dryness under reduced pressure. The residue was treated with hex-
ane (10 mL) at 0 °C for 1 h. The precipitate of acyl chloride was
filtered off and dried in vacuo over P2O5 to give the acyl chloride
(0.48 g, 95%) as a white solid that was used for further reaction
without additional purification. Et3N (0.14 mL, 1.0 mmol) was
added to a solution of the acyl chloride (0.393 g, 1.0 mmol) in
CH2Cl2 (2 mL). The reaction mixture was kept at room tempera-
ture for 1 d, then washed with aqueous HCl (5%, 3ϫ1 mL), water
(3ϫ1 mL), aqueous Na2CO3 (5%, 3ϫ1 mL) and water (3ϫ1 mL)
and then dried with Na2SO4. The solvent was evaporated to dry-
ness under reduced pressure. Crystallization from EtOAc gave com-
(2S,4S)-4-(tert-Butyloxycarbonyl)amino-1-(4-methoxyphenyl)-5-oxo-
proline (9): According to the procedure outlined for 8 and starting
from compound 7, compound 9 (65% yield) was obtained as a
white solid. M.p. 225–228 °C (decomp.) (EtOH). [α]D = –26.2 (c =
1
0.4, acetone). H NMR (400 MHz, [D6]DMSO): δ = 1.40 (s, 9 H,
2
3
3
CH3 Boc), 1.90 (ddd, J3B,3A = 11.9 Hz, J3B,4 = 10.8 Hz, J3B,2
=
2
3
9.6 Hz, 1 H, 3B-H), 2.68 (ddd, J3A,3B = 11.9 Hz, J3A,4 = 8.8 Hz,
3J3A,2 = 7.0 Hz, 1 H, 3A-H), 3.74 (s, 3 H, OCH3), 4.40 (ddd, 3J4,3B
3
3
= 10.8 Hz, J4,3A = 8.8 Hz, J4,NH = 9.1 Hz, 1 H, 4-H), 4.75 (dd,
3J2,3B = 9.6 Hz, J2,3A = 7.0 Hz, 1 H, 2-H), 6.94 (d, J = 9.0 Hz, 2
3
3
H, m-H), 7.27 (d, 3JNH,4 = 9.1 Hz, 1 H, NH), 7.30 (d, J = 9.0 Hz,
3
2 H, o-H), 12.97 (br. s, 1 H, CO2H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 28.18 [(CH3)3 Boc], 29.61 (C-3), 51.12 (C-4), 55.18
(OCH3), 56.97 (C-2), 78.17 (C Boc), 113.73 (C-m), 123.26 (C-o),
131.60 (C-i), 155.30 (CO Boc), 156.54 (C-p), 171.56 (C-5), 172.19
(CO2H) ppm. C17H22N2O6 (350.38): calcd. C 58.28, H 6.33, N 7.99;
found C 58.12, H 6.28, N 7.94.
pound 12 (0.28 g, 59%) as a white solid. M.p. 159–164 °C. [α]D
=
1
+63.2 (c = 0.9, acetone). H NMR (400 MHz, CDCl3): δ = 2.31 (s,
2
3
3
3 H, CH3), 2.57 (dt, J7B,7A = 10.7 Hz, J7B,4 = J7B,1 = 1.9 Hz, 1
2
3
3
(2S,4S)-4-[(4-Methylbenzenesulfonyl)amino]-5-oxo-1-phenylproline
(10): To a stirred solution of compound 6 (5.0 g, 22.7 mmol) and
Et3N (10 mL, 71.7 mmol) in a mixture of water (90 mL) and THF
(45 mL) was portionwise added para-toluenesulfonyl chloride
(6.5 g, 34.1 mmol) over 30 min, and the reaction mixture was
stirred at room temperature for 2–5 h. The organic solvent was
evaporated under reduced pressure, and the residual solution was
H, 7B-H), 2.60 (dt, J7A,7B = 10.7 Hz, J7A,4 = J7A,1 = 1.9 Hz, 1
H, 7A-H), 4.42 (q, J4,7B = 3J4,7A = 4J4,1 = 1.9 Hz, 1 H, 4-H), 4.88
3
3
3
(q, J1,7B = 3J1,7A = 4J1,4 = 1.9 Hz, 1 H, 1-H), 6.99 (d, J = 8.5 Hz,
2 H, m-H Ts), 7.11 (m, 1 H, p-H), 7.16–7.25 (m, 4 H, m-H, o-H
Ph), 7.83 (d, 3J = 8.5 Hz, 2 H, o-H Ts) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.55 (CH3), 42.31 (C-7), 64.38 (C-1), 65.23 (C-4),
120.51 (C-o Ph), 125.72 (C-p Ph), 128.27 (C-o Ts), 128.98 (C-m
diluted with water followed by filtration. The pH of the filtrate was Ph), 129.53 (C-m Ts), 133.76 (C-i Ts), 136.43 (C-i Ph) 145.70 (C-p-
adjusted to 2 with HCl (1 ). The precipitate was filtered off to
give compound 10 as a white solid (5.36 g, 63%). M.p. 241–243 °C.
[α]D = –6.8 (c = 1.0, acetone). 1H NMR (400 MHz, [D6]DMSO): δ
Ts), 168.95, 169.03 (C-3, C-6) ppm. C18H16N2O4S (356.40): calcd.
C 60.67, H 4.49, N 7.87, S 8.99; found C 60.60, H 4.46, N 7.92, S
8.93.
Eur. J. Org. Chem. 2008, 1802–1810
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1807

V. P. Krasnov et al.
FULL PAPER
(1S,4S)-5-(4-Methoxyphenyl)-2-(4-methylbenzenesulfonyl)-2,5-diaza- 2 H, m-H), 8.32 (s, 1 H, N-1–H) ppm. 13C NMR (100 MHz, [D6]-
bicyclo[2.2.1]heptane-3,6-dione (13): Oxalyl chloride (0.4 mL, DMSO): δ = 33.17 (C-3), 51.65 (C-2), 52.11 (CO2CH3), 53.84 (C-
4.6 mmol) and DMF (0.01 mL) were added to a suspension of 4), 55.28 (OCH3), 113.85 (C-o), 114.45 (C-m), 141.99 (C-i), 151.13
compound 11 (0.404 g, 1.0 mmol) in dry benzene (5 mL). The reac-
tion mixture was stirred at room temperature for 1 h and then evap-
orated to dryness under reduced pressure. The residue was dried in
vacuo over P2O5 and then dissolved in dry benzene (6 mL). Et3N
(0.3 mL, 2.17 mmol) was added to the solution. The reaction mix-
ture was stirred at room temperature for 1 h, then diluted with
EtOAc (20 mL) and washed with aqueous HCl (5%, 3ϫ3 mL),
water (3 ϫ 5 mL), aqueous Na2CO3 (5 %, 3 ϫ 5 mL) and brine
(3ϫ5 mL) and dried with Na2SO4. The solvent was evaporated to
dryness under reduced pressure to give compound 13 (0.317 g,
(C-p), 172.32 (CO2H), 175.06 (C-5) ppm. C13H16N2O4 (264.28):
calcd. C 59.08, H 6.10, N 10.60; found C 59.16, H 5.95, N 10.54.
(2S,4S)-5-Oxo-4-phenylaminoproline (16): NaOH (1 , 1.2 mL,
1.2 mmol) was added to a solution of compound 14 (0.117 g,
0.50 mmol) in acetone (1.5 mL). The reaction mixture was stirred
at room temperature for 1 h. Acetone was evaporated under re-
duced pressure. The aqueous solution was acidified with concen-
trated HCl to pH 6–7 and evaporated to dryness under reduced
pressure, and the residue was purified by flash-column chromatog-
raphy (CHCl3/MeOH) to afford compound 16 (0.042 g, 38%) as a
pale-yellow solid. M.p. 157–162 °C. [α]D = +88.9 (c = 0.5, MeOH).
1H NMR (400 MHz, [D6]DMSO): δ = 1.64 (ddd, 2J3B,3A = 12.2 Hz,
82 %) as a pale-yellow solid. M.p. 179–182 °C (EtOAc). [α]D
=
+55.4 (c = 0.9, acetone). 1H NMR (400 MHz, [D6]DMSO): δ =
2
3
2.39 (s, 3 H, CH3), 2.61 (dt, J7B,7A = 10.8 Hz, J7B,4
=
3J7B,1
=
=
=
3
2
3J3B,4 = 9.9 Hz, J3B,2 = 9.2 Hz, 1 H, 3B-H), 2.74 (ddd, J3A,3B
=
2
3
3
1.9 Hz, 1 H, 7B-H), 2.64 (dt, J7A,7B = 10.8 Hz, J7A,4 = J7A,1
3
3
12.2 Hz, J3A,4 = 7.9 Hz, J3A,2 = 6.9 Hz, 1 H, 3A-H), 3.82 (dd,
3
3
1.9 Hz, 1 H, 7A-H), 3.71 (s, 3 H, OCH3), 4.76 (q, J4,7B = J4,7A
3J2,3B = 9.2 Hz, J2,3A = 6.9 Hz, 1 H, 2-H), 3.95 (dd, J4,3B
=
3
3
4J4,1 = 1.9 Hz, 1 H, 4-H), 4.84 (q, J1,7B = J1,7A = J1,4 = 1.9 Hz,
3
3
4
9.9 Hz, 3J4,3A = 7.9 Hz, 1 H, 4-H), 4.5 (br. s, 1 H, CO2H), 5.60 (br.
3
1 H, 1-H), 6.83 (m, AAЈBBЈ, 4 H Ph), 7.40 (d, J = 8.6 Hz, 2 H,
3
4
s, 1 H, Ph-NH), 6.54 (tt, J = 7.2 Hz, J = 1.1 Hz, 1 H, p-H), 6.65
m-H Ts), 7.75 (d, 3J = 8.6 Hz, 2 H, o-H Ts) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 21.04 (CH3), 41.58 (C-7), 55.26
(OCH3), 64.71 (C-1), 65.42 (C-4), 114.05 (C-m Ph), 122.50 (C-o
Ph), 127.86 (C-o Ts), 129.50 (C-i Ph), 129.74 (C-m Ts), 133.93 (C-
i Ts) 145.66 (C-p-Ts), 156.85 (C-p Ph), 169.62, 169.74 (C-3, C-6)
ppm. C19H18N2O5S (386.43): calcd. C 59.06, H 4.69, N 7.25, S
8.30; found C 59.07, H 4.49, N 7.28, S 8.40.
3
4
3
3
(dd, J = 8.7 Hz, J = 1.1 Hz, 2 H, o-H), 7.05 (dd, J = 8.7 Hz, J
= 7.2 Hz, 2 H, m-H), 7.99 (s, 1 H, N-1–H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 34.55 (C-3), 53.95 (C-2), 54.14 (C-4),
112.73 (C-o), 116.05 (C-p), 128.74 (C-m), 148.23 (C-i), 174.71,
177.79 (C-5, CO2H) ppm. MS (Q-array scan, MeCN): m/z (%) =
219 (100) [M – H]–, 260 (15.8) [M – H + MeCN]–.
(2S,4S)-4-(4-Methoxyphenyl)amino-5-oxoproline (17): According to
the procedure outlined for 16 and starting from compound 15
(0.132 g, 0.50 mmol), compound 17 (0.055 g, 44%) was obtained
as a slightly coloured solid. M.p. 164–166 °C. [α]578 = +40.4 (c =
0.5, MeOH). 1H NMR (400 MHz, [D6]DMSO): δ = 1.67 (ddd,
Methyl (2S,4S)-5-Oxo-4-phenylaminoprolinate (14): An aqueous
solution of hydrazine hydrate (64%, 0.3 mL, 3.80 mmol) was added
to a solution of compound 2 (0.72 g, 1.81 mmol) in MeOH/benzene
(1:1, 20 mL). The reaction mixture was stirred at room temperature
for 1 h and then acidified with concentrated HCl to pH 6–7. The
precipitate was filtered off, and the filtrate was evaporated to dry-
ness under reduced pressure. The residue was heated in vacuo at
70 °C for 2 h and then treated with CHCl3 (20 mL). The precipitate
was filtered off, the filtrate was evaporated to dryness under re-
duced pressure and the residue was purified by flash-column
chromatography (benzene/CHCl3) to afford compound 14 (0.243 g,
57%) as a white solid. M.p. 159–161 °C. [α]D = +159.8 (c = 1.0,
3
3
2J3B,3A = 12.3 Hz, J3B,4 = 9.5 Hz, J3B,2 = 9.0 Hz, 1 H, 3B-H),
3
3
2.84 (ddd, 2J3A,3B = 12.3 Hz, J3A,4 = 8.2 Hz, J3A,2 = 7.3 Hz, 1 H,
3
3
3A-H), 3.64 (s, 3 H, OCH3), 3.95 (dd, J4,3B = 9.5 Hz, J4,3A
=
3
3
8.2 Hz, 1 H, 4-H), 4.10 (dd, J2,3B = 9.0 Hz, J2,3A = 7.3 Hz, 1 H,
3
2-H), 5.3 (br. s, 1 H, Ph-NH), 6.61 (d, J = 9.1 Hz, 2 H, o-H) 6.70
(d, J = 9.1 Hz, 2 H, m-H), 8.24 (s, 1 H, N-1–H), 12.3 (br. s, 1 H,
3
CO2H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 33.38 (C-3),
51.70 (C-2), 54.02 (C-4), 55.29 (OCH3), 113.84 (C-m), 114.45 (C-
o), 142.06 (C-i), 151.10 (C-p), 173.37 (CO2H), 175.02 (C-5) ppm.
MS (Q-array scan, MeCN): m/z (%) = 249 (100) [M – H]–, 290
(17.8) [M – H + MeCN]–. C12H14N2O4 (250.26): calcd. C 57.60, H
5.64, N 11.19; found C 57.20, H 5.62, N 11.08.
1
2
CHCl3). H NMR (400 MHz, [D6]DMSO): δ = 1.72 (ddd, J3B,3A
3
3
= 12.2 Hz, J3B,4 = 9.6 Hz, J3B,2 = 8.8 Hz, 1 H, 3B-H), 2.86 (ddd,
2J3A,3B = 12.2 Hz, J3A,4 = 8.3 Hz, J3A,2 = 7.5 Hz, 1 H, 3A-H),
3
3
3
3
3.68 (s, 3 H, CO2CH3), 4.09 (ddd, J4,3B = 9.6 Hz, J4,3A = 8.3 Hz,
3J4,NH = 6.6 Hz, 1 H, 4-H), 4.24 (dd, J2,3B = 8.8 Hz, J2,3A
=
3
3
7.5 Hz, 1 H, 2-H), 5.72 (d, 3JNH,4 = 6.6 Hz, 1 H, Ph-NH), 6.56 (tt,
Dimethyl (2S,4S)-4-(2,3-Dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)-
amino-N-phthaloylglutamate (18): 4-Aminoantipyrine (8.46 g,
41.7 mmol) was added to a solution of compound 1 (4.0 g,
10.4 mmol) in MeCN (40 mL). The reaction mixture was heated
at reflux under an Ar atmosphere for 12 h. The reaction mixture
contained (2S,4S)-/(2R,4S)-diastereoisomers in a ratio of 78:22 ac-
cording to HPLC [LiChrosorb Si-60 (4ϫ250 mm, 5 µm); hexane/
iPrOH, 3:1]: tR = 10.74 [(2S,4S)], 13.71 [(2R,4S)] min. The reaction
mixture was evaporated under reduced pressure to a volume of
10 mL, poured into water (50 mL) and kept at 0 °C for 1 d. The
mother solution was decanted from the oily precipitate. The latter
was twice reprecipitated with water from acetone solution to give
3J = 7.3 Hz, 4J = 1.1 Hz, 1 H, p-H), 6.65 (dd, 3J = 8.7 Hz, 4J =
3
3
1.1 Hz, 2 H, o-H), 7.06 (dd, J = 8.7 Hz, J = 7.3 Hz, 2 H, m-H),
8.35 (s, 1 H, N-1–H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
32.88 (C-3), 51.61 (C-2), 52.12 (CO2CH3), 53.01 (C-4), 112.64 (C-
o), 116.27 (C-p), 128.76 (C-m), 147.88 (C-i), 172.27 (CO2H), 174.85
(C-5) ppm. C12H14N2O3 (234.26): calcd. C 61.53, H 6.02, N 11.96;
found C 61.15, H 5.64, N 11.72.
Methyl (2S,4S)-4-(4-Methoxyphenyl)amino-5-oxoprolinate (15): Ac-
cording to the procedure outlined for 14 and starting from com-
pound 3 (1.50 g, 3.52 mmol), compound 15 (0.251 g, 27%) was ob-
tained as a white solid. M.p. 144–146 °C. [α]D = +145.0 (c = 1.0,
1
2
CHCl3). H NMR (400 MHz, [D6]DMSO): δ = 1.70 (ddd, J3B,3A
compound 18 (2.1 g, 40 %). M.p. 178–181 °C (MeOH). [α]D
=
3
3
= 12.7 Hz, J3B,4 = 9.4 Hz, J3B,2 = 8.8 Hz, 1 H, 3B-H), 2.85 (ddd,
–102.2 (c = 1.0, CHCl3). 1H NMR (400 MHz, [D6]DMSO): δ =
3
3
2
3
2J3A,3B = 12.7 Hz, J3A,4 = 8.3 Hz, J3A,2 = 7.5 Hz, 1 H, 3A-H),
2.12 (s, 3 H, C-3Ј-CH3), 2.43 (ddd, J3B,3A = 14.0 Hz, J3B,4 =
3
3.64 (s, 3 H, OCH3), 3.68 (s, 3 H, CO2CH3), 3.97 (ddd, J4,3B
=
11.3 Hz, 3J3B,2 = 4.3 Hz, 1 H, 3B-H), 2.76 (s, 3 H, N-2Ј-CH3), 2.78
9.4 Hz, 3J4,3A = 8.3 Hz, 3J4,NH = 6.1 Hz, 1 H, 4-H), 4.23 (dd, 3J2,3B
(ddd, 2J3A,3B = 14.0 Hz, 3J3A,2 = 11.9 Hz, 3J3A,4 = 4.1 Hz, 1 H, 3A-
3
3
= 8.8 Hz, J2,3A = 7.5 Hz, 1 H, 2-H), 5.28 (d, JNH,4 = 6.1 Hz, 1 H), 3.51 (s, 3 H, C-5-OCH3), 3.68 (s, 3 H, C-1-OCH3), 4.25 (ddd,
3
3
H, Ph-NH), 6.62 (d, J = 9.1 Hz, 2 H, o-H), 6.71 (d, J = 9.1 Hz, 3J4,3B = 11.3 Hz, 3J4,NH = 10.9 Hz, 3J4,3A = 4.1, Hz, 1 H, 4-H), 4.57
1808
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Eur. J. Org. Chem. 2008, 1802–1810

Structure and Properties of 4-Amino Derivatives of 5-Oxoproline
3
3
3
(d, JNH,4 = 10.9 Hz, 1 H, NH), 5.28 (dd, J2,3A = 11.9 Hz, J2,3B
tifaceted crystal. Data for compound 18 were collected with a Syn-
tex P21 diffractometer by using graphite-monochromated Mo-Kα
= 4.3 Hz, 1 H, 2-H), 7.16 (dd, 3J = 8.5 Hz, J = 1.3 Hz, 2 H, o-H),
4
7.20 (tt, J = 7.4 Hz, J = 1.3 Hz, 1 H, p-H), 7.37 (dd, 3J = 8.5 Hz, radiation. Absorption correction was calculated by integration in
3
4
4J = 1.3 Hz, 2 H, m-H), 7.87 (m, 4 H, Phth) ppm. 13C NMR model of multifaceted crystal. The structures were solved by direct
(100 MHz, [D6]DMSO): δ = 9.83 (C-5Ј-CH3), 30.60 (C-3), 37.52
(N-1Ј-CH3), 48.83 (C-2), 51.62 (C-5-OCH3), 52.82 (C-1-OCH3), the structure was accomplished with the SHELXL-97 program.
53.20 (C-4), 118.31 (C-4Ј), 122.09 (C-o), 123.30 (C-3 Phth), 125.23 The non-hydrogen atoms were refined anisotropically. The hydro-
methods and expanded by using Fourier techniques. Refinement of
(C-p), 128.74 (C-m), 131.35 (C-2a Phth), 134.66 (C-4 Phth), 135.22 gen atoms involved in hydrogen bonding were located in electron-
(C-i), 141.85 (C-3Ј), 160.92 (C-5Ј), 167.33 (C-2 Phth), 169.81 (C- density maps. The remainder of the hydrogen atoms were placed in
1), 173.83 (C-5) ppm. C26H26N4O7 (506.52): calcd. C 61.66, H 5.17, idealized positions and allowed to ride on the C atoms to which
N 11.06; found C 61.46, H 5.23, N 11.08. de 100% HPLC [LiChro-
sorb Si-60 (4ϫ250 mm, 5 µm); hexane/iPrOH, 3:1]: tR = 10.74 min.
they are bonded.
Crystal Data for 4: From MeOH (solvate with MeOH 1:1); Mr
= 382.36; 0.35ϫ0.24ϫ0.18 mm; colourless fragment; T = 295 K;
monoclinic; space group P21; a = 5.1198(8) Å, b = 20.399(3) Å, c
(2S,4S)-4-Amino-1-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)-
5-oxoproline (19): Solution of compound 18 (2.3 g, 4.5 mmol) in
HCl (6 , 20 mL) was heated at reflux for 8 h. The reaction mixture
was cooled to room temperature, and the precipitate of phthalic
acid was filtered off. The filtrate was evaporated to dryness under
reduced pressure. The dried residue was dissolved in EtOH (15 mL)
and Et3N was added to the solution to pH 6–7. The reaction mix-
ture was kept at 0 °C for 1 d, and the precipitate was filtered off
and dried in vacuo over P2O5 to give compound 19 (0.65 g, 42%)
= 18.056(3) Å; β = 95.337(13)°; V = 1877.6(5) Å3; pcalcd.
=
1.353 gcm–3; θmax = 26.37°; R1 = 3.23% [IϾσ(I)], wR2 = 3.28%,
S = 0.988.
Crystal Data for 10: Mr = 374.40; 0.43ϫ0.37ϫ0.29 mm; colourless
prism; T = 295 K; triclinic; space group P1; a = 5.3741(16) Å, b =
6.2299(4) Å, c = 14.592(4) Å; α = 101.34(2)°, β = 99.041(4)°, V =
469.28(18) Å3; pcalcd. = 1.325 gcm–3; θmax = 26.36°; R1 = 5.02%
[IϾσ(I)], wR2 = 9.02%, S = 1.005.
1
as a white solid. M.p. 220–222 °C. [α]D = –29.3 (c = 1.0, H2O). H
2
3
NMR (400 MHz, D2O): δ = 2.22 (ddd, J3B,3A = 13.5 Hz, J3B,4
=
Crystal Data for 12: 1.2ϫ0.48ϫ0.31 mm; colourless prism; T =
295 K; orthorhombic; space group P212121; a = 6.3867(6) Å, b =
13.377(1) Å, c = 20.039(1) Å; V = 1712.0(2) Å3; µ = 0.215 mm–1,
transmission 0.9129–0.9420, pcalcd. = 1.383 gcm–3; θmax = 25.00°;
R1 = 2.90% [IϾσ(I)], wR2 = 8.21%, S = 1.064; Flack parameter
–0.3(1); Flack parameter for inverted structure 1.1(1).
3
8.3 Hz, J3B,2 = 7.4 Hz, 1 H, 3B-H), 2.29 (s, 3 H, CH3), 3.04 (ddd,
2J3A,3B = 13.5 Hz, J3A,4 = 9.2 Hz, J3A,2 = 7.4 Hz, 1 H, 3A-H),
3
3
3
3
3.31 (s, 3 H, N-CH3), 4.39 (dd, J4,3A = 9.2 Hz, J4,3B = 8.3 Hz, 1
3
3
H, 4-H), 4.53 (t, J2,3A = J2,3B = 7.4 Hz, 1 H, 2-H), 7.41 (m, 2 H,
Ph), 7.57–7.64 (m, 3 H, Ph) ppm. 13C NMR (100 MHz, D2O): δ =
12.63 (CH3), 30.80 (C-3), 35.90 (NCH3), 52.79 (C-4), 64.34 (C-2),
103.92 (C-4Ј), 131.00 (C-o), 132.65 (C-m), 133.12 (C-p), 134.62 (C-
i), 151.76 (C-3Ј), 162.58 (C-5Ј), 174.64 (C-5), 179.25 (CO2H) ppm.
C16H18N4O4·H2O (348.36): calcd. C 55.17, H 5.79. N 16.08; found
C 55.13, H 5.74, N 16.02.
Crystal Data for 14: Mr = 234.25; 0.35ϫ0.24ϫ0.12 mm; colourless
prism; T = 295 K; orthorhombic; space group P212121; a =
6.3613(9) Å, b = 10.3157(12) Å, c = 18.145(5) Å; V = 1190.7(4) Å3;
pcalcd. = 1.307 gcm–3; θmax = 26.38°; R1 = 3.26% [IϾσ(I)], wR2 =
3.92%, S = 1.001.
(2S,4S)-4-(tert-Butyloxycarbonyl)amino-1-(2,3-dimethyl-5-oxo-1-
phenyl-3-pyrazolin-4-yl)-5-oxoproline (20): To a solution of com-
pound 19 (0.5 g, 1.43 mmol) and K2CO3 (0.22 g, 1.59 mmol) in
water (1.5 mL) was added a solution of Boc2O (0.40 g, 1.82 mmol)
in iPrOH (1 mL). The reaction mixture was stirred at 40 °C for 3 h,
cooled and then water (7.5 mL) was added. The reaction mixture
was treated with hexane (2ϫ1.5 mL). The aqueous layer was acidi-
fied with citric acid to pH 4. The precipitate was filtered off and
crystallized from EtOH to give compound 20 (0.43 g, 67%) as a
white solid. M.p. 235–238 °C (decomp.). [α]D = –19.1 (c = 1.0,
MeOH). 1H NMR (400 MHz, [D6]DMSO6): δ = 1.40 (s, 9 H, Boc),
1.92 (br. q, J = 10.6 Hz, 1 H, 3B-H), 2.20 (s, 3 H, CH3), 2.72 (ddd,
Crystal Data for 18: Mr = 506.51; 1.00ϫ0.75ϫ0.08 mm; yellow
plate;
T = 296 K; monoclinic; space group P212121; a =
11.409(4) Å, b = 8.170(3) Å, c = 14.595(5) Å; β = 111.71(3)°, V =
1263.9(8) Å3; µ = 0.098 mm–1, transmission 0.9418–0.99920, pcalcd.
= 1.331 gcm–3; θmax = 25.02°; R1 = 5.01% [IϾσ(I)], wR2 = 11.87%,
S = 1.099.
CCDC-669786, -669787, -669788, -669789 and -669790 contain the
supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
3
3
2J3A,3B = 11.7 Hz, J3A,4 = 8.9 Hz, J3A,2 = 7.4 Hz, 1 H, 3A-H),
3.10 (s, 3 H, NCH3), 4.26 (br. q, J = 9.2 Hz, 1 H, 4-H), 4.62 (dd,
Acknowledgments
3
3J2,3B = 9.3 Hz, J2,3A = 7.4 Hz, 1 H, 2-H), 7.31–7.36 (m, 4 H, o-
H, p-H, NH), 7.50 (m, 2 H, m-H), 12.9 (br. s, 1 H, CO2H) ppm.
13C NMR (100 MHz, [D6]DMSO6): δ = 11.20 (CH3), 28.24
[(CH3)3 Boc], 29.97 (C-3), 35.61 (NCH3), 50.52 (C-4), 55.64 (C-2),
78.33 (C Boc), 106.42 (C-4Ј), 124.00 (C-o), 126.69 (C-p), 129.21
(C-m), 134.66 (C-i),154.37 (C-3Ј), 155.29 (CO Boc), 160.88 (C-5Ј),
172.08 (CO2H), 172.29 (C-5) ppm. C21H26N4O6·H2O (448.48):
calcd. C 56.24, H 6.29, N 12.49; found C 56.37, H 6.11, N 12.17.
This work was financially supported by the Russian Foundation
for Basic Research (grants 06–03–32791 and 08–03–00479) and the
State Program for Supporting of Leading Scientific Schools of the
Russian Federation (grant NSh 9178.2006.3).
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Eur. J. Org. Chem. 2008, 1802–1810
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1809

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Received: December 5, 2007
Published Online: February 15, 2008
1810
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 1802–1810