Parallel solution-phase synthesis of (2S,4E)-4-(arylaminomethylidene) pyroglutamic acids

Article abstract of DOI:10.1515/znb-2010-0707

A library of twelve N(4')-substituted di-tert-butyl (2S,4E)-4- arylaminomethylidene-5-oxopyrrolidine-1,2-dicarboxylates 6/6'a-l were prepared in 47-90% yield by parallel acid-catalysed treatment of di-tert-butyl (2S,4E)-4-[(dimethylamino)methylidene]-5-oxopyrrolidine-1,2-dicarboxylate (4) with anilines 5a - j, ethyl glycinate (5k), and ethyl β-alaninate (31). Acidolytic deprotection of compounds 6a - c, e - j afforded the corresponding (2S,4E)-4-arylaminomethylidene-5-oxopyrrolidine-2-carboxylic acids 7a - c, e - j in 39-99% yield. The configuration around the C=C double bond in the enaminones 6 and 7 was determined by NMR spectroscopy.

Full text of DOI:10.1515/znb-2010-0707

Parallel Solution-phase Synthesis of
(2S,4E)-4-(Arylaminomethylidene)pyroglutamic Acids
Jurij Svetea, Urosˇ Grosˇelja, Jernej Basˇkovcˇa, Georg Dahmannb, and Branko Stanovnika
a Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5,
P. O. Box 537, 1000 Ljubljana, Slovenia
b Boehringer Ingelheim Pharma GmbH & Co. KG, Dept. Chemical Research, 88397 Biberach,
Germany
Reprint requests to Prof. Jurij Svete. Fax: +386 1 2419 220. E-mail: jurij.svete@fkkt.uni-lj.si
Z. Naturforsch. 2010, 65b, 811 – 820; received January 26, 2010
A library of twelve N(4ꢀ)-substituted di-tert-butyl (2S,4E)-4-arylaminomethylidene-5-oxopyrrol-
idine-1,2-dicarboxylates 6/6ꢀa – l were prepared in 47 – 90 % yield by parallel acid-catalysed treat-
ment of di-tert-butyl (2S,4E)-4-[(dimethylamino)methylidene]-5-oxopyrrolidine-1,2-dicarboxylate
(4) with anilines 5a – j, ethyl glycinate (5k), and ethyl β-alaninate (3l). Acidolytic deprotection of
compounds 6a – c, e – j afforded the corresponding (2S,4E)-4-arylaminomethylidene-5-oxopyrrol-
idine-2-carboxylic acids 7a – c, e – j in 39 – 99 % yield. The configuration around the C=C double
bond in the enaminones 6 and 7 was determined by NMR spectroscopy.
Key words: Pyroglutamic Acid, Enaminones, Amines, Combinatorial Synthesis, Pyrrolidinone
Introduction
(S)-Pyroglutamic acid (1) is a naturally occurring
heterocyclic α-amino acid which is abundant in pep-
tides and proteins, and its structure can also be found
in a variety of other biologically important compounds.
On the other hand, 1 is also a useful chiral build-
ing block, which is frequently used as a commer-
cially available starting material in chiral-pool syn-
theses of peptidomimetics, natural products, and their
Fig. 1. α-Enamino (S)-pyroglutamic acid 7 as a confor-
mationally constrained heterocyclic analogue of ∆-β-Ala-
AlaOH.
analogues. Therefore it is not surprising, that several erocyclic analogues of dipeptides containing the (S)-
reviews on the chemistry of (S)-pyroglutamic acid (1) pyroglutamic acid structural motif [5c, 8]. Previously,
have recently been published [1].
we reported the synthesis of a series of N(4ꢀ)-
2-Substituted alkyl 3-(dimethylamino)prop-2-eno- substituted methyl (2S,4E)-1-acyl-4-(aminomethyl-
ates and related enaminones are a group of enamino- idene)-5-oxopyrrolidine-2-carboxylates as stable in-
termediates in the ‘ring switching’ synthesis of 3-
masked alkyl α-formylacetates, which are easily avail-
able and versatile reagents in heterocyclic synthe- heteroarylalanines [9]. Recently, this type of com-
sis [2]. In addition to their extensive use in the syn- pounds attracted our attention again, since such α-
thesis of various heterocyclic systems, recent appli- enamino pyroglutamic acids are conformationally
cations of enaminones have mostly focused on the constrained heterocyclic dipeptides comprising α,β-
synthesis of functionalised heterocyclic compounds dehydro-β-alanine (∆-β-Ala) and (S)-alanine (L-Ala)
including natural product analogues [2 – 4], and on structural units (Fig. 1).
combinatorial syntheses of functionalised heterocy-
Therefore, we were intrigued to study the syn-
cles [5]. Within this context, various functionalised thesis of γ-enamino pyroglutamic acids 7, which
enaminones have been prepared and used as key in- might be interesting and useful building blocks for
termediates in the synthesis of 3-heteroarylalanine further derivatisation. Herein, we report the result
derivatives [6], histamine analogues [5b, 7], and het- of this study – a simple parallel solution-phase
c
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812
J. Svete et al. · (2S,4E)-4-(Arylaminomethylidene)pyroglutamic Acids
Table 1. Selected experimental data of the di-tert-butyl
(2S,4E)-4-arylaminomethylidene-5-oxopyrrolidine-1,2-di-
carboxylates 6a – l and 7a – c, e – j.
synthesis of di-tert-butyl (S)-4-arylaminomethyl-
idene-5-oxopyrrolidine-1,2-dicarboxylates
and (S)-4-arylaminomethylidene-5-oxopyrrolidine-
6/6ꢀa – l
Compound Ar
Yield (%)
E : Za
Purity (%)b
1,2-dicarboxylates 7a – c, e – j.
6a/6ꢀa
6/6ꢀb
6/6ꢀc
6d
phenyl
90
65
83
62
69
73
73
79
65
81
47
68
39
96
90
37
99
87
86
90
88
56 : 44c,d
21 : 79
17 : 83
100 : 0
100 : 0
16 : 84
15 : 85
15 : 85
100 : 0
100 : 0
85 : 15
88 : 12
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0
100 : 0d
100 : 0c,d
100 : 0d
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
> 95
3-methylphenyl
4-methylphenyl
3-hydroxyphenyl
4-hydroxyphenyl
3-methoxyphenyl
3-bromophenyl
4-bromophenyl
3-nitrophenyl
4-nitrophenyl
CH2COOEt
CH2CH2COOEt
phenyl
Results and Discussion
The key intermediate, di-tert-butyl (2S,4E)-4-[(di-
6e
methylamino)methylidene]-5-oxopyrrolidine-1,2-di- 6/6ꢀf
6/6ꢀg
carboxylate (4), was prepared in three steps from (S)-
6/6ꢀh
6ꢀi
H
N
6j
HOOC
O
6/6ꢀk
6/6ꢀl
7a
1
7b
7c
3-methylphenyl
4-methylphenyl
4-hydroxyphenyl
3-methoxyphenyl
3-bromophenyl
4-bromophenyl
3-nitrophenyl
Ref. [10]
AcOBut, HClO4 (cat.), r. t.
7e
7f
7g
7h
7i
7j
H
N
Boc
O
2
4-nitrophenyl
a
b
Determined by 1H-NMR spectroscopy; determined by CHN-
analyses and 1H-NMR spectroscopy. The values found for C, H,
and N were within 0.4 % with respect to the calculated values;
Ref. [11]
Boc2O, MeCN, DMAP (cat.), r. t.
c
the configuration around the C=C double bond was determined
Boc
N
d
by HMBC NMR spectroscopy; the configuration around the C=C
double bond was determined by NOESY spectroscopy.
Boc
O
3
pyroglutamic acid (1) following the literature proce-
dures [5c, 10, 11]. Thus, acid-catalysed esterification
of (S)-pyroglutamic acid (1) with tert-butyl acetate
gave tert-butyl pyroglutamate (2) [10], which was
N-acylated with Boc2O in acetonitrile in the pres-
ence of catalytic amounts of 4-dimethylaminopyridine
(DMAP) to afford di-tert-butyl (2S)-5-oxopyrrol-
idine-1,2-dicarboxylate (3) [11]. Finally, heating of
3 with one equivalent of tert-butoxy-bis(dimeth-
ylamino)methane (Bredereckꢀs reagent, TBDMAM)
furnished di-tert-butyl (2S,4E)-4-[(dimethylamino)-
methylidene]-5-oxopyrrolidine-1,2-dicarboxylate (4)
in 70 % yield over three steps [5c] (Scheme 1).
Further parallel treatment of the enamino lactam 4
with 1.2 equivalents of amine hydrochlorides 5a – l
in 50 % aqueous ethanol at r. t. resulted in the for-
mation of the dimethylamine substitution products,
N(4ꢀ)-substituted di-tert-butyl (2S,4EZ)-4-amino-
methylidene-5-oxopyrrolidine-1,2-dicarboxylates 6/6ꢀ
a – l, which precipitated from the reaction mixtures
and were isolated by filtration. Upon washing with
water and thorough drying in vacuo over P4O10, a
library of twelve analytically pure esters 6/6ꢀa – l was
t-BuOCH(NMe2)2,
toluene, 100 °C
Ref. [5c]
Boc
N
Boc
O
Me2N
4
MiniBlockTM
−
ArNH2 (5a l), EtOH-H2O, HCl, r. t.
Boc
1 N
H
N
5
HCl-EtOAc
HOOC
O
Boc
O
2
3
4
H
4'
HN
HN
Ar
Ar
7a−c e−j
,
−
6/6'a l
(E)-isomers 6a l
(Z)-isomers 6'a c, f g, k, l
−
−
−
Scheme 1.
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J. Svete et al. · (2S,4E)-4-(Arylaminomethylidene)pyroglutamic Acids
813
Fig. 2. Structure determination by
HMBC and NOESY spectroscopy.
obtained in 47 – 90 % yield. In the final step, parallel measured from the antiphase splitting of cross peaks.
acidolytic deprotection of compounds 6/6ꢀa – l was Generally, the magnitude of this coupling constant,
carried out. Stirring of esters 6/6ꢀ with 2 M HCl/EtOAc 3JC−H, for nuclei with cis-configuration around the
at r. t. for 12 h resulted in the initial formation of clear C=C double bond is smaller (2 – 6 Hz) than that
colourless or yellow solutions followed by formation for trans-oriented nuclei (8 – 12 Hz) [2, 12]. In com-
of precipitates, which were then collected by filtration, pounds 6a and 7i, the magnitude of the coupling con-
washed with EtOAc, and dried in vacuo over P4O10. In stants, 3JC(1)−H(4ꢀ) = 4 Hz (cis) and 5 Hz (cis), respec-
this manner, analytically pure carboxylic acids 7a – c, tively, confirmed the (E)-configuration around the exo-
e – j were prepared in 37– 99 % yield. Acidolysis cyclic C=C double bond. In the minor isomer 6ꢀa, on
of compounds 6d, k, l did not produce precipitates. the other hand, a large coupling constant, 3JC(1)−H(4ꢀ) =
Attempts to isolate the final products 7d, k, l by 10 Hz (trans), confirmed the (Z)-configuration around
evaporation of the reaction mixtures followed by the C=C double bond (Fig. 2). Additionally, the config-
crystallisation and/or chromatographic workup failed. uration around the exocyclic C=C double bond in com-
Since we were particularly interested in a simple and pounds 6a, 6ꢀa, and 7h – j was confirmed by NOESY
practical procedure using just a filtration work-up, no spectroscopy. A NOE between the NH and the CH2
further attempts to isolate compounds 7d, k, l were group in compounds 6a and 7h – j was in agreement
made (Scheme 1, Table 1).
with the (E)-configuration around the exocyclic C=C
double bond, whilst a NOE between the 4ꢀ-H and the
The structures of the novel compounds 6/6ꢀa – l and
7a – c, e – j were determined by spectroscopic (NMR, CH2 group in the minor isomer 6ꢀa supported the (Z)-
configuration (Fig. 2).
IR, MS) methods and by elemental analyses. The con-
figuration around the exocyclic C=C bond in com-
Finally, the configurations around the C=C double
pounds 6a, 6ꢀa, and 7i was determined by HMBC bond in compounds 6 and 7 were confirmed by corre-
NMR spectroscopy on the basis of the long-range cou- lation of chemical shifts for 4ꢀ-H and NH and vicinal
pling constant (3JC−H) between the methylidene pro- coupling constants, JH−H. The major and most char-
3
ton (H–C(4ꢀ)) and the carbonyl carbon atom (O=C(5)), acteristic difference was observed in chemical shifts δ
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814
J. Svete et al. · (2S,4E)-4-(Arylaminomethylidene)pyroglutamic Acids
Table 2. Correlation between
the chemical shifts for 4ꢀ-H
and (4ꢀ)N-H and coupling con-
Compound
Solvent
δ (ppm)
4ꢀ-NH
(2S,4E)-Isomers 6 and 7
3JH-H (Hz)
4ꢀ-H
3 – 4ꢀ
3a – 3b
CHNH
3
3
stants, JH3−H4 and JCH−NH
,
6a
6b
6c
6d
6e
6f
6g
6h
6i
CDCl3
CDCl3
CDCl3
[D6]DMSO
[D6]DMSO
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
[D6]DMSO
CDCl3
CDCl3
[D6]DMSO
[D6]DMSO
[D6]DMSO
[D6]DMSO
[D6]DMSO
[D6]DMSO
[D6]DMSO
[D6]DMSO
[D6]DMSO
7.79
7.79
7.76
7.50
7.47
7.76
7.70
7.68
7.74
7.74
7.79
7.11
7.17
7.37
7.37
7.33
7.29
7.33
7.27
7.28
7.37
7.43
6.09
6.14
6.09
8.89
8.77
6.09
6.24
6.42
7.39
7.18
9.62
∼ 4.5c
4.65
8.59
8.53
8.47
8.34
8.53
8.65
8.65
9.04
9.44
2.2
15.8
13.7
13.5
13.6
13.1
13.4
13.5
13.3
13.4
13.0
in compounds 6a – l, 6ꢀa – c, f –
h, k, l, and 7a – c, e – j.
a
a
a
a
1.9
16.4
1.8
16.1
a
a
a
a
2.1
2.3
2.2
2.4
2.0
1.9
2.1
2.1
2.1
2.0
2.2
2.1
2.2
2.2
2.4
16.1
16.4
16.5
17.0
15.4
15.3
16.7
16.7
16.7
16.7
16.7
16.9
16.7
17.0
16.7
6j
6j
13.2
b
6k
6l
7a
7b
7c
7e
7f
13.2
13.6
11.6
12.0
10.4
b
12.3
12.3
12.7
12.3
12.2
7g
7h
7i
7j
(2S,4Z)-Isomers 6ꢀ
6ꢀa
6ꢀb
6ꢀc
6ꢀf
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
7.17
7.17
7.13
9.95
9.89
9.90
9.92
9.94
9.94
7.96
∼ 7.9c
1.3
1.2
1.2
1.3
1.4
15.2
15.2
15.1
15.3
15.4
12.3
12.2
12.3
12.4
12.0
12.1
12.6
12.6
7.14
6ꢀg
6ꢀh
6ꢀk
6ꢀl
∼ 7.1a
a Overlapped by other signals; b the
signals for the CHNH fragment
appeared as two broad singlets;
7.09
1.4
15.4
a
a
6.46
6.56
a
a
c
broad signal.
4
for the aminomethylidene –NH–CH= protons. In the (Z), and JH3H4ꢀ ∼ 2 Hz (E) >4 JH3H4ꢀ ∼ 1.3 Hz (Z).
1H-NMR spectra of the E/Z-mixtures 6/6ꢀa – c, f – h, These characteristic values are also in agreement with
k, l taken in CDCl3, the NH protons of the (E)-isomers the literature data for related aminomethylidene com-
6a – c, f – h, k, l had lower δ values (∼ 6.2 ppm) pounds [2 – 4, 13] (Table 2, Fig. 2).
than the 4ꢀ-H protons (∼ 7.7 ppm), while in the (Z)-
isomers 6ꢀa – c, f – h, k, l the NH protons exhibited
Conclusion
higher δ values (∼ 9.9 ppm) than the 4ꢀ-H protons
(∼ 7.2 ppm). Such a difference in chemical shifts of the
Di-tert-butyl(2S,4E)-4-[(dimethylamino)methylid-
NH protons in CDCl3 solution could be explained by
intramolecular N–H ···O=C hydrogen bonding, which
is possible only in the (Z)-isomers 6ꢀa – c, f – h, k,
l and not in the (E)-isomers 6a – c, f – h, k, l. Ac-
cordingly, in [D6]DMSO as a hydrogen bond accep-
tor, the NH protons of the (E)-isomers 6d, e, j and
7a – c, e – j appear at ∼ 8.5 ppm. Similarly, small
yet characteristic differences between typical coupling
ene]-5-oxopyrrolidine-1,2-dicarboxylate (4) is an eas-
ily available reagent, which is suitable for two-step
parallel solution-phase synthesis of 4-arylaminometh-
ylidene-substituted (S)-pyroglutamic acids 7 as con-
formationally constrained analogues of N-[N-(aryl)-
α,β-didehydro-β-alanyl]-(S)-alanine (c. f. Fig. 1). The
synthesis comprises acid-catalysed substitution of the
dimethylamino group in the enamino lactam 4 with
aromatic and aliphatic primary amines 5 to give the
substitution products 6/6ꢀ, followed by acidolytic de-
protection to furnish the title compounds 7 in good
yields over two steps. Furthermore, all intermediates
2
3
4
ꢀ
constant values, JH3aH3b, JNHCH, and JH3H4 , were
also observed; typical values were larger in case of
2
the (E)-isomers: JH3aH3b ∼ 16 Hz (E) >2 JH3aH3b
∼
15 Hz (Z), 3JNHCH ∼ 13.5 Hz (E) >3 JNHCH ∼ 12.5 Hz
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J. Svete et al. · (2S,4E)-4-(Arylaminomethylidene)pyroglutamic Acids
815
20
589
6a – l and final products 7a – c, e – j were obtained solid. – M. p. 177 – 180 ◦C; 6a : 6ꢀa = 56 : 44. – [α] +19.5
(c = 0.33, CH2Cl2). – IR (KBr): ν = 3237, 3120, 3040, 2978,
1757, 1710, 1686, 1639, 1594, 1495, 1445, 1369, 1313,
1231, 1151, 1000, 959, 866, 806, 775, 753, 692 cm−1. –
1H-NMR (CDCl3), major (E)-isomer 6a: δ = 1.48 and 1.53
in analytical purity following a simple parallel filtra-
tion work-up protocol in both synthetic steps. In con-
clusion, this synthetic method offers an easy access
to diversity-oriented libraries of (S)-4-[(substituted
amino)methylidene]pyroglutamic acid derivatives in
search for novel bioactive compounds.
t
(18H, 2s, 1 : 1, 2× -Bu), 2.54 (1H, ddd, J = 2.2, 3.6, 15.8 Hz,
3-Ha), 2.98 (1H, ddd, J = 2.2, 10.7, 15.8 Hz, 3-Hb), 4.56
(1H, dd, J = 3.6, 10.7 Hz, 2-H), 6.09 (1H, d, J = 13.7 Hz,
NH), 6.90 – 7.05 (3H, m, o, p-C6H5), 7.24 – 7.35 (2H, m, m-
C6H5), 7.79 (1H, dt, J = 1.9, 13.7 Hz, 4ꢀ-H); minor (Z)-
Experimental Section
t
isomer 6ꢀa: δ = 1.48 and 1.54 (18H, 2s, 1 : 1, 2× -Bu), 2.61
Melting points were determined on a Stanford Research
Systems MPA100 OptiMelt automated melting point sys-
tem. The NMR spectra were obtained on a Bruker Avance
DPX 300 spectrometer at 300 MHz for 1H and 75.5 MHz for
13C, using CDCl3 and [D6]DMSO (with TMS as the inter-
nal standard) as solvents. Mass spectra were recorded on a
Q-TOF Premier spectrometer, IR spectra on a Perkin-Elmer
Spectrum BX FTIR spectrophotometer. Microanalyses were
performed on a Perkin-Elmer CHN analyser 2400 II.
(S)-Pyroglutamic acid (1), di-tert-butoxy-bis(dimethyl-
amino)methane (Bredereckꢀs reagent), and amines 5a – l
are commercially available (Sigma Aldrich). Di-tert-butyl
(2S,4E)-4-[(dimethylamino)methylidene]-5-oxopyrrolidine-
1,2-dicarboxylate (4) was prepared from 1 following the
literature procedures [5c, 10, 11].
(1H, ddd, J = 1.3, 3.5, 15.2 Hz, 3-Ha), 3.06 (1H, ddd, J = 1.3,
10.6, 15.2 Hz, 3-Hb), 4.51 (1H, dd, J = 3.7, 10.6 Hz, 2-H),
6.90 – 7.05 (3H, m, o, p-C6H5), 7.17 (1H, br d, J = 12.3 Hz,
4ꢀ-H), 7.24 – 7.35 (2H, m, m-C6H5), 9.95 (1H, d, J = 12.3 Hz,
NH). – C21H28N2O5 (388.5): calcd. C 64.93, H 7.27, N 7.21;
found C 65.11, H 7.48, N 7.44.
Di-tert-butyl (2S,4Z)-4-[(3-methylanilino)methylidene]-
5-oxopyrrolidine-1,2-dicarboxylate (6ꢀb) and its minor
(4E)-isomer 6b
Compound 6ꢀb was prepared from 4 and 3-methylaniline
hydrochloride (5b). Yield: 260 mg (65 %) of a pale-beige
20
solid. – M. p. 155 – 157 ◦C; 6b : 6ꢀb = 21 : 79. – [α] +17.4
589
(c = 0.48, CH2Cl2). – IR (KBr): ν = 3464, 3318, 2979,
2933, 1756, 1686, 1632, 1599, 1368, 1321, 1246, 1231,
1155, 1001, 1155, 781 cm−1. – 1H-NMR (CDCl3), major
Parallel stirring and filtrations were carried out on a
Mettler-Toledo Bohdan MiniBlockTM Compact Shaking and
Washing Station and Vacuum Collection Base (12 positions,
Vortex stirring, 400 r. p. m. in all cases).
t
(Z)-isomer 6ꢀb: δ = 1.48 and 1.54 (18H, 2s, 1 : 1, 2 × -Bu),
2.31 (3H, s, Me), 2.60 (1H, ddd, J = 1.2, 3.6, 15.2 Hz, 3-
Ha), 3.06 (1H, ddd, J = 1.2, 10.6, 15.2 Hz, 3-Hb), 4.50 (1H,
dd, J = 3.6, 10.6 Hz, 2-H), 6.69 – 6.85 (3H, m, o, p-C6H4),
7.12 – 7.20 (1H, m, m-C6H4), 7.17 (1H, br d, J = 12.2 Hz, 4ꢀ-
H), 9.89 (1H, d, J = 12.2 Hz, NH); minor (E)-isomer 6b: δ =
2.32 (3H, s, Me), 4.55 (1H, dd, J = 3.4, 10.7 Hz, 2-H), 6.14
(1H, broad signal, NH), 7.79 (1H, br d, J = 13.5 Hz, 4ꢀ-H). –
C22H30N2O5 (402.5): calcd. C 65.65, H 7.51, N 6.96; found
C 65.81, H 7.72, N 7.17.
Parallel solution-phase synthesis of N(4ꢀ)-substituted
di-tert-butyl (2S)-4-aminomethylidene-5-oxopyrrolidine-
1,2-dicarboxylates 6/6ꢀa – l
The MiniBlockTM was assembled with 12 fritted vessels,
and the frits were wetted with ethanol (0.5 mL each). A stock
solution of enaminone 4 (0.25 M in ethanol, 12 × 4 mL,
12 × 1 mmol) was added followed by addition of aqueous
solutions of amines 5a – l hydrochlorides∗ (0.25 M in water,
12 × 5 mL, 12 × 1.2 mmol). The MiniBlockTM was closed
and the reaction mixtures were stirred at 20 ◦C for 24 h. The
precipitates were collected by filtration, washed with water
(12×3 mL), and dried in vacuo at r. t. over P4O10 for 24 h to
give 6/6ꢀa – l.
Di-tert-butyl (2S,4Z)-4-[(4-methylanilino)methylidene]-
5-oxopyrrolidine-1,2-dicarboxylate (6ꢀc) and its minor
(4E)-isomer 6c
Compound 6ꢀc was prepared from 4 and 4-methylaniline
hydrochloride (5c). Yield: 334 mg (83 %) of a pale-beige
The following compounds were prepared in this manner:
20
solid. – M. p. 163 – 170 ◦C; 6c : 6ꢀc = 17 : 83. – [α] +21.5
589
(c = 0.40, CH2Cl2). – IR (KBr): ν = 3454, 3285, 2980, 2930,
Di-tert-butyl (2S,4E)-4-anilinomethylidene-5-oxopyrrolid-
ine-1,2-dicarboxylate (6a) and its minor (4Z)-isomer 6ꢀa
1761, 1710, 1684, 1641, 1524, 1454, 1366, 1307, 1233,
1
1153, 999, 962, 870, 810, 774 cm−1. – H-NMR (CDCl3t),
major (Z)-isomer 6ꢀc: δ = 1.48 and 1.54 (18H, 2s, 1 : 1, 2× -
Bu), 2.28 (3H, s, Me), 2.60 (1H, ddd, J = 1.2, 3.7, 15.1 Hz,
3-Ha), 3.05 (1H, ddd, J = 1.2, 10.6, 15.1 Hz, 3-Hb), 4.50
(1H, dd, J = 3.7, 10.6 Hz, 2-H), 6.83 (2H, br d, J = 8.3 Hz,
m-C6H4), 7.08 (2H, br d, J = 8.3 Hz, o-C6H4), 7.13 (1H, br
Compound 6a was prepared from 4 and aniline hy-
drochloride (5a). Yield: 365 mg (90 %) of a pale-beige
∗In the case of anilines 5i, j, the solid-free nitroanilines 5i
and 5j were added to ethanolic solutions of 4, followed by addition
of 0.25 M aq. HCl.
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d, J = 12.3 Hz, 4ꢀ-H), 9.90 (1H, d, J = 12.3 Hz, NH); minor 2s, 1 : 1, 2 × -Bu), 1.58 (0.7 H, s, /3H2O), 2.61 (1H, ddd,
(E)-isomer 6c: δ = 2.29 (3H, s, Me), 4.55 (1H, dd, J = 3.6, J = 1.3, 3.6, 15.3 Hz, 3-Ha), 3.06 (1H, ddd, J = 1.3, 10.6,
10.6 Hz, 2-H), 6.09 (1H, broad signal, NH), 6.83 (2H, br d, 15.3 Hz, 3-Hb), 3.79 (3H, s, OMe), 4.51 (1H, dd, J = 3.6,
J = 8.3 Hz, m-C6H4), 7.76 (1H, br d, J = 13.6 Hz, 4ꢀ-H). – 10.6 Hz, 2-H), 6.46 (1H, br t, J = 2.2 Hz, o-C6H4), 6.52 (1H,
C22H30N2O5 (402.5): calcd. C 65.65, H 7.51, N 6.96; found d, J = 8.1 Hz, p-C6H4), 6.53 (1H, d, J = 8.1 Hz, o-C6H4),
t
1
C 65.73, H 7.72, N 7.28.
7.14 (1H, dt, J = 1.3, 12.3 Hz, 4ꢀ-H), 7.17 (1H, t, J = 8.1 Hz,
m-C6H4), 9.92 (1H, d, J = 12.3 Hz, NH); minor (E)isomer
6f: δ = 3.80 (3H, s, OMe), 6.09 (1H, br d, J = 13.5 Hz, NH),
Di-tert-butyl (2S,4E)-4-[(3-hydroxyanilino)methylidene]-
5-oxopyrrolidine-1,2-dicarboxylate (6d)
7.76 (1H, br d, J = 13.5 Hz, 4ꢀ-H). – C22H30N2O6 · /3H2O
1
(424.5): calcd. C 62.25, H 7.28, N 6.60; found C 62.35,
H 7.34, N 6.58.
Compound 6d was prepared from 4 and 3-hydroxyaniline
hydrochloride (5d). Yield: 251 mg (62 %) of a pale-grey
solid. – M. p. 180 – 181 ◦C; 6d : 6ꢀd = 100 : 0. – [α]
+2.0
20
Di-tert-butyl (2S,4Z)-4-[(3-bromoanilino)methylidene]-
5-oxopyrrolidine-1,2-dicarboxylate (6ꢀg) and its minor
(4E)-isomer 6g
589
(c = 0.49, EtOH). – IR (KBr): ν = 3383, 3307, 2978,
1757, 1709, 1688, 1634, 1612, 1500, 1460, 1392, 1369,
1346, 1305, 1240, 1156, 979, 959, 779 cm−1. – 1H-NMR
Compound 6ꢀg was prepared from 4 and 3-bromoaniline
hydrochloride (5g). Yield: 341 mg (73 %) of a pale-grey
t
([D6]DMSO): δ = 1.42 and 1.44 (18H, 2s, 1 : 1, 2 × -Bu),
2.53 (1H, ddd, J = 1.9, 3.4, 16.4 Hz, 3-Ha), 2.99 (1H, ddd,
J = 1.9, 10.7, 16.4 Hz, 3-Hb), 4.52 (1H, dd, J = 3.4, 10.7 Hz,
2-H), 6.36 (1H, dd, J = 1.6, 7.9 Hz, o-C6H4), 6.49 – 6.57 (2H,
m, o,m-C6H4), 7.06 (1H, t, J = 8.0 Hz, m-C6H4), 7.50 (1H,
br d, J = 13.1 Hz, 4ꢀ-H), 8.89 (1H, d, J = 13.1 Hz, NH), OH
exchanged. – C21H28N2O6 (404.5): calcd. C 62.36, H 6.98,
N 6.93; found C 62.62, H 7.22, N 6.92.
20
solid. – M. p. 163 – 166 ◦C; 6g : 6ꢀg = 15 : 85. – [α] +29.0
589
(c = 1.00, CH2Cl2). – IR (KBr): ν = 3447, 3295, 3260, 2979,
2933, 1763, 1734, 1716, 1686, 1638, 1594, 1475, 1368,
1312, 1236, 1223, 1154, 964, 899, 964, 773, 680 cm−1. –
1H-NMR (CDCl3), major (Z)-isomer 6ꢀg: δ = 1.48 and 1.54
t
(18H, 2s, 1 : 1, 2× -Bu), 2.61 (1H, ddd, J = 1.4, 3.5, 15.4 Hz,
3-Ha), 3.06 (1H, ddd, J = 1.4, 10.5, 15.4 Hz, 3-Hb), 4.51
(1H, dd, J = 3.5, 10.5 Hz, 2-H), 6.82 (1H, br dt, J = 1.8,
7.4 Hz, o-C6H4), 7.05 – 7.16 (4H, m, 3H of C6H4 and 4ꢀ-
H), 9.94 (1H, d, J = 12.0 Hz, NH); minor (E)-isomer 6g:
δ = 6.24 (1H, br d, J = 13.3 Hz, NH), 7.70 (1H, br d, J =
13.3 Hz, 4ꢀ-H). – C21H27BrN2O5 (467.4): calcd. C 53.97,
H 5.82, N 5.99; found C 54.01, H 5.95, N 6.01.
Di-tert-butyl (2S,4E)-4-[(4-hydroxyanilino)methylidene]-
5-oxopyrrolidine-1,2-dicarboxylate (6e)
Compound 6e was prepared from 4 and 4-hydroxyaniline
hydrochloride (5e). Yield: 279 mg (69 %) of a pale-grey
◦
20
solid. – M. p. 167 – 168 C; 6e : 6ꢀe = 100 : 0. – [α]
−2.1
589
(c = 0.34, EtOH). – IR (KBr): ν = 3402, 3321, 2978, 2935,
1724, 1695, 1634, 1519, 1433, 1391, 1369, 1321, 1225,
1150, 1005, 962, 822, 791, 745, 673 cm−1. – 1H-NMR
Di-tert-butyl (2S,4E)-4-[(4-bromoanilino)methylidene]-
5-oxopyrrolidine-1,2-dicarboxylate (6h) and its minor
(4Z)-isomer 6ꢀh
t
([D6]DMSO): δ = 1.42 and 1.44 (18H, 2s, 1 : 1, 2 × -Bu),
Compound 6ꢀh was prepared from 4 and 4-bromoaniline
hydrochloride (5h). Yield: 369 mg (79 %) of a pale-grey
2.48 (1H, ddd, J = 1.8, 3.5, 16.1 Hz, 3-Ha), 2.96 (1H, ddd, J =
1.8, 10.7, 16.1 Hz, 3-Hb), 4.51 (1H, dd, J = 3.5, 10.8 Hz, 2-
H), 6.70 (2H, d, J = 8.8 Hz, o-C6H4), 6.95 (2H, d, J = 8.8 Hz,
m-C6H4), 7.47 (1H, br d, J = 13.4 Hz, 4ꢀ-H), 8.77 (1H, d, J =
13.4 Hz, NH), OH exchanged. – C21H28N2O6 (404.5): calcd.
C 62.36, H 6.98, N 6.93; found C 62.66, H 7.21, N 7.09.
20
solid. – M. p. 175 – 177 ◦C; 6h : 6ꢀh = 85 : 15. – [α] −17.4
589
(c = 0.35, CH2Cl2). – IR (KBr): ν = 3264, 2980, 2934, 1759,
1725, 1687, 1638, 1588, 1485, 1454, 1368, 1312, 1231,
1152, 999, 960, 820, 775 cm−1. – 1H-NMR (CDCl3), ma-
t
jor(E)isomer 6h: δ = 1.47 and 1.52 (18H, 2s, 1 : 1, 2× -Bu),
2.55 (1H, ddd, J = 2.1, 3.5, 16.1 Hz, 3-Ha), 2.99 (1H, ddd,
J = 2.1, 10.6, 16.1 Hz, 3-Hb), 4.53 (1H, dd, J = 3.5, 10.6 Hz,
2-H), 6.42 (1H, d, J = 13.4 Hz, NH), 6.87 (2H, d, J = 8.8 Hz,
o-C6H4), 7.39 (2H, d, J = 8.8 Hz, m-C6H4), 7.68 (1H, dt,
Di-tert-butyl (2S,4Z)-4-[(3-methoxyanilino)methylidene]-
5-oxopyrrolidine-1,2-dicarboxylate (6ꢀf) and its minor
(4E)-isomer 6f
Compound 6ꢀf was prepared from 4 and 3-methoxyaniline J = 2.1, 13.4 Hz, 4ꢀ-H); minor (Z)isomer 6ꢀh: δ = 1.53 (9H,
t
hydrochloride (5◦f). Yield: 304 mg (73 %) of a grey solid. – s, -Bu), 2.60 (1H, ddd, J = 1.4, 3.5, 15.4 Hz, 3-Ha), 3.05
M. p. 151 – 156 C; 6f : 6ꢀf = 16 : 84. – [α]
+19.5 (c = (1H, ddd, J = 1.4, 10.5, 15.4 Hz, 3-Hb), 4.51 (1H, dd, J =
20
589
1.00, CH2Cl2). – IR (KBr): ν = 3453, 3251, 3127, 2978, 3.5, 10.5 Hz, 2-H), 6.80 (2H, br d, J = 8.8 Hz, o-C6H4), 7.09
2934, 1761, 1733, 1682, 1637, 1593, 1537, 1497, 1481, (1H, br d, J = 12.2 Hz, 4ꢀ-H), 7.37 (2H, br d, J = 8.8 Hz, m-
1456, 1391, 1368, 1310, 1286, 1244, 1223, 1196, 1155, C6H4; 9.94 (1H, br d, J = 12.2 Hz, NH). – C21H27BrN2O5
1146, 1047, 997, 964, 929, 842, 768, 688 cm−1. – 1H-NMR (467.4): calcd. C 53.97, H 5.82, N 5.99; found C 54.18,
(CDCl3), major (Z)-isomer 6ꢀf: δ = 1.48 and 1.54 (18H, H 5.96, N 6.00.
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J. Svete et al. · (2S,4E)-4-(Arylaminomethylidene)pyroglutamic Acids
817
Di-tert-butyl (2S,4E)-4-[(3-nitroanilino)methylidene]-
5-oxopyrrolidine-1,2-dicarboxylate (6i)
2.42 (1H, ddd, J = 2.0, 3.6, 15.4 Hz, 3-Ha), 2.87 (1H, ddd, J =
2.0, 10.6, 15.4 Hz, 3-Hb), 3.96 (2H, d, J = 5.5 Hz, NHCH2),
4.23 (2H, q, J = 7.1 Hz, CH2CH3), 4.40 – 4.52 (1H, broad
signal, NH), 4.49 (1H, dd, J = 3.6, 10.6 Hz, 2-H), 7.11 (1H,
dt, J = 2.0, 13.2 Hz, 4ꢀ-H); minor (Z)isomer 6ꢀk: δ = 3.85
(1H, dd, J = 1.1, 6.3 Hz, NHCH2), 4.20 (2H, q, J = 7.2 Hz,
CH2CH3), 4.44 (1H, dd, J = 4.0, 10.7 Hz, 2-H), 6.46 (1H,
br d, J = 12.6 Hz, 4ꢀ-H), 7.96 (1H, br dt, J = 6.3, 12.6 Hz,
NH). – C19H30N2O7 (398.5): calcd. C 57.27, H 7.59, N 7.03;
found C 57.54, H 7.78, N 7.33.
Compound 6i was prepared from 4 and 3-nitrolaniline
(5i) in the presence of one equivalent of hydrochloric acid.
Yield: 282 mg (65 %) of a yellow solid. – M. p. 149 – 152 ◦C;
20
6i : 6i = 100 : 0. – [α]
−16.0 (c = 0.50, CH2Cl2). – IR
589
(KBr): ν = 3458, 3285, 3090, 2981, 2935, 1761, 1719, 1688,
1648, 1616, 1588, 1535, 1749, 1369, 1352, 1317, 1238,
1224, 1155, 999, 966, 845, 814, 777, 737, 674 cm−1. – 1H-
t
NMR (CDCl3): δ = 1.48 and 1.51 (18H, 2s, 1 : 1, 2 × -Bu),
2.67 (1H, ddd, J = 2.3, 2.9, 16.4 Hz, 3-Ha), 3.09 (1H, ddd,
J = 2.3, 10.5, 16.4 Hz, 3-Hb), 4.56 (1H, dd, J = 3.3, 10.5 Hz,
2-H), 7.07 (2H, d, J = 9.2 Hz, o-C6H4), 7.39 (1H, br d, J =
13.0 Hz, NH), 7.71 (1H, br dt, J = 2.3, 13.0 Hz, 4ꢀ-H), 8.17
(2H, d, J = 9.2 Hz, m-C6H4). – C21H27N3O7 (433.5): calcd.
C 58.19, H 6.28, N 9.69; found C 58.34, H 6.44, N 9.73.
Di-tert-butyl (2S,4E)-4-[(3-ethoxy-3-oxopropylamino)meth-
ylidene]-5-oxopyrrolidine-1,2-dicarboxylate (6l) and its
minor (4Z)-isomer 6ꢀl
Compound 6l was prepared from 4 and ethyl β-alaninate
hydrochloride (5l). Yield: 279 mg (68 %) of a pale-yellow
◦
20
solid. – M. p. 85 – 87 C; 6l : 6ꢀl = 88 : 12. – [α]
−20.2
589
(c = 0.50, CH2Cl2). – IR (KBr): ν = 3447, 3291, 3259,
2981, 2935, 1750, 1678, 1626, 1458, 1369, 1317, 1253,
1155, 1081, 1024, 1001, 952, 848, 773 cm−1. – 1H-NMR
(CDCl3), major (E)isomer 6l: δ = 1.27 (3H, t, J = 7.1 Hz,
Di-tert-butyl (2S,4E)-4-[(4-nitroanilino)methylidene]-
5-oxopyrrolidine-1,2-dicarboxylate (6j)
Compound 6j was prepared from 4 and 4-nitrolaniline (5j)
in the presence of one equivalent of hydrochloric acid. Yield:
t
CH3CH2), 1.47 and 1.51 (18H, 2s, 1 : 1, 2× -Bu), 2.33 (1H,
◦
351 mg (81 %) of a pale-grey solid. – M. p. 169 – 170 C;
ddd, J = 1.9, 3.7, 15.3 Hz, 3-Ha), 2.56 (2H, t, J = 5.9 Hz,
CH2COOEt), 2.79 (1H, ddd, J = 1.9, 10.7, 15.3 Hz, 3-Hb),
3.46 (2H, deg q, J = 6.0 Hz, NHCH2), 4.17 (2H, q, J = 7.1 Hz,
CH2CH3), 4.46 (1H, dd, J = 3.8, 10.7 Hz, 2-H), 4.65 (1H,
deg. quintet, J = 6.4 Hz, NH), 7.17 (1H, dt, J = 1.7, 13.6 Hz,
4ꢀ-H); minor (Z)isomer 6ꢀl: δ = 2.51 (2H, t, J = 6.4 Hz,
CH2COOEt), 4.15 (2H, q, J = 7.1 Hz, CH2CH3), 4.41 (1H,
dd, J = 4.3, 10.9 Hz, 2-H), 6.56 (1H, br d, J = 12.6 Hz, 4ꢀ-H),
7.84 – 7.96 (1H, broad signal, NH). – C20H32N2O7 (412.5):
calcd. C 58.24, H 7.82, N 6.79; found C 58.35, H 8.13,
N 6.71.
20
6j : 6ꢀj = 100 : 0. – [α] −2.1 (c = 0.34, EtOH). – IR (KBr):
589
ν = 3480, 3379, 3260, 3224, 3188, 2977, 1760, 1726, 1686,
1648, 1589, 1506, 1492, 1371, 1315, 1285, 1236, 1224,
1153, 1109, 999, 965, 876, 844, 775, 753, 693 cm−1. – 1H-
t
NMR (CDCl3): δ = 1.48 and 1.52 (18H, 2s, 1 : 1, 2 × -Bu),
2.65 (1H, ddd, J = 2.2, 3.4, 16.5 Hz, 3-Ha), 3.08 (1H, ddd,
J = 2.2, 10.5, 16.5 Hz, 3-Hb), 4.56 (1H, dd, J = 3.4, 10.5 Hz,
2-H), 7.08 (2H, dt, J = 2.6, 9.1 Hz, o-C6H4), 7.18 (1H, br
d, J = 13.2 Hz, NH), 7.74 (1H, br dt, J = 2.2, 13.2 Hz,
4ꢀ-H), 8.18 (2H, dt, J = 2.6, 9.1 Hz, m-C6H4). – 1H-NMR
t
([D6]DMSO): δ = 1.54 and 1.55 (18H, 2s, 1 : 1, 2 × -Bu),
2.72 (1H, br dt, J = 2.4, 17.0 Hz, 3-Ha), 3.18 (1H, ddd, J =
2.4, 10.6, 17.0 Hz, 3-Hb), 4.68 (1H, dd, J = 3.3, 10.6 Hz, 2-
H), 7.44 (2H, br d, J = 9.2 Hz, o-C6H4), 7.79 (1H, br s, 4ꢀ-H),
8.26 (2H, br d, J = 9.2 Hz, m-C6H4), 9.62 (1H, br s, NH). –
Parallel solution-phase synthesis of (2S,4E)-4-(anilinometh-
ylidene)pyroglutamic acids 7a – c, e – j
The MiniBlockTM was assembled with 12 fritted vessels
C21H27N3O7 (433.5): calcd. C 58.19, H 6.28, N 9.69; found and charged with compounds 6/6ꢀa – l (12 × 0.5 mmol) and
C 58.12, H 6.45, N 9.62.
2M HCl-EtOAc (12 × 5 mL). The MiniBlockTM was closed
and the reaction mixtures were stirred at 20 ◦C for 12 h. The
precipitates were collected by filtration, washed with EtOAc
(4×3 mL), and dried in vacuo at r. t. with P4O10 for 24 h to
give 7a – c, e – j. Compounds 7d, k, l, which did not precipi-
tate from the reaction mixtures, were not isolated.
Di-tert-butyl (2S,4E)-4-[(2-ethoxy-2-oxoethylamino)meth-
ylidene]-5-oxopyrrolidine-1,2-dicarboxylate (6k) and its
minor (4Z)-isomer 6ꢀk
Compound 6ꢀk was prepared from 4 and ethyl glycinate
hydrochloride (5k). Yield: 188 mg (47 %) of a colourless
The following compounds were prepared in this manner:
20
solid. – M. p. 128 – 132 ◦C; 6k : 6ꢀk = 85 : 15. – [α] −20.2
589
(2S,4E)-4-(Anilinomethylidene)pyroglutamic acid
hydrochloride (7a)
(c = 1.00, CH2Cl2). – IR (KBr): ν = 3286, 2979, 2936, 1755,
1728, 1686, 1622, 1458, 1370, 1314, 1257, 1194, 1152,
1094, 1025, 989, 945, 861, 846, 778, 764, 739, 716 cm−1. –
Compound 7a was prepared from 6/6ꢀa. Yie◦ld: 49 mg
1H-NMR (CDCl3), major (E)isomer 6k: δ = 1.29 (3H, t, J = (39 %) of a light-yellow so◦lid. – M. p. 159 – 163 C (partial
t
20
7.1 Hz, CH3CH2), 1.47 and 1.51 (18H, 2s, 1 : 1, 2 × -Bu), decomposition above 125 C). – [α]
+116.3 (c = 0.52,
589
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J. Svete et al. · (2S,4E)-4-(Arylaminomethylidene)pyroglutamic Acids
MeOH). – IR (KBr): ν = 3269, 3236, 3086, 2543,2473, 1732, 1508, 1321, 1310, 1265, 1234, 1209, 1171, 1091, 827, 785,
1666, 1595, 1575, 1500, 1323, 1247, 1203, 1086, 924, 804, 691 cm−1. – 1H-NMR ([D6]DMSO): δ = 2.70 (1H, ddd,
754, 719, 687 cm−1. – 1H-NMR ([D6]DMSO): δ = 2.77 (1H, J = 2.0, 3.9, 16.5 Hz, 3-Ha), 3.05 (1H, ddd, J = 2.0, 10.0,
ddd, J = 2.1, 3.7, 16.8 Hz, 3-Ha), 3.06 (1H, ddd, J = 2.1, 9.9, 16.5 Hz, 3-Hb), 4.16 (1H, dd, J = 3.9, 10.0 Hz, 2-H), 6.66
16.7 Hz, 3-Hb), 4.19 (1H, dd, J = 3.8, 9.9 Hz, 2-H), 6.85 (2H, br d, J = 8.8 Hz, o-C6H4), 6.86 (2H, br d, J = 8.8 Hz, m-
+
(1H, br t, J = 7.3 Hz, p-C6H5), 7.05 (2H, br d, J = 7.8 Hz, C6H4), 7.29 (1H, br s, 4ꢀ-H), 8.34 (1H, br s, NH), 1-NH2
,
o-C6H5), 7.05 (2H, br dd, J = 7.3, 7.8 Hz, m-C6H5), 7.37 OH, and COOH exchanged. – C12H12N2O4 · HCl (284.7):
(1H, br d, J = 11.5 Hz, 4ꢀ-H), 8.59 (1H, d, J = 11.7 Hz, calcd. C 50.63, H 4.60, N 9.84; found C 50.24, H 4.67,
+
NH), 1-NH2 and COOH exchanged. – C12H12N2O3 · HCl N 9.54.
(268.7): calcd. C 53.64, H 4.88, N 10.43; found C 53.52,
H 4.83, N 10.15.
(2S,4E)-4-(3-Methoxyanilinomethylidene)pyroglutamic acid
hydrochloride (7f)
(2S,4E)-4-(3-Methylanilinomethylidene)pyroglutamic acid
hydrochloride (7b)
Compound 7f was prepared from 6/6ꢀf. Yield: 153 mg
(99 %) of a yellowish soli◦d. – M. p. 153 – 155 ◦C (partial
Compound 7b was prepared from 6/6ꢀb. Yield: 136 mg decomposition above 130 C). – [α]
+106.6 (c = 0.65,
20
589
(96 %) of a colourless solid. – M. p. 169 – 173 ◦C (par- MeOH). – IR (KBr): ν = 3225, 3068, 2619, 2471, 1731,
20
tial decomposition above 140 ◦C). – [α]
+104.8 (c = 1669, 1603, 1513, 1495, 1485, 1322, 1244, 1208, 1197,
589
0.65, MeOH). – IR (KBr): ν = 3269, 2920, 1738, 1665, 1159, 1088, 1050, 985, 804, 766, 720, 681 cm−1. – 1H-NMR
1616, 1508, 1309, 1264, 1219, 1171, 1108, 1091, 827, 785, ([D6]DMSO): δ = 2.75 (1H, ddd, J = 2.2, 3.8, 16.7 Hz, 3-
706 cm−1. – 1H-NMR ([D6]DMSO): δ = 2.26 (3H, s, Me), Ha), 3.05 (1H, ddd, J = 2.2, 9.9, 16.7 Hz, 3-Hb), 3.73 (3H,
2.76 (1H, ddd, J = 2.1, 3.7, 16.7 Hz, 3-Ha), 3.05 (1H, ddd, s, OMe), 4.18 (1H, dd, J = 3.8, 9.9 Hz, 2-H), 6.44 (1H, dd,
J = 2.1, 9.9, 16.7 Hz, 3-Hb), 4.19 (1H, dd, J = 3.7, 9.9 Hz, J = 2.1, 8.1 Hz, o-C6H4), 6.59 (1H, t, J = 2.1 Hz, o-C6H4),
2-H), 6.68 (1H, br d, J = 7.4 Hz, o-C6H4), 6.84 (1H, br t, 6.63 (1H, dd, J = 2.1, 8.1 Hz, p-C6H4), 7.14 (1H, t, J =
J = 8.1 Hz, p-C6H4), 6.88 (1H, br s, o-C6H4), 7.12 (1H, t, 8.1 Hz, m-C6H4), 7.33 (1H, br d, J = 12.3 Hz, 4ꢀ-H), 7.72
J = 7.7 Hz, m-C6H4), 7.37 (1H, br d, J = 8.2 Hz, 4ꢀ-H), 7.66 (2H, br s, 1-NH2+), 8.53 (1H, d, J = 12.3 Hz, NH), COOH
(2H, broad signal, 1-NH2+), 8.53 (1H, d, J = 12.0 Hz, NH), exchanged. – C13H14N2O4 · 11/4HCl (307.8): calcd. C 50.72,
COOH exchanged. – C13H14N2O3 · 11/8HCl (287.3): calcd. H 4.99, N 9.10; found C 50.77, H 5.04, N 8.81.
C 54.35, H 5.31, N 9.75; found C 54.15, H 5.39, N 9.51.
(2S,4E)-4-(3-Bromoanilinomethylidene)pyroglutamic acid
(2S,4E)-4-(4-Methylanilinomethylidene)pyroglutamic acid
(7g)
hydrochloride (7c)
Compound 7g was prepared from 6g. Yield: 152 mg
Compound 7c was prepared from 6/6ꢀc. Yield: 127 mg (87 %) of a colourless solid. – M. p. 188 – 190 C (partial
◦
(90 %) of a light-yellow solid. – M. p. 162 – 167 ◦C (par- decomposition above 140 ◦C). – [α]
+85.6 (c = 1.03,
20
589
tial decomposition above 130 ◦C). – [α] +81.6 (c = 0.91, MeOH). – IR (KBr): ν = 3267, 3233, 2707, 2635, 2471,
20
589
MeOH). – IR (KBr): ν = 3268, 3233, 3084, 3037, 2546, 1731, 1666, 1592, 1479, 1326, 1246, 1206, 1088, 985, 923,
1732, 1665, 1597, 1514, 1326, 1246, 1204, 1087, 984, 812, 888, 766, 717, 674 cm−1. – 1H-NMR ([D6]DMSO): δ = 2.73
718, 661 cm−1. – H-NMR ([D6]DMSO): δ = 2.21 (3H, s, (1H, ddd, J = 2.2, 3.7, 16.9 Hz, 3-Ha), 3.03 (1H, ddd, J = 2.2,
1
Me), 2.74 (1H, ddd, J = 2.1, 3.8, 16.7 Hz, 3-Ha), 3.04 (1H, 9.8, 16.9 Hz, 3-Hb), 4.15 (1H, dd, J = 3.7, 9.8 Hz, 2-H), 6.98
ddd, J = 2.1, 9.9, 16.7 Hz, 3-Hb), 4.17 (1H, dd, J = 3.8, (1H, br d, J = 7.8 Hz, o-C6H4), 7.04 (1H, br d, J = 8.0 Hz,
9.9 Hz, 2-H), 6.94 (2H, d, J = 8.4 Hz, o-C6H4), 7.05 (2H, br
p-C6H4), 7.16 (1H, t, J = 8.0 Hz, m-C6H4), 7.22 (1H, br
d, J = 8.4 Hz, m-C6H4), 7.33 (1H, br d, J = 10.4 Hz, 4ꢀ-H), s, o-C6H4), 7.27 (1H, br d, J = 12.3 Hz, 4ꢀ-H), 7.75 (2H,
8.47 (1H, d, J = 10.4 Hz, NH), 10.32 (1H, br s, COOH), 1- br s, 1-NH2+), 8.65 (1H, d, J = 12.3 Hz, NH), COOH ex-
+
9
NH2 exchanged. – C13H14N2O3 · 11/6HCl (288.8): calcd. changed. – C12H11BrN2O3 · /10HCl (343.9): calcd. C 41.90,
C 54.06, H 5.29, N 9.70; found C 54.15, H 5.39, N 9.51.
H 3.49, N 8.14; found C 41.94, H 3.27, N 8.11.
(2S,4E)-4-(4-Hydroxyanilinomethylidene)pyroglutamic acid
(2S,4E)-4-(4-Bromoanilinomethylidene)pyroglutamic acid
hydrochloride (7e)
(7h)
Compound 7e was prepared from 6e. Yield: 53 mg (37 %)
Compound 7h was prepared from 6h. Yield: 149 mg
of a colourless solid. – M. p. 153 – 156 ◦C (partial decompo- (86 %) of a light-yellow solid. – M. p. 170 – 174 ◦C (par-
◦
20
20
sition above 130 C). – [α]
+93.0 (c = 0.54, MeOH). – tial decomposition above 114 ◦C). – [α]
−23.6 (c =
589
589
IR (KBr): ν = 3263, 2926, 2566, 1740, 1665, 1616, 1605, 0.45, MeOH). – IR (KBr): ν = 3269, 3231, 3073, 2538,
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J. Svete et al. · (2S,4E)-4-(Arylaminomethylidene)pyroglutamic Acids
819
1730, 1665, 1587, 1489, 1325, 1244, 1204, 1086, 1075, 984, calcd. C 45.95, H 3.86, N 13.40; found C 45.95, H 3.66,
819, 718, 652 cm−1. – 1H-NMR ([D6]DMSO): δ = 2.75 N 13.32.
(1H, ddd, J = 2.2, 3.8, 16.9 Hz, 3-Ha), 3.04 (1H, ddd, J =
2.2, 9.9, 16.9 Hz, 3-Hb), 4.17 (1H, dd, J = 3.8, 9.9 Hz,
2-H), 7.02 (2H, d, J = 8.9 Hz, o-C6H4), 7.28 (1H, br d,
J = 12.7 Hz, 4ꢀ-H), 7.38 (2H, br d, J = 8.9 Hz, m-C6H4),
(2S,4E)-4-(4-Nitroanilinomethylidene)pyroglutamic acid
(7j)
Compound 7j was prepared from 6j. Yield: 137 mg (88 %)
+
8.65 (1H, d, J = 12.7 Hz, NH), 1-NH2 and COOH ex-
of a yellow solid. – M. p. 177 – 180 ◦C (partial decomposition
changed. – C12H11BrN2O3 · HCl (347.6): calcd. C 41.46,
20
above 140 ◦C). – [α] +90.6 (c = 0.63, MeOH). – IR (KBr):
589
H 3.48, N 8.06; found C 41.50, H 3.32, N 7.95.
ν = 3296, 2920, 2533, 2440, 1725, 1669, 1593, 1556, 1500,
1317, 1242, 1218, 1111, 840, 750, 686 cm−1. – 1H-NMR
([D6]DMSO): δ = 2.89 (1H, ddd, J = 2.4, 3.5, 17.3 Hz, 3-
Ha), 3.17 (1H, ddd, J = 2.4, 9.7, 17.3 Hz, 3-Hb), 4.26 (1H,
dd, J = 3.5, 9.7 Hz, 2-H), 7.29 (2H, br d, J = 9.2 Hz, o-
C6H4), 7.43 (1H, br d, J = 12.2 Hz, 4ꢀ-H), 8.01 (2H, br s,
1-NH2+), 8.17 (2H, br d, J = 9.2 Hz, m-C6H4), 9.44 (1H, d,
J = 12.2 Hz, NH), COOH exchanged. – C12H11N3O5 · HCl
(313.7): calcd. C 45.95, H 3.86, N 13.40; found C 46.26,
H 4.12, N 13.31.
(2S,4E)-4-(3-Nitroanilinomethylidene)pyroglutamic acid
(7i)
Compound 7i was prepared from 6i. Yield: 141 mg (90 %)
of a yellow solid. – M. p. 190 – 194 ◦C (partial decomposition
20
above 150 ◦C). – [α] +52.3 (c = 0.78, MeOH). – IR (KBr):
589
ν = 3233, 3072, 2615, 2524, 2445, 1728, 1669, 1621, 1602,
1532, 1483, 1447, 1347, 1328, 1244, 1206, 1087, 986, 930,
814, 796, 739, 720, 663 cm−1. – 1H-NMR ([D6]DMSO): δ =
2.79 (1H, ddd, J = 2.2, 3.7, 17.0 Hz, 3-Ha), 3.09 (1H, ddd,
J = 2.2, 9.8, 17.0 Hz, 3-Hb), 4.20 (1H, dd, J = 3.7, 9.8 Hz,
2-H), 7.37 (1H, br d, J = 12.3 Hz, 4ꢀ-H), 7.44 – 7.55 (2H, m,
Acknowledgements
We thank Boehringer Ingelheim Pharma GmbH & Co.
2H of C6H4), 7.62 – 7.69 (1H, m, 1H of C6H4), 7.84 – 7.87 KG (Biberach, Germany) for financial support. The financial
(1H, m, 1H of C6H4), 9.04 (1H, d, J = 12.3 Hz, NH), 1- support from the Slovenian Research Agency through grant
+
NH2 and COOH exchanged. – C12H11N3O5 · HCl (313.7): P1-0179 is gratefully acknowledged.
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