Unnatural amino acids. 3*. Aziridinyl ketones from esters and amides of aziridine-2-carboxylic acids

Article abstract of DOI:10.1007/s10593-007-0028-7

A series of N-substituted amides and esters of aziridine-2-carboxylic acids have been prepared and have been subjected to deprotonation with lithium diisopropylamide. The intermediate carbanions reacted more readily with the carbonyl groups of the substrates than with methyl iodide. So, in place of the expected amides or esters of methylaziridine-2-carboxylic acids, amides or esters of 2-aziridinylcarbonylaziridine-2-carboxylic acids were isolated.

Full text of DOI:10.1007/s10593-007-0028-7

Chemistry of Heterocyclic Compounds, Vol. 43, No. 2, 2007
UNNATURAL AMINO ACIDS. 3*. AZIRIDINYL KETONES FROM ESTERS
AND AMIDES OF AZIRIDINE-2-CARBOXYLIC ACIDS
B. Shtrumfs, J. Hermane, I. Kalvinsh, and P. Trapencieris
A series of N-substituted amides and esters of aziridine-2-carboxylic acids have been prepared and have
been subjected to deprotonation with lithium diisopropylamide. The intermediate carbanions reacted
more readily with the carbonyl groups of the substrates than with methyl iodide. So, in place of the
expected amides or esters of methylaziridine-2-carboxylic acids, amides or esters of
2-aziridinylcarbonylaziridine-2-carboxylic acids were isolated.
Keywords: aziridinyl ketones, esters and amides of aziridin-2-carboxylic acids, deprotonation.
Esters and amides of aziridine-2-carboxylic acids are suitable starting materials for the
preparation of derivatives of α- and β-amino acids after opening the aziridine ring [2,3]. Unlike other esters of α-
amino acids, aziridine-2-carboxylates do not have a tendency to dimerize to form diketopiperazines. Our interest
in esters and amides of aziridine-2-carboxylic acids is connected with the study of the conditions for
deprotonation of the α-center of the aziridine ring to prepare sterically hindered cyclic unnatural α-amino acids,
required for the synthesis of different derivatives of α- and β-amino acids.
Deprotonation of esters of aziridine-2-carboxylic acid was first carried out by Seebach [4,5]. However
isolation of the reaction products was unsuccessful. Only after moving to thiol esters was isolation of the
products from the reactions with electrophiles successful [4]. In this paper [4]it was first postulated that
carbanions were configurationally stable at low temperatures. In 1997 Vedejs published a paper on lithiated
complexes of aziridines with BH3 [6]. It was shown that the increased s-character of the CH bonds in the
aziridine ring accelerated lithiation in position 2 of the aziridine ring, facilitating the reaction with electrophiles.
The stability of carbanions in a series of esters of aziridine-2-carboxylic acids has been demonstrated
recently [7, 8]. A methoxymethyl protecting group on the aziridine nitrogen atom stabilizes the intermediate
carbanion and permits the preparation of a series of 2-substituted esters of aziridine-2-carboxylic acids [8].
Alkylation of 3-substituted esters of 1-(diphenylmethyl)aziridine-2-carboxylic acids gave a mixture of
2-alkylated aziridines and diaziridinyl ketones [9].
We have studied the deprotonation of derivatives of aziridine-2-carboxylic with different substituents in
the aziridine ring to determine the limits of use of this reaction. As substituents we chose well known protecting
groups which are readily removed after the reaction was completed. We have developed a method for synthesis
of the 1-substituted dimethylamides of the aziridine-2-carboxylic acids 2a-c (scheme 1) required for this study.
__________________________________________________________________________________________
Latvian Institute of Organic Synthesis, Riga LV1006, Latvia; e-mail: boriss@asi.lv e-mail:
peteris@asi.lv. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, 220-225, February, 2007.
Original article submitted October 10, 2006
0009-3122/07/4302-0169©2007 Springer Science+Business Media, Inc.
169

Scheme 1
O
O
O
a). Boc2O, DCM,
5-20°C, 1h
Me2NH, MeOH
5-20°C, 48 h
NMe2
NMe2
OMe
b) Ph3CCl, Et3N,
Me2CO, 20°C, 12 h
N
H
N
X
N
H
1
2a,c
O
O
Me2NH, MeOH
5-20°C, 48 h
OMe
NMe2
N
N
Ph
Ph
2 a X = COOBu-t, с X = Ph3C
2b
The methyl ester of aziridine-2-carboxylic acid [10] and the dimethylamide of aziridine-2-carboxylic
acid [11] were prepared by known methods. The methyl ester of 1-benzylaziridine-2-carboxylic acid (2d)
reacted readily with dimethylamine even at low temperature to give the dimethylamide 2b in 73% yield.
However the methyl esters of 1-tert-butoxycarbonyl- and 1-tritylaziridine-2-carboxylic acids gave difficult to
separate reaction mixtures. An alternative reaction scheme was therefore used in the dimethylamide of aziridine-
2-carboxylic acid (1) as the starting material. The dimethylamides 2a and 2c prepared by this method were
readily isolated in yields of 71 and 91% and were suitable for the reactions studied.
In the initial study we carried out deprotonation of the amides 2a-c with the aim of trapping the
carbanions formed with the simple electrophile – methyl iodide – to obtain the 2-methyl-substituted compounds
3 (Scheme 2). However after addition of methyl iodide to the reaction mixture only aziridine 4c (33% yield) was
isolated. The same product 4c (58% yield) was isolated after treatment of the mixture with water.
We used the same conditions for deprotonation of the esters 2d-g. The corresponding aziridinyl ketones
4d and 4f were formed from 1-benzyl-substituted 2d and 2f. The aziridinyl ketones 4 are difficult to make by
other methods.
Scheme 2
O
O
1. LDA, THF,
-78°C, 15-60 min
2. MeI
O
O
1. LDA, THF,
-78°C, 15-60 min
2. H2O
R
R
R
N
X
N
X
N
X
N
X
4
2
3
a R = NMe2, X = COOBu-t; b R = NMe2, X = Bn; c R = NMe2, X = CPh3, d R = OMe, X = Bn,
e R = OMe, X = CPh3; f R = OBu-t, X =Bn, g R = OBu-t, X = CPh3
It should be noted that not all of these reactions gave only the aziridinyl ketones. For example, the
dimethylamide of 1-tert-butoxycarbonylaziridine-2-carboxylic acid (2a) gave a mixture of ketone 4a and another
bisaziridine, the structure of which was not established, which was difficult to separate. In the synthesis of
170

TABLE 1. 1H NMR Spectra of aziridinyl ketones 4
H2
O
O
H3
N
R
X
H4
H1
N
X
H5
Com-
pound
X
R
Chemical shifts, δ, ppm (J, Hz)
4c
CPh3
NMe2
1.44 (1H, dd, 2J = 1.6, 3Jcis = 6.6, cis-H-3); 1.91 (1H,
unresolved dd, trans-H-3); 2.05 (1H, d, J = 6.8, H-5);
2.38 (3H, s, N(CH3)2); 2.50 (1H, d, J = 6.8, H-4);
2.54 (3H, s, N(CH3)2); 2.89 (1H, dd, 3Jtrans = 2.3, 3Jcis = 6.6, H-2);
7.05-7.28 (20H, m, arom,.); 7.36-7.54 (10H, m, arom,.)
3
4d
Bn
Bn
OMe
1.75 (1H, unresolved dd, Jcis = 6.5, cis-H-3); 2.13-2.17 (1H, m,
H-5); 2.26-2.29 (1H, m, H-4); 2.37 (1H, unresolved dd,
trans-H-3); 2.59 (1H, dd, 3Jtrans = 2.7, 3Jcis = 6.5, H-2);
3.41 and 3.56 (1H and 1H, AB system, J = 13.4, C6H5CH2);
3.64 (3H, s, CH3); 3.79 and 3.95 (1H and 1H, AB system,
J = 13.6, C6H5CH2); 7.20-7.38 (10H, m, arom,.)
1.41 (9H, s, (CH3)3C-t; 1.71 (1H, dd, 2J = 1.2, 3Jcis = 6.5,
cis-H-3); 2.15-2.19 (1H, m, H-5); 2.25-2.28 (1H, m, H-4);
2.30 (1H, unresolved dd, trans-H-3); 2.52 (1H, dd, 3Jtrans = 3.0,
3Jcis = 6.5, H-2); 3.41 and 3.55 (1H and 1H, AB system, J = 13.9,
PhCH2); 3.78 and 3.96 (1H and 1H, AB system, J = 13.8, PhCH2);
7.17-7.50 (10H, m, arom,.)
4f
OBu-t
ketone 4e an inseparable reaction mixture was formed, which contained the corresponding aziridinyl ketone 4e,
the methyl 1-tritylaziridine-2-carboxylate starting material (2e) with a small amount (<5%) of the
diisopropylamide of 1-tritylaziridine-2-carboxylic acid.
The carbanions obtained from the amide 2b and the tert-butyl ester 2g (observed by the characteristic
orange-red color of the reaction mixture) captured water to form the corresponding starting materials. In its turn,
ketone 4c was formed only by raising the temperature to room temperature for 3 h with subsequent treatment
with water.
Hence, the bulky trityl substituent on the nitrogen atom decreased the reactivity of the substrates 2.
Formation of the aziridinyl ketones occurred only with the dimethylamides and not the esters of the
1-tritylaziridine-2-carboxylic acid.
In the future we shall extend the investigation of the behavior of carbanions generated from
N-substituted esters and amides of aziridine-2-carboxylic acids.
EXPERIMENTAL
1H NMR spectra of CDCl3 solutions with TMS as internal standard were recorded with a Varian
Mercury (200 MHz) spectrometer. Elemental analyses were determined with Carlo Erba EA-1108 machine.
Mass spectra were obtained with a Micromass Q-ToF micro. Melting points were recorded with a Gallenkamp
heating block and were not corrected. TLC was carried out on DC Aluflien strips with Kiesel-60 absorbent.
HPLC of compounds 2 was carried out on a Gilson chromatographic system with an Ultrasphere Si (4.6×250
mm) column with 96:4 hexane-isopropanol eluant (10 ml/min), 254 nm UV detector). Dry methylene chloride
was distilled from CaH2. Dry THF was distilled twice over sodium (the second time in the presence of
benzoquinone). Dry isopropanol was prepared by distillation twice from CaH2. Dry dimethylamine was prepared
heating an aqueous solution of dimethylamine and passing the product through dry NaOH.
171

Dimethylamide of aziridine-2-carboxylic acid (1). Absolute methanol (100 ml) was added to methyl
aziridine-2-carboxylate [10] (10.1 g, 100 mmol). The solution was cooled to 5°C and saturated with dry
dimethylamine for 20 min. The mixture obtained was stirred at room temperature for 48 h under argon. The
methanol was evaporated at low pressure and the residue was purified by chromatography on silica gel (eluant
9:1 chloroform-methanol) to give compound 1 (10.0 g, 88%), mp 85-87°C (in [14] compound 1 was prepared by
1
aziridination of the dimethylamide of acrylic acid in 40% yield). H NMR Spectrum, δ, ppm: 1.40 (1H, br. s,
NH), 1.67-1.83 (2H, m, H-3), 2.5-2.68 (1H, m, H-2), 2.95 (3H,s, N(CH3)2), 3.13 (3H,s, N(CH3)2).
Dimethylamide of 1-benzylaziridine-2-carboxylic acid (2b) [13] was obtained from methyl
1
1-benzylaziridine-2-carboxylate [12] was made analogously to amidation by method [11]. Yield 73%. H NMR
3
Spectrum, δ, ppm: 1.69 (1H, unresolved, dd, Jcis = 6.2, cis-H-3), 2.23-2.35 (2H, m, trans-H-2,3), 2.94 (3H, s,
N(CH3)2), 2.99 (3H, s, N(CH3)2), 3.50 and 3.65 (1H and 1H, AB system, J = 13.4, PhCH2), 7.2-7.43 (5H, M,
arom).
Dimethylamide of 1-(tert-butoxycarbonyl)aziridine-2-carboxylic acid (2a). Dry methylene chloride
(20 ml) was added with stirring to dimethylamide 1 (11.4 g, 100 mmol). The mixture was cooled to 5°C and
(t-BuOCO)2O) (21.8 g, 100 mmol) in dry methylene chloride (10 ml) was added over 5 min. The mixture
obtained was stirred for 1 h at room temperature under argon. Methylene chloride was evaporated at reduced
pressure. The residue was purified by chromatography on silica gel with 1:1 petroleum ether-ethyl acetate as
eluant to give compound 2a (15.2 g, 71%, oil) (the optically active analog of 2a was prepared by the Mitsunoba
method from the L-serine derivative [15]). 1H NMR Spectrum, δ, ppm, (J, Hz): 1.25 (9H, s, C(CH3)3), 2.15 (1H,
dd, 2J = 1.2, 3Jcis = 5,3, cis-H-3), 2.42 (1H, dd, 2J = 1.2, 3Jtrans = 3.1, trans-H-3), 2.79 (3H, s, N(CH3)2), 3.05 (1H
dd, 3Jtrans = 3.1, 3Jcis =5.3), 3.08 (3H, s, N(CH3)2.
Dimethylamide of 1-tritylaziridine-2-carboxylic acid (2c). Acetone (20 ml) triethylamine (7.0 ml,
50 mmol), and a solution of trityl chloride (13.9 g, 50 mmol) in acetone (10 ml) were added with stirring to the
dimethylamide 1. The mixture was stirred at room temperature for 12 h in an atmosphere of argon. The mixture
was then poured into ice water (20 ml) and extracted with ether (3×20 ml). The ether extracts were combined,
washed with water (2×20 ml) and saturated NaCl solution (20ml), dried over Na2SO4, filtered and the solvent
was removed at low pressure. The product was purified by chromatography on silica gel with 3:1 petroleum
ether-ethyl acetate as eluant to give compound 2c (16,2 g, 91%), mp 141°C (from 2:1 petroleum ether-ethyl
1
3
acetate). H NMR Spectrum, δ, ppm (J, Hz): 1.35 (1H, unresolved dd, Jcis = 6.0, cis-H-3), 1.94 (1H, dd,
3Jtrans = 2.9, 3Jcis = 6.0, H-2), 2.36 (1H, unresolved dd, trans-H-3), 2.80 (3H, s, N(CH3)2), 2.99 (3H, s, N(CH3)2),
7.15-7.34 (9H, m, arom), 7.50-7.59 (6H, m, arom). Found, %: C 80.44, H 6.79, N 7.71. Calculated for
C24H24N2O, %: C 80.87, H 6.79, N 7.86.
Esters of aziridine-2-carboxylate acid 2d-g are described in the literature. Methyl ester 2d was
obtained by method [12]. The tert-butyl esters 2f and 2g were prepared from the corresponding methyl esters 2d
and 2e and have been characterized by us previously [1].
Methyl 1-tritylaziridine-2-carboxylate (2e) was made previously by a different method, a 97% yield
being obtained by cyclization of O-methylsulfonyl derivatives of serine [16]. Triethylamine (4.5 ml, 32 mmol)
and trityl chloride (9.0 g, 32 mmol) were added with stirring at 0-5°C to a solution of methyl aziridine-
2-carboxylate (2.9 ml, 32 mmol) in acetone (40 ml). Within a minute of the dissolution of trityl chloride
precipitation of triethylammonium chloride began. The mixture was stirred for 12h and then filtered. The filtrate
was evaporated at low pressure to give compound 2e (10.0 g, 91%), m.p. 133°C (from 5:1 ether-hexane).
2
3
3
1H NMR Spectrum, δ, ppm (J, Hz): 1.41 (1H, dd, J = 1.9, Jcis =6.0, cis-H-3), 1.89 (1H, dd, Jtrans = 2.6,
3Jcis = 6.1, H-2), 2.26 (1H, dd, J = 1.9, Jtrans= 2.6, trans-H-3), 3.76 (3H, s, OCH3), 7.16-7.33 (9H, m, arom),
7.46-7.54 (6H, m, arom). Found, %: C 80.51, H 6.16, N 4.10. Calculated for C23H21NO2, %: C 80.44, H 6.16,
N 4.08.
2
3
172

Condensation of derivatives of esters and dimethylamides of aziridine-2-carboxylic acids in the
presence of lithium diisopropylamide and methyl iodide or dimethyl sulfate (general method A). A round-
bottomed flask (100 ml) was heated at 150°C for 5 h and then cooled to room temperature in a stream of argon.
Absolute THF (10 ml was placed in the flask and dry diisopropylamine (0,51 g, 5 mmol) was added. The
solution was cooled to -20°C in a stream of argon and n-BuLi (2.0 ml, 5 mmol) as a 2.5 M hexane solution was
added drop wise. The solution of lithium diisopropylamide obtained was stirred for 15 min at -20°C and then
cooled to -78°C in a stream of argon and solution of an ester r a dimethyl amide of an aziridine-2-carboxylic acid
2a-g in abs. THF (5 ml) was added drop wise. The reaction mixture was then stirred for 15-60 min at -78°C and
the mixture became orange red in color. Then methyl iodide (1.42 g, 10 mmol) (in experiments with esters of
aziridine-2-carboxylic acids) or dimethyl sulfate (1.26 g, 10 mmol) (in experiments with dimethylamides of
aziridine-2-carboxylic acids) was added to the reaction mixture. Then 1:1 H2O-TYF (10 ml) was added.
After the color had disappeared the solution was heated to room temperature, poured into ice water
(20 ml), and extracted with ether (3×20 ml). The ether extracts were combined, washed with water (2×20 ml)
and saturated NaCl solution (20 ml), dried over Na2SO4 (20 ml), filtered, and evaporated under low pressure.
The products were purified by chromatography on silica gel with petroleum ether-ethyl acetate as eluant. Only
condensation products 4 were obtained. The 1H NMR Spectra are given in the Table.
Condensation of derivatives of esters and dimethylamides of aziridine-2-carboxylic acids in the
presence of lithium diisopropylamide (general method B). A round-bottomed flask (100 ml) was heated at
150°C for 5 h and then cooled to room temperature in a stream of argon. Absolute THF (10 ml was placed in the
flask and dry diisopropylamine (0,51 g, 5 mmol) was added. The solution obtained was cooled to -20°C in a
stream of argon and n-BuLi (2.0 ml, 5 mmol) as a 2.5 M hexane solution was added drop wise. The solution of
lithium diisopropylamide formed was stirred at -20°C for 15 min and then cooled to -78°C in a stream of argon.
An ester or a dimethylamide of an aziridine-2-carboxylic acid (2a-g) (5 mmol) in absolute THF (5 ml) was then
added drop wise. The reaction mixture was then stirred for 15-60 min at -78°C, and the mixture became orange-
red in color. The 1:1 H2O-THF (10 ml) was added. After the color had disappeared the solution was raised to
room temperature, poured into ice water (20 ml), and extracted with ether (3×20 ml). The ether extracts were
,
combined, washed with water (2×20 ml) and saturated NaCl solution (20 ml), and dried over Na2SO4 filtered,
and the solvent was evaporated under reduced pressure. The condensation products were purified
chromatographically on silica gel with petroleum ether–ethyl acetate as eluant.
Dimethylamide of 1-trityl-2-(1-tritylaziridine-2-carbonyl)aziridine-2-carboxylic acid (4c) was
obtained from compound 2c (1.78 g) by either general method A or B. The reaction took 60 min. No product
was obtained by "extinguishing" the reaction mixture with water at -78°C. In a second experiment, after slowly
raising the temperature of the reaction mixture to room temperature over 3 h with subsequent "extinction" with
water, product 4c was obtained as an oil (1.10 g, 33%) by method A or (1.94 g, 58%) by method B Found:
m/z: 690.3132 [M + Na]-, C46H41N3O2. M + Na = 690.3096.
Methyl 1-benzyl-2-(1-benzylaziridine-2-carbonyl)aziridine-2-carboxylate (4d) was obtained from
compound 2d (0.96 g, 5 mmol) by either method A or B. Length of reaction 50 min. Yield 0.54 g (31%,
oil)(general method A) or 0.90 g (46%, oil) (general method B). Found: m/z: 350.1736 [M + H]- C21H22N2O3.
M + H = 350.1756
Tert-Butyl 1-benzyl-2-(1-benzylaziridine-2carbonyl)aziridine-2-carboxylate (4f) was obtained from
tert-butyl 1-tritylaziridin-2-carboxylate (2f) (1.17 g 5 mmol) by either method A or B. Reaction time 15 min.
Yield 0.82 g (42%, oil) (general method A) or 0.90 g (46%, oil) (general method B). Found, m/z: 393.2165
[M + H]- C24H28N2O3 M + H = 393.2178.
This work was carried out with financial assistance from the Latvian Council of Science
(grant LZP 01.192).
173

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