Synthesis of N-protected cyano aziridines

Article abstract of DOI:10.1055/s-2004-820047

A concise and inexpensive route to 2-cyano aziridine-2-carboxylates and 2,2-dicyano aziridines is reported by reaction of the easily obtainable corresponding α,β-unsaturated nitriles with sulfonyloxycarbamates in the presence of calcium oxide.

Full text of DOI:10.1055/s-2004-820047

LETTER
1083
Synthesis of N-Protected Cyano Aziridines
Synthesis of
N
t
-Protec
e
ted Cyano
f
A
ziridin
a
es nia Fioravanti,* Alberto Morreale, Lucio Pellacani,* Paolo A. Tardella*
Dipartimento di Chimica, Università degli Studi di Roma ‘La Sapienza’, P.le Aldo Moro 2, 00185 Roma, Italy
Fax +39(064)90631; E-mail: lucio.pellacani@uniroma1.it
Received 9 February 2004
phenylsulfonyl)10 and calcium oxide gave the full conver-
sion of the intermediate alkenes into the desired 2-cyano
aziridines 2a–n in good yields and with high purity, after
only a fast filtration of crude mixtures through plugs of
silica gel.11
Abstract: A concise and inexpensive route to 2-cyano aziridine-2-
carboxylates and 2,2-dicyano aziridines is reported by reaction of
the easily obtainable corresponding a,b-unsaturated nitriles with
sulfonyloxycarbamates in the presence of calcium oxide.
Key words: aminations, Michael additions, nitriles, carbamates,
ring closure
Table 1 Aziridination of a,b-Unsaturated Nitriles
2-Cyanoaziridine and related compounds such as imexon
and ciamexon have shown carcinostatic activity and low
toxicity.1 The studies seem to assign a very important role
of the cyano group for the pharmacological activity.2 The
patent literature contains claims to numerous 2-cyano
aziridines N-substituted with esters of carboxylic acids,
acylcarboxamides, sulfonylcarboxamides, and phospho-
rylcarboxamides.3 Some of these compounds have alkyl
or phenyl substituents at position 3, and others have the
cyano group replaced by a carboxamide or a carboxylic
ester function. Recently a multi-step synthesis of N-sub-
stituted 2-cyano aziridine-2-carboxylates has been report-
ed.4
The aziridine ring5 itself is known as a versatile building
block for the synthesis of nitrogen-containing compounds
and of modified amino acids or other biologically active
compounds. The aziridine ring substituents can also play
an important role in the medical potentialities of these
compounds, modifying their chemical reactivity and in-
fluencing their toxicity, lipophilicity, and alkylating pow-
er.6 Aziridine-2-carboxylates have been used in the
construction of peptidomimetics and tested as different
enzyme inhibitors.7
Entry
1
R
2
a
b
c
d
e
f
Molar ratioa
1:2:1
Yield (%)b
Et
93
94
90
93
89
82
76
74
62
68
91
95
98
92
2
Pentyl
Me
1:2:1
3
1:2:1
4
Bu
1:2:1
5
Bn
1:2:1
6
i-Bu
i-Pr
Neopentyl
t-Bu
Cy
1:4:2c
1:6:3c
1:6:3c
1:10:8d
1:10:8d
1:2:1
7
g
h
i
8
9
10
11
12
13
14
j
Et
k
l
Pentyl
Me
1:2:1
We are currently engaged in the study of simple and effi-
cient aziridination of EWG-substituted olefins.8 Aiming
to validate a straightforward and general synthetic method
leading to substituted 2-cyano aziridine-2-carboxylates
and 2,2-dicyano aziridines, we decided to investigate
the direct conversion of (E)-2-cyano acrylates 1a–j and
a,b-unsaturated 1,1-dinitriles 1k–n into the target prod-
ucts by aza-Michael addition of N-protected O-sulfonyl
hydroxylamine derivatives.
m
n
1:2:1
Bu
1:2:1
a Substrate:CaO:NsONHCO2Et.
b After purification.
c Stirred for 6 h.
d Stirred overnight.
The reactivity was found to be influenced by steric hin-
drance of the R substituents on acrylates. Usually, the re-
action reached completion in two hours using equimolar
amounts of substrate and carbamate and a two-fold excess
of the inorganic base. As expected, increasing the steric
hindrance, longer times and higher molar ratios were re-
quired (entries 6–10), nevertheless a high stereoselectivity
was observed in all pertinent cases (entries 1–10).
The reaction results are shown in Table 1. Starting from
different aldehydes and ethyl cyanoacetate or malononi-
trile through Knoevenagel condensation,9 the addition of
ethyl nosyloxycarbamate (NsONHCO2Et, Ns = 4-nitro-
SYNLETT 2004, No. 6, pp 1083–1085
0
6.
0
5.
2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-820047; Art ID: G04104ST
© Georg Thieme Verlag Stuttgart · New York

1084
S. Fioravanti et al.
LETTER
It is noteworthy that high chemoselectivity in the amina-
tion reaction is induced by CaO even in the presence of the
cyano group, that is reported to give also the correspond-
ing oxadiazoles under homogeneous reaction condi-
tions.12
References
(1) (a) Bicker, U. W. In Immune Modulation Agents and their
Mechanisms; Fenical, R. G.; Chirigos, M. A., Eds.; Marcel
Dekker: New York and Basel, 1984, 447. (b) Iyengar, B. S.;
Dorr, R. T.; Alberts, D. S.; Hersh, E. M.; Salmon, S. E.;
Remers, W. A. J. Med. Chem. 1999, 42, 510.
Aziridines were also obtained starting from a,b-unsaturat-
ed 1,1-dinitriles 1k–n (entries 11–14), showing no differ-
ences in reactivity and yields.
(2) Iyengar, B. S.; Dorr, R. T.; Remers, W. A. J. Med. Chem.
2004, 47, 218.
(3) (a) Remers, W.; Iyengar, B. US 6476236, 2002; Chem.
Abstr. 2002, 137, 337772. (b) Lopez-Berestein, G.; Remers,
W. A.; Hersh, E. M. PCT Int. Appl. 2002041871, 2002;
Chem. Abstr. 2002, 137, 10970. (c) Kitagawa, S.; Minafuji,
M.; Yokoi, T. Jpn. Kokai Tokkyo Koho JP 61140561, 1986;
Chem. Abstr. 1987, 106, 50009. (d) Bosies, E.; Berger, H.;
Kampe, W.; Bicker, U.; Grafe, A. US 4410532, 1983; Chem.
Abstr. 1984, 100, 68151. (e) Berger, H.; Gall, R.; Kampe,
W.; Bicker, U.; Kuhn, R. Ger. Offen DE 2948832, 1981;
Chem. Abstr. 1981, 95, 115257.
In order to extend the study of the sulfonyl-activated hy-
droxycarbamate reactivity, reagents with Cbz,13 Boc,14 or
Fmoc15 groups rather than ethoxycarbonyl group were
tested in the reactions on some a,b-unsaturated nitriles 1.
Table 2 Aziridination of a,b-Unsaturated Nitriles Using Different
Sulfonyloxycarbamates
(4) Boukhris, S.; Souizi, A. Tetrahedron Lett. 2003, 44, 3259.
(5) (a) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994, 33, 599.
(b) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997,
97, 2341. (c) Stamm, H. J. Prakt. Chem. 1999, 4, 319.
(d) Atkinson, R. S. Tetrahedron 1999, 55, 1519.
(e) McCoull, W.; Davis, F. A. Synthesis 2000, 1347.
(f) Sweeney, J. B. Chem. Soc. Rev. 2002, 31, 247.
(6) (a) Goodridge, T. H.; Huntress, W. T.; Bratzell, R. P. Cancer
Chemother. Rep. 1963, 26, 341. (b) Dermer, O. C.; Ham, G.
E. Ethyleneimine and other Aziridines; Academic Press:
New York and London, 1969, 425.
(7) (a) Dauban, P.; Dodd, R. H. Tetrahedron Lett. 1998, 39,
5739. (b) Schirmeister, T.; Peric, M. Bioorg. Med. Chem.
2000, 8, 1281.
(8) (a) Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A.
Synthesis 2001, 1975. (b) Fioravanti, S.; Morreale, A.;
Pellacani, L.; Tardella, P. A. J. Org. Chem. 2002, 67, 4972.
(c) Colantoni, D.; Fioravanti, S.; Pellacani, L.; Tardella, P.
A. Org. Lett. 2004, 6, 197.
Entry
Substratea
Z
Yield (%)b
1
2
3
4
5
6
7
8
1a
1a
1a
1k
1b
1b
1b
1l
Cbz
Boc
Fmoc
Boc
Cbz
Boc
Fmoc
Boc
86
81
92
82
81
78
96
80
(9) Texier-Boullet, F.; Foucaud, A. Tetrahedron Lett. 1982, 23,
4927.
(10) Lwowski, W.; Maricich, T. J. J. Am. Chem. Soc. 1965, 87,
3630.
a Substrate:CaO:NsONHZ = 1:2:1 (molar ratio).
b After purification.
(11) Typical Experimental Procedure: All compounds were
synthesized with a Carousel Reaction Station from Radleys
Discovery Technologies (UK). The synthesis involved the
following sequential steps. To the stirred solutions of 2.0
mmol of ethyl cyanoacetate or malononitrile in CH2Cl2, 2.4
mmol of aldehyde and 1.0 g of basic Al2O3 were added.
Upon completion, reaction mixtures were filtered. To the so
obtained unsaturated nitriles in CH2Cl2, CaO and
nosyloxycarbamates were added in the amounts reported in
Table 1 and Table 2. After completion (TLC), the crude
aziridines were filtered through plugs filled with silica gel
using a 9:1 hexane/EtOAc mixture and obtained as pale
yellow oils after solvent removal. Selected spectral data of
new compounds. Compound 2a: IR (CCl4): 2253, 1761,
1731 cm–1. 1H NMR (300 MHz, CDCl3): d = 1.13 (t, J = 7.2
Hz, 3 H), 1.24 (t, J = 7.2 Hz, 3 H), 1.34 (t, J = 7.2 Hz, 3 H),
1.68–1.82 (m, 2 H), 3.08 (t, J = 6.6 Hz, 1 H), 4.09–4.23 (m,
2 H), 4.23–4.45 (m, 2 H). 13C NMR (75 MHz, CDCl3):
d = 10.4, 14.0, 14.2, 23.3, 38.6, 51.3, 63.4, 64.1, 113.3,
157.2, 162.6. GC/MS: m/z (%) = 240 (9) [M+], 114 (24), 95
(46), 94 (12), 68 (100), 67 (10). HRMS (ES Q-TOF) calcd
for C11H17N2O4 (M + H)+: 241.1188; found: 241.1200.
Compound 2k: IR (CCl4): 2253, 1756 cm–1. 1H NMR (200
MHz, CDCl3): d = 1.18 (t, J = 7.3 Hz, 3 H), 1.35 (t, J = 7.3
Hz, 3 H), 1.66–1.89 (m, 2 H), 3.19 (t, J = 6.6 Hz, 1 H), 4.22–
4.48 (m, 2 H). 13C NMR (50 MHz, CDCl3): d = 9.9, 14.0,
As shown in Table 2, different N-protected 2-cyano aziri-
dine-2-carboxylates and 2,2-dicyano aziridines were ob-
tained in high yields and with complete stereoselectivity
(entries 1–3 and 5–7).
In summary, a general procedure for the synthesis of
highly functionalized aziridines was reported. Despite
their potential use and application, only few examples of
general synthetic methods of cyano aziridines are reported
in the literature.16 This concise and inexpensive route may
be considered as an efficient protocol for a parallel syn-
thesis of a large number of different cyano aziridines.
Acknowledgment
We thank the Italian Ministero dell’Istruzione, dell’Università e
della Ricerca (MIUR) and the Università degli Studi di Roma La
Sapienza (National Project ‘Stereoselezione in Sintesi Organica.
Metodologia ed Applicazioni’) for financial support.
Synlett 2004, No. 6, 1083–1085 © Thieme Stuttgart · New York

LETTER
Synthesis of N-Protected Cyano Aziridines
1085
23.1, 25.0, 52.4, 64.9, 110.3, 110.8, 156.2. GC/MS: m/z
reactivity, see ref.13 and: Fioravanti, S.; Marchetti, F.;
Morreale, A.; Pellacani, L.; Tardella, P. A. Org. Lett. 2003,
5, 1019.
(%) = 193 (3) [M+], 121 (21), 94 (100), 93 (53), 83 (10), 68
(15), 67 (75), 66 (38), 65 (10), 56 (23), 54 (11). HRMS (ES
Q-TOF) calcd for C9H12N3O2 (M + H)+: 194.0930; found:
194.0927.
(15) 9-Fluorenylmethyl nosyloxycarbamate (NsONHFmoc) was
synthesized in 80% yield, starting from commercial 9-
fluorenylmethyl N-hydroxycarbamate (HONHFmoc) and
nosyl chloride following the standard procedure, see ref.10
(16) (a) De Kimpe, N.; Sulmon, P.; Verhé, R.; De Buyck, L.;
Schamp, N. J. Org. Chem. 1983, 48, 4320. (b) Charrier, J.;
Foucaud, A.; Person, H.; Loukakou, E. J. Org. Chem. 1983,
48, 481.
(12) Lwowski, W. In Nitrenes; Lwowski, W., Ed.; John Wiley
and Sons: New York, 1970, Chap. 6.
(13) Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella, P. A.
Eur. J. Org. Chem. 2003, 4549.
(14) (a) Banks, M. R.; Cadogan, J. I. G.; Gosney, I.; Hodgson, P.
K. G.; Langridge-Smith, P. R. R.; Millar, J. R. A.; Taylor, A.
T. J. Chem. Soc., Chem. Commun. 1995, 885. (b) N-Boc-
protected O-sulfonyl hydroxylamine showed no predictable
Synlett 2004, No. 6, 1083–1085 © Thieme Stuttgart · New York