Synthesis of 1-arylmethyl-2-(cyanomethyl)aziridines and their ring transformation into methyl N-(2-cyanocyclopropyl)benzimidates

Article abstract of DOI:10.1021/jo060425p

1-Arylmethyl-2-(cyanomethyl)aziridines were prepared in high yields from the corresponding 2-(bromomethyl)aziridines upon treatment with potassium cyanide in DMSO. Ring opening of the aziridine moiety with N-chlorosuccinimide in CCL₄ and subseq

Full text of DOI:10.1021/jo060425p

Synthesis of 1-Arylmethyl-2-(cyanomethyl)aziridines and Their Ring
Transformation into Methyl N-(2-Cyanocyclopropyl)benzimidates
Matthias D’hooghe, Sven Mangelinckx, Evelien Persyn, Willem Van Brabandt, and
Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent UniVersity,
Coupure Links 653, B-9000 Ghent, Belgium
Norbert.Dekimpe@UGent.be
ReceiVed February 28, 2006
1-Arylmethyl-2-(cyanomethyl)aziridines were prepared in high yields from the corresponding 2-(bro-
momethyl)aziridines upon treatment with potassium cyanide in DMSO. Ring opening of the aziridine
moiety with N-chlorosuccinimide in CCl4 and subsequent treatment of the thus formed 4-chloro-3-(N-
chloro-N-(R,R-dichlorobenzyl)amino)butanenitriles with sodium methoxide in methanol resulted in novel
methyl N-(2-chloro-1-(cyanomethyl)ethyl)benzimidates, although in low yields. The latter γ-chloro nitriles
were smoothly converted into methyl N-(2-cyanocyclopropyl)benzimidates as precursors of biologically
relevant â-ACC derivatives through a 1,3-cyclization protocol by reaction with potassium tert-butoxide
in THF.
Introduction
and straightforward approach toward novel 2-(cyanomethyl)-
aziridines with high synthetic potential is described in a one-
step procedure starting from 1-arylmethyl-2-(bromomethyl)-
aziridines. The former 2-(cyanomethyl)aziridines were transformed
into biologically interesting N-(2-cyanocyclopropyl)benzimidates
as â-ACC precursors via intermediate 4-chloro-3-(N-chloro-N-
(R,R-dichlorobenzyl)amino)butanenitriles and methyl N-(2-
chloro-1-(cyanomethyl)ethyl)benzimidates, respectively. Con-
venient approaches toward â-ACC derivatives are limited due
to the push-pull substitution on the cyclopropane ring, and
therefore, an appropriate N-protecting group has to be introduced
during the synthesis. This is the first report of the use of
γ-(leaving-group)-â-aminobutanenitriles as substrates for the
synthesis of â-aminocyclopropyl nitriles via an intramolecular
1,3-cyclization protocol.
The search for new pathways toward amino nitriles as pre-
cursors of the corresponding amino acids is an important chal-
lenge in organic synthesis.1 The interesting pharmacological pro-
perties of, e.g., â- and γ-amino acids and their use in the syn-
thesis of the corresponding â- and γ-peptides have, especially
in the past decade, renewed the interest of organic chemists.2
The conformationally restricted 2-aminocyclopropanecarboxyl-
ates (â-ACC’s) comprise a peculiar class of â-amino acids with
interesting applications in peptide chemistry, hence the recent
efforts in the literature toward new and improved synthetic
approaches.3
The combination of an aziridine moiety and a nitrile group
in the same molecule results in a versatile substrate, allowing
the synthesis of a whole variety of functionalized amino nitriles
due to the reactivity of the constrained aziridine ring. However,
the synthesis of e.g., 2-(cyanomethyl)aziridines has hardly been
investigated in the literature up to now. In this report, an efficient
Results and Discussion
1-Alkyl-2-(bromomethyl)aziridines 1 are suitable synthetic
equivalents for the aziridinylmethyl cation, providing easy access
(1) (a) Groger, H. Chem. ReV. 2003, 103, 2795. (b) Enders, D.; Shilvock,
J. P. Chem. Soc. ReV. 2000, 29, 359. (c) Winkler, M.; Martinkova, L.; Knall,
A. C.; Krahulec, S.; Klempier, N. Tetrahedron 2005, 61, 4249. (d) Preiml,
M.; Honig, H.; Klempier, N. J. Mol. Catal. B: Enzymol. 2004, 29, 115.
(2) (a) Juaristi, E.; Soloshonok, V. EnantioselectiVe Synthesis of â-Amino
Acids, 2nd ed.; John Wiley & Sons: Hoboken, 2005. (b) Abele, S.; Seebach,
D. Eur. J. Org. Chem. 2000, 1. (c) Juaristi, E.; Lu¨pez-Ruiz, H. Curr. Med.
Chem. 1999, 6, 983. (d) Cole, D. C. Tetrahedron 1994, 50, 9517. (e) Fu¨lo¨p,
F. Chem. ReV. 2001, 101, 2181. (f) Trabocchi, A.; Guarna, F.; Guarna, A.
Curr. Org. Chem. 2005, 9, 1127.
(3) (a) Miller, J. A.; Nguyen, S. T. Mini-ReV. Org. Chem. 2005, 2, 39.
(b) Mangelinckx, S.; De Kimpe, N. Synlett 2006, 369. (c) Su, J. T.; Qiu,
G. F.; Liang, S. C.; Hu, X. M. Synth. Commun. 2005, 35, 1427. (d)
Mangelinckx, S.; De Kimpe, N. Synlett 2005, 1521. (e) Mangelinckx, S.;
De Kimpe, N. Tetrahedron Lett. 2003, 44, 1771. (f) Beumer, R.; Reiser,
O. Tetrahedron 2001, 57, 6497. (g) Beumer, R.; Bubert, C.; Cabrele, C.;
Vielhauer, O.; Pietzsch, M.; Reiser, O. J. Org. Chem. 2000, 65, 8960. (h)
Bubert, C.; Cabrele, C.; Reiser, O. Synlett 1997, 827. (i) Voigt, J.;
Noltemeyr, M.; Reiser, O. Synlett 1997, 202. (j) Reissig, H. U.; Zimmer,
R. Chem. ReV. 2003, 103, 1151.
10.1021/jo060425p CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/05/2006
4232
J. Org. Chem. 2006, 71, 4232-4236

Synthesis of 1-Arylmethyl-2-(cyanomethyl)aziridines
SCHEME 1
SCHEME 2
to 2-substituted 1-alkylaziridines upon treatment with carbon-
centered (lithium dialkylcuprates) as well as heteroatom-centered
nucleophiles.4 Further elaboration of this approach using a
different type of carbon-centered nucleophiles, i.e., cyanide,
resulted in the preparation of the corresponding new 2-(cya-
nomethyl)aziridines 2 in excellent yields upon treatment of
2-(bromomethyl)aziridines 1 with 1 equiv of potassium cyanide
in DMSO and heating at 60-70 °C for 3 h (Scheme 1). Only
one similar 2-(cyanomethyl)aziridine has been reported in the
literature, i.e., 1-tert-butyl-2-(cyanomethyl)aziridine, prepared
from 4-tert-butylamino-3-hydroxybutyronitrile upon mesylation
and treatment with a base, although the reaction mixture
contained only 10% of the desired aziridine besides two
elimination products.5 The present methodology offers a very
efficient and convenient alternative for the preparation of a
variety of 2-(cyanomethyl)aziridines as valuable substrates for
the synthesis of â- and γ-amino nitriles with potential applica-
tions in medicinal chemistry. Other examples of 2-(cyano-
methyl)aziridines (e.g., with a rather complex 1- or 2-substituent
in their structure) are scarce in the literature,6 and no general
synthetic approach has been available to date. In one case, a
2-(iodomethyl) substituent was transformed into a 2-(cyano-
methyl) group in a complex 1,2,3-trisubstituted aziridine toward
the synthesis of biologically relevant aziridinomitosenes.6b
2-(Cyanomethyl)aziridines 2 constitute versatile substrates for
further elaboration due to the presence of the constrained
aziridine moiety. To evaluate ring-opening reactions toward
valuable amino nitriles, the reactivity of aziridines 2 with regard
to N-chlorosuccinimide (NCS) was investigated. Activation of
the aziridine ring by means of an electrophilic chlorine delivered
by NCS followed by ring opening of the resulting N-chloro-
aziridinium intermediate 3 by a nucleophilic chloride (derived
from in situ liberated chlorine gas from NCS) would give rise
to the corresponding 3-amino-4-chlorobutanenitriles 4 (Scheme
2). Alternatively, formation of N-chloroamines 4 can be the
result of a radical-mediated ring-opening process instead of
nucleophilic ring opening of aziridinium salts 3. Treatment of
2-(cyanomethyl)aziridines 2 with 2 equiv of NCS in refluxing
CCl4 did not always give reproducible results, as sometimes a
partial conversion was observed, whereas in other cases using
exactly the same reaction conditions all the starting material
was consumed (Scheme 2). Furthermore, a set of two experi-
ments was performed simultaneously using 2 equiv of NCS in
refluxing CCl4, and in one of them a catalytic amount of
SCHEME 3
potassium iodide (0.1 equiv) was added to see whether iodide
could promote this conversion. However, addition of potassium
iodide only resulted in a decrease of reactivity when compared
to the experiment without potassium iodide, and substantial
amounts of the starting material were recovered (29-33%).
Presumably, this can be explained considering a halophilic attack
of iodide onto the electrophilic N-chloro atom of the aziridinium
intermediates. An increase in the amount of reagent (2.5, 3, 3.5,
and 5 equiv of NCS) usually resulted in higher conversion rates
(>25%). Attempts to purify amino nitriles 4 by means of column
chromatography for complete characterization failed due to the
unstable nature of these compounds. The use of NCS for the
N-chlorination of N-benzyl-N-butylamine in pentane toward the
corresponding N-chloroamine has been described previously.7
Surprisingly, after treatment of aziridines 2 with an excess
of 5 equiv of NCS in CCl4 and heating under reflux for 3 days,
the substrate was completely consumed and the reaction mixture
contained one major product in 61-88% yield, which was
identified as 4-chloro-3-(N-chloro-N-(dichloro(aryl)methyl)-
amino)butanenitrile 5. Since the double chlorination in the
benzylic position of compounds 5 probably proceeded through
radical intermediates, benzoylperoxide (BPO) was added in
order to improve the reaction conditions. Eventually, trichlori-
nated amino nitriles 5 were obtained in optimal yields and
acceptable purity for further elaboration using 5 equiv of NCS
and 0.1 equiv of BPO after reflux for 40 h (Scheme 3). The
radical chlorination of benzylic hydrogens by NCS has recently
been reported in the literature.8 Due to the unstable nature of
N-chloro amines 5, although quite stable in carbon tetrachloride
(4) (a) D’hooghe, M.; Rottiers, M.; Kerkaert, I.; De Kimpe, N.
Tetrahedron 2005, 61, 8746. (b) D’hooghe, M.; Rottiers, M.; Jolie, R.; De
Kimpe, N. Synlett 2005, 931. (c) D’hooghe, M.; Kerkaert, I.; Rottiers, M.;
De Kimpe, N. Tetrahedron 2004, 60, 3637. (d) D’hooghe, M.; Waterinckx,
A.; Vanlangendonck, T.; De Kimpe, N. Tetrahedron 2006, 62, 2295.
(5) Gaertner, V. R. J. Org. Chem. 1970, 35, 3952.
(6) (a) Krasnova, L. B.; Hili, R. M.; Chernoloz, O. V.; Yudin, A. K.
ArkiVoc 2005, iV, 26. (b) Vedejs, E.; Naidu, B. N.; Klapars, A.; Warner, D.
L.; Li, V. S.; Na, Y.; Kohn, H. J. Am. Chem. Soc. 2003, 125, 15796. (c)
Subbaraj, A.; Rao, O. S.; Lwowski, W. J. Org. Chem. 1989, 54, 3945.
(7) Bartsch, R. A.; Cho, B. R. J. Org. Chem. 1979, 44, 145.
(8) Mavromatis, H.; Karimi, S.; Svoronos, P.; Irigoyen, P.; Locke, D.
C. Abstracts of Papers, 230th ACS National Meeting, Washington, DC,
Aug 28-Sept 1, 2005; American Chemical Society: Washington, DC, 2005.
J. Org. Chem, Vol. 71, No. 11, 2006 4233

D’hooghe et al.
TABLE 1. Spectroscopic Evidence for Compounds 4 and 5
SCHEME 4
solution, these compounds had to be used immediately for
further elaboration after immediate characterization by means
of NMR and IR. Distinction between amines 4 and 5 can be
made based on spectroscopic analysis (Table 1). Treatment of
the latter amines 5a-d with 2 equiv of sodium methoxide in
methanol (2 N) resulted in rather complex reaction mixtures,
although spectral analysis of these mixtures (NMR and IR)
clearly showed the presence of an imidate functionality. Despite
the low yields, the novel methyl benzimidates 6a-d were
isolated in high purity by means of column chromatography on
silica gel (Scheme 3). For imidates 6, only one stereoisomer
was obtained, which was assigned to the Z-isomer due to steric
hindrance. Imidates are useful building blocks in organic
synthesis, especially for heterocyclic compounds and as precur-
sors for biologically active amidines, hence the interest in their
preparation.9,10 Furthermore, several imidates are of interest in
agrochemistry for their fungicidal and herbicidal properties.11
In Scheme 4 a tentative proposal for the reaction mechanism
has been suggested. Treatment of aziridines 2 with an excess
of NCS affords 3-amino-4-chlorobutanenitriles 4 through ring
opening of the intermediate aziridinium salt 3 (as depicted in
Scheme 2) or via a radical reaction, followed by double
chlorination of the radical intermediates 7 at the benzylic
position (initiated by BPO) resulting in 4-chloro-3-(N-chloro-
N-(dichloro(aryl)methyl)amino)butanenitrile 5. It is clear that
further research is required for a complete understanding of the
reaction mechanism of the ring opening of aziridines by means
of NCS. Abstraction of the electrophilic N-chloro atom by
methoxide via a halophilic protocol affords imidoyl chloride 8,
which subsequently undergoes nucleophilic addition across the
imino bond by the excess of methoxide toward imidates 6
(Scheme 4).
The presence of a γ-chloro nitrile moiety in imidates 6 allows
the 1,3-intramolecular ring closure toward cyclopropyl nitriles
upon R-deprotonation with respect to the nitrile moiety using
an appropriate base and subsequent chloride expulsion. Several
reaction conditions were evaluated, such as 1 equiv of lithium
diisopropyl amide (LDA) in THF and 1.5 equiv of KOtBu in
diethyl ether, tert-butyl alcohol, and tetrahydrofuran. In the
former case (LDA), the desired cyclopropyl nitriles could be
prepared in good yields, although some minor impurities were
present in the reaction mixtures. When KOtBu was used in
tBuOH, no reaction occurred, whereas with KOtBu in Et2O a
complex reaction mixture was obtained. However, the premised
cyclization proceeded very nicely utilizing 1.5 equiv of KOtBu
in THF and reflux for 5-9 h (Scheme 5). In this way, methyl
N-(2-cyanocyclopropyl)benzimidates 10a-d were prepared for
the first time by means of an elegant 1,3-cyclization protocol
via intermediates 11 starting from 4-chlorobutanenitriles 6a-
d. The ratio of cis- and trans-isomers of compounds 10 was
(9) (a) Neilson, D. G. In The Chemistry of Amidines and Imidates; Patai,
S., Ed.; John Wiley & Sons: London, 1975; pp 385-489.(b) Saluste, C.
G.; Crumpler, S.; Furber, M.; Whitby, R. J. Tetrahedron Lett. 2004, 45,
6995. (c) Restituyo, J. A.; Comstock, L. R.; Petersen, S. G.; Stringfellow,
T.; Rajski, S. R. Org. Lett. 2003, 5, 4357.(d) Kraft, A.; Peters, L.; Powell,
H. R. Tetrahedron 2002, 58, 3499. (e) Saluste, C. G.; Whitby, R. J.; Furber,
M. Tetrahedron Lett. 2001, 42, 6191. (f) Peters, L.; Froehlich, R.; Boyd,
A. S. F.; Kraft, A. J. Org. Chem. 2001, 66, 3291. (g) Katritzky, A. R.;
Stevens, C. V.; Zhang, G.-F.; Jiang, J.; De Kimpe, N. Heterocycles 1995,
40, 231. (h) Alanine, A. I. D.; Fishwick, C. W. G. Tetrahedron Lett. 1989,
30, 4443.
(10) Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203.
(11) (a) Chene, A.; Borrod, G. Ger. Offen. 1985; Chem. Abstr. 1985,
103, 160205. (b) Wilson, J. R. H. Brit. UK Pat. Appl. 1990; Chem. Abstr.
1991, 114, 143411. (c) Gerusz, V.; Mansfield, D. J.; Perez, J.; Vors, J.-P.
Eur. Pat. Appl., 2002; Chem. Abstr. 2002, 136, 183603.
1
determined by H NMR and GC analysis. These constrained
carbocycles 10 can be considered as precursors of biologically
relevant â-aminocyclopropanecarboxylates (â-ACC’s), which
are important building blocks in the synthesis of peptides with
improved properties and in SAR studies,12 since a few specific
examples are known regarding the enzymatic hydrolysis of
cyclopropane nitriles toward the corresponding carboxylic acids
by Rhodococcus sp.13 It is known that â-ACC’s are extremely
sensitive to ring-opening reactions and that they are only stable
4234 J. Org. Chem., Vol. 71, No. 11, 2006

Synthesis of 1-Arylmethyl-2-(cyanomethyl)aziridines
SCHEME 5
2.48-2.62 (2H, m), 3.58 and 3.65 (2H, 2d, J ) 14.9 Hz), 7.19-
7.38 and 7.59-7.62 (3H and 1H, 2m). 13C NMR (75 MHz,
CDCl3): δ 21.6, 33.3, 34.4, 60.7, 117.2, 127.0, 128.4, 129.25 and
129.32, 133.0, 136.1. IR (NaCl, cm-1): νCN ) 2253. MS (70 eV):
m/z 207/9 (M+ + 1; 100); 125/7 (78). Anal. Calcd for C11H11-
ClN2: C, 63.93; H, 5.36; N, 13.55. Found: C, 64.15; H, 5.53; N,
13.71.
4-Chloro-3-(N-chloro-N-(dichloro(phenyl)methyl)amino)bu-
tanenitrile 5a. The synthesis of 4-chloro-3-(N-chloro-N-(dichloro-
(phenyl)methyl)amino)butanenitrile 5a is described as a represen-
tative example for the synthesis of butanenitriles 5. To a stirred
solution of 1-benzyl-2-(cyanomethyl)aziridine 2a (0.17 g, 1 mmol)
in CCl4 (4 mL) was added NCS (0.67 g, 5 equiv) and BPO (0.02
g, 0.1 equiv), and the resulting mixture was heated under reflux
for 40 h. Cooling of the reaction mixture at -20 °C (1 h), filtration
(succinimide), and evaporation of the solvent afforded 4-chloro-
3-(N-chloro-N-(dichloro(phenyl)methyl)amino)butanenitrile 5a. Yield
1
85%, yellow oil. H NMR (300 MHz, CDCl3): δ 2.87 and 2.91
if the amino moiety is protected by at least one electron-
withdrawing group,14 in this case an imidate functionality.
In conclusion, 1-arylmethyl-2-(cyanomethyl)aziridines have
been prepared from the corresponding 2-(bromomethyl)aziri-
dines in a very efficient and straightforward approach using
KCN in DMSO. The former aziridines are valuable substrates
for the synthesis of biologically relevant â- and γ-amino nitriles.
1-Arylmethyl-2-(cyanomethyl)aziridines were ring opened to-
ward 4-chloro-3-(N-chloro-N-(R,R-dichlorobenzyl)amino)bu-
tanenitriles in high yields utilizing NCS in CCl4, and these
reactive N-chloro amines were subsequently transformed into
methyl N-(2-chloro-1-(cyanomethyl)ethyl)benzimidates, al-
though in low yields. Furthermore, methyl N-(2-chloro-1-
(cyanomethyl)ethyl)benzimidates proved to be excellent sub-
strates for the 1,3-intramolecular ring closure by means of
KOtBu in THF toward biologically important N-(2-cyanocy-
clopropyl)benzimidates as â-ACC precursors. The net conver-
sion of this methodology concerns a ring transformation of an
aziridine into a cyclopropylamine derivative.
(2H, 2dd, J ) 16.4, 6.1, 5.4 Hz), 3.71-3.83 (2H, m), 4.46-4.53
(1H, m), 7.42-7.56 and 8.03-8.14 (5H, 2m). 13C NMR (75 MHz,
CDCl3): δ 21.7, 44.8, 60.4, 96.1, 116.6, 129.1, 131.5, 129.5, 147.1.
IR (NaCl, cm-1): νCN ) 2254. Due to the lability of compounds
5 in general, no suitable mass spectral data could be obtained.
Methyl N-(2-Chloro-1-(cyanomethyl)ethyl)-4-methylbenzimi-
date 6c. The synthesis of methyl N-(2-chloro-1-(cyanomethyl)-
ethyl)-4-methylbenzimidate 6c is described as a representative
example for the synthesis of benzimidates 6. To nitrile 5c (0.33 g,
1 mmol) was added a solution of NaOMe in MeOH (1 mL, 2 equiv,
2 N), and the resulting solution was stirred at room temperature
for 3 h. The reaction mixture was poured into water (5 mL) and
extracted with Et2O (3 × 5 mL). Drying (MgSO4), filtration of the
drying agent, and evaporation of the solvent afforded a mixture
containing methyl N-(2-chloro-1-(cyanomethyl)ethyl)-4-methyl-
benzimidate 6c, which was purified by means of column chroma-
tography (hexane/EtOAc 3/1). Yield 17%, yellow oil. Flash
1
chromatography on silica gel: hexane/EtOAc 3/1, Rf ) 0.29. H
NMR (300 MHz, CDCl3): δ 2.39 (3H, s), 2.60 and 2.62 (2H, 2dd,
J ) 16.4, 6.5, 5.2 Hz), 3.47 and 3.54 (2H, 2dd, J ) 11.0, 6.9, 6.1
Hz), 3.81-3.87 (1H, m), 3.83 (3H, s), 7.23-7.25 (4H, m). 13C NMR
(75 MHz, CDCl3): δ 21.4, 23.6, 47.1, 53.8, 56.5, 117.4, 127.5,
129.4, 128.6, 140.1, 165.3. IR (NaCl, cm-1): νCtN ) 2254, νCdN
) 1661. MS (70 eV): m/z 251/3 (M+ + 1; 100). Anal. Calcd for
C13H15ClN2O: C, 62.28; H, 6.03; N, 11.17. Found: C, 62.50; H,
6.22; N, 10.96.
Experimental Section
1-(2-Chlorobenzyl)-2-(cyanomethyl)aziridine 2d. The synthesis
of 1-(2-chlorobenzyl)-2-(cyanomethyl)aziridine 2d is described as
a representative example for the synthesis of 2-(cyanomethyl)-
aziridines 2. 1-(2-Chlorophenyl)methyl-2-(bromomethyl)aziridine
1d (1.30 g, 5 mmol) and potassium cyanide (0.33 g, 5 mmol, 1
equiv) were heated in dimethyl sulfoxide (25 mL) at 65 °C for 3 h.
Subsequently, the reaction mixture was poured into water (50 mL)
and extracted with Et2O (3 × 20 mL). The combined organic
extracts were washed with water (2 × 35 mL) and brine (35 mL).
Drying (MgSO4), filtration of the drying agent, and evaporation of
the solvent afforded 1-(2-chlorobenzyl)-2-(cyanomethyl)aziridine
2d. Yield 79%, colorless oil. Flash chromatography on silica gel:
hexane/EtOAc 3/2, Rf ) 0.35. 1H NMR (300 MHz, CDCl3): δ 1.62
(1H, d, J ) 5.6 Hz), 1.90 (1H, d, J ) 3.3 Hz), 1.88-1.93 (1H, m),
Methyl N-(2-Cyanocyclopropyl)benzimidate 10a. The synthe-
sis of methyl trans-N-(2-cyanocyclopropyl)benzimidate trans-10a
and methyl cis-N-(2-cyanocyclopropyl)benzimidate cis-10a is de-
scribed as a representative example for the synthesis of cyclopropyl
nitriles 10. To an ice-cooled solution of benzimidate 6a (0.04 g,
0.2 mmol) in dry THF (2 mL) was added KOtBu (0.04 g, 1.5 equiv),
and the resulting mixture was heated under reflux for 5 h. The
reaction mixture was poured into water (2 mL) and extracted with
Et2O (3 × 2 mL). Washing of the combined organic extracts with
brine (1 mL), drying (MgSO4), filtration of the drying agent, and
evaporation of the solvent afforded a mixture of methyl trans-N-
(2-cyanocyclopropyl)benzimidate trans-10a and methyl cis-N-(2-
cyanocyclopropyl)benzimidate cis-10a, which were separated by
preparative thin-layer chromatography (hexane/EtOAc 9/1), result-
ing in very small amounts (insufficient for 13C NMR). Methyl trans-
N-(2-cyanocyclopropyl)benzimidate trans-10a: Yellow oil. TLC
(12) (a) Paulini, K.; Reissig, H. U. Liebigs Ann. Chem. 1994, 549-554.
(b) D´ıaz, M.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1996, 7, 3465-3478.
(c) Voigt, J.; Noltemeyer, M.; Reiser, O. Synlett 1997, 202-204. (d) D´ıaz,
M.; Jime´nez, J.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1997, 8, 2465-
2471. (e) Godier-Marc, E.; Aitken, D. J.; Husson, H.-P. Tetrahedron Lett.
1997, 38, 4065-4068. (f) Hibbs, D. E.; Hursthouse, M. B.; Jones, I. G.;
Jones, W.; Abdul Malik, K. M.; North, M. Tetrahedron 1997, 53, 17417-
17424. (g) Bubert, C.; Cabrele, C.; Reiser, O. Synlett 1997, 827-829. (h)
Zorn, C.; Gnad, F.; Salmen, S.; Herpin, T.; Reiser, O. Tetrahedron Lett.
2001, 42, 7049-7053. (i) Koglin, N.; Zorn, C.; Beumer, R.; Cabrele, C.;
Bubert, C.; Sewald, N.; Reiser, O.; Beck-Stickinger, A. G. Angew. Chem.,
Int. Ed. 2003, 42, 202-205.
1
on silica gel: hexane/EtOAc 9/1, Rf ) 0.14. H NMR (300 MHz,
CDCl3): δ 1.35-1.40 (2H, m), 1.63 (1H, ddd, J ) 8.0, 7.4, 3.1
Hz), 3.38 (1H, ddd, J ) 6.5, 5.9, 3.1 Hz), 3.72 (3H, s), 7.47-7.49
(5H, m). MS (70 eV): m/z 200 (M+; 28), 199 (23), 185 (4), 173
(5), 169 (9), 160 (4), 146 (6), 132 (8), 120 (4), 105 (100), 77 (39),
51 (9). Anal. Calcd for C12H12N2O: C, 71.98; H, 6.04; N, 13.99.
Found: C, 72.17; H, 6.24; N, 13.74. Methyl cis-N-(2-cyanocyclo-
propyl)benzimidate cis-10a: Yellow oil. TLC on silica gel: hexane/
(13) (a) Cohen, M. A.; Sawden, J.; Turner, N. J. Tetrahedron Lett. 1990,
31, 7223. (b) Wang, M.-X.; Feng, G.-Q. Tetrahedron Lett. 2000, 41, 6501.
(14) Reissig, H. U. Top. Curr. Chem. 1988, 144, 73.
J. Org. Chem, Vol. 71, No. 11, 2006 4235

D’hooghe et al.
EtOAc 9/1, Rf ) 0.20. 1H NMR (300 MHz, CDCl3): δ 1.31-1.43
(2H, m), 1.59-1.66 (1H, m), 3.24 (1H, ddd, J ) 6.7, 6.7, 5.0 Hz),
3.84 (3H, s), 7.45-7.49 (5H, m). MS (70 eV): m/z 200 (M+; 29),
199 (23), 185 (4), 173 (7), 169 (10), 160 (5), 146 (7), 132 (9), 120
(5), 105 (100), 77 (40), 51 (9). Spectral data derived from the
mixture of cis- and trans-10a: 13C NMR (75 MHz, CDCl3) δ 6.9,
16.2, 16.6, 37.0, 40.1, 53.5, 53.9, 119.7, 120.8, 128.1, 128.6, 128.7,
130.1, 130.3, 164.1, 164.3. IR (NaCl, cm-1): νCtN ) 2238, νCdN
) 1661. Anal. Calcd for C12H12N2O: C, 71.98; H, 6.04; N, 13.99.
Found: C, 72.16; H, 6.20; N, 13.71.
Acknowledgment. The authors are indebted to the “Fund
for Scientific Research-Flanders (Belgium)” (F.W.O.-Vlaan-
deren) and Ghent University (GOA) for financial support.
Supporting Information Available: General information and
all spectroscopic data of compounds 2a-c, 5b-d, 6a,b,d, and 10b-
d. This material is available free of charge via the Internet at
http://pubs.acs.org.
JO060425P
4236 J. Org. Chem., Vol. 71, No. 11, 2006