Synthesis of 1-arylmethyl-2-(2-cyanoethyl)aziridines and their rearrangement into novel 2-(aminomethyl)cyclopropanecarbonitriles

Article abstract of DOI:10.1021/jo701302a

(Chemical Equation Presented) 1-Arylmethyl-2-(bromomethyl)aziridines were transformed into novel 2-(2-cyanoethyl)aziridines upon treatment with α-lithiated trimethylsilylacetonitrile in THF in an efficient and straightforward approach. The latter aziridin

Full text of DOI:10.1021/jo701302a

Synthesis of 1-Arylmethyl-2-(2-cyanoethyl)aziridines and Their
Rearrangement into Novel
2-(Aminomethyl)cyclopropanecarbonitriles
Matthias D’hooghe, Karel Vervisch, 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 June 19, 2007
1-Arylmethyl-2-(bromomethyl)aziridines were transformed into novel 2-(2-cyanoethyl)aziridines upon
treatment with R-lithiated trimethylsilylacetonitrile in THF in an efficient and straightforward approach.
The latter aziridines underwent ring opening by reaction with benzyl bromide in acetonitrile, affording
5-amino-4-bromopentanenitriles through a regiospecific ring opening of intermediate aziridinium salts
by bromide. Further elaboration of these γ-bromonitriles resulted in the synthesis of novel 2-[N,N-bis-
(arylmethyl)aminomethyl]cyclopropanecarbonitriles in high yields by means of a 1,3-cyclization protocol
upon treatment with KOtBu in THF.
Introduction
synthesis of 2-(aminomethyl)cyclopropanecarbonitriles was
envisaged as constrained analogues of the neurotransmitter
γ-aminobutyric acid (GABA). 2-(Aminomethyl)cyclopropane-
carboxylates 1 are considered to be valuable compounds in
medicinal chemistry with a broad applicability, ranging from
GABAC (ant)agonists6 to a potential use in the treatment of
diabetes II,7 cancer,8 and hepatitis C.9 Also in peptide chemistry,
interesting applications of analogous compounds have been
reported, such as the recent discovery of a parallel sheet structure
In recent years, many efforts have been devoted to the
development of new methods for the biocatalytic conversion
of aminonitriles into the corresponding amino acids.1 Conse-
quently, the search for novel types of functionalized aminonitrile
derivatives has gained much interest and has become an
important challenge in organic synthesis.2 Furthermore, con-
formationally constrained amino acids have attracted special
attention because of their potential usefulness in medicinal
chemistry,3 although synthetic approaches toward these com-
pounds or their precursors are rather scarce. In continuation of
our interest in the preparation of 2-aminocyclopropanecarboxy-
lates (â-ACC’s)4 and 2-aminocyclopropanecarbonitriles,5 the
(5) D’hooghe, M.; Mangelinckx, S.; Persyn, E.; Van, Brabandt, W.; De
Kimpe, N. J. Org. Chem. 2006, 71, 4232.
(6) (a) Duke, R. K.; Chebib, M.; Balcar, V. J.; Allan, R. D.; Mewett, K.
N.; Johnston, G. A. R. J. Neurochem. 2000, 75, 2602. (b) Johnston, G. A.
R. Curr. Med. Chem. 2002, 2, 903. (c) Crittenden, D. L.; Park, A.; Qiu,
Jian, S.; Richard, B.; Duke, R. K.; Johnston, G. A. R.; Jordan, M. J. T.;
Chebib, M. Bioorg. Med. Chem. 2006, 14, 447. (d) Carland, J. E.;
Moorhouse, A. J.; Barry, P. H.; Johnston, G. A. R.; Chebib, M. J. Biol.
Chem. 2004, 279, 54153. (e) Carland, J. E.; Moore, A. M.; Hanrahan, J.
R.; Mewett, K. N.; Duke, R. K.; Johnston, G. A. R.; Chebib, M.
Neuropharmacology 2004, 46, 770.
(7) Foley, L. H.; Wang, P.; Dunten, P.; Ramsey, G.; Gubler, M.;
Wertheimer, S. J. Bioorg. Med. Chem. Lett. 2003, 13, 3871.
(8) Mallams, A. K.; Dasmahaptra, B.; Neustadt, B. R.; Demma, M.;
Vaccaro, H. A. U.S. Pat. Appl. US 2007015774 A1, Jan 18, 2007; Chem.
Abstr. 2007, 146, 163135.
(1) (a) Fitz, M.; Lundell, K.; Lindroos, M.; Fu¨lo¨p, F.; Kanerva, L. T.
Tetrahedron: Asymmetry 2005, 16, 3690. (b) Winkler, M.; Martinkova,
L.; Knall, A. C.; Krahulec, S.; Klempier, N. Tetrahedron 2005, 61, 4249.
(c) Preiml, M.; Honig, H.; Klempier, N. J. Mol. Catal. B: Enzym. 2004,
29, 115. (d) Preiml, M.; Hillmayer, K.; Klempier, N. Tetrahedron Lett.
2003, 44, 5057. (e) Sugai, T.; Yamazaki, T.; Yokoyama, M.; Ohta, H.
Biosci., Biotechnol., Biochem. 1997, 61, 1419.
(2) (a) Groger, H. Chem. ReV. 2003, 103, 2795. (b) Enders, D.; Shilvock,
J. P. Chem. Soc. ReV. 2000, 29, 359.
(3) (a) Miller, J. A.; Nguyen, S. T. Mini-ReV. Org. Chem. 2005, 2, 39.
(b) Reissig, H. U.; Zimmer, R. Chem. ReV. 2003, 103, 1151.
(4) (a) Mangelinckx, S.; De Kimpe, N. Synlett 2006, 369. (b) Mange-
linckx, S.; De Kimpe, N. Synlett 2005, 1521. (c) Mangelinckx, S.; De Kimpe,
N. Tetrahedron Lett. 2003, 44, 1771.
(9) Donghi, M.; Ferrara, M.; Koch, U.; Narjes, F.; Ontoria Ontoria, J.
M.; Summa, V. PCT Int. Appl. WO 2007028789 A1, Mar 15, 2007; Chem.
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10.1021/jo701302a CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/17/2007
J. Org. Chem. 2007, 72, 7329-7332
7329

D’hooghe et al.
in cyclopropane γ-peptides.10 Despite their biological relevance,
very few synthetic approaches toward 2-(aminomethyl)cyclo-
propanecarboxylic acid derivatives are available in the literature.
These methods comprise the cyclopropanation of allylic amines
by means of diazoacetates,11 the reaction of allylsulfonamides
with phenyl(alkynyl)iodonium salts,12 and the ring opening of
3-azabicyclo[3.1.0]hexan-2-one derivatives.13
SCHEME 1
silylacetonitrile with an equimolar amount of n-BuLi in THF
at 0 °C) in THF after reflux for 4 h (Scheme 1). Only by utilizing
1.5 equiv of R-lithiated trimethylsilylacetonitrile and heating
under reflux for 4 h could the reaction be driven to completion.
If fewer equivalents were used or shorter reaction times were
applied, the reaction mixture contained a certain amount of
starting material. The trimethylsilyl group was cleaved off from
the initially formed silylated aziridine intermediate during
workup by means of an aqueous NaOH solution (1 N).
1-Arylmethyl-2-(2-cyanoethyl)aziridines 3 were obtained in high
purity by means of column chromatography on silica gel. The
reactive nature of the constrained aziridine ring in 2-(2-
cyanoethyl)aziridines 3 enables the preparation of a variety of
new aminonitrile derivatives, complementary to the synthetic
usefulness of 1-arylmethyl-2-(cyanomethyl)aziridines.
It should be noted that the use of methyl or ethyl trimethylsilyl
acetate instead of trimethylsilylacetonitrile, applying either
exactly the same reaction conditions or slightly modified
conditions according to a literature procedure,18 did not result
in any reaction, and the starting material was recovered
completely each time. In the literature, only very few isolated
examples of 2-(2-alkoxycarbonylethyl)aziridines have been
reported, and no general approach is available toward these
azaheterocycles.19
Treatment of 2-(2-cyanoethyl)aziridines 3 with 1 equiv of
benzyl bromide in acetonitrile afforded novel 5-amino-4-
bromopentanenenitriles 5 in excellent yields after reflux for 5
h (Scheme 2). These δ-aminonitriles were purified by means
of column chromatography on silica gel (hexane/EtOAc 9/1)
in order to obtain analytically pure samples. In this transforma-
tion, benzyl bromide is responsible for both the activation of
the aziridine ring toward an aziridinium intermediate 4 and the
delivery of the nucleophilic bromide anion which induces ring
opening of the aziridinium ion.
In the present report, the synthesis of 2-(2-cyanoethyl)-
aziridines is disclosed as a new and versatile class of building
blocks in organic chemistry. Whereas the chemistry of 2-(cya-
nomethyl)aziridines has been studied previously for the prepara-
tion of different types of aminonitriles,5,14 the synthesis and
reactivity of their higher homologues 2-(2-cyanoethyl)aziridines
comprises an unexplored field of research, as only one similar
compound has been reported so far, i.e., 1-butyl-2-(2-cyano-
ethyl)aziridine-2-carbonitrile obtained via cycloaddition of butyl
azide with the appropriate olefin.15 In this paper, 1-arylmethyl-
2-(2-cyanoethyl)aziridines were subsequently transformed into
novel 2-[N,N-bis(arylmethyl)aminomethyl]cyclopropanecarbo-
nitriles in an efficient and straightforward approach by means
of an intramolecular 1,3-cyclization protocol of intermediate
5-amino-4-bromopentanenitriles, obtained through ring opening
with benzyl bromide. This is the first report of the use of γ-halo-
δ-aminopentanenitriles as substrates for a 3-exo-tet cyclization
toward 2-(aminomethyl)cyclopropanecarbonitriles.
Results and Discussion
1-Arylmethyl-2-(bromomethyl)aziridines 2, prepared from the
corresponding benzaldehydes in a three-step procedure,16 are
suitable synthetic equivalents for the aziridinylmethyl cation,
providing an easy access to 2-substituted 1-(arylmethyl)aziri-
dines upon treatment with carbon-centered as well as hetero-
atom-centered nucleophiles.17 Further elaboration of this ap-
proach resulted in the synthesis of 1-arylmethyl-2-(2-cyano-
ethyl)aziridines 3 as a novel class of compounds upon treatment
of 2-(bromomethyl)aziridines 2 with 1.5 equiv of R-lithiated
trimethylsilylacetonitrile (prepared by treatment of trimethyl-
(10) Qureshi, M.; Khurram, N.; Smith, M. D. Chem. Commun. 2006,
5006.
(11) (a) Bergbreiter, D. E.; Morvant, M.; Chen, B. Tetrahedron Lett.
1991, 32, 2731. (b) Paulini, K.; Reisig H. Liebigs Ann. Chem. 1991, 455.
(12) Lee, H.-Y.; Lee, Y.-H. Synlett 2001, 1656.
(13) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron: Asymmetry 1997,
8, 133.
(14) (a) D’hooghe, M.; Vervisch, K.; Van Nieuwenhove, A.; De Kimpe,
N. Tetrahedron Lett. 2007, 48, 1771. (b) D’hooghe, M.; Van Speybroeck,
V.; Van, Nieuwenhove, A.; Waroquier, M.; De Kimpe, N. J. Org. Chem.
2007, 72, 4733.
(15) Broeckx, W.; Overbergh, N.; Samyn, C.; Smets, G.; L’Abbe, G.
Tetrahedron 1971, 27, 3527.
(16) (a) De Kimpe, N.; Jolie, R.; De Smaele, D. J. Chem. Soc., Chem.
Commun. 1994, 1221. (b) De Kimpe, N.; De Smaele, D.; Szakonyi, Z. J.
Org. Chem. 1997, 62, 2448. (c) D’hooghe, M.; Waterinckx, A.; De Kimpe,
N. J. Org. Chem. 2005, 70, 227. (d) D’hooghe, M.; Rottiers, M.; Jolie, R.;
De Kimpe, N. Synlett 2005, 931.
(17) (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. (e)
D’hooghe, M.; De Kimpe, N. ARKIVOC 2008, (ix), 6.
In accordance with the previously observed reactivity of
2-(bromomethyl)-, 2-(aryloxymethyl)-, 2-(alkanoyloxymethyl)-,
and 2-(cyanomethyl)aziridines toward arylmethyl bromides in
acetonitrile,14b,20 a regiospecific ring opening of the intermediate
2-(2-cyanoethyl)aziridinium salts 4 by bromide occurred at the
(18) Gilday, J. P.; Gallucci, J. C.; Paquette, L. A. J. Org. Chem. 1989,
54, 1399.
(19) Only very few isolated examples of 2-(2-alkoxycarbonylethyl)-
aziridines have been reported: (a) Vesely, J.; Ibrahem, I.; Zhao, G.-L.; Rios,
R.; Cordova, A. Angew. Chem., Int. Ed. 2007, 46, 778. (b) Fioravanti, S.;
Pellacani, L.; Stabile, S.; Tardella, P. A.; Ballini, R. Tetrahedron 1998, 54,
6169. (c) Ho, M.; Chung, J. K. K.; Tang, N. Tetrahedron Lett. 1993, 34,
6513. (d) Gustavson, L. M.; Rao, T. N.; Jones, D. S.; Fritzberg, A. R.;
Srinivasan, A. Tetrahedron Lett. 1991, 32, 5485.
(20) (a) D’hooghe, M.; Van Brabandt, W.; De Kimpe, N. J. Org. Chem.
2004, 69, 2703. (b) D’hooghe, M.; Waterinckx, A.; Vanlangendonck, T.;
De Kimpe, N. Tetrahedron 2006, 62, 2295. (c) D’hooghe, M.; Van
Speybroeck, V.; Waroquier, M.; De Kimpe, N. Chem. Commun. 2006, 1554.
(d) D’hooghe, M.; De Kimpe, N. Synlett 2006, 2089.
7330 J. Org. Chem., Vol. 72, No. 19, 2007

Synthesis of 1-Arylmethyl-2-(2-cyanoethyl)aziridines
SCHEME 2
SCHEME 3
more hindered aziridine carbon atom, affording â-bromoamines
5 as the sole reaction products in high purity. Detailed spectral
analysis confirmed the structural identity of these novel N-(2-
bromo-4-cyanobutyl)amines 5, excluding the formation of the
corresponding regioisomers.
It should be remarked that this novel approach offers a direct
method toward a functionalized γ-bromonitrile moiety, which
is a new structural entity suitable for further elaboration and
difficult to prepare via other routes. Only one alternative
approach toward 5-amino-4-bromopentanenitriles can be found
in the literature, involving an exchange reaction of xanthates
with bromine in refluxing chlorobenzene.21
The presence of this γ-bromonitrile moiety in aminonitriles
5 allows a formal 1,3-intramolecular ring closure toward
cyclopropanecarbonitriles upon R-deprotonation with respect to
the nitrile moiety and subsequent bromide expulsion through
nucleophilic displacement. In accordance with the previously
reported 3-exo-tet ring closure of N-[2-chloro-1-(cyanomethyl)-
ethyl]benzimidates toward N-(2-cyanocyclopropyl)benzimi-
dates,5 the premised cyclization of γ-bromonitriles 5 proceeded
very nicely utilizing 1.5 equiv of KOtBu in THF at room
temperature for 5 h, affording novel 2-(aminomethyl)cyclopro-
panecarbonitriles 6 in good yields (Scheme 3). Almost no
information regarding this type of compounds can be found in
the literature,22 and no general synthetic approach toward
2-(aminomethyl)cyclopropanecarbonitriles is available to date.
These constrained carbocycles can be considered as precursors
of the corresponding biologically relevant 2-(aminomethyl)-
cyclopropanecarboxylic acids with diverse applications in
medicinal and peptide chemistry.
Based on literature data, it is generally observed that the
substituted cyclopropane carbon atoms in trans-disubstituted
cyclopropane derivatives are characterized by a downfield shift
in 13C NMR as compared to their cis isomers.5,23 Also in
2-(aminomethyl)cyclopropanecarbonitriles 6, the C2-carbon
atoms (CHCH2N) of the major isomers resonated at considerably
higher δ values (19.1-19.2 ppm, CDCl3) as compared to the
minor isomers (17.0 ppm, CDCl3), confirming the formation
of trans-2-(aminomethyl)cyclopropanecarbonitriles 6 as the
major constituents. The trans isomers of compounds 6a-e were
obtained in pure form after separation by means of column
chromatography on silica gel (hexane/EtOAc 14/1), allowing
full spectroscopic characterization. The diastereomeric ratio of
cyclopropanes 6 (cis/trans 32-35/65-68) was determined by
1
means of H NMR. This ratio appeared to be independent of
the reaction temperature, as the same values were obtained upon
treatment with 1.5 equiv of KOtBu in THF after reflux for 30
min or after stirring at 0 °C for 6 h.
In conclusion, 1-arylmethyl-2-(bromomethyl)aziridines have
been converted into 2-(2-cyanoethyl)aziridines upon treatment
with R-lithiated trimethylsilylacetonitrile in THF in an efficient
and straightforward approach. The latter novel aziridines can
serve as substrates for the preparation of a variety of aminonitrile
derivatives via elaboration of the aziridine moiety. 1-Arylmethyl-
2-(2-cyanoethyl)aziridines were further transformed into 5-amino-
4-bromopentanenitriles through a regiospecific ring opening of
intermediate aziridinium salts upon treatment with benzyl
bromide in acetonitrile. The latter γ-bromonitriles proved to be
excellent substrates for the 1,3-intramolecular ring closure
toward novel 2-(aminomethyl)cyclopropanecarbonitriles by
means of KOtBu in THF. The net conversion of this methodol-
ogy concerns a novel ring transformation of an aziridine into
an (aminomethyl)cyclopropane derivative.
(21) Barbier, F.; Pautrat, F.; Quiclet-Sire, B.; Zard, S. Z. Synlett 2002,
811.
(22) (a) Grundstrom, K.; Dahlbom, R. Acta Pharm. Suec. 1972, 9, 491.
(b) Frydman, B.; Blokhin, A. V.; Brummel, S.; Wilding, G.; Maxuitenko,
Y.; Sarkar, A.; Bhattacharya, S.; Church, D.; Reddy, V. K.; Kink, J. A.;
Marton, L. J.; Valasinas, A.; Basu, H. S. J. Med. Chem. 2003, 46, 4586.
(23) (a) Csuk, R.; Kern, A. Tetrahedron 1999, 55, 8409. (b) Theberge,
C. R.; Verbicky, A. C.; Zercher, C. K. J. Org. Chem. 1996, 61, 8792.
J. Org. Chem, Vol. 72, No. 19, 2007 7331

D’hooghe et al.
Synthesis of 2-[N,N-Bis(arylmethyl)aminomethyl]cyclopro-
panecarbonitriles 6. General procedure: To a solution of 5-[bis-
(arylmethyl)amino]-4-bromopentanenitrile 5a (2 mmol) in dry
tetrahydrofuran (15 mL) was added potassium tert-butoxide (3
mmol, 1.5 equiv) at room temperature. After being stirred for 5 h
at room temperature, the reaction mixture was poured into water
(30 mL) and extracted with diethyl ether (3 × 25 mL). The
combined organic extracts were washed with water (2 × 50 mL)
and brine (1 × 50 mL). Drying (MgSO4), filtration of the drying
agent, and removal of the solvent afforded 2-[N,N-bis(arylmethyl)-
aminomethyl]cyclopropanecarbonitrile 6 as a mixture of cis/trans
isomers. The trans isomer was isolated in pure form by means of
column chromatography on silica gel (hexane/EtOAc 14/1). trans-
2-[N,N-Bis(benzyl)aminomethyl]cyclopropanecarbonitrile trans-
Experimental Part
Synthesis of 1-Arylmethyl-2-(2-cyanoethyl)aziridines 3. Gen-
eral procedure: To an ice-cooled solution of trimethylsilylaceto-
nitrile (7.5 mmol, 1.5 equiv) in dry THF (10 mL) was added n-BuLi
(1.5 equiv, 2.5 M) via a syringe under nitrogen atmosphere, and
the resulting solution was stirred for 1 h at 0 °C. Subsequently, a
solution of 1-arylmethyl-2-(bromomethyl)aziridine 2 (5 mmol) in
THF (10 mL) was added via a syringe at 0 °C, followed by heating
under reflux for 4 h. The reaction mixture was poured into a 1 N
NaOHaq solution (25 mL) and extracted with Et2O (3 × 20 mL).
Drying (MgSO4), filtration of the drying agent, and evaporation of
the solvent afforded 1-arylmethyl-2-(2-cyanoethyl)aziridine 3, which
was purified by means of column chromatography on silica gel.
1-Benzyl-2-(2-cyanoethyl)aziridine 3a. Yellow oil. Yield: 45%.
Rf ) 0.43 (hexane/EtOAc/Et3N 40/10/1). 1H NMR (300 MHz,
CDCl3): δ 1.45-1.52 (1H, m); 1.56 (1H, d, J ) 6.1 Hz); 1.60-
1.67 (1H, m); 1.75 (1H, d, J ) 3.3 Hz); 1.83-1.94 (1H, m); 2.17
(1H, d × d × d, J ) 16.9, 7.9, 7.0 Hz); 2.26 (1H, d × d × d, J )
16.9, 7.2, 6.0 Hz); 3.22 and 3.64 (2H, 2 × d, J ) 12.8 Hz); 7.26-
7.39 (5H, m). 13C NMR (75 MHz, CDCl3): δ 15.3 (CH2), 29.0
(CH2), 34.4 (CH2), 37.5 (CH), 64.9 (CH2), 119.5 (C), 127.5 (CH),
128. 5 (CH), 128.7 (CH), 138.9 (C). IR (NaCl, cm-1): νCN ) 2246.
MS (70 eV) m/z: 187 (M+ + 1, 100). Anal. Calcd for C12H14N2:
C, 77.38; H, 7.58; N, 15.04. Found: C, 77.54; H, 7.77; N, 14.93.
Synthesis of 5-[Bis(arylmethyl)amino]-4-bromopentanenitriles
5. General procedure: To a stirred solution of 1-arylmethyl-2-(2-
cyanoethyl)aziridine 3 (5 mmol) in acetonitrile (10 mL) was added
benzyl bromide (5 mmol, 1.0 equiv), and the resulting mixture was
heated under reflux for 5 h. Evaporation of the solvent afforded
5-[bis(arylmethyl)amino]-4-bromopentanenitrile 5, which was puri-
fied by means of column chromatography on silica gel (hexane/
EtOAc 9/1) in order to obtain an analytically pure sample.
5-[Bis(benzyl)amino]-4-bromopentanenitrile 5a. Yellow oil.
Yield: 84%. Rf ) 0.24 (hexane/EtOAc 9/1). 1H NMR (300 MHz,
CDCl3): δ 1.75-1.88 (1H, m); 2.12-2.40 (3H, 2 × m); 2.78 and
2.88 (2H, 2 × d × d, J ) 13.4, 9.5, 5.4 Hz); 3.49 and 3.72 (4H,
2 × d, J ) 13.2 Hz); 3.91-3.99 (1H, m); 7.22-7.38 (10H, m).
13C NMR (75 MHz, CDCl3): δ 15.1 (CH2), 31.5 (CH2), 50.9 (CH),
59.6 (CH2), 60.1 (CH2), 119.1 (C), 127.6 (CH), 128.6 (CH), 129.2
(CH), 138.7 (C). IR (NaCl, cm-1): νCN ) 2250. MS (70 eV) m/z:
357/9 (M+ + 1, 24), 277 (100). Anal. Calcd for C19H21BrN2: C,
63.87; H, 5.92; N, 7.84. Found: C, 64.02; H, 6.05; N, 7.71.
1
6a. Colorless oil. Rf ) 0.15 (hexane/EtOAc 14/1). H NMR (300
MHz, CDCl3): δ 0.65-0.72 (1H, m); 0.82-0.95 (1H, m); 1.10-
1.28 (1H, m); 1.53-1.63 (1H, m); 2.33 and 2.38 (2H, 2 × d × d,
J ) 13.8, 6.6, 6.1 Hz); 3.60 and 3.64 (2 × 2H, 2 × d, J ) 13.6
Hz); 7.19-7.37 (10H, m). 13C NMR (75 MHz, CDCl3): δ 2.4 (CH),
13.2 (CH2), 19.2 (CH), 55.6 (CH2), 58.6 (CH2), 121.7 (C), 127.3
(CH), 128.6 (CH), 129.8 (CH), 139.3 (C). IR (NaCl, cm-1): νCN
) 2238. MS (70 eV) m/z: 277 (M+ + 1, 100). Anal. Calcd for
C19H20N2: C, 82.57; H, 7.29; N, 10.14. Found: C, 82.73; H, 7.44;
N, 10.07. cis-2-[N,N-Bis(benzyl)aminomethyl]cyclopropanecarbo-
1
nitrile cis-6a. Colorless oil. Rf ) 0.05 (hexane/EtOAc 14/1). H
NMR (300 MHz, CDCl3): δ 0.73-0.79 (1H, m); 0.83-0.90 (1H,
m); 1.10-1.17 (1H, m); 1.35-1.42 (1H, m); 2.61 and 2.77 (2H, 2
× d × d, Jgem ) 13.4, 5.6, 5.0 Hz); 3.65 and 3.72 (2 × 2H, 2 × d,
J ) 13.8 Hz); 7.21-7.42 (10H, m). 13C NMR (75 MHz, CDCl3):
δ 2.4 (CH), 13.3 (CH2), 17.0 (CH), 54.9 (CH2), 58.7 (CH2), 120.3
(C), 127.1 (CH), 128.4 (CH), 128.8 (CH), 139.5 (C). IR (NaCl,
cm-1): νCN ) 2238. MS (70 eV) m/z: 277 (M+ + 1, 100).
Acknowledgment. We are indebted to the “Fund for
Scientific Research - Flanders (Belgium)” (F.W.O.-Vlaanderen)
and to Ghent University (GOA) for financial support.
Supporting Information Available: Spectroscopic data of
compounds 3b-e, 5b-e, and 6b-e. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO701302A
7332 J. Org. Chem., Vol. 72, No. 19, 2007