Synthesis of 2-[(arylmethylene)amino]cyclopropanecarbonitriles via a two-step ring transformation of 2-(cyanomethyl)aziridines

Article abstract of DOI:10.1055/s-0028-1088000

Reaction of 2-(cyanomethyl)aziridines with N-bromosuccinimide in dichloromethane results in the formation of 3-[(arylmethylene) amino]-4-bromobutanenitriles in high yield. The latter α-amino-γ- bromobutanenitriles were converted into separable trans- and

Full text of DOI:10.1055/s-0028-1088000

PAPER
1105
Synthesis of 2-[(Arylmethylene)amino]cyclopropanecarbonitriles via a
Two-Step Ring Transformation of 2-(Cyanomethyl)aziridines
Synthesis of
2v
e
n
opropanecarbonitri
M
les angelinckx,1 Matthias D’hooghe, Sietske Peeters, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 22 August 2008; revised 5 December 2008
Abstract: Reaction of 2-(cyanomethyl)aziridines with N-bromo-
R
R
succinimide in dichloromethane results in the formation of 3-[(aryl-
methylene)amino]-4-bromobutanenitriles in high yield. The latter
b-amino-g-bromobutanenitriles were converted into separable
trans- and cis-2-[(arylmethylene)amino]cyclopropanecarbonitriles
through a 1,3-cyclization by reaction with potassium tert-butoxide,
thus culminating in a two-step ring transformation of 2-(cyano-
methyl)aziridines into 2-[(arylmethylene)amino]cyclopropanecar-
bonitriles.
N
CN
N
H2N COOH
CN
1 (R = H)
2 (R = Ph)
3 (α-ACC)
4 (R = H)
5 (R = Ph)
6 (R = OMe)
Key words: amino nitriles, cyclizations, 2-(cyanomethyl)aziri-
dines, carbocycles, ring opening
Figure 1
According to a literature procedure,17,18 2-(cyanometh-
yl)aziridines 8 were prepared in excellent yield upon treat-
ment of 2-(bromomethyl)aziridines 7 with 1 equivalent of
potassium cyanide in dimethyl sulfoxide and heating at
60–70 °C for 2–3 hours (Scheme 1). The N-benzhydryl-
aziridine 7f was prepared by treatment of 2,3-dibromo-
propylamine hydrobromide with (diphenylmethyl-
ene)amine, followed by reduction with sodium boro-
hydride.19
In the literature, 1-(benzylideneamino)- and 1-[(diphenyl-
methylene)amino]cyclopropanecarbonitrile (1) and (2)
have received considerable attention as synthetic precur-
sors of 1-aminocyclopropanecarboxylic acid (3) (a-
ACC),2–4 1-amino-1-(aminomethyl)cyclopropane,5 1,2-
diaminocyclobutane,6 functionalized dichloroaziridines,7
2-azetidinones,8 and, more recently, 1-aminocyclopro-
panecarbonitriles acting as cysteine protease inhibitors.9
The synthesis of the b-analogues of cyclopropanes 1 and
2, i.e. 2-(benzylideneamino)- and 2-[(diphenylmethyl-
R2
R2
R1
R1
ene)amino]cyclopropanecarbonitrile
(4)
and
(5)
KCN (1 equiv), DMSO
60–70 °C, 2–3 h
(Figure 1), has not been described so far, probably due to
the potential occurrence of cis/trans-diastereomers and
the fact that vicinally donor–acceptor-substituted cyclo-
propanes undergo rapid ring-opening reactions.10 Howev-
er, b-amino nitriles 4 and 5 are of interest as potential
precursors of b-aminocyclopropanecarboxylic acids (b-
ACCs), which are known to be useful, conformationally
constrained b-amino acid derivatives11,12 and intermedi-
ates in further synthesis.13 Furthermore, b-aminocyclo-
propanecarbonitriles 4 and 5 are closely related to N-
cyclopropylimines,14 which have found synthetic applica-
tion in the thermal15 and photochemical16 rearrangement
to 1-pyrrolines.
N
N
Br
CN
8a (R1 = H, R2 = H, 82%)
8b (R1 = H, R2 = 4-Br, 88%)
8c (R1 = H, R2 = 4-Me, 70%)
8d (R1 = H, R2 = 2-Cl, 79%)
8e (R1 = H, R2 = 4-Cl, 93%)
8f (R1 = Ph, R2 = H, 65%)
7a–f
Scheme 1
Subsequently, the 1-(arylmethyl)-2-(cyanomethyl)aziri-
dines 8 were ring opened and oxidized to the 3-[(aryl-
methylene)amino]-4-bromobutanenitriles 9 by reaction
with 1.05–1.5 equivalents of N-bromosuccinimide (NBS)
in dichloromethane under reflux (71–97% crude yield)
(Scheme 2, method A). Besides imines 9, some minor side
products resulting from hydrolysis were observed in the
reaction mixtures. Aldimines 9a–e were used as such in
the next step due to their hydrolytic instability, and no at-
tempt was made to purify these aldimines. Only the more
stable ketimine 9f was isolated in high purity by column
chromatography on silica gel. The transformation of azir-
idines 8 into imines 9 bears some analogy with the conve-
nient conversion of a-(benzylamino)-g-chloro nitriles into
Recently, the first transformation of 2-(cyanomethyl)azir-
idines into methyl N-(2-cyanocyclopropyl)benzimidates
(see the parent 6) (Figure 1) was reported,17 albeit in low
overall yield (5–10%). In the present paper, an alternative
and synthetically improved approach to 2-[(arylmethyl-
ene)amino]cyclopropanecarbonitriles 4 and 5 is de-
scribed.
SYNTHESIS 2009, No. 7, pp 1105–1112
x
x
.
x
x
.2
0
0
9
Advanced online publication: 06.03.2009
DOI: 10.1055/s-0028-1088000; Art ID: T14408SS
© Georg Thieme Verlag Stuttgart · New York

1106
S. Mangelinckx et al.
PAPER
R2
R2
R1
R1
A: NBS (1.05–1.5 equiv)
CH2Cl2, reflux, 6–14 h
or
N
hydrolysis
products
N
CN
+
CN
B: NBS (1.05 equiv)
AIBN (0.1 equiv)
CH2Cl2, reflux, 5 h
or
C: NBS (1.05 equiv)
hν, 60 W tungsten
CH2Cl2, 0 °C, 2 h
Br
9a [R1 = H, R2 = H, A: 72% (crude)]
9b [R1 = H, R2 = 4-Br, A: 97% (crude)]
9c [R1 = H, R2 = 4-Me, A: 94% (crude)]
9d [R1 = H, R2 = 2-Cl, A: 95% (crude)]
9e [R1 = H, R2 = 4-Cl, A: 71% (crude)]
9f [R1 = Ph, R2 = H, A: 61% (isolated)]
B: 61% (isolated), C: 64% (isolated)]
8a–f
1) NBS (1.05 equiv)
BHT (1.05 equiv)
CH2Cl2, reflux, 5 h
2) HCl, Et2O, 0 °C
2 N aq NaOH
EtOAc
HCl⋅HN
HN
CN
CN
Br
Br
10 (88%)
11 (100%)
Scheme 2
a-(benzylideneamino)-g-chloro nitriles via transient N- with an anion-stabilizing group at C1, a suitable protected
chloroamines using tert-butyl hypochlorite.20
amino function at C2 and a leaving group at C3 has been
studied only to a limited extent. All attempts to cyclize
tert-butyl 4-bromo-3-(dialkylamino)butanoates to tert-
butyl b-aminocyclopropanecarboxylates under basic con-
ditions have been described as unsuccessful and resulted
in the synthesis of tert-butyl 4-(dialkylamino)alk-2-
enoates via ring opening of an aziridinium bromide inter-
mediate.23 Recently, interesting results were published on
the diastereoselective synthesis of N-(diphenylmethyl-
ene)-2-[2-(phenylsulfonyl)vinyl]cyclopropylamines via
ring closure of N-(diphenylmethylene)-1-iodo-5-(phenyl-
sulfonyl)pent-3-en-2-amines in a basic medium.24 More-
over, it was reported that if the nitrogen was protected
with a single protecting group (such as tosyl, Boc or meth-
oxycarbonyl), or even together with an additional benzyl
group, basic treatment did not result in the desired cyclo-
propanes.
In order to investigate the mechanism of the transforma-
tion of aziridines 8 into imines 9 by means of NBS, the re-
action was performed under various reaction conditions.
Upon treatment of aziridine 8f with NBS (1.05 equiv) and
AIBN (0.1 equiv) in dichloromethane under reflux
(Scheme 2, method B), the conversion was complete after
five hours, and ketimine 9f was isolated in 61% yield.
More interesting was the fact that the reaction of aziridine
8f with NBS was also very efficient upon irradiation by
means of a 60-W tungsten lamp for two hours at 0 °C
(Scheme 2, method C). The formation of imines 9 could
also be accomplished upon reaction with bromine, al-
though more side products resulting from hydrolysis (e.g.,
benzaldehyde) were formed after aqueous workup. The
transformation of aziridine 8f into ketimine 9f with NBS
was inhibited in the presence of a radical inhibitor such as
2,2-diphenyl-1-picrylhydrazyl (DPPH) or 3,5-di-tert-bu-
tyl-4-hydroxytoluene (BHT). Treatment of aziridine 8f
with NBS (1.05 equiv) in dichloromethane in the presence
of BHT (1.05 equiv) under reflux afforded benzhydryl-
amine 11 in high yield after neutralization of the initially
isolated hydrochloride 10.
Taking this information into account, the cyclization of b-
amino-g-bromobutanenitriles 9, in which the nitrogen is
protected as an (arylmethylene)amino moiety, to 2-ami-
nocyclopropanecarbonitriles 4 and 5 was studied with
confidence. The intended cyclopropanation of 3-[(arylm-
ethylene)amino]-4-bromobutanenitriles 9 was investigat-
ed with potassium tert-butoxide17 under different reaction
conditions (Scheme 4 and Table 1).25 The aldimines 9a–e
could be cyclized to cyclopropanes 4a–e with moderate to
The above-described observations led to the mechanistic
proposal as shown in Scheme 3, involving a radical ben-
zylic bromination to give aziridine 12, followed by ring
opening and formation of the imine 9. The transformation
is initiated by the generation of small amounts of bromo
radicals, formed by photolysis of NBS or, more likely, by
homolytic dissociation of bromine, present as an impurity
in the NBS or formed by the reaction of NBS with catalyt-
ic amounts of hydrogen bromide.21,22
R2
R2
R2
Br
N
R1
R1
R1
NBS
N
N
CN
CN
CN
Br
Br
g-Bromobutanenitriles 9 comprise a suitable molecular
framework to perform a 1,3-cyclization protocol; howev-
er, the base-induced ring closure of a three-carbon unit
9
8
12
Scheme 3
Synthesis 2009, No. 7, 1105–1112 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-[(Arylmethylene)amino]cyclopropanecarbonitriles
1107
good diastereoselectivity (trans-4/cis-4 = 69:31 to 74:26)
upon treatment with potassium tert-butoxide in tetrahy-
drofuran at room temperature (3–14 h) (Table 1, entries 1
and 3–6). These cyclopropanes 4a–e could be isolated by
column chromatography on aluminum oxide, albeit in low
yield (14–35%) due to partial hydrolysis and ring opening
of the labile N-benzylidene-protected donor–acceptor-
substituted aminocyclopropanes. The cyclopropanes cis-
4b,c,e were isolated along with the corresponding N-ben-
zylbenzamide 13b,c,e as a minor impurity resulting from
a formal disproportionation reaction.26 The identification
R2
R2
R1
R1
N
KOt-Bu (1.5 equiv)
THF or t-BuOH
N
Br
NC
CN
4a (R1 = H, R2 = H, 17–26%
4b (R1 = H, R2 = 4-Br, 35%)
4c (R1 = H, R2 = 4-Me, 14%)
4d (R1 = H, R2 = 2-Cl, 20%)
4e (R1 = H, R2 = 4-Cl, 26%)
5 (R1 = Ph, R2 = H, 50–53%)
)
9a–f
1
of amides 13 was based on H NMR spectroscopic data
O
(300 MHz, CDCl3) with a typical resonance around 4.6
ppm (d, J = 5.5–5.8 Hz, 2 H, CH2) and a broad singlet at
6.3–6.4 ppm (NH), along with an IR band observed at
3305–3318 cm–1 (NH) and (GC–)MS data showing the
molecular ion peaks (367/369/371 for [M+] of 13b, 240
for [M + H]+ of 13c and 280/282/284 for [M + H]+ of 13e).
A slightly higher isolated yield (26%) of the mixture of
cyclopropanes 4a was achieved via bulb-to-bulb high-
vacuum distillation (Table 1, entry 2). Increasing the tem-
perature of the cyclization reaction of 9a with potassium
tert-butoxide in tetrahydrofuran to reflux temperature re-
sulted in an increased reaction rate (reaction time of 1 h),
but in a lower trans diastereoselectivity (Table 1, entry 2).
The trans diastereoselectivity was also diminished upon
performing the cyclization reaction in the presence of 1.5
equivalents of 18-crown-6 (Table 1, entry 7). Cyclopropa-
nation of the ketimine 9f to the more stable cyclopropane
5 was also investigated upon treatment of 9f with potassi-
um tert-butoxide (Table 1, entries 8–11). When tetrahy-
drofuran was used as solvent, the ratio of cyclopropanes
trans-5/cis-5 was 57:43 after 0.5 hour at reflux tempera-
ture, whereas the ratio increased to 63:37 after 1.75 hours
at 0 °C. Lowering the reaction temperature to –78 °C at
the start of the reaction and subsequently increasing the
temperature to –20 °C for 5 hours resulted in a mixture of
trans-5/cis-5 of 72:28. Upon treatment of imine 9f with
potassium tert-butoxide in tert-butyl alcohol for 1.5 hours
at 40 °C, cyclopropanes 5 were formed in an inverted dia-
stereomeric ratio trans/cis of 41:59 with 100% conversion
of the starting material 9f (Table 1, entry 11). The diaste-
reomers trans-5 and cis-5 were separated in high purity
and reasonable yield by column chromatography on silica
gel. It should be noted that the observed diastereoselectiv-
ity in the formation of cyclopropanes 5 is lower than the
reported diastereoselectivity in the synthesis of the more
sterically substituted N-(diphenylmethylene)-2-[2-(phe-
nylsulfonyl)vinyl]cyclopropylamines in tetrahydrofuran
at –78 °C.24 Besides the temperature effect on the diaste-
reoselectivity, a solvent effect also seems to be operative
(Table 1, entry 11).
N
R2
H
R2
13b,c,e
(minor impurity with cis-4b,c,e)
Scheme 4
Table 1 Overview of the Reaction of 3-Amino-4-bromobutane-
nitriles 9a–f with 1.5 Equivalents of Potassium tert-Butoxide
Entry Product Reaction conditions
Yielda
(%)
drb
(trans/cis)
1
2
4a
4a
4b
4c
4d
4e
4e
5
THF, r.t., 3 h
17c
72:28
65:35
74:26
74:26
69:31
72:28
59:41
57:43
63:37
72:28
41:59
THF, reflux, 1 h
THF, r.t., 14 h
26c
3
35c,d
14c,d
20c
4
THF, r.t., 14 h
5
THF, r.t., 14 h
6
THF, r.t., 3 h
26c,d
n.d.f
53
7
THF, r.t., 3 he
8
THF, reflux, 0.5 h
THF, 0 °C, 1.75 h
THF, –78 to –20 °C, 5 h
t-BuOH, 40 °C, 1.5 h
9
5
n.d.f,g
50
10
11
5
5
52
a Combined yield of the two (trans/cis) diastereomers.
b Determined via GC or 1H NMR (300 MHz, CDCl3) analysis of the
crude reaction mixture.
c Partial decomposition during purification by column chromatogra-
phy or on distillation.
d The isolated cis-isomer 4 was contaminated with small amounts of
the corresponding N-benzylbenzamide 13.
e Reaction performed in the presence of 1.5 equivalents of 18-crown-
6.
f Yield not determined.
g Conversion of imine 9f was 94%.
The herein reported transformation of 2-(cyanometh-
yl)aziridines 8 into N-(arylmethylene)-protected 2-ami-
of a three-step procedure with poor overall yield (5–10%),
the present transformation involves only two steps with an
overall yield up to 34%. Furthermore, in contrast to the
imidates 6, imines 4, and especially benzophenone imine
5, can be separated into the diastereomerically pure trans-
and cis-cyclopropanes on a preparative scale via column
nocyclopropanecarbonitriles
4
and
5
has several
advantages over the previously reported synthesis of
methyl N-(2-cyanocyclopropyl)benzimidates 6 from azir-
idines 8.17 While the latter ring transformation consisted
Synthesis 2009, No. 7, 1105–1112 © Thieme Stuttgart · New York

1108
S. Mangelinckx et al.
PAPER
IR (NaCl): 2253 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.64 (d, J = 6.1 Hz, 1 H), 1.85–
ene)amine instead of an imidate functionality offers a 1.92 (m, 1 H), 1.93 (d, J = 3.3 Hz, 1 H), 2.45 (dd, J = 5.6, 17.2 Hz,
chromatography. Moreover, protection of the amino func-
tion of the b-ACC precursors as a (diphenylmethyl-
1 H), 2.61 (dd, J = 4.8, 17.2 Hz, 1 H), 3.57 (s, 1 H), 7.19–7.44 (m,
more convenient N-protection for further synthetic elabo-
ration.27 To demonstrate the inherent reactivity of the do-
10 H).
13C NMR (75 MHz, CDCl3): d = 21.3, 33.4, 34.3, 77.7, 117.1,
127.2, 127.4, 128.4, 128.5, 142.6, 142.8.
nor–acceptor-substituted cyclopropanecarbonitriles 4, the
reductive ring opening of cyclopropane 4a to g-amino ni-
trile 1428 was performed in 47% isolated yield utilizing so-
dium borohydride in methanol at room temperature for 26
hours (Scheme 5). g-Amino nitriles can be considered as
precursors of pharmacologically important g-amino
acids.29
MS (ES, +): m/z (%) = no [M+], 167 (100).
Anal. Calcd for C17H16N2: C, 82.22; H, 6.49; N, 11.28. Found: C,
81.90; H, 6.73; N, 11.05.
(E)-4-Bromo-3-[(diphenylmethylene)amino]butanenitrile (9f);
Typical Procedure
The following procedure for imine 9f is representative for the syn-
thesis of the 3-[(arylmethylene)amino]-4-bromobutanenitriles 9. To
a soln of aziridine 8f (0.25 g, 1 mmol) in anhyd CH2Cl2 (5 mL) was
added NBS (0.19 g, 1.05 mmol). The reaction mixture was stirred
under reflux for 6 h. The solvent was evaporated under reduced
pressure and the residue was redissolved in CCl4 (5 mL) and cooled
at –20 °C for 1 h. Succinimide was filtered off and the filtrate was
concentrated under reduced pressure to afford ketimine 9f [crude
yield: 0.32 g (97%)], which was purified by column chromatogra-
phy (silica gel; PE–Et2O, 4:1).
H
NaBH4 (2 equiv)
N
H
CN
N
MeOH, r.t., 26 h
CN
4a
14 (47%)
Scheme 5
Yield: 61%; colorless viscous oil; Rf = 0.13 (PE–Et2O, 4:1).
In conclusion, the stepwise efficient synthesis of b-[(aryl-
methylene)amino]-g-bromobutanenitriles has been ac-
complished via ring opening of 1-(arylmethyl)-2-
(cyanomethyl)aziridines with N-bromosuccinimide. The
former g-halogenated nitriles were a-deprotonated and
cyclized with moderate to good diastereoselectivity to the
corresponding b-[(arylmethylene)amino]cyclopropane-
carbonitriles. These new donor–acceptor-substituted cy-
clopropanes can be considered as precursors of the
biologically relevant b-aminocyclopropanecarboxylic
acid and are potentially useful building blocks in synthetic
chemistry.
IR (NaCl): 2251, 1624 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.74 (d, J = 6.1 Hz, 2 H, CH2CN),
3.44 (dd, J = 6.1, 10.2 Hz, 1 H, CHHBr), 3.53 (dd, J = 6.9, 10.5 Hz,
1 H, CHHBr), 3.92 (m, 1 H, CHN), 7.23–7.67 (m, 10 H, 10 × CHAr).
13C NMR (75 MHz, CDCl3): d = 23.5, 34.7, 58.6, 117.2, 127.5,
128.1, 128.7, 128.8, 128.9, 130.8, 135.4, 138.6, 171.6.
MS (ES, +): m/z (%) = 327/329 (100) [M + H]+.
(E)-3-(Benzylideneamino)-4-bromobutanenitrile (9a)
Yield: 72%; brown viscous oil.
IR (NaCl): 2249, 1639 cm–1.
1H NMR (270 MHz, CDCl3): d = 2.79 (dd, J = 16.6, 7.3 Hz, 1 H),
2.91 (dd, J = 16.9, 7.1 Hz, 1 H), 3.52 (dd, J = 11.3, 8.7 Hz, 1 H),
3.59 (dd, J = 11.8, 8.7 Hz, 1 H), 3.68–3.76 (m, 1 H), 7.29–7.69 (m,
5 H), 8.34 (s, 1 H).
1H NMR spectra were recorded on Jeol JNM-EX 270 NMR or Jeol
Eclipse FT 300 NMR instruments at 270 or 300 MHz with CDCl3
as solvent and TMS as internal standard. 13C NMR spectra were re-
corded at 68 or 75 MHz with CDCl3 as solvent. IR spectra were re-
corded on a Perkin–Elmer Spectrum One spectrometer or on a
Perkin–Elmer Spectrum BX FT-IR spectrometer with an ATR ac-
cessory. Mass spectra were recorded on an Agilent 1100 Series
mass spectrometer using a direct inlet system (ES, 4000 V) via LC–
MS. GC–MS was performed with a Hewlett-Packard 6890 GC Plus
coupled with a FID Detector equipped with a CIS-4-PTC (Pro-
grammed Temperature Vaporization) Injector (Gerstel), and HP5-
MS capillary column (fused silica, AT-1, film thickness 0.25 µm,
length 30 m, i.d. 0.25 mm, He as carrier gas), ionization EI at 70 eV.
High-resolution mass spectra were recorded on a Finnigan MAT 95
XP-API-GC-Trap tandem mass spectrometer system (ES, 5000 V).
Melting points were measured with a Büchi B-540 apparatus. THF
was distilled over sodium benzophenone ketyl. CH2Cl2 and t-BuOH
were distilled from CaH2, while other solvents were used as re-
ceived from the supplier.
13C NMR (68 MHz, CDCl3): d = 23.4, 34.5, 66.4, 117.0, 128.3,
128.39, 128.43, 134.3, 164.0.
MS (EI, 70 eV): m/z (%) = 252 (1) [M+], 212 (13), 157 (13), 128
(19), 105 (81), 91 (22), 77 (100), 59 (16).
(E)-4-Bromo-3-{[(4-bromophenyl)methylene]amino}butaneni-
trile (9b)
Yield: 97%; brown viscous oil.
IR (NaCl): 2250, 1643 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.78 (dd, J = 16.7, 7.6 Hz, 1 H),
2.88 (dd, J = 16.8, 4.7 Hz, 1 H), 3.49 (dd, J = 10.5, 6.6 Hz, 1 H),
3.61 (dd, J = 10.5, 6.1 Hz, 1 H), 3.72–3.81 (m, 1 H), 7.57 (d, J = 8.5
Hz, 2 H), 7.66 (d, J = 8.5 Hz, 2 H), 8.33 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 23.7, 34.5, 66.9, 117.0, 126.1,
130.1, 131.8, 133.7, 162.9.
MS (EI, 70 eV): m/z (%) = 328/330/332 (18) [M+], 288/290/292
(100), 235/237 (45), 208/210 (18), 195/197 (34), 182/184 (20), 155/
157 (14), 130 (36), 102 (14), 89 (18), 75 (11).
1-(Arylmethyl)-2-(cyanomethyl)aziridines 8
Aziridines 8 were prepared according to a method previously de-
scribed.17
(E)-4-Bromo-3-{[(4-methylphenyl)methylene]amino}butaneni-
trile (9c)
Yield: 94%; brown viscous oil.
1-Benzhydryl-2-(cyanomethyl)aziridine (8f)
Yield: 65%; white crystals; mp 81 °C; Rf = 0.18 (PE–EtOAc, 4:1).
Synthesis 2009, No. 7, 1105–1112 © Thieme Stuttgart · New York

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Synthesis of 2-[(Arylmethylene)amino]cyclopropanecarbonitriles
1109
IR (NaCl): 2250, 1642 cm–1.
MS (ES, +): m/z (%) = no [M + H]+, 167 (100).
1H NMR (300 MHz, CDCl3): d = 2.40 (s, 3 H), 2.77 (dd, J = 16.8,
7.4 Hz, 1 H), 2.89 (dd, J = 16.8, 4.7 Hz, 1 H), 3.49 (dd, J = 10.5, 6.3
Hz, 1 H), 3.62 (dd, J = 10.5, 6.6 Hz, 1 H), 3.71–3.79 (m, 1 H), 7.24
(d, J = 8.3 Hz, 2 H), 7.67 (d, J = 8.0 Hz, 2 H), 8.34 (s, 1 H).
Anal. Calcd for C17H18BrClN2: C, 55.83; H, 4.96; N, 7.66. Found:
C, 56.16; H, 4.59; N, 7.66.
3-(Benzhydrylamino)-4-bromobutanenitrile (11)
To a suspension of hydrochloride 10 (44 mg, 0.12 mmol) in EtOAc
(2 mL) was added 2 N aq NaOH (0.5 mL). The reaction mixture was
stirred at r.t. for 5 min. After separation of the organic layer, drying
(MgSO4), filtration and concentration under reduced pressure,
benzhydrylamine 11 was obtained [yield: 40 mg (100%)], and was
not purified further.
13C NMR (75 MHz, CDCl3): d = 21.5, 23.8, 34.8, 67.1, 117.2,
128.7, 129.4, 132.4, 142.1, 164.0.
MS (EI, 70 eV): m/z (%) = 264/266 (5) [M+], 224/226 (100), 171
(72), 144 (63), 131 (90), 118 (50), 91 (27).
(E)-4-Bromo-3-{[(2-chlorophenyl)methylene]amino}butaneni-
trile (9d)
Yield: 95%; brown viscous oil.
Colorless viscous oil.
IR (neat): 3318, 2249 cm–1.
IR (NaCl): 2251, 1635 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.95 (br s, 1 H, NH), 2.58 (dd,
J = 6.9, 16.8 Hz, 1 H, CHHCN), 2.67 (dd, J = 6.3, 16.8 Hz, 1 H,
CHHCN), 3.10–3.16 (m, 1 H, CHN), 3.59 (dd, J = 3.2, 10.9 Hz, 1
H, CHHBr), 3.67 (dd, J = 5.2, 10.7 Hz, 1 H, CHHBr), 4.94 (s, 1 H,
CHPh2), 7.21–7.48 (m, 10 H, 10 × CHAr).
1H NMR (300 MHz, CDCl3): d = 2.82 (dd, J = 16.7, 7.0 Hz, 1 H),
2.89 (dd, J = 16.8, 5.0 Hz, 1 H), 3.51 (dd, J = 10.5, 6.6 Hz, 1 H),
3.64 (dd, J = 10.5, 6.3 Hz, 1 H), 3.81–3.89 (m, 1 H), 7.29–7.42 (m,
3 H), 8.07 (dt, J = 7.7, 1.1 Hz, 1 H), 8.82 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 22.6, 35.6, 51.6, 64.1, 117.3,
127.2, 127.3, 127.66, 127.69, 128.79, 128.85, 142.1, 143.0.
13C NMR (75 MHz, CDCl3): d = 23.8, 34.4, 67.0, 116.9, 127.1,
128.7, 129.8, 132.0, 132.5, 135.6, 161.0.
MS (ES, +): m/z (%) = no [M + H]+, 167 (100).
MS (EI, 70 eV): m/z (%) = 284/286/288 (8) [M+], 244/246/248
(100), 191/193 (60), 164/166 (50), 151/153 (70), 138/140 (42), 130
(36), 102 (31), 89 (26), 75 (22).
trans- and cis-2-[(Diphenylmethylene)amino]cyclopropanecar-
bonitrile (5); Typical Procedures
The following procedures for cyclopropane 5 are representative for
the synthesis of the cyclopropanes 4 and 5.
(E)-4-Bromo-3-{[(4-chlorophenyl)methylene]amino}butaneni-
trile (9e)
Yield: 71%; brown viscous oil.
Procedure A
IR (NaCl): 2251, 1643 cm–1.
To a soln of nitrile 9f (0.16 g, 0.5 mmol) in anhyd THF (2 mL) was
added KOt-Bu (84 mg, 0.75 mmol). The reaction mixture was heat-
ed under reflux for 0.5 h. The solvent was evaporated, the residue
was redissolved in Et2O (10 mL), and the resulting solution was fil-
tered over MgSO4 and concentrated under reduced pressure to af-
ford a mixture of cyclopropanes trans-5 and cis-5 (81% crude
yield), which was separated by column chromatography (silica gel;
cyclohexane–EtOAc, 4:1); yield of trans-5: 31%; yield of cis-5:
22%.
1H NMR (300 MHz, CDCl3): d = 2.78 (dd, J = 16.7, 7.6 Hz, 1 H),
2.89 (dd, J = 16.7, 4.5 Hz, 1 H), 3.49 (dd, J = 10.5, 6.6 Hz, 1 H),
3.62 (dd, J = 10.5, 6.3 Hz, 1 H), 3.73–3.81 (m, 1 H), 7.41 (d, J = 8.5
Hz, 2 H), 7.72 (d, J = 8.5 Hz, 2 H), 8.34 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 23.8, 34.5, 67.1, 117.0, 129.0,
129.9, 133.4, 137.6, 162.9.
MS (EI, 70 eV): m/z (%) = 284/286/288 (12) [M+], 244/246/248
(100), 191/193 (67), 164/166 (46), 151/153 (63), 138/140 (40), 130
(29), 102 (15), 89 (25), 75 (17).
Procedure B
To a soln of nitrile 9f (0.16 g, 0.5 mmol) in anhyd t-BuOH (10 mL)
was added KOt-Bu (84 mg, 0.75 mmol). An immediate purple-
brown coloring was observed and the reaction mixture was stirred
at 40 °C for 1.5 h. The solvent was evaporated, the residue was re-
dissolved in Et2O (10 mL), and the resulting solution was poured
into H2O (5 mL) and extracted with Et2O (3 × 5 mL). Washing of
the combined organic extracts with brine (5 mL), drying (MgSO4),
filtration and evaporation of the solvent under reduced pressure af-
forded a mixture of cyclopropanes trans-5 and cis-5 (92% crude
yield), which was separated by column chromatography (silica gel;
PE–EtOAc, 9:1); yield of trans-5: 21%; yield of cis-5: 31%.
3-(Benzhydrylamino)-4-bromobutanenitrile Hydrochloride
(10)
To a soln of aziridine 8f (0.124 g, 0.5 mmol) in anhyd CH2Cl2 (3
mL) was added NBS (0.093 g, 0.525 mmol) and BHT (0.116 g,
0.525 mmol). The reaction mixture was stirred under reflux for 5 h,
then was poured into 0.5 N aq NaOH (5 mL) and extracted with
CH2Cl2 (3 × 10 mL). After drying (MgSO4) of the combined organic
extracts, filtration and concentration under reduced pressure, the
residue was redissolved in anhyd Et2O (20 mL). At 0 °C, a saturated
soln of anhyd HCl in anhyd Et2O was added and the resulting pre-
cipitate was collected by filtration to afford hydrochloride 10; yield:
0.161 g (88%).
trans-2-[(Diphenylmethylene)amino]cyclopropanecarbonitrile
(trans-5)
White crystals; mp 72 °C; Rf = 0.14 (PE–EtOAc, 9:1).
White solid; mp 151.4–151.8 °C.
IR (KBr): 3006, 2944, 2911, 2690, 2644, 2478, 2360, 2256 (w),
1572, 1488, 1466, 1455 cm–1.
IR (KBr): 2237, 1617 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.48 (ddd, J = 7.5, 6.2, 5.2 Hz, 1
H, CHH), 1.62 (ddd, J = 9.6, 4.9, 4.9 Hz, 1 H, CHH), 1.94 (ddd,
J = 9.4, 6.2, 3.2 Hz, 1 H, CHCN), 3.43 (ddd, J = 7.6, 4.7, 3.0 Hz, 1
H, CHN), 7.25–7.57 (m, 10 H, 10 × CHAr).
1H NMR (300 MHz, CDCl3): d = 2.66 (dd, J = 4.7, 17.3 Hz, 1 H,
CHHCN), 2.80 (dd, J = 9.8, 17.2 Hz, 1 H, CHHCN), 3.32 (dd,
J = 4.4, 12.7 Hz, 1 H, CHHBr), 3.42–3.49 (m, 1 H, CHN), 3.66 (dd,
J = 2.6, 12.5 Hz, 1 H, CHHBr), 5.55 (s, 1 H, CHPh2), 7.41–7.52 (m,
6 H, 6 × CHAr), 7.59–7.61 (m, 2 H, 2 × CHAr), 7.75–7.77 (m, 2 H,
2 × CHAr), 10.36 and 10.96 (each br s, each 1 H, NH·HCl).
13C NMR (75 MHz, CDCl3): d = 8.0, 17.2, 43.3, 120.5, 128.2,
128.3, 128.5, 128.9, 129.3, 130.6, 136.0, 139.0, 170.8.
13C NMR (75 MHz, CDCl3): d = 19.2, 28.4, 52.7, 65.2, 115.8,
128.8, 129.2, 129.9, 130.1, 130.6, 132.2, 133.0.
MS (ES, +): m/z (%) = 247 (100) [M + H]+.
Synthesis 2009, No. 7, 1105–1112 © Thieme Stuttgart · New York

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S. Mangelinckx et al.
PAPER
Anal. Calcd for C17H14N2: C, 82.90; H, 5.73; N, 11.37. Found: C,
82.63; H, 5.82; N, 11.26.
1H NMR (300 MHz, CDCl3): d = 1.56–1.63 (m, 2 H), 1.89 (ddd,
J = 8.3, 7.7, 3.0 Hz, 1 H), 3.54 (ddd, J = 6.7, 5.4, 3.0 Hz, 1 H), 7.55
(m, 4 H), 8.44 (s, 1 H).
cis-2-[(Diphenylmethylene)amino]cyclopropanecarbonitrile
(cis-5)
White crystals; mp 95–96 °C; Rf = 0.07 (PE–EtOAc, 9:1).
13C NMR (75 MHz, CDCl3): d = 6.8, 16.3, 48.5, 120.1, 125.6,
129.4, 131.9, 134.2, 161.4.
MS (EI, 70 eV): m/z (%) = 248/250 (10) [M+], 195/197 (92), 169
(18), 168/170 (18), 116 (100), 89 (92), 63 (19).
IR (ATR): 2239, 1620 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.39–1.49 (m, 1 H, CHH), 1.63–
1.75 (m, 2 H, CHH and CHCN), 3.24 (ddd, J = 7.0, 6.0, 5.3 Hz, 1
H, CHN), 7.24–7.54 (m, 8 H, 8 × CHAr), 7.65–7.70 (m, 2 H, 2 ×
CHAr).
Anal. Calcd for C11H9BrN2: C, 53.04; H, 3.64; N, 11.25. Found: C,
52.83; H, 3.44; N, 10.99.
cis-4b
Yield: 4%; light yellow crystals; mp 110–111 °C; Rf = 0.10 (silica
gel; PE–EtOAc, 4:1).
13C NMR (75 MHz, CDCl3): d = 8.1, 16.8, 40.1, 119.5, 128.2,
128.78, 128.83, 129.1, 130.6, 136.3, 139.0, 170.5.
HRMS: m/z calcd for C17H14N2: 246.1152; found: 246.1148.
IR (KBr): 2239, 1630 cm–1.
Anal. Calcd for C17H14N2: C, 82.90; H, 5.73; N, 11.37. Found: C,
82.56; H, 5.71; N, 11.32.
1H NMR (300 MHz, CDCl3): d = 1.50–1.70 (m, 2 H), 1.88 (ddd,
J = 9.1, 6.5, 6.5 Hz, 1 H), 3.36 (ddd, J = 6.7, 6.7, 4.7 Hz, 1 H), 7.54
(d, J = 8.5 Hz, 2 H), 7.65 (d, J = 8.3 Hz, 2 H), 8.46 (s, 1 H).
2-(Benzylideneamino)cyclopropanecarbonitrile (4a)
Combined yield of trans-4a and cis-4a: 26%, after bulb-to-bulb
high-vacuum distillation (Toven = 100–130 °C, P = 0.3 Torr); 17%,
after column chromatography (basic aluminum oxide, PE–EtOAc,
4:1).
13C NMR (75 MHz, CDCl3): d = 7.0, 16.1, 45.5, 118.9, 125.6,
129.6, 131.9, 134.4, 161.3.
MS (EI, 70 eV): m/z (%) = 248/250 (42) [M+], 195/197 (92), 169
(15), 168/170 (18), 116 (100), 89 (84), 63 (18).
2-{[(4-Methylphenyl)methylene]amino}cyclopropanecarboni-
trile (4c)
Combined yield of trans-4c and cis-4c: 14%, after column chroma-
tography (basic aluminum oxide; PE–EtOAc, 4:1).
trans-4a
Yield: 6% (after column chromatography); light yellow oil;
Rf = 0.26 (silica gel; PE–EtOAc, 4:1); spectroscopic data obtained
from a 7:3 mixture of trans-4a/cis-4a.
IR (NaCl): 2239, 1637 cm–1.
trans-4c
Yield: 10%; light yellow crystals; mp 82 °C; Rf = 0.31 (silica gel;
PE–EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): d = 1.55–1.64 (m, 2 H), 1.89 (ddd,
J = 8.9, 7.0, 3.0 Hz, 1 H), 3.54 (ddd, J = 7.0, 5.1, 3.0 Hz, 1 H), 7.37–
7.47 (m, 3 H), 7.66–7.70 (m, 2 H), 8.49 (s, 1 H).
IR (KBr): 2239, 1631 cm–1.
13C NMR (75 MHz, CDCl3): d = 6.7, 16.3, 48.6, 120.3, 128.0,
128.7, 131.2, 135.3, 162.7.
1H NMR (300 MHz, CDCl3): d = 1.53–1.63 (m, 2 H), 1.87 (ddd,
J = 8.9, 6.7, 3.0 Hz, 1 H), 2.39 (s, 3 H), 3.52 (ddd, J = 7.0, 5.1, 3.0
Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.3 Hz, 2 H), 8.46
(s, 1 H).
MS (EI, 70 eV): m/z (%) = 170 (21) [M+], 169 (7), 117 (100), 90
(55), 89 (30), 77 (5), 63 (8), 51 (5).
Anal. Calcd for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found: C,
77.28; H, 6.24; N, 16.08.
13C NMR (75 MHz, CDCl3): d = 6.6, 16.2, 21.6, 48.7, 120.4, 128.0,
129.5, 132.8, 141.7, 162.7.
MS (ES, +): m/z (%) = 185 (100) [M + H]+.
cis-4a
Yield: 2% (after column chromatography); light yellow crystals;
mp 64 °C; Rf = 0.13 (silica gel; PE–EtOAc, 4:1).
Anal. Calcd for C12H12N2: C, 78.23; H, 6.57; N, 15.21. Found: C,
77.88; H, 6.60; N, 14.84.
IR (KBr): 2237, 1634 cm–1.
cis-4c
Yield: 4%; light yellow crystals; mp 110 °C; Rf = 0.14 (silica gel;
PE–EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): d = 1.49–1.56 (m, 1 H), 1.65–1.70 (m,
1 H), 1.87 (ddd, J = 9.4, 6.5, 6.5 Hz, 1 H), 3.37 (ddd, J = 6.7, 6.7,
4.8 Hz, 1 H), 7.37–7.47 (m, 3 H), 7.76–7.80 (m, 2 H), 8.51 (s, 1 H).
IR (KBr): 2239, 1631 cm–1.
13C NMR (75 MHz, CDCl3): d = 6.9, 16.0, 45.6, 119.1, 128.3,
128.6, 131.2, 135.6, 162.5.
1H NMR (300 MHz, CDCl3): d = 1.51 (ddd, J = 9.2, 6.7, 5.6 Hz, 1
H), 1.66 (ddd, J = 6.3, 5.5, 4.9 Hz, 1 H), 1.85 (ddd, J = 9.4, 6.5, 6.5
Hz, 1 H), 2.39 (s, 3 H), 3.35 (ddd, J = 6.7, 6.7, 4.9 Hz, 1 H), 7.21 (d,
J = 7.7 Hz, 2 H), 7.67 (d, J = 8.0 Hz, 2 H), 8.47 (s, 1 H).
MS (EI, 70 eV): m/z (%) = 170 (27) [M+], 169 (11), 117 (100), 90
(49), 89 (27), 77 (7), 63 (9), 51 (7).
Anal. Calcd for C11H10N2: C, 77.62; H, 5.92; N, 16.46. Found: C,
77.37; H, 6.03; N, 16.24.
13C NMR (75 MHz, CDCl3): d = 6.8, 16.0, 21.6, 45.6, 119.2, 128.2,
129.3, 133.0, 141.5, 162.4.
MS (ES, +): m/z (%) = 185 (100) [M + H]+.
2-{[(4-Bromophenyl)methylene]amino}cyclopropanecarboni-
trile (4b)
Combined yield of trans-4b and cis-4b: 35%, after column chroma-
tography (basic aluminum oxide; PE–EtOAc, 4:1).
2-{[(2-Chlorophenyl)methylene]amino}cyclopropanecarboni-
trile (4d)
Combined yield of trans-4d and cis-4d: 20%, after column chroma-
tography (basic aluminum oxide; PE–EtOAc, 4:1).
trans-4b
Yield: 8%; light yellow crystals; mp 90–91 °C; Rf = 0.28 (silica gel;
PE–EtOAc, 4:1).
trans-4d
Yield: 11%; light yellow crystals; mp 50 °C; Rf = 0.43 (silica gel;
PE–EtOAc, 4:1).
IR (KBr): 2239, 1639 cm–1.
Synthesis 2009, No. 7, 1105–1112 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-[(Arylmethylene)amino]cyclopropanecarbonitriles
1111
IR (KBr): 2241, 1630 cm–1.
bined organic extracts, filtration and evaporation of the solvent
under reduced pressure, the amino nitrile 14 was obtained in suffi-
ciently pure form by acid–base extraction using the following pro-
cedure. The mixture was redissolved in Et2O (10 mL) and 2 N aq
HCl (5 mL) was added. After separation of the aqueous phase, 2 N
aq NaOH was added until basic pH and the mixture was extracted
with CH2Cl2 (3 × 5 mL). After drying (MgSO4) of the combined or-
ganic extracts, filtration and evaporation of the solvent under re-
duced pressure, the amino nitrile 14 was obtained.
1H NMR (300 MHz, CDCl3): d = 1.60–1.65 (m, 2 H), 1.92 (ddd,
J = 8.7, 7.3, 2.9 Hz, 1 H), 3.63 (ddd, J = 6.3, 5.8, 3.0 Hz, 1 H), 7.25–
7.43 (m, 3 H), 7.89–7.92 (m, 1 H), 8.94 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 7.1, 16.5, 48.7, 120.1, 127.0,
128.0, 129.9, 132.1, 132.4, 135.1, 159.4.
MS (ES, +): m/z (%) = 205/207 (60) [M + H]+.
Anal. Calcd for C11H9ClN2: C, 64.56; H, 4.43; N, 13.69. Found: C,
64.29; H, 4.56; N, 13.53.
Yield: 47%; yellow oil.
IR (NaCl): 3314, 2246 cm–1.
cis-4d
Yield: 2%; light yellow crystals; mp 60–61 °C; Rf = 0.31 (silica gel;
PE–EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): d = 1.82 (quintet, J = 6.9 Hz, 2 H,
CH2CH2CH2), 2.47 (t, J = 7.1 Hz, 2 H, CH2CN), 2.77 (t, J = 6.6 Hz,
2 H, CH2CH2NH), 3.79 (s, 2 H, CH2C6H5), 7.25–7.37 (m, 5 H,
C6H5).
IR (KBr): 2240, 1630 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.53–1.61 (m, 1 H), 1.70 (ddd,
J = 6.3, 5.5, 4.7 Hz, 1 H), 1.91 (ddd, J = 9.1, 6.5, 6.5 Hz, 1 H), 3.45
(ddd, J = 6.7, 6.7, 4.7 Hz, 1 H), 7.28–7.40 (m, 3 H), 8.12–8.15 (m,
1 H), 8.97 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.9, 25.8, 47.4, 53.7, 119.8,
127.1, 128.0, 128.5, 140.1.
MS (ES, +): m/z (%) = 175 (100) [M + H]+.
13C NMR (75 MHz, CDCl3): d = 7.2, 16.3, 45.8, 119.0, 127.2,
128.8, 129.7, 132.1, 132.6, 134.9, 159.3.
Acknowledgment
MS (EI, 70 eV): m/z (%) = 204/206 (28) [M+], 151/153 (100), 124/
126 (28), 89 (38).
The authors are indebted to the Research Foundation – Flanders
(FWO-Vlaanderen) and to Ghent University (GOA) for financial
support.
Anal. Calcd for C11H9ClN2: C, 64.56; H, 4.43; N, 13.69. Found: C,
64.18; H, 4.51; N, 13.60.
References
2-{[(4-Chlorophenyl)methylene]amino}cyclopropanecarboni-
trile (4e)
(1) Postdoctoral Fellow of the Research Foundation – Flanders
(FWO).
Combined yield of trans-4e and cis-4e: 26%, after column chroma-
tography (basic aluminum oxide; PE–EtOAc, 4:1).
(2) (a) O’Donnell, M. J.; Bruder, W. A.; Eckrich, T. M.;
Shullenberger, D. F.; Staten, G. S. Synthesis 1984, 127.
(b) Isogai, K.; Sakai, J.-i.; Yamauchi, K.; Watanabe, K. Bull.
Chem. Soc. Jpn. 1986, 59, 2839. (c) Salaün, J.; Marguerite,
J.; Karkour, B. J. Org. Chem. 1990, 55, 4276. (d) Gaucher,
A.; Ollivier, J.; Salaün, J. Synlett 1991, 151. (e) Salaün, J.;
Tondu, S. Fr. Demande FR2652082 A1, 1991; Chem. Abstr.
1991, 115, 207567.
(3) For some recent reviews on the synthesis of a-ACC, see:
(a) Brackmann, F.; de Meijere, A. Chem. Rev. 2007, 107,
4493. (b) Cativiela, C.; Díaz-de-Villegas, M. D.
Tetrahedron: Asymmetry 2000, 11, 645.
trans-4e
Yield: 14%; light yellow crystals; mp 89–90 °C; Rf = 0.30 (silica
gel; PE–EtOAc, 4:1).
IR (KBr): 2240, 1638 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.55–1.63 (m, 2 H), 1.89 (ddd,
J = 8.3, 7.7, 3.0 Hz, 1 H), 3.54 (ddd, J = 6.6, 5.5, 3.0 Hz, 1 H), 7.39
(d, J = 8.5 Hz, 2 H), 7.62 (d, J = 8.3 Hz, 2 H), 8.45 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 6.8, 16.4, 48.5, 120.2, 129.0,
129.2, 133.8, 137.2, 161.3.
MS (ES, +): m/z (%) = 205/207 (100) [M + H]+.
(4) For a review on a-amino nitriles, see: Enders, D.; Shilvock,
J. P. Chem. Soc. Rev. 2000, 29, 359.
(5) Vergne, F.; Aitken, D. J.; Husson, H.-P. J. Org. Chem. 1992,
57, 6071.
Anal. Calcd for C11H9ClN2: C, 64.56; H, 4.43; N, 13.69. Found: C,
64.33; H, 4.49; N, 13.59.
(6) Vergne, F.; Partogyan, K.; Aitken, D. J.; Husson, H.-P.
Tetrahedron 1996, 52, 2421.
(7) Khlebnikov, A. F.; Novikov, M. S.; Nikiforova, T. Y.;
Kostikov, R. R. Russ. J. Org. Chem. 1999, 35, 91.
(8) Khlebnikov, A. F.; Nikiforova, T. Y.; Kostikov, R. R. Russ.
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042968, 2008; Chem. Abstr. 2008, 148, 449919.
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cis-4e
Yield: 4%; light yellow crystals; mp 91 °C; Rf = 0.13 (silica gel;
PE–EtOAc, 4:1).
IR (KBr): 2241, 1632 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.50–1.57 (m, 1 H), 1.64–1.70 (m,
1 H), 1.88 (ddd, J = 9.4, 6.4, 6.3 Hz, 1 H), 3.36 (ddd, J = 6.7, 6.7,
4.7 Hz, 1 H), 7.38 (d, J = 8.5 Hz, 2 H), 7.72 (d, J = 8.5 Hz, 2 H),
8.47 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 7.0, 16.1, 45.5, 118.9, 129.0,
129.4, 134.0, 137.2, 161.1.
MS (ES, +): m/z (%) = 205/207 (100) [M + H]+.
4-(Benzylamino)butanenitrile (14)
To a soln of cyclopropane 4a (0.19 g, 1.1 mmol) in MeOH (2 mL)
at 0 °C was added NaBH4 (83 mg, 2.2 mmol). The reaction mixture
was stirred at r.t. for 26 h, then was poured into H2O (5 mL) and ex-
tracted with CH2Cl2 (3 × 10 mL). After drying (MgSO4) of the com-
Synthesis 2009, No. 7, 1105–1112 © Thieme Stuttgart · New York

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PAPER
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