A straightforward synthesis of enantiopure 2-cyano azetidines from β-amino alcohols

Article abstract of DOI:10.1016/S0957-4166(02)00076-9

Enantiopure 2-cyano azetidines were prepared in high yields from β-amino alcohols. This synthesis was shown to be general and is based on two important steps: (i) chlorination of a N-cyanomethylated β-amino alcohol and (ii) a 4-exo-trig ring closure through the alkylation of a lithiated α-amino nitrile. The former step is stereoselective when ephedrine-derived β-amino alcohols are used. In the case of a phenylglycinol-derived β-amino alcohol, this step also involves a rearrangement.

Full text of DOI:10.1016/S0957-4166(02)00076-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 297–302
A straightforward synthesis of enantiopure 2-cyano azetidines
from b-amino alcohols
Claude Agami,b Franc¸ois Coutya,* and Gwilherm Evanob
bLaboratoire de Synthe`se Asyme´trique, UMR 7611, Universite´ Pierre et Marie Curie, 4 place Jussieu, 75005 Paris, France
aSIRCOB, UPRESA CNRS 8086, Universite´ de Versailles, 45 avenue des Etats-Unis, 78035 Versailles Ce´dex, France
Received 6 February 2002; accepted 13 February 2002
Abstract—Enantiopure 2-cyano azetidines were prepared in high yields from b-amino alcohols. This synthesis was shown to be
general and is based on two important steps: (i) chlorination of a N-cyanomethylated b-amino alcohol and (ii) a 4-exo-trig ring
closure through the alkylation of a lithiated a-amino nitrile. The former step is stereoselective when ephedrine-derived b-amino
alcohols are used. In the case of a phenylglycinol-derived b-amino alcohol, this step also involves a rearrangement. © 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results
a-Amino nitriles are popular intermediates in organic
synthesis and they continue to find numerous
applications1 in the preparation of nitrogen-containing
molecules. This is due to their dual reactivity as Umpol-
ung acyl anion or iminium ion precursors, as well as
their well-known transformation into a-amino acids.
The synthesis of an a-amino nitrile most often involves
a Strecker reaction which has been studied extensively
and catalytic versions have recently appeared in the
literature.2 When the iminium ion involved in this
reaction results from an intramolecular condensation
between amine and carbonyl moieties, then 2-cyano
piperidines3 and 2-cyano pyrrolidines4 can be prepared,
and these compounds are useful intermediates in alka-
loid syntheses. However, the Strecker reaction has not
been reported, to our knowledge, for the preparation of
2-cyano azetidines, despite the growing interest in these
four-membered nitrogen heterocycles;5 this might be
attributed to the difficulty of generating highly strained
azetidinium ions. Herein, we report a straightforward
entry to 2-cyano azetidines in enantiomerically pure
form starting from available b-amino alcohols. This
preparation relies on a 4-exo-trig ring closure through
the alkylation6 of a lithiated amino nitrile (Scheme 1).
This strategy has been reported only once, to our
knowledge, for the preparation of 2-cyano
pyrrolidines.7
Four enantiopure commercially available b-amino alco-
hols 1–4 were selected in order to investigate the scope
of this anionic cyclization. Transformation of these
amino alcohols into N-alkyl,N-cyanomethyl derivatives
was effected as shown in Scheme 2: while (1R,2S)-
ephedrine 1 and (1S,2S)-pseudoephedrine 2 were alkyl-
ated in excellent yields with bromoacetonitrile to give 5
and 6, (R)-N-benzyl phenylglycinol 7 and (S)-N-benzyl
phenylalaninol 8, prepared through reductive alkyla-
tion, were conveniently cyanomethylated in a two-step
procedure involving ring opening of intermediate oxa-
zolidines 9 and 10. Actually, in these cases, direct
alkylation of the secondary amine with bromoacetoni-
trile occurred in low yield, which might be attributed to
the high steric hindrance of these amines.
The chlorination of these cyanomethylated amino alco-
hols was studied next. The most simple case refers to
(S)-phenylalaninol-derived substrate 12: treatment of
this compound with two equivalents of thionyl chloride
in dichloromethane at 0°C, followed by heating under
reflux for 4 h gave, after aqueous alkaline workup, the
stable chloride 13 in high yield.
R2
R3
R1
R1
R2
X
R1
HN
R2
R3
N
N
X
-
R3
NC
NC
HCN
O
Scheme 1. Synthesis of 2-cyano azetidines through
intramolecular alkylation.
* Corresponding author. Tel.: 33(1)39254455; fax: 33(1)39254452;
e-mail: couty@chimie.uvsq.fr
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00076-9

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C. Agami et al. / Tetrahedron: Asymmetry 13 (2002) 297–302
hand, compound 13, unsubstituted at the electrophilic
center, produced in this case a 1:1 mixture of azetidines
18 and 19 that could not be separated by chromatogra-
phy. Nonetheless, azetidines 20–25 were conveniently
separated, and, assuming that an SN2 process is oper-
ating in these cyclizations, the relative configurations in
1
these heterocycles were determined by H NMR and
radiocrystallography. First, X-ray crystallography per-
formed on crystalline azetidines 20 and 24 allowed the
determination of relative configurations in these com-
pounds and therefore in 21 and 25. Furthermore, NOE
experiments performed on azetidines 22 and 23 permit-
ted the determination of the relative configurations in
these heterocycles.
The enantiomeric purity of the azetidines 20 or 21
resulting from alkylation of the rearranged chloride 14
had to be checked since the above-mentioned rear-
rangement might proceed with some degree of racem-
ization. To this end, compounds 21 and ent-21
Scheme 2. Synthesis of N-alkyl,N-cyanomethyl-b-amino alco-
hols.
When the same reaction was performed using (R)-
phenylglycinol as substrate, the rearranged chloride 14
was produced (Scheme 3). This rearrangement, previ-
ously reported7 for a related substrate, probably
involves concerted nucleophilic attack of the chloride
anion at the benzylic carbon of the intermediate sulfi-
nate ester, the intermediacy of an aziridinium ion being
improbable since both compound 14 and the trifl-
uoromethanesulfonate derivative of 11 were shown to
be stable upon reflux in dichloromethane.
On the other hand, chlorination of compounds 5 and 6
were highly stereoselective and occurred in both cases
with retention of configuration (Scheme 4). This was
indirectly proven through examination of the azetidines
obtained from these chlorides (vide infra). Further-
more, chlorination of (−)-ephedrine is known8a to occur
with total inversion of configuration under the same
conditions to give 17. Alkylation of this chlorinated
ephedrine 17 with bromoacetonitrile gave a complex
mixture in which only 16 could be detected by NMR
(ca. 15% of the mixture) besides other uncharacterized
products. No traces of isomer 15 were present. This is,
to our knowledge, the first case of stereospecific chlori-
nation of ephedrin family-derived amino alcohols, and
there is no doubt that the N-cyanomethyl group plays
an important part in the stereochemical outcome of this
reaction.
Scheme 3. Chlorination of 11 and 12: radically different
reactivity.
Cyclization of the chlorinated N-cyanomethylated com-
pounds 13–16 was next effected by treatment with
LiHMDS in THF at −78°C. This reaction proceeded in
all cases rapidly at this temperature and afforded in
good to excellent yields 2-cyano azetidines 18–25 as
mixtures of stereoisomers at C(2) (Scheme 5). Starting
from phenyl-substituted compounds 14–16, the corre-
sponding trans 2-cyano-3-phenyl azetidines 21, 23 and
25 were predominant in the mixture. On the other
Scheme 4. Stereospecificity in the chlorination of the
ephedrine-derived family of b-amino alcohols.

C. Agami et al. / Tetrahedron: Asymmetry 13 (2002) 297–302
299
mixtures of diethyl ether (Et2O), ethyl acetate (AcOEt)
and petroleum ether (PE). TLC were run on Merck
Kieselgel 60F254 plates. Melting points are uncorrected.
THF and ether were distilled from sodium/benzophe-
none ketyl. Dichloromethane was distilled from calcium
hydride. Mention of ‘usual workup’ means: (i) decanta-
tion of the organic layer; (ii) extraction of the aqueous
layer with ether; (iii) drying of the combined organic
phases over MgSO4, and (iv) solvent evaporation under
reduced pressure. The composition of stereoisomeric
mixtures was determined by NMR analysis on crude
products before any purification.
3.2. (1R,2S)-N-Cyanomethyl-ephedrine 5
A suspension of (1R,2S)-ephedrine 1 (4.0 g, 24.2
mmol), bromoacetonitrile (2.0 mL, 28.7 mmol) and
potassium carbonate (4.7 g, 34.0 mmol) in acetonitrile
(150 mL) was stirred at rt for 4 h. Evaporation of the
solvent under reduced pressure was followed by addi-
tion of water and ether to the residue. Usual workup
gave quantitatively (4.9 g) the title compound as white
crystals that were washed with a small portion of PE.
Mp 59°C; Rf 0.55 (E/PE: 8/2); [h]2D0 +19 (c 1.7, CHCl3);
1
IR 3165, 2233, 1265, 1201, 1122, 1004 cm−1; H NMR
0.84 (d, J=6.7 Hz, 3H), 2.45 (s, 3H), 2.69–2.77 (m,
2H), 3.56 (s, 2H), 4.87 (d, J=3.2 Hz, 1H), 7.16–7.28
(m, 5H); 13C NMR 10.2, 40.3 (CH3), 43.2 (CH2), 63.4,
72.6 (CH), 116.0 (Cq), 126.2, 127.8, 128.7 (CH), 141.8
(Cq); anal. calcd for C12H16N2O: C, 70.56; H, 7.90; N,
13.71. Found: C, 70.44; H, 7.86; N, 13.91%.
Scheme 5. Synthesis of 2-cyano azetidines through a 4-exo-
trig alkylation of a metallated a-amino nitrile. Functionaliza-
tion of 21 and ent-21.
3.3. (1S,2S)-N-Cyanomethyl-pseudoephedrine 6
(prepared starting from (S)-phenylglycinol ent-3) were
reacted with methylmagnesium bromide and gave 2-
acetyl azetidines 26 and ent-26 (Scheme 5). The enan-
tiomeric excesses of these compounds were determined
Following the procedure described for the preparation
of 5, and starting with (1S,2S)-pseudoephedrine 2 (4.0
g, 24.2 mmol), the title compound 6 was quantitatively
obtained as a white solid (4.90 g). Mp 69°C; Rf 0.55
(E/PE: 8/2); [h]2D0 +33 (c 2.1, CHCl3); IR 3339, 2228,
1598, 1157, 778, 748, 702 cm−1; 1H NMR 0.79 (d,
J=6.7 Hz, 3H), 2.40 (s, 3H), 2.70 (dq, J=9.5 and 6.7
Hz, 1H), 3.52 (s, 2H), 3.90 (bs, 1H), 4.16 (d, J=9.5 Hz,
1H), 7.18–7.27 (m, 5H); 13C NMR 8.8, 35.8 (CH3), 43.1
(CH2), 65.9, 75.1 (CH), 116.6 (Cq), 127.3, 128.2, 128.5
(CH), 140.8 (Cq).
1
by H NMR through complexation with Eu(hfc)3. In
these spectra, the isolated acetyl signal allowed accurate
determination of the e.e. and it appeared that these
compounds are enantiomerically pure within the preci-
sion of NMR (250 MHz).
In conclusion, we have shown that enantiopure 2-cyano
azetidines can be prepared in a few steps and with high
overall yields (59–82%) from b-amino alcohols. This
reaction is of broad scope and further functionalization
of these heterocycles are currently studied in our group
and will be reported in due course.
3.4. (S)-3,4-Dibenzyloxazolidine 10
A suspension of (S)-N-benzyl-phenylalaninol 8 (3.0 g,
12.4 mmol) and paraformaldehyde (1.90 g, 62.2 mmol)
in toluene (100 mL) was heated under aezotropic reflux
for 3 h. Evaporation of the solvent followed by flash
chromatography gave oxazolidine 10 as colorless crys-
tals (4.85 g, 90%). Mp 50°C; Rf 0.6 (E/PE: 8/2); [h]D20
3. Experimental
1
−67 (c 0.7, CHCl3); IR 1306, 1280, 1260, 1147 cm−1; H
3.1. General comments
NMR 2.53 (dd, J=13.7 and 7.7 Hz, 1H), 2.80 (dd,
J=13.7 and 6.9 Hz, 1H), 3.13–3.24 (m, 1H), 3.41 (dd,
J=8 and 5.2 Hz, 1H), 3.63 (AB syst, J=13.2, 2H), 3.87
(dd, J=8.0 and 6.7 Hz, 1H), 4.23 (d, J=5.7 Hz, 1H),
4.34 (d, J=5.7 Hz, 1H), 7.04–7.21 (m, 10H); 13C NMR
40.0, 59.0 (CH2), 64.9 (CH), 69.5, 86.1 (CH2), 126.3,
127.2, 128.4, 128.5, 128.8, 129.3 (CH), 139.0, 139.1
(Cq); anal. calcd for C17H19NO: C, 80.60; H, 7.56; N,
5.53. Found: C, 80.56; H, 7.70; N, 5.50%.
1H and 13C spectra (CDCl3 solution) were, respectively,
recorded on a Bruker ARX 250 spectrometer at 250
and 62.9 MHz; chemical shifts are reported in ppm
from TMS. Optical rotations were determined with a
Perkin Elmer 141 instrument. All reactions were carried
out under argon. Column chromatography was per-
formed on silica gel 230–400 mesh by using various

300
C. Agami et al. / Tetrahedron: Asymmetry 13 (2002) 297–302
3.5. (R)-N-Benzyl-N-cyanomethyl-phenylglycinol 11
followed by flash chromatography (E/PE: 1/1) gave 14
as white crystals (2.55 g, quant.). Mp 90°C; Rf 0.66
(E/PE: 1/1); IR 3047, 2230 cm−1; [h]D20 +83 (c 0.7,
A suspension of oxazolidine 9 (1.37 g, 5.7 mmol), citric
acid (1.1 g, 5.7 mmol) and potassium cyanide (1.37 g,
21 mmol) in ethanol (50 mL) was heated under reflux
for 1 h. To this mixture was then added a saturated
aqueous solution of NaHCO3 (30 mL), and the ethanol
was distilled off. Usual workup followed by flash chro-
matography (E/PE: 1/1) gave 11 as a white solid (1.46
g, 96%). Mp 76°C; Rf 0.58 (E/PE: 6/4); [h]2D0 −54 (c 1.5,
1
CHCl3); H NMR 3.29 (dd, J=14.0 and 6.7 Hz, 1H);
3.38 (dd, J=14.0 and 7.5 Hz, 1H), 3.50 (d, J=17.6 Hz,
1H), 3.61 (d, J=17.6, 1H), 3.89 (AB system, J=13.7
Hz, 2H), 5.04 (dd, J=7.5 and 6.7 Hz, 1H) 7.39–7.53
(m, 10H); 13C NMR 42.2, 58.9 (CH2), 60.7 (CH), 61.9
(CH2), 115.1 (Cq), 127.4, 128.1, 128.8, 128.9, 129.1
(CH), 136.7, 139.5 (Cq); anal. calcd for C17H17ClN2: C,
71.70; H, 6.02; N, 9.84. Found: C, 71.64; H, 6.09; N,
9.74%.
1
CHCl3); IR 3513, 2228, 1060, 927 cm−1; H NMR 1.96
(bs, 1H), 3.61 (AB system, J=17.6 Hz, 2H), 3.84 (AB
system, J=13.4 Hz, 2H), 3.97 (dd, J=10.4 and 5.1 Hz,
1H), 4.10 (bt, J=5.1 Hz, 2H), 7.37–7.60 (m, 10H); 13C
NMR 39.1, 55.7, 64.2 (CH2), 68.1 (CH), 115.4 (Cq),
128.0, 128.4, 128.6, 128.9, 129.0, 129.2 (CH), 137.1,
138.4 (Cq); anal. calcd for C17H18N2O: C, 76.66; H,
6.81; N, 10.52. Found: C, 76.82; H, 6.74; N, 10.30%.
3.9. (1R,2S)-N-Cyanomethyl-N-methyl-1-phenyl-2-
chloro-ethylamine 15
To
a
solution of
5
(4.8 g, 24.0 mmol) in
dichloromethane (200 mL) was added thionyl chloride
(3.5 mL, 48.2 mmol). The mixture was heated under
reflux for 2 h and treated with saturated aqueous
NaHCO3 until neutral. Usual workup (dichloro-
methane) then gave 15 as white crystals (5.2 g, 97%)
that were washed with a small portion of pentane. Mp
64°C; Rf 0.56 (E/PE: 1/1); [h]2D0 −85 (c 1.5, CHCl3); IR
3.6. (S)-N-Benzyl-N-cyanomethyl-phenylalaninol 12
Following the procedure described for the preparation
of 11, compound 12 was obtained as a clear oil after
flash chromatography (E/PE: 6/4). Yield 78%; Rf 0.66
(E/PE: 7/3); [h]2D0 −14 (c 2.8, CHCl3); IR 3454, 3027,
1
2226, 1331, 1209, 1162, 1122, 717 cm−1; H NMR 1.16
(d, J=6.4 Hz, 3H), 2.33 (s, 3H), 3.05 (quint., J=6.4
Hz, 1H), 3.41 (s, 2H), 4.88 (d, J=6.4 Hz, 1H), 7.17–
7.31 (m, 5H); 13C NMR 11.7, 38.3 (CH3), 43.5 (CH2),
64.0, 65.4 (CH), 116.2 (Cq), 127.5, 128.3, 128.5 (CH),
139.6 (Cq); anal. calcd for C12H15ClN2: C, 64.71; H,
6.79; N, 12.58. Found: C, 64.77; H, 7.07; N, 12.35%.
1
2930, 2230, 1600 cm−1; H NMR 2.35 (s, 1H), 2.55 (dd,
J=14.5 and 10.7 Hz, 1H), 3.05–3.14 (m, 2H), 3.43 (s,
2H), 3.47–3.50 (m, 2H), 3.74 (AB system, J=13.4 Hz,
2H), 7.10–7.26 (m, 10H); 13C NMR 33.5, 38.5, 54.0,
60.9 (CH2), 65.9 (CH), 117.0 (Cq), 126.6, 126.9, 128.0,
128.7, 128.9, 129.0, 129.1 (CH), 136.9, 138.4 (Cq); anal.
calcd for C18H20N2O: C, 72.35; H, 6.41; N, 9.38.
Found: C, 72.41; H, 6.45; N, 9.30%.
3.10. (1S,2S)-N-Cyanomethyl-N-methyl-1-phenyl-2-
chloro-ethylamine 16
3.7. (S)-N-Benzyl-N-cyanomethyl-1-benzyl-2-chloro-
To a solution of 6 (1.0 g, 4.9 mmol) in dichloromethane
(40 mL) was added thionyl chloride (0.575 mL, 7.9
mmol). The mixture was stirred for 1 h at rt and treated
with saturated aqueous NaHCO3 until neutral. Usual
workup (dichloromethane) followed by flash chro-
matography gave 16 as white crystals (1.0 g, 92%). Mp
41°C; Rf 0.84 (E/PE: 7/3); [h]2D0 +130 (c 1.7, CHCl3); IR
ethylamine 13
To
a
solution of 12 (5.2 g, 0.018 mol) in
dichloromethane (130 mL) was added dropwise thionyl
chloride (2.7 mL, 0.037 mol) at 0°C. The mixture was
then heated under reflux for 4 h and hydrolyzed by
addition of a saturated aqueous solution of NaHCO3
(100 mL). Usual workup (dichloromethane) followed
by flash chromatography (AcOEt/PE: 8/92) gave 13 as
white crystals (5.4 g, 97%). Mp 44°C; Rf 0.77 (E/PE:
1
2228, 1332, 1209, 1163, 1122, 717 cm−1; H NMR 0.99
(d, J=7.0 Hz, 3H), 2.48 (s, 3H), 3.15–3.35 (m, 1H),
3.62 (s, 2H), 4.74 (d, J=8.2 Hz, 1H), 7.33–7.76 (m,
5H); 13C NMR 12.2, 36.7 (CH3), 43.8 (CH2), 64.5, 66.0
(CH), 117.0 (Cq), 127.9, 128.7, 128.8 (CH), 139.3 (Cq);
anal. calcd for C12H15ClN2: C, 64.71; H, 6.79; N, 12.58.
Found: C, 64.617; H, 6.91; N, 12.56%.
3/7); [h]2D0 −14 (c 1.8, CHCl3); IR 2855, 1456 cm−1; H
1
NMR 2.87 (dd, J=13.7 and 8.7 Hz, 1H), 3.05 (dd,
J=13.7 and 5.8 Hz, 1H), 3.25 (ddt, J=8.7, 5.8 and 5.5
Hz, 1H), 3.50 (d, J=3.2 Hz, 2H), 3.59 (d, J=5.5 Hz,
2H), 3.88 (s, 2H), 7.12–7.28 (m, 10H); 13C NMR 35.3,
38.6, 44.5, 54.5 (CH2), 65.3 (CH), 117.0 (Cq), 126.9,
128.0, 128.9, 129.3 (CH), 137.1, 138.2 (Cq); anal. calcd
for C18H19ClN2: C, 72.35; H, 6.41; N, 9.38. Found: C,
72.41; H, 6.45; N, 9.36%.
3.11. (2RS,4S)-1,4-Dibenzyl-azetidin-2-carbonitrile 18
and 19
To a solution of 13 (500 mg, 1.67 mmol) in THF (30
mL) was added dropwise at −90°C a THF solution of
lithium bis-trimethylsilylamide (1 M, 2 mL, 2 mmol).
The mixture was then gradually (3 h) allowed to reach
0°C and hydrolyzed by addition of a saturated aqueous
solution of NH4Cl. Usual workup followed by flash
chromatography (AcOEt/PE: 8/92) gave azetidines 18
and 19 as a 1/1 mixture of isomers (400 mg, 91%).
Faster eluting isomer: Rf 0.75 (AcOEt/PE: 8/92); 1H
NMR 2.17–2.24 (m, 2H), 2.70 (d, J=6.5 Hz, 2H), 3.57
3.8. (R)-N-Benzyl-N-cyanomethyl-2-chloro-2-phenyl-
ethylamine 14
A solution of 11 (2.29 g, 8.63 mmol) and thionyl
chloride (1.25 mL, 17.2 mmol) in dichloromethane (60
mL) was heated under reflux for 2.5 h and hydrolyzed
by addition of
a saturated aqueous solution of
NaHCO3 (30 mL). Usual workup (dichloromethane)

C. Agami et al. / Tetrahedron: Asymmetry 13 (2002) 297–302
301
(s, 2H), 3.70–3.80 (m, 1H), 3.99 (ddd, J=6.5, 3.2 and
0.7 Hz, 1H), 7.06–7.28 (m, 10H); 13C NMR 29.1, 42.2
(CH2), 49.6 (CH), 57.0 (CH2), 65.9 (CH), 118.1 (Cq),
126.7, 127.6, 128.2, 128.7, 128.9, 129.2 (CH), 136.9,
137.4 (Cq). Slower eluting isomer: Rf: 0.67 (AcOEt/PE:
1H), 3.48 (d, J=8.0, 1H), 7.12–7.32 (m, 5H); 13C NMR
20.3, 42.6 (CH3), 49.8, 57.5, 68.6 (CH), 119.1 (Cq),
127.0, 127.8, 128.9 (CH), 137.4 (Cq); anal. calcd for
C12H14N2: C, 77.38; H, 7.58; N, 15.04. Found: C, 77.13;
H, 7.35; N, 15.19. Compound 23: Mp 42°C; Rf 0.31
(E/PE: 7/3); [h]2D0 −95 (c 1.4, CHCl3); IR 3020, 2215,
1265, 1127, 730, 700 cm−1; 1H NMR 1.22 (d, J=5.5 Hz,
3H), 2.38 (s, 3H), 3.49–3.62 (m, 2H), 4.55 (d, J=6.7
Hz, 1H), 7.17–7.33 (m, 5H); 13C NMR 19.7, 38.3
(CH3), 47.1, 59.2, 66.8 (CH), 115.9 (Cq), 127.9, 128.0,
128.7 (CH), 135.6 (Cq); anal. calcd for C12H14N2: C,
77.38; H, 7.58; N, 15.04. Found: C, 77.33; H, 7.60; N,
15.09%.
1
8/92); H NMR 2.25–2.35 (m, 2H), 2.66 (d, J=6.5 Hz,
2H), 3.23–3.35 (m, 1H), 3.38–3.55 (m, 3H), 7.06–7.28
(m, 10H); 13C NMR 29.2, 42.8 (CH2), 47.9 (CH), 61.1
(CH2), 64.8 (CH), 119.6 (Cq), 126.7, 127.9, 128.6, 128.2,
129.2, 129.4 (CH), 136.7, 137.5 (Cq); IR (mixture of
isomers): 3085, 3062, 3028, 2960, 2239, 1495, 1453
cm−1; anal. calcd for C18H18N2: C, 82.40; H, 6.92; N,
10.68. Found: C, 82.14; H, 7.01; N, 10.79%.
3.14. (2S,3R,4S)-1,4-Dimethyl-3-phenyl-azetidine-2-car-
bonitrile 24 and (2R,3R,4S)-1,4-dimethyl-3-phenyl-aze-
tidine-2-carbonitrile 25
3.12. (2S,3R)-1-Benzyl-3-phenyl-azetidine-2-carbonitrile
20 and (2R,3R)-1-benzyl-3-phenyl-azetidine-2-carboni-
trile 21
Following the procedure reported above for the prepa-
ration of 22 and 23 and starting with 16 (1.0 g, 4.5
mmol), a crude mixture was obtained. Flash chro-
matography (AcOEt/EP: 8/92 then 15/85) gave 25
(faster eluting stereoisomer, 470 mg, 56%), followed by
24 (slower eluting stereoisomer, 125 mg, 15%). Overall
yield: 71%. Compound 24: Mp 93–95°C; Rf 0.63 (E/PE:
1/1); [h]2D0 −148 (c 1.0, CHCl3); IR 2238, 1236, 1291,
To a solution of 14 (2.55 g, 8.96 mmol) in dry THF
(170 mL) was added dropwise at −90°C a solution of
lithium bis-trimethylsilylamide in THF (1 M solution,
10.7 mL, 10.7 mmol). The mixture was gradually (1.5 h)
warmed at −10°C and hydrolyzed by addition of an
aqueous saturated solution of NH4Cl (30 mL). Usual
workup followed by flash chromatography (E/PE: 15/
85) first gave 21 as a clear oil (1.40 g, 63%), followed by
20 as colorless crystals (700 mg, 31%). Compound 20:
Mp 101–102°C; Rf 0.57 (E/PE: 4/6); IR 2854, 2240,
1455 cm−1; [h]D20 −37 (c 0.5, CHCl3); GC (OV 17,
200°C): tR 7.31 min; 1H NMR 3.53–3.61 (m, 2H),
3.71–3.99 (m, 3H), 4.43 (d, J=7.7 Hz, 1H), 7.17–7.36
(m, 10H); 13C NMR 39.0 (CH), 58.0 (CH2), 58.6 (CH),
60.1 (CH2), 116.7 (Cq), 127.7, 128.0, 128.6, 128.8, 128.9
(CH), 136.3, 137.4 (Cq); anal. calcd for C17H16N2: C,
82.22; H, 6.49; N, 11.28. Found: C, 82.01; H, 6.42; N,
11.18. Compound 21: Rf 0.71 (E/PE: 4/6); IR 3030,
2842, 2238, 1454 cm−1; [h]D20 −42 (c 0.6, CHCl3); GC
1
1249, 1219, 1183 cm−1; H NMR 0.86 (d, J=6.2 Hz,
3H), 2.43 (s, 3H), 3.45 (quint., J=6.6 Hz, 1H), 3.71 (t,
J=7.7 Hz, 1H), 4.04 (d, J=7.5 Hz, 1H), 7.26–7.43 (m,
3H), 7.53–7.56 (m, 2H); 13C NMR 15.3, 42.5 (CH3),
45.1, 56.9, 65.5 (CH), 117.6 (Cq), 127.9, 128.40, 130.0
(CH), 134.7 (Cq). Compound 25: Oil, Rf 0.79 (E/PE:
1/1); [h]2D0 −74 (c 2.7, CHCl3); IR 2223, 1260, 1229,
1
1203, 743, 697 cm−1; H NMR 0.79 (d, J=6.2 Hz, 3H),
2.44 (s, 3H), 3.73 (dd, J=7.9 and 2.6 Hz, 1H), 3.77–
3.89 (m, 1H), 4.33 (dd, J=2.6 and 0.9 Hz, 1H), 7.26–
7.38 (m, 5H); 13C NMR 15.2, 38.3 (CH3), 45.8, 56.9,
65.1 (CH), 117.5 (Cq), 127.6, 128.5, 128.6 (CH), 136.4
(Cq); anal. calcd for C12H14N2: C, 77.38; H, 7.58; N,
15.04. Found: C, 77.49; H, 7.79; N, 15.13%.
1
(OV 17, 200°C): tR 6.62 min; H NMR 3.24 (dd, J=7.7
and 6.7 Hz, 1H), 3.72 (d, J=12.6 Hz, 1H), 3.74–3.87
(m, 2H), 3.84 (d, J=12.6 Hz, 1H), 3.96 (quint., J=7.4
Hz, 1H), 7.23–7.38 (m, 10H); 13C NMR 41.3, 58.3
(CH), 58.4, 61.4 (CH2), 118.7 (Cq), 126.9, 127.8, 127.9,
128.7, 128.9, 129.0 (CH), 135.9, 138.5 (Cq); anal. calcd
for C17H16N2: C, 82.22; H, 6.49; N, 11.28. Found: C,
82.26; H, 6.45; N, 11.18%.
3.15. (2R,3R)-2-Acetyl-1-benzyl-3-phenyl-azetidine 26
To a solution of 21 (300 mg, 1.21 mmol) in THF (15
mL) was added dropwise a solution of methylmagne-
sium bromide (3 M in ether, 1.6 mL, 4.8 mmol). After
stirring at rt for 24 h, the mixture was hydrolyzed by
addition of saturated aqueous NH4Cl. Usual workup,
followed by flash chromatography (AcOEt/EP: 2/8)
gave 26 as a clear oil (241 mg, 75%). Rf 0.52 (E/PE:
1/1); [h]2D0 −10 (c 1.5, CHCl3); IR 3027, 2832, 1701,
3.13. (2R,3S,4S)-1,4-Dimethyl-3-phenyl-azetidine-2-car-
bonitrile 22 and (2S,3S,4S)-1,4-dimethyl-3-phenyl-aze-
tidine-2-carbonitrile 23
1
1490, 1357, 1234, 697 cm−1; H NMR 1.94 (s, 3H), 3.01
To a solution of 15 (5.4 g, 24.2 mmol) in dry THF (400
mL) at −90°C was added dropwise a solution (1 M in
THF, 30 mL, 30 mmol) of LiHMDS. The reaction
mixture was gradually (1 h) warmed to −30°C and
quenched by addition of a saturated aqueous solution
of NH4Cl. Usual workup, followed by flash chromatog-
raphy (AcOEt/EP: 15/85 then 30/70) gave 22 (faster
eluting isomer: 1 g, 22%), followed by 23 (slower elut-
ing isomer, 2.51 g, 56%). Overall yield 78%. Compound
22: Mp 24°C; Rf 0.63 (E/PE: 7/3); [h]2D0 +42 (c 1.0,
CHCl3); IR 3027, 2218, 1270, 1178, 1127, 733, 702
(dd, J=8.0 and 6.0 Hz, 1H), 3.53–3.73 (m, 5H), 7.12–
7.24 (m, 10H); 13C NMR 26.1 (CH3), 40.2 (CH), 57.6,
62.8 (CH2), 78.3 (CH), 127.0, 127.2, 127.5, 128.5, 128.6,
129.1 (CH), 137.0, 140.1, 209.1 (Cq); anal. calcd for
C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.33;
H, 7.32; N, 5.40%.
Acknowledgements
1
cm−1; H NMR 1.25 (d, J=6.0 Hz, 3H), 2.39 (s, 3H),
Dr. Louis Hamon (Universite´ P. et M. Curie) is
acknowledged for helpful discussions and Dr. Jacque
3.09 (dq, J=7.5 and 6.0 Hz, 1H), 3.42 (t, J=7.8 Hz,

302
C. Agami et al. / Tetrahedron: Asymmetry 13 (2002) 297–302
line Vaissermann (Universite´ P. et M. Curie) is
acknowledged for the X-ray radiocrystallographic
analysis9 performed on azetidines 20 and 24.
Chem. 1999, 64, 9596; (f) Ohno, H.; Hamaguchi, H.;
Tanaka, T. J. Org. Chem. 2001, 66, 1867; (g) Ohno, H.;
Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka, T.;
Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904.
For syntheses of racemic 2-cyano azetidines, see: (h) Sul-
mon, P.; De Kimpe, N.; Schamp, N.; Tinant, B.; Declerq,
J.-P. Tetrahedron 1988, 44, 3653; (i) Chowdurry, A. R.;
Kumar, V. V.; Roy, R.; Bhaduri, A. P. J. Chem. Res. (S)
1997, 254; (j) Nishio, T.; Omote, Y. J. Org. Chem. 1985,
50, 1370; (k) Aelterman, W.; De Kimpe, N.; Declerq, J. P.
J. Org. Chem. 1998, 63, 6.
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9. Crystallographic data have been deposited at the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK. Copies of the
data can be obtained free of charge. CCDC numbers:
167424 for 20 and 167425 for 24.