Synthesis of enantiopure 2-acyl azetidines and the application of amino alcohols derived therefrom in enantioselective catalysis

Article abstract of DOI:10.1016/S0957-4166(02)00710-3

Enantiopure 2-acyl azetidines were prepared in good yields from 2-cyano azetidines. The ketones produced were then stereoselectively reduced with sodium borohydride (with or without zinc bromide) or transformed into tertiary azetidinic amino alcohols by addition of phenyllithium. The latter compounds were found to be highly efficient catalysts for the enantioselective addition of diethylzinc to aldehydes, giving enantioselectivities up to 98%.

Full text of DOI:10.1016/S0957-4166(02)00710-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2619–2624
Synthesis of enantiopure 2-acyl azetidines and the application of
amino alcohols derived therefrom in enantioselective catalysis
Franc¸ois Couty* and Damien Prim
SIRCOB, UPRESA CNRS 8086, Universite´ de Versailles, 45, avenue des Etats-Unis, 78035, Versailles Ce´dex, France
Received 21 October 2002; accepted 24 October 2002
Abstract—Enantiopure 2-acyl azetidines were prepared in good yields from 2-cyano azetidines. The ketones produced were then
stereoselectively reduced with sodium borohydride (with or without zinc bromide) or transformed into tertiary azetidinic amino
alcohols by addition of phenyllithium. The latter compounds were found to be highly efficient catalysts for the enantioselective
addition of diethylzinc to aldehydes, giving enantioselectivities up to 98%. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results
2-Acyl azetidines of general structure 2 are scarcely
reported heterocycles1 and to our knowledge, not a
single member of this family has been described in
enantiomerically pure form. We recently reported a
straightforward synthesis of 2-cyano azetidines 1 start-
ing from readily available enantiopure b-amino alco-
hols.2 Herein, we wish to describe a facile method for
the preparation of 2-acyl azetidines 2 starting from 1,
and the transformation of the former ketones into
2-a-hydroxyaryl azetidines 3 (Scheme 1). We undertook
the evaluation of these novel strained enantiopure b-
amino alcohols as ligands for the catalytic addition of
diethylzinc to aldehydes. This reaction, initially studied
by Mukaiyama and Soai,3 is now a benchmark for the
evaluation of new ligands, and our results in this area
are also presented.
2.1. Synthesis of 2-acyl azetidines
2-Cyano azetidines 4 and 5, readily prepared from
(−)-ephedrine2 were first used as substrates to investi-
gate their transformations into the corresponding 2-acyl
azetidines. Treatment of these compounds with phenyl-
lithium in benzene cleanly afforded imines 6 and 7. On
purification by flash chromatography, these imines
underwent hydrolysis, and complete epimerization at
C-2 was observed when imine 7 was subjected to chro-
matography, so that ketone 8 forms when starting from
either 4 or 5. When the same reaction is performed
using stereoisomer 9, the imine 10 was formed and,
after chromatography, a 7:3 mixture of epimeric
ketones 11 and 12 was isolated. Finally, treatment of
the (R)-phenylglycinol-derived azetidine 13 gave imine
14 and subsequently stereoisomerically pure ketone 15
after chromatography (Scheme 2).
It should be noted that no substitution of the nitrile
moiety by the phenyl group is observed in these reac-
tions. As a matter of fact, a-amino nitriles are consid-
ered as useful precursors of iminium ions through the
loss of cyanide ion under the influence of Lewis acids4
and treatment of such a functional group with an
organometallic reagent usually yields the corresponding
amine through an elimination/addition sequence. This
old-standing Bruylants reaction5 is disfavored in our
case since it would generate a highly strained iminium
ion intermediate, which accounts for the exclusive addi-
Scheme 1. 2-Acyl azetidines are easily prepared from the
corresponding amino nitrile.
* 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)00710-3

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F. Couty, D. Prim / Tetrahedron: Asymmetry 13 (2002) 2619–2624
Scheme 3. Reduction of 2-acyl azetidines gives predominantly
anti isomers.
tion control to give stereoselectively anti isomers.7 Sec-
ondly, a cyclic derivative 26 of a close analogue8 of 17a
was synthesized as shown in Scheme 4: (R)-phenylgly-
cinol 18 was first N-monoallylated,9 and transformed
via a three-step sequence into a 64:35 epimeric mixture
of 2-cyano azetidines 22 and 23 following our previ-
ously reported procedure.2 Treatment of this mixture
with phenyllithium followed by chromatography gave
ketone 24 (de: 90%) that was reduced using zinc bro-
mide as an additive to give alcohol 25 (de: 98%). The
carbonate derivative of this alcohol, upon treatment
with Grubb’s catalyst,10 underwent N-deallylation to
give oxazolidinone 26 together with carbamate 27.
Scheme 2. Synthesis of 2-acyl azetidines.
tion of the organolithium reagent to the cyano moiety
in this case. The epimerization which occurs during
chromatography of the intermediate imines highlights
the ease of enolization of such aryl ketones. 2,3-trans-
Ketones were obtained either exclusively or as the
major component of the epimeric mixture, and the
relative stereochemistry of these compounds were deter-
mined by NMR6 and indirectly by the sense of the
enantioselectivities observed when their derivatives were
used as ligands in enantioselective catalysis (vide supra).
The ratio resulting from epimerization is reflective of
the thermodynamic control in the system. Indeed, AM1
calculations performed with ketones 8 (and its C-2
epimer), 11 and 12 show that the 2,3-trans isomers are
more stable by ca. 3–4 kcal mol−1 compared to their cis
epimers, irrespective of the configuration of the tertiary
amine.
3
Examination of the J coupling constant in the former
compound establishes unambiguously the relative
configuration of the two vicinal stereocenters.
Addition of phenyllithium to ketones 8 and 15 also
afforded tertiary alcohols 28 and 29 (Scheme 5).
Having in hand enantiopure 2-acyl azetidines, we began
to investigate the outcome of nucleophilic additions of
organometallic reagents on the keto moiety.
2.2. Synthesis of 2-a-hydroxyaryl azetidines
Reduction of the phenacyl moiety in 8 and 15 with
sodium borohydride in ethanol at −78°C occurred
stereoselectively to give 16 (de: 86%) and 17a,b (de:
60%). In the first case, chromatography gave pure 16 in
74% yield whilst in the case of 17, diastereoisomerically
pure anti-17a and syn-17b were isolated in 66 and 17%
yield, respectively (Scheme 3). When zinc bromide was
used as an additive in these reactions, following a
recently described procedure performed on a related
aziridinic substrate,7 the diastereoselectivity increased
to >98% in both cases. The attribution of the relative
anti stereochemistry in the alcohols produced was
deduced from the following points.
Scheme 4. Determination of the stereochemistry of the alco-
hols through the synthesis of a cyclic oxazolidinone derivative
26. Reagents and conditions: (a) DBU, toluene, allyl bromide,
59%; (b) BrCH2CN, K2CO3, CH3CN, 65%; (c) SOCl2,
CH2Cl2, quant.; (d) LiHMDS, −78°C, THF, 90%; (e) PhLi,
PhH, then chromatography, 69%; (f) NaBH4, ZnBr2, EtOH,
61%; (g) i-BuOCOCl, DMAP, CH2Cl2, reflux; (ii) Grubb’s
catalyst, toluene, reflux then chromatography.
First, it is reported for closely related substrates that
the addition of ZnBr2 in such reductions favors chela-

F. Couty, D. Prim / Tetrahedron: Asymmetry 13 (2002) 2619–2624
2621
bined with the absolute configuration of the alcohols
produced is indirect proof for the establishment of the
relative configurations at positions 2 and 3 in 28 and
29.
Scheme 5. Addition of phenyllithium on 2-acyl azetidines.
2.3. Evaluation of 2-a-hydroxymethyl azetidines in
enantioselective catalysis
In conclusion, we have reported a new synthesis of
enantiopure azetidinic amino alcohols, some of them
being very efficient ligands for enantioselective cataly-
sis. Further work is in progress in our group in order to
get further insights in the chemistry of these understud-
ied heterocycles.
Our newly synthesized azetidinic amino alcohols were
then evaluated as chiral ligands during the catalytic
enantioselective addition of diethylzinc on aldehydes. In
this extensively studied field,11 the unreported structural
feature of our azetidinic ligands include the following
points: (i) the presence of an extra substituent at C-4
and/or C-3 and (ii) the presence of a stereogenic center
bearing the hydroxyl moiety (e.g. alcohols 16, 17a,b).
Our results, using a standardized ratio of aldehyde/
diethylzinc/ligand=1/2/0.1 in toluene for 24 h at room
temperature, are gathered in Table 1 and deserve some
comments. First, modest enantioselectivities are
obtained when secondary alcohols came to be used in
this reaction (entries 1–3). It is interesting to note that
the absolute configuration of the stereogenic center
bearing the hydroxyl moiety has a dramatic influence
on the outcome of the reaction since the enantioselec-
tivity is reversed when isomers 17a and 17b are used as
catalysts (entries 2, 3). Secondly, tertiary alcohols 28
and 29 are very efficient ligands in this reaction. As a
matter of fact, the presence of substituents on the
azetidinic ring at C-4 and/or C-3 has little effect on the
enantioselectivity since compounds 30 and 31 depicted
hereafter and that are devoid of extra substituents
compared to 28 and 29 were reported11a,d to give
respective enantioselectivities of 98 (S configuration)
and 88% (R configuration) in this reaction. A modest
match effect is however observed in case of 29 com-
pared to 31. The absolute configuration at C-2 on the
azetidinic ring therefore seems to be the controlling
factor for stereoinduction, and this observation, com-
3. Experimental
3.1. General comments
1H and 13C spectra (CDCl3 solution) were respectively
recorded on a Bruker ARX 300 spectrometer at 300
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 car-
ried out under argon. Column chromatography was
performed on silica gel 230–400 mesh by using various
mixtures of diethyl ether (E), ethyl acetate (AcOEt) and
petroleum ether (PE). TLC were run on Merck
Kieselgel 60F254 plates. Melting points are uncorrected.
Benzene and THF were distilled from sodium/benzo-
phenone ketyl. Dichloromethane was distilled from cal-
cium hydride. Mention of ‘usual workup’ means: (i)
decantation of the organic layer, (ii) extraction of the
aqueous layer with ether, (iii) drying of the combined
organic phases over MgSO4, (iv) solvent evaporation
under reduced pressure. Composition of stereoisomeric
mixtures was determined by NMR analysis on crude
products before any purification.
Table 1.
Entry
Aldehyde
Liganda
Yieldb (%)
E.e.c
Abs. conf.
1
2
3
4
5
6
7
8
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
Benzaldehyde
2-Furylaldehyde
Nonanal
16
17a
17b
28
97
88
98
98
97
97
62
50
57
98
94
98
93
86f
S
R
S
S
S
R
S
S
28d
29
e
28
28
–
e
–
a Unless otherwise stated, 10 mol% of catalyst were used.
b Determined by GC, using dodecane as internal standard.
c Unless otherwise stated, determined by GC using Lipodex-A as chiral phase.
d In this case, 5 mol% of ligand was used.
e Not determined.
f Determined on the benzoylated derivative by HPLC using (R,R) whelk 01 as chiral column (isopropanol/heptane: 0.5/99.5).

2622
F. Couty, D. Prim / Tetrahedron: Asymmetry 13 (2002) 2619–2624
3.2. (2S,3S,4S)-(1,4-Dimethyl-3-phenylazetidin-2-yl)-
phenylmethanone, 8
80%) was obtained as an oil after chromatography (E/PE:
2/8). Rf: 0.32 (E/PE: 4/6); [h]2D0: −56.4 (c 1.1, CHCl3); IR
(film): 1690 (CO), 1450, 1380, 721 cm−1; 1H NMR:
To a solution of cyanoazetidine 5 (215 mg, 1.14 mmol)
in dry benzene (10 mL) was added dropwise at 0°C a
solution of phenyllithium in cyclohexane/ether (1.8 M
sol., 1.25 mL, 2.27 mmol). The solution was stirred for
15 min at 0°C and hydrolyzed by addition of an aqueous
saturated solution of NH4Cl (10 mL). Addition of water
and etherwasthen followed by usual workup to givecrude
imine 7 as an oil. Flash chromatography of this residue
(E/PE: 7/3) gave ketone 8 as a white solid (275 mg, 91%).
Intermediate crude imine 7: 1H NMR: 1.28 (d, J=6.2 Hz,
3H, Me), 2.49 (s, 3H, NMe), 2.84 (t, J=7.7 Hz, 1H, H3),
3.32 (qd, J=6.2 and 7.7 Hz, 1H, H4), 3.99 (d, J=7.7 Hz,
1H, H2), 6.85–6.95 (m, 2H, Ar), 7.12–7.68 (m, 20H, Ar),
10.8 (bs, 1H, NH); 13C NMR: 20.5, 42.1, 50.4, 53.0, 67.2,
75.4, 115.6 to 156.8: aromatic carbons including impuri-
ties from the reagent, 176.5. Ketone 8: mp: 91°C; Rf: 0.6
(E/PE: 7/3); [h]2D0: +2.3 (c 0.3, CHCl3); IR (film): 1680
3.27–3.36 (m, 1H, H3), 3.76–3.86 (m, 3H, H4, H4 and
%
NCHHPh), 3.90 (d, J=12.9 Hz, 1H, NCHHPh), 4.61–
4.67 (broad d, J=7.3 Hz, 1H, H2), 7.22–7.34 (m, 13H,
Ar), 7.65 (d, J=7.2 Hz, 2H, Ar); 13C NMR: 41.9, 57.2,
62.1, 75.8, 127.3, 127.4, 127.8, 128.2, 128.4, 128.6, 128.7,
129.3, 133.0, 135.5, 136.9, 140.0, 151.9, 197.8. Anal. calcd
forC23H21NO:C, 84.37;H, 6.46;N, 4.28. Found:C, 84.25;
H, 6.55; N, 4.23%.
3.5. (2R,3R)-(1-Allyl-3-phenylazetidin-2-yl)phenyl-
methanone, 24
Following the above procedure and starting from various
mixturesofcyanoazetidines22and23(300mg, 1.5mmol),
ketone 24 was obtained as a 10:1 epimeric mixture after
flash chromatography (E/PE: 4/6) (290 mg, 69%). Major
epimer 24: Rf: 0.36 (E/PE: 4/6); IR (film): 1680 (CO), 1598,
1
1
(CO), 1444, 1229, 743 cm−1; H NMR: 1.28 (d, J=5.9
917, 743 cm−1; H NMR: 3.27 (dd, J=8.7 and 6.6 Hz,
Hz, 3H, Me), 2.55 (s, 3H, NMe), 3.23–3.26 (m, 2H, H3,
H4), 4.27 (d, J=7.7 Hz, 1H, H2), 7.21–7.34 (m, 7H, Ar),
7.45 (t, J=6.9 Hz, 1H, Ar para), 7.65 (d, J=6.9 Hz, 2H,
Ar ortho/ortho%); 13C NMR: 29.7, 43.3, 50.4, 67.5, 75.4,
127.3, 128.1, 128.6, 128.7, 133.1, 135.3, 138.1, 197.7. Anal.
calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found:
C, 81.31; H, 7.39; N, 5.26%.
1H, H4), 3.37 (d, J=6.5 Hz, 2H, NCH2CH), 3.92 (q,
J=7.5 Hz, 1H, H3), 4.01 (t, J=5.8 Hz, 1H, H4 ), 4.56 (d,
J=8.3Hz, 1H, H2), 5.24–5.40(m, 2H, CH2CH),%5.88–6.01
(m, 1H, CH2CH), 7.20–7.35 (m, 8H, Ar), 7.65 (d, J=7.2
Hz, 2H, Ar); 13C NMR: 42.0, 57.5, 61.3, 77.9, 118.1, 127.3,
127.5, 127.8, 128.0, 128.1, 128.15, 128.2, 128.5, 128.6,
133.1, 133.9, 135.1, 139.6, 197.5.
Starting from cyano azetidine 4 and following the same
procedure, the same ketone was obtained in 76% yield.
The intermediate crude imine 6 showed the following
signals in NMR: 1H NMR: 1.52 (d, J=6.2 Hz, 3H, Me),
2.41 (s, 3H, NMe), 3.47 (dd, J=3.0 and 8.8 Hz, 1H, H3),
3.92 (qd, J=6.6 and 3.0 Hz, 1H, H4), 4.71 (d, J=8.8 Hz,
3.6. (1%R,2S,3S,4S)-(1,4-Dimethyl-3-phenylazetidin-2-
yl)phenylmethanol, 16
To a solution of 8 (197 mg, 0.74 mmol) in ethanol (8 mL)
and cooled to −78°C was added in one portion sodium
borohydride (33.7 mg, 0.891 mmol). After 1.5 h of stirring
at −78°C, the reaction mixture was allowed to reach
gradually rt and was quenched by addition of a saturated
aqueous solution of NH4Cl (2 mL). Water was then added
and ethanol was evaporated under reduced pressure.
Basification with an aqueous 1 M solution of NaOH and
addition of diethylether was followed by usual workup
to give an oil that was chromatographed (Et2O). Amino
alcohol 16 was obtained as a clear oil that crystallized
on standing (146 mg, 74%). Rf: 0.50 (E/Ethanol: 9/1); mp:
37°C; [h]2D0: −26.1 (c 0.4, CHCl3) IR (KBr): 3416 (OH),
1593, 1321, 1163 cm−1; 1H NMR: 1.31 (d, J=6.3 Hz, 3H,
Me), 2.46 (s, 3H, NMe), 3.03–3.10 (m, 1H, H4), 3.20 (t,
J=7.7 Hz, 1H, H3), 3.29 (dd, J=3.4 and 7.4 Hz, 1H, H2),
1H, H2), 7.11–7.78 (m, 18H, Ar), 10.6 (bs, 1H, NH); 13
C
NMR: 15.4, 35.8, 49.5, 62.3, 70.3, 115.8 to 145.7: aromatic
carbons including impurities from the reagent, 173.5.
3.3. (2R,3R,4S)- and (2S,3R,4S)-(1,4-Dimethyl-3-phenyl-
azetidin-2-yl)phenylmethanone, 11 and 12
Following the above procedure and starting from
cyanoazetidine 9 (250 mg, 1.34 mmol), crude imine 10 was
obtained, that gave a 7:3 epimeric mixture of ketones
11:12 as an oil after chromatography (E/PE: 6/4) (274 mg,
1
77%). Major epimer 11: Rf: 0.57 (E/PE: 7/3); H NMR:
0.91 (d, J=6.3 Hz, 3H, Me), 2.51 (s, 3H, NMe), 3.50 (qd,
1H, J=6.6 and 7.7 Hz, 1H, H4), 4.07 (bt, J=7.7 Hz, 1H,
H3), 4.48 (d, J=8.1 Hz, 1H, H2), 7.01–7.15 (m, 2H, Ar),
7.20– 7.35 (m, 8H, Ar), 7.65 (d, J=6.9 Hz, 2H, Ar
ortho/ortho%); 13C NMR: 15.1, 36.7, 44.4, 69.7, 76.7, 126.7,
126.9, 127.7, 127.8, 127.9, 128.1, 128.5, 128.8, 132.8,
136.1, 197.9. The following selected signals belong to the
minor epimer 12: 1H NMR: 0.90 (d, J=6.3 Hz, 3H, Me),
2.44 (s, 3H, NMe) 5.10 (d, J=5.9 Hz, 1H, H2); 13C NMR:
13.9, 36.7, 44.4, 73.8.
4.30 (bs, 1H, OH), 4.79 (d, J=3.5 Hz, 1H, H1 ), 6.66 (dd,
%
J=1.5 and 6.6 Hz, 2H, Ar), 7.05–7.42 (m, 8H, Ar). The
following selected signals belong to the minor isomer in
the crude reaction mixture: 2.13 (s, NMe), 4.65 (bs, H2);
13C NMR: 20.3, 41.3, 43.7, 66.5, 75.8, 125.8, 127.1, 127.2,
128.2, 139.7, 140.7. Anal. calcd for C18H21NO: C, 80.86;
H, 7.92; N, 5.24. Found: C, 80.77; H, 8.05; N, 5.11%.
Following the procedure described in Ref. 7, the same
product was obtained with >98% de.
3.4. (2R,3R)-(1-Benzyl-3-phenylazetidin-2-yl)phenyl-
methanone, 15
3.7. (1%S,2R,3R)- and (1%R,2R,3R)-(1-Benzyl-3-phenyl-
azetidin-2-yl)phenylmethanol, 17a and 17b
Following the above procedure and starting from
cyanoazetidine 13 (198 mg, 0.8 mmol), ketone 15 (287 mg,
Following the above procedure and starting from ketone
15 (1.51 g, 4.6 mmol), alcohols 17a and 17b were obtained,

F. Couty, D. Prim / Tetrahedron: Asymmetry 13 (2002) 2619–2624
2623
after chromatography (E/PE: 4/6) in 66 and 17% yield,
respectively. 17a: mp: 79°C; Rf: 0.35 (E/PE: 4/6); [h]2D0:
+29 (c 0.9, CHCl3); IR (KBr): 3401 (OH), 1598, 1490,
85.89; H, 6.71; N, 3.45. Found: C, 85.92; H, 6.71; N,
3.33%.
1
733 cm−1; H NMR: 3.11 (dd, J=6.3 and 7.2 Hz, 1H,
3.10. (R)-2-Allylamino-2-phenylethanol, 19
H2), 3.62–3.88 (m, 5H, H3, H4, H4 and NCH2Ph), 4.53
%
To a stirred solution of (R)-phenylglycinol (2 g, 14.6
mmol) and DBU (2.2 mL, 14.6 mmol) in toluene (60
mL) was added dropwise allylbromide (1.3 mL, 15
mmol). The solution was stirred for 30 min at 40°C and
hydrolyzed by addition of water (50 mL). Extraction of
the aqueous layer with ether, was then followed by
usual workup to give crude alcohol that was chro-
matographed (E/ethanol: 95/5) to give 19 (1.53 g, 59%).
Rf: 0.74 (E/ethanol: 95/5); [h]2D0: −6.8 (c 1, CHCl3) IR:
(d, J=3.7 Hz, 1H, H1 ), 6.59–6.62 (m, 2H, Ar), 7.04–
%
7.24 (m, 13H, Ar); 13C NMR: 34.9, 57.5, 61.4, 71.0,
77.5, 125.8, 125.9, 127.0, 127.2, 127.5, 127.9, 128.2,
128.5, 128.8, 137.6, 139.4, 141.3. Anal. calcd for
C23H23NO: C, 83.85; H, 7.04; N, 4.25. Found: C, 83.74;
H, 7.07; N, 4.10%.
Compound 17b: mp: 95°C; Rf: 0.17 (E/PE: 4/6); [h]2D0:
+109 (c 1, CHCl3); IR (KBr): 3426 (OH), 1590, 1060,
1
3421 (OH), 1634, 763 cm−1; H NMR: 2.86 (bs, 2H,
1
743 cm−1; H NMR: 3.06 (dd, J=6.6 and 7.1 Hz, 1H,
NH, OH), 3.04–3.11 (m, 1H, NCH2), 3.17–3.25 (m, 1H,
NCH2), 3.56 (dd, J=10.8 and 8.9 Hz, 1H, H1), 3.75
H2), 3.35 (AB syst., J=13.2 Hz, 2H, H5), 3.66–3.84 (m,
3H, H4, H4 , H3), 4.25 (bs, 1H, OH), 4.74 (bs, 1H, H1 ),
%
7.16–7.26 (%m, 15H, Ar); 13C NMR: 38.5, 57.8, 62.3,
72.8, 78.5, 126.1, 127.5, 127.9, 128.0, 128.1, 129.1,
129.2, 129.3, 129.4, 138.3, 141.9, 144.1. Anal. calcd for
C23H23NO: C, 83.85; H, 7.04; N, 4.25. Found: C, 83.73;
H, 7.10; N, 4.10%.
(dd, J=10.8 and 4.3 Hz, 1H, H1 ), 3.81 (dd, J=8.6 and
%
4.3 Hz, 1H, H2), 5.08–5.18 (m, 2H, CH2CH), 5.82–5.88
(m, 1H, CH2CH), 7.22–7.40 (m, 5H, Ar); 13C NMR:
49.8, 63.9, 66.6, 116.2, 127.4, 127.6, 128.6, 140.5, 136.5,
140.5.
3.11. (R)-[Allyl-(2-hydroxy-1-phenylethyl)amino]-
acetonitrile, 20
3.8. (2S,3R,4S)-(1,4-Dimethyl-3-phenylazetidin-2-yl)di-
phenylmethanol, 28
A suspension of 19 (1.5 g, 8.47 mmol), bromoacetoni-
trile (1.2 g, 11 mmol) and potassium carbonate (1.8 g,
13 mmol) in acetonitrile (70 mL) was stirred at rt for 4
h. Evaporation of the solvent under reduced pressure
was followed by addition of water and diethylether to
the residue. Usual workup and further flash chromatog-
raphy (E/PE: 1/1) gave 20 (1.4 g, 65%). Rf: 0.56 (E/PE:
1/1); [h]2D0: −11.6 (c 0.4, CHCl3); IR (film): 3431 (OH),
To a solution of 8 (211 mg, 0.796 mmol) in benzene (9
mL) cooled to 0°C was added dropwise was added
dropwise at 0°C a solution of phenyllithium in cyclo-
hexane/ether (1.8 M sol., 880 mL, 1.59 mmol). The
solution was stirred for 15 min at 0°C and hydrolyzed
by addition of water (10 mL). Extraction of the
aqueous layer with diethylether, washing of the organic
layer with aqueous 1M NaOH was then followed by
usual workup to give crude alcohol that was chro-
matographed (E/PE: 15/85) to give 28 as a crystalline
solid (248 mg, 91%). Rf: 0.45 (E/PE: 2/8); mp: 144°C;
[h]2D0: −20.7 (c 0.8, CHCl3); IR (KBr): 3288 (OH), 1490,
1
2233 (CN), 1644, 758 cm−1; H NMR: 2.28 (bs, 1H,
OH), 3.18–3.25 (m, 2H, NCH2CH), 3.51 (dd, J=17.4
and 0.7 Hz, 2H, CH2CN), 3.72–3.78 (m, 1H, H2), 3.78
(d, J=5.3 Hz, 2H, H1), 5.21–5.35 (m, 2H, CH2CH),
5.69–5.75 (m, 1H, CH2CH), 7.22–7.41 (m, 5H, Ar); 13C
NMR: 39.2, 54.6, 63.9, 67.6, 115.6, 119.4, 128.9, 129.3,
134.1, 138.3. Anal. calcd for C13H16N2O(+0.5H2O): C,
69.31; H, 7.61; N, 12.43. Found: C, 69.55; H, 7.50; N,
12.70%.
1
1450, 732 cm−1; H NMR: 1.25 (d, J=5.9 Hz, 3H, Me),
2.13 (s, 3H, NMe), 3.07–3.19 (m, 2H, H3 and H4), 4.13
(d, J=7.3 Hz, 1H, H2), 5.29 (bs, 1H, OH), 6.94 (dd,
J=1.5 and 6.6 Hz, 2H, Ar), 7.06–7.08 (m, 3H, Ar),
7.20–7.33 (m, 8H, Ar), 7.69 (d, J=8 Hz, 2H, Ar); 13C
NMR: 20.0, 42.2, 46.4, 66.7, 75.6, 78.2, 126.0, 126.1,
126.3, 126.5, 126.6, 127.7, 128.0, 128.1, 128.8, 139.7,
143.1, 146.9. Anal. calcd for C24H25NO: C, 83.93; H,
7.34; N, 4.08. Found: C, 83.89; H, 7.34; N, 4.05%.
3.12. (R)-[2-Allyl-(2-chloro-2-phenylethyl)-amino]-
acetonitrile, 21
To
a
solution of 20 (1.28 g, 5.9 mmol) in
dichloromethane (60 mL) was added dropwise thionyl
chloride (0.86 mL, 11.8 mmol) at 0°C. The mixture was
then heated under reflux for 4 h and hydrolyzed by
addition of a saturated aqueous solution of NaHCO3
(50 mL). Usual workup followed by flash chromatogra-
phy (E/PE: 1/1) gave quantitatively 21. Rf: 0.60 (E/PE:
1/1); [h]2D0: +10 (c 1.1, CHCl3); IR (film): 2228 (CN),
3.9. (2R,3R)-(1-Benzyl-3-phenylazetidin-2-yl)phenyl-
methanol, 29
Following the above procedure and starting from
ketone 15, alcohol 29 was obtained, after chromatogra-
phy (E/PE: 2/8) in 63% yield. Rf: 0.6 (E/PE: 2/8); mp:
79°C; [h]2D0: +268 (c 2.6, CHCl3); IR (KBr): 3288 (OH),
1
1639, 1495, 763 cm−1; H NMR: 3.07 (dd, J=14.0 and
1
1588, 1480, 743 cm−1; H NMR: 3.10 (t, J=7.5 Hz,
6.6 Hz, 1H, H2), 3.17 (dd, J=14.0 and 7.7 Hz, 1H, H2 ),
3.23 (d, J=6.2 Hz, 2H, NCH2CH), 3.46 (d, J=17.6 H%z,
1H, CH2CN), 3.60 (d, J=17.6 Hz, 1H, CH2CN), 4.91
(d, J=7.7 Hz, 1H, H1), 5.21–5.33 (m, 2H, CH2CH),
5.68–5.79 (m, 1H, CH2CH), 7.36–7.41 (m, 5H, Ar); 13C
NMR: 42.3, 57.9, 60.7, 61.5, 115.1, 119.7, 127.3, 128.7,
133.7, 139.5. Anal. calcd for C13H15ClN2: C, 66.52; H,
6.44; N, 15.10. Found: C, 66.51; H, 6.62; N, 15.21%.
1H,H2), 3.35 3.35 (AB syst., J=13.1 Hz, 2H, H5),
3.54–3.65 (m, 2H, H4, H4 ), 4.48 (d, J=6.9 Hz, 1H, H3),
%
5.46 (bs, 1H, OH), 6.87 (m, 2H, Ar), 7.06–7.18 (m,
16H, Ar), 7.70 (d, J=8.1 Hz, 2H, Ar); 13C NMR: 37.7,
57.4, 60.9, 77.5, 79.5, 126.1, 126.2, 126.5, 126.7, 126.8,
127.2, 127.8, 128.0, 128.2, 128.25, 128.4, 128.7, 137.5,
141.6, 142.8, 146.7. Anal. calcd for C29H27NO: C,

2624
F. Couty, D. Prim / Tetrahedron: Asymmetry 13 (2002) 2619–2624
3.13. (2R,3R)- and (2S,3R)-1-Allyl-3-phenylazetidin-2-
was then vigorously stirred for 30 min, filtered over a
Celite pad and dried over MgSO4. Flash chromatogra-
phy (E/pentane: 6/4) followed by preparative TLC (E/
cyclohexane: 5/5) gave a mixture of 26 and 27 (0.080 g).
26 and 27 have been undoubtedly identified by HRMS:
26 (m/z) [M+H]+ calcd for C17H16O2N, 266.1181;
found, 266.1172 and 27 (m/z) [M+H]+ calcd for
C21H26O3N, 340.1913; found, 340.1910.
carbonitrile, 22 and 23
To a solution of 21 (1 g, 4.27 mmol) in THF (70 mL)
was added dropwise at −90°C a THF solution of
lithium bis-trimethylsilylamide (1 M, 5.6 mL, 5.6
mmol). The mixture was then gradually (3 h) allowed to
reach 0°C and hydrolyzed by addition of saturated
aqueous solution of NH4Cl. Usual workup followed by
flash chromatography (E/PE: 2/8) gave azetidines 22
and 23 as a 2/1 mixture of isomers (780 mg, 90%).
Faster eluting isomer 22: Rf: 0.43 (E/PE: 20/80); [h]2D0:
−19.6 (c 7.4, CHCl3); IR (film): 2233 (CN), 1639, 917,
1H NMR: the following signals belong to oxazolidinone
26: 3.99 (m, 1H, H6), 4.16 (t, J=9 Hz, 1H, H7), 4.32 (t,
J=9.1 Hz, 1H, H7 ), 4.85 (t, J=7.7 Hz, 1H, H5), 5.85
(d, J=7.7 Hz, 1H,% H4), 6.77 (m 2H, Ar), 7.22 (m, 2H,
Ar), 7.33 (m, 2H, Ar), 7.42 (m, 4H, Ar); 13C NMR
(DEPT 135): 44.0 (CH), 57.8 (CH2), 72.0 (CH), 78.6
(CH), 124.9, 126.6, 127.5, 128.7, 128.7, 129.0 (aromatic
CH).
1
748 cm−1; H NMR: 3.19 (dd, J=7.9 and 6.5 Hz, 1H,
H4), 3.24 (d, J=6.2 Hz, 2H, NCH2CH), 3.79 (m, 2H,
H4 and H2), 3.95 (q, J=7.5 Hz, 1H, H3), 5.24–5.40 (m,
%
2H, CH2CH), 5.85–5.91 (m, 1H, CH2CH), 7.28–7.37
(m, 5H, Ar); 13C NMR: 41.3, 58.2, 58.4, 60.3, 118.9,
119.1, 126.9, 127.7, 128.9, 132.8; 138.4. Anal. calcd for
C13H14N2: C, 78.75; H, 7.12; N, 14.13. Found: C, 78.52;
H, 7.23; N, 14.05. Slower eluting isomer 23: Rf: 0.43
(E/PE: 20/80); [h]2D0: −3.2 (c 0.1, CHCl3); IR (film): 2233
Acknowledgements
1
(CN), 1644, 927, 748 cm−1; H NMR: 3.29 (d, J=6.2
Alexandra Weber is acknowledged for skilful technical
help. Abel Carlin-Sinclair is acknowledged for the
determination of e.e.s by HPLC.
Hz, 2H, NCH2CH), 3.87–3.91 (m, 1H, H3), 3.57 (d,
J=6.6 Hz, 2H, H4), 4.39 (d, J=8.1 Hz, 1H, H2), 5.26
(m, 2H, CH2CH), 5.84 (m, 1H, CH2CH), 7.36 (m, 5H,
Ar); 13C NMR: 38.9, 57.9, 58.4, 59.0, 116.8, 118.8,
126.8, 127.9, 128.7, 132.9; 137.4.
References
1. (a) Rodebaugh, R. M.; Cromwell, N. H. J. Heterocycl.
Chem. 1971, 421–430; (b) Kulkarni, S. B.; Cromwell, N.
H. J. Heterocycl. Chem. 1977, 981–983; (c) Arnould, J.
C.; Cossy, J.; Pete, J. P. Tetrahedron 1980, 36, 1585–1592.
2. Agami, C.; Couty, F.; Evano, G. Tetrahedron: Asymme-
try 2002, 13, 297–302.
3. Soai, K.; Niwa, S. Chem. Rev. 1992, 833–856.
4. Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359.
5. Bruylants, P. Bull. Soc. Chem. Belg. 1924, 33, 467.
6. The signal for the C-2 proton in these ketones appears
systematically more shielded to an amount of ca. 1 ppm
in 2,3-trans-isomers compared to the cis-isomers due to
the field effect of the a-phenyl substituent. See Section 3.
7. Besev, M.; Engman, L. Org. Lett. 2002, 4, 3023–3025.
8. N-Debenzylation of alcohol 17a failed in our hands. This
is the reason why we turned to the synthesis of an N-allyl
azetidine.
3.14. (1%S,2R,3S)-(1-Allyl-3-phenylazetidin-2-yl)-phenyl-
methanol, 25
Following the procedure described in Ref. 7 and start-
ing from ketone 24, alcohol 25 was obtained, after
chromatography (E/pentane: 1/1) in 68% yield. Rf: 0.5
(E/pentane: 1/1); mp: 55°C; [h]2D0: +9.4 (c 6.6, CHCl3);
IR (film): 3405 (OH), 2245 (CN), 1454, 1373, 732 cm−1;
1H NMR: 2.70 (bs, H, OH), 3.07 (t, J=7.3 Hz, 1H,
H4), 3.20 (m, 1H, NCH2CH), 3.33 (m, 1H, NCH2CH),
3.55 (m, 1H, H2), 3.70 (q, J=7.3 Hz, 1H, H3), 4.01 (t,
J=6.1 Hz, 1H, H4 ), 4.82 (d, J=3.3 Hz, 1H, CH(OH)),
%
5.17–5.31 (m, 2H, CH2CH), 5.82–5.93 (m, 1H,
CH2CH), 6.60 (m, 2H, Ar), 7.04 (m, 3H, Ar), 7.17–7.25
(m, 5H, Ar), 13C NMR: 34.8, 57.1, 59.9, 71.1, 77.5,
117,8, 125.8, 125.9, 127.0, 127.2, 127.9, 128.1, 134.2,
139.5, 141.2. Anal. calcd for C19H21NO: C, 81.68; H,
7.58; N, 5.01. Found: C, 81.41; H, 7.54; N, 5.01%.
9. Upon screening of different bases and solvents, the
described conditions were found to be the best for mini-
mizing the amount of diallylation.
3.15. (4S,5R,6S)-4,6-Diphenyl-3-oxa-1-aza-bicyclo[3.2.0]-
heptan-2-one, 26
10. Alcaide, B.; Almendros, P.; Alonso, J. M.; Aly, M. F.
Org. Lett. 2001, 3, 3781–3784.
11. For previously reported use of azetidinic amino alcohols
in this reaction, see: (a) Behnen, W.; Mehler, T.; Martens,
J.; Tetrahedron: Asymmetry 1993, 4, 1413–1416; (b) Shi,
M.; Jiang, J. K. Tetrahedron: Asymmetry 1999, 10, 1673–
1679; (c) Wilken, J.; Erny, S.; Wassman, S.; Martens, J.
Tetrahedron: Asymmetry 2000, 11, 2143–2148; (d)
Hermsen, P. J.; Cremers, J. G. O.; Thijs, L.; Zwanenburg,
B. Tetrahedron Lett. 2001, 42, 4243–4245.
To a solution protected from light of compound 25
(0.130 g, 0.34 mmol) in anhydrous toluene (8 mL), was
added in portions Cl2(Cy3P)2RuꢀCHPh (0.024 g, 0.03
mmol) under argon. The resulting mixture was heated
at reflux until complete disappearance of the starting
material and was concentrated under reduced pressure.
The residue was dissolved in CH2Cl2 and silica gel
followed by water were added. The resulting mixture