A novel and efficient method for the synthesis of 1,2-diazetidines

Article abstract of DOI:10.1016/j.tetlet.2006.07.075

A novel and efficient method has been developed for the preparation of racemic or optically pure 1,2-diazetidine from 1-(1-hydroxy-propan-2-yl)hydrazine-1,2-dicarboxylate under very mild conditions with excellent yield.

Full text of DOI:10.1016/j.tetlet.2006.07.075

Tetrahedron Letters 47 (2006) 6835–6837
A novel and efficient method for the synthesis of 1,2-diazetidines
Wei Miao, Weiliang Xu, Zhiliu Zhang, Rujian Ma,* Shu-Hui Chen and Ge Li
WuXi PharmaTech Co. Ltd., 288 FuTe Zhong Road, No.1 Building, WaiGaoQiao Free Trade Zone, Shanghai 200131, PR China
Received 15 May 2006; revised 13 July 2006; accepted 14 July 2006
Available online 8 August 2006
Abstract—A novel and efficient method has been developed for the preparation of racemic or optically pure 1,2-diazetidine from
1-(1-hydroxy-propan-2-yl)hydrazine-1,2-dicarboxylate under very mild conditions with excellent yield.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
the desired 1,2-diazetidine derivative 1a was obtained
in 88% yield.
1,2-Diazetidine is an important moiety in organic and
medicinal chemistry.1,2 So far, there have been a limited
number of efficient synthetic methods developed for its
synthesis. Currently, the most popular synthetic method
involves the use of [2+2] cycloaddition reaction.1 A few
examples utilizing intramolecular cyclization to prepare
1,2-diazetidine have also been reported.2,3 As one of our
on-going programs, we need to develop a more efficient
method to prepare 1,2-diazetidines, particularly the 3-
substituted 1,2-diazetidine 1. We envisioned the prepa-
ration of such compounds via intramolecular cyclization
of 1-(1-hydroxy-3-propan-2-yl)hydrazine derivatives 2
as illustrated in Figure 1.
Despite the success achieved with Mitsunobu reaction as
shown in Scheme 1, we encountered problems with the
final product purification (removal of triphenyl phos-
phine oxide). In light of this issue, we decided to develop
other milder and cleaner reaction conditions for such
cyclizations. We considered activation of the hydroxyl
group to a better leaving group such as mesylate, which
could then be displaced by the nitrogen nucleophile
(within 2a) through an intramolecular cyclization
process to give the desired 1,2-diazetidine (such as 1a)
as depicted in Scheme 2.
Treatment of dichloromethane solution of 2a with
1.5 equiv of MsCl along with 3 equiv of Et3N resulted
in only trace amount of the desired product 1a. The
major product formed was the intermediate 3 as judged
by LC–MS (entry A). No improvement was observed
even under prolonged heating. When the same reaction
was tried in the presence of 8 equiv of Et3N, the desired
product 1a was obtained in 25% yield (entry B). Interest-
ingly, replacement of Et3N with DIEA led to only 5% of
the desired product (entry C). In contrast, replacing
Et3N by DBU afforded the desired product 1a in almost
quantitative yield (entry D). Detailed experimental pro-
cedure for this intramolecular cyclization is provided in
Ref. 5. When K2CO3 or Cs2CO3 was used as base in
conjunction with acetonitrile as solvent, the desired
diazetidine 1a was produced in 85% or 92% yield,
respectively (entries E and F) (Scheme 3).
We firstly tested the intramolecular Mitsunobu reaction
of the dibenzyl 1-(1-hydroxy-3-phenylpropan-2-yl)-
hydrazine-1,2-dicarboxylate 2a, which was in turn
prepared readily from 3-phenylpropanal according to
the protocol described by List.4 To our satisfaction,
OH
R1
R1
N
N
N
H
R2
R2
R2
N
R2
1
2
Figure 1. Retrosynthetic analysis for the synthesis of 1-substituted 1,2-
diazetidine.
To further probe the generality of above method, we
examined the cyclizations with a series of 1-(1-hydr-
oxy-propan-2-yl)hydrazine-1,2-dicarboxylate derivatives
*
Corresponding author. Tel.: +86 21 5046 1111; fax: +86 21
50463718; e-mail: marj@pharmatechs.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.075

6836
W. Miao et al. / Tetrahedron Letters 47 (2006) 6835–6837
Cbz
N
OH
Cbz
N
Ph
Proline
then NaBH4
DEAD, THF
88%
Ph
Cbz
CHO
N
N
Ph
3-phenylpropanal
N
H
Cbz
Cbz
N
Cbz
2a
1a
Scheme 1. Intramolecular Mitsunobu cyclization method.
OMs
OH
Ph
MsCl (1.5 eq.), Base
solvent, rt
Ph
Cbz
Ph
Cbz
N
H
N
N
N
N
H
N
Cbz
Cbz
Cbz
Cbz
2a
3
1a
Scheme 2. One-pot synthesis of 1-substituted 1,2-diazetidine.
N
Cbz
OH
Cbz
N
Ph
MsCl, DBU
(R)-Proline
then NaBH
Ph
Cbz
CHO
Ph
3-phenylpropanal
N
N
N
H
CH Cl
2
2
N
Cbz
Cbz
4
Cbz
96%
(S)-2a
(S)-1a
98% ee
98% ee
Scheme 3. The synthesis of the optically pure 1,2-diazetidine.
bearing different R1 and R2 groups under the reaction
conditions described in entry D of Table 1. The results
are summarized in Table 2. To our satisfaction, all of
the substrates examined (entries G–N), regardless of
the nature of R1 and R2 moieties used, gave the corre-
sponding 1,2-diazetidines in excellent yield.
Table 2. Generation of cyclizations
OH
1
2
1
R
R
R
MsCl (1.5 eq.), DBU (8 eq.)
CH Cl , rt
N
H
N
N
2
R
N
2
2
2
R
2
R
2
1
Since the acyclic intermediate 2a can be prepared in ena-
tiomerically pure form,4 we envisioned that the two-step
sequence discussed in this letter could be used to prepare
optically pure 1,2-diazetidine derivatives. Thus, the opti-
cally pure precursor (S)-2a was prepared from proline-
catalyzed amination of 3-phenylproponal with Cbz pro-
tected azodicarboxylate according to the protocol of
List.4 Further treatment of (S)-2a with MsCl in the pres-
ence of DBU led to the formation of enatiomerically
pure (S)-1-benzyl-1,2-diazetidine 1a in 96% yield. The
ee value of 1a was determined to be 98% on the basis
of chiral HPLC analysis.6
Entry
R1
R2
Yield (%)
G
H
I
PhCH2–
PhCH2–
PhCH2–
PhCH2–
Cbz
96
90
90
85
96
95
93
93
COOEt
COOiPr
Boc
Cbz
Cbz
J
K
L
M
N
CH3–
CH3CH2CH2–
(CH3)2CH2–
CH3(CH2)3À
Cbz
Cbz
2. Conclusions
We describe herein a general and efficient method for the
synthesis of 3-substituted racemic or chiral 1,2-diazeti-
dine from 1-(1-hydroxy-propan-2-yl) hydrazine-1,2-
dicarboxylate under very mild conditions in excellent
yield.
Table 1. Optimization of the reaction conditions
Entry
Base
Equivalent
Solvent
Reaction
time
Yield
(%)
A
B
C
D
E
F
Et3N
Et3N
DIEA
DBU
K2CO3
Cs2CO3
3
8
8
8
8
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3CN
2 days
2 days
2 days
6 h
2 days
1 day
Trace
25
5
96
85
References and notes
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92
6376–6385; (b) Abarca-Gonzalez, B.; Jones, R. A.; Medio-

W. Miao et al. / Tetrahedron Letters 47 (2006) 6835–6837
6837
Simon, M.; Quiliz-Pardo, J.; Sepulveda-Arques, J.; Zabal-
los-Garcia, E. Synth. Commun. 1990, 20, 321–331; (c)
Paquette, L. A.; Webber, P.; Simpson, L. Org. Lett. 2003, 5,
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for 5–8 h (monitored by TLC) at room temperature. The
reaction mixture was cooled to 0 ꢁC and neutralized with
saturated aqueous citric acid to pH 7, the phases were
separated and the aqueous phase was extracted with
CH2Cl2 (2 · 20 mL). The organic layers were combined
and washed with saturated aqueous NaHCO3 (30 mL),
brine, dried (Na2SO4), filtered, and evaporated under
vacuum to afford the crude product. Purification by
chromatography on silica gel (Hexane/ethyl acetate 15:1)
afforded 1,2-diazetidine 1a (2.02 g, yield 96%). 1H NMR of
1a (400 MHz, CDCl3) d: 7.50–7.10 (m, 15H), 5.30–5.10 (m,
4H), 4.45–4.54 (m, 1H), 4.18 (d, J = 10.8 Hz, 1H), 4.14 (d,
J = 10.8 Hz, 1H), 2.95 (dd, J = 12.8 and 5.2 Hz, 1H), 2.80
(dd, J = 12.8 and 10.0 Hz, 1H).
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(b) Alder, R. W.; Sessions, R. B.; Bennet, A. J.; Moss, R. E.
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Wu, J.; Sandstroem, A.; Chattopadhyaya, J. Tetrahedron
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3. Intramolecular cyclization to generate 1,2-pyrazolidine and
1,2-piperazine have been reported using strong base: (a)
Schmidt, U.; Braun, C.; Sutoris, H. Synthesis 1996, 2, 223–
229; (b) Hale, K. J.; Cai, J.; Delisser, V.; Manaviazar, S.;
Peak, S. A. Tetrahedron 1996, 52, 1047–1068; (c) Kamene-
cka, T. M.; Danishefsky, S. J. Chem. Eur. J. 2001, 7, 41–63;
(d) Henmi, Y.; Makino, K.; Yoshitomi, Y.; Hara, O.;
Hamada, Y. Tetrahedron: Asymmetry 2004, 15, 3477–3482.
4. List, B. J. Am. Chem. Soc. 2002, 124, 5656–5657.
5. Typical cyclization procedure of 2: To a solution of 2a
(2.20 g, 5.1 mmol) and DBU (6.16 g, 40.6 mmol) in anhy-
drous CH2Cl2 (50 mL) was added dropwise MsCl (0.6 mL,
7.6 mmol) in anhydrous CH2Cl2 at 0 ꢁC. After addition, the
ice-bath was removed and the reaction mixture was stirred
6. In order to determine the ee% value of (S)-1a and (S)-2a,
(R)-1a and (R)-2a were prepared following a similar
procedure using (S)-proline for the asymmetric hydrazin-
ation step. The ee% value measured for 2a was 98% using
chiral HPLC (Daicel Chiralcel AD-H, 0.46 · 25 cm · 5 lm;
MeOH/CO2 (3:7), 2.35 mL/min; 100 bar; 30 ꢁC; Rt =
6.90 min for R-isomer; Rt = 8.01 min for S-isomer). The
ee% value measured for 1a was 98% using chiral HPLC
(Daicel Chiralcel AS-H, 0.46 · 25 cm · 5 lm; isopropanol/
CO2 (1:9) 2.35 mL/min; 100 bar; 30 ꢁC; Rt = 7.32 min for
R-isomer; Rt = 8.13 min for S-isomer).