Critical importance of leaving group 'softness' in nucleophilic ring closure reactions of ambident anions to 1,2-diazetidines

Article abstract of DOI:10.1016/j.tetlet.2009.11.024

Highly strained, four-membered 1,2-diazetidine rings are produced in good yields (50-98%) in nucleophilic ring closure reactions provided 'soft' leaving groups such as iodide are used, a finding that can be rationalised in terms of the Hard Soft Acids and Bases principle.

Full text of DOI:10.1016/j.tetlet.2009.11.024

Tetrahedron Letters 51 (2010) 382–384
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Critical importance of leaving group ‘softness’ in nucleophilic ring closure
reactions of ambident anions to 1,2-diazetidines
Michael J. Brown a, Guy J. Clarkson a, David J. Fox a, Graham G. Inglis b, Michael Shipman a,
*
a Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly strained, four-membered 1,2-diazetidine rings are produced in good yields (50–98%) in nucleo-
philic ring closure reactions provided ‘soft’ leaving groups such as iodide are used, a finding that can
be rationalised in terms of the Hard Soft Acids and Bases principle.
Received 1 October 2009
Revised 5 November 2009
Accepted 9 November 2009
Available online 12 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Since the discovery of the potent biological effects of the b-lac-
tam antibiotics,1,2 there has been significant interest in the synthe-
sis and properties of four-membered heterocycles.3 However,
much of this work has been hampered by the difficulty associated
with the preparation of these systems, largely because of the
intrinsic ring strain associated with four-membered rings.4 An
interesting case in point is the 1,2-diazetidine nucleus which has
two adjacent nitrogen atoms within the four-membered ring.
Although the biological effects of various 1,2-diazetidinones have
been assessed because of their structural similarity to b-lactams,5
systematic studies into the chemistry of 1,2-diazetidines have been
severely impeded by the lack of general routes for their prepara-
tion. For example, simple 1,2-diazetidines such as 1a–d bearing
Boc, Cbz, Ms and SO2Ph groups, respectively, on the nitrogen atoms
have not been made (Fig. 1). In this Letter, we disclose an efficient
synthesis of a range of 1,2-diazetidines including 1a–d, by nucleo-
philic ring closure. We show that the nature of the leaving group is
critical to facilitating four-membered ring formation, observations
that can be understood qualitatively in terms of the Hard Soft Acids
and Bases (HSAB) principle.6 These findings are expected to have
broader significance in relation to effecting other ‘difficult’ nucleo-
philic ring closure reactions. Moreover, these studies call into
doubt earlier work7 purporting the synthesis of 1,2-diazetidines
by nucleophilic ring closure.
limited.9 Of the ring closure methods, bisalkylation of 1,2-dial-
kylhydrazines with 1,2-dibromoethane provides 1,2-diazetidines
directly, although yields are moderate at best.10 In a related study,
Miao et al. reported that the intramolecular ring closure of
1-(1-hydroxy-propan-2-yl)hydrazine-1,2-dicarboxylate derivatives
provides an efficient route to enantiomerically enriched 1,2-diazeti-
dines in high yields.7 Most recently, Ma disclosed an efficient ring
closure method based upon the reaction of 2,3-allenyl hydrazines
with aryl halides under palladium catalysis.11
Our studies began with the examination of the ring closure of
alcohol 2a (X = OH), which was readily synthesised by treatment
of commercially available 2-hydroxyethyl-hydrazine with di-tert-
butyl dicarbonate in 94% yield. Reaction of 2a under Mitsunobu
conditions led solely to the formation of oxadiazine 3 in 64% iso-
lated yield by way of ring closure through the carbamate oxygen
to form a six-membered ring (Scheme 1 and Table 1, entry 1). Ring
closure of the corresponding mesylate 2b using Cs2CO3 (8 equiv) in
MeCN led to the same product in essentially quantitative yield.
However, formation of the required 1,2-diazetidine was encour-
t
1a (X = CO2 Bu);
X
X
1b (X = CO2Bn);
1c (X = SO2Me);
1d (X = SO2Ph)
N
N
Both cycloaddition and ring closure strategies have been
explored in the search for preparatively useful routes to 1,2-diaz-
etidines.7–11 The most direct approach centres on [2
p p] cycload-
+2
ditions of azodicarbonyl compounds with electron-rich alkenes.8
However, competing [4 +2 ] cycloadditions and ene rearrange-
ments are often the main results in these attempts. High yielding
[2 +2 +2 ] cycloadditions of azodicarboxylate derivatives with
Figure 1.
p
p
Boc
NHBoc
N
Boc
Boc
N
N
O
base
see
Table 1
r
r p
N
N
OtBu
quadricyclane have been reported, although substrate scope is very
Boc
X
2a-e
1a
3
* Corresponding author. Tel.: +44 247 652 3186; fax: +44 247 652 4112.
E-mail address: m.shipman@warwick.ac.uk (M. Shipman).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.024

M. J. Brown et al. / Tetrahedron Letters 51 (2010) 382–384
383
Table 1
Table 2
Cyclisation to 1,2-diazetidine 1a and/or 1,3,4-oxadiazine 3
Selected geometric parameters and spectral data for 1a compared to EtO2CNHNH-
CO2Et (4)
Entry
Substrate
X
Conditionsa
1a:3b
Yieldc
Parameter
1a
4d
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2e
2e
2e
2e
2e
OH
OMs
Cl
Br
I
I
I
I
I
PPh3, DEAD, THF, 0 °C
Cs2CO3, MeCN
Cs2CO3, MeCN
Cs2CO3, MeCN
Cs2CO3, MeCN
sec-BuLi, THF
NaOtBu, THF
0:100
3:97
64% (3)
96% (3)
—
—
C6–N7
C6–O6
N7–N70
1.3915 Å
1.2083 Å
1.4505 Å
101.51°
33.4°
30.67°
1739
160.2
1.352 Å
1.209 Å
1.379 Å
83.92°
4.3°
n.d.
1712
158.7
27:73
40:60
54:46
0:100
6:94
53% (1a)
C6–N7–N70–C60
sa
—
—
—
—
—
Pyram(N7)b
C@O stretch/cmꢀ1
NMR d (C@O)c
KOtBu, THF
7:93
TBD,d MeCN
DBU, MeCN
50:50e
55:45
10
I
a
The amide twist angle (s
) as defined by Winkler and Dunitz,13 and modified by
a
Procedures are provided in the Supplementary data.
Determined by 1H NMR analysis of the crude reaction mixture. Complete con-
Yamada.14
P
P
b
b
The pyramidalisation of the nitrogen atoms is defined as 360 ꢀ
where
is
sumption of starting material unless otherwise stated.
the sum of the valence angles of the nitrogen atom.
c
c
Yield after silica gel chromatography.
TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene.
Reaction did not go to completion.
In CDCl3.
d
d
Crystallographic data from Linke and Kalker,15 spectroscopic data from Çavdar
e
and Saraçologlu.16
aged by the use of a halide as the leaving group. Using 2c (X = Cl), a
small amount of diazetidine 1a was observed. Improved results
were achieved with bromide 2d (X = Br), and using iodide 2e
(X = I), bis-Boc diazetidine 1a was the major product and could
be isolated in appreciable quantities (53%). Moreover, the use of
large, diffuse cations favoured diazetidine formation (Table 1,
entries 5–10).
of temperatures (223–373 K). The barrier to inversion in 1,2-dim-
ethyldiazetidine is 16.4 kcal molꢀ1 10a
indicating that the presence
,
of electron-withdrawing Boc groups results in a greater rate of
N-inversion.17
The optimised cyclisation conditions were applied to the
synthesis of 1,2-diazetidines 1b–d (Scheme 2). Again, conversion
of iodide 5 into 1b was accompanied by production of quantities
The structures of diazetidine 1a (Fig. 2) and oxadiazine 3 (see
Supplementary data) were deduced unambiguously by X-ray crys-
tallography.12 It is instructive to compare selected data for 1a
alongside diethyl hydrazinedicarboxylate (4) (Table 2). The crystal-
lographically identical nitrogen atoms within 1a are highly pyra-
of the corresponding 1,3,4-oxadiazine 6 (56:44 ratio before
purification) by way of cyclisation through the carbamate oxygen.
Interestingly, cyclisation to sulfonamides 1c and 1d, which can
only occur through nitrogen, works much better using iodides 7b
or 8b instead of the corresponding sulfonate esters 7a or 8a.
The sensitivity of these cyclisations to the nature of the leaving
group can be understood in terms of the Hard Soft Acids and Bases
(HSAB) principle introduced by Pearson.6 The ambident carbamate
nucleophile closes through nitrogen or oxygen producing either
the four or six-membered ring, respectively. Cyclisation to
six-membered rings is normally faster,4,18 and with a substrate
containing a ‘hard’ leaving group the reaction proceeds via oxygen
giving 3 as essentially the sole product (Table 1, entries 1 and 2).
Using a much ‘softer’ leaving group based on a polarisable C–I
bond, closure through the nitrogen to produce the strained four-
membered ring becomes competitive (Table 1, entry 5). Matching
of the reacting centres in this way allows the kinetic preference
for the formation of the six-membered ring to be overcome, and
provides a synthetically useful route to 1,2-diazetidines.
midal, displaying significant amide twist angles (s) and bond
lengths consistent with poor overlap between the nitrogen lone
pair and the C@O bond. By adopting this conformation, electron
repulsion between the nitrogen lone pairs, and steric clash be-
tween the carbamate groups are minimised. Moreover, the diazeti-
dine ring suffers less Baeyer strain than would occur if the nitrogen
atoms were planar. DFT calculations (B3LYP) produce ground state
structures that closely match the experimental structures of 1a and
3 (see Supplementary data).
In the 1H NMR spectrum (CDCl3, 300 MHz), all the ring hydro-
gens of 1a are chemically equivalent producing a single resonance
at d 4.12 (4H, s), suggesting fast pyramidal inversion on the NMR
timescale. No changes to this signal occurred over a wide range
Cbz
Cs2CO3, rt
MeCN, 5 h
NHCbz
N
Cbz
Cbz
N
N
O
N
N
OBn
+
Cbz
I
5
1b (50%)
6 (42%)
Cs2CO3, rt
MeCN, 5 h
NHSO2Me
MeO2S
SO2Me
N
N
N
MeO2S
X
13% (X = OMs);
73% (X = I)
1c
7a (X = OMs);
7b (X = I);
Cs2CO3, rt
MeCN, 5 h
NHSO2Ph
N
PhO2S
SO2Ph
N
N
PhO2S
X
0% (X = OSO2Ph);
98% (X = I)
8a (X = OSO2Ph);
8b (X = I)
1d
Figure 2. ORTEP representation of the X-ray structure of 1a with thermal ellipsoids
drawn at 50% probability.
Scheme 2.

384
M. J. Brown et al. / Tetrahedron Letters 51 (2010) 382–384
MsCl, DBU
Acknowledgements
Cbz
nPr
Cbz
Cbz
nPr
N
OBn
Cbz
NHCbz
OH
CH2Cl2, 0 °C
N
N
N
N
NOT
O
This work was supported by GlaxoSmithKline and the Engineer-
ing and Physical Sciences Research Council. We thank the EPSRC
Crystallographic Service for recording the data for 1a. The Oxford
Diffraction Gemini XRD system was obtained, through the Science
City Advanced Materials project: Creating and Characterizing Next
Generation Advanced Materials, with support from Advantage
West Midlands.
nPr
36%
9
10
11
Scheme 3.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.024.
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