Synthesis and functionalization of 3-alkylidene-1,2-diazetidines using transition metal catalysis

Article abstract of DOI:10.1021/ol200193n

An efficient two-step synthesis of a wide range of 3-methylene-1,2- diazetidines has been developed through application of a Cu(I)-catalyzed 4-exo ring closure. The double bond of this new class of strained heterocycle can be functionalized in a stereocon

Full text of DOI:10.1021/ol200193n

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1686–1689
Synthesis and Functionalization of
3-Alkylidene-1,2-diazetidines Using
Transition Metal Catalysis
Michael J. Brown,† Guy J. Clarkson,† Graham G. Inglis,‡ and Michael Shipman*,†
Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom,
and GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage,
Hertfordshire, SG1 2NY, United Kingdom
m.shipman@warwick.ac.uk
Received January 21, 2011
ABSTRACT
An efficient two-step synthesis of a wide range of 3-methylene-1,2-diazetidines has been developed through application of a Cu(I)-catalyzed 4-exo
ring closure. The double bond of this new class of strained heterocycle can be functionalized in a stereocontrolled manner by using palladium-
catalyzed Heck reactions. Moreover, chemoselective reduction of 3-alkylidene-1,2-diazetidines gives access to saturated 1,2-diazetidines and
vicinal diamines.
Four-membered heterocycles play an important role
in modern medicine. For example, the highly strained
β-lactam nucleus is a vital component of several essential
classes of antibiotics including the penicillins, cephalospor-
ins, carbapenems, and monobactams.1 More recently,
oxetanes2 and azetidines3 have emerged as important tools
in medicinal chemistry primarily because of their useful
physicochemical properties. Hence, the development of
related four-membered heterocyclic templates for drug
discovery programs seems attractive. For instance, the
1,2-diazetidine nucleus 1 (Figure 1), containing two
adjacent nitrogen atoms within a four-membered ring,
could have a number of potential uses. Indeed, they have
been studied computationally as components of β-turn
mimetics.4 Unfortunately, systematic exploration of the
practical applications of 1,2-diazetidines in medicinal
chemistry has been severely hampered by a lack of high-
yielding, general routes for their preparation and func-
tionalization.5 The best synthetic methods developed to
date involve the following: [2π þ 2π] cycloadditions of
azodicarbonyl compounds with electron-rich alkenes,6
(4) Che, Y.; Marshall, G. R. J. Org. Chem. 2004, 69, 9030.
(5) For a review, see: Lohray, B. B.; Bhushan, V. In Comprehensive
Heterocyclic Chemistry II; Padwa, A., Ed.; Pergamon: New York, 1996;
Vol. 1B, pp 911-968.
† University of Warwick.
‡ GlaxoSmithKline, Medicines Research Centre.
(1) (a) Singh, G. S. Mini Rev. Med. Chem. 2004, 4, 69. (b) Singh, G. S.
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(b) Paquette, L. A.; Webber, P.; Simpson, I. Org. Lett. 2003, 5, 177. (c)
Breton, G. W.; Shugart, J. H.; Hughey, C. A.; Perala, S. M.; Hicks, A. D.
Org. Lett. 2001, 3, 3185. (d) Abarca-Gonzalez, B.; Jones, R. A.; Medio-
Simon, M.; Quiliz-Pardo, J.; Sepulveda-Arques, J.; Zaballos-Garcia, E.
Synth. Commun. 1990, 20, 321. (e) Cheng, C. C.; Seymour, C. A.; Petti,
M. A.; Greene, F. D. J. Org. Chem. 1984, 49, 2910. (f) Jensen, F.; Foote,
C. S. J. Am. Chem. Soc. 1987, 109, 6376. (g) Hall, J. H.; Jones, M. L. J.
Org. Chem. 1983, 48, 822. (h) Seymour, C. A.; Greene, F. D. J. Am.
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Ye, Y.; Wang, H.; Fan, R. Org. Lett. 2010, 12, 2802. (c) Burkett, B. A.;
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cited therein.
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10.1021/ol200193n
Published on Web 03/02/2011
2011 American Chemical Society

triphenylphosphine in THF readily provided hydrazine
5a in 92% yield after purification by column chromato-
graphy (Scheme 1). In an identical manner, hydrazines 5b-j
were made by coupling of the appropriate allylic alcohols
3b-g with commercially available DEAD (4), dibenzyl
azodicarboxylate, or di-tert-butyl azodicarboxylate. Good
to excellent yields were observed in all cases. Full details are
provided in the Supporting Information.
Figure 1. Structure of 1,2-diazetidine (1) and 3-methylene-1,2-
diazetidine (2).
“on water” [2σ þ 2σ þ 2π] cycloadditions of azodicarbox-
ylates with quadricyclane,7 Pd-catalyzed ring closure of
2,3-allenyl hydrazines,8 bisalkylation of 1,2-dialkylhydra-
zines with 1,2-dibromoethane,9 and Hard-Soft Acids and
Bases (HSAB) controlled ring closure.10 However, signifi-
cant limitations exist with all these methods in terms of
efficiency and/or substrate scope.
Scheme 1. Synthesis of Hydrazines 5a-j
We sought to develop a somewhat different synthetic
strategy, electing to explore the preparation and reactivity
of 3-methylene-1,2-diazetidine 2 and its substituted deri-
vatives (Figure 1). Importantly, this previously unknown
class of diazetidine might be expected to be readily synthe-
sized by using copper-catalyzed ring closure of the corre-
sponding 2-halo-2-propenyl hydrazines.11 Moreover, the
potentially rather strained double bond within 2 could
provide a useful handle for conversion into a wide range
of other 1,2-diazetidines by way of cycloadditions, Heck
couplings, cross-metathesis, or simple addition reactions.
In this Letter, we report an efficient, two-step synthesis of
a wide range of 3-alkylidene-1,2-diazetidines. We further
demonstrate that they can be used in diastereoselective Pd-
catalyzed Heck reactions without concomitant cleavage
of the diazetidine ring, and chemoselectively reduced to
either saturated 1,2-diazetidines or vicinal 1,2-diamines in
a stereocontrolled manner.
With ready access to a wide range of suitably func-
tionalized hydrazines, attention turned to the Cu-cat-
alyzed ring closure. Our investigations focused on the
use of the conditions developed by Li for the synthesis
of other 4-membered carbocycles and heterocycles.11
Heating bromide 5a in THF with CuI (20 mol %) in the
presence of dimethylethylenediamine (DMEDA, 40
mol %) and Cs2CO3 (2 equiv) induced facile ring closure
to methylene-1,2-diazetidine 6a in 98% yield (Scheme 1).
This compound is produced in comparable yield (99%) by
using iodide 5b as substrate (see the Supporting Infor-
mation). This cyclization tolerates variation in the nature
of the N-substituent as illustrated by the formation of Boc
(e.g., 6b and 6e) and Cbz (e.g., 6c and 6g) derivatives. Sub-
stitution of the alkene double bond is possible as estab-
lished by the ring closure of gem-dimethyl substituted 5f
into 3-isopropylidene-1,2-diazetidine 6e. Moreover, phe-
nyl-substituted (Z)-5e cyclizes to (Z)-6d through retention
of configuration at the sp2-hybridized carbon. By using
secondary hydrazines 5g and 5h, it is possible to make
highly strained diazabicyclo[4.2.0]octenes 6f and 6g, re-
spectively, in near-quantitative yields.
To prepare the hydrazine-containing cyclization precur-
sors 5a-j, a variation on the Mitsunobu reaction was
employed in which the external nucleophile was omitted.12
In this way, direct substitution of the alcohol group by
the reduced azodicarboxylate takes place. For example,
treatment of commercially available 2-bromoallyl alcohol
(3a) with diethyl azodicarboxylate (DEAD, 4a) and
(7) (a) Narayan, S.; Muldoon, J.; Finn, M. G.; Folkin, V. V.; Kolb,
H. C.; Sharpless, K. B. Angew. Chem., Int. Ed. 2005, 44, 3275. See also:
(b) Rieber, N.; Alberts, J.; Lipsky, J. A.; Lemal, D. M. J. Am. Chem. Soc.
1969, 91, 5668.
(8) Cheng, X.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 4581.
(9) (a) Hall, J. H.; Bigard, W. S. J. Org. Chem. 1978, 43, 2785. (b)
Nelsen, S. F.; Peacock, V. E.; Weisman, G. R.; Landis, M. E.; Spencer,
J. A. J. Am. Chem. Soc. 1978, 100, 2806.
(10) Brown, M. J.; Clarkson, G. J.; Fox, D. J.; Inglis, G. G.; Shipman,
M. Tetrahedron Lett. 2010, 51, 382.
(11) For the efficient synthesis of other 4-membered ring systems by
Cu-catalyzed ring closure, see: (a) Lu, H.; Li, C. Org. Lett. 2006, 8, 5365.
(b) Fang, Y.; Li, C. J. Am. Chem. Soc. 2007, 129, 8092. (c) Zhao, Q.; Li,
C. Org. Lett. 2008, 10, 4037. (d) Chen, L.; Shi, M.; Li, C. Org. Lett. 2008,
10, 5285. (e) Zhao, Q.; Li, L.; Fang, Y.; Sun, D.; Li, C. J. Org. Chem.
2009, 74, 459.
(12) Dow, R. L.; Kelly, R. C.; Schletter, I.; Wierenga, W. Synth.
Commun. 1981, 11, 43. This reaction is more commonly seen as an
unwanted side reaction in conventional Mitsunobu reactions, see for
example: Sammes, P. G.; Smith, S. J. Chem. Soc., Chem. Commun. 1983,
682.
The relative propensity of competing cyclization mani-
folds has been explored by using dihalogenated substrates
Org. Lett., Vol. 13, No. 7, 2011
1687

5i and 5j. With (E)-5i, Cu-catalyzed 4-exo ring closure to
1,2-diazetidine 6h is observed, although small quantities
of pyrazole 7 (15%) arising from competitive 5-endo ring
closure were also isolated. By using diodide 5j, this selec-
tivity is reversed with pyrazole 7 formed in 94% yield as
the only discernible product (Scheme 2). Recent reports
have described four-membered ring closure as being fun-
damentally preferred over other modes of cyclization in
Cu(I)-catalyzed C-, O-, N-, and S-vinylation.11 To the best
of our knowledge, the selective formation of pyrazole 7
from diodide 5j represents the first demonstration of a
preference for a 5-endo over a 4-exo ring closure in such
cyclizations.
Scheme 3. Stereocontrolled Heck Coupling of 3-Methylene-1,2-
diazetidine 6a
Scheme 2. Synthesis of 3-Methylene-1,2-diazetidines
Assuming that (Z)- and (E)-6d are produced from 8 and
9, respectively, which differ only in the conformation
around the C-C single bond, then one can account for
the preferred product observed by suggesting a lower
energy for the transition state from 9 leading to (E)-6d as
it does not experience the destabilizing nonbonded inter-
actions between the Ph and CO2Et groups (Scheme 3). An
attractive feature of this chemistry is that it provides 6d
withthe opposite stereochemistry tothataccessedbydirect
Cu(I)-catalyzed ring closure (Scheme 2). Although the
yield of this reaction is relatively modest, it is notable that
the N-N bond of these highly strained heterocycles is
stable to the reaction conditions, and does not undergo
oxidative insertion by the Pd catalyst.14
Scheme 4. Chemoselective Reductions of 1,2-Diazetidine 6f
a Using 5b, formed in 99% yield. b Configuration determined by
NOE measurements. For (Z)-6d, this assignment verified by comparison
with (E)-6d (Scheme 3).
With a selection of 3-alkylidene-1,2-diazetidines to hand,
efforts to explore their reactivity have been initiated. For
example, it is possible to functionalize the double bond
ofthesecompounds throughPd-catalyzedHeckcouplings.
Thus, treatment of 3-methylene-1,2-diazetidine 6a with
phenyl iodide using the phosphane-free catalyst system
developed by Buchwald13 provides (E)-6d in 46% isolated
yield (Scheme 3). The structure of this product was con-
firmed by single-crystal X-ray diffraction (see the Support-
ing Information). The high degree of diastereoselectivity
observed in this transformation can be rationalized
through consideration of the presumed organopalladium
intermediate prior to syn-elimination of the β-hydride.
Using 6f as a representative substrate, we have examined
chemoselective reductions of this new compound class.
Catalytic hydrogenation under heterogeneous conditions
provides 1,2-diazetidine 10 exclusively as the cis-stereo-
isomer (Scheme 4). Significantly, littleN-N bond cleavage
was observed under these reaction conditions, indicating
that this approach may provide a useful entry point into
(14) Less strained 3-alkyl-1,2-diazetidines are known to be stable to
Pd-catalyzed cross-coupling conditions, see ref 7.
€
(13) Gurtler, C.; Buchwald, S. L. Chem.;Eur. J. 1999, 5, 3107.
1688
Org. Lett., Vol. 13, No. 7, 2011

saturated 1,2-diazetidines.6-10 Further cleavage to cis-
diamine 11 was achieved by using lithium di-tert-butyl-
biphenyl (LiDBB) as reductant.15 At this point, the cis-
stereochemistry of 11, and hence 10, was confirmed by
spectroscopic comparison of 11 with authentic samples
of cis- and trans-11 prepared from the corresponding,
commercially available 1,2-diaminocyclohexanes by re-
action with ethyl chloroformate (see the Supporting
Information). Interestingly, direct treatment of 6f with
LiDBB provides enamide 12 through chemoselective
reduction of the N-N bond (Scheme 4).
In conclusion, we have developed an efficient, two-step
synthesis of 3-methylene-1,2-diazetidines through applica-
tion of Cu(I)-catalyzed 4-exo ring closure. The methodol-
ogy is high yielding and has broad substrate scope.
Preliminary studies indicate that this new class of N-het-
erocycle will serve as useful templates for the synthesis of
functionalized 1,2-diazetidines, vicinal diamines, and other
valued N-containing systems. Further exploration of func-
tionalization reactions of these systems and efforts toward
their enantioselective reduction are currently underway in
our laboratory.
Acknowledgment. This work was supported by Glax-
oSmithKline and the Engineering and Physical
Sciences Research Council. We thank Advantage West
Midlands and the European Regional Development
Fund for funding for the Oxford Diffraction Gemini
XRD system.
Supporting Information Available.
Experimental
procedures, characterization data, and NMR spectra
for 5a-j, 6a-h, 7, and 10-12. This material is
available free of charge via the Internet at http://
pubs.acs.org.
(15) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924.
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