Strategic applications of Baylis-Hillman adducts to general syntheses of 3-nitroazetidines

Article abstract of DOI:10.1039/c1ob06274c

A novel one-pot highly diastereoselective synthesis of substituted 3-nitroazetidines via an anionic domino process is described. The synthesis involves a high yielding annulation of Baylis-Hillman alcohols and their aldehydes with either N-aryl/tosylphosphoramidates or N-aryl/ tosylphosphoramidates in combination with a task-specific ionic liquid [bmim][X-Y] to afford the corresponding 1,2,3-tri- and 1,2,3,4-tetrasubstituted azetidines, respectively. Plausible mechanisms for the formation of various 3-nitroazetidines have been suggested. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1ob06274c

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PAPER
Strategic applications of Baylis–Hillman adducts to general syntheses of
3-nitroazetidines†
Ankita Rai and Lal Dhar S. Yadav*
Received 27th July 2011, Accepted 31st August 2011
DOI: 10.1039/c1ob06274c
A novel one-pot highly diastereoselective synthesis of substituted 3-nitroazetidines via an anionic
domino process is described. The synthesis involves a high yielding annulation of Baylis–Hillman
alcohols and their aldehydes with either N-aryl/tosylphosphoramidates or
N-aryl/tosylphosphoramidates in combination with a task-specific ionic liquid [bmim][X–Y] to afford
the corresponding 1,2,3-tri- and 1,2,3,4-tetrasubstituted azetidines, respectively. Plausible mechanisms
for the formation of various 3-nitroazetidines have been suggested.
forming reaction which affords densely functionalised molecules in
Introduction
high yields.15 The BH adducts have been a stimulus for developing
Azetidines are fascinating synthetic targets because of their
remarkable chemical and biological properties.1–3 The azetidine
art in organic synthesis via a multitude of functional group
manipulations leading to their applications as versatile building
ring system prominently features in many medicinally important
blocks for various useful bioactive compounds and synthetic
intermediates.15
molecules some of which are markedly active against influenza
A H2N2 virus,4 and have anti-HIV-1, anti-HSV-1 and HSV-
2 potential.5 Although the inherent strain associated with the
azetidine ring leads to difficulties in its construction, functionali-
sations and modifications, it is advantageous for its synthetic ap-
plications involving ring-opening reactions. For example, several
functionalised azetidines have been used as masked 1,4-dipoles
for the synthesis of five- and six-membered aza-heterocycles.6
3-Substituted azetidines are the most important constituent of
various potential therapeutic moieties.3 The literature records
several reports on the synthesis of 3-substituted azetidines,7,8 but
the chemistry of 3-nitroazetidines has been scarcely investigated.
Moreover, 3-nitroazetidines are of special interest because their
nitro group can be served other functional groups such as to
oximes, hydroxylamines, amines and ketones (Nef reaction).
Amongst various methods available for the synthesis of trisub-
stituted azetidines, the most general involves the cyclisation of g-
amino alcohols or their derivatives.8a,9–12 De Kimpe and co-workers
have reported elegant synthetic methods for functionalised aze-
tidines that are based on the reaction of b-chloro or b-mesyloxy
imines with nucleophiles such as hydride, cyanide, and alkoxides.13
We have recently reported the synthesis of 1,2,4-triarylazetidines
via a reductive cyclization of N-aryl-N-(1,3-diaryl-3-oxopropyl)
phosphoramidates.14
The lack of a convenient synthetic method for 3-nitroazetidines
and our ongoing efforts to devise new stereoselective cyclisation
processes14,16 prompted us to develop a general highly diastereos-
elective route to substituted 3-nitroazetidines 4 and 6 from BH
adducts as depicted in Scheme 1. The present study would also
widen the scope of synthetic applications of BH adducts.
The Baylis–Hillman (BH) reaction has attracted synthetic
chemists because it is a highly economical carbon–carbon bond
Scheme 1 Synthesis of 3-nitroazetidines 4 and 6.
Green Synthesis Lab, Department of Chemistry, University of Allahabad,
Allahabad, 211002, India. E-mail: ldsyadav@hotmail.com; Fax: +91
5322460533; Tel: +91 5322500652
† Electronic supplementary information (ESI) available: Experimental
details and analytical and spectral characterisation data. See DOI:
10.1039/c1ob06274c
Results and discussion
We herein report the first examples of the aza-Michael ad-
dition of N-aryl/tosylphosphoramidates to nitroalkene derived
BH adducts and their aldehydes followed by anion induced
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Table 1 Synthesis of 1,2,3-trisubstituted azetidines 4a
Table 2 Synthesis of 1,2,3,4-tetrasubstituted azetidines 6a
Entry Ar1
Ar2 X–Y
Product
Time (h)b Yield %c,d
Entry Ar1
Ar2
Product
Time (h)b
Yield %c,d
1
2
3
4
5
6
7
8
Ph
4-ClC6H4
2-ClC6H4
4-CH3OC6H4 Ph SCN 6d
Ph
4-ClC6H4
2-ClC6H4
4-CH3OC6H4 Ph SPh
Ph
Ph
Ph SCN 6a
Ph SCN 6b
Ph SCN 6c
4
4.5
5
5
5
87
94
88
91
84
93
87
90
84
89
92
91
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
4-FPh
4-FPh
4-FPh
4-FPh
Ts
4a
4b
4c
4d
4e
4f
3
85
92
90
89
82
91
88
87
91
88
4-ClC6H4
2-ClC6H4
4-CH3OC6H4
Ph
4-ClC6H4
2-ClC6H4
4-CH3OC6H4
Ph
3.5
4.5
4
5
3
4.5
3.5
3.5
4
Ph SPh
Ph SPh
Ph SPh
6e
6f
6g
6h
6i
5
4.5
4.5
4
4.5
4.5
5
4g
4h
4i
9
Ts NO3
Ts TfO
Ts SCN 6k
10
11
12
6j
10
3-Furyl
Ts
4j
3-Furyl
3-Furyl
a Reaction conditions: 1 (5 mmol), 2 (5 mmol) and NaH (10 mmol) were
used in dry THF (5 mL). b Time required for completion of step (ii).
c Yield of isolated and purified product. d All compounds gave C, H and N
analyses within 0.37% and satisfactory spectral (IR, 1H NMR, 13C NMR
and EIMS) data.
Ph SCN 6l
a Reaction conditions: 2 (5 mmol), 3 (5 mmol), NaH (10 mmol) and
[bmim][X–Y] were used in dry THF (5 mL). b Time required for completion
of step (ii). c Yield of isolated and purified product. d All compounds gave
C, H and N analyses within 0.37% and satisfactory spectral (IR, 1H
NMR, 13C NMR and EIMS) data.
cyclisation to afford 3-nitroazetidines in excellent yields with high
diastereoselectivity. This divergent route can be used to produce
skeletally diverse azetidine scaffolds from the same precursor.
At the outset, we synthesised 1,2,3-trisubstituted aze-
tidines 4 by a novel one-pot procedure. Thus, diethyl N-
aryl/tosylphosphoramidates 2 were treated with sodium hydride
in dry THF to the generate anion 7, which in situ underwent
aza-Michael addition to BH adducts 1 followed by cyclisation to
afford azetidines 4 in 82–92% yields (Table 1). The formation of
azetidines 4 is best explained through an anionic domino process
as outlined in (Scheme 2). This presumption is supported by the
isolation of representative alkoxide 8a as its parent alcohol 9a in
42% yield and its easy conversion to azetidine 4a 96% yield under
the same reaction conditions. In order to enhance the generality
and scope of the method and introduce further functionalities into
the azetidine ring, we undertook for the first time the oxidation of
BH alcohols 1 to their aldehydes employing IBX in DMSO17 as it is
a mild oxidant, and a variety of functional groups are compatible
with its use. The aldehydes 3 underwent aza-Michael addition
with N-aryl/tosylphosphoramidates 2 followed by anion-induced
cyclisation with a task-specific ionic liquid (TSIL) [bmim][X–Y]
to afford azetidines 6 in 84–94% yields (Table 2) as depicted in
Scheme 3.
The reaction can be best explained through the attack of
a nucleophile (-X–Y) on the carbonyl carbon followed by the
intramolecular attack of the alkoxide ion 12 on the phosphorus
atom. Then the lone pair of X forms a bond with carbon,
and carbon-oxygen bond breaks leading to the formation of
products 6 through 13 and 14 (Scheme 3). Furthermore, during
the formation of products 6 an iminium ion comes into play which
sets equilibrium to furnish the more favourable trans-trans product
as depicted in Scheme 3. A comparison of [bmim]SCN/SPh
with KSCN/PhSNa for the synthesis of 6 was carried out under
similar conditions by stirring Baylis–Hillman adduct15a 1 and in
situ generated phosphoramidate anion 7 with 1.5 equivalents of
KSCN or PhSNa in THF for 4–5 h at room temperature. In the
case of KSCN/PhSNa, the anion induced cyclisation afforded
the corresponding 6 in relatively lower yields (41–53%). This
indicates that the nucleophilicity of SCN or PhS anion from
[bmim]SCN or [bmim]SPh is considerably higher compared to
that from KSCN or PhSNa. After isolation of products 6, the
Scheme 2 A plausible mechanism for the formation of 3-nitroazetidines 4.
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Scheme 3 A plausible mechanism for the formation of 3-nitroazetidines 6.
residue was treated with concentrated HCl followed by stirring
with KSCN or PhSNa at room temperature for 48 h to obtain
the corresponding recycled task-specific ionic liquid (TSIL). The
high affinity of phosphorus for oxygen is the main driving force for
both of the present cyclisation reactions depicted in Schemes 2 and
3. Furthermore, in order to improve the utility of this synthetic
method, an additional experiment to remove tosyl group from
azetidine ring nitrogen was also performed. Azetidines can be
easily detosylated using SmI2 in a refluxing mixture of THF and
DMPU (N,N¢-dimethylpropyleneurea) employing the method of
Vedejs and Lin.18
2-H or between 1-H(Ar2) and 4-H were not so significant and
conclusive (hence not shown in the Fig. 1) as observed in the case
of 2-H(Ar1) and 3-H. The exclusive formation of trans isomer 4
is understandable in view of most of the Michael additions which
usually give anti/trans products. The formation of the most stable
trans-trans isomers 6 with complete diastereoselectivity indicates
that the reaction is under thermodynamic control and a Y–X-
addition/elimination equilibrium is at play through an iminium
ion (Scheme 3). The intermediacy of the iminium ion was proved
by placing compound 6a in the presence of PhSNa under the
reaction conditions and stirring for 5 h, which led to the isolation
compound 6e as well. This rationalizes the complete trans-trans
diastereoselectivity in the formation of 6.
The annulation of BH alcohols 1 and their aldehydes 3 to func-
tionalised azetidines was entirely diastereoselective and afforded
exclusively the trans isomers. The configurational assignment of
1
azetidines 4 and 6 was made on the basis of H NMR coupling
Conclusions
constants Jtrans H/H of 2-H, 3-H, and 3-H, 4-H of the heterocycle
which are in the range of 6.5–7.7 Hz as already reported for tri-
and tetrasubstituted azetidines.19 The relative configuration was
further confirmed by NOE experiments as shown in Fig. 1. The
absence of any measurable NOE between 2-H and 3-H, and the
presence of measurable NOE between 3-H and aryl protons at
C-2, indicates that 2-H and 3-H protons are on opposite faces of
the molecule, confirming the trans and trans-trans stereochemistry
of 4 and 6, respectively. However, the NOE between 1-H(Ar2) and
In summary, we have developed a novel one-pot procedure for
a highly diastereoselective synthesis of 1,2,3-tri- and 1,2,3,4-
tetrasubstituted azetidines from BH alcohols and their aldehydes,
respectively. The synthetic protocol presents the first application of
BH alcohols and their aldehydes to the synthesis of nitroazetidines
via an anionic domino process, thereby it also widens the scope of
synthetic utility of BH adducts.
Experimental
General procedure for the synthesis of of 1,2,3-trisubstituted
azetidines 4 and 1,2,3,4-tetrasubstituted azetidines 6
To a solution of diethyl N-arylphosphoramidate 2 (5 mmol) in dry
THF (5 mL) was added dropwise a suspension of NaH (240 mg,
10 mmol) in dry THF (10 mL) with stirring at rt. After the addition
was complete and evolution of hydrogen gas (◦effervescence) had
ceased, the reaction mixture was stirred at 60 C for 30 min and
Fig. 1 NOE for 3-nitroazetidines.
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then cooled to rt. Next, a solution of Baylis Hillman alcohol 1
(5 mmol) in dry THF (5 mL) was added, and the reaction mixture
was stirred at rt for 3–5 h. Water (20 mL) was added, the mixture
was extracted with ether (3 ¥ 30 mL), the combined organic layers
were dried over anhydrous sodium sulfate, filtered, and evaporated
under reduced pressure. The crude product thus obtained was
purified by silica gel column chromatography (hexane/EtOAc,
95 : 5) to afford an analytically pure sample of 4.
Similarly, 6 were synthesised using aldehydes 3 instead of
alcohols 1 followed by TSILs 5. The structure of the products
4 and 6 were confirmed by their elemental and spectral analyses
(see ESI†).
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Acknowledgements
We sincerely thank SAIF, Punjab University, Chandigarh, for
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