Chalcones to functionalized azetidines via anion-induced cyclization using task-specific ionic liquids

Article abstract of DOI:10.1055/s-2008-1042757

The first example of the application of task-specific ionic liquids (TSIL) to a new and practical synthesis of functionalized azetidines is reported. Aza-Michael addition of diethyl N-arylphosphoramidates to chalcones affords diethyl N-aryl-N-(1,3-diaryl-

Full text of DOI:10.1055/s-2008-1042757

LETTER
583
Chalcones to Functionalized Azetidines via Anion-Induced Cyclization Using
Task-Specific Ionic Liquids
C
halcones toFu
a
nctionaliz
e
l
d
A
zetidine
s
Dhar Singh Yadav,* Rajesh Patel, Vishnu Prabhakar Srivastava
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Fax +91(532)2460533; E-mail: ldsyadav@hotmail.com
Received 15 December 2007
relatively little attention has been paid to their intrinsic re-
Abstract: The first example of the application of task-specific ionic
liquids (TSIL) to a new and practical synthesis of functionalized
azetidines is reported. Aza-Michael addition of diethyl N-arylphos-
phoramidates to chalcones affords diethyl N-aryl-N-(1,3-diaryl-3-
activity. Besides their use as green reaction media, ionic
liquids also play significant roles as catalysts,29–31 and re-
agents,32,33 and are easy to recycle.32,33 A recent review26
oxopropyl)phosphoramidates, which undergo cyclization to func- is focused on the reactivity of ionic liquids, as opposed to
tionalized azetidines. The cyclization is induced by anions (NCS–,
reactivity in ionic liquids, showing their ever-increasing
PhS–) of TSIL and gives excellent yields with high diastereoselec-
importance.
tivity in a one-pot procedure. The use of KSCN or PhSNa instead of
The continued interest of synthetic chemists in azetidines
and our ongoing efforts to devise new cyclization process-
es under environmentally benign conditions34–38 has en-
couraged us to develop a practical synthesis of
functionalized azetidines from chalcones using task-spe-
cific ionic liquids (TSIL) as outlined in Table 1. This is
the first illustration of the application of TSIL to azetidine
chemistry and the first example of a straightforward syn-
thesis of C-sulfur-functionalized azetidines.
the corresponding TSIL, [bmim]SCN or [bmim]SPh, resulted in
significantly lower yields of products. After isolation of the product,
the ionic liquid could be recycled for further use.
Key words: azetidines, Michael addition, chalcones, ionic liquids,
phosphoramidates
Azetidines constitute an important class of small-ring aza-
heterocycles with interesting pharmacological activities.
Furthermore, some other compounds incorporating the
azetidine structure have been reported to exhibit remark-
able activity against influenza A H2N2 virus,1 and to pos-
sess anti-HIV-1, anti-HSV-1, and anti-HSV-2 potential.2
Whereas the strain associated with the azetidine ring sys-
tem leads to difficulties in its synthesis, functionaliza-
tions, and modifications, it is advantageous for its
synthetic applications involving ring-opening reactions.
Over the past few years, several functionalized azetidines
have been utilized as masked 1,4-dipoles for the construc-
tion of five- and six-membered azaheterocycles.3–6
The strategy reported herein was successfully realized in
two steps. In the initial step, diethyl N-arylphosphorami-
dates 2 were treated with sodium hydride in dry benzene
to generate anions 6 in situ, which underwent aza-Michael
addition to chalcones 1 to afford adducts 3 in 77–86%
yields39 (Scheme 1). The second step involved stirring of
adduct 3 in 1.5 equivalents of TSIL 4 for 3–4 h at room
temperature (for 4, X = SCN) or at 60–65 °C (for 4,
X = PhS) to produce functionalized azetidines 5 in 76–
89% yields.40 The cis/trans relationships of substituents in
azetidines 5 were confirmed by NOE experiments. The
17.6% NOE at 2-Ar1/4-Ar2 upon irradiation of 3-Hb (for
example, at d = 3.05 ppm for 5a) combined with the ab-
sence of any measurable intensity enhancement at 2-Ar1/
4-Ar2 upon irradiation of 3-Ha indicates that 3-Hb and 2-
Ar1/4-Ar2 are located on the same face of the molecule,
that is, azetidines 5 have 2,4-cis configuration with re-
spect to the aryl groups.
Among the various general procedures available for the
synthesis of azetidines, the most general involves cycliza-
tion of g-amino alcohols or their derivatives.7–13 Function-
alized small-ring heterocycles play an important role in
the drug discovery process.14–17 De Kimpe and co-work-
ers have reported elegant synthetic methods for function-
alized azetidines that are based on the reaction of b-chloro
or b-mesyloxy imines with nucleophiles such as hydride,
cyanide, and alkoxides.18–24 A very recently reported syn-
thesis of 1,2,4-triarylazetidines involves reductive cy-
The formation of azetidines 5 is best explained through at-
tack of a nucleophile (NCS– or PhS–) on the carbonyl car-
bon of 3 followed by intramolecular attack of the alkoxide
ion on the phosphorus atom (Scheme 1). A comparison
with TSIL 4 was carried out by stirring phosphoramidates
3 in [bmim]BF4 with 1.5 equivalents of KSCN or PhSNa
for 3–4 hours at room temperature or at 60–65 °C, respec-
tively. In this case, the anion-induced cyclization afforded
the corresponding 5 in relatively lower yields (41–53%).
This indicates that the nucleophilicty of SCN or PhS anion
is considerably higher in [bmim]SCN or [bmim]SPh com-
pared to that from KSCN or PhSNa. After isolation of
products 5, the residue was treated with concentrated HCl
clization
of
N-aryl-N-(1,3-diaryl-3-
oxopropyl)phosphoramidates.25 To our knowledge, the
literature does not report any direct synthetic method for
the synthesis of C-sulfur-functionalized azetidines, i.e. the
target molecules of the present synthesis.
Ionic liquids (IL) have gained considerable current inter-
est as environmentally benign reaction media26–29 and yet
SYNLETT 2008, No. 4, pp 0583–0585
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.02.2008
DOI: 10.1055/s-2008-1042757; Art ID: G37407ST
© Georg Thieme Verlag Stuttgart · New York

584
L. D. S. Yadav et al.
LETTER
O
Table 1 Synthesis of Functionalized Azetidines 5
O
Ar1
Ar2
O
O
(i) 2 (1 equiv), NaH (1 equiv)
benzene, 60 °C, 30 min
O
–
NaH
1
(EtO)2PNAr3
(EtO)2PNHAr3
(EtO)2PNHAr3
Ar1
Ar2
Ar1
(ii) 1 (1 equiv), benzene
50–60 °C, 3 h
1
6
2
2
Ar1
Ar1
X
[bmim]X (1.5 equiv)
[bmim]X
O
O
O
O
P
O
Ar2
Ar1
O
P
(4)
(4)
EtO
EtO
Ar2
N
Ar3
X
EtO
EtO
EtO
– [bmim]+
N
Ar3
Ar2
Ar2
r.t. or 60–65 °C, 3–4 h
P
N
Ar3
N
Ar3
76–89%
[bmim]X (4) =
X = SCN, SPh
3
5
EtO
N
3
+
X –
Ar1
N
Ar1
X
Ar1
Ar2
X
EtO
EtO
O
O
N
Ar3
O
P
P
–
X
– (EtO)2PO2
O
Ar2
N
Ar2
N
Ar3
EtO
Ar3
OEt
5
Product
Ar1
Ar2
Ar3
X
Yield
(%)a
Scheme 1 Plausible mechanism for the formation of azetidines 5
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
–
–
–
–
–
–
78
81
79
86
81
77
4-ClC6H4
Ph
Acknowledgment
4-MeOC6H4
4-MeOC6H4
Ph
We sincerely thank SAIF, Punjab University, Chandigarh, for pro-
viding microanalyses and spectra.
4-ClC6H4
4-ClC6H4 Ph
References and Notes
Ph
Ph
Ph
Ph
Ph
4-MeOC6H4 Ph
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5a
5b
5c
5d
5e
5f
Ph
Ph
SCN 81
SCN 76
SCN 84
SCN 85
SCN 87
SCN 83
4-ClC6H4
Ph
Ph
4-MeOC6H4
4-MeOC6H4
Ph
4-ClC6H4
4-ClC6H4 Ph
Ph
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4-MeOC6H4 Ph
5g
5h
5i
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82
80
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89
84
4-ClC6H4
Ph
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4-MeOC6H4
4-MeOC6H4
Ph
5j
4-ClC6H4
5k
5l
4-ClC6H4 Ph
Ph 4-MeOC6H4 Ph
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followed by stirring with KSCN or PhSNa at room tem-
perature for 48 hours to obtain the corresponding recycled
TSIL 4.
In summary, we have developed a practical synthesis of
functionalized azetidines by anion-induced cyclization of
chalcone-derived phosphoramidates using task-specific
ionic liquids in a one-pot procedure, which may be useful
for the synthesis of this class of azetidines.
Synlett 2008, No. 4, 583–585 © Thieme Stuttgart · New York

LETTER
Chalcones to Functionalized Azetidines
585
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from n-hexane to afford an analytically pure sample of 3.
Physical Data of a Representative Compound
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Compound 3a: white crystals yield 87%, mp 186–187 °C. IR
(KBr): nmax = 3052, 2990, 1692, 1605, 1582, 1456 cm–1. 1H
NMR (400 MHz, CDCl3/TMS): d = 1.23 (t, 6 H, J = 7.5 Hz,
2 ´ Me), 3.06 (dd, 1 H, J = 12.9, 8.5 Hz, 2-Ha), 3.38 (dd, 1 H,
J = 12.9, 3.5 Hz, 2-Hb), 4.16 (q, 4 H, J = 7.5 Hz, 2 ´ OCH2),
4.65 (dd, 1 H, J = 8.5, 3.5 Hz, 3-H), 7.08–7.43 (m, 13 Harom),
7.81–7.89 (m, 2 Harom). 13C NMR (100 MHz, CDCl3/TMS):
d = 16.3 (Me), 41.7 (CHPh), 50.3 (CH2O), 69.9 (CH2CO),
126.5, 127.5, 128.3, 129.4, 131.4, 132.7, 133.4, 134.2, 135.5
(3 ´ Ph), 193.2 (CO). MS (EI): m/z = 437 [M+]. Anal. Calcd
(%) for C25H28NO4P: C, 68.64; H, 6.45; N, 3.20. Found: C,
68.92; H, 6.74; N, 3.07.
(40) General Procedure for the Synthesis of Functionalized
Azetidines 5
A mixture of adduct 3 (5 mmol) and [bmim]SCN or
[bmim]SPh (4, 7.5 mmol) with a few drops of distilled H2O
was taken in a 50 mL round-bottomed flask and stirred for
3–4 h at r.t. (for [bmim]SCN) or at 60–65 °C (for
[bmim]SPh). After completion of the reaction as indicated
by TLC, the product was extracted with Et2O (3 × 20 mL),
dried over anhyd MgSO4, filtered, and evaporated to
dryness. The crude product 5 thus obtained was
recrystallized twice from n-hexane to afford an analytically
pure sample.
Physical Data of Representative Compounds
Compound 5a: white crystals, yield 81%, mp 98–99 °C. IR
(KBr): nmax = 3082, 2965, 2892, 2813, 2132, 1604, 1495,
1451, 753, 706 cm–1. 1H NMR (400 MHz, CDCl3/TMS): d =
2.75 (dd, 1 H, J = 11.3, 8.7 Hz, 3-Ha), 3.05 (dd, 1 H, J = 11.3,
6.6 Hz, 3-Hb), 4.90 (dd, 1 H, J = 8.7, 6.6 Hz, 4-H), 7.11–7.43
(m, 15 Harom). 13C NMR (100 MHz, CDCl3/TMS): d = 41.1
(3-C), 55.7, 78.5 (2-C, 4-C), 111.7 (SCN), 123.6, 124.5,
125.3, 126.7, 129.8, 130.7, 131.6, 132.4, 133.5, 134.3,
139.0, 141.7 (3 × Ph). MS (EI): m/z = 342 [M+]. Anal. Calcd
(%) for C22H18N2S: C, 77.16; H, 5.30; N, 8.18. Found: C,
76.81; H, 5.53; N, 8.39.
Compound 5g: white crystals, yield 82%, mp 58–59 °C. IR
(KBr): nmax = 3073, 2968, 2896, 2818, 1600, 1492, 1456,
758, 696 cm–1. 1H NMR (400 MHz, CDCl3/TMS): d = 2.79
(dd, 1 H, J = 11.3, 8.7 Hz, 3-Ha), 3.10 (dd, 1 H, J = 11.3, 6.6
Hz, 3-Hb), 4.92 (dd, 1 H, J = 8.7, 6.6 Hz, 4-H), 7.01–7.53 (m,
20 Harom). 13C NMR (100 MHz, CDCl3/TMS): d = 41.2 (3-
C), 55.9, 79.0 (2-C, 4-C), 123.5, 124.6, 125.3, 126.3, 127.2,
128.0, 129.8, 130.6, 131.5, 132.6, 133.4, 134.5, 135.8,
138.2, 139.7, 141.3 (4 × Ph). MS (EI): m/z = 393 [M+]. Anal.
Calcd (%) for C27H23NS: C, 82.40; H, 5.89; N, 3.56. Found:
C, 82.76; H, 5.52; N, 3.85.
(38) Yadav, L. D. S.; Kapoor, R. J. Org. Chem. 2004, 69, 8118.
(39) General Procedure for the Synthesis of Diethyl N-Aryl-
N-(1,3-diaryl-3-oxopropyl)phosphoramidates 325
To a solution of diethyl N-arylphosphoramidate 2 (5 mmol)
in dry benzene (5 mL) was added dropwise a solution of
NaH (120 mg, 5 mmol) in dry benzene (10 mL) with stirring
at r.t. 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 then cooled to
r.t. Next, a solution of chalcone 1 (5 mmol) in dry benzene
(5 mL) was added and the reaction mixture was stirred at 50–
60 °C for 3 h. The solvent was evaporated under reduced
pressure, the residue washed with H2O and recrystallized
Synlett 2008, No. 4, 583–585 © Thieme Stuttgart · New York

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