Phosphonitrilic chloride as an efficient reagent for the synthesis of β-sultams

Article abstract of DOI:10.1016/j.tetlet.2012.12.069

A novel and efficient route for the conversion of imines and sulfonic acids into β-sultams using phosphonitrilic chloride at room temperature in dry CH₂Cl₂ is described. Optimization of the conditions was performed. This method is ve

Full text of DOI:10.1016/j.tetlet.2012.12.069

Tetrahedron Letters 54 (2013) 1100–1102
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Phosphonitrilic chloride as an efficient reagent for the synthesis of b-sultams
⇑
Maaroof Zarei
Department of Chemistry, College of Sciences, Hormozgan University, Bandar Abbas 71961, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient route for the conversion of imines and sulfonic acids into b-sultams using phospho-
nitrilic chloride at room temperature in dry CH2Cl2 is described. Optimization of the conditions was per-
formed. This method is very convenient and the water-soluble by-product is removed by simple aqueous
work-up.
Received 16 September 2012
Revised 29 November 2012
Accepted 13 December 2012
Available online 25 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
b-Sultam
Phosphonitrilic chloride
Sulfene
Schiff base
Cycloaddition
b-Lactam antibiotics show a broad spectrum of antimicrobial
activity with their biological properties being due to the b-lactam
(2-azetidinone) ring, 1. However, antibiotic-resistant strains are
arising at an alarming rate and hence new antibiotics are necce-
sary.1 The sulfonamide moiety present in the sulfa antibiotics of
the 1930s was central to the advent of the synthetic drug therapy.2
b-Sultams (1,2-thiazetidine 1,1-dioxides) 2 have attracted atten-
tion due to their structural similarity with the b-lactams.3 The
reactivity of b-sultams is usually higher than the analogous b-lac-
tam systems (approximately 103-fold)4 and at least 107-fold more
reactive than acyclic sulfonamides.5 Inhibition of elastases such as
human neutrophil elastase (HNE),6 b-lactamase,7 and D,D-pepti-
dase,8 and anti-inflammatory9 activity are some of the reported
biological activities of b-sultams. If a hetero bond of a b-sultam is
cleaved selectively, then it can be used as a synthon of several or-
ganic compounds which contain the three atoms, C, N, and S.10
Although a number of methods for the preparation of b-sultams
have been introduced,11 the [2+2] cycloaddition reaction of sulfen-
es with imines is used commonly.12 Sulfenes are molecules of the
formula R1R2C@SO2 and may be regarded as sulfonyl analogs of
ketenes.13 They are most often formed by the action of a base on
sulfonyl chlorides during which elimination of HCl occurs.14 How-
ever, the preparation, isolation, and handling of sulfonyl chlorides
are difficult and they are unstable, highly corrosive, and hygro-
scopic. Therefore, alkoxymethylene-N,N-dimethyliminium salts15
have been used as activating agents for the synthesis of b-sultams
from imines and sulfonic acids.16
Phosphonitrilic chloride (3) (1,3,5-triaza-2,4,6-triphosphorin-
2,2,4,4,6,6-hexachloride or hexachlorocyclotriphosphazene or
hexachlorotriphosphazene) can be prepared by the reaction of
PCl5 and NH4Cl, although it is commercially available.17 This com-
pound is a precursor to poly(dichlorophosphazene) or inorganic
rubber,18 and is a reagent for the synthesis of dandelion dendri-
mers.19 It has been widely used in organic reactions20 for the acti-
vation of carboxylic acids to give amides and hydrazides,21
aldoximes to give nitriles,22 and for the Beckmann rearrangement
of ketoximes into lactams.23 Recently, Bahrami reported the con-
version of sulfonic acids into the corresponding sulfonyl chlorides
using phosphonitrilic chloride.24 The objective of this work was to
investigate the application of phosphonitrilic chloride for the syn-
thesis of b-sultams.
Cl
Cl
P
R3
O
R2
R1
R3
R2
R1
N
P
P
Cl
Cl
N
N
N
O
S
N
O
Cl Cl
1
2
3
Reaction of imine 4a, phenylmethanesulfonic acid (5a), and
phosphonitrilic chloride (3) in the presence of triethylamine in
dry dichloromethane at room temperature for 10 h gave pure cis
b-sultam 6a after purification by short column chromatography.
The cis stereochemistry of the b-sultam 6a was determined from
the H-3 and H-4 coupling constant in the 1H NMR spectrum
(J = 8.8 Hz). The b-sultam ring is more distorted than a b-lactam
ring, which presumably causes a decrease in its outer H–C–C bond
angles and results in the higher J value of the cis-configured b-sul-
tam compared to the corresponding b-lactam.16 The conditions
⇑
Tel.: +98 761 766 0063; fax: +98 761 667 0714.
E-mail addresses: mzarei@hormozgan.ac.ir, maaroof1357@yahoo.com
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.069

M. Zarei / Tetrahedron Letters 54 (2013) 1100–1102
1101
Table 1
Optimization of the reaction conditions for the synthesis of b-sultam 6a
Cl
Cl
P
O
S
N
P
N
P
Cl
Et3N
- H+
Cl
3
Ph
C6H4-4-Cl
R3CH2SO3
R3CH2SO3H
Cl
R3H2C
O
3
N
PhCH2SO3H
4-EtO-C6H4-N=CH-C6H4-4-Cl
+
O
Cl
O
S
N
Et3N
Cl
C6H4-4-OEt
O
P
Cl
5a
Cl
4a
6a
N
P
N
O
O
S
O
P
O
Cl
- Et3NH Cl
NEt3
P
Cl
N
P
S
N
P
R3CH
R3HC
H
Entry
Solvent
Temp
Phosphonitrilic chloride (equiv)
Yield (%)
N
+
Cl
Cl
O
O
N
1
2
3
4
5
6
7
Toluene
CH2Cl2
THF
rt
rt
rt
rt
rt
rt
0 °C
0.3
0.3
0.3
0.3
0.5
0.7
0.5
27
66
40
47
89
88
76
Cl
sulfene
7
O
O
O
P
DMF
R3CH2SO3
N
P
N
P
R3CH
sulfene
S
+
7
CH2Cl2
CH2Cl2
CH2Cl2
+
O
O
N
8
R2
H
H
R3
O
O
O
R3
R2
R1N=CHR2
R3CH
S
+
H
H
N
S
N
O
S
N
R3
O
R2
R1
R1
CH2Cl2
3,
R1
R3CH2SO3H
R1N=CHR2
O
O
+
sulfene
6
S
Et3N, rt
O
Scheme 2.
4
5
6a-n
Scheme 1.
of a sulfonic acid. Conversion of the sulfonic acid into a sulfonyl
chloride was not observed in this reaction, which was confirmed
using TLC monitoring with an authentic sample. This activated
form of the sulfonic acid generates, in situ, the corresponding sulf-
ene in the presence of triethylamine (Scheme 2). Intermediate 7
acts as a new activator which reacts with the sulfonic acid, and
the in situ generation of the sulfene is repeated in the same man-
ner. It is significant that by-product 8 is soluble in water and can be
removed by simple aqueous work-up.
In conclusion, phosphonitrilic chloride is an efficient reagent for
the one-pot synthesis of b-sultams from imines and sulfonic acids
under mild conditions. Simple aqueous work-up removes the by-
product of phosphonitrilic chloride and any resulting salts. More-
over, this method is convenient for the synthesis of b-sultams from
alkyl sulfonic acids.
Table 2
Synthesis of b-sultams 6a–n using phosphonitrilic chloride
Entry
Product
R1
R2
R3
Isolated yield (%)
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
4-EtOC6H4
4-MeOC6H4
PhCH2
4-ClC6H4
4-NO2C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Me
Me
Me
Ph
Me
Ph
Ph
89
92
90
88
91
85
73
75
69
66
68
37
74
88
c-C6H11
c-C6H11
Me
c-C6H11
4-EtOC6H4
c-C6H11
c-C6H11
c-C6H11
c-C6H11
Me
4-ClC6H4
4-MeC6H4
4-MeOC6H4
Ph
4-ClC6H4
4-MeC6H4
4-ClC6H4
n Bu
9
10
11
12
13
14
n Bu
2-Furyl
2-Furyl
4-MeOC6H4
Acknowledgement
Thanks are due to the Hormozgan University Research Council
for the financial support of this study.
were optimized using this reaction. The effect of solvent, tempera-
ture, and quantity of reagent was investigated. In all the reactions,
1.0 mmol of imine 4a and three times the equivalents of sulfonic
acid 5a with respect to the amount of phosphonitrilic chloride
(3) were used (4a:5a:3 = 1.0:1.5:0.5). According to Table 1, CH2Cl2
gave the best results among the dry solvents tested. It was also
found that the yield at room temperature was better than at 0 °C.
The highest yield of b-sultam 6a was obtained using 0.5 equiv of
phosphonitrilic chloride (3).
Using the optimized conditions [1.0 mmol of imine 4, 1.5 mmol
of sulfonic acid 5, and 0.5 mmol of phosphonitrilic chloride (3) in
the presence of triethylamine in dry dichloromethane at room
temperature for 8–10 h], cis b-sultams 6a–n were synthesized
(Scheme 1, Table 2), and were purified by short column chroma-
tography on silica gel (EtOAc/hexane, 3:7).25 All the products were
characterized from spectral data and elemental analyses. The lower
stability of alkyl sulfenes compared to that of aryl sulfenes led to
lower yields of b-sultams 6g–j and 6l. Also, b-sultams 6k–m were
obtained in poorer yields because of the lower stability of imines
derived from aliphatic amines and aldehydes. Notably, the reaction
of an aliphatic imine derived from an aliphatic amine (cyclohexyl-
amine) and an aliphatic aldehyde (pentanal) with an alkyl sulfonic
acid (ethanesulfonic acid) gave b-sultam 6l in 37% yield.
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silica-gel
(EtOAc/hexane,
3:7).
4-Methyl-2-(p-ethoxyphenyl)-3-(p-
chlorophenyl)-1,2-thiazetidine 1,1-dioxide (6h). White solid mp: 116–118 °C.
IR (KBr) cmÀ1: 1138, 1309 (SO2); 1H NMR (300 MHz, CDCl3) d 1.14 (Me, d, 3H,
J = 7.1 Hz), 1.33 (Me, t, 3H, J = 6.8 Hz), 4.06 (OCH2, q, 2H, J = 6.8 Hz), 4.37 (H-4,
dq, 1H, J = 7.1, 8.7 Hz), 4.87 (H-3, d, 1H, J = 8.7 Hz), 6.81–8.11 (ArH, m, 8H); 13
C
NMR (75 MHz, CDCl3) d 12.7, 15.1 (2Me), 56.2 (C-4), 57.0 (C-3), 61.4 (OCH2),
115.2, 117.7, 123.1, 125.9, 126.5, 129.3, 143.1, 155.8 (aromatic carbons); Anal.
Calcd for C17H18ClNO3S: C, 58.03; H, 5.16; N, 3.98; S, 9.11. Found: C, 58.16; H,
5.31; N, 4.07; S, 9.20. 3-(Furan-2-yl)-2-(p-methoxyphenyl)-4-phenyl-1,2-
thiazetidine 1,1-dioxide (6n). White solid mp: 153–155 °C. IR (KBr) cmÀ1
:
1133, 1311 (SO2); 1H NMR (300 MHz, CDCl3) d 3.62 (OMe, s, 3H), 4.43 (H-4, d,
1H, J = 8.5 Hz), 4.85 (H-3, d, 1H, J = 8.5 Hz), 6.52–7.94 (ArH, m, 12H); 13C NMR
(75 MHz, CDCl3) d 55.8 (OMe), 56.6 (C-4), 58.3 (C-3), 108.2, 109.5, 115.9, 118.1,
125.0, 129.7, 130.4, 131.1, 136.8, 148.5, 152.9, 157.3 (aromatic carbons); Anal.
Calcd for C19H17NO4S: C, 64.21; H, 4.82; N, 3.94; S, 9.02. Found: C, 64.34; H,
4.97; N, 3.86; S, 9.11.