The First aza-Wittig Reaction Involving a non-Cumulated Sulfoxy Group

Article abstract of DOI:10.1055/s-2003-43352

3-(Aryliminophosphoranyl)-5-phenyl-4-arylsulfoxy-isoxazoles undergo ring closure via an intramolecular aza-Wittig type reaction of an iminophosphorane onto a non-cumulated sulfoxide. The products obtained are isoxazolo[4,3-c]-2,1- benzothiazines, a hither

Full text of DOI:10.1055/s-2003-43352

LETTER
101
The First aza-Wittig Reaction Involving a non-Cumulated Sulfoxy Group
T
he First aza-Witt
a
igReaction
r
Involvin
l
ga non-Cum
H
ulatedSulfoxy
G
r
e
oup mming,*a Christina Loukou,a Sinem Elkatip,b Robert K. Smalleyc
a
Department of Chemical and Biological Sciences, University of Huddersfield, Queensgate, Huddersfield, HD1 3DH, UK
Fax +44(1484)472182; E-mail: k.hemming@hud.ac.uk
b
c
Graduate Centre, Philosophy Department, City University of New York, 365 Fifth Avenue, New York, 10016–4309, USA
Department of Chemistry, University of Salford, Salford, M5 4WT, UK
Received 22 September 2003
chemistry, in this letter we report the first example of the
synthesis of a cyclic sulfimide involving an intramolecu-
lar aza-Wittig type ring-closure process between a sulfox-
ide and an iminophosphorane. This is the first example of
Abstract: 3-(Aryliminophosphoranyl)-5-phenyl-4-arylsulfoxy-isox-
azoles undergo ring closure via an intramolecular aza-Wittig type
reaction of an iminophosphorane onto a non-cumulated sulfoxide.
The products obtained are isoxazolo[4,3-c]-2,1-benzothiazines, a
hitherto unreported heterocyclic system. This is the first example of an aza-Wittig type reaction between an iminophospho-
the construction of the sulfimide linkage (S=N) via a Wittig type
rane and a non-cumulated ‘S=O’ bond.
process involving non-cumulated sulfoxides. The requisite imino-
phosphoranes were synthesised using the Staudinger reaction of an
Our interest in this area was aroused by our investigations
into the chemistry of 2-[(o-iminophosphoranyl)benzene-
sulfonyl]-1,2-thiazine-1-oxides 1 (R1, R2, R3, R4 = H or
Me or Ph), species that we have previously converted into
benzothiadiazepines using chemistry developed in this
laboratory that has been reported elsewhere.4c In the cur-
rent study, 2-[(o-iminophosphoranyl)benzenesulfonyl]-
1,2-thiazine-1-oxides 1, Scheme 1, were heated in toluene
the strict absence of water, and it was noted (NMR tube
experiment) that triphenylphosphine oxide was formed.
We assign this to the putative aza-Wittig type reaction
shown in Route A of Scheme 1. We were unable to isolate
the proposed initial heterocyclic product 2 of this reaction,
but could isolate, after silica gel chromatography, o-ami-
nobenzenesulfonamide, triphenylphosphine oxide and,
occasionally (see below), dienes. The formation of o-ami-
nobenzenesulfonamide is intriguing, and we believe it
may arise as a result of intermediate 2 undergoing a retro-
Diels–Alder reaction followed by ready hydrolysis, on the
column, of the resultant cyclic sulfur diimide species 3.
azide with triphenylphosphine. Other key steps include the regio-
selective addition of a carbanion to a nitrile oxide in the presence of
an azide, and the synthesis and use of the little reported o-azidoben-
zonitrile oxide.
Key words: aza-Wittig reaction, sulfoxides, 1,3-dipolar cycloaddi-
tions, sulfimide, 2,1-benzothiazine
The aza-Wittig reaction1 is the nitrogen analogue of the
Wittig olefination process and involves the reaction of an
iminophosphorane2 with a carbonyl. The reaction is of use
in the synthesis of acyclic imines,3 and in the intramolec-
ular formation of carbon-nitrogen double bonds in hetero-
cyclic synthesis.4 The use of iminophosphoranes in other
aza-Wittig type reactions for the formation of hetero-
bonds other than C=N is rare. In particular, the only exam-
ples that detail the synthesis of the N=S (sulfimide) bond
involve the use of cumulated S=O functionality.5 The syn-
thesis of sulfimides (also known as sulfilimines or imino-
sulfuranes)6 is the focus of much interest,6–8 particularly in
the development of new reagents for asymmetric cataly-
sis. Whilst sulfoxides are often used for the synthesis of
acyclic sulfimides,7 the corresponding intramolecular sul-
foxide reactions, leading to cyclic sulfimides, have not
been reported to the best of our knowledge, although sev-
eral methods for the cyclisation of sulfoxides into the well
known cyclic sulfoximides [–S(=O)(=NR)–] are known.9
Intermolecular8 and intramolecular10 methods for the
sulfimidation of sulfides, the later leading to cyclic
sulfimides have been reported. Other methods for the syn-
thesis of cyclic sulfimides involve the use of sulfuryl ha-
lides,11 thiazyl fluoride12 and trithiazyl trichloride.13
Sulfimides are also of interest because of their inherent bi-
ological activity,14 and as precursors, via oxidation, to the
synthetically15 and biologically9,15 useful sulfoximides. In
a continuation of our studies3b,4c in the area of aza-Wittig
With 1,2-thiazine-1-oxides 1 (R1 = R4 = Ph; R2 = R3 = H)
and 1a (see Scheme 3), we could isolate dienes from the
reaction mixture in yields of 76% and 70%, respectively,
as shown for 1,2-thiazine-1-oxide 1a in Scheme 2.
We cannot, of course, exclude the possibility that species
1 undergo retro-Diels–Alder reaction first to give the im-
inophosphoranyl heterocumulene 4, and then aza-Wittig
type reaction to furnish the cyclic sulfur diimide 3, as
shown in Route B of Scheme 1. However, a sample of im-
inophosphoranyl heterocumulene 4, synthesised either
from the Staudinger reaction of the corresponding azide or
from sulfinylation16 of the corresponding iminophos-
phoranyl sulfonamide, when subjected to the identical
reaction conditions did not give o-aminobenzenesulfon-
amide, thus indicating that Route A is followed. Despite
the instability of the heterocyclic aza-Wittig adducts 2,
these observations gave us our first hint that an imino-
phosphorane could react in an intramolecular fashion with
a non-cumulated S=O functionality, and prompted further
investigation.
SYNLETT 2004, No. 1, pp 0101–0105
0
5.
0
1.
2
0
0
4
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43352; Art ID: D23603ST
© Georg Thieme Verlag Stuttgart · New York

102
K. Hemming et al.
LETTER
R1
R2
ROUTE A
O2
S
R1
R2
R3
O2
S
Heat, dry toluene
R3
N
S
N
– R3P=O
S
N
R4
N
R4
O
PR3
2
1
R1
O2
S
O2
S
R2
R3
Wet silica
– SO2
NH2
N
S
+
NH2
N
R4
Wet silica
– SO2
3
R1
O2
S
ROUTE B
Heat, dry toluene
Dry toluene
R2
R3
S
O
N
3
+
1
– R3P=O
N
R4
PR3
4
Scheme 1 Formation of o-aminobenzenesulfonamide from 1,2-thiazine-1-oxides 1.
Ph
Ph
O
O2
S
O2
S
NH2
O
S
N
+
+
Ph3P=O
89%
Ph
2
NH2
N
O
Ph
PPh3
59%
70%
1a
Scheme 2 The products of thermolysis of 1,2-thiazine-1-oxide 1a.
We hence focused our attention on bringing about an in-
tramolecular reaction between an iminophosphorane and
a sulfoxide that would give a stable heterocyclic product.
Iminophosphoranes are most easily accessed by the
Staudinger reaction between an azide and a phosphine or
phosphite.2 Thus, our initial target was to synthesise an
azide bearing a tethered sulfoxide group. We decided to
use the readily available o-azidobenzaldehyde17 as the
starting material, with a view to installing the sulfoxide
tether via elaboration of the aldehyde functionality. At-
tempted olefination of the aldehyde via the Wittig reaction
and attempted aldol condensations were unsuccessful,
possibly due to the interaction of the azide with the car-
banions, a known reaction of the azide group.18 We there-
fore chose to convert the aldehyde into a chloro oxime and
thence into a nitrile oxide, as it had previously been shown
that o-azidobenzonitrile oxide reacts with carbanions
solely via its nitrile oxide function.19 The conversion of o-
azidobenzaldehyde (5) into chloro oxime 6 via the oxime
proceeded in high yield (two steps: 92% and 95%) with-
out incident, as shown in Scheme 3.
OH
Cl
O
N
H
i
ii
– HCl
N3
N3
6
5
O
O
S
Ar
Ph
8a,b
/Et3N
O
N
C
N3
7
OH
Ph
Ar
O
O
N
N
Ph
Ar
S
S
H
– H2O
O
N3
O
N3
9a,b
10a,b
Scheme 3 Reagents and conditions: (i) NH2OH·HCl, NaOAc,
EtOH, 25 °C then NCS, CHCl3, C5H5N, 25 °C; (ii) Et3N, EtOH,
25 °C.
The reaction of the chloro oxime 6 with the b-keto sulfox-
ides 8a (Ar = p-Tol) and 8b (Ar = Ph) in the presence of
triethylamine gave the 3-azidoaryl-4-sulfoxy-isoxazoles
Synlett 2004, No. 1, 101–105 © Thieme Stuttgart · New York

LETTER
The First aza-Wittig Reaction Involving a non-Cumulated Sulfoxy Group
103
10a (Ar = p-Tol) and 10b (Ar = Ph) in 46% and 52% reaction of chloro oxime 6 with the relevant b-keto sul-
yields, respectively. The only other products recovered fone. Previous work by one of us has shown that imino-
were small amounts of the nitrile oxide dimer and unreact- phosphoranyl sulfones derived from saccharin similarly
ed b-keto sulfoxide, thereby demonstrating that carban- show no evidence of cyclisation at the sulfone group.24
ions/enolates derived from b-keto sulfoxides do indeed
To summarise, the cyclisation of 3-(aryliminophosphora-
nyl)-4-sulfoxyaryl-isoxazoles via an intramolecular aza-
Wittig type reaction resulted in the formation of cyclic
sulfimides, giving the hitherto unreported heterocyclic
system, the isoxazolo[4,3-c]-2,1-benzothiazine. This is
the first example of a non-cumulated sulfoxy system un-
react regiospecifically with o-azidobenzonitrile oxide.
This reaction proceeds via the generation of a carbanion/
enolate and its addition to the nitrile oxide 7, both species
being generated in-situ. Subsequent loss of water from the
adducts 9 gives the isoxazoles 10.20
The Staudinger reaction between the 3-(o-azidophenyl)- dergoing an aza-Wittig type reaction. Work on the use of
4-sulfoxyaryl-isoxazoles 10 and triphenylphosphine, optically pure sulfoxides in the reaction is underway and
shown in Scheme 4, gave the corresponding arylimino- further applications to the synthesis of other heterocyclic
phosphoranyl 4-sulfoxyaryl-isoxazoles21 11a (Ar = p- systems as well as intermolecular versions of the reaction
Tol) and 11b (Ar = Ph) in yields of 91% and 95%. Treat- are being explored.
ment of compounds 11 in anhydrous toluene at reflux for
5–8 hours gave, after column chromatography, an 80–
85% yield of triphenylphosphine oxide together with the
Acknowledgement
We thank the EPSRC for funding via a standard research grant, Dr
N. McLay and Ms L. Harding of the University of Huddersfield for
NMR and mass spectra, and the EPSRC National Mass Spectro-
metry Service at the University of Wales Swansea.
isoxazolo[4,3-c][2,1]benzothiazines 12a (Ar = p-Tol) and
12b (Ar = Ph), a hitherto unreported heterocyclic system,
in yields of 50% and 48%, respectively.22
O
N
O
N
Ph
Ar
References
Ph
Ar
i
S
(1) For reviews, see: (a) Wamhoff, H.; Richardt, G.; Stölben, S.
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S
O
N
– N2
O
N3
PPh3
10a,b
11a,b
(2) For reviews, see: (a) Gololobov, Y. G.; Kasukhin, L. F.
Tetrahedron 1992, 48, 1353. (b) Gololobov, Y. G.;
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1565.
O
N
Ph
ii
– Ph3P=O
iii
S
N
Ar
12a,b
(4) See, for example: (a) Eguchi, S.; Yamashita, K.; Matsushita,
Y.; Kakehi, A. J. Org. Chem. 1995, 60, 4006. (b) O’Neil, I.
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P.; Hemming, K.; Karajniewski, M.; Loukou, C.
O
O
N
N
Ph
Ph
Ar
Ar
O
S
S
O
N3
O
NH2
13a,b
Tetrahedron Lett. 2000, 41, 10107.
14a,b
(5) Staudinger, H.; Hauser, E. Helv. Chim. Acta 1921, 4, 861.
(6) For a review, see: Johnson, C. R. In Comprehensive Organic
Chemistry, Vol 3; Barton, D. H. R.; Ollis, W. D., Eds.;
Pergamon: New York, 1979, Chap. 11.10, 215.
Scheme 4 Reagents and conditions: (i) PPh3, THF, 25 °C;
(ii) reflux, toluene, 5 h; (iii) THF, H2O (10%), 25 °C, 16 h.
(7) See, for example: (a) Tarbell, D. S.; Weaver, C. J. Am.
Chem. Soc. 1941, 63, 2939. (b) Varkey, T. E.; Whitfield, G.
F.; Swern, D. J. Org. Chem. 1974, 39, 3365; and references
cited therein. (c) Takada, H.; Oda, M.; Oyamada, A.; Ohe,
K.; Uemura, S. Chirality 2000, 12, 299. (d) Cram, D. J.;
Day, J.; Rayner, D. R.; von Schriltz, D. M.; Duchamp, D. J.;
Garwood, D. C. J. Am. Chem. Soc. 1970, 92, 7369.
(e) Johnson, C. R.; Rigau, J. J. J. Org. Chem. 1968, 33,
4340. (f) Kise, H.; Whitfield, G. F.; Swern, D. J. Org. Chem.
1972, 37, 1121.
(8) See, for example: (a) Mann, F. G.; Pope, W. J. J. Chem. Soc.
1922, 1052. (b) For a review, see: Gilchrist, T. L.; Moody,
C. J. Chem. Rev. 1977, 77, 409. (c) Shiraishi, Y.; Naito, T.;
Hirai, T.; Komasawa, I. Chem. Commun. 2001, 1256.
(d) Shiraishi, Y.; Naito, T.; Hirai, T.; Komasawa, I. Ind. Eng.
Chem. Res. 2002, 41, 4376. (e) Johnson, C. R.; Mori, K.;
Nakanishi, A. J. Org. Chem. 1979, 44, 2065. (f) Marzinzik,
The isoxazolo[4,3-c]-2,1-benzothiazines 12a and 12b
were sufficiently stable to allow characterisation by mass
spectrometry (including HRMS), infra-red spectroscopy,
1
micro-analysis and H NMR and 13C NMR spectrosco-
py.22 Treatment of isoxazolo[4,3-c][2,1]benzothiazines
12 in wet THF at room temperature gave the hydrolysis
products 13, in high yield,23 further confirming our struc-
tural assignment.
Attempted Staudinger reaction and subsequent aza-Wittig
type ring closure of 3-(o-azidoaryl)-4-arylsulfonyl-isox-
azoles 14 was unsuccessful, showing that the correspond-
ing sulfone will not undergo the analogous reaction. The
requisite sulfones 14 were easily synthesised from the
Synlett 2004, No. 1, 101–105 © Thieme Stuttgart · New York

104
K. Hemming et al.
LETTER
A. L.; Sharpless, K. B. J. Org. Chem. 2001, 66, 594.
(g) Nishikori, H.; Ohta, C.; Oberlin, E.; Irie, R.; Katsuki, T.
Tetrahedron 1999, 55, 13937. (h) Hayashi, Y.; Swern, D. J.
Am. Chem. Soc. 1973, 95, 5205. (i) Tamura, Y.; Uchida, T.;
Katsuki, T. Tetrahedron Lett. 2003, 44, 3301. (j) Bach, T.;
Körber, C. Tetrahedron Lett. 1998, 39, 5015. (k) Bach, T.;
Körber, C. Eur. J. Org. Chem. 1999, 1033. (l) Tomooka, C.
S.; Carreira, E. M. Helv. Chim. Acta 2002, 85, 3773.
(m) Armstrong, A.; Cooke, R. S. Chem. Commun. 2002,
904.
H, J = 7.5, 0.7 Hz, 1 × ArH), 7.45 (m, 2 H, 2 × ArH), 7.57
(m, 3 H, 3 × ArH), 8.08, (dd, 2 H, J = 8.1, 1.7 Hz, 2 × ArH).
13C NMR (100 MHz, CDCl3): d = 21.1 (CH3), 118.0 (CH),
118.7 (quat.), 119.1 (quat.), 124.3 (CH), 124.4 (CH), 125.6
(quat.), 128.8 (quat.), 128.9 (CH), 129.0 (CH), 131.3 (CH),
131.9 (CH), 132.6 (CH), 137.7 (quat.), 138.8 (quat.), 140.5
(quat.), 160.1 (quat.), 172.5 (quat.). IR: 2925 (m), 2128 (s),
1604 (w), 1581 (w), 1556 (m), 1448 (m), 1300 (s), 1084 (m),
1054 (m) cm–1. MS (EI): m/z (%) = 372 (100) [M – 28], 237
(80), 189 (70), 119 (30), 91 (40), 77 (98). HRMS (ES+):
found MH+ 401.1066, C22H16N4O2S requires MH 401.1072.
(21) Synthesis 3-[o-N-(Triphenylphosphoranylidene)phenyl]-
4-(p-tolylsulfoxy)-5-phenylisoxazole (11a): To a solution
of 3-(o-azidophenyl)-4-(p-tolyl-sulfoxy)-5-phenyl-
(9) (a) For a review, see: Kennewell, P. D.; Taylor, J. B. Chem.
Soc. Rev. 1980, 9, 477. (b) Jones, S. D.; Kennewell, P. D.;
Tulley, W. R.; Westwood, R.; Sammes, P. G. J. Chem. Soc.,
Perkin Trans. 1 1990, 447. (c) Harmata, M.; Claassen, R. J.
II.; Barnes, C. L. J. Org. Chem. 1991, 56, 5059.
isoxazole (10a) (0.2000 g, 0.50 mmol, 1 equiv) in anhyd
toluene (10 mL) was added at r.t., under an atmosphere of
dry nitrogen, a solution of triphenylphosphine (0.1311 g,
0.50 mmol, 1 equiv) in anhyd toluene (5 mL). The reaction
mixture was stirred for a total of 5 h whilst being monitored
by TLC. After completion of the reaction, the solvent was
removed in vacuo and the crude product was purified by
flash silica column chromatography (eluent: petroleum
ether–EtOAc, 2:1) to give 3-[o-N-(triphenylphosphoranyl-
idene)phenyl]-4-(p-tolylsulfoxy)-5-phenylisoxazole as a
bright yellow solid (0.2890 g, 91% yield), mp 102–104 °C.
1H NMR (400 MHz, CDCl3): d = 2.16 (s, 3 H, Me), 6.54 (d,
1 H, J = 8.25 Hz, 1 × ArH), 6.74 (t, 1 H, J = 7.5 Hz, 1 ×
ArH), 6.81 (d, 2 H, J = 8.1 Hz, 2 × ArH), 7.03 (td, 1 H,
J = 7.7, 1.7 Hz, 1 × ArH), 7.14 (d, 2 H, J = 8.1 Hz, 2 × ArH),
7.27–7.46 (m, 10 H, 10 × PhH), 7.50 (m, 3 H, 3 × ArH),
7.73–7.85 (m, 6 H, 6 × ArH), 8.13 (dd, 2 H, J = 7.7, 1.9 Hz,
2 × ArH). 13C NMR (100 MHz, CDCl3): d = 21.1 (CH3),
116.7 (CH), 121.1 (CH), 121.3 (CH), 124.4 (CH), 126.8
(quat.), 126.9 (quat.), 128.3 (CH), 128.4 (CH), 128.5 (CH),
129.3 (CH), 130.0 (quat.), 130.3 (CH), 130.4 (CH), 130.5
(CH), 130.9 (CH), 131.0 (CH), 131.6 (CH), 132.0 (quat.),
132.1 (quat.), 132.7 (CH), 132.8 (CH), 139.7 (quat.), 140.4
(quat.), 150.7 (quat.), 164.8 (quat.), 171.1 (quat.). IR: 3018
(m), 1677 (m), 1606 (m), 1560 (m), 1438 (m), 1345 (m),
1181 (s), 1119 (m), 694 (m), 666 (m) cm–1. HRMS (ES+):
found MH+ 635.1928, C40H31N2O2PS requires MH+
(10) (a) Hori, M.; Kataoka, T.; Shimizu, H.; Matsua, K.
Tetrahedron Lett. 1979, 20, 3969. (b) Shimizu, H.; Ikedo,
K.; Hamada, K.; Matsumoto, H.; Ozawa, M.; Kataoka, T.;
Hori, M. Tetrahedron Lett. 1990, 31, 7021. (c) Shimizu, H.;
Hamada, K.; Ozawa, M.; Kataoka, T.; Hori, M.; Kobayashi,
K.; Tuda, Y. Tetrahedron Lett. 1991, 32, 4359.
(d) Shimizu, H.; Ikedo, K.; Hamada, K.; Ozawa, M.;
Matsumoto, H.; Kamata, K.; Nakamuru, H.; Ji, M.; Kataoka,
T.; Hori, M. J. Chem. Soc., Perkin Trans. 1 1991, 1733.
(e) Grant, R. D.; Moody, C. J.; Rees, C. W.; Tsoi, S. C. J.
Chem. Soc., Chem. Commun. 1982, 884. (f) Moody, C. J.;
Rees, C. W.; Tsoi, S. C.; Williams, D. J. J. Chem. Soc.,
Chem. Commun. 1981, 927. (g) Gairns, R. S.; Grant, R. D.;
Moody, C. J.; Rees, C. W.; Tsoi, S. C. J. Chem. Soc., Perkin
Trans. 1 1986, 483.
(11) Gilchrist, T. L.; Rees, C. W.; Vaughan, D. J. Chem. Soc.,
Chem. Commun. 1978, 1049; and references cited therein.
(12) Bludssus, W.; Mews, R. J. Chem. Soc., Chem. Commun.
1978, 35.
(13) Rees, C. W.; Yue, T.-Y. Chem. Commun. 1998, 1207.
(14) (a) Strekowski, L.; Henary, M.; Kim, N.; Michniak, B. B.
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Photochem. Photobiol., B 2001, 61, 68.
(15) For a review, see: Reggelin, M.; Zur, C. Synthesis 2000, 1.
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Acc. Chem. Res. 1988, 21, 313.
635.1922.
(22) Synthesis of 3-Phenyl-2-(p-tolyl)-isoxazolo[4,3-
c][2,1]benzothiazine (12a): A solution of 3-[o-N-
(17) Azadi-Ardakani, M.; Smalley, R. K.; Smith, R. H. J. Chem.
Soc., Perkin Trans. 1 1983, 2501.
(triphenylphosphoranylidene)phenyl]-4-(p-tolylsulfoxy)-5-
phenylisoxazole (11a) (0.2500 g, 0.3939 mmol, 1 equiv) in
freshly distilled anhyd toluene (10 mL) was heated at reflux
under a dry nitrogen atmosphere for a total of 8 h, whilst
being monitored by TLC. After completion of the reaction,
the solvent was removed in vacuo and the crude product was
purified by flash silica column chromatography (eluent:
petroleum ether–EtOAc, 5:1) to give 3-phenyl-2-(p-tolyl)-
isoxazolo[4,3-c][2,1]benzothiazine as a bright green oil
(0.0700 g, 50% yield), a sample of which solidified on
standing. CHN: found (%) C, 74.4; H, 4.4; N, 7.6; S, 9.5.
C22H16N2OS requires (%): C, 74.1; H, 4.5; N, 7.9; S, 9.0. 1H
NMR (400 MHz, CDCl3): d = 2.17 (s, 3 H, Me), 6.53 (d, 2
H, J = 8.1 Hz, 2 × ArH), 6.71, (d, 2 H, J = 8.1 Hz, 2 × ArH),
7.11 (t, 1 H, J = 7.5 Hz, 1 × ArH), 7.33 (t, 1 H, J = 7.4 Hz,
1 × ArH), 7.40 (m, 3 H, 3 × ArH), 7.52 (t, 1 H, J = 7.3 Hz,
1 × ArH), 7.83 (d, 1 H, J = 7.9 Hz, 1 × ArH), 8.20 (d, 2 H,
J = 7.4 Hz, 2 × ArH). 13C NMR (100 MHz, CDCl3): d = 21.0
(CH3), 110.8 (CH), 121.0 (CH), 122.3 (CH), 123.7 (quat.),
127.5 (CH), 128.5 (CH), 128.9 (CH), 129.3 (CH), 129.6
(CH), 133.1 (CH), 133.3 (quat.), 135.9 (quat.), 137.6 (quat.),
144.7 (quat.), 145.7 (quat.), 168.2 (quat.). IR: 3019 (m),
2925 (m), 1681 (m), 1596 (m), 1478 (m) 1449 (m), 908 (s),
(18) (a) L’Abbe, G. Ind. Chim. Belg. 1971, 36, 3. (b)L’Abbe, G.
Ind. Chim. Belg. 1969, 34, 519. (c) L’Abbe, G.; Hassner, A.
J. Heterocycl. Chem. 1970, 7, 361. (d) L’Abbe, G.; Mathys,
G.; Toppet, S. J. Org. Chem. 1975, 40, 1549. (e) Bourgois,
J.; Bourgois, M.; Texier, T. Bull. Soc. Chim. Fr. 1978, 485.
(19) Purwono, B.; Smalley, R. K.; Porter, T. C. Synlett 1992, 231.
(20) Synthesis of 3-(o-Azidophenyl)-4-(p-tolylsulfoxy)-5-
phenylisoxazole (10a): To a solution of phenacyl p-tolyl
sulfoxide (1.3140 g, 5.09 mmol, 1 equiv) and freshly
distilled Et3N (1.42 mL, d = 0.726, 10.17 mmol, 2 equiv) in
anhyd EtOH (15 mL) was added, dropwise over 4 h, a
solution of o-azido benzohydroximoyl chloride (1.0000 g,
5.09 mmol, 1 equiv) in anhyd EtOH (15 mL), under an
atmosphere of dry nitrogen. The mixture was concentrated in
vacuo and the crude residue was purified by flash silica
column chromatography (eluent: petroleum ether–EtOAc,
3:1) to give 3-(o-azidophenyl)-4-(p-tolylsulfoxy)-5-
phenylisoxazole as a yellow solid (0.9470 g, 46% yield), mp
148–149 °C. 1H NMR ( 400 MHz, CDCl3): d = 2.17 (s, 3 H,
Me), 7.04 (t, 1 H, J = 7.5 Hz, 1 × ArH), 7.07 (d, 2 H, J = 8.2
Hz, 2 × ArH), 7.12 (d, 2 H, J = 8.2 Hz, 2 × ArH), 7.19 (dt, 1
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LETTER
The First aza-Wittig Reaction Involving a non-Cumulated Sulfoxy Group
105
805 (m), 668 (m) cm–1. MS (ES+): m/z (%) = 379 (100) [M
ArH), 7.10 (t, 1 H, J = 7.3 Hz, 1 × ArH), 7.20 (m, 3 H, 3 ×
ArH), 7.26 (m, 3 H, 3 × ArH), 7.36 (d, 2 H, J = 8.1 Hz, 2 ×
ArH), 7.94 (d, 2 H, J = 8.2 Hz, 2 × ArH). 13C NMR (100
MHz, CDCl3): d = 21.6 (CH3), 111.8 (quat.), 116.0 (CH),
117.5 (quat.), 117.6 (CH), 122.8 (quat.), 124.3 (CH), 128.3
(CH), 128.8 (CH), 129.7 (CH), 130.0 (CH), 130.8 (CH),
132.0 (CH), 140.6 (quat.), 142.6 (quat.), 145.3 (quat.), 161.5
(quat.), 173.8 (quat.). IR: 3476 (m, broad), 3381 (m, broad),
3062 (m), 2925 (w), 1671 (s), 1580 (m), 1557 (m), 1499 (s),
1475 (m), 1444 (m), 1374 (m), 1083 (m), 1038 (s), 668
(m)cm–1. MS (ES+): m/z (%) = 375 (100) [M + H], 397 (55)
[M + Na]. HRMS (ES+): found MH+ 375.1172,
+ 23]. HRMS (ES+): found MH+ 357.1058, C22H16N2OS
requires MH+ 357.1056.
(23) Synthesis of 3-(o-aminophenyl)-5-(phenyl)-4-(p-
tolylsulfoxy)-isoxazole (13a): To a solution of the 3-
phenyl-2-(p-tolyl)-isoxazolo[4,3-c][2,1]benzothiazine(12a)
(0.0500 g, 0.14 mmol) in THF (5 mL) was added, at r.t., H2O
(1 mL). The reaction mixture was stirred for a total of 20 h
whilst being monitored by TLC. After completion of the
reaction, the solvent was removed in vacuo and the crude
product was purified by flash column chromatography
(eluent: petroleum ether–EtOAc, 5:3) to give 3-(o-
aminophenyl)-5-(phenyl)-4-(p-tolylsulfoxy)-isoxazole as a
pale yellow oil (0.0452 g, 86% yield). 1H NMR (400 MHz,
CDCl3): d = 2.27 (s, 3 H, Me), 4.43 (broad s, 2 H, NH2), 6.59
(d, 1 H, J = 8.0 Hz, 1 × ArH), 6.65 (t, 1 H, J = 7.5 Hz, 1 ×
C22H18N2O2S requires MH 375.1167.
(24) Luheshi, A.-B. N.; Salem, S. M.; Smalley, R. K.; Kennewell,
P. D.; Westwood, R. Tetrahedron Lett. 1990, 31, 6561.
Synlett 2004, No. 1, 101–105 © Thieme Stuttgart · New York