Facile synthesis of N-substituted isothiazol-3(2H)-ones using a hypervalent iodine(III) reagent

Article abstract of DOI:10.1002/jccs.200100174

Treatment of N-substituted (Z)-3-(benzylsulfanyl)propenamides (4) with phenyliodine(III) bis(trifluoroacetate) containing trifluoroacetic acid resulted in an interrupted Pummerer-type reaction to give N-substituted isothiazol-3(2H)-ones (5) rather than th

Full text of DOI:10.1002/jccs.200100174

JournaloftheChineseChemicalSociety, 2001, 48, 1185-1188
1185
FacileSynthesisofN-SubstitutedIsothiazol-3(2H)-ones Using a
Hypervalent Iodine(III)Reagent
Iou-Jiun Kanga (
Hsin-Yu Huanga (
), Huey-Min Wangb (
),
) and Ling-Ching Chena* (
)
aGraduateInstituteofPharmaceuticalSciences,KaohsiungMedicalUniversity,
Kaohsiung, Tai wan 807, R.O.C.
bChungHwaCollegeofMedicalTechnology,Tainan,Taiwan717,R.O.C.
TreatmentofN-substituted( Z)-3-(benzylsulfanyl)propenamides (4) with phenyliodine(III) bis(trifluoro-
acetate) con tain ing trifluoroacetic acid re sulted in an in ter rupted Pummerer-type re ac tion to give N-sub sti-
tuted isothiazol-3(2H)-ones (5) rather than the nor mal Pummerer-type prod ucts.
INTRODUCTION
The Pummerer re ac tion of sulfoxides nor mally pro-
ready avail abil ity and easy han dling.8 As a con tin u a tion of
ourstudiesconcerninghypervalentiodine(III)chemistry,we
have re ported a Pummerer-type re ac tion that pro vides a very
simpleandconvenientprocedureforthepreparationof4H-
pyrrolo[2,1-c][1,4]benzothiazines by treat ment of -acyl
sul fides with phenyliodine(III) bis(trifluoroacetate) (PIFA).9
WereporthereaninterruptedPummerer-typereactionofsul-
fides us ing PIFA has been ap plied to pre pare N-substituted
isothiazol-3(2H)-ones via intramolecular N-S bond for ma-
tion.
ceeds via an ac ti vated sulfoxide (1) and then a thionium ion
(2) which re acts with a nucleophile at car bon to af ford an
-substitutedsulfide.1 In an in ter rupted Pummerer re ac tion,
thetricoordinatesulfurintermediate(1)undergoesreaction
with a nucleophile at sul fur lead ing to un ex pected prod uct
(Scheme I).2
Scheme I
RESULTS AND DISCUSSION
O
OCOCF3
TFAA or
OCOCF3
S
S
+
other
electrophilic
reagent
The req ui site amides (4) were readily pre pared from
(Z)-3-benzylsulfanylpropenoic acid (3) with Ph3P/CCl4-com-
plexfollowedbytreatmentwithappropriateamines.10 Thus,
treat ment of 4 with PIFA containing trifluoroacetic acid
(TFA) in CH2Cl2 caused cyclization to give N-substituted
isothiazol-3(2H)-ones (5) in mod er ate yields. Un der these
con di tions no sulfoxides or nor mal Pummerer-type prod ucts
were ob tained (Scheme II). The yields are sum ma rized in Ta-
ble 1.
1
Nu
+
S
Nu
CH
CF3CO2H Pummerer
S
CH
+
2
1
Nu
Nu
Nu
OCOCF3
Interrupted
OCOCF3
+
S
+
S
Pummerer
Isothiazol-3(2H)-ones have found a range of in dus trial
applicationsandarewidelyusedasantimicrobialandalgicidal
additives.3 The meth ods used for their syn the sis in volve the
cyclization of cis-3-thiocyanoacrylamides by treat ment with
acid,4 ox i da tive annelation of 3,3 -dithiopropionamides us-
ing ei ther chlo rine or sulfuryl chlo ride as ox i dant,5 nucleo-
philic dis place ment ofN-sub sti tuted of 5-aroyl-3(2H)-iso-
thiazolones by treat ment with base,6 and cyclization of sul-
foxidesubstratesactingassulfenylhalideequivalents.7
Re cently, hypervalent io dine re agents have been used
ex ten sively in or ganic syn the sis due to their low tox ic ity,
Scheme II
O
O
O
complex
OH
Ph
1) Ph3P / CCl4
2) RNH2
NHR
Ph
PIFA TFA
CH2Cl2
NR
S
S
3
S
4
5
n
i
t
a) R = Pr b) R = Pr c) R = Bu d) R= Ph
e) R = 4-MeOC6H4 f) R= 4-ClC6H4

1186 J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001
Kang et al.
Table 1. Preparation of Amides 4 and N-Substituted Isothiazol-
3(2H)-ones 5
NMR and 13C NMR spec tra were re corded on a Varian Gem-
ini-200 or Varian Unity Plus 400 MHz. Chem i cal shifts were
measuredinppm( ) with re spect to TMS. MS were ob tained
on a JEOL JMS D-300 in stru ment.
Isolated Yield (%)
Product
R
4
5
a
b
c
d
e
f
Prn
Pri
But
Ph
4-MeOC6H4
4-ClC6H4
70
72
71
75
74
70
71
65
67
72
65
60
General Procedure for the Prep a ra tion of Amides 4a-4f
Triphenylphosphine (315 mg, 1.2 mmol) was added
portionwise over 5 min to a so lu tion of (Z)-3-benzyl sul-
fanylpropenoic acid (3) (194 mg, 1 mmol), CCl4 (308 mg, 2
mmol), and the req ui site amine (2.1 mmol) in MeCN (25
mL). The re sult ing mix ture was heated at 80 C for 2 h. Af ter
removalofthesolvent,theresiduewasextractedwithCH2Cl2.
The organic layer was washed with brine and dried over
MgSO4. The sol vent was evap o rated off and the res i due was
chromatographed on sil ica gel with n-hexane:ethylacetate
(2:1) to give the prod ucts 4a-4f.
Amechanisticsequencefor1,2-benzisothiazol-3(2H)-
one ring for ma tion us ing PIFA is shown in Scheme III. The
cyclization from 4 to 5is as sumed to pro ceed through in ter-
ruptedPummerer-typereactionintermediate(7) which would
be formed by at tack of PIFA on the sul fur atom of4,followed
by si mul ta neous elim i na tion of the iodobenzene and trifluo-
ro acetic acid from the re sul tant sul fon ium salt (6). Ap par-
ently, with out the elec tron with draw ing group on the car bon
al pha to the sul fide group, trifluoroacetate ion is not ba sic
enough to gen er ate the thionium ion.
(Z)-3-(Benzylsulfanyl)-N-propylpropenamide (4a)
Col or less nee dles; mp 107-108 C (lit.,7 108-109 C).
1
IR (neat) : 3310, 1625, 1580 cm-1; H NMR (CDCl3, 400
MHz) : 0.90 (t,J = 7.6 Hz, 3H), 1.52 (tq, J = 7.6 and 7.2 Hz,
2H), 3.25 (dt, J = 7.2 and 5.6 Hz, 2H), 3.90 (s, 2H), 5.50 (br s,
1H), 5.71 (d,J = 10.0 Hz, 1H), 6.78 (d,J = 10.0 Hz, 1H), 7.30
(m, 5H); EI-MS m/z (relative in ten sity) 235 (M+, 5), 144
(100), 91 (52), 65 (9).
Scheme III
O
S
O
O
(Z)-3-(Benzylsulfanyl)-N-isopropylpropenamide (4b)
Col or less nee dles; mp 120-122 C (lit.,7 120-121 C).
IR (neat) : 3275, 1645, 1575, 1545 cm-1; 1H NMR (CDCl3,
400 MHz) : 1.16 (d, J = 6.6 Hz, 6H), 3.91 (s, 2H), 4.13 (m,
1H), 5.66 (d, J = 9.9 Hz, 1H), 6.78 (d, J = 9.9 Hz, 1H),
7.24-7.36 (m, 5H); EI-MS m/z (relativeintensity)235(M+,
12), 144 (100), 102 (39), 91 (57), 65 (11).
NHR
Ph
NHR
PIFA
NR
_
+
+
S
S
Ph
OCOCF3
_
OCOCF3
PhI
CF3CO2H
I
Ph
Ph
OCOCF3
4
7
6
O
NR
S
PhCH2 OCOCF3
(Z)-3-(Benzylsulfanyl)-N-tert-butylpropenamide (4c)
Colorlessneedles;mp100-101 C (lit.,7 99-100 C). IR
(neat) : 3300, 1635, 1575 cm-1; 1H NMR (CDCl3, 400 MHz)
: 1.37 (s, 9H), 3.90 (s, 2H), 5.21 (br s, 1H), 5.63 (d, J = 10.0
Hz, 1H), 6.74 (d, J = 10.0 Hz, 1H), 7.30 (m, 5H); EI-MS m/z
(relativeintensity)249(M+, 3), 158 (90), 102 (100), 91 (66),
65 (9).
5
Insummary, ourresultshereindemonstratethattheuse
of a com bined re agent PIFA-TFA in CH2Cl2 is a con ve nient
and use ful method for the in ter rupted Pummerer-type re ac-
tion of sul fides to pre pare N-substitutedisothiazol-3(2H)-
ones.
(Z)-3-(Benzylsulfanyl)-N-phenylpropenamide (4d)
Col or less nee dles; mp 166-167 C (lit.,7 167-169 C).
IR (neat) : 3225, 1635, 1590, 1565 cm-1; 1H NMR (CDCl3,
400 MHz) : 3.95 (s, 2H), 5.88 (d,J = 10.0 Hz, 1H), 6.98 (d, J
= 10.0 Hz, 1H), 7.06-7.37 (m, 8H), 7.18 (br s, 1H), 7.56 (m,
2H); EI-MS m/z (relativeintensity)269(M+, 5), 178 (80), 93
EXPERIMENTALSECTION
Allmeltingpointsareuncorrected.TheIRspectrawere
1
recorded on a Shimadzu IR-27 G spectrophotometer. H

SynthesisofN-SubstitutedIsothiazol-3(2H)-ones
J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001 1187
(44), 91 (100), 65 (15).
C6H9NOS: 143.0404. Found: 143.0404.
(Z)-3-(Benzylsulfanyl)-N-(4-methoxyphenyl)propenamide
(4e)
N-tert-Butylisothiazol-3(2H)-one (5c)
Byusingaproceduresimilartothatdescribedfor5a, 4c
gave 5c (67%); mp 84-85 C (lit.,5 85-86 C). IR (neat) :
2960, 2920, 1725, 1620 cm-1; 1H NMR (CDCl3, 200 MHz) :
1.36 (s, 9H), 6.20 (d, J= 6.3 Hz, 1H), 7.92 (d, J = 6.3 Hz, 1H);
13C-NMR (50 MHz, CDCl3): 28.9, 58.6, 128.7, 130.8, 167.7;
EI-MS m/z (relativeintensity)157(M+, 40), 102 (100), 73
(7), 57 (33).
Col or less nee dles; mp 110-112 C (lit.,7 111-112 C).
IR (neat) : 3275, 1635, 1565, 1510 cm-1; 1H NMR (CDCl3,
200 MHz) : 3.78 (s, 3H), 3.95 (s, 2H), 5.84 (d, J = 10.0 Hz,
1H), 6.83 (m, 2H), 6.95 (d, J = 10.0 Hz, 1H), 7.04 (br s, 1H),
7.25-7.35 (m, 7H), 7.47 (m, 2H); EI-MS m/z (relativeinten-
sity) 299 (M+, 2), 208 (26), 123 (100), 91 (80).
(Z)-3-(Benzylsulfanyl)-N-(4-chlorophenyl)propenamide
(4f)
N-Phenylisothiazol-3(2H)-one (5d)
By us ing a pro ce dure sim i lar to that de scribed for5a,
4d gave 5d (72%); mp 91-92 C (lit.,5 91-92 C). IR (neat) :
3255, 3080, 1640, 1490 cm-1; 1H NMR (CDCl3, 200 MHz) :
6.34 (d, J = 6.4Hz, 1H), 7.33-7.60 (m, 5H), 8.17 (d, J = 6.4
Hz, 1H); 13C-NMR (50 MHz, CDCl3): 120.2, 124.3, 129.3,
129.7, 130.2, 144.0, 167.7; EI-MS m/z (relativeintensity)
177 (M+, 100), 104 (21), 77 (16), 58 (8).
Col or less nee dles; mp 129-130 C. IR (neat) : 3375,
1
1650, 1565, 1510 cm-1; H NMR (CDCl3, 400 MHz) : 3.96
(s, 2H), 5.85 (d, J = 10.0 Hz, 1H), 7.02 (d, J = 10.0 Hz, 1H),
7.09 (br s, 1H), 7.22-7.36 (m, 7H), 7.52 (m, 2H); EI-MS m/z
(relativeintensity)303(M+, 2), 212 (18), 177 (31), 127 (26),
91 (100), 65 (10). Anal. Calcd. for C16H14ClNOS: C, 4.60; H,
63.30; N, 4.60. Found: C, 4.59; H, 63.17; N, 4.61.
N-(4-Methoxyphenyl)isothiazol-3(2H)-one (5e)
N-propylisothiazole-3(2H)-ones (5a)
Byusingaproceduresimilartothatdescribedfor5a, 4e
gave 5e (65%); mp 92-93 C (lit.,7 92-93 C). IR (neat) :
3070, 1645, 1610 cm-1; 1H NMR (CDCl3, 200 MHz) : 3.83
(s, 3H), 6.33 (d, J = 6.4 Hz, 1H), 6.97 (m, 2H), 7.44 (m, 2H),
8.15 (d,J = 6.4 Hz, 1H);13C-NMR (50 MHz, CDCl3): 55.5,
114.5, 114.6, 126.9, 128.9, 139.3, 159.0, 167.8; EI-MS m/z
(relativeintensity)207(M+, 100), 192 (25), 164 (21), 134
(38), 121 (21), 106 (16).
A so lu tion of (Z)-3-(benzylsulfanyl)-N-propylpropen-
amide (4a) (235 mg, 1 mmol) in CH2Cl2 (5 mL) was added
dropwise to a so lu tion of the mix ture of PIFA (538 mg, 1.25
mmol) and TFA (228 mg, 2 mmol) in CH2Cl2 at 0 C and the
mix ture was stirred at the same tem per a ture for 1 h. Then the
mixturewasrefluxedfor2htocompletethereaction. There-
sul tant mix ture was quenched with wa ter and ex tracted with
CH2Cl2. The mix ture was dried (MgSO4)andconcentrated
underreducedpressureandtheresiduewaspurifiedbychro-
matographyonasilicagelcolumn,elutingwithethylacetate
to give 102 mg (71%) of 5a as an oil. IR (neat) : 3100, 1620,
1460 cm-1; 1H NMR (CDCl3, 400 MHz) : 0.97 (t,J = 7.6 Hz,
3H), 1.75 (dt,J = 7.6 and 7.2 Hz, 2H), 3.76 (t, J = 7.2 Hz, 2H),
6.28 (d, J = 6.4 Hz, 1H), 8.06 (d, J = 6.4 Hz, 1H); 13C-NMR
(100 MHz, CDCl3): 11.0, 23.1, 45.4, 114.7, 138.5, 168.9;
EI-MS m/z (relativeintensity)143(M+, 44), 114 (27), 101
(100), 87 (23), 58 (14). HRMS m/z Calcd for C6H9NOS:
143.0404. Found: 143.0404.
N-(4-Chlorophenyl)isothiazol-3(2H)-one (5f)
Byusingaproceduresimilartothatdescribedfor5a, 4f
gave 5f (60%); mp 141-142 C (lit.,5 142-144 C). IR (neat)
1
: 3070, 1640, 1490 cm-1; H NMR (CDCl3, 400 MHz) :
6.34 (d, J = 6.4 Hz, 1H), 7.42 (m, 2H), 7.56 (m, 2H), 8.15 (d,J
= 6.4 Hz); 13C-NMR (100 MHz, CDCl3): 114.9, 125.7,
129.4, 132.9, 135.0, 139.5, 167.4; EI-MS m/z (relativeinten-
sity) 211 (M+, 100), 148 (40), 138 (32), 111 (12), 90 (16), 58
(11).
N-Isopropylisothiazol-3(2H)-one (5b)
ACKNOWLEDGEMENT
By us ing a pro ce dure sim i lar to that de scribed for 5a,
4b gave 5b (65%) as an oil. IR (neat) : 2970, 1620, 1460
cm-1; 1H NMR (CDCl3, 200 MHz) : 1.38 (d, J = 6.8 Hz, 6H),
4.80 (m, 1H), 6.26 (d, J = 6.4 Hz, 1H), 8.04 (d, J = 6.4 Hz,
1H); 13C-NMR (50 MHz, CDCl3): 22.5, 46.1, 115.2, 138.4,
168.5; EI-MS m/z (relative intensity) 143 (M+, 33), 101
(100), 87 (9), 73 (12), 58 (10). HRMS m/z Calcd for
WegratefullyacknowledgetheNationalScienceCoun-
cil for fi nan cial sup port of this work (Grant No. NSC 89-
2113-M-037-018).
Received May 29, 2001.

1188 J. Chin. Chem. Soc., Vol. 48, No. 6B, 2001
Kang et al.
Key Words
7. Beeley, N. R. A.; Har wood, L. M.; Hedger, P. C. J. Chem.
Perkin Trans. 1 1994, 2245.
Pummerer reaction; Thionium ion;
Phenyliodine(III) bis(trifluoroacetate).
8. Re views, see: (a) Banks, D. F. Chem. Rev. 1966, 66, 243.
(b) Varvoglis, A. Chem. Soc. Rev. 1981, 10, 377. (c) Koser,
G. F. In The Chemisyry of Func tional Groups, Sup ple-
ment D; Patai, S.; Rappoport, Z., Eds.; Wiley: New York,
1983, Ch. 18 and 25. (d) Varvoglis, A. Synthesis 1984,
709. (e) Moriaty, R. M.; Prakash, O. Acc. Chem. Res.
1986, 19, 244. (f) Ochiai, M.; Nagao, Y. Yuki Gosei
Kagaku Kyokaishi 1986, 44, 660. (g) Mori arty, R. M.;
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A. The Or ganic Chem is try of Polycoordinated Io dine;
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Trends Org. Chem. 1992, 3, 113. (j) Kita, Y.; Tohma, H.
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