π-aromatic and sulfur nucleophilic partners in cationic π-cyclizations: Intramolecular amidoalkylation and thioamidoalkylation cyclization via ω-carbinol lactams

Article abstract of DOI:10.1021/jo0156316

NaBH4 reduction of imides 1 and 6a,b,c followed by a π-cyclization of the resultant N-acyliminium ions, generated in trifluoroacetic acid conditions, afforded two positional isomers, isoindolobenzothiazolinones 4 and 8, respectively. These ring closures proceeded via an intramolecular α-amidoalkylation with the classical α-aromatic or the atypical sulfur atom as an internal nucleophile. A ready access to the related six-membered N,S-heterocyclic compounds such as isoindolobenzothiazinones 20a and 21a is also described. During this reaction, we have shown that ω-carbinol lactam precursor 14a led to endocyclic and exocyclic N-acyliminium ions 18a and 19a in equilibrium via the cyclic aza-sulfonium ion A. The latter furnished the expected products 20a and 21a in good yields. Similarly, different ω-carbinol lactams 14b-e substituted at C-angular position afforded the corresponding isoindolobenzothiazinones 20b-e and 21b-e bearing an angular alkyl, aralkyl, or aryl group. In the case of methyl 14b and benzyl 14e groups, an additional amount of the dehydration products 16b and 31 was isolated. These results indicate that the isomerization-π-cyclization takes place via the cleavage of the thioether linkage in acidic medium.

Full text of DOI:10.1021/jo0156316

J . Org. Chem. 2001, 66, 4695-4703
4695
π-Ar om a tic a n d Su lfu r Nu cleop h ilic P a r tn er s in Ca tion ic
π-Cycliza tion s: In tr a m olecu la r Am id oa lk yla tion a n d
Th ioa m id oa lk yla tion Cycliza tion via ω-Ca r bin ol La cta m s1,2
Nicolas Hucher, Bernard Decroix, and Adam Da¨ıch*
Laboratoire de Chimie, URCOM, Faculte´ des Sciences & Techniques de l’Universite´ du Havre,
25, rue Philippe Lebon, B.P: 540, F-76058 Le Havre Cedex, France
Adam.Daich@univ-lehavre.fr
Received March 13, 2001
NaBH4 reduction of imides 1 and 6a ,b,c followed by a π-cyclization of the resultant N-acyliminium
ions, generated in trifluoroacetic acid conditions, afforded two positional isomers, isoindoloben-
zothiazolinones 4 and 8, respectively. These ring closures proceeded via an intramolecular
R-amidoalkylation with the classical π-aromatic or the atypical sulfur atom as an internal
nucleophile. A ready access to the related six-membered N,S-heterocyclic compounds such as
isoindolobenzothiazinones 20a and 21a is also described. During this reaction, we have shown that
ω-carbinol lactam precursor 14a led to endocyclic and exocyclic N-acyliminium ions 18a and 19a
in equilibrium via the cyclic aza-sulfonium ion A. The latter furnished the expected products 20a
and 21a in good yields. Similarly, different ω-carbinol lactams 14b-e substituted at C-angular
position afforded the corresponding isoindolobenzothiazinones 20b-e and 21b-e bearing an angular
alkyl, aralkyl, or aryl group. In the case of methyl 14b and benzyl 14e groups, an additional amount
of the dehydration products 16b and 31 was isolated. These results indicate that the isomerization-
π-cyclization takes place via the cleavage of the thioether linkage in acidic medium.
Ch a r t 1. Com m on ly Kn ow n (Typ es A a n d B) a n d
In tr od u ction
th e New ly (Typ e C) N-Acylim in iu m s Sp ecies
While the chemistry of the exocyclic N-acyliminium ion
(Type A) is only known in succinimides series,3-5b the
utilization of the endocyclic N-acyliminium ion (Type B)
in intramolecular R-amidoalkylation cyclizations with
various internal nucleophiles has been largely estab-
lished. The π-aromatics, olefins, diolefins, alkynes, allyls,
homoallyls, allylsilanes, active methylenes, and sulfur or
silicon directive π-electron rich which constitute a class
of nucleophiles (Type B) are well explored in organic
synthesis.4 They lead to numerous diverse natural alka-
loids containing pyrrolizidine, indolizidine, or quinolizi-
dine moieties.5a-c The use of a heteroatom as an external
nucleophile has been also discussed. On the other hand,
the sulfur atom as an internal nucleophile (Type C) was
unprecedented before our previous work (Type C with
R1 ) benzyl group)6 (Chart 1).
Ch a r t 2. Ta r gets Str u ctu r es: Isoin d oloben zo(or
iso)th ia zolin on es a n d Isoin d oloben zoth ia zin on es
As a part of our continuing investigations of forma-
tion-cleavage of the thioether linkage for the preparation
of isoindole derivatives containing heterocyclic systems,
we wish to report herein the synthesis of some isoindolo-
[1,2 or 1,3]benzothiazoles (Chart 2, Type D: n ) m ) 0;
Type E: i ) 0) and isoindolo[1,3]benzothiazines (Chart
2, Type D: n ) 1, m ) 0; Type E: i ) 1). These ring
closure reactions proceed via a nucleophilic attack of the
electron π-aromatic and/or the lone pair of the sulfur
atom onto the endo- and/or the exocyclic N-acyliminium
ions (Types A, B, and C) generated from the correspond-
ing ω-carbinol lactams under strong acidic conditions.
* To whom correspondence should be addressed. Phone: (+33) 02-
32-74-44-03. Fax: (+33) 02-32-74-43-91. e-mail: Nicolas.Hucher@
univ-lehavre.fr, Bernard.Decroix@univ-lehavre.fr.
(1) This work was presented in part at the XVIIIth European
Colloquium on Heterocyclic Chemistry (ECHC 98), Rouen, France,
October 4-7, 1998.
(2) This work was also presented at the American Chemical Society
National Meeting, Poster 367, San Francisco, CA, March 26-30, 2000.
(3) (a) Castelhano, A. L.; Krantz, A. J . Am. Chem. Soc. 1984, 106,
1877. (b) Hart, D. J .; Yang, T. K. J . Org. Chem. 1985, 50, 235.
(4) (a) Speckamp, W. N. Rec. Trav. Chim. Pays Bas 1981, 100, 345.
(b) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.
(5) (a) Hiemstra, H.; Speckamp, W. N. In The Alkaloids; Brossi, A.,
Ed.; Academic Press: New York, 1988; Vol. 32, chapter 4, pp 271-
339. (b) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M.; Fleming, I.; Eds.; Pergamon Press: Oxford,
1991; Vol. 2, pp 1047-1082. (c) Speckamp, W. N.; Moolenaar, M. J .
Tetrahedron 2000, 56, 3817.
Resu lts a n d Discu ssion
(6) (a) Hucher, N.; Da¨ıch, A.; Netchita¨ılo, P.; Decroix, B. Tetrahedron
Lett. 1999, 40, 3363. (b) For more experimental details, see experi-
mental procedures in the Supporting Information, Part.
In previous papers7,8 we have described the acid-
catalyzed conversion of aromatic isocyanates and cyclic
10.1021/jo0156316 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/26/2001

4696 J . Org. Chem., Vol. 66, No. 13, 2001
Hucher et al.
Sch em e 1. Bicyclic Th iola cta m 4 via
In tr a m olecu la r Am id oa lk yla tion P r ocess
Sch em e 2.a Bicyclic Th iola cta m 8 via th e New ly
In tr a m olecu la r Th ioa m id oa lk yla tion P r ocess
thiepinones into thiazolinones and isothiazolinones, re-
spectively, instead of the possible aromatic thiazocinones.
More recently,6 we have reported the first synthesis of
isoindolo(or pyrrolo)[1,3]benzothiazines from ω-carbinol
lactam in acid conditions. Such cyclization-rearrange-
ments occurred through an cyclic sulfonium intermediate,
respectively, by interaction of sulfur lone electron pair
with electron-deficient nitrogen,7,8 carbon9,10 or N-acylimin-
ium ion6 followed by cleavage of the thioether bond
with6,7,9,10 or without8 the loss of the stable benzylic group.
J ust as Bates et al.11 outlined the loss of an ethyl group
during the intramolecular cyclization of 1-, 2-, and
3-acylpyrrole derivatives.
Isoin d olo[2,1-b]ben zoisoth ia zolin -7(11bH)-on e (4)
an d Isoin dolo[1,2-b]ben zoth iazolin -6-(10bH)-on e (8).
As depicted in Scheme 1, reduction12 of the commercially
available N-phenylthiophthalimide (1) with a large excess
of sodium borohydride in dry methanol at 0 °C under
carefully controlled conditions gave ω-carbinol lactam 2
(60%) which was converted into the title product 4 (82%).
This reaction occurred via the intramolecular π-cycliza-
tion of the classical endocyclic N-acyliminium ion precur-
sor 3 during the treatment of 2 with neat trifluoroacetic
acid (TFA) at room temperature.
Our approach to the isoindolo[1,2-b]benzothiazolin-
6(11bH)-one (8),13a the positional isomer of 4, focused on
the construction of the C(10b)-S(11) bond and started
with the amino derivatives 5 as shown in Scheme 2.
Thus, the o-aminothiophenol (5a ) was transformed into
phthalimide derivative 6a (96%) when warming under
azeotropic conditions with catalytic amount of anhydrous
triethylamine.13b Reduction of 6a with sodium borohy-
dride in methanol at 0-5 °C gave the desired N-
acyliminium ion precursor 7a . Because of the difficulty
a
Key: (i) Phthalic anhydride, toluene, NEt3, reflux. (ii) NaBH4,
MeOH, 0-5 °C. (iii) 20% HCl or TFA, rt. (iv) MeONa or NaH,
DMF, MeI or BnCl. (v) TFA, rt.
encountered during isolation of this ω-carbinol lactam,
the unpurified crude reaction mixture was reacted with
20% hydrochloric acid solution14 or TFA for 12 h at room
temperature and yielded the cyclized product 8 in a 60%
or 72% yield, respectively. The same product was isolated
in comparable yield when an ethanolic hydrogen chloride
solution (3/1 in v/v) was added at regular intervals during
the reduction reaction of the imide 6a . For a generaliza-
tion of this unusual intramolecular R-heteroamidoalkyl-
ation cyclization, we decided to examine the effect of a
good leaving group such as methyl and benzyl groups on
the sulfur atom nucleophilicity. So, S-alkylation of 5a into
5c was accomplished with sodium methoxide (or sodium
hydride) and benzyl chloride in dry DMF at room tem-
perature in 84% yield15a (this product was also obtained
in 72% yield by comparable procedure).15b Amines 5b9
and 5c were then transformed into imides 6b and 6c in
91 and 96% yields,16 respectively; selective reduction
using the same procedure outlined above gave the
expected ω-carbinol lactams 7b (95%) and 7c (62%) (6b
and 6c could also be prepared in 64 and 71% yields,
respectively, by S-alkylation of 6a using MeONa(or NaH)
as a base and methyl iodide or benzyl chloride as an
alkylating agent in DMF at room temperature. Exposure
of 7b or 7c to TFA at room temperature for 12 h
furnished the bicyclic thiolactam 8 in 60 and 62% yields,
respectively. The cyclized product 8 is the result of the
nucleophilic attack of the sulfur atom onto the endocyclic
N-acyliminium ion in the intermediates 9a -c, followed
by the loss of the methyl or the benzylic cation of the
cyclic sulfonium salts 10a -c (Scheme 3, path A).
(7) J ilale, A.; Decroix, B.; Morel, J . Chem. Script. 1987, 27, 423.
(8) Da¨ıch, A.; Decroix, B. J . Heterocycl. Chem. 1991, 28, 1881.
(9) Stacy, G. W.; Villaescusa, F. W.; Wollner, T. E. J . Org. Chem.
1965, 30, 4074.
(10) Stacy, G. W.; Eck, D. L.; Wollner, T. E. J . Org. Chem. 1970,
35, 3495.
(11) (a) Bates, D. K.; Winters, R. T.; Picard, J . A. J . Org. Chem.
1992, 57, 3095. (b) Tafel, K. A.; Bates, D. K. J . Org. Chem. 1992, 57,
3676. (c) Bates, D. K.; Tafel, K. A. J . Org. Chem. 1994, 59, 8076. (d)
Xia, M.; Chen. S.; Bates, D. K. J . Org. Chem. 1996, 61, 9289.
(12) The reduction was performed with addition or not at regular
intervals of hydrochloric acid and was monitored by TLC (silica gel,
dichloromethane/hexane: 9.5/0.5). To use similar conditions see: Pigeon,
P.; Decroix, B. J . Heterocycl. Chem. 1996, 33, 129.
(13) (a) This product 8 was obtained by thermal dehydration of 2-(o-
carboxyphenyl)benzothiazoline, and it should be added that the
reported mp for 8 is 172-174 °C: Oliver, G. L.; Dann, J . R.; Gates, J .
W., J r. J . Am. Chem. Soc. 1958, 80, 702. (b) Alkhathlan, H. Z. J . Chem.
Res. (S) 1992, 260.
The stability of the leaving group R1+ (R1 ) H, Me, Bn)
from cleavage of the thioether bond in acidic medium,
as mentioned above,6-11 combined with the good nucleo-
(14) The hydrochloric acid solution (20%) was prepared in methylene
chloride as solvent. The use of the concentrated hydrochloric acid
caused some complications during the separation procedure of the
cyclized product 8.
(15) (a) J ilale, A.; Decroix, B. Chem. Script. 1987, 27, 417. (b) Chen,
L. C.; Wang, H. M.; Kang, I. J . Heterocycles 1999, 51, 1437.
(16) An alternative way for synthesis of 6c was explored from 6a
by S-alkylation with 1.2 equiv of benzyl chloride and 1 equiv of sodium
methoxide unvariably in DMF or DMSO as solvent at 45-50 °C. The
reaction yield is about 70% in both cases; see ref 15 and Supporting
Information, Part.

Thiolactams via Intramolecular R-(Thio)amidoalkylation
J . Org. Chem., Vol. 66, No. 13, 2001 4697
Sch em e 3. Mech a n ism of th e In tr a m olecu la r
r-Th ioa m id oa lk yla tion Cycliza tion P r ocess
Sch em e 4. Access to
Isoin d olo[1,3]ben zoth ia zin on es 20a a n d 21a via
Isom er iza tion of th e N-Acylim in iu m Ion s
In ter m ed ia tes 18a a n d 19a
philicity of the sulfur atom constitutes a significant
competing process for the cyclization reaction to the
detriment of the π-aromatic R-amidoalkylation cyclization
(Scheme 3, path B), leading to 11. Modifications of the
experimental conditions (presence of solvents, variation
of the temperature or the volume of TFA, etc.) did not
change the reaction. Compound 8 and some derivatives
have been previously synthesized from substituted o-
aminothiophenol and o-acylbenzoic acid by a cyclodehy-
dration process.13a,17 It was also mentioned that these
products have antiinflammatory properties, analgesic
activity, and immunosuppressive effects.18
6,12b-Dih yd r oisoin d olo[2,1-c][1,3]ben zoth ia zin -8-
on e (20a ), 5,11b -Dih yd r oisoin d olo[1,2-b][1,3]b en -
zoth ia zin -7-on e (21a ), 12b-Alk yl(or a r yl)-6,12b-d i-
h ydr oisoin dolo[2,1-c][1,3]ben zoth iazin -8-on es (20b-
e), an d 11b-Alkyl(or ar yl)-5,11b-dih ydr oisoin dolo[1,2-
b][1,3]ben zoth ia zin -7-on es (21b-e). On the basis of
the preceding results, it was envisioned that this strategy
could be applied to imides including a N-CH2-S-Ar
sequence which could give access to endo- and/or exocyclic
N-acyliminium ion intermediate precursors of isoindolo-
benzo[1,3]thiazine systems as an attractive target. The
model imide 1319a (Scheme 4), was obtained by condensa-
tion of N-chloromethylphthalimide (12)19b with sodium
thiophenate in DMF at room temperature for 5 h
(90%).15a Reduction reaction of 13 into 14a (R2 ) H) was
carried out with 6 equiv of NaBH4 in MeOH at 0 °C with
portionwise addition of an ethanolic hydrochloric acid
solution according to the previously reported procedure
(95%).20 On the other hand, the addition of Grignard
reagents (R2-MgX with R2X ) MeI, PhBr, p-ClPhBr, and
BnCl) occurred with moderate to excellent yields (69-
98%) to give ω-substituted-ω-carbinol lactams 14b-e.
To our knowledge, the N-arylthiomethylhydroxylactam
function is not explored extensively in the literature.
Regarding the reactivity of this group in acidic medium,
we have previously reported the synthesis of thienothi-
azinoisoindolones.21 In a similar manner, the hydroxy
lactam 14a was allowed to react under various cyclization
conditions (Scheme 4). 14a with neat acetic acid for 3 h
at room temperature (Scheme 4, path A) led to the
acetate derivative 16a in a yield of 47%, and the
prolonged reaction time (12 h) left 16a unchanged.
Stirring 14a with neat TFA, HCl, or H2SO4 at room
temperature for 3 h (Scheme 4, path B) gave 17a in
acceptable yields of 32, 30, and 27%, respectively (in these
conditions, 17a may be obtained at maximum efficiency
in 50% yield). Interestingly, in the case of TFA with a
reaction time of 12 h (Scheme 4, path C), the reaction
afforded a mixture of the cyclized products 20a and 21a
in an excellent yield of 96%.
Mechanistically, these cyclization reactions involve an
intramolecular cationic π-cyclization of aromatic tethered
to endocyclic N-acyliminium ion as in 18a and 19a . Thus
a 5.5/4.5 mixture of cyclic lactams 20a and 21a was
obtained. Evidence of the rearrangement of the initially
formed endocyclic N-acyliminium ion 18a to the exocyclic
one 19a was obtained while examining the behavior of
the adduct 17a . Thus, treatment of this ω-phenylthio
lactam with TFA (Scheme 4, path D) in the presence of
2 to 5 equiv of water at reflux quickly produced a mixture
of 20a and 21a in the same ratio (92%). From these
results we concluded that generation of the endocyclic
N-acyliminium ion 18a could be obtained classically from
14a or from 17a (Scheme 4, path B) by the loss of
thiophenol.22 In our knowledge, this process constitutes
the first example in the generation of N-acyliminium ions
in the phthalimide series (Scheme 4).23 As for the
exocyclic N-acyliminium ion 19a , its formation could be
explained by isomerization of 18a via the cyclic aza-
(17) Hoehn, H.; Schulze, E. United States Patent 3,591,599; Chem.
Abstr. 1971, 75, 76777c.
(18) See ref 13a for synthesis. (b) see the US patent in ref 17. (c)
Martens, A.; Zilch, H.; Ko¨nig, B.; Scha¨fer, W.; Poll, T.; Kampe, W.;
Seidel, H.; Leser, U.; Leinert, H. J . Med. Chem. 1993, 36, 2526 and
references therein.
(19) (a) Bo¨hme, H.; Mu¨ller, A. Arch. Pharm. (Weinheim, Ger.) 1964,
296, 54. (b) Cherbuliez, E.; Sulzer, G. Helv. Chem. Acta 1925, 8, 567.
(20) (a) Arai, Y.; Matsui, M.; Koizumi, T.; Shiro, M. J . Org. Chem.
1991, 56, 1983. (b) Arai, Y.; Kontani, T.; Koizumi, T. J . Chem. Soc.,
Perkin Trans. 1 1994, 15. When the reduction time exceed more than
1 h, the hydroxylactam 14a was accompanied with small amounts (12-
17%) of the opened amide-alcohol 15a which resulted from an ad-
ditional reduction of R-hydroxylacatm 14a .
(21) Netchita¨ılo, P.; Othman, M.; Decroix, B. J . Heterocycl. Chem.
1997, 34, 321.

4698 J . Org. Chem., Vol. 66, No. 13, 2001
Hucher et al.
Sch em e 6. Ch em ica l Sep a r a tion of
Sch em e 5. Mech a n ism of th e In tr a m olecu la r
Am id o- a n d r-Th ioa m id oa lk yla tion Cycliza tion
Isoin d olo[1,3]ben zoth ia zin es 20a a n d 21a by
m -CP BA Oxid a tion
sulfonium ion A or by departure of thiophenol under
acidic medium in the intermediate 17a (Scheme 4, path
A) as shown in Scheme 5.
Sch em e 7. Str u ctu r e Con fir m a tion of
Isoin d olo[1,3]ben zoth ia zin on e 21a via a n
In tr a m olecu la r Th ioa m id oa lk yla tion Str a tegy
The rate of cyclization of both 14a and 17a decreased
in the presence of methylene chloride as solvent at room
temperature (3 days to 1 week were necessary for
complete cyclization) or at lower temperature in the
presence or absence of solvent (at -20 °C the cyclization
reaction occurred after 1 week but in the presence of CH2-
Cl2 as solvent at the same temperature, more than 1
week was necessary), but when the reaction temperature
was increased, the reaction proceeded swiftly. In all these
cases, the cylization reaction furnished the same mixture
of 20a and 21a with insignificant change of the 5.5/4.5
ratio. In conclusion, the preferred method for preparation
of 20a and 21a of superior quality is to add 14a or 17a
to neat TFA, respectively, at room temperature or under
reflux under magnetic stirring.
Compounds 20a and 21a have comparable Rf values
in numerous solvents, thus rendering their complete
separation uncertain and difficult (nevertheless pure 20a
was separated by fractional recrystallization), and the
structures of these products were established by spec-
troscopic analyses. The infrared spectrum indicated the
absence of a O-H stretch; the 1H NMR spectrum showed
two methylene groups (H-6 and H-5) which appear as
an AB system with coupling constants of J ) 12.4 Hz
(20a ) and 17.5 Hz (21a ) characteristic of geminate
protons and two others protons (H-12b and H-11b) on a
tertiary carbon which were shifted downfield compared
to the same protons in ω-carbinol- and ω-phenylthio
lactams precursors 14a (∆δ ) +0.02 to +0.08 ppm) and
17a (∆δ ) +0.05 to +0.11 ppm), respectively. Likewise,
the 13C NMR spectra of 20a and 21a revealed the
presence of an additional quaternary carbon. These data,
the microanalyses, and the coupling GC-MS which showed
a molecular ion at m/z ) 253, clearly established the
structure for 20a and 21a as 6,12b-dihydroisoindolo-
[2,1-c][1,3]benzothiazin-8-one and 5,11b-dihydroisoindolo-
[1,2-d][1,3]benzothiazin-7-one, respectively.
Interestingly, the oxidation of the mixture 20a and 21a
by m-CPBA in dry methylene chloride afforded a mixture
of sulfones 22a and 23a (96%) which were separated by
crystallization in methylene chloride (Scheme 6). As for
23a , the 1H NMR spectrum revealed an important
deshielding of about +0.59 ppm of proton H-11b adjacent
to sulfur atom compared to the corresponding one in 21a
while the same proton in sulfone 22a is hardly affected
by this oxidation (Scheme 6).
This result confirmed the proposed structures for 20a
and 21a and structural similarities with other isoindolo-
[1,3]benzothiazines recently described by us.6 Indeed,
according to the sequential method illustrated in Scheme
7, the ω-carbinol lactam 29 was easily obtained from
bromide 25.24 Subjected to an acidic treatment, 29 yielded
the cyclized lactam 21a through the intramolecular
sulfuration of the intermediate N-acyliminium ion and
debenzylation. This process was extended successfully to
the succinimide series. Thus, the pyrrolo[1,3]benzothiazine
30 was prepared in good yield via the ω-carbinol lactam
28.
(22) Similar compounds using thiophenol in N-alkyl- or N-aryl-4-
hydroxypyrrolidin-2-one series had been prepared and used success-
fully as cyclization radical precursors of pyrrolizidine and indolizidine
alkaloids. For example see: (a) Burnett, D. A.; Choi, J . K.; Hart, D. J .;
Tsai, Y. M. J . Am. Chem. Soc. 1984, 106, 8201. (b) Clauss, R.; Hunter,
R. J . Chem. Soc., Perkin Trans.1 1997, 71.
(23) Few reports concerning the generation of N-acyliminium ions,
from corresponding ω-alkylthio- and ω-arylthio lactams, has been
mentioned in the literature. For example see: Padwa, A.; Waterson,
A. G. J . Org. Chem. 2000, 65, 235. Padwa, A.; Waterson, A. G.
Tetrahedron 2000, 56, 10159 and references therein. J ust now, only
the hydroxy,5a,b alkoxy,5a,b chloro,5b (see also: (a) Zaugg, H. E.; Martin,
W. B. Org. React. 1965, 14, 52. (b) Uray, G.; Ziegler, E. Z. Naturforsch.
1975, 30B, 245. (c) Bo¨hme, U.; Hartke, K. Chem. Ber. 1963, 96, 600)
mesyl lactams (see: Chamberlin, A. R.; Nguyen, H. D.; Chung, J . Y.
L. J . Org. Chem. 1984, 49, 1682), carbamates were used intensively.
For reviews concerning N-acyliminium ions chemistry see refs 5a-c.
(24) The chloride derivative, isomer to the bromide 25, was prepared
according to the procedure reported in the literature (78%)9 but its
use in the N-alkylation process, apparently, affected the reaction yield
whatever the experimental conditions.

Thiolactams via Intramolecular R-(Thio)amidoalkylation
J . Org. Chem., Vol. 66, No. 13, 2001 4699
Sch em e 8.a r-Meth yl-r-h yd r oxyla cta m 14b tow a r d
Sch em e 9.a In tr a m olecu la r Am id oa lk yla tion
Cycliza tion of r-Su bstitu ted r-Hyd r oxyla cta m s
14c-e
Am id oa lk yla tion Cycliza tion Con d ition s
a
Key: (i) TFA, rt, 3 h or TFA, rt, 12 h, CH2Cl2. (ii) TFA, rt, 12
a
Key: (i) TFA, rt, 12 h (conditions ii described in Scheme 8).
h. b Yields of reaction were given in brackets. c Ratio of compounds
was given in percent and was determined by GC-MS and H NMR
b
The ratio of compounds 20 and 21 was given in percent and was
1
determined by GC-MS and 1H NMR analyses. c Compound 31 as
a Z form was also obtained easily in 86% yield by treatment of
ω-carbinol lactam 14e with catalytic amount of PTSA in dry
CH2Cl2 at room temperature for 12 h.
analyses.
We next examined the effect of a C-angular substituted
product 14b in the rearrangement-cyclization step.
Thus, as depicted in Scheme 8 ω-carbinol-ω-methyl
lactam 14b upon treatment with TFA for 3 h or TFA-
dichloromethane for 12 h at room temperature (condi-
tions i) gave a mixture of the cyclized products 20b (22%),
21b (18%), the ω-methylidene lactam 16b (20%), and the
ω-phenylthio lactam 17b (40%) in a low yield of 47% due
to the presence of an important tar. With neat TFA at
room temperature for 12 h (conditions ii), 14b gave only
three products 16b (25%), 20b (41%), and 21b (34%) in
good yield (85%). Invariably, the cyclized products 20b
and 21b were obtained in a ratio of 5.5/4.5 identical to
that reported above for 20a and 21a (Scheme 8).
treatment of the ω-benzyl-ω-carbinol lactam 14e with
PTSA in dry methylene chloride at room temperature for
12 h. It seems that the ratio Z/ E depends from the
reaction temperature and that 31 (Z) is the stable
thermodynamic isomer. Finally, the inversion ratio be-
tween product 20 and 21 seems to be sensitive to the class
and range of the R2 group while the dehydration product
is favored by the high conjugation existing in the aro-
matic enamidone to the detriment of the cyclized prod-
ucts.
Indeed, the formation of methylidene(or benzylidene)-
phthalimidine 16b or 31, easily separated by chroma-
tography on silica gel and dichloromethane as eluent,
could be explained by the dehydration reaction in acidic
medium. Thus, this reaction is analogous to that already
observed in phthalimidin-2-yl acetic acid derivatives
series and methyl o-(phthalimidin-2-yl-methyl)benzene
carboxylate series, respectively, when the mixture of 10%
hydrochloric acid-acetic chloride26 and PTSA in azeo-
tropic conditions27 were used as dehydrating agents.
Furthermore, in the cases of phenyl or p-chlorophenyl
groups, a high selectivity of the π-cyclization reaction was
observed. This effect could be due probably to the fact
that the steric hindrance of the phenyl group was
favorable, as illustrated in Chart 3, for approach in form
D (in equilibrium with form C) of the incoming π-aro-
matic system during the π-cationic cyclization step.
Consequently, the ratio of the cyclized products were
respectively 0.6/9.4 (for 20c/21c) 0.4/9.6 (for 20d /21d ) in
contrast to these observed for R2 ) H, Me and benzyl
groups.
From these results it seemed that both dilution and
shorter reaction time favored the formation of the ω-
phenylthio lactam 17b (conditions i, 40%; conditions ii,
0%) which was separated from the mixture and easily
purified by chromatography on silica gel (SiO2 with CH2-
Cl2 as eluent). We next investigated other groups such
as phenyl, p-chlorophenyl, and benzyl. Thus, as depicted
in Scheme 9, according to conditions ii cited above, 14c
(R2 ) Ph), 14d (R2 ) p-ClPh) or 14e (R2 ) Bn)25 produced
the mixture of the two cyclized products 20c,d ,e and
21c,d ,e in comparable yields of 92%, 98%, and 92%
respectively.
In the case of benzyl derivative, the reaction was
straightforward and furnished 31 as a major product
(80%) accompanied with cyclized products 20e and 21e
in proportions of 15% and 5%, respectively. The dehy-
drated benzylidenephthalimidine product 31 as a 1/1 (Z/
E) mixture were easily separated by chromatography on
a silica gel column. The Z form of product 31 could be
also obtained as a single product in 86% yield by
(26) Scartoni, V.; Fiaschi, R.; Catalano, S.; Morelli, I.; Marsili, A. J .
Chem. Soc., Perkin Trans. 1 1979, 1547.
(27) Da¨ıch, A.; Marchalin, S.; Pigeon, P.; Decroix, B. Tetrahedron
Lett. 1998, 39, 9187.
(25) Subjection of 14e to TFA led to the expected formation of a six-
membered rings 20e and 21e rather than a four-membered spiro-
lactam derivative.

4700 J . Org. Chem., Vol. 66, No. 13, 2001
Hucher et al.
workup, the resulting solid was recrystallized from EtOH to
give 1.6 g (60%) of the expected ω-carbinol lactam 2: mp 152
°C (decomposition); IR (KBr) 3302, 3015, 1701 cm-1; 1H NMR
(DMSO-d6, 200 MHz) δ 5.91 (d, 1H exchangeable with D2O,
J ) 8.9 Hz), 6.39 (d, 1H, J ) 8.9 Hz), 7.32-7.48 (m, 5H), 7.51-
7.71 (m, 4H); 13C NMR (DMSO-d6, 50 MHz) δ 78.1 (CH), 122.3
(CH), 123.6 (CH), 127.1 (2CH), 127.6 (CH), 129 (CH), 129.3
(2CH), 131.8 (CH), 131.9 (C), 135.7 (C), 146.8 (C), 168.4 (CO);
MS (m/z) 257 (M+•). Anal. Calcd for C14H11NO2S: C, 65.35; H,
4.31; N, 5.44. Found: C, 65.12; H, 4.28; N, 5.32.
Ch a r t 3. Cor r ela tion of Cycliza tion Ra tio a n d
N-Acylim in iu m Ion Geom etr y in th e Ca se of 14c,d
Isoin d olo[2,1-b]ben zoisoth ia zol-7(11bH)-on e (4). To 257
mg (1 mmol) of hydroxylactam 2 was added 5 mL of TFA. After
12 h of reaction at room temperature under stirring, the
reaction mixture was concentrated in vacuo and diluted with
CH2Cl2 (10 mL). The organic layer was neutralized with 10%
NaHCO3 solution, separated, dried over MgSO4, and evapo-
rated to give after recrystallization from EtOH the expected
bicyclic product 4 as a yellow solid (196 mg, 82%): mp 155 °C
(decomposition); IR (KBr) 3029, 1688 cm-1; 1H NMR (DMSO-
d6, 200 MHz) δ 5.72 (s, 1H), 7.15-7.35 (m, 5H), 7.39-7.89 (m,
3H); 13C NMR (DMSO-d6, 50 MHz) δ 58.9 (CH), 122.9 (CH),
123.4 (CH), 127.2 (2CH), 127.5 (CH), 127.7 (CH), 129.4 (2CH),
131.3 (C), 135.8 (C), 139.2 (C), 147.7 (C), 169.6 (CO); MS (m/z)
239 (M+•). Anal. Calcd for C14H9NOS: C, 70.27; H, 3.79; N,
5.85. Found: C, 70.21; H, 3.75; N, 5.78.
Con clu sion
Novel five-ring N,S-heterocyclic compounds 4 and 8,
are produced under acidic conditions via capture of an
endocyclic N-acyliminium ions 3 and 9a ,b,c with an
internal nucleophile as the π-aromatic or sulfur atom
followed by the departure of a proton, a methyl, or a
benzyl group.
The related isoindolobenzothiazinones 20a and 21a
analyzed by GC-MS and separated at the sulfone oxida-
tion state were also formed by reaction of ω-carbinol
lactam precursor 14a with TFA. From 17a , evidence of
the isomerization of the initially formed endocyclic N-
acyliminium ion 18a to the corresponding exocyclic one
19a (not yet known in isoindolone series) leading to
cyclized products 20a and 21a was observed. On the
other hand, compound 21a was obtained univocally via
the model imide 27 in four steps as illustrated in Scheme
7.6 The generalization of this reaction process was
accomplished with C-angular substituted ω-carbinol lac-
tam precursors 14b-e (R2 ) Me, Ph, p-ClPh, Bn).
Finally, applications of this strategy to the synthesis
of more functionalized novel five-, six-, seven-, and eight-
membered N,S-heterocyclic systems are in progress, and
the results will be reported in due course.
o-Ben zylth ioa n ilin e (5c). To a stirred solution under an
atmosphere of dry argon of o-amino-thiophenol (12.52 g, 0.1
mol) in 60 mL of dry DMF was added 5.94 g (0.11 mol) of
sodium methoxide. After stirring for 30 min at room temper-
ature, benzyl chloride (12.66 g, 0.1 mol) was added slowly
dropwise over a period of 10 min. The mixture was then
allowed to react at the same temperature for 12 h. The solution
was filtered and the filtrate was concentrated in vacuo. The
oily residue after trituration with a mixture Et2O/hexane
(1/1) was recrystallized from hexane to give amino derivative
5c (18.06 g, 84% (72%)15b) as a yellow solid: mp < 45 °C (oil);15b
IR (KBr) 3025, 2098, 1305, 760 cm-1 1H NMR (CDCl3, 200
;
MHz) δ 3.83 (s, 2H), 3.96 (br, 2H exchangeable with D2O),
6.52-6.60 (m, 2H), 7.00-7.29 (m, 7H); MS (m/z) 215 (M+•).
Anal. Calcd for C13H13NS: C, 72.51; H, 6.08; N, 6.50. Found:
C, 72.46; H, 6.00; N, 6.41.
Gen er a l P r oced u r e for P r ep a r a tion of Im id es 6a , 6b,
a n d 6c. A mixture of 10 mmol of o-amino-thiophenol (o-
methylthioaniline or o-benzylthioaniline (5c)), phthalic anhy-
dride (1.48 g, 10 mmol), and two drops of dry triethylamine in
toluene (50 mL) was refluxed with a Dean-Stark apparatus
for 3 to 5 h. The reaction mixture was cooled and then was
concentrated under reduced pressure. The residue was dis-
solved into CH2Cl2 (50 mL) and washed with 5% HCl solution
and then with a 10% NaHCO3 solution. The organic layer was
dried over MgSO4 and concentrated under reduced pressure,
and recrystallization of the residue from ethanol gave the
desired imide 6a (96%), 6b (91%), or 6c (96%).
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. IR spectra of
solids (potassium bromide) were recorded on a Perkin-Elmer
FTIR paragon 1000 spectrophotometer. 1H and 13C NMR
spectra were measured on a Bruker AC-200 instrument (200
MHz), and chemical shifts are reported relative to CDCl3 at δ
7.24 ppm (or to DMSO-d6 at δ 2.49 ppm) and tetramethylsilane
as an internal standard. MS spectral measurements were
carried out on a AEI MS 902 S spectrometer (70 eV, electron
impact). Reagents were obtained from commercial suppliers
and used without further purification. Solvents were dried and
purified by standard methods. A Merck silica gel 60 was used
for both column chromatography (70-230 mesh) and flash
chromatography (230-400 mesh). Ascending TLC was per-
formed on precoated plates of silica gel 60 F 254 (Merck), and
the spots were visualized using an ultraviolet lamp or iodine
vapor. Elemental analyses (C, H, N) were performed by the
microanalysis laboratory of INSA at Rouen, F-76130 Mt-St-
Aignan, France.
2,3-Dih yd r o-3-h yd r oxy-2-p h e n ylt h io-1H -isoin d ol-1-
on e (2).12 To a well-stirred solution of N-phenylthiophthal-
imide (2.55 g, 10 mmol) in dry MeOH (30 mL) was added in
portions at 0 °C sodium borohydride (1.89 g, 50 mmol) over a
period of 10 min. After complete addition of sodium borohy-
dride, 3 drops of ethanolic hydrochloric acid solution was added
at regular intervals (10 min) (prepared from 9 drops of
concentrated hydrochloric acid in 15 mL of EtOH) until the
reaction was complete (40 min) (monitored by TLC using CH2-
Cl2 as eluent). The excess of sodium borohydride was decom-
posed by careful addition of 10% HCl solution to pH ) 3. After
removal of the solvent, the residue was diluted with H2O (40
mL) and extracted with 30 mL of CH2Cl2. After a classical
S-Methylation (or S-benzylation) of imide 6a leading to
imide 6b in 64% yield (or 6c in 71% yield) was carried out in
standard manner as reported above for S-benzylation of 5a
into 5c.
N-(o-Mer ca p top h en yl)p h th a lim id e (6a ). This product
was isolated as a green solid: mp 202-206 °C (decomposition);
IR (KBr) 3289, 3037, 1715 cm-1; 1H NMR (DMSO-d6, 200 MHz)
δ 3.37 (s, 1H exchangeable with D2O), 7.45-7.54 (m, 3H),
7.60-7.69 (m, 1H), 7.89-7.94 (m, 2H), 7.95-8.02 (m, 2H); 13
C
NMR (DMSO-d6, 50 MHz) δ 148.3 (2CH), 153.6 (CH), 153.9
(CH), 154.7 (CH), 154.9 (CH), 155 (C), 155.7 (2C), 159.5 (C),
159.6 (2CH), 191.2 (2CO); MS (m/z) 255 (M+•). Anal. Calcd for
C
14H9NO2S: C, 65.86; H, 3.55; N, 5.48. Found: C, 65.75; H,
3.47; N, 5.31.
N-(o-Meth ylth iop h en yl)p h th a lim id e (6b). This product
was isolated as a white solid: mp 138 °C; IR (KBr) 3012, 2095,
1
1702 cm-1; H NMR (CDCl3, 200 MHz) δ 2.37 (s, 3H), 7.17-
7.31 (m, 2H), 7.34-7.47 (m, 2H), 7.70-7.78 (m, 2H), 7.87-
7.95 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 15.9 (CH3), 123.8
(2CH), 126.1 (CH), 127.5 (CH), 129.5 (CH), 129.7 (C), 130.1
(CH), 131.8 (2C), 134.3 (2CH), 138.4 (C), 167.1 (2CO); MS

Thiolactams via Intramolecular R-(Thio)amidoalkylation
J . Org. Chem., Vol. 66, No. 13, 2001 4701
(m/z) 269 (M+•). Anal. Calcd for C15H11NO2S: C, 66.89; H, 4.11;
N, 5.20. Found: C, 66.75; H, 4.07; N, 5.13.
J ) 13.8 Hz), 5.07 (d, 1H, J ) 13.8 Hz), 5.88 (d, 1H, J ) 11.3
Hz), 7.15-7.18 (m, 3H,), 7.36-7.41 (m, 4H), 7.52-7.57 (m, 2H);
13C NMR (CDCl3, 50 MHz) δ 42.9 (CH2), 80.3 (CH), 123.2 (CH),
123.5 (CH), 127.3 (CH), 129.1 (2CH), 129.7 (CH), 130.4 (C),
130.9 (2CH), 132.7 (CH), 133.2 (C), 143.7 (C), 167.0 (CO); MS
(m/z) 271 (M+•). Anal. Calcd for C15H13NO2S: C, 66.40; H, 4.83;
N, 5.16. Found: C, 66.35; H, 4.67; N, 5.10.
Isoin dolo[1,2-b]ben zoth iazolin -6(11bH)-on e (8). Meth od
A. The unpurified 7a , obtained by standard borohydride
reduction of 6a as indicated for 6b and 6c, was treated with
20% HCl in CH2Cl2 (40 mL)14 or neat TFA (10 mL) at room
temperature for 12 h. After concentration in vacuo, the crude
solid was extracted with CH2Cl2 and the organic layer was
washed successively with water, 5% NaHCO3, and saturated
brine and then separated. The organic phase was dried over
MgSO4 and evaporated under reduced pressure to afford after
recrystallization from ethanol the cyclized product 8 in 60%
or 62% yield, respectively.
N-(o-Ben zylth iop h en yl)p h th a lim id e (6c). This product
was isolated as a white solid: mp 108-110 °C (decomposition);
IR (KBr) 3024, 2092, 1712 cm-1; 1H NMR (CDCl3, 200 MHz) δ
4.03 (s, 2H), 7.07-7.27 (m, 5H), 7.32-7.39 (m, 4H), 7.72-7.81
(m, 2H), 7.91-7.98 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 39.1
(CH2), 127.3 (CH), 127.6 (CH), 128.4 (2CH), 128.9 (2CH), 129.6
(CH), 129.8 (CH), 131.5 (CH), 131.9 (C), 134.2 (2CH), 136.3
(C), 136.5 (C), 167.2 (2CO); MS (m/z) 345 (M+•). Anal. Calcd
for C21H15NO2S: C, 73.02; H, 4.37; N, 4.05. Found: C, 73.05;
H, 4.21; N, 4.00.
N-(P h en ylth iom eth yl)p h th a lim id e (13).28 To a stirred
solution under an atmosphere of dry argon of thiophenol (11.02
g, 0.1 mol) in 25 mL of dry DMF was added 5.94 g (0.11 mol)
of sodium methoxide. After stirring for 20 min at room
temperature, N-chloromethylphthalimide (19.56 g, 0.1 mol) in
15 mL of dry DMF was added slowly dropwise over a period
of 15 min. The mixture was then allowed to react at the same
temperature for 5 h and hydrolyzed. The resulting solid was
filtered off and recrystallized from EtOH to give the expected
imide 13 (24.24 g, 90%) as a white solid: mp 128 °C (127 °C);19a
IR (KBr) 3031, 2092, 1715 cm-1; 1H NMR (CDCl3, 200 MHz) δ
5.03 (s, 2H), 7.24-7.28 (m, 3H), 7.45-7.50 (m, 2H), 7.63-7.67
(m, 2H), 7.77-7.82 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 42.2
(CH2), 123.5 (2CH), 128 (CH), 129 (2CH), 131.8 (2C), 132.6
(CH+C), 133.1 (CH), 134.2 (2CH), 166.9 (2CO); MS (m/z) 269
(M+•). Anal. Calcd for C15H11NO2S: C, 66.89; H, 4.11; N, 5.20.
Found: C, 66.82; H, 4.04; N, 5.11.
Gen er a l P r oced u r e for Red u ction of Im id es 6b, 6c,
a n d 13. To a solution of imide 6b, 6c, or 13 (10 mmol) in dry
MeOH (40 mL) at 0-5 °C was added in portions 6 equiv of
sodium borohydride (2.27 g, 60 mmol). After complete addition
of sodium borohydride, the mixture was allowed to react under
stirring for a required time (monitored by TLC using CH2Cl2
as eluent). The excess of sodium borohydride was destroyed
carefully by addition of 10% HCl solution and alkalinized by
a saturated NaHCO3. After removal of the solvent under
reduced pressure, the residue was diluted with cold water (40
mL) and allowed to stir at room temperature for an additional
1 h. The resulting solid was filtered off and recrystallized from
EtOH to give pure ω-carbinol lactam 7b, 7c, or 14a in 95%,
62%, or 95% yield, respectively.
Meth od B. To a stirred solution of hydroxylactam 7b or 7c
(10 mmol) was added neat TFA (10 mL). After 12 h of reaction
at room temperature under stirring, the reaction mixture was
diluted with water (30 mL) and neutralized with 10% NaOH
aqueous solution. The solution was extracted twice with CH2-
Cl2 (20 mL). The organic layer was washed with water,
separated, dried over MgSO4, and evaporated. The resulting
crude residue was purified by flash chromatography (SiO2,
CH2Cl2/hexane (4/1)) to give the tricyclic product 8 as white
crystals in 95% (2.27 g) or 62% (1.48 g) yield, respectively: mp
168-171 °C (decomposition) (172-174 °C);13a IR (KBr) 3015,
1
1692 cm-1; H NMR (CDCl3, 200 MHz) δ 6.97 (s, 1H), 7.06-
7.25 (m, 4H), 7.50-7.67 (m, 3H), 7.95 (d, 1H, J ) 7.6 Hz); 13
C
NMR (CDCl3, 50 MHz) δ 69.2 (CH), 118.4 (CH), 123.0 (CH),
123.5 (CH), 125.1 (CH), 125.7 (CH), 125.8 (CH), 129.8 (CH),
132.6 (C), 133.1 (CH), 135.7 (C), 136.5 (C), 143.1 (C), 168.5
(CO); MS (m/z) 239 (M+•). Anal. Calcd for C14H9NOS: C, 70.27;
H, 3.79; N, 5.85. Found: C, 70.19; H, 3.80; N, 5.75.
Gen er a l P r oced u r e for Gr ign a r d Ad d ition on to N-
(P h en ylth iom eth yl)p h th a lim id e (13). To a well stirred and
cold solution of imide 13 (10 mmol) under dry nitrogen
atmosphere in anhydrous CH2Cl2 (20 mL) was added slowly
in dropwise a 0.5 M solution of Grignard reagent (methylmag-
nesium iodide, phenylmagnesium bromide, p-chlorophenyl-
magnesium bromide, or benzylmagnesium chloride (11 to 15
mmol)) freshly prepared according to the classical procedure
in dry ether over a period of 30 min. After 1 h of reaction at
0-5 °C, the reaction was allowed to stir for an additional 2 h
at room temperature. After hydrolysis under stirring with
water (30 mL) and then with 0.5 M NH4Cl solution (40 mL),
the solution was passed through Celite. After separation, the
organic layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. Recrystallization of the
reaction residue from a mixture of ether/hexane gave suitable
R-hydroxylactams in yields of 96% (14b), 98%, (14c), 96%
(14d ), and 69% (14e), respectively.
2,3-Dih ydr o-3-h ydr oxy-2-(o-m eth ylth ioph en yl)-1H-isoin -
d ol-1-on e (7b). This product was isolated as a white solid:
1
mp 159 °C; IR (KBr) 3299, 3021, 2090, 1692 cm-1; H NMR
(CDCl3, 200 MHz) δ 2.35 (s, 3H), 3.71 (d, 1H exchangeable
with D2O, J ) 7.8 Hz), 6.13 (d, 1H, J ) 7.8 Hz), 7.09-7.42 (m,
4H), 7.43-7.50 (dd, 1H, J ) 4.2 and 7.8 Hz), 7.54-7.63 (m,
2H), 7.72 (d, 1H, J ) 7.8 Hz); 13C NMR (CDCl3, 50 MHz) δ
15.2 (CH3), 83.2 (CH), 123.4 (CH), 123.9 (CH), 125.6 (CH),
126.2 (CH), 129.2 (CH), 129.8 (CH), 130.2 (C), 130.9 (C), 132.5
(CH), 133.1 (C), 138.6 (C), 143.9 (C), 166.7 (CO); MS (m/z) 271
(M+•). Anal. Calcd for C15H13NO2S: C, 66.39; H, 4.82; N, 5.16.
Found: C, 66.77; H, 4.69; N, 5.08.
2,3-Dih ydr o-3-h ydr oxy-3-m eth yl-2-(ph en ylth iom eth yl)-
2,3-Dih ydr o-3-h ydr oxy-2-(o-ben zylth ioph en yl)-1H-isoin -
d ol-1-on e (7c). This product was isolated as a white solid:
mp 142 °C (decomposition); IR (KBr) 3306, 3031, 2089, 1702
1H-isoin d ol-1-on e (14b). This product was obtained as yellow
needles: mp 124 °C; IR (KBr) 3290, 3018, 2085, 1675 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 1.67 (s, 3H), 3.94 (s, 1H
exchangeable with D2O), 4.59 (d, 1H, J ) 14 Hz), 4.74 (d, 1H,
J ) 14 Hz), 7.23-7.28 (m, 2H), 7.38-7.43 (m, 4H), 7.50-7.56
(m, 3H); 13C NMR (CDCl3, 50 MHz) δ 24.7 (CH3), 43.2 (CH2),
88.7 (C), 121.7 (CH), 123.5 (CH), 127.3 (CH), 129.1 (2CH),
129.5 (C), 129.6 (CH), 131.6 (2CH), 132.9 (CH), 134.6 (C), 148.1
1
cm-1; H NMR (CDCl3, 200 MHz) δ 3.21 (d, 1H exchangeable
with D2O, J ) 7.4 Hz), 4.02 (s, 2H), 5.98 (d, 1H, J ) 7.4 Hz),
7.06-7.25 (m, 5H), 7.37-7.45 (m, 4H), 7.52-7.61 (m, 2H),
7.71-7.75 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 38.5 (CH2),
83.7 (C), 123.4 (CH), 123.9 (CH), 127.3 (CH), 127.4 (CH), 128.5
(2CH), 128.8 (2CH), 129.1 (CH), 129.9 (CH), 130.4 (CH), 130.6
(CH), 131.1 (C), 132.6 (CH), 135.2 (C), 136.5 (C), 136.8 (C),
143.8 (C), 166.9 (CO); MS (m/z) 347 (M+•). Anal. Calcd for
(C), 167.9 (CO); MS (m/z) 285 (M+•). Anal. Calcd for C16H15
-
NO2S: C, 67.34; H, 5.29; N, 4.91. Found: C, 67.15; H, 5.27;
N, 4.94.
2,3-Dih ydr o-3-h ydr oxy-3-ph en yl-2-(ph en ylth iom eth yl)-
C
21H17NO2S: C, 72.59; H, 4.93; N, 4.03. Found: C, 72.44; H,
4.88; N, 4.10.
1H-isoin d ol-1-on e (14c). This compound was obtained as a
2,3-Dih yd r o-3-h yd r oxy-2-(p h en ylth iom eth yl)-1H-isoin -
d ol-1-on e (14a ). This product was isolated as a white solid:
yellow solid: mp 166 °C; IR (KBr) 3329, 3020, 2096, 1709 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 3.77 (s, 1H exchangeable with
D2O), 4.27 (d, 1H, J ) 13.5 Hz), 5.22 (d, 1H, J ) 13.5 Hz),
7.20-7.24 (m, 5H), 7.28-7.34 (m, 5H), 7.42-7.46 (m, 3H),
7.75-7.79 (m, 1H); 13C NMR (CDCl3, 50 MHz) δ 44.1 (CH2),
91.5 (C), 122.7 (CH), 123.6 (CH), 126.2 (2CH), 127.2 (CH),
1
mp 124 °C; IR (KBr) 3279, 3026, 2089, 1679 cm-1; H NMR
(CDCl3, 200 MHz) δ 3.65 (d, 1H, J ) 11.3 Hz), 4.43 (d, 1H,
(28) Hucher, N.; Da¨ıch, A.; Decroix, B. Org. Lett. 2000, 2, 1201.

4702 J . Org. Chem., Vol. 66, No. 13, 2001
Hucher et al.
128.6 (2CH), 128.7 (CH), 128.9 (2CH), 129.4 (C), 129.5 (CH),
131.2 (2CH), 133.2 (CH), 134.5 (C), 137.8 (C), 148.8 (C), 167.4
(CO); MS (m/z) 347 (M+•). Anal. Calcd for C21H17NO2S: C,
72.60; H, 4.93; N, 4.03. Found: C, 72.54; H, 4.88; N, 4.10.
lization from a mixture of ether/hexane (9.5/0.5) as a white
solid: mp 142 °C (decomposition); IR (KBr) 3021, 1701 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 4.63 (d, 1H, J ) 12.4 Hz), 5.29
(d, 1H, J ) 12.4 Hz), 5.86 (s, 1H), 7.19-7.25 (m, 4H), 7.56-
7.61 (m, 2H), 7.82-7.86 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ
41.3 (CH2), 59.6 (CH), 123.6 (CH), 124.1 (CH), 126.1 (CH),
127.0 (CH), 127.6 (CH), 128.8 (CH), 129.4 (CH), 131.8 (C),
132.0 (C), 132.2 (CH), 132.4 (C), 144.0 (C), 175.6 (CO); MS (m/
z) 253 (M+•). Anal. Calcd for C15H11NOS: C, 71.12; H, 4.38; N,
5.53. Found: C, 71.08; H, 4.34; N, 5.50.
3-p-Ch lor oph en yl-2,3-dih ydr o-3-h ydr oxy-2-(ph en ylth io-
m eth yl)-1H-isoin d ol-1-on e (14d ). This compound was a
obtained as yellow solid: mp 182 °C; IR (KBr) 3331, 3018,
2098, 1713 cm-1 1H NMR (CDCl3, 200 MHz) δ 3.12 (s, 1H
;
exchangeable with D2O), 4.33 (d, 1H, J ) 13.7 Hz), 5.06 (d,
1H, J ) 13.7 Hz), 7.18-7.21 (m, 5H), 7.35-7.38 (m, 4H), 7.44-
7.49 (m, 3H), 7.72-7.75 (m, 1H); 13C NMR (CDCl3, 50 MHz) δ
44.1 (CH2), 91.1 (C), 122.7 (CH), 123.7 (CH), 127.3 (CH), 127.7
(2CH), 128.8 (2CH), 128.9 (2CH), 129.3 (C), 129.8 (CH), 131.2
(2CH), 133.3 (CH), 134.3 (C), 134.7 (C), 136.5 (C), 148.4 (C),
167.2 (CO); MS (m/z) 381 (M+•). Anal. Calcd for C21H16ClNO2-
S: C, 66.05; H, 4.22; N, 3.67. Found: C, 66.01; H, 4.13;
N, 3.59.
6,12b -Dih yd r oisoin d olo[1,2-b][1,3]b e n zot h ia zin -7-
on e (21a ). This product was obtained in pure form univocally
by a strategy developed in Scheme 7 (see text and Supporting
Information part for more details) as a white solid: mp 159
°C (decomposition); IR (KBr) 3011, 1702 cm-1; 1H NMR (CDCl3,
200 MHz) δ 4.62 (d, 1H, J ) 17.5 Hz), 5.31 (d, 1H, J ) 17.5
Hz), 5.80 (s, 1H), 7.16-7.26 (m, 4H), 7.50-7.64 (m, 2H), 7.77-
7.96 (m, 2H); 13C NMR (CDCl3, 50 MHz) δ 38.7 (CH2), 62.1
(CH), 121.8 (CH), 123.9 (CH), 125.8 (CH), 127.2 (CH), 127.5
(CH), 128.3 (CH), 130.4 (CH), 130.9 (C), 131.2 (C), 132.7 (CH),
135.1 (C), 148.0 (C), 166.3 (CO); MS (m/z) 253 (M+•). Anal.
Calcd for C15H11NOS: C, 71.12; H, 4.38; N, 5.53. Found: C,
71.05; H, 4.29; N, 5.48.
Gen er a l P r oced u r e for Cycliza tion of Hyd r oxyla cta m s
14a -e. These products were prepared according to the method
A as described above for synthesis of 20a and 21a . But after
a standard workup, the mixture was purified by chromatog-
raphy on silica gel column using CH2Cl2 as eluent to give pure
enamides 16b, 31 (Z/ E) and the title products 20b-e and
21b-e as inseparable mixtures (see text for more details). In
the cases of Ph (20c, 21c) and p-ClPh (20d , 21d ) as angular
groups, the major products 21c and 21d were isolated in pure
form by fractional recrystallization.
3-Ben zyl-2,3-d ih yd r o-3-h yd r oxy-2-(p h en ylth iom eth yl)-
1H-isoin d ol-1-on e (14e). This compound was obtained as
yellow needles: mp 133 °C; IR (KBr) 3314, 3016, 2082, 1678
1
cm-1; H NMR (CDCl3, 200 MHz) δ 3.05 (s, 1H exchangeable
with D2O), 3.09 (d, 1H, J ) 14.1 Hz), 4.08 (d, 1H, J ) 14.1
Hz), 4.78 (d, 1H, J ) 13.5 Hz), 5.16 (d, 1H, J ) 13.5 Hz), 6.91-
6.94 (m, 2H,), 7.11-7.15 (m, 4H), 7.24-7.28 (m, 3H), 7.37-
7.42 (m, 2H), 7.54-7.59 (m, 3H); 13C NMR (CDCl3, 50 MHz) δ
43.7 (CH2), 44.1 (CH2), 90.9 (C), 123.2 (2CH), 126.9 (CH), 127.3
(CH), 127.8 (2CH), 128.9 (2CH), 129.4 (CH), 130.1 (C), 130.4
(2CH), 131.6 (2CH), 132.0 (CH), 134.5 (C), 134.8 (C), 146.1 (C),
166.7 (CO); MS (m/z) 361 (M+•). Anal. Calcd for C22H19NO2S:
C, 73.10; H, 5.29; N, 3.87. Found: C, 72.95; H, 5.19; N, 3.79.
2,3-Dih ydr o-3-acetyloxy-2-(ph en ylth iom eth yl)-1H-isoin -
d ol-1-on e (16a ). A stirred solution of 2,3-dihydro-3-hydroxy-
2-(phenylthiomethyl)-1H-isoindol-1-one (14a ) (271 mg, 1 mmol)
in 20 mL of acetic acid was allowed to react at room temper-
ature. After 3 h of reaction at room temperature, the reaction
mixture was concentrated in vacuo and diluted with CH2Cl2
(15 mL). The organic layer was neutralized with 10% NaHCO3
solution, separated, dried over MgSO4, and evaporated to give
after recrystallization from EtOH the title product 16a as a
yellow solid (147 mg, 47%): mp 151 °C (decomposition); IR
6,12b -Dih yd r o-12b -m et h ylisoin d olo[2,1-c][1,3]b en zo-
th ia zin -8-on e (20b) a n d 5,11b-Dih yd r o-11b-m eth ylisoin -
d olo[1,2-b][1,3]ben zoth ia zin -7-on e (21b). These products
were obtained as an inseparable mixture in 5.5/4.5 ratio in
85% yield and were accompanied with 16b which was isolated
in pure form.
1
P r od u ct 20b: H NMR (CDCl3, 200 MHz) δ 1.87 (s, 3H),
1
(KBr) 1681, 1652 cm-1; H NMR (CDCl3, 200 MHz) δ 2.11 (s,
4.65 (d, 1H, J ) 12.6 Hz), 5.41 (d, 1H, J ) 12.6 Hz), 7.02-
7.27 (m, 4H), 7.37-7.54 (m, 2H), 7.58-7.89 (m, 2H); MS (m/z)
267 (M+•).
3H), 5.41 (d, 1H, J ) 11 Hz), 5.62 (d, 1H, J ) 11 Hz), 6.95 (s,
1H), 7.16-7.32 (m, 5H), δ 7.51-7.56 (m, 3H), 7.78 (d, 1H, J )
6.7 Hz); MS (m/z) 313 (M+•). Anal. Calcd for C17H15NO3S: C,
65.15; H, 4.82; N, 4.47. Found: C, 65.14; H, 4.77; N, 4.45.
1
P r od u ct 21b: H NMR (CDCl3, 200 MHz) δ 1.88 (s, 3H),
4.45 (d, 1H, J ) 17.7 Hz), 5.50 (d, 1H, J ) 17.7 Hz), 7.02-
7.27 (m, 4H), 7.37-7.54 (m, 2H), 7.58-7.89 (m, 2H); MS (m/z)
267 (M+•).
2,3-Dih yd r o-3-p h en ylt h io-2-(p h en ylt h iom et h yl)-1H -
isoin d ol-1-on e (17a ). This product was obtained as a white
solid in similar manner as for 16a , using 257 mg (1 mmol) of
hydroxylactam 14a and 10 mL of TFA, 10% HCl, or 10% H2-
SO4 solution, in 32% (116 mg), 30% (109 mg) or 27% (98 mg)
yield, respectively: mp 130 °C (ethanol); IR (KBr) 3009, 1715
cm-1; 1H NMR (CDCl3, 200 MHz) δ 4.83 (d, 1H, J ) 13.7 Hz),
5.71 (d, 1H, J ) 13.7 Hz), 5.91 (s, 1H), 6.98-7.03 (m, 5H),
7.19-7.31 (m, 5H), 7.44-7.61 (m, 4H); MS (m/z) 363 (M+•).
Anal. Calcd for C21H17NOS2: C, 69.38; H, 4.71; N, 3.58.
Found: C, 69.31; H, 4.68; N, 3.88.
6,12b -Dih yd r oisoin d olo[2,1-c][1,3]b e n zot h ia zin -8-
on e (20a ) a n d 6,12b-Dih yd r oisoin d olo[1,2-b][1,3]ben zo-
th ia zin -7-on e (21a ). Meth od A. A solution containing 271
mg (1 mmol) of 2,3-dihydro-3-hydroxy-2-(phenylthiomethyl)-
1H-isoindol-1-one (14a ) and 5 mL of TFA was allowed to react
at room temperature under stirring. After 12 h of reaction at
same temperature, the mixture was concentrated in vacuo and
diluted with CH2Cl2 (20 mL). The organic layer was neutral-
ized with 10% NaHCO3 solution, separated, dried over MgSO4,
and evaporated to give 243 mg (96%) of an inseparable 20a /
21a (5.5/4.5) mixture.
1,2-Dih yd r o-3-m eth ylid en e-2-(p h en ylth iom eth yl)-1H-
isoin d ol-1-on e (16b). This product was obtained in pure form
as a white solid: mp 115 °C; IR (KBr) 3011, 1716, 1624 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 4.88 (d, 1H, J ) 2.5 Hz), 5.13 (s,
2H), 5.22 (d, 1H, J ) 2.5 Hz), 7.17-7.37 (m, 5H), 7.39-7.57
(m, 4H); MS (m/z) 267 (M+•). Anal. Calcd for C16H13NOS: C,
71.88; H, 4.90; N, 5.24. Found: C, 71.73; H, 4.87; N, 5.31.
6,12b -Dih yd r o-12b -p h en ylisoin d olo[2,1-c][1,3]b en zo-
th ia zin -8-on e (20c) a n d 5,11b-Dih yd r o-11b-p h en ylisoin -
d olo[1,2-b][1,3]ben zoth ia zin -7-on e (21c). These products
were obtained as a mixture in 0.6/9.4 ratio in 92% yield.
Compound 21c was isolated in pure form by fractional recrys-
tallization from ethanol.
P r od u ct 20c: 1H NMR (CDCl3, 200 MHz) δ 4.34 (d, 1H,
J ) 12.4 Hz), 5.27 (d, 1H, J ) 12.4 Hz), 7.06-7.38 (m, 6H),
7.41-7.54 (m, 7H); MS (m/z) 329 (M+•).
P r od u ct 21c: This product was obtained in pure form as a
white solid: mp 161 °C (ethanol); IR (KBr) 3013, 1709 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 4.22 (d, 1H, J ) 17.8 Hz), 5.51
(d, 1H, J ) 17.8 Hz), 7.06-7.17 (m, 4H), 7.25-7.31 (m, 5H),
7.47-7.51 (m, 3H), 7.91-7.96 (m, 1H); 13C NMR (CDCl3, 50
MHz) δ 39.4 (CH2), 71.4 (C), 121.9 (CH), 124.1 (CH), 125.6
(CH), 126.6 (2CH), 127 (CH), 127.1 (CH), 127.6 (CH), 128.1
(C), 128.3 (CH), 128,7 (2CH), 128.9 (CH), 129.1 (C), 129.2 (C),
132.1 (CH), 137.3 (C), 148.3 (C), 166.4 (CO); MS (m/z) 329
(M+•). Anal. Calcd for C21H15NOS: C, 76.56; H, 4.59; N, 4.25.
Found: C, 76.49; H, 4.53; N, 4.23.
Met h od B. A solution containing 728 mg (2 mmol) of
2,3-dihydro-3-phenylthio-2-(phenylthio-methyl)-1H-isoindol-1-
one (17a ), 5 mL of TFA, and 2-5 equiv of H2O was refluxed
for 12 h. After identical workup as described above, 466 mg
(92%) of a mixture of 20a /21a in a 5.5/4.5 ratio was obtained.
6,12b -Dih yd r oisoin d olo[2,1-c][1,3]b e n zot h ia zin -8-
on e (20a ). This product was obtained by fractional recystal-

Thiolactams via Intramolecular R-(Thio)amidoalkylation
J . Org. Chem., Vol. 66, No. 13, 2001 4703
12b-p-Ch lor op h en yl-6,12b-d ih yd r oisoin d olo[2,1-c][1,3]-
ben zoth ia zin -8-on e (20d ) a n d 11b-p-Ch lor op h en yl-5,11b-
d ih yd r oisoin d olo[1,2-b][1,3]b en zot h ia zin -7-on e (21d ).
These products were obtained as a mixture in 0.4/9.6 ratio in
98% yield. Compound 21d was isolated in pure form by
fractional recrystallization from ethanol.
diluted with CH2Cl2 (10 mL). The organic layer was neutral-
ized with 5% NaOH solution, separated, dried over MgSO4,
and evaporated to give after recrystallization from EtOH a
yellow solid in 86% yield (738 mg) identical to the benzylidene
derivative 31Z described above.
m -CP BA Oxid a tion of th e Mixtu r e of Isoin d olo[1,3]-
ben zoth ia zin es 20a a n d 21a . To a cold solution at 0 °C of
the mixture of thiazines 20a and 21a (1 g, 3.95 mmol) in dry
CH2Cl2 (20 mL) was added in portionwise m-chloroperbenzoic
acid (86% pure, 1.32 g, 7 mmol) in dry CH2Cl2 over a period of
20 min under vigorous stirring. After 10 min of reaction at
this temperature, the reaction was allowed to stir for an
additional 4 h at room temperature. The reaction was hydro-
lyzed carefully with saturated solution of NaHCO3 and sepa-
rated. The organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. Recrystal-
lization of the residue from dry dichloromethane or dry ethanol
afforded pure sulfone 22a . Sulfone 23a was isolated in pure
form from the mother liquor after concentration in vacuo and
recrystallization from the mixture ether/hexane (9.5/0.5).
These sulfones were obtained in 96% yield.
P r od u ct 20d : 1H NMR (CDCl3, 200 MHz) δ 4.33 (d, 1H,
J ) 12.5 Hz), 5.28 (d, 1H, J ) 12.5 Hz), 6.80-7.38 (m, 7H),
7.41-7.58 (m, 5H); MS (m/z) 364 (M+•).
P r od u ct 21d : This product was obtained in pure form as a
white solid: mp 172 °C (ethanol); IR (KBr) 3019, 1712 cm-1
;
1H NMR (CDCl3, 200 MHz) δ 4.25 (d, 1H, J ) 17.8 Hz), 5.53
(d, 1H, J ) 17.8 Hz), 7.08-7.29 (m, 8H), 7.41-7.45 (m, 1H),
7.50-7.57 (m, 2H), 7.97 (d, 1H, J ) 8.1 Hz); 13C NMR (CDCl3,
50 MHz) δ 39.8 (CH2), 71.2 (C), 122.1 (CH), 124.5 (CH), 126.1
(CH), 127.4 (CH), 127.5 (CH), 127.9 (CH), 128.3 (C), 128.5
(2CH), 128.9 (C), 129.2 (2CH), 129.4 (CH), 129.6 (C), 132.7
(CH), 134.7 (C), 136.3 (C), 148.1 (C), 166.7 (CO); MS (m/z) 363
(M+•). Anal. Calcd for C21H14ClNOS: C, 69.32; H, 3.88; N, 3.85.
Found: C, 69.29; H, 3.90; N, 3.82.
12b -Ben zyl-6,12b -d ih yd r oisoin d olo[2,1-c][1,3]b en zo-
th ia zin -8-on e (20e) a n d 11b-Ben zyl-5,11b-d ih yd r oisoin -
d olo[2,1-d ][1,3]ben zoth ia zin -7-on e (21e). These products
were obtained as an inseparable mixture 20e/21e (3/1) in 92%
yield and were accompanied with the enamide 31 as a Z/ E
mixture which was separated easily by chromatography on
silica gel column using CH2Cl2 as eluent.
6,12b-Dih yd r o-5,5-d ioxyisoin d olo[2,1-c][1,3]ben zoth i-
a zin -8-on e (22a ). This compound was obtained as yellow
needles: mp 206 °C (decomposition); IR (KBr) 3020, 1712 cm-1
;
1H NMR (DMSO-d6, 200 MHz) δ 5.05 (d, 1H, J ) 14.2 Hz),
5.65 (d, 1H, J ) 14.2 Hz), 6.81 (s, 1H), 7.58-8.10 (m, 6H),
8.12-8.17 (m, 1H), 8.40-8.44 (m, 1H); 13C NMR (DMSO-d6,
50 MHz) δ 21.5 (CH2), 73.3 (CH), 123.6 (CH), 124.8 (CH), 125.7
(CH), 128.2 (C), 130.6 (C), 131.4 (CH), 131.9 (CH), 132.2 (C),
134.8 (CH), 135.2 (CH), 135.6 (CH), 138.7 (C), 164.8 (CO); MS
(m/z) 285 (M+•). Anal. Calcd for C15H11NO3S: C, 63.14; H, 3.88;
N, 4.91. Found: C, 63.06; H, 3.92; N, 5.03.
P r od u ct 20e: 1H NMR (CDCl3, 200 MHz) δ 3.57 (d, 1H,
J ) 14.2 Hz), 3.74 (d, 1H, J ) 14.2 Hz), 4.56 (d, 1H, J ) 12.4
Hz), 5.39 (d, 1H, J ) 12.4 Hz), 6.73-7.42 (m, 7H), 7.51-8.01
(m, 6H); MS (m/z) 343 (M+•).
P r od u ct 21e: 1H NMR (CDCl3, 200 MHz) δ 3.48 (d, 1H,
J ) 14.5 Hz), 3.69 (d, 1H, J ) 14.5 Hz), 4.61 (d, 1H, J ) 18.1
Hz), 5.51 (d, 1H, J ) 18.1 Hz), 6.73-7.42 (m, 7H), 7.51-8.01
(m, 6H); MS (m/z) 343 (M+•).
6,12b -Dih yd r o-12,12-d ioxyisoin d olo[2,1-b][1,3]b en zo-
th ia zin -7-on e (23a ). This compound was obtained as white
needles: mp 197-199 °C (decomposition); IR (KBr) 3032, 1717
1
(Z)-3-Ben zylid en e-1,2-d ih yd r o-2-(p h en ylt h iom et h yl)-
1H-isoin d ol-1-on e (31). This product was obtained in pure
form as a yellow solid: mp 158 °C; IR (KBr) 3022, 1690, 1656
cm-1; H NMR (DMSO-d6, 200 MHz) δ 4.94 (d, 1H, J ) 13.7
Hz), 5.72 (d, 1H, J ) 13.7 Hz), 6.14 (s, 1H), 7.46-8.01 (m, 8H);
13C NMR (DMSO-d6, 50 MHz) δ 58.3 (CH2), 56.6 (CH), 123.5
(CH), 123.7 (CH), 124.3 (CH), 127.8 (CH), 128.8 (CH), 129.3
(CH), 129.9 (C), 133.2 (CH), 133.3 (CH), 134.7 (C), 137.1 (C),
143.8 (CH), 166.8 (CO); MS (m/z) 285 (M+•). Anal. Calcd for
1
cm-1; H NMR (CDCl3, 200 MHz) δ 5.13 (s, 2H), 6.48 (s, 1H),
7.17-7.30 (m, 10H), 7.50-7.65 (m, 2H), 7.76 (d, 1H, J ) 7.1
Hz), 7.89 (d, 1H, J ) 8.1 Hz); 13C NMR (CDCl3, 50 MHz) δ
42.9 (CH2), 103.4 (dCH), 120.1 (CH), 123.1 (CH), 126.7 (CH),
127.3 (CH), 127.8 (2CH), 127.9 (CH), 128.0 (2CH), 129.1 (CH),
129.2 (C), 129.3 (2CH), 130.2 (C), 130.5 (C), 131.4 (2CH), 133.9
(C), 134.5 (C), 166.1 (CO); MS (m/z) 343 (M+•). Anal. Calcd for
C
15H11NO3S: C, 63.14; H, 3.88; N, 4.91. Found: C, 63.09; H,
3.81; N, 4.87.
Ack n ow led gm en t. Financial support by “Region of
Haute Normandy, France” (Regional Scholarship: 1996-
99) and Scientific Council of University of Le Havre are
gratefully acknowledged. The helpful discussions ren-
dered by Dr. J ean C. Plaquevent, UMR 6014, CNRS,
IRCOF, University of Rouen, Faculty of Sciences, F-76821
Mont-Saint-Aignan, France, is greatly appreciated.
C
22H17NOS: C, 76.94; H, 4.99; N, 4.08. Found: C, 76.85; H,
5.03; N, 4.06.
(E)-3-Ben zylid en e-1,2-d ih yd r o-2-(p h en ylt h iom et h yl)-
1H-isoin d ol-1-on e (31). This product was obtained in pure
form as a yellow solid: mp 163 °C; IR (KBr) 3016, 1686, 1641
1
cm-1; H NMR (CDCl3, 200 MHz) δ 5.30 (s, 2H), 6.54 (s, 1H),
7.10-7.14 (m, 1H), 7.23-7.30 (m, 3H), 7.34-7.43 (m, 6H),
7.50-7.57 (m, 3H), 7.74 (d, 1H, J ) 7.8 Hz); MS (m/z) 343
(M+•). Anal. Calcd for C22H17NOS: C, 76.94; H, 4.99; N, 4.08.
Found: C, 76.90; H, 4.91; N, 4.00.
Su p p or t in g In for m a t ion Ava ila b le: Physical data of
all other products not described herein (6c and 25-30)
and detailed descriptions of experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org. The data may also be obtained at the
following e-mail address: Adam.Daich@univ-lehavre.fr.
Oth er Meth od for P r ep a r a tion of Ben zylid en e Der iva -
tive 31Z. To 905 mg (2.5 mmol) of R-benzyl-R-hydroxylactam
14e in dry CH2Cl2 (20 mL) was added 10 mg of p-toluene-
sulfonic acid. After 12 h of reaction at room temperature under
stirring, the reaction mixture was concentrated in vacuo and
J O0156316