Exocyclic-endocyclic n-acyliminium ion equilibration via an intramolecular α-thioamidoalkylation in the synthesis of fused N,S-heterocyclic systems: Some new parameters

Article abstract of DOI:10.1002/ejoc.200400760

The reactivity of N-[aryl(or alkyl)thio(oxo or seleno)alkylamidals 6 bearing the N-(CH2)_n-X-(CH₂)_m-Ar functionality towards neat TFA has been examined. Substrates of type 6 give, together with the products 11, 17, 19, and

Full text of DOI:10.1002/ejoc.200400760

FULL PAPER
Exocyclic–Endocyclic N-Acyliminium Ion Equilibration via an Intramolecular
α-Thioamidoalkylation in the Synthesis of Fused N,S-Heterocyclic Systems:
Some New Parameters[‡][‡‡]
Nicolas Hucher,[a] Anthony Pesquet,[a] Pierre Netchitaïlo,[a] and Adam Daïch*[a]
Dedicated to the memory of our colleague Professor Tong-Kuan Wang[‡‡‡]
Keywords: Acyliminium ion / Nitrogen heterocycles / Isomerization / Sulfur heterocycles
The reactivity of N-[aryl(or alkyl)thio(oxo or seleno)alkylami-
dals bearing the N-(CH2)n-X-(CH2)m-Ar functionality
towards neat TFA has been examined. Substrates of type 6
give, together with the products 11, 17, 19, and 25 of the
“expected” π-cyclization process, the “unexpected” products
mation of an aza-sulfonium cation A as a valuable intermedi-
ate which undergoes the π-cyclization process alone or in
tandem with the thiocyclization/isomerization to give the cy-
clized products cited above. For the latter tandem reaction,
we have established clearly that the n value should be equal
6
12, 18, and 26 resulting from a new tandem heteroamidoalk- to 1, the process can be performed independently for both
ylation/isomerization/π-cyclization. The composition of the the succinimide and phthalimide series, the reaction depends
final isomeric mixture depends on the temperature of the re- on the nucleophilicity of the heteroatom, and can be general-
action, with a high selectivity in favor of the “expected” π- ized to other heterocycles. Only the role of the benzene sub-
cyclization product 11 as a thermodynamic isomer. Further- stitution has still to be totally elucidated.
more, the results demonstrate again the relevance of TFA ca-
talysis and support two reaction pathways involving the for-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
More recently, to exploit fully this remarkable thiophi-
licity for cationic initiation reactions[5–7] to form N-acyl-
N,S-acetals, we investigated the behavior of 2,3-dihydro-3-
hydroxy-2-(phenylthiomethyl)-1H-isoindol-1-one (4, R =
H) with acids, and observed an “unexpected” mixture of
two thiazines I and II in the reaction with trifluoroacetic
acid (neat TFA, room temp., 4 h). To explain these results,
the mechanism shown in Scheme 2 was postulated.[4] Thus,
[1,3]benzothiazine (I) is accessible from the classical endo-
cyclic N-acyliminium ion B, while [1,3]benzothiazine (II)
suggests the formation of the exocyclic acyliminium ion C,
which is in equilibrium with B via the cyclic azasulfonium
cation A. The latter is the consequence of a novel intramol-
ecular α-thioamidoalkylation of the intermediate B. During
these studies, we demonstrated that only TFA among the
Brönsted acids can operate as a proton source.[8] Also, with
another acid the bis(phenylthio) derivative 5 was isolated,
and, again, its treatment with TFA at reflux led to I and II.
Finally, the substitution at the angular C atom has already
been investigated; in each case the formation of both benzo-
thiazines of type I and II was claimed (Scheme 2).[9]
Introduction
In the framework of our interest in intramolecular cat-
ionic cyclizations based on the formation and cleavage of a
thioether linkage for the preparation of complex N,S-con-
taining heterocycles,[1] we have recently demonstrated that
α-hydroxy lactams 1 (n = 0, 1) are effective precursors, in
acidic media, of the tricyclic N,S-acetals
2 and 3
(Scheme 1).[2–4] These cyclized products are the result of the
exclusive intramolecular attack of the sulfur atom onto the
endocyclic N-acyliminium ion intermediates, followed by
either deprotonation or dealkylation (R = H, Me, Bzl;
Scheme 1).
[‡] Preliminary results in this area, including part of this work,
were presented at the American Chemical Society National
Meeting, Poster 367, San Francisco, CA, March 26–30, 2000.
[‡‡] For the preceding paper in the series see ref.[4]
[a] URCOM, EA 3221, UFR des Sciences & Techniques de
l’Université du Havre,
25 rue Philippe Lebon, B. P. 540, 76058 Le Havre Cedex,
France
In this context, we wish to present herein our findings
from a related study dealing with the examination of the
influence of several other factors on the reactivity of an α-
Fax: +33-02-3274-4391
E-mail: adam.daich@univ-lehavre.fr
[‡‡‡] Deceased on January 2, 2004 in Le Havre.
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Exocyclic–Endocyclic N-Acyliminium Ion Equilibration
FULL PAPER
Scheme 1. Heterocyclization with the sulfur atom as internal nucleophile.
Scheme 2. The mechanism of the tandem intramolecular sulfuration/isomerization/π-cationic cyclization process.
hydroxy lactam precursor of type 6 during the cyclization poor solubility of the starting imides 9 and the laborious
process (Scheme 2) in order to shed further light on the work-up encountered during these processes, a small quan-
course of this tandem intramolecular sulfuration/isomeriza- tity of THF was added as co-solvent. In the next step, the
tion/cationic cyclization process, and to gain insight into five α-hydroxy lactams 10b–f examined were found to react
the mechanistic aspects of this cascade reaction.
under the conditions outlined above to give the cyclized
products in moderate to excellent yields (Scheme 3,
Table 1).
From these results, it seems that the nature and the posi-
tion of the substitution on the benzene ring have an inter-
esting effect on the reaction profile of our cyclization proto-
col. In general, two different processes occur: for 10c, the
reaction furnishes a mixture of two kinds of thiazines (11
and 12) by the well-established tandem reaction, as for 10a
(see the postulated mechanism in Scheme 2). Interestingly,
for the m-chloro substitution, in addition to the classical
inseparable couple 11cx/12cx (5.5:4.5), the regioisomers
11cy/12cy were obtained in similar proportions. These two
couples were separated by chromatography on a silica gel
column with a mixture of CH2Cl2/hexane as eluting sol-
vents. In the second process, for hydroxy lactams 10b and
10d–f, no isomerization is observed and, consequently, only
the “expected” benzo[1,3]thiazines of type I (11b and 11d–
f) are obtained by intramolecular arylation of an endocyclic
N-acyliminium ion of type B (see Scheme 2). Furthermore,
while substituents at the ortho position of the benzene ring
of 10b (R1 = o-Br) and 10f (R1 = o-CO2Me) were found
to have a very strong influence on both the regiochemical
outcome and yields (95 and 94% yields, respectively) of the
reaction, substitution at the meta and para positions gives
only mediocre yields (8 and 19% yields, respectively), al-
though with total regiocontrol in favor of the π-cyclization
process without the isomerization of the N-acyliminium ion
Results and Discussion
As indicated above, we have developed a set of efficient
and practical conditions that use neat TFA in a precise ratio
to the hydroxy lactam substrate (2 mL of TFA for 1 mmol
of reactant) and have demonstrated their efficiency in ob-
taining benzo[1,3]thiazines of types I and II.[4] In order to
collect additional information on the role of the aromatic
ring in the cyclization step, three aromatic nuclei with a
set of substituents having different electron-donating and
electron-withdrawing properties on the benzene ring were
chosen.
Influence of the Benzene Substitution and the Aromatic
Ring on the Cyclization Process
First, the synthesis of the requisite hydroxy lactams 10b–
f was accomplished in a three-step sequence, as outlined in
Scheme 3. Thus, commercially available 1-chloromethyl-
phthalimide (7) was S-alkylated with a slight excess of
substituted thiophenol 8 in an alkaline medium (yield: 54–
88%). Regioselective reduction of the resultant imides 9 was
performed with a large excess of NaBH4 (4 to 6 equiv.) in
analogy to our reports for 9a[4] to afford 10b–f in excellent
yields (81 to 99%; see Table 1). In some cases, to avoid the
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Scheme 3. Reagents and conditions: (i) MeONa, DMF, 1.5 equiv. of substituted thiophenol (8; see text for phthalimidals in thiophene
and naphthalene series 15 and 16, respectively), room temp., 5 h; (ii) 4 to 6 equiv. of NaBH4, MeOH, 0 °C, 30 min to 1 h; (iii) neat TFA,
room temp., 3 h.
Table 1. Effect of the benzene substitution and the aromatic ring on the cyclization process.
R1
Aromatic ring
Imides
(% yield)
Alcohols
(% yield)
Cyclization
(% yield)
Products ratio
Regioisomers ratio
a
b
c
d
e
f
H
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
thien-2-yl
β-naphthyl
9 (90)
9 (82)
9 (88)
9 (68)
9 (54)
9 (84)
13[15]
10 (94)
10 (89)
10 (99)
10 (81)
10 (98)
10 (98)
15[15]
92[a]
95
11:12 = 5.5:4.5
11:12 = 1.0:0.0
11:12 = 5.5:4.5
11:12 = 1.0:0.0
11:12 = 1.0:0.0
11:12 = 1.0:0.0
17:18 = 9.0:1.0
19[e]
–
–
o-Br
m-Cl
m-OMe
p-OMe
o-CO2Me
–
89[b]
8[c][d]
19[c]
94
x:y = 1:1
x:y = 9:1
–
–
–
–
–
–
87
96
–
14[3]
16[3]
[a] A mixture of thiazines 11a and 12a was obtained, see ref.[4]. [b] Four products were obtained, see Scheme 3 for details. [c] The
substituted thiophenol 8 resulting from the cleavage of the thioether linkage was also isolated. [d] Two regioisomers of thiazine 11d were
isolated in a 9:1 ratio, see Scheme 3 for details. [e] Only one product was obtained.
intermediate. This fact can be explained, not by the influ- two free ortho positions to give the 3-methoxy- and 1-meth-
ence of the methoxy group, but by the higher sensitivity oxy[6,12-b]-dihydroisoindolo[2,1-c][1,3]benzothiazines 11dx
of the thioether linkage in these acid conditions. The m- and 11dy in a 9.0:1.0 ratio (Scheme 3).
methoxythiophenol and p-methoxythiophenol isolated as
In an effort to further define the scope of the cyclization
the major products from the reaction are in agreement with process, especially the effect of the nucleophilicity of the π-
this hypothesis. In addition, for the m-methoxy hydroxy lac- aromatic nucleus, the elaboration of other aromatic models,
tam derivative 10d, the cyclization reaction occurs at the substituted by naphthyl or thienyl groups on the aromatic
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Exocyclic–Endocyclic N-Acyliminium Ion Equilibration
FULL PAPER
moiety, was explored in the same reaction protocol demon- CH2Cl2 as eluent). As can be seen from Table 2, both series
strated above (Scheme 2 and Scheme 3). Thus, the requisite of data at ambient temperature (20 °C) and 72 °C show a
2-(thien-2Ј-yl-thiomethyl)phthalimidal 15 was obtained in high selectivity in favor of 11a as the thermodynamic pro-
two steps, as described in the literature, by successive S- duct, in contrast to that performed at –20 °C. In the case
alkylation and chemoselective borohydride reduction.[15] of the run conducted at –20 °C, the reaction needed an ad-
The use of the same protocol in the naphthalene series led ditional co-solvent (CH2Cl2) and consequently a much
to hydroxy lactam derivative 16, via the sulfide imide 14 longer reaction time (240 h) was necessary for complete re-
(94%),[3] in a yield of 99%.
action. This effect has also been observed in our earlier re-
The hydroxy lactam 16 was treated with neat TFA ac- ports.[4] Because the increase of the reaction temperature
cording to the well-established cyclization protocol given (Ն80 °C) is limited by the decomposition of 10a, and taking
above. The examination of the TLC of the reaction mixture into account that we have already investigated successfully
indicated the presence of only one product, which, after a the thioamidoalkylation to give 12a,[2,4] our attention
classical work-up, was identified as 19, resulting from the turned to synthesizing 11a.
π-cyclization of the endocyclic N-acyliminium ion interme-
Indeed, according to the sequential method shown in
diate. This reaction occurs cleanly and affords the cyclic Scheme 4, 11f, obtained by a π-cationic cyclization of 10f
thiazine 19 as the sole reaction product in an excellent yield upon treatment with TFA, was hydrolyzed into 20 under
of 96%. In contrast to the results obtained in the benzene standard conditions (K2CO3, MeOH/H2O, 5:1, reflux, 3 h,
series, where thiazines 11 and 12 were obtained as a mixture 96%). Interestingly, in a parallel reaction with 10f and a
from hydroxy lactams 10, no isomerization takes place. This Lewis acid catalyst, only a limited effect was observed dur-
fact can be explained by the steric repulsion in the case of ing the cyclization (See table in Scheme 4) since the maxi-
an alternative cyclization at the α-naphthyl position. mum proportion of 12f never exceeds 15% of the benzo-
Furthermore the regioselectivity of electrophilic attack at thiazine mixture (2 equiv. of SnCl4, CH2Cl2, room temp.,
naphthalene rings is a matter of kinetic and thermodynamic 24 h, 86%). When submitted to decarboxylation in the pres-
control. The cyclized product obtained here (19) is certainly ence of quinoline and a catalytic amount of copper at
the thermodynamic isomer.
150 °C,[10] 20 yielded the expected benzothiazine 11a in
Although the presence of the naphthyl nucleus instead of 78% yield.
the phenyl one (in the N-acyliminium ion precursor 16)
seems to facilitate only the π-cyclization process in a total
regiocontrol, there is no discernible preference between the
Effect of the Chain Length [N-(CH2)n-S and S-(CH2)m-Ar]
on the Cyclization Process
phenyl and thienyl groups. In fact, in the latter case hydroxy
lactam 15 in the thiophene series gives N,S-acetals 17 and
18 in 87% yield in up to a 9.0:1.0 ratio. In this process, the
We next examined the role of the n and m spacers on the
tandem intramolecular sulfuration/isomerization/π-cationic rearrangement/cyclization step. Thus, as depicted in
cyclization occurs as in the benzene series, although with a Scheme 5, the required hydroxy lactams 22g–k were synthe-
much better selectivity for the π-cationic cyclization of the sized conveniently by the successive S-alkylation of 7 (n =
endocyclic N-acyliminium intermediate B (9.0:1.0 ratio in- 1, 2; 69 to 81% yield) and borohydride reduction of the
stead of 5.5:4.5 ratio).
resulting imides 21g–k (60 to 91% yield; Table 3). Hydroxy
lactam 22h (n = m = 1), upon treatment under the condi-
tions cited above (neat TFA, room temp., 24 h), gave a mix-
ture of the cyclized benzo[1,3]thiazepine products 11h
(95%) and 12h (5%) in a good yield of 94%. Under the
same conditions, 22i (n = 1, m = 2) furnished similarly the
two benzo[1,4]thiazocines 11i and 12i in an 8:1 ratio, al-
though in only 72% yield. In contrast, 22j led to benzo[1,4]
thiazepine 11j as the sole reaction product in an excellent
yield of 95%; 22k decomposed totally.
Temperature Effects
According to our protocol with TFA as the cyclization
promoter at ambient temperature to give benzothiazines
11a and 12a in a 5.5:4.5 ratio,[4] the reaction was tested
again with 10a as the N-acyliminium ion precursor model
at two other temperatures (Scheme 2, Table 2).
From these results it seems that only the spacer n exerts
a pivotal role on the cyclization reaction. In fact, in all cases
when n = 1 the tandem intramolecular sulfuration/isomer-
ization/π-cationic cyclization process is effective (see reac-
tion of hydroxy lactams 22h,i in Scheme 5). In addition,
irrespective of the m value, the reaction failed to give the
corresponding benzothiazoline (12g) and benzo[1,4]thiazep-
ine (12j) products when n = 0 and n = 2, respectively (12g
has already been described by us in the preceding paper).[4]
Table 2. Effect of the temperature on the product ratio.
Entry T [°C] Time [h]
Thiazine
Thiazine
% Yield
11a[a]
12a[a]
1
2
3
–20[b]
20
72
240
3
1.5
4.5
5.5
7.0
5.5
4.5
3.0
92
90
84
1
[a] The ratio was determined by H NMR spectroscopy. [b] With
CH2Cl2 as solvent.
The reaction was carried out under the standard condi- In these cases only the products resulting from the classical
tions (neat TFA) until complete disappearance of α-hydroxy π-cyclization were isolated. The formation of the cyclic cat-
lactam 10a (the reaction was monitored by TLC with ion species (type A with n = 1), as the key step to the “unex-
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Scheme 4. Conditions and reagents: (i) 4 equiv. of NaBH4, MeOH, 0 °C, 35 min; (ii) See conditions in table; (iii) K2CO3, MeOH/H2O,
5:1, reflux, 3 h; (iv) Cu, quinoline, 150 °C, 3.5 h.
Scheme 5. Conditions and reagents: (i) MeONa, DMF, 1.5 equiv. of thiol derivative 8, room temp., 5 h; (ii) 4 to 6 equiv. of NaBH4,
MeOH, 0 °C, 30 to 45 min; (iii) neat TFA, 24 h.
Table 3. Effect of the n and m spacers on the cyclization process.
Effect of the Heteroatom Nucleophilicity on the Cyclization
Reaction
n
m
% Yield of imide 21 % Yield of alcohol 22
[a]
g
h
i
0
1
1
2
2
0
1
2
0
1
–
60[b]
90
82
91
83
In order to consider the impact of the heteroatom nu-
cleophilicity on the cyclization transposition step, instead
of the sulfur atom two heteroatoms (oxygen, less nucleo-
philic, and selenium, more nucleophilic) were chosen. For
81
72
69
77
j
k
[a] Imide 21g was purchased from Aldrich. [b] The cyclized product comparison reasons, hydroxy lactams of type 10 with X =
22g was accompanied by an appreciable tar.[4]
Se were considered (Scheme 7).
We have demonstrated previously that treatment of hy-
droxy lactams 10 (X = O) and 10a (X = S) with TFA (neat
TFA, room temp., 24 h, 86%),[11] under similar conditions,
pected” product 12, can be related to the fact that only this gives isoindolo[1,3]benzoxazines 11 (X = O), as a single iso-
species can furnish the exocyclic N-acyliminium ion of type mer in good yield (86%),[11] and a mixture of isoindolo[1,3]
C because of the nitrogen lactam electron-donating effect. benzothiazines 11a and 12a, respectively, in only a short
This fact cannot occur when n = 0 (cation of type D) and time (3 h).[4] In this context, N-phenylselenomethylamidal
n = 2 (cation of type F), as shown in Scheme 6.
10 (X = Se) was prepared as outlined in Scheme 7 in an
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Exocyclic–Endocyclic N-Acyliminium Ion Equilibration
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generated from succinimides and related five- and six-mem-
bered rings,[12] we decided to investigate the behavior of
(phenylthiomethyl)succinamidal (24) as an N-acyliminium
ion precursor (Scheme 8).
Scheme 6. Azasulfonium ions as potential intermediates in the tan-
dem cyclization process.
Scheme 8. Effect of the nature of the N-acyliminium species: (i)
1.0 equiv. of thiophenol, NaH, DMF, 5 h; (ii) 6 equiv. of NaBH4,
MeOH, 0 °C, 35 min; (iii) neat TFA, room temp., 2 h; (iv) 2.2 equiv.
of m-CPBA, CH2Cl2, 0 °C to room temp., 2 min and 1 h.
Thus, alkylation of the known N-chloromethylsuc-
cinimide[13] with thiophenol in the presence of NaH as a
base gave, after 5 h of reaction in dry DMF at room temp.,
the desired imide 23 (57% yield). Selective reduction of 23
with a large excess of NaBH4 (6 equiv.) in methanol gave
α-hydroxy lactam 24 in an excellent yield (93%). This latter,
Scheme 7. Influence of the heteroatom on the cyclization: (i) upon treatment with TFA at room temp., furnished a
1.1 equiv. of selenophenol, MeONa, DMF, 12 h; (ii) 5 equiv. of
NaBH4, MeOH, 0 °C, 45 min; (iii) neat TFA, room temp., 3 h.
3.0:2.0 isomeric mixture of two tricyclic thiolactams 25 and
26 in 67% yield after chromatographic purification. This
suggests that the cyclic azasulfonium cation H, similar to A
(Scheme 8), is formed an intermediate. At this stage, it
overall yield of 77.5% and treated with TFA according to
our standard cyclization protocol. This type of function-
should be pointed out that (i) the regioselectivity of the re-
ality has never been studied in the literature and this is the
action is in favor of 25 to the detriment of 26 (3.0:2.0 ratio)
first study of its behavior in an acid medium. After the
work-up of the reaction only the isoindolo[1,3]benzoselena-
zine 11 (X = Se) was isolated in a very good yield of 91%.
Finally, since no traces of isoindolo[1,3]benzoselenazine
12 (X = Se), the regional isomer of 11 (X = Se), were de-
tected in the reaction medium (the crude mixture of the
reaction was also analyzed by GS-MS prior the final work-
up), it is clear that the heteroatom nucleophilicity is a cru-
cial factor in the tandem cyclization/transposition process
observed in the sulfur series.
and is comparable to that observed in the isoindolone
series, (ii) the reaction proceeds with lower yield (67%),
thus confirming the instability difference evoked between
the iminium species in the pyrrolidinone and isoindolone
series, and (iii) all attempts to separate the mixture of 25
and 26 failed, although the recovered unreacted mixture
contained further unknown impurities. This is due to the
instability of these thiolactams.
Compounds 25 and 26 have comparable Rf values in nu-
merous solvents and, consequently, their complete separa-
tion failed. Since the minor product has been isolated by us
Role of the N-Acyliminium Aromaticity on the Cyclization
by the linear thiocyclization of an N-acyliminium ion,[2,4]
Reaction
and by others by radical cyclization with Bu3SnH as a pro-
Taking into account that N-acyliminium ions derived moter,[14] a chemical separation protocol was envisioned, as
from phthalimide derivatives are more stable than those reported by us for the related thiolactams.[4] Thus, oxidation
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sium bromide for solids and without solvent (neat) for liquids).
The 1H and 13C NMR spectra were recorded on Bruker AC-200
(200 MHz) and Varian VXR-300 (300 MHz) instruments with
CDCl3 (δ = 7.24 ppm) or [D6]DMSO (δ = 2.49 ppm) as solvents;
chemical shifts (δ) are expressed in ppm relative to TMS or HMDS
as internal standard. Thin layer chromatography (TLC) was per-
formed with silica gel analytical plates Merck 5715 (F254) of
0.25 mm thickness. The detection on TLC plates was performed
with UV light at 254 or 365 nm or using iodine vapor. Mass spec-
tral measurements were recorded on an AEI MS 902 S spectropho-
of the mixture of 25 and 26 with 2.2 equiv. of m-CPBA in
dry dichloromethane at room temperature afforded a mix-
ture of sulfones 27 and 28 (100%), which were separated by
simple crystallization from dichloromethane (Scheme 8).
The spectroscopic data and microanalysis confirmed the
1
structures of these compounds. For instance, the H NMR
spectra of 27 and 28 reveal the presence of a triplet for
27 at δ = 4.35 ppm and a doublet for 28 at δ = 4.92 ppm
corresponding to the angular proton. The spectra also con-
tain two doublets of an AB system for the methylene group tometer (70 eV, electron impact). The elemental analyses (C, H, N)
were carried out by the microanalysis laboratory of INSA, F-76130
Mt. St. Aignan, France.
due to the diastereotopic effect, with a coupling constant of
14.0 Hz for 27 and 17.7 Hz for 28, characteristic of geminal
protons. Of particular note for product 27 (Scheme 8), the
1H NMR spectrum shows an “unexpected” important
shielding of about 0.51 ppm of the angular proton H-10a
compared to the corresponding one in the tricyclic N,S-ace-
tal 25, while the same proton H-9a in sulfone 28 is barely
affected by this oxidation (in this case only a small deshield-
ing effect was observed: Δδ = 0.05 ppm) in spite of the prox-
imity of the sulfur atom. Interestingly, these results are sim-
ilar to that obtained for sulfones in related isoindolo[1,3]
benzothiazines, which show, however, an important de-
shielding effect.[4] Moreover, the sequence of chemical shifts
of the angular protons in sulfides 25 and 26 is inverted com-
pared to the corresponding signals in the related N,S-ace-
tals of the isoindolone series 11a and 12a (in the latter the
values decrease from 11a to 12a).
General Procedure for S-Alkylation of N-(Chloromethyl)- or N-(Bro-
moethy)lphthalimide (7) and N-(Chloromethyl)succinimide: Sodium
methoxide (0.1 to 0.15 mol) was added to a stirred solution of aryl
mercaptan derivative 8 (0.1 to 0.15 mol) in 40 mL of dry DMF
under an atmosphere of dry argon. After stirring for 40 min at
room temperature, the halide (0.1 mol) was added slowly dropwise
over a period of 5 min. The mixture was then stirred at ambient
temperature for 4 to 12 h (monitored by TLC with CH2Cl2/cyclo-
hexane as eluent, see text, schemes, and tables for the reaction time)
and hydrolyzed with crushed ice. The solution was filtered and the
solid was recrystallized from suitable solvent to give the expected
imide. If a solid was not formed, the solution was extracted three
times with diethyl ether, the organic layer was dried with MgSO4,
and concentrated in vacuo. The oily residue was passed through
a short celite column and used in the next step without further
purification (the products obtained in these cases were, in general,
sufficiently pure).
N-(2-Bromophenylthiomethyl)phthalimide (9b): This compound was
isolated as a white solid in 82% yield (see ref.[3]) after recrystalli-
zation from ethanol according to the general procedure for the S-
Conclusions
alkylation. M.p. 97 °C. IR: ν
= 1710 cm–1 (C=O). 1H NMR
In conclusion, the obtained results show that the N-acyli-
˜
max
minium ion precursor in neat TFA at ambient temperature (CDCl3): δ = 5.06 (s, 2 H, CH2), 7.11–7.18 (m, 2 H, benzene), 7.53–
7.65 (m, 2 H, benzene), 7.66–7.74 (m, 2 H, phthalimide), 7.78–7.85
(m, 2 H, phthalimide) ppm. 13C NMR (CDCl3): δ = 41.5 (CH2),
123.6 (CHAr), 127.9 (C), 128.0 (CHAr), 129.6 (CHAr), 131.9 (C),
133.4 (CHAr), 134.2 (CHAr), 134.3 (CHAr + C), 167 (C=O) ppm.
MS (EI): m/z = 348 [M+]. C15H10BrNO2S (348.22): calcd. C 51.74,
H 2.89, N 4.02; found C 51.63, H 2.91, N 3.97.
gives two categories of processes involving the cyclic aza-
thionium species (type A or type H) as the reaction interme-
diate. From the latter cation, obtained by the intramolecu-
lar thioamidoalkylation of the classical endocyclic N-acyli-
minium ion, an isomerization into the “unexpected” exocy-
clic one occurs that leads to original triheterocyclic systems
containing fused six-, seven-, and eight-membered N,S-,
and/or N,Se-acetals. Under these acidic conditions, we have
found that a value of n = 1 is necessary for the occurrence
of the “unexpected” pathway to give 11:12, 17:18, and 25:26
ratios that depend on the benzene substitution, the nature
of the aryl nucleus, and the nature of the heteroatom.
Furthermore, this tandem process seems to be general to
nonaromatic N-acyliminium ions derived from the suc-
cinimide ring. Finally, we anticipate that the novel transfor-
mations developed in this project will find further applica-
tion in synthesis, and the systems currently under investiga-
tion in our laboratory will be published soon as a full ac-
count.
N-(3-Chlorophenylthiomethyl)phthalimide (9c): This compound was
isolated as a white solid in 88% yield after recrystallization from
ethanol according to the general procedure for the S-alkylation.
1
M.p. 101 °C (98 °C from ref.[16]). IR: ν
= 1719 cm–1 (C=O). H
˜
max
NMR (CDCl3): δ = 5.05 (s, 2 H, CH2-S), 7.22 (m, 2 H, benzene),
7.36–7.40 (m, 1 H, benzene), 7.47–7.51 (m, 1 H, benzene), 7.70–
7.72 (m, 2 H, phthalimide), 7.81–7.85 (m, 2 H, phthalimide) ppm.
13C NMR (CDCl3): δ = 41.3 (CH2), 123.7 (CHAr), 128 (CHAr), 130
(CHAr), 130.1 (CHAr), 131.8 (CHAr), 131.85 (C), 134.4 (CHAr),
134.6 (C), 135.3 (C), 166.9 (C=O) ppm. MS (EI): m/z = 303 [M+].
C15H10ClNO2S (303.77): calcd. C 59.31, H 3.32, N 4.61; found C
59.19, H 3.21, N 4.68.
N-(3-Methoxyphenylthiomethyl)phthalimide (9d): This compound
was isolated as a white solid in 68% yield after recrystallization
from ethanol according to the general procedure for the S-alky-
lation. M.p. 98 °C. IR: ν
= 1712 cm–1 (C=O). 1H NMR
˜
max
(CDCl3): δ = 3.73 (s, 3 H, O-Me), 5.05 (s, 2 H, CH2-S), 6.77–6.79
(m, 1 H, benzene), 7.03–7.06 (m, 2 H, benzene), 7.16–7.20 (m, 1
H, benzene), 7.67–7.71 (m, 2 H, phthalimide), 7.80–7.83 (m, 2 H,
phthalimide) ppm. 13C NMR (CDCl3): δ = 41.8 (CH2), 55.3 (CH3),
114.1 (CHAr), 116.7 (CHAr), 123.6 (CHAr), 124.1 (CHAr), 129.9
Experimental Section
General Remarks: Melting points were measured on a Boetius
micro hot-stage and are uncorrected. The IR spectra were recorded
on a Philips analytical PV 9 800 FT IR spectrophotometer (potas-
2764
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 2758–2770

Exocyclic–Endocyclic N-Acyliminium Ion Equilibration
FULL PAPER
(CHAr), 131.9 (C), 134.3 (CHAr), 134.5 (C), 159.8 (C), 166.9 (C=O) [M+]. C16H13NO2S (283.35): calcd. C 67.82, H 4.62, N 4.94; found
ppm. MS (EI): m/z = 299 [M+]. C16H13NO3S (299.35): calcd. C
C 67.95, H 4.94, N 5.03.
64.20, H 4.38, N 4.68; found C 64.42, H 4.19, N 4.78.
N-(Phenethylthiomethyl)phthalimide (21i): This compound was iso-
N-(4-Methoxyphenylthiomethyl)phthalimide (9e): This compound
was isolated as a white solid in 54% yield after recrystallization
from ethanol according to the general procedure for the S-alky-
lated as a yellow solid in 72% yield after recrystallization from
ethanol according to the general procedure for the S-alkylation.
1
M.p. 105 °C. IR: ν
= 1711 cm–1 (C=O). H NMR (CDCl3): δ =
˜
max
lation. M.p. 112 °C. IR: ν
= 1711 cm–1 (C=O). 1H NMR 2.92 (s, 4 H, CH2-CH2-S), 4.75 (s, 2 H, N-CH2-S), 7.23–7.28 (m, 5
˜
max
(CDCl3): δ = 3.72 (s, 3 H, OMe), 4.88 (s, 2 H, CH2-S), 6.74 (d, J H, benzene), 7.70–7.76 (m, 2 H, phthalimide), 7.82–7.87 (m, 2 H,
= 8.8 Hz, 2 H, benzene), 7.36 (d, J = 8.8 Hz, 2 H, benzene), 7.64–
7.68 (m, 2 H, phthalimide), 7.75–7.78 (m, 2 H, phthalimide) ppm.
13C NMR (CDCl3): δ = 43.4 (CH2), 55.3 (CH3), 114.6 (CHAr),
123.4 (C), 123.5 (CHAr), 131.9 (C), 134.2 (CHAr), 135.8 (CHAr),
phthalimide) ppm. 13C NMR (CDCl3): δ = 33.8 (CH2), 36.3 (CH2),
39 (CH2), 123.6 (CHAr), 126.4 (CHAr), 128.5 (CHAr), 128.7 (CHAr),
132 (C), 134.3 (CHAr), 140.1 (C), 167.6 (C=O) ppm. MS (EI): m/z
= 297 [M+]. C17H15NO2S (297.38): calcd. C 68.66, H 5.08, N 4.71;
160.2 (C), 166.9 (C=O) ppm. MS (EI): m/z
=
299 [M+]. found C 68.75, H 4.97, N 4.66.
C16H13NO3S (299.35): calcd. C 64.20, H 4.38, N 4.68; found C
63.95, H 4.41, N 4.61.
N-(2-Phenylthioethyl)phthalimide (21j): This compound was iso-
lated as a yellow oil in 69% yield according to the general pro-
N-[2-(Methoxycarbonyl)phenylthiomethyl]phthalimide (9f): This cedure for the S-alkylation. IR: νmax = 1712 cm–1 (C=O). 1H NMR
˜
compound was isolated as a white solid in 84% yield after
recrystallization from ethanol according to the general procedure
(CDCl3): δ = 3.19 (t, J = 7.0 Hz, 2 H, C–CH2–S), 3.90 (t, J =
7.0 Hz, 2 H, N-CH2-C), 7.19–7.23 (m, 2 H, benzene), 7.36–7.41 (m,
3 H, benzene), 7.64–7.71 (m, 2 H, phthalimide), 7.74–7.82 (m, 2 H,
phthalimide) ppm. 13C NMR (CDCl3): δ = 31.6 (CH2), 37.5 (CH2),
123.3 (CHAr), 126.4 (CHAr), 129 (CHAr), 129.6 (CHAr), 132 (C),
134 (CHAr), 134.9 (C), 168 (C=O) ppm. MS (EI): m/z = 283 [M+].
for the S-alkylation. M.p. 112 °C. IR: ν
= 1702, 1720 cm–1
˜
max
1
(C=O). H NMR (CDCl3): δ = 3.83 (s, 3 H, OMe), 5.13 (s, 2 H,
CH2-S), 7.23–7.26 (m, 2 H, benzene), 7.43–7.48 (m, 1 H, benzene),
7.67–7.72 (m, 3 H, phthalimide + benzene), 7.81–7.85 (m, 2 H,
phthalimide) ppm. 13C NMR (CDCl3): δ = 40.3 (CH2), 52.3 (CH3), C16H13NO2S (283.35): calcd. C 67.82, H 4.62, N 4.94; found C
123.5 (CHAr), 126.5 (CHAr), 130.6 (CHAr), 130.8 (CHAr), 131.4 (C),
132 (C), 132.2 (CHAr), 134.2 (CHAr), 136.3 (C), 166.8 (C=O), 167.1
(C=O) ppm. MS (EI): m/z = 327 [M+]. C17H13NO4S (327.36):
calcd. C 62.37, H 4.00, N 4.28; found C 62.18, H 3.86, N 4.21.
67.78, H 4.42, N 4.78.
N-(2-Benzylthioethyl)phthalimide (21k): This compound was iso-
lated as a yellow solid in 77% yield after recrystallization from
ethanol according to the general procedure for the S-alkylation.
1
N-(Phenylselenomethyl)phthalimide [9 (X = Se)]: This compound
was isolated as a white solid in 97% yield after recrystallization
from ethanol according to the general procedure for the S-alky-
M.p. 45 °C. IR: ν
= 1710 cm–1 (C=O). H NMR (CDCl3): δ =
˜
max
2.68 (t, J = 7.0 Hz, 2 H, C-CH2-S), 3.76 (s, 2 H, CH2-S), 3.84 (t, J
= 7.0 Hz, 2 H, N-CH2-C), 7.25–7.31 (m, 5 H, benzene), 7.67–7.71
lation. M.p. 114 °C. IR: ν
= 1710 cm–1 (C=O). 1H NMR (m, 2 H, phthalimide), 7.80–7.84 (m, 2 H, phthalimide) ppm. 13C
˜
max
(CDCl3): δ = 5.08 (s, 2 H, CH2–Se), 7.23–7.28 (m, 3 H, benzene),
7.58–7.65 (m, 2 H, benzene), 7.67–7.72 (m, 2 H, phthalimide),
7.77–7.82 (m, 2 H, phthalimide) ppm. 13C NMR (CDCl3): δ = 33.1
NMR (CDCl3): δ = 29.1 (CH2), 35.5 (CH2), 36.7 (CH2), 123.4
(CHAr), 127.1 (CHAr), 128.6 (CHAr), 129.0 (CHAr), 132.1 (C), 134.0
(CHAr), 137.9 (C), 168.2 (C=O) ppm. MS (EI): m/z = 297 [M+].
(CH2), 123.5 (CHAr), 128.2 (CHAr), 128.4 (C), 129.1 (CHAr), 132.4 C17H15NO2S (297.38): calcd. C 68.66, H 5.08, N 4.71; found C
(C), 134.2 (CHAr), 134.8 (CHAr), 166.8 (C=O) ppm. MS (EI): m/z
= 316 [M+]. C15H11NO2Se (316.22): calcd. C 56.98, H 3.51, N 4.43;
found C 56.91, H 3.41, N 4.52.
68.91, H 5.12, N 4.61.
N-(Phenylthiomethyl)succinimide (23): This compound was isolated
as an colorless oil in 57% yield after filtration through celite ac-
N-(2-Naphthylthiomethyl)phthalimide (14): This compound was iso-
lated as a white solid in 94% yield after recrystallization from etha-
nol according to the general procedure for the S-alkylation. M.p.
cording to the general procedure for the S-alkylation by using NaH
1
as base. IR: ν
= 1710 cm–1 (C=O). H NMR (CDCl3): δ = 2.62
˜
max
(s, 4 H, succinimide), 4.80 (s, 2 H, CH2-S), 7.26–7.31 (m, 3 H,
111 °C (see ref.[3]). IR: νmax = 1718 cm–1 (C=O). 1H NMR (CDCl3): benzene), 7.41–7.46 (m, 2 H, benzene) ppm. 13C NMR (CDCl3): δ
˜
δ = 5.14 (s, 2 H, CH2-S), 7.42–7.45 (m, 2 H, naphthalene), 7.55–
7.59 (m, 2 H, naphthalene), 7.65–7.69 (m, 2 H, phthalimide), 7.75–
7.79 (m, 4 H, phthalimide + naphthalene), 7.96 (s, 1 H, naphtha-
= 28.5 (CH2), 42.7 (CH2), 128.3 (CH), 128.9 (CH), 129.2 (CH),
136.1 (C), 177.2 (CO) ppm. MS (EI): m/z = 221 [M+]. C11H11NO2S
(221.28): calcd. C 59.71, H 5.01, N 6.33; found C 59.58, H 4.83, N
lene) ppm. 13C NMR (CDCl3): δ = 41.9 (CH2), 123.6 (CHAr), 126.4 6.04.
(CHAr), 126.6 (CHAr), 127.6 (CHAr), 127.8 (CHAr), 128.8 (CHAr),
General Procedure for Reduction of Imides: Sodium borohydride
129.2 (CHAr), 130.5 (C), 131.1 (CHAr), 131.9 (C), 132.6 (C), 133.6
(C), 134.2 (CHAr), 167 (C=O) ppm. MS (EI): m/z = 319 [M+].
C19H13NO2S (319.38): calcd. C 71.45, H 4.10, N 4.39; found C
71.36, H 4.03, N 4.51.
(60 mmol, 4–6 equiv.) was added in portions to a solution of the
imide obtained above (10 mmol) in dry methanol (30 mL) at 0–
5 °C. After complete addition of sodium borohydride the mixture
was allowed to react whilst stirring for the required time (moni-
tored by TLC with CH2Cl2 as eluent). The unreacted sodium
borohydride was destroyed by careful addition of 5% HCl solution
and basified with a saturated NaHCO3 aqueous solution. After
N-(Benzylthiomethyl)phthalimide (21h): This compound was iso-
lated as a yellow solid in 81% yield after recrystallization from
ethanol/water according to the general procedure for the S-alky-
lation. M.p. 118 °C. IR: ν
= 1724 cm–1 (C=O). 1H NMR evaporation of the solvent under reduced pressure, the residue was
˜
max
(CDCl3): δ = 3.89 (s, 2 H, CH2-S), 4.69 (s, 2 H, N-CH2-S), 7.07– diluted with cold water (30 mL) and allowed to stir at room tem-
7.11 (m, 1 H, benzene), 7.29–7.34 (m, 2 H, benzene), 7.38–7.42 (m,
2 H, benzene), 7.68–7.71 (m, 2 H, phthalimide), 7.80–7.85 (m, 2 H,
perature for an additional hour. The resulting solid was filtered off
and recrystallized from dry ethanol to give pure ω-carbinol lactam
phthalimide) ppm. 13C NMR (CDCl3): δ = 36.6 (CH2), 38.7 (CH2), in good to excellent yield. For oily products, the solution was ex-
123.5 (CHAr), 127.1 (CHAr), 128.5 (CHAr), 129.1 (CHAr), 132 (C), tracted with CH2Cl2 and the organic layer was washed with water,
134.2 (CHAr), 137.9 (C), 167.6 (C=O) ppm. MS (EI): m/z = 283
brine, dried with MgSO4, and concentrated in vacuo at room tem-
Eur. J. Org. Chem. 2005, 2758–2770
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2765

N. Hucher, A. Pesquet, P. Netchitaïlo, A. Daïch
FULL PAPER
perature to give the desired ω-carbinol lactam in pure form and
comparable yield to the solid.
solid in 98% yield after recrystallization from ethanol/water ac-
cording to the general procedure for the reduction. M.p. 135 °C.
IR: νmax = 1674, 1709 (C=O), 3325 (OH) cm–1. 1H NMR (CDCl3):
˜
2-(2-Bromophenylthiomethyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-
one (10b): This compound was isolated as a white solid in 89%
yield after recrystallization from ethanol according to the general
δ = 3.81 (s, 3 H, CH3), 4.28 (d, J = 9.9 Hz, 1 H, OH), 4.63 (d, J =
14.0 Hz, 1 H, CH2), 5.38 (d, J = 14.0 Hz, 1 H, CH2), 6.05 (d, J =
9.9 Hz, 1 H, CH), 7.17 (t, J = 7.3 Hz, 1 H, benzene), 7.36–7.41 (m,
2 H, benzene), 7.54–7.59 (m, 2 H, isoindole), 7.63–7.71 (m, 2 H,
isoindole), 7.85 (d, J = 7.1 Hz, 1 H, benzene) ppm. 13C NMR
(CDCl3): δ = 41.5 (CH2), 52.3 (CH3), 80.5 (CH), 123.4 (CHAr),
123.6 (CHAr), 125.4 (CHAr), 128.3 (CHAr), 129.0 (C), 129.9 (CHAr),
130.9 (C), 131.2 (CHAr), 132.7 (CHAr), 137.6 (C), 143.7 (C), 167.1
(C=O), 167.2 (C=O) ppm. MS (EI): m/z = 329 [M+]. C17H15NO4S
(329.38): calcd. C 61.99, H 4.59, N 4.25; found C 62.07, H 4.61, N
4.12.
procedure for the reduction. M.p. 159 °C. IR: ν
= 1702 (C=O),
˜
max
3341 (OH) cm–1. 1H NMR (CDCl3): δ = 3.42 (d, J = 11.3 Hz, 1 H,
OH), 4.53 (d, J = 14.0 Hz, 1 H, CH2), 5.23 (d, J = 14.0 Hz, 1 H,
CH2), 6.01 (d, J = 11.3 Hz, 1 H, CH), 7.00–7.12 (m, 1 H, benzene),
7.18–7.26 (m, 1 H, benzene), 7.50–7.54 (m, 6 H, benzene + isoin-
dole) ppm. 13C NMR (CDCl3): δ = 42.6 (CH2), 80.5 (CH), 123.6
(CHAr), 123.6 (CHAr), 125.5 (C), 128.1 (CHAr), 128.4 (CHAr), 130.0
(CHAr), 130.7 (C), 131.3 (CHAr), 132.9 (CHAr), 133.2 (CHAr), 134.8
(C), 143.6 (C), 166.9 (C=O) ppm. MS (EI): m/z = 350 [M+].
C15H12BrNO2S (350.24): calcd. C 51.44, H 3.45, N 4.00; found C
51.53, H 3.29, N 4.11.
3-Hydroxy-2-(phenylselenomethyl)-2,3-dihydro-1H-isoindol-1-one
[10 (X = Se)]: This compound was isolated as a yellow solid in 80%
yield after recrystallization from ethanol according to the general
2-(3-Chlorophenylthiomethyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-
one (10c): This compound was isolated as a white solid in 99%
yield after recrystallization from ethanol according to the general
procedure for the reduction. M.p. 112 °C. IR: ν
= 1678 (C=O),
˜
max
3290 (OH) cm–1. 1H NMR (CDCl3): δ = 3.97 (d, J = 11.8 Hz, 1 H,
OH), 4.54 (d, J = 12.1 Hz, 1 H, CH2–Se), 5.08 (d, J = 12.1 Hz, 1
H, CH2–Se), 5.85 (d, J = 11.8 Hz, 1 H, CH), 7.18–7.25 (m, 3 H,
benzene), 7.39–7.44 (m, 2 H, benzene), 7.48–7.61 (m, 4 H, isoin-
dole) ppm. 13C NMR (CDCl3): δ = 36.4 (CH2), 80.9 (CH), 123.3
(CHAr), 123.6 (CHAr), 127.8 (CHAr), 128.6 (C), 129.3 (CHAr), 129.8
(CHAr), 130.7 (C), 132.8 (CHAr), 133.8 (CHAr), 143.7 (C), 166.8
(C=O) ppm. MS (EI): m/z = 318 [M+]. C15H13NO2Se (318.24):
calcd. C 56.61, H 4.12, N 4.40; found C 56.49, H 4.09, N 4.22.
procedure for the reduction. M.p. 134 °C. IR: ν
= 1690 (C=O),
˜
max
3323 (OH) cm–1. 1H NMR (CDCl3): δ = 3.60 (d, J = 11.6 Hz, 1 H,
OH), 4.47 (d, J = 14.0 Hz, 1 H, CH2), 5.09 (d, J = 14.0 Hz, 1 H,
CH2), 5.93 (d, J = 11.6 Hz, 1 H, CH), 7.13–7.19 (m, 2 H, benzene),
7.23–7.29 (m, 2 H, benzene), 7.45–7.51 (m, 1 H, isoindole), 7.56–
7.62 (m, 3 H, isoindole) ppm. 13C NMR (CDCl3): δ = 43.0 (CH2),
80.4 (CH), 123.6 (CHAr), 123.7 (CHAr), 127.4 (CHAr), 128.5
(CHAr), 130.1 (CHAr), 130.2 (CHAr), 130.3 (CHAr), 130.6 (C), 133.0
(CHAr), 134.7 (C), 135.7 (C), 143.5 (C), 166.9 (C=O) ppm. MS
(EI): m/z = 305 [M+]. C15H12ClNO2S (305.79): calcd. C 58.92, H
3.96, N 4.58; found C 58.86, H 4.01, N 4.71.
3-Hydroxy-2-(2-naphthylthiomethyl)-2,3-dihydro-1H-isoindol-1-one
(16): This compound was isolated as a yellow solid in 99% yield
after recrystallization from ethanol/water according to the general
procedure for the reduction. M.p. 168 °C. IR: ν
= 1682 (C=O),
˜
max
3-Hydroxy-2-(3-methoxyphenylthiomethyl)-2,3-dihydro-1H-isoindol-
1-one (10d): This compound was isolated as a white solid in 81%
yield after recrystallization from ethanol according to the general
3302 (OH) cm–1. 1H NMR (CDCl3): δ = 3.15 (d, J = 11.3 Hz, 1 H,
OH), 4.63 (d, J = 14.0 Hz, 1 H, CH2), 5.31 (d, J = 14.0 Hz, 1 H,
CH2), 5.97 (d, J = 11.3 Hz, 1 H, CH), 7.39–7.75 (m, 10 H, isoindole
+ naphthalene), 7.87 (s, 1 H, naphthalene) ppm. 13C NMR
(CDCl3): δ = 42.9 (CH2), 80.5 (CH), 123.5 (CHAr), 123.6 (CHAr),
126.2 (CHAr), 126.6 (CHAr), 127.4 (CHAr), 127.7 (CHAr), 128.0
(CHAr), 128.8 (CHAr), 129.3 (CHAr), 129.9 (CHAr), 130.7 (C), 130.9
(C), 132.2 (C), 132.8 (CHAr), 133.6 (C), 143.6 (C), 166.9 (C=O)
ppm. MS (EI): m/z = 321 [M+]. C19H15NO2S (321.40): calcd. C
71.01, H 4.70, N 4.36; found C 70.89, H 4.65, N 4.41.
procedure for the reduction. M.p. 131 °C. IR: ν
= 1680 (C=O),
˜
max
1
3274 (OH) cm–1. H NMR (CDCl3): δ = 3.69 (s, 3 H, CH3), 3.75
(d, J = 11.0 Hz, 1 H, OH), 4.46 (d, J = 14.0 Hz, 1 H, CH2), 5.08
(d, J = 14.0 Hz, 1 H, CH2), 5.93 (d, J = 11.0 Hz, 1 H, CH), 6.69
(dd, J = 1.8 and 7.0 Hz, 1 H, benzene), 6.95 (dd, J = 1.8 and
7.0 Hz, 1 H, benzene), 6.96 (s, 1 H, benzene), 7.12 (t, J = 7.0 Hz,
1 H, benzene), 7.43–7.48 (m, 1 H, isoindole), 7.52–7.57 (m, 3 H,
isoindole) ppm. 13C NMR (CDCl3): δ = 42.8 (CH2), 55.3 (CH3),
80.5 (CH), 113.5 (CHAr), 115.2 (CHAr), 122.5 (CHAr), 123.4
(CHAr), 123.6 (CHAr), 129.8 (CHAr), 129.9 (CHAr), 130.7 (C), 132.8
(CHAr), 134.8 (C), 143.7 (C), 159.9 (C), 167.0 (C=O) ppm. MS
(EI): m/z = 301 [M+]. C16H15NO3S (301.37): calcd. C 63.77, H 5.02,
N 4.65; found C 63.68, H 4.93, N 4.72.
2-(Benzylthiomethyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one
(22h): This compound was isolated as a white solid in 90% yield
after recrystallization from ethanol according to the general pro-
cedure for the reduction. M.p. 120 °C. IR: ν
= 1686 (C=O),
˜
max
3264 (OH) cm–1. 1H NMR (CDCl3): δ = 3.63 (d, J = 13.7 Hz, 1 H,
S-CH2), 3.74 (d, J = 13.7 Hz, 1 H, S-CH2), 3.87 (d, J = 11.0 Hz, 1
H, OH), 4.07 (d, J = 14.2 Hz, 1 H, N-CH2-S), 4.71 (d, J = 14.2 Hz,
1 H, N-CH2-S), 5.87 (d, J = 11.0 Hz, 1 H, CH), 7.08–7.29 (m, 5
H, benzene), 7.36–7.40 (m, 1 H, isoindole), 7.50–7.56 (m, 3 H, iso-
indole) ppm. 13C NMR (CDCl3): δ = 35.9 (CH2), 40.8 (CH2), 80.3
(CH), 123.3 (CHAr), 123.5 (CHAr), 126.9 (CHAr), 128.4 (CHAr),
128.8 (CHAr), 129.8 (CHAr), 130.7 (C), 132.7 (CHAr), 138.0 (C),
143.7 (C), 167.5 (C=O) ppm. MS (EI): m/z = 285 [M+ ].
C16H15NO2S (285.37): calcd. C 67.34, H 5.30, N 4.91; found C
67.43, H 5.25, N 4.78.
3-Hydroxy-2-(4-methoxyphenylthiomethyl)-2,3-dihydro-1H-isoindol-
1-one (10e): This compound was isolated as a white solid in 98%
yield after recrystallization from ethanol according to the general
procedure for the reduction. M.p. 125 °C. IR: ν
= 1680 (C=O),
˜
max
3340 (OH) cm–1. H NMR (CDCl3): δ = 3.70 (s, 3 H, OMe), 4.05
(d, J = 11.0 Hz, 1 H, OH), 4.32 (d, J = 13.7 Hz, 1 H, CH2), 4.87
(d, J = 13.7 Hz, 1 H, CH2), 4.90 (d, J = 11.0 Hz, 1 H, CH), 6.72
(d, J = 8.9 Hz, 2 H, benzene), 7.27 (d, J = 8.9 Hz, 2 H, benzene),
7.45–7.48 (m, 2 H, isoindole), 7.53–7.59 (m, 2 H, isoindole) ppm.
13C NMR (CDCl3): δ = 45.0 (CH2), 55.3 (CH3), 80.5 (CH), 114.8
(CHAr), 123.5 (CHAr), 123.58 (CHAr), 123.6 (C), 130.0 (CHAr),
130.9 (C), 132.7 (CHAr), 134.5 (CHAr), 143.5 (C), 159.7 (C), 166.6
(C=O) ppm. MS (EI): m/z = 301 [M+]. C16H15NO3S (301.37):
calcd. C 63.77, H 5.02, N 4.65; found C 63.43, H 5.15, N 4.81.
1
3-Hydroxy-2-(2-phenethylthiomethyl)-2,3-dihydro-1H-isoindol-1-one
(22i): This compound was isolated as a yellow oil in 82% yield after
filtration through a short celite column according to the general
procedure for the reduction. IR: ν
= 1673 (C=O), 3318 (OH)
˜
max
3-Hydroxy-2-[2-(methoxycarbonyl)phenylthiomethyl]-2,3-dihydro-
cm–1. 1H NMR (CDCl3): δ = 2.56–2.98 (m, 4 H, S-CH2-CH2), 4.08
1H-isoindol-1-one (10f): This compound was isolated as a yellow
(d, J = 14.0 Hz, 1 H, N-CH2-S), 4.75 (d, J = 14.0 Hz, 1 H, N-CH2-
2766
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2758–2770

Exocyclic–Endocyclic N-Acyliminium Ion Equilibration
FULL PAPER
S), 5.91 (s, 1 H, CH), 7.12–7.17 (m, 5 H, benzene), 7.40–7.47 (m,
1 H, isoindole), 7.54–7.59 (m, 3 H, isoindole) ppm. 13C NMR
tallized from a mixture of ethanol/water to give the cyclized pro-
duct 11f in pure form in a similar yield to that obtained with
(CDCl3): δ = 31.6 (CH2), 35.2 (CH2), 40.5 (CH2), 80.7 (CH), 122.3 method A. The minor product 12f has never been isolated but its
(CHAr), 122.8 (CHAr), 124.7 (CHAr), 127.3 (CHAr), 127.5 (CHAr), 1H NMR spectrum was deduced from that of the mixture.
128.0 (CH), 129.6 (C), 132.2 (CHAr), 138.9 (C), 142.9 (C), 166.6
4-Bromo-6,12b-dihydroisoindolo[2,1-c][1,3]benzothiazin-8-one (11b):
(C=O) ppm. MS (EI): m/z = 299 [M+]. C17H17NO2S (299.39):
This compound was isolated as a white solid in 95% yield after
calcd. C 68.20, H 5.72, N 4.68; found C 68.00, H 5.39, N 4.49.
recrystallization from ethanol according to the general procedure
1
= 1715 (C=O) cm–1. H
3-Hydroxy-2-[(2-phenylthio)ethyl]-2,3-dihydro-1H-isoindol-1-one
(22j): This compound was isolated as a yellow solid in 91% yield
after recrystallization from diethyl ether/hexane according to the
for the cyclization. M.p. 185 °C. IR: ν
˜
max
NMR (CDCl3): δ = 4.55 (d, J = 12.4 Hz, 1 H, CH2), 5.37 (d, J =
12.4 Hz, 1 H, CH2), 5.85 (s, 1 H, CH), 7.07–7.11 (m, 1 H, benzene),
7.41–7.46 (m, 2 H, benzene), 7.59–7.66 (m, 2 H, isoindole), 7.69–
7.76 (m, 1 H, isoindole), 7.79–7.86 (m, 1 H, isoindole) ppm. 13C
NMR (CDCl3): δ = 41.4 (CH2), 59.5 (CH), 123.4 (CHAr), 123.9
(C), 124.2 (CHAr), 126.0 (CHAr), 126.3 (CHAr), 129.0 (CHAr), 131.6
(CHAr), 131.8 (C), 132.5 (CHAr), 133.6 (C), 134.1 (C), 143.9 (C),
167.9 (CO) ppm. MS (EI): m/z = 332 [M+]. C15H10BrNOS (332.22):
calcd. C 54.23, H 3.03, N 4.22; found C 54.06, H 3.01, N 3.97.
general procedure for the reduction. M.p. Ͻ30 °C. IR: νmax = 1674
˜
(C=O), 3325 (OH) cm–1. 1H NMR (CDCl3): δ = 3.08 (t, J = 7.0 Hz,
2 H, N-CH2), 3.49 (t, J = 7.0 Hz, 2 H, S-CH2), 5.73 (s, 1 H, CH),
7.09–7.39 (m, 5 H, benzene), 7.44–7.54 (m, 4 H, isoindole) ppm.
13C NMR (CDCl3): δ = 31.9 (CH2), 39.1 (CH2), 82.5 (CH), 123.3
(CHAr), 123.5 (CHAr), 126.4 (CHAr), 129.1 (CHAr), 129.9 (CHAr),
131.1 (CHAr), 132.5 (C), 135.1 (CHAr), 144.0 (C), 167.8 (C=O)
ppm. MS (EI): m/z = 285 [M+]. C16H15NO2S (285.37): calcd. C
67.34, H 5.30, N 4.91; found C 67.09, H 5.19, N 4.69.
1-Chloro-6,12b-dihydroisoindolo[2,1-c][1,3]benzothiazin-8-one
(11cx), 4-Chloro-5,11b-dihydroisoindolo[1,2-b][1,3]benzothiazin-8-
one (12cx), 3-Chloro-6,12b-dihydroisoindolo[2,1-c][1,3]-benzothia-
zin-8-one (11cy), and 2-Chloro-5,11b-dihydroisoindolo[1,2-
b][1,3]benzothiazin-8-one (12cy): These products were separated by
chromatography on a silica gel column into two parts, each con-
taining an inseparable mixture of two positional isomers 11cx/12cx
and 11cy/12cy (89% yield) in a 5.5:4.5 ratio according to the gene-
ral procedure for the cyclization; they were characterized by 1H
NMR spectroscopy and GC-MS analysis.
2-(2-Benzylthioethyl)-3-hydroxy-2,3-dihydro-1H-isoindol-1-one
(22k): This compound was isolated as a yellow oil in 83% yield
after a short celite column filtration according to the general pro-
cedure for the reduction. IR: νmax = 1671 (C=O), 3316 (OH) cm–1.
˜
1H NMR (CDCl3): δ = 2.66 (t, J = 6.7 Hz, 2 H, N-CH2-C), 3.41–
3.85 (m, 4 H, S-CH2-C and S-CH2), 5.90 (s, 1 H, CH), 7.14–7.75
(m, 9 H, benzene + isoindole) ppm. 13C NMR (CDCl3): δ = 34.7
(CH2), 36.2 (CH2), 40.5 (CH2), 79.7 (CH), 121.3 (CHAr), 123.2
(CHAr), 124.2 (CHAr), 126.8 (CHAr), 127.0 (CHAr), 127.9 (CH),
128.9 (C), 133.2 (CHAr), 138.5 (C), 142.5 (C), 167.4 (C=O) ppm.
MS (EI): m/z = 299 [M+]. C17H17NO2S (299.39): calcd. C 68.20, H
5.72, N 4.68; found C 67.96, H 5.32, N 4.51.
Major Product 11cx of the Isomeric Couple 11cx/12cx: 1H NMR
(CDCl3): δ = 4.60 (d, J = 12.4 Hz, 1 H, CH2), 5.30 (d, J = 12.4 Hz,
1 H, CH2), 5.79 (s, 1 H, CH), 7.08–7.26 (m, 2 H, benzene), 7.45–
7.62 (m, 3 H, isoindole), 7.75 (d, J = 7.9 Hz, 1 H, benzene), 7.91
(t, J = 7.6 and 7.9 Hz, 1 H, isoindole) ppm.
5-Hydroxy-1-(phenylthiomethyl)pyrrolidin-2-one (24): This com-
pound was isolated as a yellow oil in 93% yield according to the
Minor Product 12cx of the Isomeric Couple 11cx/12cx: 1H NMR
(CDCl3): δ = 4.55 (d, J = 17.5 Hz, 1 H, CH2), 5.27 (d, J = 17.5 Hz,
1 H, CH2), 5.81 (s, 1 H, CH), 7.08–7.26 (m, 2 H, benzene), 7.45–
7.62 (m, 3 H, isoindole), 7.75 (d, J = 7.9 Hz, 1 H, benzene), 7.91
(t, J = 7.6 and 7.9 Hz, 1 H, isoindole) ppm.
general procedure for the reduction. IR: ν
= 1674 (C=O), 3325
˜
max
(OH) cm–1. H NMR (CDCl3): δ = 1.66–2.29 (m, 4 H, pyrrolidin-
one), 4.37 (d, J = 14.0 Hz, 1 H, CH2), 4.74 (d, J = 6.0 Hz, 1 H,
OH), 5.13 (d, J = 14.0 Hz, 1 H, CH2), 5.35–5.41 (m, 1 H, CH),
1
7.19–5.28 (m, 3 H, benzene), 7.37–5.45 (m, 2 H, benzene) ppm. 13
C
NMR (CDCl3): δ = 28.4 (CH2), 29.2 (CH2), 43.7 (CH2), 113.7
(CH), 127.9 (CH), 128.1 (CH), 129.0 (CH), 136.8 (C), 175.1 (C=O)
ppm. MS (EI): m/z = 223 [M+]. C11H13NO2S (223.30): calcd. C
59.17, H 5.87, N 6.27; found C 59.02, H 5.38, N 6.12.
Major Product 11cy of the Isomeric Couple 11cy/12cy: 1H NMR
(CDCl3): δ = 4.30 (d, J = 12.1 Hz, 1 H, CH2), 5.49 (d, J = 12.1 Hz,
1 H, CH2), 6.45 (s, 1 H, CH), 7.00–7.15 (m, 1 H, benzene), 7.25–
7.35 (m, 1 H, benzene), 7.40–7.67 (m, 3 H, isoindole), 7.75–7.90
(m, 1 H, benzene), 8.05 (d, J = 7.9 Hz, 1 H, isoindole) ppm.
General Procedure for Cyclization of Hydroxy Lactams. Method A:
Neat TFA (20 mL) was added to a stirred solution of the hydroxy
lactam (10 mmol), obtained by standard borohydride reduction of
the imide as indicated above. After 2–3 h of reaction at room tem-
perature whilst stirring, the reaction mixture was diluted with water
(45 mL) and neutralized on cooling with 5% NaOH aqueous solu-
tion. The solution was extracted twice with CH2Cl2 (25 mL) and
separated. The organic layer was washed with water, brine, sepa-
rated, dried with MgSO4, and the solvents evaporated in vacuo.
The resulting crude residue was purified by chromatography [SiO2,
CH2Cl2/hexane (4:1)] or recrystallized from the indicated solvent
to give the tricyclic product.
Minor Product 12cy of the Isomeric Couple 11cy/12cy: 1H NMR
(CDCl3): δ = 4.55 (d, J = 18.5 Hz, 1 H, CH2), 5.45 (d, J = 18.5 Hz,
1 H, CH2), 5.79 (s, 1 H, CH), 7.00–7.15 (m, 1 H, benzene), 7.25–
7.35 (m, 1 H, benzene), 7.40–7.67 (m, 3 H, isoindole), 7.75–7.90
(m, 1 H, benzene), 8.05 (d, J = 7.9 Hz, 1 H, isoindole) ppm. MS
(EI) (mixture): m/z = 287 [M+].
1-Methoxy-6,12b-dihydroisoindolo[2,1-c][1,3]benzothiazin-8-one
(11dx) and 3-Methoxy-6,12b-dihydroisoindolo[2,1-c][1,3]benzothia-
zin-8-one (11dy): These products were obtained as an inseparable
mixture of two isomers (8% yield) in a 9:1 ratio according to the
general procedure for the cyclization and were characterized by 1H
NMR spectroscopy and GC-MS analysis.
Method B (for the hydroxy lactam 10f only): Lewis acid (SbCl3,
BF3·Et2O, or SnCl4; 2 equiv.) was added in three portions to a
stirred and cold (ice bath) solution of hydroxy lactam 10f
(10 mmol) in 15 mL of dry CH2Cl2. After complete addition the
mixture was allowed to react at ambient temperature for 24–240 h.
After hydrolysis on cooling with 10% NaOH solution and separa-
tion, the organic layer was separated, washed with brine, dried with
MgSO4, and concentrated in vacuo. The crude solid was recrys-
Major Isomer 11dx: 1H NMR (CDCl3): δ = 3.74 (s, 3 H, CH3),
4.61 (d, J = 12.4 Hz, 1 H, CH2), 5.29 (d, J = 12.4 Hz, 1 H, CH2),
5.80 (s, 1 H, CH), 7.48–7.89 (m, 7 H, benzene + isoindole) ppm.
Minor Isomer 11dy: 1H NMR (CDCl3): δ = 4.03 (s, 3 H, CH3), 4.37
(d, J = 12.4 Hz, 1 H, CH2), 5.44 (d, J = 12.4 Hz, 1 H, CH2), 6.29
Eur. J. Org. Chem. 2005, 2758–2770
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2767

N. Hucher, A. Pesquet, P. Netchitaïlo, A. Daïch
FULL PAPER
(s, 1 H, CH), 7.48–7.89 (m, 7 H, benzene + isoindole) ppm. MS
5,6,8,14b-Tetrahydroisoindolo[2,1-e][3,5]benzothiazocin-10-one (11i):
This product was obtained as a mixture (11i:12i, 8:1, 72% yield)
according to the general cyclization protocol. It was isolated in
pure form as a white solid after recrystallization from ethanol. M.p.
(EI) (mixture): m/z = 283 [M+].
2-Methoxy-6,12b-dihydroisoindolo[2,1-c][1,3]benzothiazin-8-one
(11e): This compound was isolated as a white solid in 19% yield
after recrystallization from ethanol according to the general pro-
215 °C. IR: νmax = 1704 (C=O) cm–1. 1H NMR (CDCl3): δ = 2.77–
˜
2.95 (m, 1 H, S–CH2–C), 3.07–3.32 (m, 3 H, S–CH2–C), 4.50 (d, J
= 13.7 Hz, 1 H, N-CH2-S), 4.97 (s, 1 H, CH), 5.25 (d, J = 13.7 Hz,
1 H, N-CH2-S), 7.09–7.25 (m, 4 H, benzene), 7.39–7.49 (m, 3 H,
isoindole), 7.74 (d, J = 8.1 Hz, 1 H, isoindole) ppm. 13C NMR
(CDCl3): δ = 35.4 (CH2), 37.0 (CH2), 40.8 (CH2), 64.7 (CH), 123.0
(CHAr), 123.9 (CHAr), 127.5 (CHAr), 128.7 (2CHAr), 130.0 (CHAr),
130.9 (CHAr), 131.3 (C), 131.4 (CHAr), 134.0 (C), 139.5 (C), 142.2
(C), 165.5 (CO) ppm. MS (EI): m/z = 281 [M+]. C17H15NOS
(281.38): calcd. C 72.57, H 5.37, N 4.98; found C 72.49, H 5.41, N
5.02.
cedure for the cyclization. M.p. 171 °C. IR: ν
= 1697 (C=O)
˜
max
cm–1. 1H NMR (CDCl3): δ = 3.65 (s, 3 H, CH3), 4.52 (d, J =
12.4 Hz, 1 H, CH2), 5.35 (d, J = 12.4 Hz, 1 H, CH2), 5.84 (s, 1 H,
CH), 7.07 (s, 1 H, benzene), 7.40–7.45 (m, 2 H, benzene), 7.59–
7.65 (m, 2 H, isoindole), 7.70–7.76 (m, 1 H, isoindole), 7.78–7.84
(m, 1 H, isoindole) ppm. 13C NMR (CDCl3): δ = 39.9 (CH2), 82.0
(CH), 114.8 (C), 119.2 (CHAr), 121.2 (C), 123.7 (CHAr), 123.8
(CHAr), 129.9 (CHAr), 130.3 (CHAr), 131.3 (CHAr), 132.3 (C), 132.4
(CHAr), 140.5 (C), 151.1 (C), 167.5 (CO) ppm. MS (EI): m/z = 283
[M+]. C16H13NO2S (283.35): calcd. C 67.82, H 4.62, N 4.94; found
C 67.78, H 4.60, N 4.91.
5,11b,13,14-Tetrahydroisoindolo[1,2-d][3,5]benzothiazocin-7-one
1
(12i): This product was not isolated in pure form but its H NMR
Methyl 8-Oxo-6,12b-dihydroisoindolo[2,1-c][1,3]benzothiazin-4-car-
boxylate (11f): This compound was isolated as a white solid in 94%
yield after recrystallization from ethanol/water according to the ge-
spectroscopic data were deduced from the 1H NMR spectrum of
the mixture. 1H NMR (CDCl3): δ = 2.71–3.02 (m, 4 H, S-CH2-
CH2), 4.20 (d, J = 13.7 Hz, 1 H, N-CH2), 5.33 (d, J = 13.7 Hz, 1
H, N-CH2), 5.68 (s, 1 H, CH), 7.10–7.27 (m, 4 H, benzene), 7.44–
7.73 (m, 3 H, isoindole), 7.87–8.83 (m, 1 H, isoindole) ppm. MS
(EI) (mixture): m/z = 281 [M+].
neral procedure for the cyclization. M.p. 196 °C. IR: ν
= 1702,
˜
max
1703 (C=O) cm–1. 1H NMR (CDCl3): δ = 3.85 (s, 3 H, OCH3),
4.42 (d, J = 12.4 Hz, 1 H, CH2), 5.37 (d, J = 12.4 Hz, 1 H, CH2),
5.86 (s, 1 H, CH), 7.38–7.44 (m, 1 H, benzene), 7.51–7.55 (m, 2 H,
benzene), 7.67–7.72 (m, 2 H, isoindole), 7.80–7.86 (m, 2 H, isoin-
dole) ppm. 13C NMR (CDCl3): δ = 41.4 (CH2), 52.3 (CH3), 59.9
(CH), 123.4 (CHAr), 124.1 (CHAr), 124.9 (CHAr), 128.9 (CHAr),
129.9 (C), 130.2 (CHAr), 130.9 (CHAr), 132.2 (CHAr), 132.3 (C),
133.3 (C), 136.7 (C), 143.7 (C), 166.2 (CO), 168.0 (CO) ppm. MS
(EI): m/z = 311 [M+]. C17H13NO3S (311.36): calcd. C 65.58, H 4.21,
N 4.50; found C 65.66, H 4.00, N 4.67.
6,7-Dihydroisoindolo[2,1-d][1,4]benzothiazepin-9(13bH)-one (11j):
This compound was isolated as a yellow solid in 95% yield after
recrystallization from ethanol according to the general procedure
1
for the cyclization. M.p. 200 °C. IR: ν
= 1702 (C=O) cm–1. H
˜
max
NMR (CDCl3): δ = 2.92–3.25 (m, 2 H, N-CH2-CH2), 3.82–4.15
(m, 2 H, S-CH2-CH2), 6.20 (s, 1 H, CH), 6.86–6.92 (m, 1 H, ben-
zene), 7.15–7.27 (m, 2 H, benzene), 7.39–7.64 (m, 4 H, benzene +
isoindole), 7.91 (d, J = 7.8 Hz, 1 H, isoindole) ppm. 13C NMR
(CDCl3): δ = 32.7 (CH2), 42.7 (CH2), 63.6 (CH), 124.2 (CHAr),
124.3 (CHAr), 127.4 (CHAr), 128.6 (CHAr), 128.7 (CHAr), 128.8
(CHAr), 131.5 (CHAr), 132.8 (C), 134.0 (CHAr), 136.1 (C), 139.2
(C), 143.4 (C), 168.8 (CO) ppm. MS (EI): m/z = 267 [M+].
C16H13NOS (267.35): calcd. C 71.88, H 4.90, N 5.24; found C
71.93, H 4.94, N 5.27.
Methyl 7-Oxo-5,11b-dihydroisoindolo[1,2-b][1,3]benzothiazin-1-car-
boxylate (12f): This product was not isolated in pure form but its
1H NMR spectroscopic data were deduced from the 1H NMR spec-
1
trum of the mixture. H NMR (CDCl3): δ = 3.91 (s, 3 H, OCH3),
4.73 (d, J = 14.1 Hz, 1 H, S-CH2), 5.82 (d, J = 14.1 Hz, 1 H, S-
CH2), 6.81 (s, 3 H, CH), 7.11–7.23 (m, 4 H, benzene), 7.37–7.78
(m, 3 H, isoindole), 7.81–7.89 (m, 1 H, isoindole) ppm. MS (EI)
(mixture): m/z = 311 [M+].
6,12b-Dihydroisoindolo[2,1-c][1,3]benzoselenazin-8-one [11 (X =
Se)]: This compound was isolated as a yellow solid in 91% yield
after recrystallization from ethanol according to the general pro-
5,7-Dihydroisoindolo[2,1-d][2,4]benzothiazepin-9(13bH)-one (11h):
This product was obtained as a mixture (11h:12h, 9.5:0.5, 94 %
yield) according to the general cyclization protocol. It was isolated
in pure form as a white solid after recrystallization from ethanol.
cedure for the cyclization. M.p. 175 °C. IR: ν
= 1703 (C=O)
˜
max
cm–1. 1H NMR (CDCl3): δ = 4.54 (d, J = 16.9 Hz, 1 H, CH2), 5.27
(d, J = 16.9 Hz, 1 H, CH2), 6.12 (s, 1 H, CH), 7.14–7.36 (m, 4 H,
benzene), 7.47–7.72 (m, 3 H, isoindole), 7.89 (d, J = 7.3 Hz, 1 H,
isoindole) ppm. 13C NMR (CDCl3): δ = 44.1 (CH2), 52.1 (CH),
122.6 (CHAr), 124.1 (CHAr), 126.6 (CHAr), 126.7 (C), 127.8 (CHAr),
128.9 (CHAr), 129.1 (CHAr), 130.4 (CHAr), 131.1 (C), 131.3 (C),
132.1 (CHAr), 143.8 (C), 166.9(CO) ppm. MS (EI): m/z = 300 [M+].
C15H11NOSe (300.22): calcd. C 60.01, H 3.69, N 4.67; found C
60.09, H 3.72, N 4.69.
M.p. 209 °C. IR: νmax = 1703 (C=O) cm–1. 1H NMR (CDCl3): δ =
˜
3.78 (d, J = 15.0 Hz, 1 H, S-CH2), 4.23 (d, J = 15.0 Hz, 1 H, S-
CH2), 4.59 (d, J = 15.1 Hz, 1 H, N-CH2-S), 5.22 (d, J = 15.1 Hz,
1 H, N-CH2-S), 5.90 (s, 1 H, CH), 7.11–7.23 (m, 4 H, benzene),
7.37–7.48 (m, 3 H, isoindole), 7.81–7.89 (m, 1 H, isoindole) ppm.
13C NMR (CDCl3): δ = 34.1 (CH2), 46.0 (CH2), 65.3 (CH), 122.5
(CHAr), 123.8 (CHAr), 127.9 (CHAr), 128.3 (CHAr), 128.6 (CHAr),
129.2 (CHAr), 130.3 (CHAr), 131.8 (C), 131.9 (CHAr), 135.4 (C),
139.8 (C), 142.2 (C), 166.6 (CO) ppm. MS (EI): m/z = 267 [M+].
C16H13NOS (267.35): calcd. C 71.88, H 4.90, N 5.24; found C
71.66, H 4.79, N 5.11.
Pyrrolidino[2,1-c][1,3]benzothiazin-8-one (25) and Pyrrolidino[2,1-
d][1,3]benzothiazin-7-one (26): These products were obtained as an
inseparable mixture (67% yield) in a 3:2 ratio according to the ge-
neral procedure for the cyclization and were characterized by 1H
NMR spectroscopy and GC-MS analysis.
5,13-Dihydroisoindolo[1,2-c][2,4]benzothiazepin-7(11bH)-one (12h):
1
This product was not isolated in pure form but its H NMR spec-
Major Isomer 25: 1.85–2.03 (m, 1 H, pyrrolidine), 2.38–2.72 (m, 3
H, pyrrolidine), 4.30 (d, J = 11.6 Hz, 1 H, N-CH2), 4.86 (m, 1 H,
troscopic data were deduced from the 1H NMR spectrum of the
mixture. 1H NMR (CDCl3): δ = 3.70 (d, J = 15.5 Hz, 1 H, S-CH2), CH), 5.04 (d, J = 11.6 Hz, 1 H, N-CH2), 7.07–7.11 (m, 4 H, ben-
4.19 (d, J = 15.5 Hz, 1 H, S-CH2), 4.68 (d, J = 16.3 Hz, 1 H, N-
CH2-S), 5.26 (d, J = 16.3 Hz, 1 H, N-CH2-S), 6.12 (s, 1 H, CH),
7.11–7.23 (m, 4 H, benzene), 7.37–7.78 (m, 3 H, isoindole), 7.81–
7.89 (m, 1 H, isoindole) ppm. MS (EI) (mixture): m/z = 267 [M+].
zene) ppm. MS (EI) (mixture of 25 and 26): m/z = 205 [M+].
Minor Isomer 26: This product was obtained as the sole reaction
product from the hydroxy lactam 1 by the direct thiocyclization.
1
M.p. 68 °C (dry ethanol). IR: ν
= 1698 (C=O) cm–1. H NMR
˜
max
2768
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Eur. J. Org. Chem. 2005, 2758–2770

Exocyclic–Endocyclic N-Acyliminium Ion Equilibration
(CDCl3): δ = 1.85–2.05 (m, 1 H, pyrrolidine), 2.35–2.70 (m, 3 H, zene), 7.69–7.77 (m, 2 H, isoindole), 7.83–7.91 (m, 2 H, isoindole)
FULL PAPER
pyrrolidine), 4.23 (d, J = 17.0 Hz, 1 H, N-CH2), 4.85–4.92 (m, 1
H, CH), 5.04 (d, J = 17.0 Hz, 1 H, N-CH2), 7.06–7.20 (m, 4 H,
benzene) ppm. 13C NMR (CDCl3): δ = 28.7 (CH2), 28.9 (CH2),
46.8 (CH2), 62.9 (CH), 126.0 (CHAr), 126.7 (CHAr), 127.9 (CHAr),
ppm. 13C NMR (CDCl3): δ = 43.4 (CH2), 58.2 (CH), 122.4 (CHAr),
123.5 (CHAr), 124.3 (CHAr), 127.2 (CHAr), 130.1 (C), 130.2 (CHAr),
131.5 (CHAr), 132.1 (CHAr), 132.4 (C), 133.6 (C), 136.9 (C), 143.3
(C), 166.6 (CO), 171.1 (CO) ppm. MS (EI): m/z = 253 [M+ – CO2].
127.3 (CHAr), 136.2 (C), 137.2 (C), 171.9 (CO) ppm. MS (EI): C16H11NO3S (297.05): calcd. C 64.63, H 3.73, N 4.71; found C
m/z = 205 [M+]. C11H11NOS (205.28): calcd. C 64.36, H 5.40, N 64.19, H 3.55, N 4.67.
6.82; found C 64.15, H 5.22, N 6.69.
Copper/Quinoline Decarboxylation of Tricyclic Acid 20 into 11a: Fi-
nely powdered copper (0.2 g) was added to a stirred solution of
tricyclic benzothiazine acid 20 (1 g, 3.37 mmol) in 20 mL of freshly
distilled quinoline. The mixture was allowed to react whilst heating
5,11b-Dihydrothieno[3Ј,2Ј:5,6]thiazino[4,3-a]isoindol-7-one (17) and
4,10b-Dihydrothieno[2Ј,3Ј:5,6]thiazino[2,3-a]isoindol-6-one (18):
These products were obtained as a mixture (87% yield) in a 9:1
ratio according to the general procedure for the cyclization and
at 150 °C for 3.5 h. After cooling, the solution was diluted with a
were characterized by 1H NMR spectroscopy and GC-MS analysis.
mixture of water/CH2Cl2 (1:1, 60 mL) and acidified carefully with
Major Isomer 17: This compound was isolated in pure form by
fractional crystallization from dry ethanol and has identical charac-
teristics to those reported previously.[15] M.p. 168 °C (166 °C from
ref.[15]) ppm. 13C NMR (CDCl3): δ = 40.2 (CH2), 58.1 (CH), 123.4
(CHAr), 124.2 (CHAr), 124.3 (CHAr), 125.6 (C), 126.3 (C), 126.6
(CHAr), 129.1 (CHAr), 131.2 (C), 132.7 (CHAr), 143.9 (C), 167.5
(CO) ppm. MS (EI): m/z = 259 [M+]. C13H9NOS2 (259.01): calcd.
C 60.20, H 3.50, N 5.40; found C 60.42, H 3.22, N 5.29.
10% HCl solution. After decantation and separation, the organic
layer was dried with MgSO4, filtered and concentrated under re-
duced pressure to give 11a in 78% yield. This product is identical
to that described in our earlier paper.[4] 13C NMR (CDCl3): δ =
41.3 (CH2), 59.6 (CH), 123.6 (CHAr), 124.1 (CHAr), 124.9 (CHAr),
126.1 (CHAr), 127.0 (CHAr), 127.6 (CHAr), 128.8 (CHAr), 129.4
(CHAr), 131.8 (C), 132.0 (C), 132.2 (CHAr), 132.4 (C), 144.0 (C),
167.9 (CO) ppm. MS (EI): m/z = 253 [M+]. C15H11NOS (253.06):
calcd. C 71.12, H 4.38, N 5.53; found C 71.03, H 4.25, N 5.42.
Minor Isomer 18: The NMR characteristics of this product were
1
extracted from the spectra of the mixture. H NMR (CDCl3): δ =
m-CPBA Oxidation of the Mixture of Pyrrolidino[1,3]benzothiazines
25 and 26: m-Chloroperbenzoic acid (86% pure, 1 g, 5.35 mmol) in
dry CH2Cl2 was added portionwise, over a period of 5 min, with
vigorous stirring to a cold solution (–5 to 0 °C) of the mixture of
thiazines 25 and 26 (500 mg, 2.43 mmol) in dry CH2Cl2 (20 mL).
After 10 min of reaction at this temperature the mixture was al-
lowed to stir for an additional hour at ambient temperature. The
reaction was hydrolyzed carefully with a saturated solution of
NaHCO3 and separated. The organic layer was washed with brine,
dried with MgSO4, and concentrated under reduced pressure to
give, in quantitative yield, 27 and 28 in a 3:2 ratio. Recrystallization
of the residue from dry CH2Cl2 or dry ethanol afforded pure sul-
fone 27. Sulfone 28 was isolated in pure form from the mother
liquor after concentration in vacuo and recrystallization from a
mixture of CH2Cl2 and hexane (3:2).
4.63 (d, J = 17.2 Hz, 1 H, N-CH2), 5.48 (d, J = 17.2 Hz, 1 H, N-
CH2), 5.89 (s, 1 H, CH), 6.81 (d, J = 5.6 Hz, 1 H, Hβ-thiophene), 7.31
(d, J = 5.6 Hz, 1 H, Hα-thiophene), 7.31 (dd, J = 7.0 Hz, 1 H, ben-
zene), 7.64 (dt, J = 1.6, 7.0 and 7.8 Hz, 1 H, benzene), 7.77 (d, J
= 7.8 Hz, 1 H, benzene), 7.88 (d, J = 7.0 Hz, 1 H, benzene) ppm.
13C NMR (CDCl3): δ = 39.6 (CH2), 58.5 (CH), 122.7 (CHAr), 124.2
(CHAr), 124.3 (CHAr), 124.6 (CHAr), 125.9 (C), 126.1 (C), 129.6
(CHAr), 132.1 (C), 132.3 (CHAr), 145.1 (C), 167.0 (CO) ppm. MS
(EI): m/z = 259 [M+].
8,14b-Dihydroisoindolo[2,1-c]naphtho[1,2-e][1,3]thiazin-10-one (19):
This compound was isolated as a white solid in 96% yield after
recrystallization from ethanol according to the general procedure
1
for the cyclization. M.p. 196 °C. IR: ν
= 1716 (C=O) cm–1. H
˜
max
NMR (CDCl3): δ = 4.46 (d, J = 12.4 Hz, 1 H, CH2), 5.54 (d, J =
12.4 Hz, 1 H, CH2), 6.82 (s, 1 H, CH), 7.21 (d, J = 8.6 Hz, 1 H,
naphthalene), 7.35–7.41 (m, 2 H, naphthalene), 7.58–7.63 (m, 4 H,
naphthalene + isoindole), 7.81–7.85 (m, 2 H, isoindole), 8.32–8.39
(m, 1 H, isoindole) ppm. 13C NMR (CDCl3): δ = 42.7 (CH2), 58.1
(CH), 123.0 (CHAr), 124.0 (CHAr), 124.2 (CHAr), 124.6 (CHAr),
125.6 (C), 126.7 (CHAr), 127.4 (CHAr), 127.9 (CHAr), 128.8 (CHAr),
129.2 (CHAr), 131.8 (CHAr), 132.2 (C), 132.3 (C), 132.5 (C), 132.8
(CHAr), 145.1 (C), 169.7 (CO) ppm. MS (EI): m/z = 303 [M+].
C19H13NOS (303.39): calcd. C 75.22, H 4.32, N 4.62; found C
75.13, H 4.27, N 4.71.
Pyrrolidino[2,1-d][1,3]benzothiazin-7-one S,S-Dioxide (27): This
product was obtained as a white solid after recrystallization from
ethanol. M.p. 193 °C (decomposition). IR: ν
= 1709 (C=O)
˜
max
cm–1. H NMR (CDCl3/[D6]DMSO, 1:1): δ = 1.52–1.87 (m, 4 H,
pyrrolidine), 3.92 (d, J = 14.0 Hz, 1 H, N-CH2), 4.35 (t, J = 8.6 Hz,
1 H, CH), 4.53 (d, J = 14.0 Hz, 1 H, N-CH2), 6.61–6.88 (m, 4 H,
benzene) ppm. 13C NMR (CDCl3/[D6]DMSO, 1:1): δ = 25.9 (CH2),
28.5 (CH2), 54.5 (CH), 56.8 (CH2), 121.4 (CHAr), 124.7 (CHAr),
126.4 (CHAr), 131.4 (CHAr), 135.4 (C), 137.1 (C), 171.5 (CO) ppm.
MS (EI): m/z = 239 [M+]. C11H13NO3S (239.30): calcd. C 55.21, H
5.48, N 5.85; found C 55.03, H 5.72, N 5.57.
1
6,12b-Dihydro-8-oxoisoindolo[2,1-c][1,3]benzothiazin-4-carboxylic
Acid (20): A mixture of isoindolobenzothiazino ester 11f (1 g,
3.21 mmol), potassium carbonate (1.04 g, 7.5 mmol), water (5 mL),
and methanol (25 mL) was stirred under reflux for 3 h. After cool-
ing, the solution was concentrated under reduced pressure. Water
and CH2Cl2 (30 mL) were added and the organic layer was dis-
carded. The aqueous phase was washed again with CH2Cl2 and
acidified on cooling with 10% HCl solution to pH 3. The solution
was extracted with CH2Cl2 several times. After removal of the sol-
vent, the residue was recrystallized from dry ethanol/diethyl ether
to give 0.91 g (96% yield) of the expected compound 20, which
Pyrrolidino[2,1-c][1,3]benzothiazin-8-one S,S-Dioxide (28): This
product was obtained as a white solid after recrystallization from
ethanol/water. M.p. 188 °C (decomposition). IR: ν
= 1711
˜
max
(C=O) cm–1. 1H NMR (CDCl3/[D6]DMSO, 1:1): δ = 2.42–2.68 (m,
2 H, pyrrolidine), 2.73–2.93 (m, 2 H, pyrrolidine), 4.39 (d, J =
17.7 Hz, 1 H, N-CH2), 4.92 (d, J = 8.6 Hz, 1 H, CH), 5.38 (d, J =
17.7 Hz, 1 H, N-CH2), 7.25–7.59 (m, 4 H, benzene) ppm. 13C NMR
(CDCl3/[D6]DMSO, 1:1): δ = 14.5 (CH2), 27.0 (CH2), 39.9 (CH2),
70.5 (CH), 122.2 (CHAr), 125.7 (CHAr), 126.5 (CHAr), 131.2
(CHAr), 132.6 (C), 135.7 (C), 172.2 (CO) ppm. MS (EI): m/z = 239
melts at 175 °C (decomposition). IR: νmax = 3340 (OH), 1713, 1708
˜
(C=O) cm–1. 1H NMR (CDCl3): δ = 4.31 (br. s, 1 H, OH), 4.56 (d,
J = 13.2 Hz, 1 H, CH2), 5.31 (d, J = 13.2 Hz, 1 H, CH2), 5.91 (s, [M+]. C11H13NO3S (239.30): calcd. C 55.21, H 5.48, N 5.85; found
1 H, CH), 7.36–7.43 (m, 1 H, benzene), 7.50–7.56 (m, 2 H, ben- C 55.12, H 5.68, N 5.49.
Eur. J. Org. Chem. 2005, 2758–2770
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2769

N. Hucher, A. Pesquet, P. Netchitaïlo, A. Daïch
FULL PAPER
[8] The use of other acids such as AcOH, HCl, and H2SO4 gave
only the corresponding 3-acetyloxyisoindolinone and 3-phenyl-
thioisoindolinone 5, respectively. The latter product 5 was ob-
tained by a successive process including i. the cleavage of the
–N–CH–S– linkage obtained partially from hydroxy lactam 4,
and ii. the intramolecular nucleophilic attack of the generated
thiophenol on the endocyclic N-acyliminium ion of type B.
[9] The products were obtained in excellent yields of 85% (R =
Me), 92% (R = Ph), 98% (R = p-ClPh), and 92% (R = Bzl).
In the case of methyl and benzyl groups, the thiazines I and II
were accompanied by the methylidene and benzylidene deriva-
tives as the consequence of the dehydration of the α-alkyl-α-
hydroxy lactams 4 (R = Me, Bzl).
Acknowledgments
The authors thank the “Region of Haute Normandy, France”, and
the Scientific Council of University of Le Havre, France, for their
financial support for this research program. We also are grateful
for many fruitful discussions throughout the course of this work
with Professor B. Decroix. Finally, many thanks are addressed equ-
ally to T. Bousquet and J. F. Fleury for their technical assistance
during this work.
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Received: October 25, 2004
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Eur. J. Org. Chem. 2005, 2758–2770