Synthesis and reactivity of (1S)-N-(1-phenylethyl)maleimide towards nucleophiles: An application to preparation of chiral pyrroloisothiochroman and pyrrolobenzo[d]thiepine based on π-cationic cyclization

Article abstract of DOI:10.1016/S0040-4039(00)02037-2

Chiral pyrroloisothiochroman and pyrrolo[d]thiepine were obtained efficiently in four steps from N-alkylated maleimides via, successively, sulfurization, regioselective reduction followed by π-cationic cyclization of the N-acyliminium ion intermediates. These latter, in addition, led to conjugate enamides as a consequences of the dehydration reaction.

Full text of DOI:10.1016/S0040-4039(00)02037-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 573–576
Synthesis and reactivity of (1S)-N-(1-phenylethyl)maleimide
towards nucleophiles: an application to preparation of chiral
pyrroloisothiochroman and pyrrolobenzo[d]thiepine based on
p-cationic cyclization
Abderrahim Chihab-Eddine,a Adam Da¨ıch,b,* Abderrahim Jilalea and Bernard Decroixb
aLaboratoire de Bio-Organique, De´partement de Chimie, Universite´ Ibnou Zohr, Faculte´ des Sciences, B.P. 28/S,
Agadir, Morocco
bLaboratoire de Chimie, URCOM, Faculte´ des Sciences & Techniques de l’Universite´ du Havre, 25 rue Philippe Lebon,
B.P. 540, 76058 Le Havre Cedex, France
Received 14 October 2000; accepted 9 November 2000
Abstract—Chiral pyrroloisothiochroman and pyrrolo[d]thiepine were obtained efficiently in four steps from N-alkylated
maleimides via, successively, sulfurization, regioselective reduction followed by p-cationic cyclization of the N-acyliminium ion
intermediates. These latter, in addition, led to conjugate enamides as a consequence of the dehydration reaction. © 2001 Elsevier
Science Ltd. All rights reserved.
The a-amidoalkylation cyclization involving N-acyli-
minium ions is now widely regarded as a powerful
methodology for carbonꢀcarbon bond forming in
organic synthesis.1 During these processes the N-acyli-
minium ion species, which are generated in situ in
acidic conditions most widely from stable a-hydroxylac-
tams, a-alkoxylactams, carbamates and isomu¨nchnone
cycloadducts, are, in turn, capable of the capture of a
weak tethered carbon nucleophile producing azapoly-
cyclic systems, including a large variety of alkaloid
products.1,2
only a few reports concerning these species appear in
the literature.4a–d,5,6
Because we are interested in developing N-acyliminium
ion chemistry toward the formation–cleavage of the
thioether linkage in N,S-fused polyheterocyclic
systems2c–e,7 and in the continuation of our program
toward studies of N-arylthio(or aryloxo)alkylimides
functionalities (Model I) in acidic medium, we investi-
gated the cyclization process in succinimide series (form
B) bearing an aryl(or aralkyl)thio R-S- group at C3
position as an N-acyliminium ion precursor (Model II).
As shown in Scheme 1, the cyclized products resulting
in formation of a junction a as in form A are well
documented.1–3 In contrast, heterocycles obtained by
formation of junction b (form B) are little explored and
So, our strategy focused at the outset on construction
of N–C–C–S–R functionality (Model II) by sulfuriza-
tion of succinimide derivative at C3, followed by trans-
Scheme 1.
Keywords: N-acyliminium ion; p-cationic cyclization; aza-compounds; isothiochroman; benzo[d]thiepine.
* Corresponding author. Tel.: (+33) 02-32-74-44-03; fax: (+33) 02-32-74-43-91; e-mail: adam.daich@univ-lehavre.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02037-2

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A. Chihab-Eddine et al. / Tetrahedron Letters 42 (2001) 573–576
formation of its carbonyl group into hydroxy function
as key intermediate. In all cases, (1S)-N-(1-
organolithium addition onto the carbonyl group of
phthalimide bearing a chiral auxiliary.11 The chemoselec-
tivity of this organolithium addition reaction, as a
1,2-addition, was also confirmed by the formation of
enamidone 8a (84%) or 8b (78%) as a single diastereoiso-
mer from v-alkynyl-v-carbinol lactam 7a or 7b by a
Meyer–Schuster rearrangement (i.e. PTSA, EtOH,
reflux, 2 h).12
a
phenylethyl)maleimide 5 was used as a starting material.
Construction of the latter was started with commercially
available exo-3,6-epoxy-1,2,3,6-tetrahydrophthalic an-
hydride 1 by a newly tandem amine–anhydride cyclode-
hydration/retro-Diels–Alder reaction with release of
furan in a ‘one-pot’ procedure (i.e. xylene, reflux, 12 h,
88%).8,9a This precursor was also obtained in another
three-step sequence from maleic anhydride 2 with an
overall yield of 73%9b (Scheme 2).
Under carbophilic addition conditions as pointed out in
Table 1, with Grignard reagent as nucleophile, the
Michael acceptor 5 led after hydrolysis to the 1,4- and/or
1,2-addition product(s) 9 and/or 10 in good yield(s). To
avoid the formation of enamide, as a consequence of a
dehydration reaction in the cases of substrates 9 and
10b,c under an acidic influence,13 a neutral hydrolysis
under moderate temperature was necessary. Interest-
ingly, the results given above show that the reactions
proceeded with high to excellent yields and that the
regiochemistry depended upon the nature (basicity) of
the R2 group in the Grignard reagent. In fact, exclusive
1,2- and 1,4-addition was obtained with phenylmagne-
sium bromide and phenylethylmagnesium bromide to
give 10a (79%) and 9c (69%), respectively, whereas
benzylmagnesium bromide gave in quantitative yield a
separable mixture (silica gel, CH2Cl2) of the regioiso-
mers 9b and 10b in 78:22 ratio.
As depicted in Scheme 3, the substrate 5 was subjected
to reduction, thionation and carbophilic addition in
order to study the influence of steric and electronic effects
in both reduction–addition and cyclization steps. Actu-
ally, reduction reaction of enone 5 was carried out with
NaBH4 in dry methanol at 0–5°C (monitored by tlc) and
afforded only (S)-succinimide derivative 6 (98%),10
which corresponds to a product of double bond CꢁC
reduction. On the other hand, the enone–amide 5 was
reacted with pentynyl(or phenylethynyl)lithium11 in dry
ether yielding the v-carbinol lactam 7a (65%) or 7b
(70%), which showed a 58/42 or 55/45 mixture of
diastereoisomers inseparable by column chromatogra-
phy. At this stage, it is worth mentioning that compara-
ble diastereoselectivity was observed during the
Scheme 2. Reagents: (i) 1 equiv. of (S)-MeCH(CH2)Ph, CH2Cl2, 0°C then 16 h at rt; (ii) 1 equiv. of (COCl)2, 1 drop of DMF,
8 h at rt; (iii) 1 equiv. of NEt3, CH2Cl2, 1 h at rt; (iv) 1 equiv. of (S)-MeCH(NH2)Ph, xylene, 12 h at reflux.
Scheme 3. Reagents: (i) 6 equiv. of NaBH4, methanol, 0–5°C, 30 min; (ii) R1-CC-Li, Et2O, 0–25°C, 3 h; (iii) PTSA, ethanol, reflux,
2 h; (iv) R2-MgX, see Table 1 for reaction conditions.

A. Chihab-Eddine et al. / Tetrahedron Letters 42 (2001) 573–576
575
Table 1. Grignard reagent addition onto Michael acceptor enone 5; derivatives 9 and 10 produced via Scheme 3
Products
R2-MgX
Hydrolysis
conditionsa
Ratio of products
Diastereoisomeric ratio of products 9/10d
Yield %
9/10b
a
b
c
R2=Ph; 1.2 equiv.
2 M NH4Cl,
0–10°C
H2O, 10–20°C
0/100
78/22c
100/0
–; 86/14
79
>99
69
R2=PhCH2; 3.5
equiv.
R2=Ph(CH2)2; 4.0
equiv.
56/44; 55/45
57/43; –
H2O, 10–20°C
a Reaction conditions: (1) R2-MgX, CH2Cl2/ether (3/2), 1 h at 0°C then 3 h at rt. (2) Hydrolysis conditions.
b The ratios of the different diastereoisomers of products 9 and 10 has been determined, but their configurations could not be assigned with
certainty.
c Regioisomer products 9,10b were separated by chromatography on silica gel column using CH2Cl2 as eluent.
d The ratios of regio- and stereoisomer compounds were determined by 1H NMR analysis.
Scheme 4. Reagents: (i) 1–1.2 equiv. of MeONa, 1–1.2 equiv. of R2SH, C6H6, 40–60°C, 12 h; (ii) NaBH4, MeOH, 0–5°C, 30 min.
Since it was possible that imides 11a–c could provide to
cyclic lactams 17 via p-aromatic cyclization, we
explored the elaboration of different aromatic models,
substituted by phenyl, benzyl and phenylethyl groups
on the sulfur atom at C3 position of succinimide ring to
establish the generality and versatility of the synthetic
approach depicted in Scheme 4.
while 17b,c required a p-aromatic intermolecular a-ami-
doalkylation cyclization of N-acyliminium ion interme-
diates 16b,c obtained from N-acyliminium ions 13b,c by
spontaneous loss of an dihydrogen molecule (Scheme
4).14,15 These observations were in contrast to these
reported earlier for similar structures not bearing chiral
auxiliaries.4b–d,6
Imides 11a–c were readily obtained by a modified
thionation procedure from enone–amide 5 (Scheme
4).13 Regioselective reduction of chiral imides 11a–c
with NaBH4 in MeOH at 0–5°C afforded a-hydroxylac-
tams 12a–c as diastereoisomeric mixtures in 69, 82 and
73% yields, respectively. These a-hydroxylactams were
used in the next step without further purification.
The stereoselectivity observed during the p-cyclization
of a-hydroxylactams in acidic medium seems to proceed
probably through Felkin–Ahn like transition state
(Scheme 4), which involves the approach of a nucle-
ophile from the upper side to produce the adducts 17b
an 17c as a single diastereoisomer.11
In summary, we have shown that the N–C–C–S–R
functionality in pyrrolidine ring as an N-acyliminium
ion precursor, produces efficiently new ben-
zo[c]thiopyran 17b and benzo[d]thiepine 17c cycles
fused to pyrrole ring via a tandem dehydrogenation/
intramolecular arylation. However, in an interrupted
p-cationic cyclization, the iminium salt intermediate 13
undergoes a deprotonation leading to the expected dis-
ubstituted pyrrolidinone 15b,c.
The a-hydroxylactam 12a was subjected to neat TFA at
rt, and led to a stable conjugated pyrrolidinone 15a
(82%). This latter was a consequence of a deprotona-
tion of N-acyliminium ion 13a followed by isomeriza-
tion of unstable enamide 14a. Under these conditions,
a-hydroxylactams 12b,c furnished a separable mixture
of 17b (68%), 15b (32%) in a 92% yield and 17c (74%),
15c (26%) in a 86% yield, respectively. Pyrrolidinones
15b,c were formed in similar process advanced for 12a,

576
A. Chihab-Eddine et al. / Tetrahedron Letters 42 (2001) 573–576
(c) Koot, W. J.; Hiemstra, H.; Speckamp, W. N. Tetra-
Acknowledgements
hedron: Asymmetry 1993, 4, 1941–1948. (d) Luker, T. I.;
Koot, W. J.; Hiemstra, H.; Speckamp, W. N. J. Org.
Chem. 1998, 63, 220–221.
The financial help rendered by the Scientific Council of
University of Le Havre, is greatly appreciated.
5. Klaver, W. J.; Hiemstra, H.; Speckamp, W. N. J. Am.
Chem. Soc. 1989, 111, 2588–2595.
6. Brie`re, J. F.; Charpentier, P.; Que´guiner, G.; Bour-
guignon, J. Tetrahedron 1997, 53, 2075–2086.
7. Da¨ıch, A.; Decroix, B. J. Heterocycl. Chem. 1991, 28,
1881–1884.
8. A comparable method using oxabicyclic anhydride was
described for the preparation of various chiral
maleimides. The yields reported were low and in all cases
the opened chiral fumaric acid N-substituted
monoamides were recovered; see: Andrus, V.; Fisera, L.
Molecules 1997, 2, 49–53.
9. (a) Clevenger, R. C.; Turnbull, K. D. Synth. Commun.
2000, 30, 1379–1388. (b) Braish, T. F.; Fox, D. E. Synlett
1992, 979–980.
10. This product was obtained by thermal amine–anhydride
condensation in high yield (93%): Polniaszek, R. P.;
Belmont, S. E.; Alvarez, R. J. Org. Chem. 1990, 55,
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