Access to the new isoindolo[1,3]benzothiazocinones via the combination of N-acyliminium chemistry and friedel-crafts type π-cyclization

Article abstract of DOI:10.3987/COM-04-S(P)18

New racemic and chiral [4,2]- and [3,5]benzothiazocines (4) and (5) in the isoindolinone series were synthesized easily in few steps based on the combination of N-acyliminium chemistry and π-cationic cyclization of acylium ions. The chemoselectivity observed during these processes, particularly in the reduction, the thioalkylation and the cyclization stages, were also discussed.

Full text of DOI:10.3987/COM-04-S(P)18

HETEROCYCLES, Vol. 64, 2004
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HETEROCYCLES, Vol. 64, 2004, pp. 33 - 39
Received, 29th June, 2004, Accepted, 16th July, 2004, Published online, 17th July, 2004
ACCESS TO THE NEW ISOINDOLO[1,3]BENZOTHIAZOCINONES VIA
THE COMBINATION OF N-ACYLIMINIUM CHEMISTRY AND
FRIEDEL-CRAFTS TYPE π-CYCLIZATION
Armelle Cul,a Adam Daïch,a* Bernard Decroix,a Gérard Sanz,b and Luc Van
Hijfteb
aLaboratory of chemistry, URCOM, EA 3221, UFR of Sciences & Techniques,
University of Le Havre, B.P:540,25 rue Philippe Lebon,F-76058 Le Havre Cedex,
France. bJohnson & Johnson, Pharmaceutical Research & Development, Division
of Janssen-Cilag, Campus de Maigremont, B.P:615, F-27106 Val-de-Reuil Cedex,
France. adam.daich@univ-lehavre.fr
Abstract – New racemic and chiral [4,2]- and [3,5]benzothiazocines (4)and (5) in
the isoindolinone series were synthesized easily in few steps based on the
combination of N-acyliminium chemistry and π-cationic cyclization of acylium
ions. The chemoselectivity observed during these processes, particularly in the
reduction, the thioalkylation and the cyclization stages, were also discussed.
INTRODUCTION†
Benzene-fused eight-membered ring N,O-, and N,S-heterocycles have provided a rich source of central
nervous system (CNS) and cardiovascular therapeutic agents. Compounds such as nefopam (1) (an
analgesic 1H-[1,4]benzoxazocine),1 substituted methano[1,3]benzothiazocine (2) (a calcium channel
agonists),2 and pyrrolo[1,5]benzothiazocine (3) (amolecular probe of the “peripheral-type” benzodiazepine
receptors (PBR)),3 are representative of such agents with interesting biological activity.
Because of the fact that [1,3]benzothiazocines are little explored, and as a continuation of our current
research programs,we planned to access isoindolinone fused benzothiazocinones,such as the structures (4)
and (5). The use of N-acyliminium chemistry in combination with Friedel-Crafts cyclization seemed to bea
valuable strategy to provide these targets in an efficient and concise manner.
†
This paper is dedicated to Dr. Pierre Potier on the occasion of his 70th birthday

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HETEROCYCLES, Vol. 64, 2004
Chart 1. Representative polycyclic benzothia(and oxa)zocine structures and the N,S-acetal targets.
R
R
O
O
O
N
N
S
O
O
O
N
N
O
O
S
R
O
S
O
S
R
Ph
O
N
H
[4,2]Benzothiazocines (4)
[3,5]Benzothiazocines (5)
Methanobenzothiazocines (2)
Pyrrolobenzothiazocines (3)
Nefopam (1)
R=H, Br, OMe
R=H, Me
R=H, NO2
R=Me, NMe2
Because of the fact that [1,3]benzothiazocines are little explored, and as a continuation of our current
research programs,we planned to access isoindolinone fused benzothiazocinones,such as the structures (4)
and (5).The use of N-acyliminium chemistry in combination with Friedel-Crafts cyclization seemed tobea
valuable strategy to provide these targets in an efficient and concise manner.
RESULTS AND DISCUSSION
As depicted in Scheme 1,our strategy relied on the synthesis of acetic acid intermediate (9) as a π-cationic
cyclization precursor. This latter should be accessible from the halide (6) in a three step-sequence.
Scheme 1. Synthetic sequence leading to isoindolo[1,3]benzothiazocines (4a-c).
R
R
O
O
R
R
O
O
O
S
N
Cl
N
iv
ii
i
iii
S
S
N
N
S
N
O
OH
O
OH
8a,b,c
O
O
9a,b,c
7a,b,c (R=H, Br, OMe)
6
4a,b,c
Key: (i) Aryl mercaptan, MeONa, DMF, rt, 12 h (87 to 91 %); (ii) 1°- NaBH4, MeOH, 0 °C to rt, 2°- 10% HCl (97 to 98 %); (iii) 1°-
Ph3P=CHCO2Et, toluene, reflux, 2 h, 2°- K2CO3, MeOH, H2O, 60 °C, 2 h (57 to 87 %); (iv) 1°- SOCl2, DCM, reflux, 1 h, 2°- AlCl3
(99.99 %), DCM, 0 °C to rt, 1 h (35 to 78 %).
In fact, the commercially available 1-chloromethylphthalimide (6) was alkylated with slight excess of
ortho-substituted thiophenol (7a-c) in alkaline medium (87 to 91%). Regioselective reduction of the
resulted imides (7a-c) was performed with a large excess of NaBH4 (4to 6equiv.) in analogy to our earlier
reports, and afforded (8a-c) in excellent yields (97-98%, see Table 1).4b In some cases, to avoid the poor
solubility of the imide (7), allied to the laborious work-up encountered during these processes, a small
quantity of THF as co-solvent was added. The next step consisted of the conversion of hydroxy lactams
(8a-c) to the acetic acid derivatives (9a-c) by applying the tandem Wittig type condensation/alkaline
hydrolysis in one-pot procedure, followed with an acidic treatment.5 Finally, the acid (9) was treated with
1.2 equiv. of thionyl chloride in dichloromethane at reflux for 1 h and the resulting acid chloride under
Friedel-Crafts cyclization conditions using aluminum trichloride (99.99% purity) as catalyst gave the
expected tetracyclic ketone (4) in moderate (35%) to good (78%) yields (see Table 1). The modest yield

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35
obtained in the case of the methoxy-substituted derivative (4c) could be explained by the cleavage of the
thioether linkage in acidic medium.
Table 1. Yields of intermediates (7-9a,b,c) and corresponding isoindolo[1,3]benzothiazocines (4a,b,c).
Producta
R Group
Imide (7)
Hydroxy lactam (8)
Acid (9)
Tetracyclic Ketone (4)
Yield (%)
Yield (%)
Yield (%)
Yield (%)
a
b
c
H
Br
91
87
90
97
98
97
60
87
57
78
71
35b
OMe
aYields indicated were obtained after recrystallization for imides (7),hydroxy lactams (8)and acids (9) and
after chromatography purification of cyclic N,S-acetals (4). bAn important decomposition of the acid (9) as
starting material was observed.
Having established that the combination of N-acyliminium species/π-cyclization route is effective for the
preparation of the isoindolo[1,3]benzothiazocine derivatives (4a-c), we decided to elaborate another class
of acylium precursors in which asulfur atom is attached to the angular carbon of the isoindolinone nucleus.
As depicted in Scheme 2, the prerequisite acetic acid derivatives (13a-c) were obtained in a three-step
sequence. The hydroxy lactams (12a-c) were obtained in good yields from phthalimide (10, X=NH) by
N-alkylation (87 to 91%) followed by the sodium borohydride reduction of the intermediate known imides
(11a-c)(97 to 98%).7 Since it has been demonstrated that hydroxy lactams with various sulfur nucleophiles
underwent an acid-catalyzed substitution reaction involving N-acyliminium species,6 we attempted to
synthesize acid derivatives (13a-c). In fact, treatment of 12a-c with thioglycolic acid (1.5 equiv.) and a
catalytic amount of p-toluenesulfonic acid at room temperature for 24 hafforded the expected acids (13a-c)
in very good yields (89 to 95%). The separation of the acid 13 from the unreacted thioglycolic acid was
accomplished easily by treatment of the reaction mixture with potassium carbonate solution at 40 °C for 1h
followed by dichloromethane extraction, and finally acidification with aqueous hydrochloric acid (10%) at
0 °C.
The above acid derivative (13a),chosen as amodel substrate,was treated with thionyl chloride under reflux
of dichloromethane for 2 h and the resulting acid chloride in the presence of 3 equiv. of aluminum
trichloride (99.99% purity) gave the expected tricyclic thiazocinone (5a) in good yield (87%). Under
similar conditions,the thioglycolic acid derivatives (13b,c) seemed to be more fragile than 13a under acidic
conditions. In both cases, the sole product obtained from the reaction mixture was the starting hydroxy
lactams congeners (12b,c)which resulted from the departure of the sulfur fragment under acidic conditions
followed by the hydration of the N-acyliminium intermediates during the work up hydrolysis.8 This result
could be explained by the deactivation of the aromatic ring system by the bromide or the methoxy group at
the ortho position of the benzene ring. In these cases only the cleavage of the thioether linkage, which

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HETEROCYCLES, Vol. 64, 2004
constitutes a competing process to the detriment of the π-cyclization, takes place. All attempts to optimize
the reaction by different experimental conditions did not give satisfaction.
Scheme 2. Access to the positional isomers (5a-c) of isoindolo[1,3]benzothiazocines (4a-c).
O
R
R
R
R
O
O
O
O
i or
ii
N
S
X
iii
v
iv
N
N
N
R=H
O
S
O
OH
O
HO2C
5a,b,c
13a,b,c
10 (X=O, NH)
11a,b,c (R=H, Br, OMe)
12a,b,c
Key: (i) From anhydride (10: X=O): amine, toluene, NEt3, reflux, DS (see ref. 7); (ii) From imide (10: X=NH): Halide, KI, K2CO3,
18-C-6, toluene, reflux, 12 h (78 to 91 %); (iii) 1°- NaBH4, MeOH, 0 to 10°C, 2°- 10% HCl (97 to 98 %); (iv) 1°- HSCH2CO2H, PTSA,
DCM, rt, 24 h, 2°- K2CO3, H2O, 40 °C, 1 h, 3°- 10% HCl (89 to 95 %); (iv) 1°- SOCl2, DCM, reflux, 2 h, 2°-AlCl3 (99.99 %), DCM, 0
°C to rt, 2 h (87 % for 5a).
Compound (5) and all other unknown intermediates reported herein (4, 7-9, and 12-13) were identified by
1
13
spectroscopic methods including H-NMR, C-NMR, DEPT program, IR, coupling GC-MS spectra as
well as by microanalysis.
Based on our precedent work, in which the pyrrolo(or tetramethylpyrrolo)[1,3]benzothiazocinones (15)
(71-75%)9 and isoindolo[1,3]benzothiazocinones (17) (56-62%)10 were isolated in appreciable yields
(Scheme 3), we planned to extend this synthetic approach to other systems. So, the elaboration of novel
N,S-heterocyclic systems as pyrrolidone and isoindolinone was explored.
Scheme 3. Generalization of the sequence to a succinamidal (18) and a chiral isoindolone (22) series
O
O
O
O
NO2
NO2
R
R
R
S
S
R
ref. 10
N
S
N
S
N
S
ref. 9
N
S
R
R
R
R
56-62%
71-75%
O
R=H, Me
O
CO2H
CO2H
14
15
17
16
O
O
O
O
- H
N
N
N
i
ii
N
Polymerization
OH
S
HO2C
19
20
21
18
O
O
O
O
8
3
5
N
S
N
s
N
s
ii
+
i
N
s
11b S
1
10
S
14
OH
22
O
33:67
CO2H
CO2H
23
24
5d (5S,11bR)
Conditions and reagents: (i) 1°- HSCH2CO2H, PTSA, DCM, rt, 12 h, then 2°- K2CO3, MeOH, H2O, 60 °C, 1 h
(89 % for 19 and 88 % for 23/24 as a 33:67 mixture); (ii) 1°- SOCl2, DCM, reflux, 1 h, then 2°-AlCl3 (99.99 %),
DCM, 0 °C, 1 to 2 h (68 % for 5d).
As highlighted in Scheme 3 and according to our sequential set of reactions, the N-benzylsuccinamidal
(18)11 was transformed into the corresponding thioglycolic acid (19) in good yield (89 %). This acid

HETEROCYCLES, Vol. 64, 2004
37
derivative, upon treatment under our standard cyclization conditions, furnished, whatever the changes
operated in the experimental conditions, a polymeric material. This behavior of 19, could be explained
easily by the fact that the α-alkylsulfanyl lactam such as 19 could generate a N-acyliminium cation (20) in
acidic medium.8 This latter,upon acid catalyzed olefin isomerization,12 could provide the instable enamide
(21) which polymerized rapidly.13
Our next concern was the evaluation of the impact of the chirality in this process. The α-hydroxy lactam
(22) was obtained in 92 % yield in a 5.5/4.5 mixture of two diastereomers from the corresponding
enantiopure (S)-imide by the tandem sodium borohydride/methanol/hydrochloric acid reduction protocol.5
Subjection of 22 to thioglycolic acid in dichloromethane with p-toluenesulfonic acid as catalyst led to a
33:67 mixture of two thioglycolic acids as diastereomeric pairs (23) and (24) (88 %). An enriched 15:85
mixture of 23:24 was obtained by a recrystallization from dry ethanol and no enantiopure 23 and/or 24 was
isolated whatever the use of other solvent in this process. This mixture was then treated with thionyl
chloride (1.2 equiv. in dichloromethane at reflux for 1 h) followed by aluminum trichloride (3 equiv. in
dichloromethane at 0 °C for 1 to 2 h) to give the cyclic product (5d) in an equivalent diastereomeric ratio
(15:85) in 68 % yield. The elucidation of the absolute configuration of the major tricyclic ketone, which
was obtained in pure form by twice fractional crystallization from dry ethanol (all attepts of separation by
chromatography failed), was based on our prior experience in the field.5 The cis-relation-ship between H5
and the newly created stereocenter H11b was proved by NOE measurements. In this respect, the irradiation
of H11b (s, δ =5.75 ppm) shows significant NOE effect for the proton H5 (q, δ=5.79 ppm). These results
demonstrate clearly that the isoindolobenzothiazocinone (5d) have a (5S,11bR) configuration
([α]D=+124.5° (c 0.2 M, ethanol)).14
CONCLUSION
The synthetic sequence reported in this paper constitutes an excellent,short,and general protocol to access
various isoindolo[1,3]benzothiazocinones of type (4) and their positional [5,3]-isomers of type (5). These
polyheterocyclic systems were obtained in appreciable overall yields and could be obtained in alarge scale.
Consequently, these N,S-acetals might find application as building blocks in synthesis of potentially
bioactive compounds and could constitute also excellent precursors for new synthetic investigations.
ACKNOWLEDGEMENTS
We acknowledge the Johnson & Johnson, Pharmaceutical Research & Development, Division of
Janssen-Cilag, for scientific and financial support of this program. We thank also the Region of “Haute
Normandy” in France for a “Regional-Industrial Graduate Fellowship” (BRI), 1998-2001, attributed to
Armelle Cul.

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REFERENCES AND NOTES
1. M. W. Klohs, M. D. Draper, F. J. Petracek, K. H. Ginzel, and O. N. Ré, Arzneim. Forsch., 1972, 22,
132.
2. J. J. Baldwin, D. A. Claremon, P. K. Lumma, D. E. McClure, S. A. Rosenthal, R. J. Winquist, E. P.
Faison, G. J. Kaczorowski, M. J. Trumble, and G. M. Smith, J. Med. Chem., 1987, 30, 690.
3. G. Campiani, V. Nacci, I. Fiorini, M. P. De-Filippis, A. Garofalo, S. M. Ciani, G. Greco, E. Novellino,
C. Manzoni, and T. Mennini, Eur. J. Med. Chem., 1997, 32, 241.
4. (a) N. Hucher, A. Daïch, and B. Decroix, Org. Lett., 2000, 2, 1201. (b) N. Hucher, B. Decroix, and A.
Daïch, J. Org. Chem., 2001, 66, 4695.
5. A. Chihab-Eddine, A. Daïch, A. Jilale, and B. Decroix, Heterocycles, 2002, 58, 449.
6. For this subject, see: (a) W. N. Speckamp, M. J. Moolenaar, Tetrahedron, 2000, 56, 3817. (b) B. E.
Maryanoff, H. C. Zhang, J. H.Cohen, I. J. Turchi, and C.A. Maryanoff, Chem. Rev., 2004, 104, 1431.
7. For the synthesis of imides (12a-c), see respectively: (a) K. Sasaki, Y. Shibata, Y. Hashimoto, and S.
Iwasaki, Biol. Pharm. Bull., 1995, 18, 1228. (b) T. G. M. Dahr, Z. Shen, H. H. Gu, P. Chen, D. Norris,
S. H. Watterson, S. K. Ballentine, C. A. Fleener, K. A. Rouleau, J. C. Barrish, R. Townsend D. L.
Hollenbaugh, and E. J. Iwanowicz, Bioorg. Med. Chem. Lett., 2003, 13, 3557. (c) Y. Kato, M.
Takemoto, and K. Achiwa, Chem. Pharm. Bull., 1999, 47, 529.
8. Few reports concerning the generation of N-acyliminiums species, from corresponding
α–alkylsulfanyl- and α–arylsulfanyl lactams have been mentioned in the literature. For representative
examples see: (a) ref. 4 (b) and references cited therein. (b) A. Padwa and A. G. Waterson, J. Org.
Chem., 2000, 65, 135. (c) A. Padwa and A. G. Waterson, Tetrahedron, 2000, 56, 10159 and references
cited therein.
9. A. Mamouni, A. Daïch, and B. Decroix, Synth. Commun., 1997, 27, 2249.
10. A. Chihab-Eddine, A. Daïch, A. Jilale, and B. Decroix, J. Heterocycl. Chem., 2000, 37, 1543.
11. A. Guzman, M. Romero, and J. M. Muchowski, Can. J. Chem., 1990, 68, 791.
12. A. Chihab-Eddine, A. Daïch, A. Jilale, and B. Decroix, Tetrahedron Lett., 2001, 42, 573.
13. For similar profile in the oxygen series, see our previously reports in the following reference: A.
Mamouni, Š. Marchalín, A. Daïch, and B. Decroix, Heterocycles, 2001, 54, 275.
14. General protocol for the π-cationic cyclization of acetic acid and thioglycolic acid derivatives:
Representative procedure for the synthesis of (5S,11bR)-5,11b-dihydro-5-methylisoindolo[1,2- d][3,5]-
benzothiazocine-7,14(13H)-dione (5d). To a stirred solution of acids derivatives (23:24) (1.3 g, 3.97
mmol) in dry dichloromethane (50 mL) under argon atmosphere was added slowly 1.2 equivalents of
freshly distilled thionyl chloride (0.57 g, 4.76 mmol) and the mixture was allowed to react at reflux for
1 h. After cooling and concentration under vacuo, the residue was dissolved in dry dichloromethane

HETEROCYCLES, Vol. 64, 2004
39
(50 mL). The mixture was cooled at 0 °C and treated with 3 equivalents of aluminium trichloride
(99.99%) (1.58 g, 11.9 mmol) over a period of 5 min under vigorous stirring. After 1to 2hof reaction
at this temperature,the solution was poured onto amixture of cold water and crushed ice and separated.
The aqueous solution was extracted again twice with dichloromethane and the organic layers were
washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
The residue was isolated as a white solid in 68% yield and after twice recrystallization from dry
ethanol give pure 5d, mp=102 °C (decompo);[α]D=+124.5° (c0.2 M, ethanol); IR (KBr) ν3082, 2968,
1708, 1695 cm-1; 1H-NMR (CDCl3) δ1.88 (d, 3H, CH3, J=8.0 Hz), 2.78 (d,1H, CO-CH2, J=15.8 Hz),
2.96 (d, 1H, CO-CH2, J=15.8 Hz), 5.75 (s, 1H, S-CH), 5.79 (q, 1H, CH, J=8.0 Hz), 6.91-7.42 (m,4H,
4Haromatic), 7.56-7.75 (m, 3H, 3Haromatic), 7.84 (d, 1H, 1Haromatic, J=8.7 Hz); 13C-NMR (CDCl3) δ 18.1
(CH3), 36.1 (CH2), 46.2 (CH), 59.0 (CH), 120.9 (CH), 122.1 (CH), 123.2 (CH), 124.9 (CH), 126.1
(2xCH), 129.0 (CH), 131.0 (Cq), 133.1 (CH), 135.0 (Cq), 135.2 (Cq), 141.4 (Cq), 163.4 (CO), 205.2
(CO); MS EI, 70 ev) m/z: 309 (M+); Anal. Calcd for C18H15NO2S: C, 69.88; H, 4.89; N, 4.53. Found:
C, 69.51; H, 4.73; N, 4.35.