Benzoindolizine derivatives of N-acylphenothiazine. Synthesis and characterization

Article abstract of DOI:10.1039/b302662k

The synthesis and characterization of benzoindolizine derivatives of N-acylphenothiazine was discussed. The unsaturated derivatives were synthesized by using cyclocondensation of acetylenic or olefinic dipolarophiles. It was shown that the reaction could be performed with acetylenic or olefinic compounds and could also be used for the synthesis of other polycyclic indolizine-containing compounds.

Full text of DOI:10.1039/b302662k

View Article Online / Journal Homepage / Table of Contents for this issue
Benzoindolizine derivatives of N-acylphenothiazine.
Synthesis and characterization
Elena Bâcu,a Dalila Samson-Belei,a Guy Nowogrocki,b Axel Couturec and
Pierre Grandclaudon*c
a Catedra de Chimie Organica, Facultatea de Chimie, Universitatea “Al. I. Cuza”,
11 Bd Carol I, RO-6600 Iasi, Roumanie
b Laboratoire de Cristallochimie et Physicochimie du Solide, UMR 8012, ENSC Lille,
BP 108, F-59652 Villeneuve d’Ascq Cedex, France
c Laboratoire de Chimie Organique Physique, associé à l’ENSCL, UMR 8009,
Université des Sciences et Technologies de Lille 1, F-59655 Villeneuve d’Ascq Cedex, France
Received 7th March 2003, Accepted 7th May 2003
First published as an Advance Article on the web 22nd May 2003
A variety of unsaturated or partly and differentially saturated benzoindolizine derivatives of N-acylphenothiazine
1–3 has been efficiently synthesized by cyclocondensation of acetylenic or olefinic dipolarophiles with azomethine
ylide 4 derived from N-acetylisoquinolinium salt 5 flanking a phenothiazine unit.
involved in the cyclocondensation and/or the experimental
conditions used.
Introduction
During the past five decades studies devoted to the pheno-
thiazine class of compounds1–4 have been stimulated by the
discovery of the pharmacodynamic properties of a number of
derivatives in which a variety of aminoalkyl side chains are
connected to the nitrogen atom of the heterocyclic unit. Con-
sequently, drugs incorporating a phenothiazine ring system5–7
have played a crucial role in medicinal chemistry and have
occupied a place of choice in the arsenal of pharmaceutical
drugs, owing namely to their antibacterial,8 antihistamine,
tranquillizing and spasmolitic activities9,10 and more recently to
their promising antitumor properties.11–13
In the context of our research projects aimed at the synthesis
of new phenothiazine compounds for subsequent biological
evaluation, we were recently interested in the elaboration of
different models comprising the phenothiazine unit linked to a
variety of nitrogen containing heterocycles through alkyl chains
of different lengths.14–18 Curiously, to the best of our know-
ledge, compounds in which such aromatic ring systems are
connected to an N-acylphenothiazine unit have been very
rarely studied even though N-acylated models equipped with
1,4-benzodioxan,19 furan20 or benzofuran21 aromatic units have
displayed interesting neurotropic properties. Recently, two
patents emphasizing serine hydrolase modulating activities of
structurally related models connected to a pyridone moiety
have appeared in print.22,23 These rare examples encouraged us
to develop a synthetic strategy for the construction of com-
pounds incorporating totally or partially unsaturated benzo-
indolizine units which led us to embark on the synthesis of
models 1–3.
Initially ylide 4 was generated from the isoquinolinium salt 5
resulting from the condensation of isoquinoline with N-(2-
chloroacetyl)phenothiazine33 6. It was subsequently exposed to
an array of acetylenic and olefinic dipolarophiles (Scheme 1).
In these studies we were mainly concerned with the influence
of the unsaturated character of the dipolarophile, the nature
of the solvent and the degree of unsaturation of the cyclo-
condensed product. For this purpose, the ylide 4 was generated
by deprotonation of the isoquinolinium salt 5 with triethyl-
amine (TEA) in the presence of the appropriate dipolarophile,
in different mixed solvents and at temperatures varying from
room temperature to solvent reflux. Two representative proto-
cols were primarily selected and examined, i.e. reactions carried
out in refluxing dichloromethane (CH2Cl2) and those per-
formed in a mixture of benzene (C6H6)–dimethyl sulfoxide
(DMSO) at reflux.
From Table 1, it can be seen that the chemical behaviour of
the primary adduct, obtained by condensation of the ylide 4 in
the presence of acetylenic dipolarophiles, is strongly affected by
the degree of substitution of the parent alkyne.
For example, the primary adduct derived from the reaction
with the disubstituted acetylenic dipolarophile dimethyl acetyl-
enedicarboxylate (DMAD) is easily isomerized to the partly
unsaturated system 1a, characterized by a bright yellow colour.
This may tentatively be explained by the highly conjugated
character of the adduct attributable to the combined presence
of the carboxylate group of the dipolarophile associated with
the carboxamide moiety of the ylide. This particular behaviour
is not affected by experimental conditions (Table 1, entries 1, 2).
The structure of 1a was readily assigned from 1H and 13C NMR
spectra. Thus the 1H NMR spectrum exhibited an AB double-
doublet at δ 4.47 and 4.71 ppm with a high coupling constant
(3J = 13.2 Hz) characteristic of the aliphatic dihydropyrrole ring
system protons. The dihydropyridine unit was unambiguously
identified by the presence of two doublet signals at δ 5.54 and
6.51 ppm with a coupling constant of 7.6 Hz. In the 13C NMR
spectrum the two tertiary carbons embedded in the di-
hydropyrrole skeleton displayed signals at δ 53.6 and 65.2 ppm
and these different assignments were further corroborated by
two-dimensional correlation studies (13C–1H CORR). Finally,
the structure was ultimately established by X-ray diffraction
(Fig. 1; Table 2). The structural resolution was accurate enough
to locate all the hydrogen atoms and refine their position and
Results and discussion
Quaternary salts obtained by condensation of pyridine systems
with halogenoalkylacetamide derivatives have been rarely used
for the generation of azomethine ylides.24–26 However it was
assumed that 1,3-dipolar cycloaddition between ylides gener-
ated in this way and an array of acetylenic and olefinic di-
polarophiles27–30 could undoubtedly represent a conceptually
interesting synthetic approach to the target compounds 1–3. It
has been widely demonstrated that such cycloadditions are
highly regioselective28,31,32 but the initial reaction products are
rarely isolated. Instead, isomerization or aromatization often
occurs,28–30 depending mainly on the nature of the reagents
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 7 7 – 2 3 8 2
2377

View Article Online
Table 1 Condensation of ylide 4 with acetylenic and olefinic dipolarophiles
Entry
Dipolarophile
R1
R2
Experimental conditions
Cycloadduct (yield)
1
2
᎐
1
2
3
4
5
6
7
R –C᎐C–R
COOMe
COOMe
CH2Cl2, reflux, 3 h
1a (64%)
1a (60%)
3a (49%)
3b (71%)
3b (67%)
3c (73%)
3c (70%)
᎐
C6H6–DMSO (3 : 1; v/v), reflux, 3 h
C6H6–DMF, CoPy4(HCRO4)2, reflux, 3 h
CH2Cl2, reflux, 2 h
C6H6–DMSO (3 : 1; v/v), reflux, 3 h
CH2Cl2, reflux, 2 h
COOMe
COOEt
H
H
C6H6–DMSO (3 : 1; v/v), reflux, 3 h
8
9
10
11
12
13
14
R1–CH᎐CH–R2
–CO–N(Ph)–CO–
CH2Cl2, rt, 36 h
CH2Cl2, reflux, 2 h
C6H6, reflux, 3 h
C6H6–DMSO (3 : 1; v/v), reflux, 3 h
C6H6–DMSO (3 : 1; v/v), reflux, 10 h
CH2Cl2, reflux, 2 h
7e (78%)
᎐
COOEt
H
2c (70%)
2c (66%)
2c ϩ 3c (65 : 35)
3c (56%)
2d (65%)
3d (67%)
CN
H
C6H6–DMSO (3 : 12; v/v), reflux, 3 h
Scheme 1 Reagents and conditions: (i) ClCH2COCl, C6H6, reflux; (ii) isoquinoline, CH2Cl2, rt; (iii) NEt3; (iv) dipolarophile, CH2Cl2 or C6H6–
DMSO, reflux; (v) CoPy4(HCrO4)2, DMF, reflux.
clearly confirmed the presence of two sp3 carbon atoms bearing
two hydrogen atoms in an anti configuration in the five mem-
bered ring. Compound 1a was easily converted into 3a by oxid-
ation with tetrakis(pyridino)cobalt() dichromate34 [TPCD;
CoPy4(HCrO4)2] in refluxing dimethylformamide (DMF). The
totally unsaturated fused compound 3a, obtained as white
crystals, was also straightforwardly accessible by performing
the cyclocondensation in a refluxing mixture of C6H6–DMF in
the presence of the oxidizing agent (Table 1, entry 3).35
Interestingly, whatever reaction conditions were used, mono-
substituted acetylenic dipolarophiles, as exemplified by propiol-
ates (Table 1, entries 4–7), gave rise to the unsaturated models
3b and 3c after isomerization and oxidation following form-
ation of the initial adduct. One can reasonably assume that the
absence of a stabilizing group R2 accounts for the instability of
the partly unsaturated transient system and consequently for
its spontaneous oxidation into a model possessing a marked
degree of conjugation.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 7 7 – 2 3 8 2
2378

View Article Online
Table 2 Crystallographic data for compounds 1a and 2c
1a
2c
Empirical formula
C29H22N2O5S
510.55
C28H22N2O3S
466.54
MW/g molϪ1
Temperature/K
Crystal system
100(1)
Monoclinic
293(2)
Monoclinic
Space group
a/Å
C2/c
37.608(6)
C2/c
20.180(4)
b/Å
c/Å
8.6937(14)
15.053(3)
18.259(4)
14.878(3)
α/Њ
β/Њ
90
99.163(3)
90
125.498(3)
γ/Њ
90
90
Volume/Å3
4858.8(14)
4463.0(15)
Z
8
8
Absorption coefficient/mmϪ1
Reflections measured
Independent reflections
Final R indices [I>2σ(I )]
R indices (all data)
0.178
14845
0.180
13018
4155 [R(int) = 0.0430]
R1 = 0.0459, wR2 = 0.1219
R1 = 0.0611, wR2 = 0.1295
3713 [R(int) = 0.0406]
R1 = 0.0501, wR2 = 0.1291
R1 = 0.0705, wR2 = 0.1394
been already described and discussed.31 Compound 7e was oxi-
dized with CoPy4(HCrO4)2 in DMF to afford the fully unsatur-
ated compound 3e (Scheme 2). In the case of monosubstituted
ethylenic dipolarophiles (ethyl acrylate and acrylonitrile) we
have observed a slow and progressive oxidation of the primary
adduct depending upon the reaction temperature and/or the
presence of DMSO as the co-solvent (Table 1, entries 9–14).
Reactions carried out in refluxing CH2Cl2 gave access to the
partly unsaturated compounds 2c and 2d obtained as yellow
crystals and possessing an olefinic carbon–carbon double bond
linking the ester or nitrile functional group to the hydrocarbon
1
aromatic unit. The H NMR spectra revealed the presence of
two protons in the δ 2.40–2.70 ppm region and one proton in
the δ 5.00–5.50 ppm region. The structure was further con-
firmed by 13C NMR which exhibited signals at δ 32.9 ppm
(CH2) and δ 61.4 ppm (CH) for 2c. The structure of com-
pound 2c was ultimately established by X-ray diffraction
(Fig. 2; Table 2). Furthermore compounds 2c and 2d were
readily oxidized with CoPy4(HCrO4)2 in DMF to furnish the
aromatic compounds 3c and 3d respectively. On the other
hand, compounds 3c and 3d could be directly obtained by per-
forming the cyclocondensation reaction in refluxing C6H6–
DMSO (Table 1, entries 12 and 14).
Fig. 1 X-Ray crystal structure of 1a.
For reactions carried out with ethylenic derivatives, the
primary adduct could not be isolated, except in the case of
N-phenylmaleimide as illustrated by the formation of 7e
(Scheme 2; Table 1, entry 8) and this particular behaviour has
Fig. 2 X-Ray crystal structure of 2c.
To sum up, we have developed a concise and efficient
approach to a variety of unsaturated or partly saturated benzo-
indolizine derivatives of N-acylphenothiazines. The reaction
can equally well be performed with acetylenic or olefinic com-
pounds and should be undoubtedly broadened to the synthesis
of other polycyclic indolizine-containing compounds. We also
Scheme 2 Reagents and conditions: (i) NEt3, CH2Cl2, rt; (ii) CoPy4-
(HCrO4)2, DMF, reflux.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 7 7 – 2 3 8 2
2379

View Article Online
believe that the procedural simplicity, the high efficiency and
the easy accessibility of the reaction partners should be
rewarded by giving access to a wide array of heterocyclic
frameworks equipped with a pendant phenothiazine unit.
1 hour at room temperature and then refluxed for 2 h. Then
the reaction mixture was cooled, filtered, and concentrated in
vacuum. The oily residue was washed with water and the crude
solidified residue was crystallised from acetone–EtOH or ethyl
acetate.
Experimental
Method B (reaction in C6H6–DMSO). A solution of TEA
(0.6 g, 6 mmol) in C6H6 (5 mL) was added dropwise over 15 min
to a stirred suspension of the salt 5 (2 g, 5 mmol) in a mixture
of C6H6 (20 mL) and DMSO (10 mL). Then the appropriate
dipolarophile (6 mmol) in C6H6 (5 mL) was added to the result-
ing orange mixture which was refluxed for 3–10 h and treated as
described in Method A.
General
Mps were determined on a Reichert-Thermopan apparatus and
are uncorrected. Elemental analyses were obtained using Carlo-
Erba CHNS-11110 equipment. Mass spectral analyses were
performed on a Vestec 2001 spectrometer (EI 70 eV). IR spectra
1
were recorded on a TF-IR Bomem MB 104 spectrometer. H
(300 MHz) and 13C NMR (75 MHz) spectra were recorded
{1,2-Bis(methoxycarbonyl)-1,10b-dihydropyrrolo[2,1-a]iso-
quinolin-3-yl}(10H-phenothiazin-10-yl)methanone 1a. From yl-
ide 4 and DMAD. Yellow crystals (1.63 g, 64%), mp 186–187 ЊC
(Found: C, 68.0; H, 4.2; N, 5.8. C29H22N2O5S requires C, 68.2;
H, 4.3; N, 5.5%); m/z (EI) 510 (Mϩ, 6%), 312 (100), 284 (42),
252 (32), 198 (25), 166 (22); νmax (KBr)/cmϪ1 1740 (CO), 1680
(CO); δH (400 MHz, CDCl3) 3.89 (3 H, s, OCH3), 3.90 (3 H, s,
OCH3), 4.47 (1 H, d, J 13.2, H-1), 4.71 (1 H, d, J 13.2, H-10b),
5.64 (1 H, d, J 7.6, H-6), 6.51 (1 H, d, J 7.6, H-5), 6.93 (1 H, d,
J 6.4, aromatic H), 7.16 (2 H, dd, J 7.6, 8.4, aromatic H), 7.22–
7.32 (3 H, m, aromatic H), 7.35–7.50 (4 H, m, aromatic H), 7.80
(2H, dd, J 8.0, 8.4, aromatic H); δC (100 MHz, CDCl3) 51.7
(CH3), 52.8 (CH3), 53.6 (CH-1), 65.2 (CH-10b), 105.5 (C-2),
108.5 (CH-6), 123.2 (CH-5), 123.6, 124.5, 126.0, 127.0, 127.3,
127.4, 127.5, 127.6, 127.7, 127.8, 128.0, 128.2, 129.5, 131.2,
131.4, 132.6, 136.0, 136.5, 148.6, 159.5 (CO), 164.9 (CO), 174.1
(CO).
on a Bruker AM 300 spectrometer; H (400 MHz), 13C NMR
1
(100 MHz) and 13C–1H CORR spectra were recorded on a
Bruker DRX 400 spectrometer. Chemical shifts are expressed in
ppm, positive shifts being downfield from TMS; coupling con-
stants (J) are given in Hz and rounded to the nearest 0.1 Hz.
Crystallography
Crystal data and refinement details for derivatives 1a and 2c are
presented in Table 2. All measurements were made on a Bruker
AXS Smart three-circle diffractometer using graphite-mono-
chromatized Mo-Kα radiation (λ = 0.71073 Å), and equipped
with a CCD two-dimensional detector. The structures were
solved with the SHELXTL software package.36 Direct methods
revealed the positions of all non-hydrogen atoms. After aniso-
tropic refinement, the hydrogen atoms could be located on
Fourier difference maps for compound 2c. However, for com-
pound 1a, the anisotropic displacement parameters were so
high for the methyl groups that the hydrogen atoms could not
be found. To lower the thermal agitation, another data collec-
tion was made at 100 K: in these conditions, the anisotropic
parameters were more reasonable and the position of hydrogen
atoms found without difficulty. The refinement (on F 2) con-
verged to R1 = 0.0459, Rw = 0.1219 for compound 1a and to
R1 = 0.0501, Rw = 0.1291 for 2c.†
{1-Ethoxycarbonyl-2,3-dihydropyrrolo[2,1-a]isoquinolin-3-
yl}(10H-phenothiazin-10-yl)methanone 2c. From ylide 4 and
ethyl acrylate. Yellow crystals (1.66 g, 71%), mp 203–204 ЊC
(Found: C, 72.3; H, 4.5; N, 6.2. C28H22N2O3S requires C, 72.1;
H, 4.75; N, 6.0%); m/z (EI) 466 (Mϩ, 10%), 268 (100), 240 (22),
198 (24), 166 (32); νmax (KBr)/cmϪ1 1690 (CO), 1650 (CO);
δH (DMSO-d6) 1.13 (3 H, t, J 7.0, CH3), 2.68 (2 H, br. s, CH2),
3.87–4.07 (2 H, m, OCH2), 5.59 (1 H, br. s, H-3), 6.30 (1 H, d,
J 7.0 aromatic H), 7.29 (2 H, q, J 7.0, aromatic H), 7.35–7.70
(9 H, m, aromatic H), 8.00 (1 H, br. s, Harom), 9.69 (1 H, d, J 8.3,
aromatic H); δC (DMSO-d6) 15.5 (CH3), 34.4 (CH2), 59.0 (CH3),
62.3 (CH-3), 90.2 (C-1), 106.4, 124.1, 126.2, 126.7, 128.1, 128.9,
129.2, 131.2, 134.5, 136.9, 138.2, 138.6, 151.9, 165.4 (CO), 170.7
(CO).
1-[2-Oxo-2-(10H-phenothiazin-10-yl)ethyl]isoquinolinium
chloride 5
A solution of N-(2-chloroacetyl)phenothiazine33 6 (2.75 g,
10 mmol) and isoquinoline (1.55 g, 12 mmol) in CH2Cl2
(15 mL) was stirred at room temperature for 24 h. The crude
precipitate was filtered and then recrystallized from EtOH to
afford the salt 5 as white crystals (3.24 g, 80%), mp 256–258 ЊC
(Found: C, 68.0; H, 4.2; N, 6.95. C23H17ClN2OS requires C,
68.2; H, 4.2; N, 6.9%); νmax (KBr)/cmϪ1 1676, 1640 (NCO);
δH (DMSO-d6–D2O, 1 : 1) 5.52 and 6.38 (2 H, two br. s, CH2),
7.25–7.75 (8 H, m, Hpheno), 8.01 (1 H, dt, J 1.2, 8.1, H7,iso), 8.21
(1 H, dt, J 1.0, 8.0, H6,iso), 8.27 (1 H, d, J 8.0, H5,iso), 8.43 (1 H,
d, J 8.3, H8,iso), 8.48 (1 H, d, J 6.9, H4,iso), 8.60 (1 H, d, H3,iso),
9.90 (1 H, s, H1,iso); δC (DMSO-d6–D2O, 1 : 1) 63.2 (CH2), 125.9,
127.4, 128.0, 126.0–130.0 (m, 4 Cpheno and 8 CHpheno), 131.2,
132.1, 136.9, 137.9, 138.4 (C1), 162.2 (CO).
{1-Cyano-2,3-dihydropyrrolo[2,1-a]isoquinolin-3-yl}(10H-
phenothiazin-10-yl)methanone 2d. From ylide 4 and acrylo-
nitrile. Yellow crystals (1.66 g, 71%), mp 223–225 ЊC (Found: C,
74.2; H, 3.8; N, 9.9. C26H17N3OS requires C, 74.4; H, 4.1; N,
10.0%); m/z (EI) 419 (Mϩ, 9%), 221 (100), 198 (35), 193 (34);
νmax (KBr)/cmϪ1 2168 (CN), 1680 (CO); δH (DMSO-d6) 2.57
(2 H, br. s, CH2), 6.21 (1 H, br. s, aromatic H), 7.25–7.70 (11 H,
m, aromatic H), 7.98 (1 H, br. s, aromatic H), 8.24 (1 H, d, J 6.6,
aromatic H); δC (DMSO-d6) 34.1 (CH2), 63.4 (CH-3), 105.0,
108.0, 112.6, 115.6, 122.2, 123.3, 124.0, 126.0, 127.7, 128.3,
129.0, 132.5, 133.0, 136.1, 139.6, 141.0, 153.4, 170.1 (CO).
General procedure for the synthesis of the benzoindolizine
derivatives of N-acylphenothiazine
8-(10H-Phenothiazin-10-ylcarbonyl)-10-phenyl-8a,9,10,11,
11a,11b-hexahydro-8H-pyrrolo[3Ј,4Ј:3,4]pyrrolo[2,1-a]isoquinol-
Method A (reaction in CH2Cl2). A solution of TEA (0.6 g,
6 mmol) in CH2Cl2 (5 mL) was added dropwise over 15 min to a
stirred suspension of the salt 5 (2 g, 5 mmol) in a solution of the
appropriate dipolarophile (6 mmol) in CH2Cl2 (25 mL). The
resulting orange mixture containing the ylide 4 was stirred for
ine-9,11-dione 7e. From ylide
4 and N-phenylmaleimide
(2.11 g, 78%), mp 201–203 ЊC (Found: C, 73.0; H, 4.2; N, 7.95.
C33H23N3O3S requires C, 73.2; H, 4.3; N, 7.8%); m/z (EI) 541
(Mϩ, 2%), 312 (100), 284 (37), 252 (84), 166 (30); νmax (KBr)/
cmϪ1 1705 (CO), 1675 (CO); δH (400 MHz, DMSO-d6) 3.60
(1 H, t, J 8.0, CH), 4.04 (1 H, br. s, CH), 5.00 (1 H, d, J 7.6,
CH), 5.09 (1 H, d, J 7.5, CH), 5.24 (1 H, s, CH), 5.42 (1 H,
br. s, CH), 6.81 (1 H, d, J 7.0, aromatic H), 6.94–7.10 (8 H, m,
aromatic H), 7.20 (1 H, d, J 7.6, aromatic H), 7.27–7.45 (5 H, m,
† CCDC reference numbers 205735 and 205736. See http://
www.rsc.org/suppdata/ob/b3/b302662k/ for crystallographic data in .cif
or other electronic format.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 7 7 – 2 3 8 2
2380

View Article Online
aromatic H), 7.52 (2 H, br. d, J 8.0, aromatic H); δC (100 MHz,
DMSO-d6) 47.3, 52.7, 61.9, 70.0, 100.7, 124.3, 125.8, 126.8,
127.7, 128.2, 128.4, 128.6, 129.2, 131.6, 133.1, 135.4, 139.0,
167.7 (CO), 174.3 (CO), 176.8 (CO).
8-(10H-Phenothiazin-10-yl-carbonyl)-10-phenyl-8H-pyrrolo-
[3Ј,4Ј:3,4]pyrrolo[2,1-a]isoquinoline-9,11-dione 3e. White crys-
tals (oxidation of 7e: 460 mg, 85%), mp 317–319 ЊC (Found: C,
74.0; H, 3.3; N, 7.5. C33H19N3O3S requires C, 73.7; H, 3.6; N,
7.8%); m/z (EI) 537 (Mϩ, 37%), 339 (100), 295 (92), 268 (30),
198 (36), 164 (68), 77 (31); νmax (KBr)/cmϪ1 1759 (CO), 1716
(CO); δH (400 MHz, DMSO-d6) 7.21–7.27 (7 H, m, aromatic
H), 7.36–7.40 (1 H, m, aromatic H), 7.46–7.58 (6 H, m,
aromatic H), 7.57–7.70 (2 H, m, aromatic H), 7.94–7.97 (1 H,
m, H-6), 8.63 (1 H, d, J 7.6, H-4), 8.97–9.00 (1 H, m, H-9).
General Procedure for the oxidation of cycloadducts with TPCD
[CoPy4(HCrO4)2]
A solution of the partly unsaturated cycloadduct 1a, 2c, d or 7e
(1 mmol) and TPCD (0.4 g, 0.66 mmol) in DMF (10 mL) was
refluxed for 5 h. The solution which turned green, was filtered
hot, concentrated in vacuum and then diluted with water
(10 mL). The resulting mixture was extracted with CH2Cl2 (3 ×
20 mL). The organic layer was dried (MgSO4), concentrated in
vacuum to afford 3a, c, d, e as a white solid which was recrystal-
lized in acetone (3a–d) or in acetone–EtOH (3e).
Acknowledgements
We would like to thank Dr T. G. C. Bird (Astra-Zeneca, Reims)
for helpful comments on the manuscript and Dr E. Maes
(UMR 8576, USTL) for some 400 MHz 1H NMR spectra.
{1,2-Bis(methoxycarbonyl)pyrrolo[2,1-a]isoquinolin-3-yl}-
(10H-phenothiazin-10-yl)methanone 3a. White crystals (oxid-
ation of 1a: 422 mg, 83%), mp 215–217 ЊC (Found: C, 68.7; H,
4.1; N, 5.9. C29H20N2O5S requires C, 68.5; H, 4.0; N, 5.5%); m/z
(EI) 508 (Mϩ, 3%), 310 (100), 282 (23), 198 (30), 166 (21); νmax
(KBr)/cmϪ1 1745 (CO), 1689 (CO); δH (DMSO-d6) 3.79 (3 H, s,
OCH3), 3.89 (3 H, s, OCH3), 7.20–7.26 (4 H, m, aromatic H),
7.28 (1 H, d, J 7.2, H-5), 7.45–7.61 (6 H, m, aromatic H), 7.80–
7.82 (1 H, m, H-6), 8.15–8.22 (1 H, br. d, J 7.2, H-4), 8.31–8.33
(1 H, m, H-9); δC (DMSO-d6) 52.2 (CH3), 53.3 (CH3), 110.0
(C-1), 118.9, 123.0, 123.4, 123.6, 124.5, 124.9, 126.8, 127.2,
128.2, 128.4, 128.7, 129.0, 129.7, 129.9, 132.6, 137.8, 160.5
(CO), 163.8 (CO), 167.0 (CO).
References
1 S. P. Massie, Chem. Rev., 1954, 54, 797–833.
2 C. Bodea and I. Silberg, Adv. Heterocycl. Chem., 1968, 9, 321–
460.
3 S. Saraf, F. Al-Omran and B. Al-Saleh, Heterocycles, 1987, 26,
239–273.
4 M. Sainsbury, 1,4-Thiazines, 1,4-Benzothiazines, Phenothiazines and
Related Compounds, in Rodd’s Chemistry of Carbon Compounds,
ed. M. Sainsbury, Elsevier, Amsterdam, 2nd Edition, 1998, vol 4,
Part G/Part H, pp. 575–608.
5 D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug
Synthesis, Wiley, New York, 1976, vol 1, pp. 372–392.
6 A. A. Borbely and M. Loepfe-Hinkkanen, Mod. Pharmacol.-
Toxicol., 1979, 16, 403–426.
{1-Methoxycarbonylpyrrolo[2,1-a]isoquinolin-3-yl}(10H-
phenothiazin-10-yl)methanone 3b. White crystals (from ylide 4
and methyl propioloate: 1.60 g, 71%), mp 254–256 ЊC (Found:
C, 71.7; H, 4.0; N, 6.3. C27H18N2O3S requires C, 72.0; H, 4.0;
N, 6.2%); m/z (EI) 450 (Mϩ, 15%), 252 (100), 224 (37), 198 (39),
166 (41); νmax (KBr)/cmϪ1 1704 (CO), 1646 (CO); δH (DMSO-d6)
3.84 (3 H, s, OCH3), 6.58 (1 H, s, H-2), 7.28–7.38 (4 H, m,
aromatic H), 7.44 (1 H, d, J 7.4, H-5), 7.57–7.73 (6 H, m, aro-
matic H), 7.80–7.84 (1 H, m, H-6), 8.93 (1 H, d, J 7.4, H-4),
9.44–9.48 (1 H, m, H-9); δC (DMSO-d6) 52.8 (CH3), 108.8 (C-1),
115.4, 120.3, 122.7, 125.0, 126.0, 127.6, 127.8, 128.1, 128.4,
128.8, 128.9, 130.1, 130.4, 132.7, 134.6, 139.7, 160.5 (CO), 165.4
(CO).
7 A. S. Horn, in Comprehensive Medicinal Chemistry. The Rational
Design, Mechanistic Study, and Therapeutic Application of Chemical
Compounds: Membranes and Receptors, eds. C. Hansch, P. G.
Sammes, J. B. Taylor and J. C. Emmett, Pergamon Press, Oxford,
1990, vol 3, p. 321.
8 J. E. Kristiansen, Dan. Med. Bull., 1989, 36, 178–185.
9 A. Lespagnol, Bull. Soc. Chim. Fr., 1960, 1291–1299.
10 Developments in Neuroscience. Phenothiazines and Structurally
Related Drugs: Basic and Clinical Studies, eds. E. Usdin, H. Eckert
and I. S. Forrest, Elsevier, New York, 1980, vol 7.
11 Bioactive Molecules. Phenothiazines and 1,4-Benzothiaiznes:
Chemical and Biomedical Aspects, ed. R. R. Gupta, Elsevier,
Amsterdam, 1988, vol 4.
12 N. Motohashi, S. R. Gollapudi, J. Emrani and K. R. Bhattiprolu,
Cancer Invest., 1991, 9, 305–319.
13 L. R. Morgan, A. H. Rodgers, B. W. Leblanc, S. M. Boué, Y. Yang,
B. S. Jursic and R. B. Cole, Bioorg. Med. Chem. Lett., 2001, 11,
2193–2195.
14 M. Petrovanu, E. Bâcu, P. Grandclaudon and A. Couture,
Phosphorus, Sulfur, Silicon, 1996, 108, 231–237.
15 E. Bâcu, M. Petrovanu, C. Antohie, I. Ciocoiu and O.-C. Mungiu,
Ann. Pharm. Fr., 1997, 55, 268–271.
16 E. Bâcu, M. Petrovanu, P. Grandclaudon and A. Couture,
Roum. Biotechnol. Lett., 1997, 2, 383–389.
17 E. Bâcu, M. Petrovanu, A. Couture and P. Grandclaudon,
Phosphorus, Sulfur, Silicon, 1999, 149, 207–220.
18 E. Bâcu, A. Couture and P. Grandclaudon, Synth. Commun., 2003,
33, 143–151.
19 M. Schreibman, C. E. Miller, W. H. Shelver and J. P. Vacik,
J. Pharm. Sci., 1964, 53, 985–986.
20 E. Lukevics, M. Trushule, S. Germane and I. Turovskii, Chem.
Heterocycl. Compd. (Engl. Transl.), 1997, 33, 229–233.
21 A. Prewysz-Kwinto, Khim. Geterotsikl. Soedin., 1987, 6, 756–759
(Chem. Abstr., 1988, 108, 112109).
22 S. Darvesh, D. Magee, Z. Valenta and E. Martin, PCT Int. Appl.,
2001, WO 0177078(Chem. Abstr., 2001, 135, 303780).
23 S. Darvesh, D. I. Magee, R. S. Mcdonald and E. V. Martin, PCT Int.
Appl., 2001, WO 0192240(Chem. Abstr., 2001, 136, 20279).
24 A. R. Katritzky, N. E. Graeskowiak and J. Alvarez-Builla, J. Chem.
Soc., Perkin Trans. 1, 1981, 1180–1185.
25 A. M. Shestopalov, Y. A. Sharanin, V. N. Nesterov, L. A.
Rodinovskaya, V. E. Shklover, Y. T. Struchkov and V. P. Litvinov,
Khim. Geterotsikl. Soedin., 1991, 9, 1248–1254 (Chem. Abstr., 1992,
116, 214313).
{1-Ethoxycarbonylpyrrolo[2,1-a]isoquinolin-3-yl}(10H-phen-
othiazin-10-yl)methanone 3c. White crystals (from ylide 4 and
ethyl propiolate: 1.70 g, 73%; oxidation of 2c: 377 mg, 81%),
mp 218–220 ЊC (Found: C, 72.3; H, 4.03; N, 6.1. C28H20N2O3S
requires C, 72.4; H, 4.3; N, 6.0%); m/z (EI) 464 (Mϩ, 12%), 266
(100), 238 (28), 199 (42), 166 (35); νmax (KBr)/cmϪ1 1700 (CO),
1635 (CO); δH (DMSO-d6) 1.18 (3 H, t, J 7.1, CH3), 4.15 (2 H, q,
J 7.1, CH2), 6.54 (1 H, s, H-2), 7.25–7.35 (4 H, m, aromatic H),
7.42 (1 H, d, J 7.5, H-5), 7.59–7.70 (6 H, m, aromatic H), 7.80–
7.84 (1 H, m, H-6), 9.03 (1 H, d, J 7.5, H-4), 9.56–9.60 (1 H, m,
H-9); δC (DMSO-d6) 14.9 (CH3), 60.8 (CH2), 108.8 (C-1), 115.1,
119.5, 123.3, 124.9, 127.6, 128.0, 128.2, 128.5, 128.7, 129.8,
130.2, 132.7, 134.2, 139.6, 160.0 (CO), 164.5 (CO).
{1-Cyanopyrrolo[2,1-a]isoquinolin-3-yl}(10H-phenothiazin-
10-yl)methanone 3d. White crystals (from ylide 4 and acrylo-
nitrile: 1.40 g, 67%; oxidation of 2d: 290 mg, 70%), mp 263–265
ЊC (Found: C, 74.4; H, 3.5; N, 10.2. C26H15N3OS requires C,
74.8; H, 3.6; N, 10.1%); m/z (EI) 417 (Mϩ, 21%), 219 (100), 198
(25), 192 (17), 166 (22); νmax (KBr)/cmϪ1 2216 (CO), 1650 (CO);
δH (DMSO-d6) 6.31 (1 H, s, H-2), 7.20–7.29 (4 H, m, aromatic
H), 7.32 (1 H, d, J 7.6, H-5), 7.52–7.63 (6 H, m, aromatic H),
7.81–7.84 (1 H, m, H-6), 8.65–8.70 (1 H, m, H-9), 8.98 (1 H, d,
J 7.5, H-4); δC (DMSO-d6) 84.5 (C-1), 115.3, 117.5, 120.5 (CN),
122.6, 123.3, 124.2, 125.4, 127.6, 127.7, 128.1, 128.5, 129.2,
129.5, 130.0, 132.8, 139.3, 159.4 (CO).
26 M. Travnicek, J. Pospisil and M. Potacek, Collect. Czech. Chem.
Commun., 1999, 64, 1993–2006.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 7 7 – 2 3 8 2
2381

View Article Online
27 A. W. Johnson, Ylide Chemistry, Academic Press, New York, 1966.
28 I. Zugravescu and M. Petrovanu, N-Ylide Chemistry, McGraw Hill,
New York, 1976.
29 G. Surpateanu, J. P. Catteau, P. Karafiloglou and A. Lablache-
Combier, Tetrahedron, 1976, 32, 2647–2663 and references cited
therein.
32 O. Tsuge and S. Kanemasa, Adv. Heterocycl. Chem., 1989, 45, 231–
349.
33 Y. Imakura, T. Konishi, K. Uchida, H. Sakurai, S. Kobayashi,
A. Haruno, K. Tajima and S. Yamashita, Chem. Pharm. Bull., 1994,
42, 500–511.
34 Y. Hu and H. Hu, Synth. Commun., 1992, 22, 1491–1496.
35 X. Wei, Y. Hu, T. Li and H. Hu, J. Chem. Soc., Perkin Trans. 1, 1993,
2487–2489.
30 G. Surpateanu and A. Lablache-Combier, Heterocycles, 1984, 22,
2079–2128.
31 O. Tsuge, S. Kanemasa and S. Takenaka, Bull. Chem. Soc. Jpn, 1985,
58, 3137–3157 and references cited therein.
36 G. M. Sheldrick, SHELXTL, Program for Crystal Structure
Solution and Refinement, Bruker AXS Inc., Madison, WI, 1997.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 7 7 – 2 3 8 2
2382