An alternative approach to the synthesis of functionalized pyrido[2,3-b]indoles

Article abstract of DOI:10.1016/S0040-4020(01)00404-5

A new synthesis of α-carbolines was developed starting from the easily accessible 3-substituted indol-2(3H)-one derivatives 2 and enamines 3. The intermediates 4 afforded the α-carbolines 5 and 6 by thermal cyclization with ammonium acetate in glacial acetic acid by way of pyridine ring formation.

Full text of DOI:10.1016/S0040-4020(01)00404-5

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 4787±4792
An alternative approach to the synthesis of
functionalized pyrido[2,3-b]indoles
Egle M. Beccalli,p Francesca Clerici and Alessandro Marchesini
Á Á
Istituto di Chimica Organica, Facolta di Farmacia, Universita degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
Received 8 January 2001; revised 22 March 2001; accepted 5 April 2001
AbstractÐA new synthesis of a-carbolines was developed starting from the easily accessible 3-substituted indol-2)3H)-one derivatives 2
and enamines 3. The intermediates 4 afforded the a-carbolines 5 and 6 by thermal cyclization with ammonium acetate in glacial acetic acid
by way of pyridine ring formation. q 2001 Elsevier Science Ltd. All rights reserved.
In recent years there has been little interest in the synthesis
of functionalized pyrido[2,3-b]indoles )I) )Fig. 1) until the
discovery of natural products having an a-carboline
skeleton and showing cytotoxic activity toward L1210
leukemia cells.1 Moreover, synthetic a-carbolines have
also been found to exhibit antiviral and antitumor
activities,2±4 and many of them have been patented.5 The
a-carboline )II) is a GABAA modulator which showed good
potential for the treatment of anxiety diseases.6
reaction between the N-1 and C-9a positions, starting
from the easily accessible indol-2)3H)-one substituted at
the 3-position with a 1-hydroxyalkylidene group. Only a
few examples of this strategy have been reported.10,11
The previous syntheses of the pyrido[2,3-b]indoles often
suffer from the disadvantage of starting from not easily
available precursors and the limited scope for the introduc-
tion of various substituents.
Existing synthetic routes to a-carbolines can be divided into
a number of classes as a function of the starting materials
and the bonds formed in the ®nal ring-closing steps. One of
these syntheses proceeds from a 3-substituted-2-amino
indole derivative or an equivalent masked form of an
amine. In this case the ®nal step is the formation of the
N-1ZC-2 bond.7 Another synthesis proceeds from a substi-
tuted pyridine and an aniline derivative. The B ring thus
depends on the formation of the N-9ZC-9a bond in the
®nal step.8 The intramolecular Diels±Alder reaction was
also used to obtain a-carbolines.9
By reaction of the 3-substituted 2-indolinones 1 with TEA/
ClCOOEt in dichloromethane, we obtained the correspond-
ing mixed anhydrides 2. The key synthetic step was the
reaction of compounds 2 with the appropriate enamines 3
which afforded the corresponding substituted products 4.
This reaction allowed the introduction of a wide range of
substituents )Scheme 1 and Table 1). The compounds 4
were always isolated as a mixture of inseparable isomers.
The thermal reaction of the compounds 4 with ammonium
acetate in glacial acetic acid gave the title compounds 5 by
way of the pyridine ring formation and morpholino or amino
group elimination.
We wish to present now an alternative approach for the
preparation of substituted a-carbolines by a ring-closing
In some cases, besides the a-carbolines 5 also the a-carbo-
lines 6, with loss of the N-carbethoxy group, were formed
)Scheme 2 and Table 2).
The cyclization reaction of the intermediate 4cb gave,
besides the a-carboline 5cb, a product 8cb the formation
of which is explained by hydrolysis of the enamine moiety
of the intermediate compound 4cb followed by lactoniza-
tion of the resulting enol )Scheme 3).
Figure 1.
In order to avoid the isolation of the intermediate 4, which is
sometimes problematic due to the mixture of isomers, the
sequence was realized in a one-potfashion, by rteamt ent
with AcONH4 in AcOH of the raw material of the reaction
Keywords: a-carbolines; enamines; oxindoles; thermal cyclization.
Corresponding author. Tel.: 139-2-70601774; fax: 139-2-70638473;
e-mail: egle.beccalli@unimi.it
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00404-5

4788
E. M. Beccalli et al. / Tetrahedron 57 ,2001) 4787±4792
Scheme 1.
Table 1. Data for Scheme 1
Substrate
R1
Substrate
R2
R3
R4
Productyield )%)
2a
2a
2a
2b
2c
2c
H
H
H
3a
3b
3c
3a
3a
3b
Ph
H
COOMe
Ph
Ph
H
H
)CH2)2ZOZ)CH2)2
)CH2)2ZOZ)CH2)2
H
)CH2)2ZOZ)CH2)2
)CH2)2ZOZ)CH2)2
)CH2)2ZOZ)CH2)2
4aa )84)
4ab )73)
4ac )98)
4ba )93)
4ca )58)
4cb )60)
Ph
Me
H
H
Ph
CF3
COOEt
COOEt
Scheme 2.
between the anhydride 2 and the enamine 3. Unfortunately,
in this case, besides the a-carbolines 5 and 6, also a 3,4,5,6-
tetrasubstituted pyrid-2-one 7 was obtained )Scheme 4 and
Table 3). This product was formed by nucleophilic attack of
the amino group on the C-2 position of the oxindole moiety
followed by indole ring opening. The implementation of this
strategy is under study.
Table 2. Data for Scheme 2
Substrate
R1
R2
R3
Productyield )%)
4aa
4ab
4ac
4ba
4ca
4cb
H
H
Ph
H
COOMe
Ph
H
5aa )52)
5ab )57)
5ac )47)
5ba )55)
5ca )70)
5cb )37)
±
Ph
Me
H
6ab )30)
6ac )24)
6ba )13)
±
H
CF3
COOEtPh
COOEtH
H
Ph
8cb )24)
Scheme 3.

E. M. Beccalli et al. / Tetrahedron 57 ,2001) 4787±4792
4789
Scheme 4.
Table 3. Data for Scheme 4
Substrate
R1
R2, R3
R4
Productyield )%)
2a
2a
2a
3d
3e
3f
H
H
H
Z)CH2)3Z
Z)CH2)4Z
Z)CH2)10Z
)CH2)2ZOZ)CH2)2
)CH2)2ZOZ)CH2)2
)CH2)2ZOZ)CH2)2
5ad )56)
5ae )37)
5af )33)
6ad )6)
6ae )8)
6af )19)
7ad )21)
7ae )33)
7af )25)
1. Experimental
stirred at room temperature for 12 h, then washed with H2O
)50 ml). The organic layer was dried )Na2SO4), ®ltered and
evaporated and the residue chromatographed with SiO2
Melting points were determined on a Buchi 510 or an Elec-
trothermal 9100 apparatus and are uncorrected. IR spectra
were recorded on a Jasco IR Report 100 spectrophotometer,
in nujol mull for solids and as a liquid ®lm for oils. 1H NMR
were recorded on a Varian Gemini 200, Bruker AC 200 and
Bruker Avance 300 spectrometer in CDCl3 solution unless
otherwise stated. Mass spectra were performed by an
electron impact ionization technique at 70 eV on a Finnigan
MD 800 instrument using the direct exposure probe )DEP).
Column chromatography was performed on Merck
Kieselgel 60, 0.063±0.2 mm. Evaporation was carried out
under vacuum in a rotary evaporator.
eluenthexane±CH Cl2 1:2 to CH2Cl2 to give two isomers:
2
)Z)-2c, 1.05 g, yield 39%. Mp 91±938C )yellow crystals
1
from hexane±Et2O). IR: 1755, 1722, 1630, 1595 cm21; H
NMR: 1.41 )t, 3H, Jˆ7.3 Hz); 1.44 )t, 3H, Jˆ7.3 Hz); 1.47
)t, 3H, Jˆ7.0 Hz); 4.39 )q, 2H, Jˆ7.0 Hz); 4.45 )q, 2H,
Jˆ7.3 Hz); 4.50 )q, 2H, Jˆ7.3 Hz); 7.20 )dt, 1H, Jˆ1.1,
8.1 Hz); 7.45 )dt, 1H, Jˆ1.1, 8.8 Hz); 7.98 )d, 1H,
Jˆ8.8 Hz); 8.34 )d, 1H, Jˆ8.1 Hz); m/z 333 )M1ZCO2,
37), 305 )75), 260 )64), 232 )100), 186 )85). Anal. Calcd.
for C18H19NO8: C, 57.29; H, 5.08; N, 3.71. Found: C, 57.40;
H, 5.01; N, 3.60. )E)-2c, 1.64 g, yield 61%. Mp 898C )pale
yellow crystals from hexane±Et2O). IR: 1782, 1760, 1722,
1648, 1600 cm21; 1H NMR: 1.43 )t, 3H, Jˆ7.0 Hz); 1.45 )t,
3H, Jˆ7.3 Hz); 1.46 )t, 3H, Jˆ7.3 Hz); 4.40 )q, 2H,
Jˆ7.0 Hz); 4.49 )q, 2H, Jˆ7.3 Hz); 4.50 )q, 2H,
Jˆ7.3 Hz); 7.22 )dt, 1H, Jˆ1.1, 7.7 Hz); 7.41 )dt, 1H,
Jˆ1.5, 8.1 Hz); 7.83 )dd, 1H, Jˆ1.5, 7.7 Hz); 7.94 )dd,
1H, Jˆ1.0, 8.1 Hz); m/z 333 )M1ZCO2, 6), 305 )16), 232
)100), 186 )44), 159 )62). Anal. Calcd. for C18H19NO8: C,
57.29; H, 5.08; N, 3.71. Found: C, 57.41; H, 5.17; N, 3.81.
Compounds 1a,12 1b,13 1c,14 2a,15 3a,16 3b17 were prepared
according to the literature procedure. Compounds 3c±f are
commercially available )Fluka).
1.1. Compound data
1.1.1. 1-Carbethoxy-3-+1-tri¯uoromethyl-ethoxycarbonyl-
oxy-methylene)indol-2-one 2b. Compound 1b )2.29 g,
10 mmol) was dissolved in CH2Cl2 )30 ml) and TEA
)5.5 ml, 40 mmol) was added. The stirred reaction mixture
was cooled to 08C and a solution of ClCOOEt )2.9 ml,
30 mmol) in CH2Cl2 )20 ml) was added slowly. After 1 h at
room temperature, the mixture was washed with H2O )50 ml).
The organic layer was dried )Na2SO4), ®ltered and evapo-
rated and the residue puri®ed by silica gel column chromato-
1.1.3. 3-+3-Morpholin-4-yl-2-phenyl-allylidene)-2-oxo-
2,3-dihydro-indole-1-carboxylic acid ethyl ester 4aa. To
a solution of compound 2a )915 mg, 3 mmol) in CHCl3
)30 ml), 4-styryl-morpholine 3a )945 mg, 5 mmol) was
added. The mixture was heated to 508C for 15 min then
left at room temperature for 0.5 h. The solution was evapo-
rated and the residue puri®ed by crystallization from Et2O±
CH2Cl2. Mp 1908C )lightorange crysatls), 1.015g, yield
84%. IR: 1765, 1681, 1610, 1585 cm21; 1H NMR )mixture
of two isomers): 1.44, 1.47 )2t, 3H, Jˆ7.1 Hz); 3.12, 3.30,
3.51, 3.59, 3.69, 3.73 )6t, 8H, Jˆ4.6 Hz); 4.46, 4.50 )2q, 2H,
Jˆ7.1 Hz); 5.03, 6.15 )2d, 1H, Jˆ7.8 Hz); 6.50, 6.74, 6.96
)3t, 2H, Jˆ7.8 Hz); 7.05±7.42 )m, 5H); 6.74, 7.04, 7.59,
7.82 )4s, 2H); 7.80, 7.88 )2d, 1H, Jˆ8.1 Hz); m/z 404
)M1, 100), 319 )17), 246 )86), 217 )43), 200 )96). Anal.
Calcd. For C24H24N2O4: C, 71.27; H, 5.98; N, 6.93. Found:
C, 71.32; H, 6.21; N, 7.12.
graphy, eluenthexane±CH 2Cl2 2:1 t o CHCl2, t o give 2.35 g,
2
yield 63%. Mp 37±388C )lightyellow crystals from pentane).
1
IR: 1763, 1728, 1631, 1599 cm21; H NMR: 1.47 )t , 3H,
Jˆ7.0 Hz); 1.53 )t, 3H, Jˆ7.0 Hz); 4.28 )q, 2H, Jˆ7.0 Hz);
4.50 )q, 2H, Jˆ7.0 Hz); 7.22 )dt, 1H, Jˆ1.1, 7.7 Hz); 7.41
)dt, 1H, Jˆ1.5, 8.0 Hz); 7.96 )m, 2H); m/z 329 )M1ZCO2,
16), 301 )19), 229 )38), 188 )27), 160 )100). Anal. Calcd. for
C16H14F3NO6: C, 51.48; H, 3.78; N, 3.75. Found: C, 51.29; H,
3.67; N, 3.70.
1.1.2. 3-+Ethoxycarbonyl-ethoxycarbonyloxy-methylene)-
2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester
2c. Compound 1c )2.33 g, 10 mmol) was suspended in
CHCl3 )60 ml) and TEA )4.2 ml, 30 mmol) was added
under stirring. The solution was then cooled to 08C and
ClCOOEt)2.4 ml, 25 mmol) was added. The mixut re was
1.1.4. 3-+3-Morpholin-4-yl-3-phenyl-allylidene)-2-oxo-
2,3-dihydro-indole-1-carboxylic acid ethyl ester 4ab. To
a solution of compound 2a )915 mg, 3 mmol) in THF
)40 ml), 4-)1-phenyl-vinyl)-morpholine 3b )945 mg,

4790
E. M. Beccalli et al. / Tetrahedron 57 ,2001) 4787±4792
5 mmol) was added. The mixture was heated to 508C for
15 min then left at room temperature for 0.5 h. The solution
was evaporated and the residue puri®ed by silica gel column
chromatography eluent CH2Cl2±Et2O 5:1. Mp 157±1608C
)orange crystals from Et2O), 880 mg, yield 73%. IR: 1771,
1725, 1590 cm21; 1H NMR )mixture of two isomers): 1.39,
1.46 )2t, 3H, Jˆ7.0 Hz); 3.32 )m, 4H); 3.74, 3.79 )2t, 4H,
Jˆ4.8 Hz); 4.41, 4.50 )2q, 2H, Jˆ7.0 Hz); 6.28 )d, 0.5H,
Jˆ13 Hz); 6.94 )m, 2H); 7.06±7.32 )m, 3.5H); 7.43±7.60
)m, 4H); 7.84, 7.97 )2d, 1H, Jˆ8.1 Hz); m/z 404 )M1, 83),
331 )11), 246 )37), 217 )50), 200 )100). Anal. Calcd. for
C24H24N2O4: C, 71.27; H, 5.98; N, 6.93. Found: C, 71.37; H,
6.25; N, 7.03.
1H); 7.15±7.30 )m, 7H); 7.48, 7.65, 7.83 )3d, 1H,
Jˆ7.9Hz); 7.97 )t, 0.5H, Jˆ7.7 Hz); m/z 476 )M1, 9), 389
)10), 271 )51), 232 )59), 146 )78), 105 )100). Anal. Calcd
for C27H28N2O6: C, 68.05; H, 5.92; N, 5.88; Found C, 67.87;
H, 5.83; N, 5.75.
1.1.8. 3-+1-Ethoxycarbonyl-3-morpholin-4-yl-3-phenyl-
allylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid
ethyl ester 4cb. To a solution of compound 2c )mixture
of E±Z isomers, 1.13 g, 3 mmol) in CHCl3 )40 ml), 4-)1-
phenyl-vinyl)-morpholine 3b )945 mg, 5 mmol) was added.
The mixture was heated to 508C for 15 min then left at room
temperature for 2 h. The solution was evaporated and the
residue puri®ed by crystallization. Mp 1288C )red crystals
from pentane±Et2O), 860 mg, yield 60%. IR: 1775, 1742,
1721, 1610 cm21; 1H NMR )mixture of two isomers): 1.01,
1.07, 1.39, 1.48 )4t, 6H, Jˆ7.1 Hz); 3.28 )m, 4H); 3.45 )m,
2H); 3.58, 3.69±3.79, 3.87 )3m, 4H); 4.48 )m, 2H); 6.07 )s,
0.5H); 6.90 )t, 1H, Jˆ7.9 Hz); 6.95 )t, 1H, Jˆ7.6 Hz); 7.14
)m, 1H); 7.33 )m, 2H), 7.40 )m, 3H); 7.66 )s, 0.5H); 7.75,
7.87, 7.94 )3d, 1H, Jˆ8.1 Hz); m/z 476 )M1, 100), 403 )17),
272 )43), 216 )35), 105 )36). Anal. Calcd. for C27H28N2O6:
C, 68.05; H, 5.92; N, 5.88. Found: C, 67.90; H, 5.89; N,
5.80.
1.1.5. 3-+3-Amino-2-methoxycarbonyl-but-2-enylidene)-
2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester
4ac. To a solution of compound 2a )915 mg, 3 mmol) in
THF )40 ml), methyl-3-aminocrotonate 3c )945 mg,
5 mmol) was added. The mixture was heated to re¯ux for
2.5 h. The solution was evaporated and the residue puri®ed
by silica gel column chromatography eluent CH2Cl2±Et2O
5:1. Mp 125±1288C )yellow crystals from Et2O±CH2Cl2),
970 mg, yield 98%. IR: 3380, 3210, 1768, 1730, 1718 cm21
;
1H NMR )mixture of two isomers): 1.46 )t, 3H, Jˆ7.1 Hz);
2.06, 2.18 )2s, 3H); 3.62, 3.70 )2s, 3H); 4.48 )q, 2H,
Jˆ7.1 Hz); 5.34 )bs, 1H, D2O ex.); 7.11 )m, 2H); 7.24 )t,
1H, Jˆ7.5 Hz); 7.63, 7.69 )2s, 1H); 7.86, 7.94 )2d, 1H,
Jˆ8.2 Hz); 9.20 )bs, 1H, D2O ex.); m/z 330 )M1, 94), 313
)81), 284 )87), 242 )100), 197 )77). Anal. Calcd. for
C17H18N2O5: C, 61.81; H, 5.49; N, 8.48. Found: C, 61.61;
H, 5.45; N, 8.38.
1.2. Synthesis of pyrido[2,3-b]indoles 5 and 6 from
compounds 4. General procedure
The compound 4 )1 mmol) was dissolved in AcOH )20 ml)
and AcONH4 )15 mmol) was added. The mixture was
heated to re¯ux for the reported time )see later), then the
solvent evaporated, the residue washed with H2O±NaHCO3
and extracted with CH2Cl2 )2£20 ml). The organic layer
was dried )Na2SO4), ®ltered and evaporated. The residue
was chromatographed on silica gel )eluent see later), afford-
ing compounds 5 and in some cases minor amounts of
compounds 6.
1.1.6. 3-+3-Morpholin-4-yl-2-phenyl-1-tri¯uoromethyl-
allylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid
ethyl ester 4ba. To a solution of compound 2b )1.11 g,
3 mmol) in THF )40 ml), 4-styryl-morpholine 3a )945 mg,
5 mmol) was added. The mixture was heated to 508C for 1 h
and allowed to stand at room temperature for 12 h. The
solution was evaporated and the residue puri®ed by silica
gel column chromatography eluent CH2Cl2. Mp 82±858C
dec. )orange crystals from pentane±Et2O), 1.32 g, yield
From 4aa, re¯ux 30 min, SiO2 eluentCH Cl2±Et2O 20:1:
2
5aa, 162 mg, yield 52%. Mp 108±1108C )pale yellow crys-
tals from Et2O). IR: 1731, 1605, 1585 cm21; 1H NMR: 1.58
)t, 3H, Jˆ7.1 Hz); 4.68 )q, 2H, Jˆ7.1 Hz); 7.42 )m, 2H);
7.52 )m, 3H); 7.68 )m, 2H); 8.03 )d, 1H, Jˆ7.7 Hz); 8.36 )d,
1H, Jˆ8.4 Hz); 8.44 )s, 1H); 8.85 )s, 1H); m/z 316 )M1, 41),
257 )14), 244 )100), 216 )10), 69 )50). Anal. Calcd. for
C20H16N2O2: C, 75.93; H, 5.10; N, 8.85. Found: C, 76.03;
H, 5.21; N, 8.93.
1
93%. IR: 1758, 1728, 1580 cm21; H NMR )mixture of
two isomers): 1.43, 1.48 )2t, 3H, Jˆ7.1 Hz); 3.18 )m,
4H); 3.71 )m, 4H); 4.49 )m, 2H); 6.57, 6.66 )2s, 1H); 6.98
)t, 1H, Jˆ7.9 Hz); 7.10±7.38 )m, 6H); 7.63, 7.80 )2d, 1H,
Jˆ7.8 Hz); 7.94 )m, 1H); m/z: 472 )M1, 5), 385 )45), 313
)100), 189 )83), 105 )93). Anal. Calcd. for C25H23F3N2O4: C,
63.56; H, 4.91; N, 5.93. Found: C, 63.60; H, 4.94; N, 5.99.
From 4ab, re¯ux 3 h, SiO2 eluentCH Cl2±Et2O 10:1: 5ab,
2
1.1.7. 3-+1-Ethoxycarbonyl-3-morpholin-4-yl-2-phenyl-
allylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid
ethyl ester 4ca. To a solution of compound 2c )mixture
of E±Z isomers, 1.13 g, 3 mmol) in CHCl3 )40 ml), 4-styryl-
morpholine 3a )945 mg, 5 mmol) was added. The mixture
was heated to 508C for 15 min then left at room temperature
for 1 h. The solution was evaporated and the residue puri®ed
by silica gel column chromatography eluent CH2Cl2±Et2O
20:1. Mp 71±748C )purple crystals from pentane±Et2O),
149 mg, yield 57%. Mp 137±1398C )white crystals from
1
hexane±Et2O). IR: 1709, 1628, 1590 cm21; H NMR: 1.64
)t, 3H, Jˆ7.1 Hz); 4.67 )q, 2H, Jˆ7.1 Hz); 7.41 )m, 2H);
7.51 )m, 3H); 7.83 )d, 1H, Jˆ8.1 Hz); 7.97 )d, 1H,
Jˆ7.6 Hz); 8.21 )m, 2H); 8.29 )d, 1H, Jˆ8.1 Hz); 8.42 )d,
1H, Jˆ8.4 Hz); m/z 316 )M1, 67), 271 )25), 257 )20), 244
)100), 216 )13). Anal. Calcd. for C20H16N2O2: C, 75.93; H,
5.10; N, 8.85. Found: C, 76.01; H, 5.16; N, 8.79 and 6ab,
74 mg, yield 30%. Mp 238±2408C )pale yellow crystals
1
825 mg, yield 58%. IR: 1775, 1730, 1596 cm21; H NMR
1
from hexane±Et2O). IR: 3160, 1608 cm21; H NMR: 6.98
)mixture of four isomers): 0.92, 0.94, 1.06, 1.26, 1.29, 1.38,
1.43, 1.46 )8t, 6H, Jˆ7.1 Hz); 3.15, 3.30, 3.48, 3.57, 3.65,
3.77, 3.85, 3.90 )8t, 8H, Jˆ4.8 Hz); 4.00 )q, 1H, Jˆ7.1 Hz);
4.16, 4.41, 4.48 )3m, 3H); 6.64, 6.93 )2s, 0.5H); 7.02 )m,
)d, 1H, Jˆ8.1 Hz); 7.22 )t, 1H, Jˆ7.3 Hz); 7.35 )dt, 1H,
Jˆ1.0, 8.1 Hz); 7.43±7.55 )m, 3H); 7.66 )d, 1H,
Jˆ8.0 Hz); 8.04 )d, 1H, Jˆ7.3 Hz); 8.14 )m, 2H); 8.40 )d,
1H, Jˆ8.0 Hz); 10.11 )bs, 1H, D2O ex.); m/z 244 )M1, 100),

E. M. Beccalli et al. / Tetrahedron 57 ,2001) 4787±4792
4791
216 )10), 140 )20), 122 )74), 114 )15). Anal. Calcd. for
C17H12N2: C, 83.58; H, 4.95; N, 11.47. Found: C, 83.71;
H, 5.02; N, 11.28.
Jˆ8.0 Hz); m/z 361 )M1, 75), 289 )35), 244 )15), 216
)17), 105 )100). Anal. Calcd. for C21H15NO5: C, 69.80; H,
4.18; N, 3.88. Found: C, 70.01; H, 4.32; N, 3.76.
From 4ac, re¯ux 1.5 h, SiO2 eluentCH Cl2±Et2O 20:1 to
2
1.3. Compounds 5, 6, and 7 from anhydride 2a and
enamines 3. General procedure
1:1: 5ac, 94 mg, yield 47%. Mp 127±1288C )white powder
1
from hexane±Et2O). IR: 1740, 1731, 1638, 1610 cm21; H
NMR: 1.60 )t, 3H, Jˆ7.1 Hz); 3.03 )s, 3H); 4.00 )s, 3H);
4.66 )q, 2H, Jˆ7.1 Hz); 7.43 )dt, 1H, Jˆ1.1, 7.7 Hz); 7.57
)dt, 1H, Jˆ1.5, 7.3 Hz), 8.00 )dd, 1H, Jˆ1.5, 7.7 Hz); 8.34
)dd, 1H, Jˆ1.1, 7.3 Hz); 8.85 )s, 1H); m/z 312 )M1, 45), 253
)21), 240 )100), 209 )86), 180 )47). Anal. Calcd. for
C17H16N2O4: C, 65.38; H, 5.16; N, 8.97: Found: C, 65.50;
H, 5.22; N, 8.89 and 6ac, 58 mg, yield 24%. Mp 248±2508C
)white powder from CH2Cl2±Et2O). IR: 3150, 1723,
To a solution of compound 2a )1.52 g, 5 mmol) in THF
)30 ml), the appropriate enamine 3 )7 mmol) was added.
The mixture was heated to 508C for 10 min, then cooled
to room temperature. The solvent was evaporated to dryness
then the mixture taken up with AcOH )30 ml) and treated
with AcONH4 )3 g). The mixture was heated to re¯ux for
10 min )30 min for 2a and 3f), then the solvent evaporated,
the residue washed with H2O±NaHCO3 and extracted with
CH2Cl2 )2£20 ml). The organic layer was dried )Na2SO4),
®ltered and evaporated and the residue chromatographed on
silica gel with the solvent indicated )see later), affording
compounds 5, 6 and 7.
1
1618 cm21; H NMR: 3.06 )s, 3H); 3.98 )s, 3H); 7.31 )dt,
1H, Jˆ1.5, 8.0 Hz); 7.50 )m, 2H); 8.06 )d, 1H, Jˆ7.8 Hz);
8.88 )s, 1H); 10.08 )bs, 1H, D2O ex.); m/z 240 )M1, 88), 209
)100), 180 )58), 154 )29), 127 )38). Anal. Calcd. for
C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C,
70.12; H, 5.17; N, 11.55.
From 2a and 1-morpholinocyclopentene 3d, eluent
pentane±CH2Cl2 2:1 to CH2Cl2: 5ad, 784 mg, yield 56%,
mp 152±1538C )pale yellow crystals from Et2O). IR: 1751,
From 4ba, re¯ux 30 min, SiO2 eluentCH Cl2±Et2O 40:1:
2
1
1608, 1578 cm21; H NMR: 1.55 )t, 3H, Jˆ7.1 Hz); 2.21
5ba, 212 mg, yield 55%. Mp 1008C )pale yellow crystals
from MeOH). IR: 1731, 1609, 1598 cm21; 1H NMR: 1.58 )t,
3H, Jˆ7.1 Hz); 4.68 )q, 2H, Jˆ7.1 Hz); 7.37 )m, 2H); 7.45
)m, 4H); 7.63 )t, 1H, Jˆ8.1 Hz); 8.31 )d, 1H, Jˆ8.1 Hz);
8.43 )d, 1H, Jˆ8.5 Hz); 8.58 )s, 1H); m/z 384 )M1, 74), 325
)39), 312 )100), 291 )51), 242 )31). Anal. Calcd. for
C21H15F3N2O2: C, 65.62; H, 3.93; N, 7.29. Found: C,
65.72; H, 4.02; N, 7.23 and 6ba, 42 mg, yield 13%. Mp
2108C )pale yellow crystals from CH2Cl2). IR: 3400br,
)quint, 2H, Jˆ7.5 Hz); 3.04 )t, 2H, Jˆ7.5 Hz); 3.18 )t, 2H,
Jˆ7.5 Hz); 4.63 )q, 2H, Jˆ7.1 Hz); 7.35 )t, 1H, Jˆ7.3 Hz);
7.47 )dt, 1H, Jˆ8.4, 1.3 Hz); 7.90 )d, 1H, Jˆ7.3 Hz); 8.04
)s, 1H); 8.26 )d, 1H, Jˆ8.4 Hz); m/z 280 )M1, 92), 235 )25),
221 )61), 207 )100), 179 )16). Anal. Calcd. for C17H16N2O2:
C, 72.84; H, 5.75; N, 9.99. Found: C, 72.95; H, 5.81; N,
9.88; 6ad, 63 mg, yield 6%, mp 2808C )white crystals from
CH2Cl2±Et2O). IR: 3150, 3080, 1618 cm21; 1H NMR: 2.27
)quint, 2H, Jˆ7.3 Hz); 3.13 )m, 4H); 7.25 )m, 1H); 7.47 )m,
2H); 8.02 )d, 1H, Jˆ7.7 Hz); 8.16 )s, 1H); 9.30 )bs, 1H, D2O
ex.); m/z 208 )M1, 95), 207 )100), 179 )5), 103 )19). Anal.
Calcd. for C14H12N2: C, 80.74; H, 5.81; N, 13.45. Found: C,
80.62; H, 5.79; N, 13.28 and 7ad, 300 mg, 21%, mp 167±
1688C )pale yellow crystals from Et2O). IR: 3200br, 1728,
1
1455 cm21; H NMR: 7.34 )m, 1H); 7.40±7.48 )m, 5H);
7.58 )m, 2H); 8.35 )d, 1H, Jˆ8.3 Hz); 8.49 )s, 1H); 10.51
)bs, 1H, D2O ex.); m/z 312 )M1, 100), 291 )20), 242 )21),
156 )14), 146 )19). Anal. Calcd. for C18H11F3N2: C, 69.23;
H, 3.55; N, 8.97. Found: C, 69.24; H, 3.65; N, 8.89.
1
1635, 1618 cm21; H NMR: 1.25 )t, 3H, Jˆ7.1 Hz); 2.17
From 4ca, re¯ux for 10 min, SiO2 eluentCH Cl2±Et2O
2
20:1: 5ca, 272 mg, yield 70%. Mp 848C )white crystals
from hexane±Et2O). IR: 1740, 1730, 1610 cm21;1H NMR:
1.05 )t, 3H, Jˆ7.1 Hz); 1.58 )t, 3H, Jˆ7.1 Hz); 4.28 )q, 2H,
Jˆ7.1 Hz); 4.68 )q, 2H, Jˆ7.1 Hz); 7.38 )t, 1H, Jˆ7.9 Hz);
7.46 )m, 5H); 7.58 )t, 1H, Jˆ8.1 Hz); 7.97 )d, 1H,
Jˆ7.9 Hz); 8.34 )d, 1H, Jˆ8.1 Hz); 8.67 )s, 1H); m/z 388
)M1, 79), 316 )100), 288 )51), 271 )25), 243 )19). Anal.
Calcd. for C23H20N2O4: C, 71.12; H, 5.19; N, 7.21. Found:
C, 71.25; H, 5.26; N, 7.09.
)quint, 2H, Jˆ7.5 Hz); 2.82 )t, 2H, Jˆ7.5 Hz); 3.03 )t, 2H,
Jˆ7.5 Hz); 4.16 )q, 2H, Jˆ7.1 Hz); 7.15 )t, 1H, Jˆ7.6 Hz);
7.21 )dd, 1H, Jˆ1.7 and 7.7 Hz); 7.38 )dt, 1H, Jˆ1.7,
8.4 Hz); 7.55 )s,1H); 7.79 )d, 1H, Jˆ8.2 Hz); 8.86 )s, 1H,
D2O ex.); m/z 298 )M1, 57), 281 )75), 252 )70), 225 )22),
210 )100). Anal. Calcd. for C17H18N2O3: C, 68.44; H, 6.08;
N, 9.39. Found: C, 68.36; H, 6.12; N, 9.31.
From 2a and 1-morpholinocyclohexene 3e, eluentfrom
CH2Cl2 t o CHCl2±Et2O 4:1: 5ae, 542 mg, 37%, mp 85±
868C )pale yellow crystals from hexane±Et2O). IR: 1736,
2
From 4cb, re¯ux for 30 min, SiO2 eluentpentane±Et O 6:1:
2
1
1630, 1605 cm21; H NMR: 1.55 )t, 3H, Jˆ7.1 Hz); 1.91
5cb, 144 mg, 37%, mp 868C )orange crystals from hexane±
Et2O). IR: 1737, 1607, 1595, 1586 cm21; 1H NMR: 1.54 )t,
3H, Jˆ7.1 Hz); 1.65 )t, 3H, Jˆ7.1 Hz); 4.60 )q, 2H,
Jˆ7.1 Hz); 4.68 )q, 2H, Jˆ7.1 Hz); 7.43 )m, 2H); 7.55
)m, 3H); 8.26 )m, 2H); 8.28 )s, 1H); 8.47 )d, 1H,
Jˆ8.4 Hz); 8.73 )d, 1H, Jˆ8.0 Hz); m/z 388 )M1, 97),
343 )22), 316 )100), 288 )72), 243 )29). Anal. Calcd. for
C23H20N2O4: C, 71.12; H, 5.19; N, 7.21. Found: C, 71.22; H,
5.25; N, 7.11 and 8cb, 87 mg, 24%, mp 2118C )red crystals
from CH2Cl2±Et2O). IR: 1796, 1782, 1738, 1620,
)m, 4H); 2.93 )t, 2H, Jˆ6.3 Hz); 3.11 )t, 2H, Jˆ6.3 Hz);
4.61 )q, 2H, Jˆ7.1 Hz); 7.34 )t, 1H, Jˆ7.5 Hz); 7.47 )dt,
1H, Jˆ1.3, 8.4 Hz); 7.90 )m, 2H); 8.28 )d, 1H, Jˆ8.4 Hz);
m/z 294 )M1, 70), 235 )16), 222 )100), 206 )13), 194 )37).
Anal. Calcd. for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52.
Found: C, 73.53; H, 6.25; N, 9.40; 6ae, 89 mg, yield 8%, mp
260±2628C )white crystals from CH2Cl2±Et2O). IR: 3150,
3060, 1637, 1612 cm21; 1H NMR: 1.91±2.09 )m, 4H); 3.00
)t, 2H, Jˆ6.2 Hz); 3.20 )t, 2H, Jˆ6.2 Hz); 7.25 )dt, 1H,
Jˆ1.5, 8.1 Hz); 7.45 )dt, 1H, Jˆ1.5, 8.1 Hz); 7.54 )d, 1H,
Jˆ8.1 Hz); 8.01 )d, 1H, Jˆ8.1 Hz); 8.05 )s, 1H); 10.23 )s,
1H, D2O ex.); m/z 222 )M1, 100), 221 )45), 206 )18), 194
1
1605 cm21; H NMR: 1.50 )t, 3H, Jˆ7.1 Hz); 4.53 )q, 2H,
Jˆ7.1 Hz); 7.27 )m,1H); 7.43±7.50 )m, 4H); 7.86 )m, 2H);
7.99 )d, 1H, Jˆ8.2 Hz); 8.16 )s, 1H); 9.07 )d, 1H,

4792
E. M. Beccalli et al. / Tetrahedron 57 ,2001) 4787±4792
)60), 181 )15). Anal. Calcd. for C15H14N2: C, 81.05; H, 6.35;
N, 12.60. Found: C, 81.01; H, 6.28; N, 12.50 and 7ae,
520 mg, yield 33%, mp 206±2088C dec. )white crystals
References
1. Moquin-Pattey, C.; Guyot, M. Tetrahedron 1989, 45, 3445±
3450.
from CH2Cl2±Et2O). IR: 3200br, 1732, 1641, 1628 cm21
;
1H NMR: 1.26 )t, 3H, Jˆ7.1 Hz); 1.81 )m, 4H); 2.58 )t, 2H,
Jˆ5.8 Hz); 2.81 )t, 2H, Jˆ6.0 Hz); 4.17 )q, 2H, Jˆ7.1 Hz);
7.14 )dt, 1H, Jˆ1.0, 7.7 Hz); 7.22 )dd, 1H, Jˆ1.7, 7.7 Hz);
7.39 )dt, 1H, Jˆ1.7, 8.1 Hz); 7.40 )s, 1H); 7.82 )d, 1H,
Jˆ8.1 Hz); 9.07 )s, 1H, D2O ex.); 13.60 )s, 1H, D2O ex.);
m/z 312 )M1, 30), 295 )14), 266 )65), 224 )100), 196 )15).
Anal. Calcd. for C18H20N2O3: C, 69.21; H, 6.45; N, 8.97.
Found: C, 69.15; H, 6.49; N, 8.91.
2. Semenov, A. A.; Tolstikhina, V. V. Khim. Geterotsikl. Soedin
1984, 4, 435±447.
3. Kaczmarek, L.; Nantka-Namirski, P. Pol. J. Pharmacol.
Pharm. 1981, 33, 121±127.
4. Helbecque, N.; Bernier, J. L.; Henichard, J. P.; Morel, E.;
Moquin, C.; Guyot, M. Cancer Biochem. Biophys. 1987, 9,
271±279.
5. )a) Elks, J., Webb, G.B., Gregory, G.I., Cocker, J.D. )Glaxo
Lab. Ltd). German Patent 1 913 124 )1969). )b) Glaxo Lab.
Ltd. Elks, J.; Webb, G. B.; Gregory, G. I.; Cocker, J. D. Chem.
Abstr. 1970, 72, 43636r. )c) Elks, J., Webb, G.B., Gregory,
G.I., Cocker, J.D. )Glaxo Lab. Ltd). British Patent 1 268 773
)1972). )d) Glaxo Lab. Ltd. Elks, J.; Webb, G. B.; Gregory,
G. I.; Cocker, J. D. Chem. Abstr. 1972, 76, 140760s.
6. Bolton, D.; Forbes, I. T.; Hayward, C. J.; Piper, D. C.;
Thomas, D. R.; Thompson, M.; Upton, N. Bioorg. Med.
Chem. Lett. 1993, 3, 1941±1946.
From 2a and 1-morpholinocyclododecene 3f, eluent
CH2Cl2±Et2O 6:1 to Et2O: 5af, 623 mg, yield 33%, mp
118±1208C )white crystals from Et2O). IR: 1731, 1605,
1
1572 cm21; H NMR: 1.39 )m, 6H); 1.49 )m, 6H); 1.55 )t,
3H, Jˆ7.1 Hz); 1.80 )m, 2H); 2.02 )m, 2H); 2.84 )t, 2H,
Jˆ7.4 Hz); 2.97 )t, 2H, Jˆ7.4 Hz); 4.60 )q, 2H, Jˆ
7.1 Hz); 7.35 )t, 1H, Jˆ7.5 Hz); 7.48 )t, 1H, Jˆ8.1 Hz);
7.90 )d, 1H, Jˆ7.5 Hz); 8.00 )s, 1H); 8.33 )d, 1H,
Jˆ8.1 Hz); m/z 378 )M1, 82), 321 )41), 281 )54), 268
)100), 245 )56). Anal. Calcd. for C24H30N2O2: C, 76.16;
H, 7.99; N, 7.40. Found: C, 76.26; H, 8.06; N, 7.31; 6af,
285 mg, 19%, mp 230±2328C )white crystals from CH2Cl2±
Et2O). IR: 3160, 1612, 1572 cm21; 1H NMR: 1.45 )m, 6H);
1.55 )m, 6H); 1.83 )m, 2H); 1.96 )m, 2H); 2.84 )t, 2H,
Jˆ7.6 Hz); 2.99 )t, 2H, Jˆ7.6 Hz); 7.22 )dt, 1H, Jˆ1.9,
8.1 Hz); 7.42 )m, 2H); 7.98 )d, 1H, Jˆ7.8 Hz); 8.11 )s,
1H); 8.91 )s, 1H, D2O ex.); m/z 306 )M1, 85), 305 )15),
223 )38), 209 )38), 196 )100).. Anal. Calcd. for C21H26N2:
C, 82.31; H, 8.55; N, 9.14. Found: C, 81.28; H, 8.51; N, 9.04
and 7af, 490 mg, 25%, mp 207±2088C )white crystals from
7. Forbes, I. T.; Johnson, C. N.; Thompson, M. J. Chem. Soc.,
Perkin Trans. 1 1992, 92, 275±281.
8. Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G.
Tetrahedron 1993, 49, 49±64.
9. Tahri, A.; Buysens, K. J.; Van der Eycken, E. V.;
Vandenberghe, D. M.; Hoornaert, G. J. Tetrahedron 1998,
54, 13211±13226 and references therein.
10. Abouabdellah, A.; Dodd, R. H. Tetrahedron Lett. 1998, 39,
2119±2122.
11. Barun, O.; Patra, P. K.; Ila, H.; Junjappa, H. Tetrahedron Lett.
1999, 40, 3797±3800.
12. Wenkert, E.; Bhattacharraya, N. K.; Reid, T. L.; Stevens, T. E.
J. Am. Chem. Soc. 1956, 78, 797±801.
1
Et2O). IR: 3260, 3150, 1734, 1642, 1612 cm21; H NMR:
1.27 )t, 3H, Jˆ7.1 Hz); 1.40 )m, 8H); 1.47 )m, 4H); 1.68 )m,
2H); 1.91 )m, 2H); 2.48 )t, 2H, Jˆ7.3 Hz); 2.71 )t, 2H,
Jˆ7.3 Hz); 4.17 )q, 2H, Jˆ7.1 Hz); 7.14 )t, 1H, Jˆ
7.6 Hz); 7.20 )dd, 1H, Jˆ1.7, 7.6 Hz); 7.38 )dt, 1H,
Jˆ1.7, 8.1 Hz); 7.48 )s, 1H); 7.82 )d, 1H, Jˆ7.9 Hz); 9.09
)s, 1H, D2O ex.); 12.80 )s, 1H, D2O ex.); m/z 396 )M1, 58),
379 )79), 350 )100), 308 )92), 240 )60). Anal. Calcd. for
C24H32N2O3: C, 72.70; H, 8.13; N, 7.06. Found: C, 72.53; H,
8.15; N, 6.98.
13. Rajeswaran, W. G.; Cohen, L. A. Tetrahedron Lett. 1997, 38,
7813±7814.
14. Horner, L. Ann. Chem. 1941, 548, 117±146.
15. Beccalli, E. M.; Marchesini, A.; Pilati, T. Tetrahedron 1992,
48, 5359±5374.
16. Ziegenbein, W.; Franke, W. Chem. Ber. 1957, 90, 2291±2301.
17. Hunig, S.; Hubner, K.; Benring, E. Chem. Ber. 1962, 95, 926±
936.