Divergent base-induced reactivity of cycloalkenyl-1-diazenes

Article abstract of DOI:10.1016/j.tet.2010.06.061

The different base-promoted regioselectivities of the ring closure processes in the reactions between cycloalkenyl-1-diazenes and β-ketoesters are investigated. Under the appropriate conditions it is possible to turn the synthesis towards cycloalkenyliden

Full text of DOI:10.1016/j.tet.2010.06.061

Tetrahedron 66 (2010) 6832e6841
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Divergent base-induced reactivity of cycloalkenyl-1-diazenes
,
a
a
a
a
Orazio A. Attanasi a , Stefano Berretta , Lucia De Crescentini , Gianfranco Favi , Paolino Filippone ,
*
Gianluca Giorgi b, Fabio Mantellini a
,
*
a Istituto di Chimica Organica, Università degli Studi di Urbino ‘Carlo Bo’, Via I Maggetti 24, 61029 Urbino, Italy
b Dipartimento di Chimica Organica, Università degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 April 2010
Received in revised form 27 May 2010
Accepted 21 June 2010
Available online 25 June 2010
The different base-promoted regioselectivities of the ring closure processes in the reactions between
cycloalkenyl-1-diazenes and b-ketoesters are investigated. Under the appropriate conditions it is pos-
sible to turn the synthesis towards cycloalkenyliden-pyrroles or functionalized 3-hydroxy-hydrocinno-
lines. The aromatization procedure of the heteroring counterpart of the 3-hydroxy-hydrocinnolines is
also reported.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
In order to tentatively promote the 6-exo cyclization, we have
investigated previously the reactions of 4-substituted cycloalkenyl-
Pyridazines and fused pyridazines are of considerable interest
because of their synthetic utility1 and important pharmacological
activities, many of them related to the cardiovascular or to central
nervous systems.2 On the other hand, 1,2-diaza-1,3-dienes (DDs)
are versatile precursors in organic synthesis for the preparation of
a great number of heterocyclic compounds,3 exhibiting both diene
and dienophile roles in DielseAlder reactions and acting as Michael
acceptors. Usually, DDs participate in inverse electron demand
DielseAlder reactions with electron-rich dienophiles giving rise
mainly to different tetrahydropyridazines.4,5 Alternatively, the
1-diazenes (CADs) (R1, R2¼e(CH2)ne), which lack the above-men-
tioned hydrogen, with
b-dicarbonyl compounds (Scheme 1, path
b).10 Actually, a different ‘weakly activated’ 5-exo cyclization happens
in this latter case by means of the base-mediated loss of the weakly
activated hydrogen in a-position to the hydrazone group producing
cycloalkenyliden-pyrroles F. Instead, starting from hydrazones C000
obtained from 4-chloro-DDs (EWG¼Cl) the reaction produces pyr-
idazines H or I through a 6-exo cyclization that concerns the sp3
nitrogen (Scheme 1, path c).11 The presence of Cl as a leaving group
on the C4 of the azo-ene skeleton plays a crucial role in the outcome
pyridazine derivatives were prepared from DDs and
b
-mono-
of the reaction. In fact, the key step resides in the formation of the
-unsaturated hydrazones G as a result of chloridric acid elimination,
avoiding the activation of the sp2 nitrogen.
With the aim to obtain new fused heterocycles, herein we
describe the one pot approach to unknown 3-hydroxy-3,4,5,6,7,
8-hexahydrocinnolines through a Michael additione6-exo cycliza-
a,
substituted enamines,6 or from 4-chloro-DDs and 3-dimethylami-
nopropenoates.7 The conjugated addition (Michael-type) of
activated methylene compounds B to the terminal carbon atom of
b
the azo-ene system A to produce
a-functionalized hydrazones C
was also extensively studied (Scheme 1). The following cyclization
processes involve one of the hydrazonic nitrogen atoms and ap-
propriate functionalities on the attacking nucleophile.3 Unlike what
has been reported previously by Brodka and Simon,8 we have
obtained pyrrole derivatives D or E as final products starting from
C0. The ‘strongly activated’5-exo cyclization9 (Scheme 1, path a)
involves the sp2 nitrogen and is promoted by the loss of an acidic
tion sequence starting from the same CADs and
compounds by varying the basic conditions.
b-dicarbonyl
2. Results and discussion
As previously reported,10 wehavedemonstrated thatthereaction
between CADs12 and
-dicarbonyl compounds in tetrahydrofuran
hydrogen in a-position to the hydrazonic function. This process is
b
favoured in both electron withdrawing moieties like esters or am-
ides, usually located in positions 1 (EWG2) and 4 (EWG) of the
starting DDs A, able to enhance their electrophilic character
towards the nucleophiles in the Michael additions and also from
the aromaticity of the pyrroles D,E obtained (Scheme 1, path a).
(THF) at room temperature in the presence of a catalytic amount of
sodium methoxide (MeONa) represents a useful and convenient
entry to cycloalkenyliden-pyrroles 4a (Scheme 2, path a).
Testing 2-tert-butylimino-2-diethylamino-1,3-dimethylperhy-
dro-1,3,2-diazaphosphorine (BEMP)13 as base in the reaction
between CAD 1a and methyl acetoacetate 2a, to our surprise, we
observed the formation of the new 3-hydroxy-3,4,5,6,7,8-
* Corresponding authors. E-mail addresses: orazio.attanasi@uniurb.it (O.A. Atta-
nasi), fabio.mantellini@uniurb.it (F. Mantellini).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.06.061

O.A. Attanasi et al. / Tetrahedron 66 (2010) 6832e6841
6833
hexahydrocinnoline 5a (Scheme 2, path b). This reaction was car-
ried out in dichloromethane, at room temperature, in the presence
of a stoichiometric amount of BEMP and required 14 h. This latter
synthesis proceeds by means of conjugated addition (Michael-
type) of the activated methylene group of 2a to the terminal carbon
atom of the azo-ene system of 1a producing the hydrazone in-
termediate 3. The 6-exo cyclization that converts 3 into 5a involves
the nucleophilic attack of the sp3 hydrazonic nitrogen at the ketonic
function of the methyl acetoacetate 2a. The structure of 5a was
unambiguously confirmed by X-ray analysis (Fig. 1).14
R2 R1
Michael-type addition
R1
EWG
N N EWG2
R2
H
N
A
N EWG2
EWG
R3
+
EWG1
EWG1
R3
C
B
"strongly activated"5-exo cyclization
R3
EWG
R1
Path a R2 = H
R4
N
HN
D
O
R1
EWG1 =
EWG1 =
H
EWG2
EWG
R4
H
N
N EWG2
EWG
R3
R3
H2N
C N
EWG1
R1
C'
N
HN
E
EWG2
"weakly activated"5-exo cyclization
Path b R1, R2 =
R3
EWG
H
O
R4
H
EWG1 =
N
R4
N EWG2
N
N EWG2
EWG
R3
EWG1
C
H
''
F
6-exo cyclization
EWG= Cl
Path c R2= H
R1
R1
H
H
N EWG2
H
N
H
N
N EWG2
- HCl
Cl
H
EWG1
R3
EWG1
R3
C
G
O
'''
EWG1 =C N
R3
EWG1 =
R3
R4
R4
NH2
N
N
R1
R1
I
N
N
H
Scheme 1. Possible cycloaddition behaviours in the base-mediated reactions between
DDs or CADs and compounds containing activated methylene groups.
Figure 1. ORTEP drawing of compound 5a. Ellipsoids enclose 50% probability.
Encouraged by this, other different baseesolvent combinations
were tested to promote the 6-exo cyclization (Table 1). Among the
bases screened (used in different amounts), BEMP (0.1 and 1.0 equiv)
CO2Et
N CONH2
1a
O
O
+
OMe
N
2a
Table 1
Screening activity of different basic conditions in the reaction between CAD 1a and
methyl acetoacetate 2a
MeO
EtO2C
O
O
Entry
Base
Solvent
Amount
(equiv)
Reaction
time (h)
Yielda
Yielda
(%) 4a
(%) 5a
1
2
3
4
5
6
7
8
BEMP
BEMP
t-BuONa
t-BuONa
K2CO3
K2CO3
NaH
CH2Cl2
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
0.1
1.0
0.1
1.0
1.0
4.0
0.1
1.0
0.1
1.0
1.0
1.0
0.1
1.0
72.0
14.0
8.0
d
11
26
d
N
CONH2
H
N
d
24
21
d
3
8.0
d
Path a
Path b
16.0
16.0
0.5
0.5
4.0
12.0
>96
14.0
14.0
14.0
16
27
db
db
d
"weakly activated"
5-exo cyclization
d
6-exo cyclization
db
db
51
d
BEMP
(1 equiv.)
CH2Cl2,
r.t.
MeONa
NaH
O
catalytic
O
9
MeONa
MeONa
DIPEA
DABCO
DBU
OMe
EtO2C
OMe
OH
EtO2C
10
11
12
13
14
65
dc
d
db
db
THF, r.t.
dc
N
HN
9
N
db
db
N
CONH2
CONH2
4a
5a
DBU
THF
ref. 10
this work
a
Isolated yields based on starting 1a.
The reaction gave complicated mixtures.
The reaction didn’t occur.
b
c
Scheme 2. Divergent cyclization processes induced from the different basic conditions
in the reaction of CAD 1a and methyl acetoacetate 2a.

6834
O.A. Attanasi et al. / Tetrahedron 66 (2010) 6832e6841
R1
R3
in dichloromethane, potassium carbonate (1.0 and 4.0 equiv) in THF
and MeONa (1.0 equiv) in THF all produce 3-hydroxy-3,4,5,6,7,8-
hexahydrocinnoline 5a.
( )
O
O
n
+
OR5
R4
N N CONHR2
2a−h
Instead, cycloalkenyliden-pyrrole 4a was formed using MeONa
(0.1 equiv) in THF,10 sodium tert-butylate (t-BuONa) (0.1 and
1.0 equiv) in THF and 1,4-diazabicyclo[2.2.2]octane (DABCO)
(1.0 equiv) in THF. Sodium hydride (NaH) (0.1 and 1.0 equiv) in THF,
and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.1 and 1.0 equiv) in
THF yielded a complicated reaction mixture, where neither 4a nor
5a was detected by TLC analysis. N,N-Diisopropylethylamine
(DIPEA) (1.0 equiv) in THF was ineffective. In summary, the com-
mon and cheap MeONa in stoichiometric amount, in THF, at room
temperature gave the best result to promote the 6-exo cyclization. It
is noteworthy that the amount of the sodium methoxide employed
in the reactions changes the regioselectivity of the ring closure
process: a catalytic quantity promotes the ‘weakly activated’ 5-exo
cyclization,10 while a stoichiometric amount induces the 6-exo one.
It is important to note that these cycloadditions proceed with
a high regioselectivity. In fact no mixtures of 4a and 5a were
observed.
1a−g
n = 1,2,3,4
MeONa
(1 equiv.)
THF, r.t.
O
OR5
R4
R1
( )n
R3
O
N
HN
CONHR2
3a,b
n = 1
"weakly activated"
5-exo cyclization
6-exo cyclization
O
OR5
O
OR5
R1
n = 2
n = 3,4
R1
( )n
OH
R4
R3
N
N
N
CONHR2
R3
HN
CONHR2
4b n = 3
4c n = 4
5a−i R1 = COOR
5j−l R1 = H
The use of these optimized conditions towards 6-exo cycli-
zation was extended to the reaction of CADs of different size
Scheme 3. Synthesis of
alkenyliden-pyrroles 4b,c,
a
-substituted cyclopentanone hydrazones 3a,b, cyclo-
4,4a-dialkyl-2-(aminocarbonyl)-3-hydroxy-3,4,5,6,7,8-
hexahydrocinnoline-4-4a(2H)-dicarboxylates 5aei, and alkyl-2-(aminocarbonyl)-
3-hydroxy-2,3,4,4a,5,6,7,8-octahydrocinnoline-4-carboxylates 5jel.
1aeg and various alkyl
b-ketoesters 2aeh (Scheme 3, Table 2).
The 6-exo cyclization successfully occurred only starting from
cyclohexenyl-1-diazenes 1a,cee (n¼2) producing new and func-
tionalized 4,4a-dialkyl-3-hydroxy-3,4,5,6,7,8-hexahydrocinnoline-
4-4a(2H)-dicarboxylates 5aei (R1¼COOR) and alkyl-3-hydroxy-
2,3,4,4a,5,6,7,8-octahydrocinnoline-4-carboxylates 5jel (R1¼H)
(Scheme 3, Table 2). A further confirmation of the proposed
structure derives from X-ray analysis of 5j (Fig. 2).14
hydrocinnolines were detected.10 Therefore, the regioselectivity of
the cyclization process is a result of a delicate balance that regards
both the basic conditions used and the ring size of the starting CAD
that influences the ring strain in the final fused bicyclic system. The
‘weakly activated’ 5-exo cyclization produces a carbonecarbon
double bond in the cycloalkyl portion of compounds 4 and an
incrementof this ringsize determinesa lower ringstrain (Scheme 3).
So, the ‘weakly activated’ 5-exo cyclization is favoured in the cases of
cycloheptenyl- (n¼3) 1f and cyclooctenyl-1-diazenes 1g (n¼4) as
starting materials.
Checking the progress of the reactions between 4-substituted
cyclohexenyl-1-diazenes 1a,c,d (R1¼COOEt, n¼2) and 2aeg under
the conditions previously described, after the disappearance of the
typical red colour of the azo-ene system, the TLC analysis revealed
in all cases the presence of two major products. As previously
reported,10 the more polar spots are ascribable to the respective
hydrazone intermediates 3, while the non-polar ones correspond to
The ring size of the starting CADs 1 clearly influences the course
of the reactions. In fact, cyclopentenyl-1-diazene 1b (n¼1) provided
only the corresponding
a-substituted hydrazones 3a,b. As pre-
viously reported,10 all attempts at cyclization of 3a,b failed either by
means of heat or under basic or acidic conditions. The cyclohexenyl-
1-diazenes 1a,cee (n¼2) have the suitable structural requirement
that makes possible both ring closure processes (Scheme 3, Table 2).
Instead, the reactions of cycloheptenyl-1-diazene (n¼3) 1f and
cyclooctenyl-1-diazene 1g (n¼4) with methyl acetoacetate 2a, in the
presence of a stoichiometric amount of MeONa, in THF, at room
temperature gave the corresponding cycloalkenyliden-pyrroles 4b,c
by means of ‘weakly activated’ 5-exo cyclization and no traces of
Table 2
Isolated yields of a-substituted cyclopentanone hydrazones 3a,b, cycloalkenyliden-pyrroles 4b,c, 4,4a-dialkyl-2-(aminocarbonyl)-3-hydroxy-3,4,5,6,7,8-hexahydrocinnoline-
4-4a(2H)-dicarboxylates 5aei, alkyl-2-(aminocarbonyl)-3-hydroxy-2,3,4,4a,5,6,7,8-octahydrocinnoline-4-carboxylates 5jel, 4-4a-dialkyl-2-(aminocarbonyl)-5,6,7,8-tetrahy-
drocinnoline-4,4a(2H)-dicarboxylates 6aed, alkyl 2-(aminocarbonyl)-3-methyl-2,4a,5,6,7,8-hexahydrocinnoline-4-carboxylates 6eeg, alkyl 3-methyl-2,4a,5,6,7,8-hexahy-
drocinnoline-4-carboxylates 7aec and alkyl 3-methyl-5,6,7,8-tetrahydrocinnoline-4-carboxylates 8aec
1
n
R1
R2 R3
2
R4
R5
3
Yielda (%)
4
Yielda (%)
5
Yielda (%)
6
Yieldb (%)
7
Yieldc (%)
8
Yieldd (%)
1a
1a
1a
1b
1b
1c
1c
1c
1c
1c
1d
1e
1e
1e
1f
2
2
2
1
1
2
2
2
2
2
2
2
2
2
3
4
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a Me
2b Me
2c Me
2a Me
2b Me
2c Me
2d Me
2e Me
Me
5a 65
5b 63
5c 56
CH2CH2OCH3
Bn
Me
CH2CH2OCH3 3b 75
Bn
Allyl
t-Bu
Et
3a 72
H
Ph
Ph
Ph
Ph
Ph
H
Ph
Ph
Ph
H
5d 66
5e 79
6a 82
6b 80
6c 86
6d 76
5f
61
2f
Et
5g 45
5h 58
2g 4-NO2Ph Et
Me 2a Me
Me
Me
Allyl
Et
Me
Me
5i
5j
58
63
H
H
H
H
H
2a Me
2d Me
2h Me
2a Me
2a Me
6e 85
7a 83
7b 68
7c 78
8a 92
8b 94
8c 89
H
H
5k 81
5l 72
6f
82
6g 78
CO2Me
CO2Et
4b 68
4c 63
1g
H
a
Isolated yields based on starting 1.
Isolated yields based on starting 5.
Isolated yields based on starting 6.
Isolated yields based on starting 7.
b
c
d

O.A. Attanasi et al. / Tetrahedron 66 (2010) 6832e6841
6835
H
O
O
OR5
+
N N
CONHPh
2a,d,h
MeONa
1e
THF, r.t.
Path a
(1 equiv.)
0.5 h, at the disappeareance
of the red colour
R5
O
O
OR5
O
H
H
OH
+
O
N
N
N
CONHPh
HN
5j−l
CONHPh
3 not isolable
"strongly activated"
5-exo cyclization
silica gel
R5
O
O
R5
O
H
O
- H2O
N
HN
OH
N
HN
CONHPh
10a−c
9
CONHPh
Figure 2. ORTEP drawing of compound 5j. Ellipsoids enclose 50% probability.
THF, r.t.
O
Path b
the final products 5aei. After 14e16 h, the hydrazone
intermediates disappeared and only 4,4a-dialkyl-3-hydroxy-
3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylates 5aei are
present. The attempts to isolate the intermediates 3 failed because
the hydrazones spontaneously produce the cycloalkenyliden-pyr-
roles 4 by means of ‘weakly activated’ 5-exo cyclization during the
chromatographic processes, in agreement with our previous
results.10
+
N
R5O
N
CONHPh
N
O
11a−c
12
Scheme 4. Synthesis of alkyl 1-[(anilinocarbonyl)amino]-2-methyl-4,5,6,7-tetrahydro-
1H-indole-carboxylates 10aec from CAD 1e and
11aec and 1-morpholinocyclohexene 12.
b-ketoesters 2a,d,h or from DDs
Table 3
Isolated yields of alkyl-3-hydroxy-2,3,4,4a,5,6,7,8-octahydrocinnoline-4-carboxyl-
ates 5jel and alkyl 1-[(anilinocarbonyl)amino]-2-methyl-4,5,6,7-tetrahydro-1H-in-
dole-carboxylates 10aec
Also in the case of reactions between N-1-phenyl-2-(1-cyclo-
hexenyl)-1-diazene-1-carboxamide 1e (R1¼H, n¼2) and 2a,d,h, the
TLC check at the disappearance of the red colour shows the presence
in all cases of two major products. The less polarones wereidentified
as alkyl-3-hydroxy-2,3,4,4a,5,6,7,8-octahydrocinnoline-4-carboxyl-
ated 5jel. Instead, during the chromatographic procedures the more
polar ones corresponding to the relevant hydrazone adduct
intermediates 3 were converted into the related alkyl 1-[(anilino-
carbonyl)amino]-2-methyl-4,5,6,7-tetrahydro-1H-indole-carboxyl-
ates 10aec (Scheme 4, path a, Table 3). The presence of one hydrogen
originally located in position 4 of the azo-ene system of 1e permits
a ‘strong activated’ 5-exo cyclization that yields the 2-hydroxy-
2,3,4,5,6,7-hexahydro-1H-indole intermediates 9. The final loss of
a water molecule produces 10aec. This latter 5-exo cyclization is
favoured since it furnished aromatic compounds. An alternative
route to prepare the same compounds 10aec starting from DDs
11aec and 1-morpholinocyclohexene 12 is reported from Sommer15
and Schultz et al.16 (Scheme 4, path b, Table 3). The comparison of
derivatives 10aec obtained from the two different synthetic path-
ways confirms the assigned structure. It is noteworthy that the
‘construction’ of compounds 10aec proceeds with different atomic-
assembly: choosing, for example, the cyclohexyl portion as refer-
ence, it derives from the electrophilic counterpart in the reactions of
5
Yielda (%)
10
R5
Yield (%) by 1eþ2a
47
52
41
5j
10
8
13
10a
10b
10c
Me
Allyl
Et
5k
5l
a
Isolated yields based on 1e after chromatographic columns carried out at the
disappearance of the starting materials.
the corresponding pyridazines.5,17 No instances are reported on the
conversion of octahydrocinnolines or hexahydrocinnolines into
5,6,7,8-tetrahydrocinnolines. By acidic treatment of 4,4a-dialkyl-3-
hydroxy-3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylates
5deg (R1¼COOR) and alkyl-3-hydroxy-2,3,4,4a,5,6,7,8-octahy-
drocinnoline-4-carboxylates 5jel (R1¼H) with Amberlyst 15H
(3 equiv), at room temperature, in THF, the loss of a water molecule
occurred producing the novel corresponding 4-4a-dialkyl-(amino-
carbonyl)-,5,6,7,8-tetrahydrocinnoline-4,4a(2H)-dicarboxylates
6aed or alkyl 3-methyl-2,4a,5,6,7,8-hexahydrocinnoline-4-carbox-
ylates 6eeg in highyields (Scheme 5, Table 2). In order to accomplish
the aromatization process of the pyridazine portion, potassium
carbonate (8 equiv) was added to a solution of the 4a-unsubstituted
6eeg derivatives (R1¼H), in methanol (MeOH), at room tempera-
ture. Under these conditions, the hydrolysis of the ureidic moiety
occurred and the N-unsubstituted derivatives 7aec were obtained
in good yields. The final oxidation of alkyl 3-methyl-2,4a,5,6,7,8-
hexahydrocinnoline-4-carboxylates 7aec furnished the corre-
sponding alkyl 3-methyl-5,6,7,8-tetrahydrocinnoline-4-carboxylate
CAD 1 and b-ketoesters 2 (Scheme 4, path a, Table 3), or from the
nucleophilic one starting from DDs 11 and enamine 12 (Scheme 4,
path b, Table 3).
Compounds 5 are suitable to produce further interesting de-
rivatives by means of very simple procedures. In the literature, few
reports describe the aromatization of the tetrahydropyridazines to

6836
O.A. Attanasi et al. / Tetrahedron 66 (2010) 6832e6841
compounds 8aec by addition of 2,3-dichloro-5,6-dicyano-p-ben-
zoquinone (DDQ, 1.0 equiv) in dichloromethane, at room tempera-
ture (Scheme 5, Table 2).
CADs (R1¼H) with stoichiometric amount of MeONa at the disap-
pearance of the starting materials and by chromatographing the
crude, 4,5,6,7-tetrahydro-1H-indoles 10 were achieved by means of
‘strong activated’ 5-exo cyclization.
Furthermore, derivatives 5 are powerful intermediates to pre-
pare 5,6,7,8-tetrahydrocinnolines 8. This synthetic sequence con-
stitutes a new and valid approach in the development of the
aromaticity in the heteroring portion. All these reactions proceed
under very mild conditions using easily available starting materials
and provide interesting new products in good yields without
complicated work-up procedures. It is noteworthy that these dif-
ferent hydrocinnolines are not easily available from other methods
and they represent new classes of polyheterocycles of interest in
organic,18 biological,19 medicinal20 and agricultural chemistry.21
O
5
O
5
OR
Amberlyst 15H
(3 equiv.)
OR
1
1
R
R
4
OH
R
4
R
THF, r.t.
N
2
3
N
2
3
N
CONHR
R
N
CONHR
R
-H O
2
5d−g, j−l
6a−g
1
R = H
K CO (8 equiv.)
MeOH,
r.t.
2
3
O
5
OR
O
5
OR
4
R
H
4
DDQ, (1 equiv.)
CH Cl , r.t.
R
N
N
4. Experimental section
4.1. General
3
2
2
R
N
3
N
H
R
8a−c
7a−c
Scheme 5. Synthesis of 4-4a-dialkyl-2-(aminocarbonyl)-5,6,7,8-tetrahydrocinnoline-
4,4a(2H)-dicarboxylates 6aed, alkyl 2-(aminocarbonyl)-3-methyl-2,4a,5,6,7,8-hex-
ahydrocinnoline-4-carboxylates 6eeg, alkyl 3-methyl-2,4a,5,6,7,8-hexahydrocinno-
Methyl, ethyl, 2-methoxyethyl, benzyl, allyl, tert-butyl acetoa-
cetates, ethyl propionylacetate, ethyl 4-nitrobenzoylacetate, so-
dium methoxide, sodium tert-butoxide, sodium hydride,
potassium carbonate, BEMP, DABCO, DBU, DIPEA, Amberlyst 15H,
line-4-carboxylates
7aec
and
alkyl 3-methyl-5,6,7,8-tetrahydrocinnoline-4-
carboxylates 8aec.
DDQ, silica gel 35e70
m were commercial materials and were used
3. Conclusions
without further purification. Solvents were purchased and used
without further purification with the exception of THF, which was
distilled over sodium hydroxide. Melting points were determined
on open capillary tubes. Mass spectra EI were made at an ionizing
voltage of 70 eV. 1H NMR and 13C NMR spectra were recorded at
400 and 100.32 MHz, respectively. All NMR spectra were recorded
The present investigation evidenced a different base-induced
behaviour in the reactions between CADs 1 and -ketoesters 2. As
b
a matter of fact, the synthesis indicates that 1 can react with 2
under different basic conditions showing distinct regioselectivity
(Scheme 6): (1) 4-substituted CADs (R1¼COOR) in presence of
catalytic amount of MeONa produce cycloalkenyliden-pyrroles 4 by
means of ‘weakly activated’ 5-exo cyclization; (2) 4-substituted
(R1¼COOR) and 4-unsubstituted CADs (R1¼H) with stoichiometric
amount of MeONa yield 3-hydroxy-3,4,5,6,7,8-hexahydrocinno-
lines or 3-hydroxy-2,3,4,4a,5,6,7,8-octahydrocinnolines 5 through
6-exo cyclization; (3) by stopping the reaction of 4-unsubstituted
in CDCl3 or in DMSO-d6, as specified below. Chemical shifts (dH
)
are reported in parts per million (ppm), relative to TMS as internal
standard. All coupling constants (J) values are given in hertz.
Chemical shifts (dC) are reported in parts per million (ppm), rel-
ative to CDCl3 or DMSO-d6, as internal standard in a broad band
decoupled mode; the multiplicities were obtained using 135ꢀ and
90ꢀ DEPT experiments to aid in assignment. The abbreviations
used are as follows: s, singlet; d, doublet; t, triplet; q, quartet, m,
multiplet; br, broad; cy, cycloalkyl; Ar, aromatic. All the NH and
NH2 exchanged with D2O. Precoated silica gel plates 0.25 mm
were employed for analytical thin layer chromatography and silica
R1
CO2R5
N
gel 35e70
m for column chromatography. All new compounds
HN
CONHPh
shown satisfactory elemental analysis (Cꢁ0.35; Hꢁ0.30; Nꢁ0.30).
The nomenclature was generated using ACD/IUPAC Name (version
3.50, 5 Apr. 1998), Advanced Chemistry Development Inc., Toronto,
ON (Canada).
4
MeONa
catalytic
THF, r.t.
"weakly activated"
5-exo cyclization
R1
MeONa
4.2. General procedure for the synthesis of a-substituted
O
(1 equiv.)
THF, r.t.
14−16 h
OR5
R1
cyclopentanone hydrazones 3a,b, cycloalkenyliden-pyrroles
4b,c, 4,4a-dialkyl-2-(aminocarbonyl)-3-hydroxy-3,4,5,6,7,8-
hexahydrocinnoline-4-4a(2H)-dicarboxylates 5aei and alkyl-
2-(aminocarbonyl)-3-hydroxy-2,3,4,4a,5,6,7,8-
N N CONHR2
OH
R4
1
+
N
N
CONHR2
6-exo cyclization
R1 = H, CO2R
O
O
5
OR5
R4
octahydrocinnoline-4-carboxylates 5jel
2
MeONa (1 equiv.)
THF, r.t.0.5 h
i)
To a magnetically stirred solution of CADs 1aeg (1.0 mmol) and
-ketoesters2aeh(1.0 mmol)inTHF(30 mL)astoichiometricamount
of sodium methoxidewas added (1.0 mmol). The reaction mixturewas
allowed to stand at room temperature and monitored by TLC for
14.0e16.0 h. Starting from cyclopentenyl-1-diazene 1b and
"strong activated"
5-exo cyclization
b
R1 = H
ii) silica gel
R5
O
O
b
-ketoesters 2a,b, the reagents disappeared after about 30 min
R4
yielding a polar spot. After 14.0 h, the TLC analysis showed no change,
and then the reaction solvent was evaporated under reduced pressure
and the corresponding cyclopentanone hydrazones 3a,10 b were
obtained by crystallization from ethyl acetateelight petroleum ether
(40e60 ꢀC). In the case of 4-carboxylated cyclohexenyl-1-diazenes 1a,
c,d(R1¼COOEt)or4-unsubstitutedcyclohexenyl-1-diazene1e (R1¼H)
N
HN
CONHR2
10
Scheme 6. Summary of the different base-induced behaviour in the reactions between
CADs 1 and -ketoesters 2.
b

O.A. Attanasi et al. / Tetrahedron 66 (2010) 6832e6841
6837
with 2aeg, at the disappearance of the typical red colour of the CADs
(15e30 min) the TLC check revealed the presence of two major
products. After 14.0e16.0 h the more polar spot disappeared. Then,
the reaction solvent was evaporated under reduced pressure and the
crudes were chromatographed on silica column (elution mixture: 20%
ethyl acetateecyclohexane)obtainingthecorresponding4,4a-dialkyl-
3-hydroxy-3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylate
5aei (R1¼COOEt) and alkyl-3-hydroxy-2,3,4,4a,5,6,7,8-octahy-
drocinnoline-4-carboxylate (R1¼H) 5jel. Compounds 5ael were
crystallized from ethyl acetateelight petroleum ether (40e60 ꢀC).
Starting from cycloheptenyl-1-diazene 1f or from cyclooctenyl-1-
diazene 1g and 2a, at the disappearance of the typical red colour the
TLC analysisrevealedthe presence of twospots. After4.0e6.0 h, only
the less polar one remained. The reaction solvent was evaporated
under reduced pressure and the crudes were chromatographed on
silica column (elution mixture: 20% ethyl acetateecyclohexane)
obtaining the corresponding cycloalkenyliden-pyrroles 4b,c10 that
were crystallized from diethyl etherecyclohexane.
solid; 234 mg (56%); mp 151e153 ꢀC. Found: C, 60.48; H, 6.47.
C21H27N3O6 requires C, 60.42; H, 6.52%. nmax (Nujol) 3487, 3370,
1734, 1676, 1640 cmꢂ1
; dH (400 MHz, CDCl3) 1.15e1.20 (m, 2H, cy),
1.28 (t, 3H, J¼7.2 Hz, OCH2CH3), 1.41 and 1.46 (2s, 3H, Me),
1.58e1.64 (m, 2H, cy), 1.81e1.84 (m, 1H, cy), 2.11e2.14 (m, 1H, cy),
2.49e2.55 (m, 1H, cy), 2.66e2.75 (m, 1H, cy), 3.56 (s, 1H, CH),
4.12e4.26 (m, 2H, OCH2CH3), 5.15 and 5.19 (2s, 2H, OCH2Bn), 6.02
and 6.12 (2br s, 2H, NH2), 6.57 (br s, 1H, OH), 7.25e7.37 (m, 5H, Ar)
ppm; dC (100.6 MHz, CDCl3) 14.0 (q), 21.7 (t), 25.3 (t), 26.3 (q), 26.6
(t), 26.8 (t), 33.0 (t), 34.5 (t), 48.3 (d), 54.5 (s), 62.1 (t), 66.5 (t), 83.0
(s), 84.2 (s), 128.1 (d), 128.3 (d), 128.4 (d), 135.5 (s), 145.2 (s), 148.1
(s),158.9 (s),159.4 (s),168.7 (s),171.9 (s) ppm; MS: m/z¼417 [Mþ, 2],
399 (9), 372 (34), 344 (52), 328 (160), 312 (79), 284 (100), 239 (61),
211 (73), 168 (72%).
4.2.5. 4-Benzyl 4a-ethyl 2-(anilinocarbonyl)-3-hydroxy-3-methyl-
3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylate (5d). White
solid; 325 mg (66%); mp 153e154 ꢀC. Found: C, 65.78; H, 6.26.
C27H31N3O6 requires C, 65.71; H, 6.33%. nmax (Nujol) 3395, 3289,
4.2.1. Ethyl
2-[2-(aminocarbonyl)hydrazono]-1-{1-[(2-methoxy-
3143, 1775, 1712,1689 cmꢂ1
; dH (400 MHz, CDCl3) 1.23e1.33 (m, 3H,
ethyl)carbonyl]-2-oxopropyl}cyclopentanecarboxylate (3b). White
solid; 288 mg (75%); mp 136e138 ꢀC. Found: C, 51.63; H, 6.72.
C16H25N3O7 requires C, 51.74; H, 6.78%. nmax (Nujol) 3365, 3225,
OCH2CH3), 1.36e1.43 (m, 2H, cy), 1.47 and 1.55 (2s, 3H, Me),
1.61e1.67 (m, 1H, cy), 1.83e1.90 (m, 1H, cy), 2.13e2.20 (m, 1H, cy),
2.53e2.66 (m, 2H, cy), 2.71e2.80 (m, 1H, cy), 3.16 and 3.62 (2s, 1H,
CH), 4.13e4.20 (m, 2H, OCH2CH3), 5.14e5.24 (m, 2H, OCH2Bn),
7.05e7.26 (m, 1H, Ar), 7.29e7.47 (m, 10H, Ar, OH), 9.69 and 8.72 (2br
s, 1H, NH) ppm; dC (100.6 MHz, CDCl3) 14.3 (q), 14.4 (q), 22.0 (t),
22.9 (t), 25.6 (t), 26.7 (q), 27.0 (t), 27.1 (t), 33.4 (t), 34.8 (t), 48.7 (d),
50.8 (d), 55.0 (s), 57.3 (s), 62.3 (t), 62.5 (t), 67.0 (t), 67.1 (t), 67.2 (t),
83.6 (s), 85.0 (s), 120.1 (d), 120.3 (d), 123.8 (d), 124.0 (d), 128.5 (d),
128.7 (d), 128.8 (d), 129.1 (d), 129.2 (d), 135.8 (s), 137.8 (s), 145.8 (s),
148.6 (s), 155.1 (s), 155.5 (s), 168.4 (s), 169.1 (s), 170.2 (s), 172.2 (s)
ppm; MS: m/z¼493 [Mþ, 12], 448 (7), 420 (55), 386 (48), 358 (100),
313 (42), 285 (69), 266 (62), 238 (31%).
1782, 1742 cmꢂ1
;
dH (400 MHz, DMSO-d6) 1.18 (t, 3H, J¼7.2 Hz,
OCH2CH3), 1.58e1.65 (m, 1H, cy), 1.95e2.08 (m, 2H, cy), 2.18 (s, 3H,
Me), 2.28e2.40 (m, 2H, cy), 2.58e2.71 (m,1H, cy), 3.36 (s, 3H, OMe),
3.64 (s, 1H, CH), 3.42e3.64 (m, 2H, OCH2CH2O), 4.02e4.24 (m, 4H,
OCH2CH3, OCH2CH2O), 5.17 and 6.09 (br s, 2H, NH2), 7.63 (br s, 1H,
NH) ppm; dC (100.6 MHz, DMSO-d6) 14.5 (q), 19.7 (q), 27.3 (t), 28.0
(t), 29.1 (q), 30.1 (t), 58.2 (d), 62.3 (t), 63.6 (t), 64.7 (s), 70.4 (t), 145.3
(s), 154.9 (s), 169.2 (s), 171.4 (s), 201.7 (s) ppm; MS: m/z¼371 [Mþ,
8], 340 (2), 325 (38), 297 (15), 268 (80), 254 (36), 223 (13), 195
(100%).
4.2.2. 4a-Ethyl 4-methyl 2-(aminocarbonyl)-3-hydroxy-3-methyl-
3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylate (5a). White
solid; 222 mg (65%); mp 145e147 ꢀC. Found: C, 52.70; H, 6.76.
C15H23N3O6 requires C, 52.78; H, 6.79%. nmax (Nujol) 3411, 3253,
4.2.6. 4-Allyl 4a-ethyl 2-(anilinocarbonyl)-3-hydroxy-3-methyl-
3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylate (5e). White
solid; 350 mg (79%); mp 140e142 ꢀC. Found: C, 62.35; H, 6.63.
C23H29N3O6 requires C, 62.29; H, 6.59%. nmax (Nujol) 3384, 1757,
3189, 1754, 1733,1679 cmꢂ1
;
dH (400 MHz, DMSO-d6) 1.08e1.30 (m,
1740, 1716, 1672 cmꢂ1
; dH (400 MHz, CDCl3) 1.08e1.30 (m, 2H, cy),
2H, cy), 1.25 (t, J¼7.2 Hz, 3H, OCH2CH3), 1.31 (s, 3H, Me), 1.63e1.70
(m, 1H, cy), 1.80e1.87 (m, 1H, cy), 2.01e2.08 (m, 1H, cy), 2.54e2.62
(m, 3H, cy), 3.29 and 3.33 (s, 1H, CH), 3.60 (s, 3H, OMe), 4.14e4.25
(m, 2H, OCH2CH3), 6.86 and 6.95 (2br s, 2H, NH2), 7.68 (s, 1H, OH)
ppm; dC (100.6 MHz, DMSO-d6) 13.7 (q), 13.8 (q), 21.4 (t), 25.2 (t),
26.2 (q), 32.4 (t), 34.3 (t), 47.6 (d), 51.4 (q), 51.6 (q), 54.3 (s), 62.1 (t),
82.2 (s), 142.2 (s), 159.1 (s), 168.8 (s), 171.9 (s) ppm; MS: m/z¼341
[Mþ, 15], 323 (5), 298 (20), 280 (33), 267 (100), 250 (38), 235 (13),
220 (21), 207 (84),193 (47), 151 (100%).
1.25 (t, 3H, J¼7.2 Hz, OCH2CH3), 1.31 (s, 3H, Me), 1.61e1.71 (m, 1H,
cy), 1.83e1.94 (m, 1H, cy), 2.23e2.29 (m, 1H, cy), 2.23e2.48 (m, 2H,
cy), 2.61e2.73 (m, 1H, cy), 3.54 and 3.59 (2s, 1H, CH), 4.15e4.33 (m,
2H, OCH2CH3), 4.55e4.71 (m, 2H, OCH2CH]CH2), 5.22e5.29 (m,
1H, OCH2CH]CH2), 5.37 (d, 1H, J¼17.2 Hz, OCH2CH]CH2),
5.86e5.98 (d, 1H, J¼17.2 Hz, OCH2CH]CH2), 7.07 (t, 1H, J¼7.6 Hz,
Ar), 7.21 (br s, 1H, OH), 7.32 (t, 2H, J¼7.6 Hz, Ar), 7.45 (d, 2H,
J¼8.8 Hz, Ar), 8.70 and 8.73 (2br s, 1H, NH) ppm; dC (100.6 MHz,
CDCl3) 13.8 (q), 13.9 (q), 21.7 (t), 22.0 (q), 25.3 (t), 25.5 (t), 26.1 (q),
26.3 (q), 26.8 (t), 33.1 (t), 33.2 (t), 34.6 (t), 55.6 (d), 61.9 (t), 62.2 (t),
65.5 (t), 65.6 (t), 82.2 (s), 83.3 (s), 118.5 (d), 119.2 (d), 119.6 (d), 119.8
(d), 120.0 (d), 123.3 (d), 123.4 (d), 128.8 (s), 128.9 (s), 131.2 (d), 131.7
(d),137.5 (t),137.8 (t),145.5 (s),154.6 (s),158.8 (s),168.6 (s),171.3 (s),
171.9 (s) ppm; MS: m/z¼443 [Mþ, 12], 398 (8), 386 (24), 369 (84),
358 (59), 249 (100), 238 (17), 210 (100), 193 (93), 165 (42%).
4.2.3. 4a-Ethyl 4-(2-methoxyethyl) 2-(aminocarbonyl)-3-hydroxy-3-
methyl-3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylate
(5b). White solid; 243 mg (63%); mp 138e140 ꢀC. Found: C, 52.88;
H, 7.10. C17H27N3O7 requires C, 52.98; H, 7.06%. nmax (Nujol) 3425,
3213, 3120, 1768, 1716, 1637 cmꢂ1
; dH (400 MHz, CDCl3) 1.26 (t, 3H,
J¼7.2 Hz, OCH2CH3),1.35e1.51 (m, 2H, cy),1.44 (s, 3H, Me),1.64e1.70
(m, 2H, cy), 1.84e1.90 (m, 1H, cy), 2.17e2.21 (m, 1H, cy), 2.50e2.57
(m, 1H, cy), 2.67e2.76 (m, 1H, cy), 3.33 (s, 3H, OMe), 3.53 (s, 1H, CH),
4.2.7. 4-tert-Butyl
4a-ethyl
2-(anilinocarbonyl)-3-hydroxy-3-
methyl-3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylate (5f).
White solid; 280 mg (61%); mp 145e147 ꢀC. Found: C, 62.86; H, 7.18.
C24H33N3O6 requires C, 62.73; H, 7.24%. nmax (Nujol) 3378, 1736,
3.48e3.62 (m, 2H, OCH2CH2O), 4.11e4.28 (m, 4H, OCH2CH3, OCH2
-
CH2O), 5.15 and 6.52 (br s, 2H, NH2), 7.32 (br s, 1H, OH) ppm; dC
(100.6 MHz, CDCl3) 14.0 (q), 21.7 (t), 25.2 (t), 26.3 (q), 33.0(t), 34.4 (t),
48.1 (d), 54.3 (s), 58.6 (q), 62.1 (t), 63.5 (t), 70.1 (t), 83.0 (s), 145.3 (s),
159.0 (s), 168.9 (s),172.0 (s) ppm; MS: m/z¼385 [Mþ, 5], 342 (3), 311
(22), 281 (1), 251 (100), 235 (12), 207 (13), 193 (100%).
1722, 1688, 1678 cmꢂ1
;
dH (400 MHz, CDCl3) 1.28 (t, 3H, J¼7.2 Hz,
OCH2CH3), 1.31 and 1.33 (2s, 9H, t-Bu), 1.47 and 1.53 (2s, 3H, Me),
1.58e1.68 (m, 3H, cy), 1.74e1.83 (m, 1H, cy), 1.82e1.98 (m, 1H, cy),
2.26e2.32 (m, 1H, cy), 2.41e2.47 (m, 1H, cy), 2.68e2.80 (m, 1H, cy),
3.38 and 3.40 (2s, 1H, CH), 4.18e4.32 (m, 2H, OCH2CH3), 7,08 (t, 1H,
J¼7.6 Hz, Ar), 7.18 and 7.20 (2s, 1H, OH), 7.30 (t, 2H, J¼7.6 Hz, Ar),
7.45 (d, 2H, J¼8.4 Hz, Ar), 8.74 (br s, 1H, NH) ppm; dC (100.6 MHz,
4.2.4. 4-Benzyl 4a-ethyl 2-(aminocarbonyl)-3-hydroxy-3-methyl-
3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylate (5c). White

6838
O.A. Attanasi et al. / Tetrahedron 66 (2010) 6832e6841
CDCl3) 14.0 (q), 21.9 (t), 25.5 (t), 26.6 (q), 26.8 (t), 28.0 (q), 29.6 (t),
33.2 (t), 34.4 (t), 49.1 (d), 54.3 (s), 62.1 (t), 81.7 (s), 83.6 (s), 119.6 (d),
119.9 (d), 123.5 (d), 128.9 (d), 137.6 (s), 145.7 (s), 154.8 (s), 172.2 (s)
ppm; MS: m/z¼459 [Mþ, 8], 414 (13), 386 (62), 358 (100), 313 (70),
285 (72), 266 (18), 237 (100%).
NH) ppm; dC (100.6 MHz, CDCl3) 20.4 (q), 24.4 (t), 26.1(t), 31.6 (t),
34.2 (t), 37.7 (d), 52.4 (q), 54.2 (d), 85.4 (s), 120.0 (d), 123.6 (d), 128.9
(d), 137.4 (s), 151.8 (s), 155.8 (s), 171.6 (s) ppm; MS: m/z¼345 (Mþ,
40), 327 (7), 254 (14), 253 (100), 235 (24), 208 (37), 193 (40), 179
(64), 166 (34), 149 (100), 136 (32%).
4.2.8. Diethyl 2-(anilinocarbonyl)-ethyl-3-hydroxy-3,4,5,6,7,8-hex-
ahydrocinnoline-4-4a(2H)-dicarboxylate (5g). White solid; 200 mg
(45%); mp 146e148 ꢀC. Found: C, 62.12; H, 6.97. C23H31N3O6 requires
4.2.12. Allyl 2-(anilinocarbonyl)-3-hydroxy-3-methyl-2,3,4,4a,5,6,7,8-
octahydrocinnoline-4-carboxylate (5k). White solid; 301 mg (81%);
mp 134e136 ꢀC. Found: C, 64.59; H, 6.84. C20H25N3O4 requires C,
C, 62.01; H, 7.01%. nmax (Nujol) 3405, 3372,1764,1717, 1653 cmꢂ1
;
dH
64.67; H, 6.78%. nmax (Nujol) 3447, 3368, 1741, 1710, 1688, 1670 cmꢂ1
;
(400 MHz, CDCl3) 0.95 (t, 3H, J¼7.2 Hz, OCH2CH3),1.20e1.36 (m, 7H,
1cy and 2CH2CH3),1.40e1.60 (m, 3H, cy),1.66e1.79 (m, 2H, CH2CH3),
1.91e1.97 (m, 1H, cy), 2.20e2.30 (m, 1H, cy), 2.60e2.71 (m, 1H, cy),
2.74e2.90 (m,1H, cy), 3.62 (s,1H, CH), 4.10e4.30 (m, 4H, 2OCH2CH3),
7.07 (t, 1H, J¼7.6 Hz, Ar), 7.18 (s, 1H, OH), 7.31 (t, 2H, J¼8.0 Hz, Ar),
7.45 (d, 2H, J¼8.8 Hz, Ar), 8.78 (s, 1H, NH) ppm; dC (100.6 MHz,
CDCl3) 7.40 (q), 8.19 (q),14.0 (q), 21.9 (t), 25.5 (t), 30.4 (t), 33.1 (t), 34.8
(t), 48.2 (d), 50.1 (s), 60.8 (t), 61.0 (t), 62.3 (t), 62.4 (t), 85.1 (s), 86.3 (s),
119.8 (d), 123.4 (d), 128.8 (d), 137.6 (s), 145.5 (s), 155.0 (s), 169.1 (s),
172.1 (s) ppm; MS: m/z¼445 [Mþ, 13], 399 (25), 372 (100), 327 (74),
299 (62), 280 (12), 252 (45), 207 (24%).
dH (400 MHz, CDCl3) 1.14e1.29 (m, 2H, cy), 1.41e1.52 (m, 2H, cy), 1.57
(s, 3H, Me), 1.84e2.00 (m, 3H, cy), 2.22 (dt, 1H, J¼14.0, 5.2 Hz,
CH2CHCH), 2.58 (br s, 1H, OH), 2.59e2.66 (m, 1H, cy), 2.88 (d, 1H,
J¼12.0 Hz, CH2CHCH), 4.68e4.74 (m, 2H, OCH2CH]CH2), 5.26 (dd,
1H, J¼10.8, 1.6 Hz, OCH2CH]CH2), 5.40 (dd, 1H, J¼17.2, 1.6 Hz,
OCH2CH]CH2), 5.88e6.00 (m, 1H, OCH2CH]CH2), 7.07 (t, 1H,
J¼7.6 Hz, Ar), 7.29 (t, 2H, J¼7.6 Hz, Ar), 7.45 (d, 2H, J¼7.2 Hz, Ar), 8.67
(s,1H, NH) ppm; dC (100.6 MHz, CDCl3) 20.4 (q), 24.4 (t), 26.1 (t), 31.5
(t), 34.3 (t), 37.3 (d), 54.3 (d), 65.7 (t), 85.4 (s),118.4 (t),119.9 (d),123.6
(d), 128.8 (d), 131.7 (d), 137.5 (s), 151.8 (s), 155.7 (s), 170.8 (s) ppm;
MS: m/z¼371[Mþ, 15], 353 (8), 279 (52), 261 (10), 234 (43), 205 (87),
193 (100), 177 (22), 165 (28), 149 (100), 136 (17), 119 (71%).
4.2.9. Diethyl
2-(anilinocarbonyl)-3-hydroxy-3-(4-nitrophenyl)-
3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylate (5h). White
solid; 312 mg (58%); mp 163e165 ꢀC. Found: C, 60.31; H, 5.64.
C27H30N4O8 requires C, 60.22; H, 5.61%. nmax (Nujol) 3247, 3149,
4.2.13. Ethyl 2-(anilinocarbonyl)-3-hydroxy-3-methyl-2,3,4,4a,5,6,7,8-
octahydrocinnoline-4-carboxylate (5l). White solid; 258 mg (72%);
mp 139e141 ꢀC. Found: C, 63.54; H, 7.04. C19H25N3O4 requires C,
3094, 1734, 1692, 1607 cmꢂ1
;
dH (400 MHz, DMSO-d6) 1.24 (t, 3H,
63.49; H, 7.01%. nmax (Nujol) 3421, 3355, 1732, 1680 cmꢂ1
; dH
J¼7.2 Hz, OCH2CH3), 1.29 (t, 3H, J¼7.2 Hz, OCH2CH3), 1.30e1.38 (m,
1H, cy), 1.63e1.72 (m, 1H, cy), 1.85e1.93 (m, 1H, cy), 2.03e2.11 (m,
1H, cy), 2.67e2.75 (m, 1H, cy), 2.80e2.86 (m, 1H, cy), 3.27 (s, 1H,
CH), 3.62e3.80 (m, 2H, cy), 4.08e4.27 (m, 4H, 2OCH2CH3), 6.98 (t,
1H, J¼7.2 Hz, Ar), 7.15 (s, 1H, OH), 7.24 (t, 2H, J¼7.2 Hz, Ar), 7.56 (d,
2H, J¼7.2 Hz, Ar), 7.76e7.85 (m, 1H, Ar), 8.06e8.13 (m, 1H, Ar),
8.17e8.25 (m, 1H, Ar), 8.24e8.35 (m, 1H, Ar), 9.51 and 9.64 (2s, 1H,
NH) ppm; dC (100.6 MHz, DMSO-d6) 13.5 (q), 13.9 (q), 14.1 (q), 21.4
(t), 21.8 (t), 24.7 (t), 25.1 (t), 32.4 (t), 33.7 (t), 58.6 (s), 60.5 (t), 61.3
(t), 81.4 (s), 119.5 (d), 120.2 (d), 122.2 (d), 123.6 (d), 125.8 (s), 126.8
(d), 128.4 (d), 138.8 (s), 146.0 (s), 146.3 (s), 150.8 (s), 152.3 (s), 167.9
(s), 171.0 (s) ppm; MS: m/z¼538 [Mþ, 18], 493 (51), 465 (77), 420
(84), 392 (100), 373 (64), 344 (17), 300 (10), 272 (93%).
(400 MHz, CDCl3) 1.14e1.23 (m, 1H, cy), 1.32 (t, 3H, J¼6.4 Hz,
OCH2CH3), 1.41e1.51 (m, 2H, cy), 1.57 (s, 3H, Me), 1.84e2.00 (m, 3H,
cy), 2.22 (dt, 1H, J¼13.6, 5.2 Hz, CH2CHCH), 2.58 (br s, 1H, OH),
2.61e2.66 (m, 2H, cy), 2.83 (d, 1H, J¼12.0 Hz, CH2CHCH), 4.21e4.32
(m, 2H, OCH2CH3), 7.08 (t,1H, J¼7.2 Hz, Ar), 7.34 (t, 2H, J¼7.6 Hz, Ar),
7.44 (d, 2H, J¼8.4 Hz, Ar), 8.66 (s, 1H, NH) ppm; dC (100.6 MHz,
CDCl3) 14.0 (q), 20.4 (q), 24.5 (t), 26.1 (t), 31.5 (t), 34.3 (t), 37.8 (d),
54.4 (d), 61.3 (t), 85.5 (s), 120.0 (d), 123.6 (d), 128.9 (d), 137.5 (s),
151.8 (s), 155.8 (s), 171.1 (s) ppm; MS: m/z¼359 [Mþ, 13], 341 (6),
267 (35), 249 (10), 222 (28), 193 (100), 180 (32), 149 (74%).
4.3. General procedure for the synthesis of 4-4a-dialkyl-2-
(aminocarbonyl)-5,6,7,8-tetrahydrocinnoline-4,4a(2H)-
dicarboxylates 6aed or alkyl 2-(aminocarbonyl)-3-methyl-
2,4a,5,6,7,8-hexahydrocinnoline-4-carboxylates 6eeg, of alkyl
3-methyl-2,4a,5,6,7,8-hexahydrocinnoline-4-carboxylates
7aec and alkyl 3-methyl-5,6,7,8-tetrahydrocinnoline-4-
carboxylate compounds 8aec
4.2.10. 4a-Ethyl 4-methyl 2-(aminocarbonyl)-3-hydroxy-3,7-di-
methyl-3,4,5,6,7,8-hexahydrocinnoline-4-4a(2H)-dicarboxylate (5i).
White solid; 206 mg (58%); mp 143e145 ꢀC. Found: C, 54.14; H, 7.11.
C16H25N3O6 requires C, 54.07; H, 7.09%. nmax (Nujol) 3323, 1781,
1712, 1695, 1655 cmꢂ1
; dH (400 MHz, DMSO-d6) 0.86 (d, 3H,
J¼6.8 Hz, CH3CH), 1.25 (t, 3H, 7.2 Hz, OCH2CH3), 1.31 (s, 3H, CH3C),
1.43e1.57 (m, 3H, cy), 1.84e1.88 (m, 1H, cy), 2.12e2.20 (m, 1H, cy),
2.23e2.31 (m, 1H, cy), 2.81 and 2.84 (2d, 1H, J¼6.0 and 5.8 Hz,
CHCH3), 3.30 and 3.32 (s, 1H, CH), 3.59 and 3.60 (s, 3H, OCH3),
4.13e4.27 (m, 2H, OCH2CH3), 6.87 and 6.92 (2br s, 2H, NH2), 7.67 (s,
1H, OH) ppm; dC (100.6 MHz, DMSO-d6) 13.7 (q), 13.8 (q), 17.6 (t),
26.1 (t), 26.3(q), 27.0 (t), 27.6 (t), 27.7 (t), 28.2 (d), 47.4 (d), 51.4 (q),
54.6 (s), 62.2 (t), 82.3 (s), 142.3 (s), 159.1 (s), 169.0 (s), 171.9 (s) ppm;
MS: m/z¼335 [Mþ, 8], 324 (27), 310 (56), 269 (100), 282 (62), 251
(50), 238 (82), 223 (100), 179 (84%).
4,4a-Dialkyl-2-(aminocarbonyl)-3-hydroxy-3,4,5,6,7,8-hexahy-
drocinnoline-4-4a(2H)-dicarboxylates 5deg and alkyl-2-(amino-
carbonyl)-3-hydroxy-2,3,4,4a,5,6,7,8-octahydrocinnoline-4-carboxy-
lates 5jel were dissolved in THF (20 mL) and 3 equiv of Amberlyst
15 was added. The reaction mixture was magnetically stirred gently
for 4.0e5.0 h at room temperature until the disappearance of
the starting materials (monitored by TLC). 4-4a-Dialkyl-2-
(aminocarbonyl)-5,6,7,8-tetrahydrocinnoline-4,4a(2H)-dicarboxy-
lates 6aed were obtained from 5deg and alkyl 2-(aminocarbonyl)-
3-methyl-2,4a,5,6,7,8-hexahydrocinnoline-4-carboxylates
6eeg
were obtained from 5jel. Products 6aeg were purified by column
chromatography on silica gel (elution mixture: 15% ethyl aceta-
teecyclohexane) and by subsequent crystallization from diethyl
etherecyclohexane. In order to prepare alkyl 3-methyl-2,4a,5,6,7,8-
hexahydrocinnoline-4-carboxylates 7aec, to a solution of 6eeg in
MeOH (20 mL) potassium carbonate (8 equiv) was added. The
reaction mixture was allowed to stand at room temperature
under magnetic stirring until the disappearance of the starting
6eeg (4.0e6.0 h, monitored by TLC). The reaction solvent was
then evaporated under reduced pressure, the crudes were
4.2.11. Methyl 2-(anilinocarbonyl)-3-hydroxy-3-methyl-2,3,4,4a,5,6,7,8-
octahydrocinnoline-4-carboxylate (5j). White solid; 217 mg (63%); mp
135e137 ꢀC. Found: C, 62.66; H, 6.75. C18H23N3O4 requires C, 62.59;
H, 6.71%. nmax (Nujol) 3470, 3369, 1739, 1668, 1592 cmꢂ1
; dH
(400 MHz, CDCl3) 1.10e1.22 (m, 1H, cy), 1.38e1.50 (m, 2H, cy), 1.56
(s, 3H, Me), 1.85e2.00 (m, 3H, cy), 2.22 (dt, 1H, J¼13.2, 5.2 Hz,
CH2CHCH), 2.58 (br s, 1H, OH), 2.59e2.66 (m, 2H, cy), 2.86 (d, 1H,
J¼12.0 Hz, CH2CHCH), 3.79 (s, 3H, OMe), 7.08 (t, 1H, J¼7.6 Hz, Ar),
7.32 (t, 2H, J¼7.6 Hz, Ar), 7.44 (d, 2H, J¼7.6 Hz, Ar), 8.67 (br s, 1H,

O.A. Attanasi et al. / Tetrahedron 66 (2010) 6832e6841
6839
chromatographed on silica column (elution mixture: 15% ethyl
acetateecyclohexane) and products 7aec were collected pure by
crystallization from ethyl acetateecyclohexane. Alkyl 3-methyl-
5,6,7,8-tetrahydrocinnoline-4-carboxylates 8aec were obtained by
addition of DDQ (1 equiv) to a solution of 7aec in dichloromethane.
The mixture was magnetically stirred at room temperature until
the disappearance of the starting material (0.5e3.0 h, monitored by
TLC). Then, the reaction solvent was evaporated under reduced
pressure and the crudes were chromatographed on silica column
(elution mixture: 10% ethyl acetateecyclohexane) obtaining the
desired compounds 8aec that were crystallized from diethyl
etherelight petroleum ether (40e60 ꢀC).
2.28e2.35 (m, 1H, cy), 249e2.66 (m, 3H, cy CH2CH3), 4.13e4.29 (m,
4H, 2OCH2CH3), 7.09 (t, 1H, J¼7.6 Hz, Ar), 7.33 (t, 2H, J¼8.0 Hz, Ar),
7.51 (d, 2H, J¼7.6 Hz, Ar), 8.93 (s,1H, NH) ppm; dC (100.6 MHz, CDCl3)
13.7 (q), 14.0 (q), 22.4 (t), 23.6 (q), 25.4 (t), 29.7 (t), 33.2 (t), 34.0 (t),
46.7 (s), 60.9 (t), 61.7 (t),109.8 (s),119.8 (d),123.6 (d),128.9 (d),137.9
(s),142.0 (s),150.3 (s),151.5 (s),166.4 (s),169.8 (s) ppm; MS: m/z¼427
[Mþ,1], 354 (2), 263(2), 235(100), 207(23),179(7),149 (9),119(21%).
4.3.5. Methyl
2-(anilinocarbonyl)-3-methyl-2,4a,5,6,7,8-hexahy-
drocinnoline-4-carboxylate (6e). White solid; 278 mg (85%); mp
79e81 ꢀC. Found: C, 66.13; H, 6.44. C18H21N3O3 requires C, 66.04; H,
6.47%. nmax (Nujol) 3368, 1728, 1693, 1614 cmꢂ1
; dH (400 MHz,
CDCl3) 1.39e1.49 (m, 1H, cy), 1.57e1.70 (m, 2H, cy), 1.84e1.90 (m,
1H, cy), 1.93e2.00 (m, 1H, cy), 2.08e2.12 (m, 1H, cy), 2.19e2.27 (m,
1H, cy), 2.48e2.54 (m, 1H, cy), 2.59 (s, 3H, Me), 3.45 (dd, 1H, J¼12.0,
4.0 Hz, CH), 3.76 (s, 3H, OMe), 7.08 (t, 1H, J¼7.2 Hz, Ar), 7.33 (t, 2H,
J¼7.6 Hz, Ar), 7.52 (d, 2H, J¼7.6 Hz, Ar), 8.92 (s, 1H, NH) ppm; dC
(100.6 MHz, CDCl3) 19.1 (q), 26.0 (t), 29.4 (t), 34.9 (t), 35.2 (t), 37.8
(d), 51.5 (s), 106.2 (s), 119.6 (d), 123.5 (d), 128.9 (d), 137.9 (s), 143.3
(s), 151.1 (s), 159.1 (s), 167.9 (s) ppm; MS: m/z¼327 [Mþ, 8], 208 (57),
193 (67), 179 (100), 166 (62), 149 (33), 119 (47%).
4.3.1. 4-Benzyl 4a-ethyl 2-(anilinocarbonyl)-3-methyl-5,6,7,8-tetra-
hydrocinnoline-4,4a(2H)-dicarboxylate (6a). White solid; 388 mg
(82%); mp 92e94 ꢀC. Found: C, 68.28; H, 6.17. C27H29N3O5 requires
C, 68.19; H, 6.15%. nmax (Nujol) 3373, 1741, 1713, 1697, 1684 cmꢂ1
; dH
(400 MHz, CDCl3) 1.17 (t, 3H, J¼7.2 Hz, OCH2CH3), 1.47e1.67 (m, 2H,
cy), 1.71e1.85 (m, 2H, cy), 1.91e1.98 (m, 1H, cy), 2.23e2.35 (m, 2H,
cy), 2.47 (s, 3H, Me), 2.49e2.60 (m, 1H, cy), 4.07e4.20 (m, 2H,
OCH2CH3), 5.14e5.26 (m, 2H, OCH2Bn), 7.09 (t, 1H, J¼7.6 Hz, Ar),
7.30e7.40 (m, 7H, Ar), 7.50 (d, 2H, J¼7.6 Hz, Ar), 8.92 (s, 1H, NH)
ppm; dC (100.6 MHz, CDCl3) 13.9 (q), 18.3 (q), 22.4 (t), 25.7 (t), 33.3
(t), 34.6 (t), 47.0 (s), 61.7 (t), 66.8 (t), 109.3 (s), 119.7 (s), 123.6 (d),
128.3 (d), 128.5 (d), 128.6 (d), 128.9 (d), 135.2 (d), 137.5 (s), 137.7 (s),
150.6 (s), 151.4 (s), 166.4 (s), 169.9 (s) ppm; MS: m/z¼475 [Mþ, 1],
402 (6), 283 (100), 192 (69), 148 (18), 119 (38%).
4.3.6. Allyl
2-(anilinocarbonyl)-3-methyl-2,4a,5,6,7,8-hexahy-
drocinnoline-4-carboxylate (6f). White solid; 289 mg (82%); mp
84e86 ꢀC. Found: C, 68.09; H, 6.62. C20H23N3O3 requires C, 67.97; H,
6.56%. nmax (Nujol) 3384, 1746, 1674, 1630 cmꢂ1
; dH (400 MHz,
CDCl3) 1.41e1.49 (m, 1H, cy), 1.60e1.69 (m, 2H, cy), 1.83e1.89 (m,
1H, cy), 1.96e2.03 (m, 1H, cy), 2.07e2.14 (m, 1H, cy), 2.18e2.24 (m,
1H, cy), 2.46e2.53 (m, 1H, cy), 2.60 (s, 3H, Me), 3.47 (dd, 1H, J¼12.0,
4.0 Hz, CH), 4.65e4.69 (m, 2H, OCH2CH]CH2), 5.25 (dd, 1H, J¼12.0,
1.6 Hz, OCH2CH]CH2), 5.34 (dd, 1H, J¼17.2, 1.6 Hz, OCH2CH]CH2),
5.91e6.01 (m, 1H, OCH2CH]CH2), 7.07 (t, 1H, J¼7.6 Hz, Ar), 7.32 (t,
2H, J¼7.6 Hz, Ar), 7.51 (d, 2H, J¼8.8 Hz, Ar), 8.93 (s, 1H, NH) ppm; dC
(100.6 MHz, CDCl3) 19.0 (q), 25.9 (t), 29.3 (t), 34.8 (t), 35.0 (t), 37.8
(d), 64.9 (t), 106.0 (s), 117.9 (t), 117.9 (d), 123.4 (d), 128.8 (d), 132.2
(d), 137.8 (s), 143.5 (s), 151.0 (s), 159.0 (s), 166.8 (s) ppm; MS: m/
z¼353 [Mþ, 13], 296 (62), 268 (100), 191 (62), 176 (83), 149 (39%).
4.3.2. 4-Allyl 4a-ethyl 2-(anilinocarbonyl)-3-methyl-5,6,7,8-tetrahy-
drocinnoline-4,4a(2H)-dicarboxylate (6b). White solid; 340 mg
(80%); mp 87e89 ꢀC. Found: C, 64.81; H, 6.34. C23H27N3O5 requires
C, 64.93; H, 6.40%. nmax (Nujol) 3381, 1735,1717, 1709, 1703 cmꢂ1
; dH
(400 MHz, CDCl3) 1.23 (t, 3H, J¼7.2 Hz, OCH2CH3), 1.51e1.66 (m, 3H,
cy), 1.74e1.86 (m, 2H, cy), 1.91e1.98 (m, 1H, cy), 2.25e2.34 (m, 1H,
cy), 2.49 (s, 3H, Me), 2.52e2.58 (m, 1H, cy), 4.14e4.25 (m, 2H,
OCH2CH3), 4.60e4.70 (m, 2H, OCH2CH]CH2), 5.26 (dt, 1H,
J2¼10.4 Hz, J3¼1.2 Hz, OCH2CH]CH2), 5.36 (dt, 1H, J2¼17.2 Hz,
J3¼1.2 Hz, OCH2CH]CH2), 5.88e5.97 (m, 1H, OCH2CH]CH2), 7.07
(t, 1H, J¼7.6 Hz, Ar), 7.29 (t, 2H, J¼7.6 Hz, Ar), 7.48 (d, 2H, J¼8.8 Hz,
Ar), 8.90 (s, 1H, NH) ppm; dC (100.6 MHz, CDCl3) 14.2 (q), 18.4 (q),
22.7 (t), 26.0 (t), 33.6 (t), 34.9 (t), 47.3 (s), 62.0 (t), 65.8 (t), 109.7 (s),
119.1 (t), 120.0 (d), 123.9 (d), 129.2 (d), 131.9 (d), 137.8 (s), 138.1 (s),
150.9 (s), 151.8 (s),166.5 (s), 170.2 (s) ppm; MS: m/z¼425 [Mþ, 1],
352 (4), 249 (3), 233 (100), 192 (14), 175 (5), 148 (8%).
4.3.7. Ethyl
2-(anilinocarbonyl)-3-methyl-2,4a,5,6,7,8-hexahy-
drocinnoline-4-carboxylate (6g). White solid; 266 mg (78%); mp
76e78 ꢀC. Found: C, 66.79; H, 6.82. C19H23N3O3 requires C, 66.84; H,
6.79%. nmax (Nujol) 3392, 1763, 1713, 1645 cmꢂ1
; dH (400 MHz,
CDCl3) 1.32 (t, 3H, J¼7.2 Hz, OCH2CH3), 1.42e1.49 (m, 1H, cy),
1.60e1.70 (m, 2H, cy), 1.84e1.92 (m, 1H, cy), 1.95e2.03 (m, 1H, cy),
2.06e2.13 (m, 1H, cy), 2.17e2.27 (m, 1H, cy), 2.44e2.56 (m, 1H, cy),
2.59 (s, 3H, Me), 3.45 (dd, 1H, J¼12.0, 4.0 Hz, CH), 4.17e4.28 (m, 2H,
OCH2CH3), 7.08 (t,1H, J¼7.2 Hz, Ar), 7.33 (t, 2H, J¼7.6 Hz, Ar), 7.52 (d,
2H, J¼7.6 Hz, Ar), 8.91 (s, 1H, NH) ppm; dC (100.6 MHz, CDCl3) 14.3
(q), 19.9 (q), 26.0 (t), 29.3 (t), 34.8 (t), 35.1 (t), 37.8 (d), 60.3 (t), 106.6
(s), 119.6 (d), 123.5 (d), 128.9 (d), 138.0 (s), 142.8 (s), 151.1 (s), 158.9
(s), 167.4 (s) ppm; MS: m/z¼341 [Mþ, 34], 296 (73), 268 (100), 191
(43), 176 (100), 149 (15%).
4.3.3. 4-tert-Butyl 4a-ethyl 2-(anilinocarbonyl)-3-methyl-5,6,7,8-
tetrahydrocinnoline-4,4a(2H)-dicarboxylate
(6c). White
solid;
379 mg (86%); mp 74e77 ꢀC. Found: C, 65.18; H, 7.13. C24H31N3O5
requires C, 65.29; H, 7.08%. nmax (Nujol) 3294, 1776, 1737, 1682,
1637 cmꢂ1
;
dH (400 MHz, CDCl3) 1.26 (t, 3H, J¼7.2 Hz, OCH2CH3),
1.50 (s, 9H, t-Bu), 1.55e1.69 (m, 3H, cy), 1.73e1.84 (m, 2H, cy),
1.90e2.01(m, 1H, cy), 2.22e2.31 (m, 1H, cy), 2.46 (s, 3H, Me),
2.50e2.60 (m, 1H, cy), 4.17e4.26 (m, 2H, OCH2CH3), 7.10 (t, 1H,
J¼7.6 Hz, Ar), 7.31 (t, 2H, J¼7.6 Hz, Ar), 7.50 (d, 2H, J¼8.8 Hz, Ar),
8.90 (s, 1H, NH) ppm; dC (100.6 MHz, CDCl3) 14.1 (q), 17.9 (q), 22.5
(t), 25.7 (t), 28.0 (q), 33.5 (t), 34.3 (t), 47.0 (s), 61.7 (t), 82.0 (s), 111.2
(s), 119.7 (s), 123.5 (d), 128.9 (d), 135.2 (d), 137.9 (s), 150.8 (s), 151.3
(s), 165.7 (s), 169.8 (s) ppm; MS: m/z¼441 (Mþ, 1), 368 (11), 295
(11), 249 (100), 193 (100), 175 (20), 148 (25), 119 (29%).
4.3.8. Methyl 3-methyl-2,4a,5,6,7,8-hexahydrocinnoline-4-carboxyl-
ate (7a). White solid; 173 mg (83%); mp 125e127 ꢀC. Found: C,
63.53; H, 7.70. C11H16N2O2 requires C, 63.44; H, 7.74%. nmax (Nujol)
3307, 1706, 1684 cmꢂ1
; dH (400 MHz, CDCl3) 1.32e1.43 (m, 1H, cy),
1.46e1.57 (m, 2H, cy), 1.70e1.78 (m, 1H, cy), 1.88e2.02 (m, 3H, cy),
2.07 (s, 3H, Me), 2.19e2.25 (m, 1H, cy), 3.30 (dd, 1H, J¼12.0, 4.0 Hz,
CH), 3.61 (s, 3H, OMe), 7.35 (br s, 1H, NH) ppm; dC (100.6 MHz,
CDCl3) 17.7 (q), 26.2 (t), 29.2 (t), 35.2 (t), 35.6 (t), 36.5 (d), 50.4 (q),
91.7 (s), 145.5 (s), 156.9 (s), 168.3 (s) ppm; MS: m/z¼208 [Mþ, 37],
206 (80), 193 (26), 179 (100), 149 (90), 125 (60), 111 (100%).
4.3.4. Diethyl 2-(anilinocarbonyl)-3-ethyl-5,6,7,8-tetrahydrocinno-
line-4,4a(2H)-dicarboxylate (6d). White solid; 324 mg (76%); mp
81e83 ꢀC. Found: C, 64.59; H, 6.87. C23H29N3O5 requires C, 64.62; H,
6.84%. nmax (Nujol) 3301,1753,1737,1697 cmꢂ1
; dH (400 MHz, CDCl3)
1.20 (t, 3H, J¼7.2 Hz, CH2CH3), 1.24e1.32 (m, 6H, 2OCH2CH3),
4.3.9. Allyl 3-methyl-2,4a,5,6,7,8-hexahydrocinnoline-4-carboxylate
(7b). White solid; 159 mg (68%); mp 118e120 ꢀC. Found: C, 66.72;
1.55e1.63 (m, 3H, cy), 1.77e1.81 (m, 2H, cy), 1.90e1.96 (m, 1H, cy),

6840
O.A. Attanasi et al. / Tetrahedron 66 (2010) 6832e6841
H, 7.68. C13H18N2O2 requires C, 66.64; H, 7.74%. nmax (Nujol) 3328,
1712, 1671 cmꢂ1
dH (400 MHz, CDCl3) 1.39e1.48 (m, 1H, cy),
chromatographed on silica column (elution mixture: 20% ethyl ace-
tateecyclohexane) obtaining the unchanged less polar products that
were identified as alkyl-3-hydroxy-2,3,4,4a,5,6,7,8-octahydrocinno-
line-4-carboxylates 5jel. Instead, during the chromatographic pro-
cess the more polar derivatives were converted into a different
products that were identified as alkyl 1-[(anilinocarbonyl)amino]-2-
methyl-4,5,6,7-tetrahydro-1H-indole-carboxylates 10aec. Com-
pounds 10aec were crystallized from ethyl acetateecyclohexane.
;
1.52e1.63 (m, 2H, cy), 1.76e1.83 (m, 1H, cy), 1.92e2.08 (m, 3H, cy),
2.12 (s, 3H, Me), 2.22e2.31 (m, 1H, cy), 3.31e3.40 (m, 1H, CH),
4.53e4.60 (m, 2H, OCH2CH]CH2), 5.17 (dd, 1H, J¼12.0, 1.6 Hz,
OCH2CH]CH2), 5.28 (dd, 1H, J¼17.2, 1.6 Hz, OCH2CH]CH2),
5.86e5.97 (m, 1H, OCH2CH]CH2), 6.94 (br s,1H, NH) ppm; dC
(100.6 MHz, CDCl3) 17.9 (q), 26.4 (t), 29.3 (t), 35.3 (t), 35.7 (t), 36.7
(d), 63.9 (t), 92.2 (s), 117.0 (t), 133.1 (d), 145.6 (s), 157.2 (s), 167.5 (s)
ppm; MS: m/z¼234 [Mþ, 59], 193 (100), 149 (38), 111 (100%).
4.4.1. Methyl 1-[(anilinocarbonyl)amino]-2-methyl-4,5,6,7-tetrahy-
dro-1H-indole-3-carboxylate (10a). White solid; 154 mg (47%); mp
216e218 ꢀC. Found: C, 66.10; H, 6.49. C18H21N3O6 requires C, 66.04;
4.3.10. Ethyl 3-methyl-2,4a,5,6,7,8-hexahydrocinnoline-4-carboxyl-
ate (7c). White solid; 173 mg (78%); mp 124e126 ꢀC. Found: C,
64.92; H, 8.20. C12H18N2O2 requires C, 64.84; H, 8.16%. nmax (Nujol)
H, 6.47%. nmax (Nujol) 3279, 1705, 1648, 1600, 1574 cmꢂ1
; dH
(400 MHz, DMSO-d6) 1.61e1.72 (m, 4H, cy), 2.13e2.25 (m, 1H, cy),
2.32 (s, 3H, Me), 2.36e2.47 (m, 1H, cy), 2.48e2.61 (m, 2H, cy), 3.68
(s, 3H, OMe), 6.98 (t, 1H, J¼7.2 Hz, Ar), 7.28 (t, 2H, J¼7.2 Hz, Ar), 7.45
(d, 2H, J¼7.6 Hz, Ar), 9.22 (br s, 1H, NH), 9.26 (s, 1H, NH) ppm; dC
(100.6 MHz, DMSO-d6) 10.5 (q), 20.2 (t), 22.2 (t), 23.0 (t), 23.1 (t),
50.2 (q), 106.8 (s), 115.0 (s), 118.8 (d), 122.3 (s), 128.3 (d), 128.7 (d),
135.7 (s), 139.3 (s), 154.1 (s), 165.5 (s) ppm; MS: m/z¼327 (Mþ, 22),
192 (100), 175 (3), 160 (16), 132 (11%).
3363, 1758, 1654 cmꢂ1
;
dH (400 MHz, CDCl3) 1.28 (t, 3H, J¼7.2 Hz,
OCH2CH3), 1.31e1.44 (m, 1H, cy), 1.50e1.59 (m, 2H, cy), 1.61e1.69
(m,1H, cy),1.77e2.06 (m, 3H, cy), 2.09 (s, 3H, Me), 2.17e2.30 (m,1H,
cy), 3.36 (dd, 1H, J¼11.6, 4.0 Hz, CH), 4.04e4.19 (m, 2H, OCH2CH3),
6.64 (br s, 1H, NH) ppm; dC (100.6 MHz, CDCl3) 14.5 (q), 17.9 (q),
26.4 (t), 29.4 (t), 35.3 (t), 35.7 (t), 36.7 (d), 59.1 (t), 92.8 (s), 145.0 (s),
157.1 (s), 167.9(s) ppm; MS: m/z¼222 [Mþ, 62], 193 (9), 177 (100),
149 (84), 125 (62), 111 (100%).
4.4.2. Allyl 1-[(anilinocarbonyl)amino]-2-methyl-4,5,6,7-tetrahydro-
1H-indole-3-carboxylate (10b). White solid; 184 mg (52%); mp
222e224 ꢀC. Found: C, 68.04; H, 6.51. C20H23N3O3 requires C, 67.97;
4.3.11. Methyl 3-methyl-5,6,7,8-tetrahydrocinnoline-4-carboxylate
(8a). White solid; 190 mg (92%); mp 74e76 ꢀC. Found: C, 64.14; H,
6.91. C11H14N2O2 requires C, 64.06; H, 6.84%. nmax (Nujol)
H, 6.56%. nmax (Nujol) 3316,1747,1664 cmꢂ1
;dH (400 MHz, DMSO-d6)
1736 cmꢂ1
;
dH (400 MHz, CDCl3) 1.75e1.83 (m, 2H, cy), 1.85e1.92
1.28e1.41 (m, 2H, cy), 1.53e1.79 (m, 4H, cy), 2.28 (s, 3H, Me),
2.42e2.53 (m, 1H, cy), 2.64e2.73 (m, 1H, cy), 4.62e4.74 (m, 2H,
OCH2CH]CH2), 5.21 (dd, 1H, J¼12.0, 1.6 Hz, OCH2CH]CH2), 5.36
(dd,1H, J¼17.2,1.6 Hz, OCH2CH]CH2), 5.86e5.94 (m,1H, OCH2CH]
CH2) 7.10 (t, 1H, J¼7.6 Hz, Ar), 7.34 (t, 2H, J¼7.6 Hz, Ar), 7.57 (d, 2H,
J¼8.8 Hz, Ar), 7.90 (s, 1H, NH), 7.97 (s, 1H, NH) ppm; dC (100.6 MHz,
DMSO-d6) 14.4 (q), 20.2 (t), 22.3 (t), 22.9 (t), 23.2 (t), 65.7 (t),107.3 (s),
114.8 (s), 118.4 (t), 119.9 (d), 123.6 (d), 124.0 (s), 128.8 (d), 131.7 (d),
135.7 (s), 137.5 (s), 154.2 (s), 166.1 (s) ppm; MS: m/z¼353 (Mþ, 30),
296 (13), 268 (100), 261 (6), 233 (17), 176 (64), 148 (53%).
(m, 2H, cy), 2.60 (s, 3H, Me), 2.72 (t, 2H, J¼6.4 Hz, cy), 3.11 (t, 2H,
J¼6.4 Hz, cy), 3.92 (s, 3H, OMe) ppm; dC (100.6 MHz, CDCl3) 20.1 (q),
21.5 (t), 21.9 (t), 25.5 (t), 30.0 (t), 52.5 (q), 130.8 (s), 133.1 (s), 152.8
(s),158.6 (s), 166.9 (s) ppm; MS: m/z¼206 [Mþ,100],175 (9),163 (4),
150 (10), 117 (27%).
4.3.12. Allyl
3-methyl-5,6,7,8-tetrahydrocinnoline-4-carboxylate
(8b). White solid; 218 mg (94%); mp 82e85 ꢀC. Found: C, 67.29; H,
7.00. C13H16N2O2 requires C, 67.22; H, 6.94%. nmax (Nujol)
1762 cmꢂ1
; dH (400 MHz, CDCl3) 1.75e1.82 (m, 2H, cy), 1.87e1.92
(m, 2H, cy), 2.61 (s, 3H, Me), 2.74 (t, 2H, J¼6.4 Hz, cy), 3.12 (t, 2H,
J¼6.4 Hz, cy), 4.80e4.84 (m, 2H, OCH2CH]CH2), 5.33 (d, 1H,
J¼9.6 Hz, OCH2CH]CH2), 5.41 (d, 1H, J¼17.2 Hz, OCH2CH]CH2),
5.91e5.99 (m, 1H, OCH2CH]CH2) ppm; dC (100.6 MHz, CDCl3) 20.0
(q), 21.5 (t), 21.8 (t), 25.4 (t), 29.9 (t), 66.5 (t), 120.3 (t), 131.8 (s),
133.6 (d),152.9 (s), 158.7 (s), 166.0 (s) ppm; MS: m/z¼232 [Mþ, 100],
191 (5), 175 (6), 147 (11%).
4.4.3. Ethyl
1-[(anilinocarbonyl)amino]-2-methyl-4,5,6,7-tetrahy-
dro-1H-indole-3-carboxylate (10c). White solid; 140 mg (41%); mp
212e214 ꢀC. Found: C, 66.78; H, 6.82. C19H23N3O3 requires C, 66.84;
H, 6.79%. IR (Nujol): nmax 3247, 1713, 1673 cmꢂ1
; dH (400 MHz,
DMSO-d6) 1.34 (t, 3H, J¼6.8 Hz, OCH2CH3), 1.70e1.84 (m, 4H, cy),
2.38e2.48 (m, 2H, cy), 2.46 (s, 3H, Me), 2.62e2.68 (m, 2H, cy), 4.26
(q, 2H, J¼7.2 Hz, OCH2CH3), 6.55 (br s, 1H, NH), 7.05e7.11 (m, 2H,
Ar), 7.21e7.28 (m, 3H, Ar), 7.81 (s, 1H, NH) ppm; dC (100.6 MHz,
DMSO-d6) 10.5 (q), 14.4 (q), 20.6 (t), 22.4 (t), 23.1 (t), 23.3 (t), 59.4
(t), 108.7 (s), 118.0 (s), 120.6 (d), 124.5 (s), 128.1 (d), 129.0 (d), 135.7
(s), 136.8 (s), 155.0 (s), 165.8 (s) ppm; MS: m/z¼341 (Mþ, 16), 206
(100), 189 (6), 174 (41%).
4.3.13. Ethyl
3-methyl-5,6,7,8-tetrahydrocinnoline-4-carboxylate
(8c). White solid; 196 mg (89%); mp 89e91 ꢀC. Found: C, 65.35; H,
7.32. C12H16N2O2 requires C, 65.43; H, 7.38%. nmax (Nujol)
1763 cmꢂ1
;
dH (400 MHz, CDCl3) 1.41 (t, 3H, J¼7.2 Hz, OCH2CH3),
1.79e1.85 (m, 2H, cy), 1.91e1.96 (m, 2H, cy), 2.65 (s, 3H, Me), 2.77 (t,
2H, J¼6.4 Hz, cy), 3.15 (t, 2H, J¼6.4 Hz, cy), 4.44 (q, 2H, J¼7.2 Hz,
OCH2CH3) ppm; dC (100.6 MHz, CDCl3) 13.6 (q), 20.3 (q), 21.4 (t),
21.9 (t), 25.6 (t), 30.2 (t), 62.4 (t), 130.5 (s), 132.7 (s), 152.6 (s), 158.9
(s), 167.3 (s) ppm; MS: m/z¼220 [Mþ, 100], 175 (18), 163 (3%).
Acknowledgements
This work was supported by the financial assistance from the
Ministero dell’Università, dell’Istruzione e della Ricerca (MIUR)-
PRIN and the Università degli Studi di Urbino ‘Carlo Bo’.
4.4. General procedure for the synthesis of alkyl 1-
[(anilinocarbonyl)amino]-2-methyl-4,5,6,7-tetrahydro-1H-
indole-carboxylates 10aec
References and notes
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a
ra-
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diation (l¼0.71073 A) were used for data collections at 120(2) and 293(2) K,