Toward new camptothecins. Part 6: Synthesis of crucial ketones and their use in Friedl?nder reaction

Article abstract of DOI:10.1016/j.tet.2010.07.048

In the context of the preparation of camptothecin and luotonin A analogs, the synthesis of some key keto-precursors and their use in Friedl?nder condensation are described. This paper also focuses on the stability of these keto intermediates and emphasizes the major differences between indolizinones and pyrroloquinazolinones series. Noteworthy is also the report of some original structures isolated as by-products of some experiments.

Full text of DOI:10.1016/j.tet.2010.07.048

Tetrahedron 66 (2010) 7544e7561
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Toward new camptothecins. Part 6: Synthesis of crucial ketones and their use in
€
Friedlander reaction
,
,
,
,b,
*
Laurent Gavara a b, Thomas Boisse a b, Jean-Pierre Hénichart a c, Adam Daïch d, Benoît Rigo a
,
Philippe Gautret a
a Univ Lille Nord de France, F-59000 Lille, France
b UCLille, EA GRIIOT, Laboratoire de Pharmacochimie, HEI, 13 rue de Toul, F-59046 Lille, France
c UDSL, EA 2679, Laboratoire de Toxicologie, UFR Pharmacie, 3 rue du Professeur Laguesse, F-59006 Lille, France
d URCOM, EA 3221, INC3M, FR-CNRS 3038, UFR des Sciences & Techniques de l’Université du Havre, 25 rue Philippe Lebon, F-76058 Le Havre, France
,b,
*
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 April 2010
Received in revised form 12 July 2010
Accepted 19 July 2010
Available online 22 July 2010
In the context of the preparation of camptothecin and luotonin A analogs, the synthesis of some key
€
keto-precursors and their use in Friedlander condensation are described. This paper also focuses on the
stability of these keto intermediates and emphasizes the major differences between indolizinones and
pyrroloquinazolinones series. Noteworthy is also the report of some original structures isolated as by-
products of some experiments.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
As part of a program directed toward the synthesis of potential
anticancer agents,6 we wished to elucidate the influence of a car-
The concept of ‘privileged structures’ was first introduced by
Evans in the late 80s.1 In the anticancer area, the quinazolin-4-one
ring system and the quinoline skeleton can be considered as priv-
ileged scaffolds. In particular, they can be found in a large number
of natural and unnatural cytotoxic agents such as camptothecin
(1),2 luotonin A (2),3 benzopyrrolizinoquinoline 3,4 and mack-
inazolinone 45 derivatives (Fig. 1).
bonyl (acid, ester, amide) substituent on position-5 of cycle C of
condensed quinolines 5 and 6, along with modification of the
E-rings of these camptothecin and luotonin analogs.7e10 In our
retrosynthetic scheme (Fig. 2), a strategic point consisted in the
condensation of aminobenzaldehydes with ketoindolizines 7 or
ketopyrroloquinazolinones 8. In this paper, we report some details
11
€
about the synthesis and their use in Friedlander reaction of ke-
tones 7 and 8, starting from precursors 9 and 10 (already described
by us10).
7
7
9
9
5
5
O
O
10
11
10
11
N
N
N
A
B
A
B
C
C
D
D
N
N
2. Results and discussion
O
O
E
E
2.1. Synthesis of protected o-aminobenzaldehydes
OH
Luotonin-A 2
Camptothecin 1
€
Some of the aminobenzaldehydes needed for the Friedlander
reaction11 were not commercial and had to be synthesized. Since
many aminobenzaldehydes are unstable compounds, prone to di-
merization and polymerization, they were protected as imines by
reaction with p-toluidine.12 We have already reported13 that re-
duction of nitrobenzaldimines was more reproducible, easier and
giving better yields of the expected amines, when performed with
anhydrous sodium sulfide than with its nonahydrate form.14
Nitration of piperonal (11) in nitric acid at 0 ꢀC was reported in
literature to yield a mixture of nitroaldehyde 12 and 4-nitro-
methylenedioxybenzene.15 It is also possible to perform this re-
action by using nitric acid in the presence of acetic anhydride.16
Under these conditions, only diacetoxy compound 13 was
O
O
N
N
MeO
N
N
N
HO
OH
MeO
3
4
Figure 1. Representative cytotoxic agents owning a quinazolin-4-one or quinoline ring
system.
* Corresponding authors. E-mail address: benoit.rigo@hei.fr (B. Rigo).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.07.048

L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
7545
CO2Me
O
N
CO2Me
O
N
CO2Me
O
N
CO2Me
O
N
R3
R3
R1
R1
R1
X
N
N
Y
O
CO2Me
CO2Me
CO2Me
HO
O
CHO
NH2
5
7
9
Y=H , Me NCH
R3
2
2
CO2Me
O
N
CO2Me
O
N
CO2Me
O
N
CO2Me
O
N
R3
R3
N
N
O
Y
N
N
N
N
R2
R2
R2
R2
6
8
10
Figure 2. Retrosynthetic scheme leading to camptothecin and luotonin A analogs 5 and 6.
isolated in 55% yield. However, reduction of this protected nitro-
aldehyde with anhydrous Na2S13 as well as with Fe17 or Zn18 and
ammonium chloride failed. Hydrolysis of 13 was then realized by
sulfuric acid in ethanol and the nitroaldehyde product 12 (66%)
thus obtained was reacted with p-toluidine, then reduced with
anhydrous Na2S. According to this sequence, the overall yield in the
protected dimethoxyaminobenzaldehyde 15 was 20% (Scheme 1).
order to avoid the formation of a diacetoxylated compound, nitra-
tion of known aldehydes 18 and 19 (quantitatively formed by
methylation of vanillin (26) by using dimethylsulfate in acetone19
)
was performed with HNO3 in H2SO418 providing nitroaldehydes 20
and 21 in 84% and 80% yields, respectively. Noteworthy, re-
crystallization of product 20 in EtOH yielded a small amount of
acetal 22, and 6-nitroaldehyde 21 was accompanied by 9% of the
4-nitro isomer 23, which was easily removed upon re-
crystallization. Protection of 20 and 21 followed by their reduction
was performed as for the nitroaldehyde 12, leading to 16 and 17 in
a total yield of 42% and 11%, respectively.
OAc
OAc
NO2
OAc
OAc
NH2
CHO
O
O
O
O
O
O
(i)
In the camptothecin series, a hydroxy substituent placed at C-
10 position was reported to lead to significant increase in activity
due to formation of new interactions in the DNA/topoisomerase
I complex.20 In order to introduce this group in some final
compounds, m-hydroxybenzaldehyde (27) was used as starting
material. The phenol function of this substrate was protected as
a methyl carbamate by using methyl chloroformate in pyridine.
The resulting aldehyde 28 was formed in 75% yield, and
unreacted compound 27 could rapidly be recovered. The use of
acetic anhydride as co-reagent for nitration of 28 led only to 1,1-
diacetate 29 (83%), but the desired nitroaldehyde 30 was
obtained in 75% yield when the reaction was carried out in sul-
furic acid. Regeneration of the phenol group of 30 led to nitro-
aldehyde 31 (NaOH, 70%), and then imine 32 was easily obtained
13
11
(ii)
N
N
CHO
NO2
O
O
O
O
O
O
(iii)
(iv)
NH2
NO2
14
12
15
Scheme 1. Reagents and conditions: (i) HNO3/Ac2O, 0 ꢀC, 2 h, 55%; (ii) H2SO4, EtOH,
reflux, 10 h, 66%; (iii) p-toluidine, EtOH, reflux, 30 min, 85%; (iv) Na2S anhyd, EtOH,
reflux, 5 min, 65%.
The protected dimethoxyaminobenzaldehyde 16 and the 3-
chloro analog 17 were obtained in a similar fashion (Scheme 2). In
CHO
Cl
CHO
CHO
CHO
CHO
Cl
Cl
ii
+
O2N
NO2
18
21
(iii)
23
N
N
O
(v)
R
R
HO
NO2
NH2
26
24 R = 3,4-(OMe)2 80%
25 R = 3-Cl 31%
16 R = 3,4-(OMe)2 63%
17 R = 3-Cl 45%
(i)
(iii)
OEt
OEt
CHO
(iv)
O
O
O
O
O
ii
O
NO2
NO2
19
20
22
Scheme 2. Reagents and conditions: (i) Me2SO4, Me2CO, K2CO3, reflux, 90 min, 99%; (ii) HNO3/H2SO4, 15 ꢀC, 1 h, 84% for 20 and 80% for 21; (iii) p-toluidine, EtOH, reflux, 30 min; (iv)
EtOH, reflux, 15%; (v) Na2S anhyd, EtOH, reflux, 5 min.

7546
L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
in 71% yield according to the previous standard protocol. How-
ever, due to the free OH function of this compound combined
with the sensitivity of the imine group toward hydrolysis, it was
not possible to isolate the amine 33 formed by reduction of the
nitroimine 32 under the usual conditions (Scheme 3). Thus,
acetylation of compound 32 was performed, leading to nitroimine
35 (76%), whose reduction gave 70% of the expected aminoimine
36. This product could not be easily purified because of its de-
composition upon exposure to silica gel during the chromato-
graphic purification, and was used ‘crude’ in the following
2.2.1. Reactivity of tricyclic diester 49. Acetate 49 was a by-product
isolated in 40% yield during the oxidation of desoxyvasicinone
analog 57 by lead tetracetate (Scheme 5).10 It was considered that
alcohol 58a, easily generated from the acetate-ester 49, could react
as a precursor of the N-acyliminium salt A in equilibrium with
its vinylogous form B. Thus, treatment of 58a with amino-
benzaldehyde could give quinoline 6a as depicted in Scheme 5.
However, compound 58a, obtained in a 65% crude yield by treat-
ment of diester 49 with MeONa, then HCl, was not stable and
rapidly ring opened to functionalized quinazoline 60a (Scheme 5).
Compound 58a was mainly identified from similarities of its 1H
€
Friedlander reaction.
OAc
OAc
HO
CHO
MeOCO2
CHO
MeOCO2
(i)
(ii)
27
28
(iii)
29
N
N
RO
CHO
NO2
RO
RO
MeO2CO
CHO
NO2
(v)
(iv)
(vi)
NO2
NH2
30
33 R = H
0%
31 R = H
34 R =
32 R = H
35 R = Ac
38 R =
71%
(ix)
(vii)
36 R = Ac
39 R =
70%
76%
N
OH
O
(viii)
(viii)
N
N
61%
93%
0%
56%
37 R = Me
MeO
MeO
CHO
NO2
41 R = Me
40 R = Me
+
NO2
42
43
Scheme 3. Reagents and conditions: (i) CH3OCOCl, pyridine, rt, 4 h, 75%; (ii) HNO3/Ac2O, 0 ꢀC, 1 h, 83%; (iii) HNO3/H2SO4, 0 ꢀC, 1 h, 75%; (iv) NaOH (10%), rt, 1 h, 70%; (v) p-toluidine,
EtOH, reflux, 30 min, 71%; (vi) Na2S anhyd, EtOH, reflux, 5 min; (vii) Cl(CH2)2NC5H10$HCl, K2CO3, DMF, 80 ꢀC, 4 h, 94%; (viii) MeI, K2CO3, DMF or acetone, 80 ꢀC, 4 h, 66%; (ix) Ac2O,
pyridine, rt, 2 h, 76%.
Introduction of the same amino chain as found in the quinoline
N
N
3 (Fig. 1) was also attempted. Thus, alkylation of nitrophenol 31 to
give 34, then protection leading to 38 were realized without diffi-
culty. However, reduction of 38 proved to be problematic and
synthesis of 39 was not pursued. Starting from the same
hydroxynitrobenzaldehyde 31, the same reaction sequence led,
after methylation of the phenol group, to the imine 40 then to the
protected amine 41. Methylation of 31 to give 42 needed to be
performed in DMF instead of acetone because in the latter solvent,
an aldolization reaction occurred, and only hydroxyketone 43 was
isolated in 80% yield (Scheme 3).22
CHO
(i)
(ii)
NHAc
NH2
44
NHAc
45
46
(
iii) Lit.23
CHO
O2N
CHO
NH2
O2N
(iv)
NHAc
47
48
Synthesis of 2-amino-5-nitrobenzaldehyde (48) from 2-amino-
benzaldehyde was already described (60%).23 Because of the in-
stability of this product, we chose to start from the imine 44.13
Acetylation of the amino group of 44 (Ac2O/Pyridine) then hydro-
lysis of the protecting group (HCl/EtOH) of 45 led in two steps to
78% of acetamidobenzaldehyde 46. Nitration of this compound was
performed as described,23 yielding 74% in 47, whose hydrolysis in
HCl gave 90% of aminoaldehyde 48. Noteworthy, these two steps
were poorly reproducible and the reported yields were the best
obtained (Scheme 4).
Scheme 4. Reagents and conditions: (i) Ac2O, pyridine, rt, 12 h; (ii) EtOH, HCl (5%), rt,
2 h, 78% in two steps; (iii) HNO3/H2SO4, AcOH, 0 ꢀC, 30 min then rt, 4 h, 74%; (iv) HCl
(5%), reflux, 8 h, 90%.
NMR spectrum with that of 49,10 and structure of 60a was deduced
from the newly created carbonyl group (
d
¼179.7 ppm) and the
coupling constant value of the double bound compatible with the
trans isomer (J¼16.2 Hz). A similar rearrangement pattern was also
observed in another part of this work.
2.2.2. Reactivity of tricyclic alcohol 50. In the desoxyvasicinone
series, oxidation of the alcohol function was generally realized with
Jones reagent.24,25 By using either this oxidant or pyridinium
chlorochromate or under Swern26 or Oppenauer27 oxidation con-
ditions, it was not possible to obtain even a little amount of ketone
8a starting from tricyclic alcohol 50. However, when this com-
pound was treated with chromic acid, 7% in diketoester 61 was
isolated. Hydroxylactam C could be considered as a key in-
termediate for this cleavage, which pointed out the sensitivity of
2.2. Reactivity of precursors of quinolines
Various precursors are possible in order to get a quinoline nu-
€
cleus. Those that we used in Friedlander reaction are shown in
Figure 3, and their syntheses were described in a preceding paper.10
Except for the tricyclic system 49, which was utilized directly, we
focused on the transformation of compounds 50e56 to the corre-
sponding ketones.

L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
7547
CO2Me
O
N
CO2Me
O
N
CO2Me
O
N
CO2Me
O
N
AcO
HO
HO
NO2
N
HO
N
N
N
N
CO2Me
MeO2C
52
Et
49
50
51
R
CO2Me
O
N
CO2Me
CO2Me
O
N
CO2Me
O
O
N
N
N
R
N
N
HN
N
N
N
CO2Me
R
R1
R
Et
53
54
55
56
€
Figure 3. Precursors used for Friedlander reaction.
MeO2C
O
O
HN
N
60a
H
CO2Me
O
N
AcO CO2Me
CO2Me
O
N
CO2Me
O
N
O
+
O
N
(i)
+
- H2O
N
N
N
N
49
58a
A
B
CO2Me
O
N
CO2Me
O
N
CO2Me
O
N
CHO
N
N
H
N
N
N
57: 5-methoxycarbonyl
6a
59a
desoxyvasicinone
Scheme 5. Reagents and conditions: (i) MeONa/MeOH, rt, 4 h, 65% (crude product).
the
a
-position of the nitrogen and of the methoxycarbonyl group to
in presence of p-benzoquinone) led to 30e46% in luotonin A (2)
(Scheme 6). Under the same conditions, 5-methoxycarbonyl luo-
tonin A (6a) was formed in the low yield of 15% (Scheme 6). Because
better results were obtained starting from pure ketone 8a (see
over-oxidation reactions (Scheme 6). It was also described by Ma
et al.3d that treatment of vasicinone (50, R¼H; Scheme 6) with
ꢀ
protected aminobenzaldehyde 44 (toluene/PTSA/4 A MS, possibly
H
O
CO2Me
O
O
MeO2C
O
N
O
HN
N
N
N
O
NH2
44
61
C
(i)
R
R
R
N
N
O
O
O
(i)
44
N
N
(ii)
(ii)
N
HO
O
N
N
50 R = CO2Me
8a R = CO2Me
6a R = CO2Me
Vasicinone R = H
2 Luotonin A R=H Lit. 28
Scheme 6. Reagents and conditions: (i) K2Cr2O7, H2SO4, H2O, EtOH, 0 ꢀC then rt, 2 h, 7%; (ii) 44, pTSA, MS 3 A, xylene, reflux, 20 h, 15% crude.
ꢀ

7548
L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
later), the product 6a was not purified but only identified with NMR
spectrum of the crude reaction mixture.
medium (Ac2O/DMAPcat./THF). However, product 64 proved to be
unstable; even adding triphenylphosphine at the end of the acyl-
ating reaction, decomposition also occurred (Scheme 7).
2.2.3. Reactivity of tricyclic oximes 51, 52, and corresponding hy-
drazones 53. Many methods have been described for the re-
generation of a carbonyl function from oximes or hydrazones.28 The
main reactions that were tested on 51, 52, and 53 without success
were hydrolysis under acidic conditions (HCl,29 HBr30), oxidation
(MnO231), nitrosation (iso-AmONO/HCl,32 NaNO2/Me3SiCl33), re-
duction (NaHSO3,34 Zn/HCl or AcOH35) or exchange reaction with
cyclohexanone or acetone.36 Generally speaking, no formation of
the expected ketones was observed starting from the hydrazones
53. However, a pink color often appeared from the oximes 51 and
52, later accompanied by a total degradation of the reaction media.
The same color, assigned to over-oxidation, was observed during
storage of some unstable ketones such as 7a and 8a (see below). It
was also reported that oxidation of oximes with bromine could lead
to ketones.37 Accordingly, only few amounts of halogenated prod-
ucts 62 and 63 were isolated in 7% and 12% yields, respectively,
when oxime 51 was reacted under these conditions (Scheme 7).
Elsewhere, we have already described that ketone 8a could not be
obtained from dibromo compound 63,10 although it was possible to
isolate 79% of an oxidized desoxyvasicinone from its dibromo
analog.38
2.2.4. Reactivity of benzylidene compounds 54. In the desoxy-
vasicinone series, it was recently described by Molina et al.44 that
€
the crucial enolizable ketone required for the Friedlander reactions
could be obtained by ozone cleavage of benzylidene precursors.
Because we did not wish to use ozonolysis technique, we studied
the oxidation of the benzylidene compound 54a by NaIO4 and
catalyzed by RuO2 in the solvent conditions already reported in the
literature: a mixture of MeCN/H2O with, possibly, CCl4 or EtOAc.45
In our hands, by using MeCN/H2O as solvent and 10% of RuO2 as
catalyst, only a 55/45 mixture of diastereoisomers of diol 65 was
obtained after 72 h of reaction at room temperature in the very low
4% yield upon silica gel purification; even if the whole starting
material was consumed in these conditions, no expected ketone 8a
was isolated. In order to accelerate the reaction, 20% of catalyst was
used. This experimental condition led instantaneously to the deg-
radation of the medium; nevertheless, by using also EtOAc as
cosolvent, the expected ketone was formed, escaping to a further
oxidization reaction, in quantitative yield in 2 h at room tempera-
ture (it can be observed by 1H NMR spectroscopy that a mixture of
ketone 8a and its enol form 80a in 9/1 ratio was obtained). However,
CO2Me
O
N
CO2Me
CO2Me
O
N
O
N
(ii)
AcO
HO
NO2
NO2
NO2
N
N
O
CO2Me
CO2Me
CO2Me
MeO2C
MeO2C
MeO2C
Et
Et
52
Et
7a
64
R1
CO2Me
CO2Me
CO2Me
O
O
O
N
N
N
N
N
N
HN
HO
N
O
N
R
R
8a R = H
8b R = Cl
51
53a R, R1 = H
53b R = Cl, R1 = H
53c R = H, R1 = NO2
(i)
CO2Me
CO2Me
O
O
N
N
N
+
Br
Br
Br
N
62
63
Scheme 7. Reagents and conditions: (i) Br2, CH2Cl2, NaHCO3, H2O, rt, 15 h, 19%; (ii) Ac2O, DMAP, THF, rt, 48 h, 100% by NMR.
€
Friedlander reactions are mainly carried out from ketones, but it
is also possible to start from the corresponding enamines.13 Liter-
ature reports that oximes can be converted to acetylenamides by
reduction/acylation with iron in acetyl chloride39 or with triethyl-
phosphine in acetic anhydride.40 However, when compound 52 was
reacted with triphenylphosphine, only degradation was observed.
Thus, we attempted to perform this transformation, in a two-step
protocol, via the intermediate acetate 64. Under standard condi-
tions (Ac2O/DMAP/Et3N,41 Ac2O/Py42 or AcCl/Et3N43), only degra-
dation of the starting material was observed, even at low
temperature. Eventually, it was possible to obtain the acetate 64
quantitatively (according to 1H NMR spectrum) by using a diluted
these compounds entirely decomposed during the work-up, and
the same pink color developed rapidly as observed previously
(Section 2.2.3). The same reactions were tested with benzylidene
compounds 54c and 54d, whose electronic density on the double
bond was different. Unfortunately, their low solubility in the nec-
essary solvent mixture (EtOAc/MeCN/H2O) limited the study, and
no interesting results were obtained (Scheme 8).
€
2.2.5. Oxidation followed by Friedlander reaction of enamines 55
and 56.
2.2.5.1. Previous results. N,N-Dimethylenamines have been
reported as carbonyl precursors, and we have already described

L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
7549
R1
solvent was used. However, by using the mixture EtOAc/MeCN/H2O
described earlier in this paper (see Section 2.2.4), N,N-dimethyl-
aminomethylidene-indolizines 55def led to the expected indoli-
zinones 7def in yields ranging from 80% to 90%. Due to their low
stability, these compounds were not purified but directly engaged
CO2Me
CO2Me
O
O
R2
R1
(i)
N
N
N
N
OH
OH
54a R1, R2 = H
54b R1, R2 = OMe
54c R1 = H, R2 = NO2
€
in Friedlander condensation. After extraction of the reaction mix-
65
ture with CH2Cl2, protected aminobenzaldehyde 44 and acetic acid
were added, dichloromethane was evaporated, and the mixture
was then heated until disappearance of the starting ketone 7
according to TLC control. Under these conditions, the new quino-
lines 66def were obtained in two steps (Scheme 10) in 52%, 71%,
and 55% yields, respectively.
Many attempts to remove the bromine atom of reactant 66f
were performed while reducing its nitro group in order to obtain
the pentacyclic lactam 67. Indeed, this compound is a direct pre-
cursor of camptothecin analog 5 (Fig. 2). Whatever the conditions
used (e.g., Pd/C, Mg/MeOH, Na2S, NaBH4, Et3SiH, SnCl2, Zn/HBr or
Zn/NH4Cl), only decomposition of initial compound was obtained.
However, by using Zn/AcOH, it was possible to observe by NMR that
lactam 66 was rapidly degraded upon attempt of isolation. In the
same way, introduction of the needed alcohol function before the
reduction process (see product 68) was unsuccessful, as well as
controlled reduction of compound 55f to give the expected tricyclic
lactam 69 (Scheme 10).
Because of these failures, we thought that it was better to first
reduce the nitro function of the bicyclic enamine 55c.46 Complex
mixtures were obtained, but ammonium formate/Pd/C/MeOH led
to formation of the tricyclic pyridone 70 (Scheme 11); this com-
pound is produced by an exchange reaction of the dimethylamino
group of 55c with ammonia. Heating compound 55c only with
ammonium formate in methanol led quantitatively to the expected
product 70 (Scheme 11).
54d R1 = OMe, R2 = OAc
CO2Me
CO2Me
O
O
N
(ii)
N
O
HO
N
N
8'a
8a
Scheme 8. Reagents and conditions: (i) 54a, NaIO4, RuO2 (10%), MeCN/H2O 3/1, rt, 3d,
4%; (ii) 54a, NaIO4, RuO2 (20%), EtOAc/MeCN/H2O 3/3/1, rt, 2 h, 100% (not isolated).
their oxidation in the synthesis of camptothecin analogs.8,9 After
a large screening, the best oxidizing agent found was NaIO4, and the
use of THF/H2O combination as solvent allowed us, starting on
enamines 55, to isolate ketones 7a and 7b in the good 96% and 80%
yields, respectively. However, products from these series exhibited
a low stability, which probably explains our inability to obtain the
ketoindolizine 7c46 (Scheme 9).
CO2Me
CO2Me
O
N
O
N
(i)
N
R1
R1
O
Lit.8,9,47
R2
R2
CO2Me
CO2Me
2.2.5.3. Reactions of quinazolines 56. As hypothesized pre-
viously, the tricyclic ketones 8 are also instable, and oxidation of
enamines 56 needs to be performed in the same way as for com-
pounds 7 shown in Scheme 9. Thus, NaIO4 in EtOAc/MeCN/H2O
Et
Et
55a R1, R2 = H
55b R1 = CH2OMe, R2 = H
55c R1 = NO2, R2 = CO2Me
7a R1, R2 = H
7b R1 = CH2OMe, R2 = H 80%
7c R1 = NO2, R2 = CO2Me 0%
96%
€
mixture was used, and then the Friedlander condensation was
performed with crude heterocycles
Scheme 9. Reagents and conditions: (i) NaIO4, THF/H2O, rt.
8 and protected amino-
benzaldehyde derivatives 15, 16, 41, 44 or aminobenzophenone 71.
Luotonin derivatives 6aef were thus obtained in yields ranging
from 39% to 75% for two steps. On the other hand, reacting
2.2.5.2. Reactions of indolizines 55. Ketones 7def decomposed
during their formation when the previous combination THF/H2O as
CO2Me
O
N
CO2Me
CO2Me
O
N
O
(i)
N
(ii)
N
R1
R1
R1
O
N
CO2Me
CO2Me
CO2Me
R2
R2
R2
Et
Et
Et
55d R1 = H, R2 = NO2
7d R1 = H, R2 = NO2 89%
66d R1 = H, R2 = NO2 57%
55e R1 = Cl, R2 = H
55f R1 = NO2, R2 = Br
7e R1 = Cl, R2 = H
89%
66e R1 = Cl, R2 = H
80%
7f R1 = NO2, R2 = Br 79%
66f R1 = NO2, R2 = Br 70%
CO2Me
O
N
CO2Me
O
N
H
N
CO2Me
O
N
H
N
NO2
N
N
N
CO2Me
O
Br
O
Br
Br
HO
Et
Et
Et
69
68
67
Scheme 10. Reagents and conditions: (i) NaIO4, MeCN, EtOAc, H2O, 45 s, 20 ꢀC; (ii) 44, AcOH, 2 h, 80 ꢀC.

7550
L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
CO2Me
O
N
CO2Me
O
N
CO2Me
O
N
(i)
- MeOH
H2N
NO2
N
NO2
NO2
CO2Me
MeO2C
CO2Me
CO2Me
N
H
MeO2C
Et
Et
O
Et
55c
D
70
Scheme 11. Reagents and conditions: (i) HCO2NH4, MeOH, 24 h, reflux, 93%.
nitroaminobenzaldehyde 48 with ketone intermediate 8a led only
to decomposition, either in reflux of acetic acid or in more acidic47
or basic11b conditions (Scheme 12).
luotonin derivative 6i in the low 25% yield and in a very impure form
(Scheme 14). From these results, it was decided to further check
other oxidizing reagents. However, all other oxidizing agents tested
R1
CO2Me
O
N
CO2Me
O
N
CO2Me
R2
R3
O
(i)
(ii)
N
N
N
N
O
N
N
R
R
R
56a R = H
56b R = Cl
8a R = H
8b R = Cl
6a R, R1,R2, R3 = H
6b R = Cl, R1, R2, R3 = H
75%
50%
6c R, R1 = H, R2,R3 = OCH2O 37%
6d R, R1 = H, R2,R3 = OMe
6e R, R1, R3 = H, R2 = OMe
6f R, R2, R3 = H, R1 = Me
42%
50%
39%
H
N
O2N
R2
R3
O
NH2
O
NH2
NH2
71
15 R2, R3 = OCH2O
48
16 R2, R3 = OMe
41 R2 = OMe, R3 = H
44 R2, R3 = H
Scheme 12. Reagents and conditions: (i) NaIO4, MeCN/EtOAc/H2O (1/1/2), rt, 25 min; (ii) AcOH, reflux, 2 h.
€
2.2.5.4. Side reactions observed during the Friedlander synthesis
of quinazolines. When cleavage of the methoxy group of luotonine
derivative 6e was attempted by using BF3 or Me3SiI, only a de-
composition of the starting material was observed. Because of this
failure, acetoxybenzaldimine 36 was reacted with ketone 8a
gave bad results, but stirring enamine 56c with oxone (acetone/
KHCO3/H2O)resulted in a mixture, which could not be completely
purified, and from which compounds 76c (w5%) and 77c (w70%)
were identified from the 1H NMR spectra of the crude products.
Characteristic values of chemical shifts (ppm) in these series are
provided in Scheme 14. Interestingly, scaffold of enamine 76c is the
same as the one of product 76a that was formed in 56% yield when
reagent 56a was oxidized with NaIO4 in THF/H2O instead of the
solvent mixture EtOAc/MeCN/H2O previously used.
€
according to Friedlander reaction, but compound 6g was not
formed and only 31% of the compound 72 was isolated. In a similar
manner with chlorobenzaldimine 17, a mixture of enaminoketones
72 (20%) and 73 (20%) was obtained along with 10% of luotonin
analog 6h (Scheme 13). These products were separated by chro-
matography on SiO2, and characterized by NMR spectroscopy.
In the beginning of the work, RuO2 was used as a catalyst for
The structure of luotonin derivative 6i shown in Scheme 14 was
interesting, since the reduction of its nitro group could provide an
amino compound. This group could lead advantageously to new
hydrogen bonds in the active site of the target enzyme. On the other
hand, it could easily be substituted to increase the solubility of such
scaffold. Considering that compound 6i was obtained in very low
yield and poor analytical purity, and since reduction of a nitro
group in the presence of N,N-dimethylaminomethylidene function
did not succeed (Scheme 11), synthesis of precursor 78 was un-
dertaken (Scheme 15). Treatment of nitrovasicinone derivative 79
by using the couple Zn/HBr led to a mixture of aminoester 78 and
the corresponding aminoacid derivative. The mixture was rees-
terified under our standard conditions by drying the ternary
€
oxidation of ketone 8a. After a Friedlander condensation between
imine 44 and crude ketone 8a, presumed to contain traces of the
catalyst, an unexpected heterocyclic system 74 was obtained in 23%
yield. Identification of the structure of this ketone was comforted
by analogies of 13C NMR spectrum with that of natural Luotonin-F
(75)3f (Scheme 13). These reactions point out the sensitivity of the
pyrroloquinazolindione scaffold 8 toward over-oxidation, and are
reminiscent of the rearrangement of alcohol intermediate 58a
(Scheme 5) and of the formation of opened compounds 60a and 61
(Schemes 5 and 6, respectively). A plausible mechanism leading to
these systems is described in Scheme 13.
48
ꢀ
azeotrope MeOH/CHCl3/H2O with 3 A molecular sieves. The pu-
rification of the resulting mixture provided 55% of aminoester 78
accompanied by 20% of reduced derivative 80 (aminoester de-
rivative of linaric acid)49 and 10% of acetal 81. The latter compound
contained the same scaffold as ketoester 60a described above
In some cases, other interesting products were obtained from the
oxidation of fused quinazolines. Indeed, the tricyclic enamine 56c10
led only to 50% of the expected ketone 8c. The subsequent
€
Friedlander reaction of this unstable product 8c gave the expected

L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
7551
CO2Me
O
N
CO2Me
O
N
N
R
(i)
R
NH2
+
+
O
N
N
NH2
N
44 R = H
36 R = OAc
17 R = Cl
8a
6a R = H
6g R = OAc
6h R = Cl
H
O
CO2Me
O
N
O
O
O
O
MeO2C
O
MeO2C
H
N
H
N
N
H
O
N
O
N
N
C
61
72
+
MeO2C
O
H
N
O
MeO2C
O
H
N
H
O
O
160.5
N
N
N
148.2
184.2
187.8
160.6
HN
N
150.9
N
N
147.6
149.8
75 Luotonin-F
74
73
Scheme 13. Reagents and conditions: (i) AcOH, reflux. Some characteristic values of 13C NMR chemical shifts are indicated in italic (and red) (ppm).
CO2Me
CO2Me
CO2Me
3.22, 3.56
3.06, 3.38
5.09
5.39
6.36
O
O
O
N
N
(i)
N
N
(ii)
N
N
N
3.17
O
N
NO2
O
NO2
NO2
56c
8c 50%
6i 25%
6.70
CO2Me
CO2Me
CO2Me
3.19, 3.53
6.51
6.21
5.07
O
O
N
(ii)
N
N
N
N
+
N
3.11
N
3.11
O
(iii)
N
3.14
R
R
77c R = NO2 70%
77a R = H 0%
56a
76c R = NO2 5%
76a R = H 56%
Scheme 14. Reagents and conditions: (i) NaIO4, CHCl3/MeCN/H2O (1/1/1), rt, 30 min; (ii) 44, AcOH, reflux, 2 h; (iii) Oxone, KHCO3, Me2CO, H2O, rt, 1 h. Some characteristic values of
1H NMR chemical shifts are indicated in italic (and red or blue) (ppm).
(Scheme 5). However, it was not possible to entirely characterize
quinazoline 80, which aromatized spontaneously to 78 during at-
tempts of recrystallization. In this sense, Shakhidoyatov et al. ob-
served analogous reduction of quinazolinone during the reduction
of nitrodesoxyvasicinone.50 As for acetal 81, we thought that it was
formed from oxidation of 78 during the esterification process; we
have already described elsewhere some oxidations of compounds
containing CONCHCO functionality, occurring by oxygen dissolved
in MeOH.51 On the other hand, reacting 79 with SnCl2 in ethanol52
gave 70% of amine 78 accompanied by 30% of the corresponding
ethyl ester. Ultimately, by performing the reduction in methanol,
methyl ester 78 was quantitatively obtained (Scheme 15).
2.2.6. On the stability of ketones. The difference between the sta-
bility of close structures described in literature and summarized in
Scheme 16, and the one of ketones 7 and 8 studied in this paper, is
very scheming. Compounds depicted in this scheme were often
purified by chromatography and/or by recrystallization and were
not claimed as unstable, except for product 85 for which it was
already reported that its “tricyclic a-hydroxy lactone substructure
[.] is rather unstable to oxidation conditions”.53 To learn more
about this question, a HUMO/LUMO study has been performed on
some of these ketones, and no significant difference was detected in
order to explain the degradation observed.
In additional investigation, aminoester derivative 78 was pro-
tected with a Boc group to obtain the carbamate 82 in low 30e71%
yield. The reaction of the latter with Bredereck’s reagent afforded
N,N-dimethylaminomethylidene compound 83 also in low 30e45%
yield (Scheme 15). However, optimization of reaction conditions
was not performed, and because the reaction occurred with low
yields and purities, no further attempts to obtain a ketone 84 from
the substrate 83 were performed.
3. Conclusion
In this paper, we have reported the first synthesis of some
5-substituted luotonin
5-substituted E-ring modified camptothecin analogs. This promp-
ted us to attempt various strategies in order to obtain unstable
key ketones for the Friedlander condensation with amino-
benzaldehydes. The study of the reactivity of some intermediates,
A derivatives, as well as some new
€

7552
L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
CO2Me
N
CO2Me
CO2Me
O
N
CO2Me
O
N
O
(v)
N
N
Me2N
O
N
NHBoc
NHBoc
NHBoc
N
N
Linaric acid
82 30%
83 30%
84
(iv)
(ii)
(iii)
CO2Me
O
N
CO2Me
O
N
CO2Me
O
H
CO2Me
MeO
MeO
N
N
N
(i)
+
+
NH2
NO2
NH2
N
N
N
NH2
79
78 55%
80 20%
81 10%
CO2Me
CO2Me
O
N
CO2Me
O
N
CO2Me
O
N
HO
HO
O
O
H
MeO2C
O
N
N
N
NH2
NH2
NH2
NH2
NH2
N
N
N
N
G
58b
60b
E
F
ꢀ
Scheme 15. Reagents and conditions: (i) (a) Zn, HBr, rt, 5 min; (b) MeOH, MeSO3H, CHCl3, MS 3 A, reflux, 78 (55%), 80 (20%); (ii) SnCl2$2H2O, MeOH, reflux, 2.5 h, 98%; (iii) air; (iv)
Boc2O, Et3N, MeOH, reflux, 12 h; (v) Bredereck’s reagent, 110 ꢀC, 2 h.
O
O
O
O
N
N
N
N
O
HO
O
O
O
O
HO
CO2H
CO2H
MeO2C
MeO2C
Lit. 56
Lit. 55
Lit. 53
85
Lit. 54
CO2Me
O
N
CO2Me
O
N
O
O
N
N
O
O
O
O
R
O
O
N
O
O
MeO2C
CO2Me
R
R
Lit. 57
Lit. 58, 59
N
7
8
O
N
O
O
N
N
N
N
O
O
N
O
O
R
O
Lit. 4
R = H Lit. 24, 44
Lit. 62
Lit. 61
R = Me, Cl Lit. 60
Scheme 16
€
and particularly the benzilidene derivatives, led to optimized con-
ditions for the oxidation of enamines derivatives. Straightforward
conditions for the synthesis of the versatile carbonyl compounds
could thus be achieved. No satisfactory conditions for the isolation
of these compounds could be met due to their high unstability.
However, an efficient two-step sequence has been demonstrated
without purification of the intermediate. In order to introduce di-
versity on the target pattern, synthesis of aminobenzaldehyde de-
rivatives was reproduced and compared with litterature results.
Interestingly, isolation and characterization of the main side-
products pointed out some key properties of both intermediates
and final products. In particular, opened pyrrolidino adducts
demonstrated the sensitivity of this scaffold to over-oxidation, ei-
ther as a tricyclic or pentacyclic ring system. This was especially
observed while attempting unfavored Friedlander condensation
with aminobenzaldehydes substituted with electroattractive
groups. A key point exposed in this paper is the unstability of keto
adducts, whose behavior is not fully rationalized, despite HOMO/
LUMO calculations. Biological testing of representative compounds
of each series are being performed and will be reported soon.
4. Experimental section
4.1. General
Melting points were determined using an Electrothermal ap-
paratus and are uncorrected. 1H and 13C NMR spectra were
obtained on a Varian Gemini 2000 at 200 and 50 MHz, respectively.

L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
7553
IR spectra were obtained in ATR mode on a FTIR Bruker Tensor 27.
(CDCl3, 200 MHz)
d
ppm: 3.85 (s, 3H, CO2CH3), 6.09 (d, J¼1.2 Hz, 1H,
Thin layer chromatographies were performed on precoated Kie-
selgel 60F254 plates. HRMS were determined by the ‘Centre Ré-
gional de Mesure Physique’, Université Blaise Pascal, Aubière,
France. Microanalyses were performed by the ‘Service de Micro-
analyses’ of LSEO, Université de Bourgogne, Dijon, France. All
products are obtained as mixtures of diastereoisomers. In the text,
atom numbering of compounds was the same as in camptothecin
series (Fig. 1).2i
CHCO2Me), 6.21 (s, 2H, OCH2O), 7.20 (s, 1H, ArH), 7.58 (ddd, J¼8.1, 7.1,
1.2 Hz,1H, ArH), 7.74 (s,1H, ArH), 7.86 (ddd, J¼8.6, 7.1,1.5 Hz,1H, ArH),
8.12 (dd, J¼8.6, 1.2 Hz, 1H, ArH), 8.33 (br s, 1H, ArH), 8.42 (dd, J¼8.1,
1.5 Hz, 1H, ArH); 13C NMR: (CDCl3, 50 MHz)
d ppm: 53.5 (CH3), 60.0
(CH), 102.4 (CH2), 102.9 (CH), 106.6 (CH), 121.4 (C), 126.5 (C), 126.7
(CH),126.8 (CH),127.1 (C),127.4 (CH),129.6 (CH),134.5 (CH),148.1 (C),
148.9(C),149.3 (C),149.9(C),152.2(C),152.3(C),159.9(C),166.5 (C); IR
n
cmꢂ1: 1208, 1240, 1602, 1631, 1672, 1754. HRMS (ESITOF) m/z calcd
for C21H14N3O5 (MþH)þ 388.0933; found 388.0944.
€
4.2. General procedure for Friedlander condensation
4.2.4. Methyl 2,3-dimethoxy-11-oxo-11,13-dihydroquino[20,30:3,4]pyr-
rolo[2,1-b]quinazoline-13-carboxylate (6d). Off-white powder; 42%
yield; mp (CH2Cl2) 234e236 ꢀC; TLC Rf (EtOAc/Hept 75/25)¼0.2; 1H
To a freshly obtained solution of the corresponding ketone
(13.4 mmol) in a dichloromethane/acetonitrile/ethyl acetate mix-
ture (450 mL) (cf. see Section 4.3) were added acetic acid (20 mL)
and the related imine (13.4 mmol, 1 equiv). Volume of the resulting
solution was partially reduced in order to remove most volatile
organic solvents prior to additional acetic acid loading (30 mL). The
reaction mixture was then refluxed for 2 h. The reaction medium
was then stripped down to an oil and the residue dissolved in
dichloromethane (75 mL). The resulting solution was then washed
with HCl 1 N (20 mL), saturated NaHCO3 (20 mL), and twice with
water (2ꢁ20 mL). The organic phase was dried over magnesium
sulfate and evaporated to dryness. The dark residue was recrys-
tallized from the appropriate solvent (generally acetone) to give the
pentacyclic derivative as a powder. Rework of the mother liquors
could be carried out to obtain some additional material. In partic-
ular, residue obtained upon evaporation of the filtrate was refluxed
in ether. Non-soluble solid was isolated by filtration and recrys-
tallized to give 10e30% of additional product with identical prop-
NMR: (CDCl3, 200 MHz)
d ppm: 3.84 (s, 3H, CO2CH3), 4.07 (s, 3H,
OCH3), 4.08 (s, 3H, OCH3), 6.11 (d, J¼1.1 Hz, 1H, CHCO2Me), 7.17 (s,
1H, ArH), 7.58 (ddd, J¼7.9, 7.2, 1.3 Hz,1H, ArH), 7.78 (s, 1H, ArH), 7.86
(ddd, J¼8.1, 7.2, 1.6 Hz, 1H, ArH), 8.10 (ddd, J¼8.1, 1.3, 0.6 Hz, 1H,
ArH), 8.36 (t, J¼1.1 Hz, 1H, ArH), 8.41 (ddd, J¼7.9, 1.6, 0.6 Hz, 1H,
ArH); 13C NMR: (CDCl3, 50 MHz)
d ppm: 53.6 (CH3), 56.3 (CH3), 56.4
(CH3), 60.1 (CH), 105.1 (CH), 108.8 (CH), 121.4 (C), 125.3 (C), 126.7
(CH), 127.1 (C), 127.4 (CH), 128.7 (CH), 129.1 (CH), 134.8 (CH), 147.4
(C), 147.9 (C), 149.4 (C), 151.8 (C), 152.3 (C), 153.9 (C), 160.1 (C), 166.7
(C); IR n
cmꢂ1: 1179, 1213, 1257, 1602, 1633, 1678, 1751. Anal. Calcd
for C22H17N3O5$5/4H2O: C, 62.04; H, 4.61; N, 9.87. Found: C, 61.89;
H, 4.22; N, 9.62.
4.2.5. Methyl 2-methoxy-11-oxo-11,13-dihydroquino[20,30:3,4]pyrrolo
[2,1-b]quinazoline-13-carboxylate (6e). Yellow powder; 50% yield;
mp (acetone) 253e251 ꢀC; TLC Rf (EtOAc/Hept 75/25)¼0.35; 1H
€
erties as first crop. When utilizing impure ketone 8a in Friedlander
NMR: (CDCl3, 200 MHz) d ppm: 3.84 (s, 3H, CO2CH3), 3.99 (s, 3H,
condensations, up to 31% of enaminoketone 72 can be isolated.
OCH3), 6.13 (d, J¼1.1 Hz, 1H, CHCO2Me), 7.20 (dd, J¼2.8, 0.7 Hz; 1H,
ArH), 7.52 (dd, J¼9.5, 2.8 Hz, 1H, ArH), 7.58 (ddd, J¼8.1, 7.2, 1.2 Hz,
1H, ArH), 7.86 (ddd, J¼8.2, 7.2, 1.7 Hz, 1H, ArH), 8.11 (dd, J¼8.2,
1.2 Hz, 1H, ArH), 8.36 (d, J¼9.5 Hz, 1H, ArH), 8.41 (dd, J¼8.1, 1.7 Hz,
4.2.1. Methyl 11-oxo-11,13-dihydroquino[20,30:3,4]pyrrolo[2,1-b]qui-
nazoline-13-carboxylate (6a). White powder; 75% yield; mp
(acetone) 237e239 ꢀC; TLC Rf (EtOAc/Hept 75/25)¼0.57; 1H NMR:
1H, ArH), 8.41 (br s, 1H, ArH); 13C NMR: (CDCl3, 50 MHz)
d ppm:
(CDCl3, 200 MHz)
d
ppm: 3.85 (s, 3H, CO2CH3), 6.18 (d, J¼1.3 Hz, 1H,
53.6 (CH3), 57.8 (CH3), 60.0 (CH), 105.3 (CH), 121.4 (C), 124.6 (CH),
126.7 (CH), 127.5 (CH), 128.4 (C), 128.8 (CH), 129.9 (CH), 130.4 (C),
132.1 (CH), 134.9 (CH), 146.2 (C), 147.9 (C), 149.3 (C), 152.1 (C), 159.6
CHCO2Me), 7.61 (ddd, J¼7.9, 7.1, 1.3 Hz, 1H, ArH), 7.73 (ddd, J¼8.3, 7.0,
1.3 Hz,1H, ArH), 7.88 (ddd, J¼8.5, 7.0,1.5 Hz,1H, ArH), 7.89 (ddd, J¼8.3,
7.1, 1.5 Hz, 1H, ArH), 8.00 (d, J¼8.3 Hz, 1H, ArH), 8.15 (d, J¼8.3 Hz, 1H,
ArH), 8.44 (dd, J¼7.9,1.5 Hz,1H, ArH), 8.50 (d, J¼8.5 Hz,1H, ArH), 8.57
(C), 160.0 (C), 166.5 (C); IR
n
cmꢂ1: 1234, 1261, 1603, 1624, 1672,
1743. Anal. Calcd for C21H15N3O4$4/5H2O: C, 65.96; H, 4.22; N,
10.99. Found: C, 66.16; H, 4.27; N, 10.59.
(br s, 1H, ArH); 13C NMR: (CDCl3, 50 MHz)
d
ppm: 53.6 (CH3), 60.0
(CH), 121.5 (C), 126.7 (CH), 127.7 (CH), 128.1 (C), 128.2 (CH), 128.7 (C),
128.8 (CH), 128.9 (CH), 130.7 (CH), 131.2 (CH), 131.7 (CH), 134.8 (CH),
4.2.6. Methyl 14-methyl-11-oxo-11,13-dihydroquino[20,30:3,4]pyrrolo
[2,1-b]quinazoline-13-carboxylate (6f). Product purified by silica gel
chromatography prior to recrystallization. Off-white powder; 39%
yield; mp (acetone/ether) 250 ꢀC (dec); TLC Rf (EtOAc/Hept 75/25)¼
149.1 (C),149.9 (C),150.4 (C), 151.2 (C), 159.9 (C), 166.3 (C); IR n :
cmꢂ1
1277, 1606, 1628, 1676, 1736. Anal. Calcd for C20H13N3O3: C, 69.97; H,
3.82; N, 12.24. Found: C, 69.68; H, 3.94; N, 12.23.
0.43; 1H NMR: (CDCl3, 200 MHz)
d ppm: 2.96 (s, 3H, CH3), 3.78 (s,
4.2.2. Methyl 8-chloro-11-oxo-11,13-dihydroquino[20,30:3,4]pyrrolo[2,1-
b]quinazoline-13-carboxylate (6b). Yellow powder; 50% yield; mp
(ether/methanol) 262e264 ꢀC; TLC Rf (EtOAc/Hept 75/25)¼0.46; 1H
3H, CO2CH3), 6.21 (s, 1H, CHCO2Me), 7.60 (ddd, J¼8.2, 7.2, 1.2 Hz, 1H,
ArH), 7.74 (ddd, J¼8.1, 6.6, 1.3 Hz, 1H, ArH), 7.88 (ddd, J¼8.4, 6.6,
1.1 Hz, 1H, ArH), 7.89 (ddd, J¼8.3, 7.2, 1.6 Hz, 1H, ArH), 8.15 (ddd,
J¼8.1, 1.1, 0.6 Hz, 1H, ArH), 8.17 (dd, J¼8.3, 1.2 Hz, 1H, ArH), 8.42
(ddd, J¼8.2, 1.6, 0.7 Hz, 1H, ArH), 8.49 (ddd, J¼8.4, 1.3, 0.6 Hz, 1H,
NMR: (CDCl3, 200 MHz)
d ppm: 3.86 (s, 3H, CO2CH3), 6.17 (d,
J¼1.3 Hz, 1H, CHCO2Me), 7.56 (dd, J¼8.7, 1.8 Hz, 1H, ArH), 7.75 (ddd,
J¼8.0, 7.0, 1.4 Hz, 1H, ArH), 7.91 (ddd, J¼8.6, 7.0, 1.7 Hz, 1H, ArH),
8.01 (dd, J¼8.0, 1.7 Hz, 1H, ArH), 8.12 (d, J¼1.8 Hz, 1H, ArH), 8.36 (d,
J¼8.7 Hz, 1H, ArH), 8.50 (d, J¼8.6 Hz, 1H, ArH), 8.58 (br s, 1H, ArH);
ArH); 13C NMR: (CDCl3, 50 MHz)
d ppm: 14.8 (CH3), 53.2 (CH3), 60.2
(CH), 121.3 (C), 123.7 (CH), 126.5 (CH), 126.9 (C), 127.5 (CH), 128.3
(CH), 128.6 (C), 128.7 (CH), 130.6 (CH), 131.2 (CH), 134.7 (CH), 141.8
(C), 149.2 (C), 150.0 (C), 152.1 (C), 159.8 (C), 166.7 (C). Anal. Calcd for
C21H15N3O3$4/5H2O: C, 67.84; H, 4.50; N, 11.30. Found: C, 67.96; H,
4.37; N, 11.42.
13C NMR: (CDCl3, 50 MHz)
d ppm: 53.7 (CH3), 60.0 (CH), 120.0 (C),
128.1 (CH), 128.1 (C), 128.2 (CH), 128.3 (2ꢁCH), 128.8 (C), 129.0 (CH),
130.8 (CH),131.4 (CH),131.7 (CH),141.1 (C),149.9 (C),150.0 (C), 150.2
(C), 153.0 (C), 159.3 (C), 166.1 (C); IR n
cmꢂ1: 1014, 1247, 1598, 1624,
1674, 1744. HRMS (ESITOF) m/z calcd for C20H13ClN3O3 (MþH)þ
4.2.7. Methyl 2-chloro-11-oxo-11,13-dihydroquino[20,30:3,4]pyrrolo[2,1-
b]quinazoline-13-carboxylate (6h), methyl 2-[(4-methylphenyl)amino]-
4-oxo-4-(4-oxo-3,4-dihydroquinazolin-2-yl)but-2-enoate (72), and
methyl 4-[(4-methylphenyl)amino]-2-oxo-4-(4-oxo-1,4-dihydro-2-qui-
nazolinyl)-3-butenoate (73). Starting from 200 mg of crude
ketone, the reaction mixture was purified by silica gel column
378.0645; found 378.0647.
4.2.3. Methyl 11-oxo-11,13-dihydro[1,3]dioxolo[60,70]quino[20,30:3,4]
pyrrolo[2,1-b]quinazoline-13-carboxylate (6c). Off-white powder;
37% yield; mp (CHCl3) 254e256 ꢀC; TLC Rf (EtOAc)¼0.76; 1H NMR:

7554
L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
chromatography using a gradient of ethyl acetate in heptane. The
compounds isolated were only characterized by NMR.
This compound was not analyzed but used directly in the following
step.
4.2.7.1. Ester 6h. Oil, 10% yield; 1H NMR: (CDCl3, 200 MHz)
4.3.2. Methyl
6-chloro-7-[1-(methoxycarbonyl)propyl]-1,5-dioxo-
d
ppm: 3.85 (s, 3H, CH3), 6.16 (d, J¼1 Hz 1H, CHCO2Me), 7.60 (ddd,
1,2,3,5-tetrahydro-3-indolizinecarboxylate (7e). The organic phase
was evaporated and the resulting oil purified by silica gel column
chromatography using a gradient of ethyl acetate in heptane. Red
oil; 89% yield; TLC Rf (EtOAc)¼0.65; 1H NMR: (CDCl3, 200 MHz)
J¼8.1, 7.0, 1.4 Hz, 1H, ArH), 7.79 (dd, J¼9.1, 6.6, 2.4 Hz, 1H, ArH), 7.87
(ddd, J¼8.6, 7.1, 1.5 Hz, 1H, ArH), 7.94 (d, J¼2.4 Hz,1H, ArH), 8.11 (dd,
J¼8.4, 1.3 Hz, 1H, ArH), 8.35e8.43 (m, 2H, ArH), 8.46 (t, J¼1 Hz, 1H,
ArH); 13C NMR: (CDCl3, 50 MHz)
d
ppm: 53.7 (CH3), 59.9 (CH), 119.8
d
ppm: 0.94 and 0.97 (2t, J¼7.3 Hz, 3H, CHCH2CH3),1.64e2.3 (m, 2H,
(C), 121.4 (C), 126.7 (CH), 126.8 (CH), 127.9 (CH), 128.9 (CH), 130.7
(CH),131.9 (C),132.1 (CH), 132.3 (CH), 133.2 (C), 134.9 (CH), 137.6 (C),
148.2 (C), 149.0 (C), 150.7 (C), 159.8 (C), 166.0 (C).
CHCH2CH3), 2.8e3.29 (m, 2H, CH2CH), 3.71 and 3.73 (2s, 3H,
CO2CH3), 3.85 (s, 3H, CO2CH3), 4.16 (t, J¼8 Hz, 1H, CHCH2CH3), 5.23
(dd, J¼9.3, 3.9 Hz, 1H, CH2CH), 7.01 and 7.03 (2s, 1H, CH); 13C NMR:
(CDCl3, 50 MHz) d ppm: 11.8, 11.9 (2s, CH3), 25.1, 25.4 (2s, CH2), 38.3
4.2.7.2. Ketone 72. Oil, 20% yield: 1H NMR: (CDCl3, 200 MHz)
ppm: 2.36 (s, 3H, CH3), 3.79 (s, 3H, CO2CH3), 7.00 (d, J¼6.0 Hz, 2H,
(CH2), 49.7 (CH), 52.5 (CH), 53.5 (CH3), 55.4 (CH3), 103.2 (CH), 136.4
(C), 148.2 (C), 156.6 (C), 166.9 (C), 169.0 (C), 171.8 (C), 193.0 (C); IR
d
ArH), 7.03 (s, 1H, ArH), 7.18 (d, J¼6.0 Hz, 2H, ArH), 7.59 (ddd, J¼8.0,
6.3, 2.0 Hz, 1H, ArH), 7.78e7.91 (m, 2H, ArH), 8.36 (ddd, J¼8.0, 1.4,
0.8 Hz, 1H, ArH), 10.22 (br s, 1H, NH), 11.93 (br s, 1H, NH); 13C NMR:
n
cmꢂ1: 1739, 1656, 1193, 1174. Anal. Calcd for C15H16ClNO6$2/3H20:
C, 50.93; H, 4.94; N, 3.96. Found: C, 50.60; H, 4.53; N, 3.82.
(CDCl3, 50 MHz)
d
ppm: 20.9 (CH3), 53.0 (CH3), 93.1 (CH), 122.1
4.3.3. Methyl 8-bromo-7-[1-(methoxycarbonyl)propyl]-6-nitro-1,5-
dioxo-1,2,3,5-tetrahydro-3-indolizinecarboxylate (7f). The organic
phase was evaporated and the resulting oil purified by silica gel col-
umnchromatographyusingagradientofethylacetateinheptane.Red
(2CH), 123.0 (C), 126.7 (CH), 128.5 (CH), 128.8 (CH), 129.9 (2CH),
134.6 (CH), 135.8 (C), 136.4 (C), 147.1 (C), 148.1 (C), 152.7 (C), 161.0
(C), 163.8 (C), 181.3 (C).
oil; 79% yield; TLC Rf (EtOAc)¼0.4; 1H NMR: (CDCl3, 200 MHz)
d ppm:
4.2.7.3. Ketone 73. Oil, 20% yield: 1H NMR: (CDCl3, 200 MHz)
0.88 and 0.91 (2t, J¼7.4 Hz, 3H, CHCH2CH3), 1.73e1.99 (m, 1H,
CHCH2CH3), 2.21e2.41(m,1H, CHCH2CH3), 2.79e2.99(m,1H, CH2CH),
3.16e3.33 (m, 1H, CH2CH), 3.65 and 3.67 (2s, 3H, CO2CH3), 3.70e3.78
(m,1H, CHCH2CH3), 3.79and 3.80(2s, 3H, CO2CH3), 5.15 and 5.16 (2dd,
d
ppm: 2.34 (s, 3H, CH3), 3.81 (s, 3H, CO2CH3), 5.53 (d, J¼2.8 Hz, 1H,
NHC]CCH), 6.00 (d, J¼2.8 Hz, 1H, NHC]CCH), 6.84 (br s, 1H,
NHC]O), 7.08 (d, J¼8.6 Hz, 2H, ArH), 7.18 (d, J¼8.6 Hz, 2H, ArH),
7.52 (ddd, J¼8.1, 5.2, 2.9 Hz, 1H, ArH), 7.76e7.86 (m, 2H, ArH), 8.36
J¼9.4, 5.8 and 9.4, 5.6 Hz,1H, CH2CH2CH); IR
n
cmꢂ1: 1742,1673,1545,
1259,1211. Anal. Calcd for C15H15BrN2O8$1/2EtOAc: C, 42.96; H, 4.03;
(ddd, J¼8.1, 1.3, 0.9 Hz, 1H, ArH); 13C NMR: (CDCl3, 50 MHz)
d
ppm:
20.1 (CH3), 52.7 (CH3), 98.2 (CH), 117.4 (2CH), 120.4 (C), 125.3 (C),
126.2 (CH), 126.4 (CH), 126.7 (CH), 129.4 (2CH), 131.5 (C), 133.9 (CH),
135.1 (C), 137.4 (C), 148.3 (C), 153.1 (C), 158.6 (C), 166.9 (C).
N, 5.89. Found: C, 42.83; H, 4.13; N, 5.14.
4.3.4. Methyl 3,9-dioxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-
1-carboxylate (8a). 1H NMR: (CDCl3, 200 MHz)
d ppm: 3.00 (dd,
4.2.8. Methyl 9-nitro-11-oxo-11,13-dihydroquino[20,30:3,4]pyrrolo[2,1-
J¼19.9, 3.5 Hz, 1H, CHCH2C]O), 3.33 (dd, J¼19.9, 9.4 Hz, 1H,
CHCH2C]O), 3.86 (s, 3H, CO2CH3), 5.35 (dd, J¼9.4, 3.5 Hz, 1H,
CHCH2C]O), 7.68 (ddd, J¼8.1, 7.2, 1.2 Hz, 1H, ArH), 7.90 (ddd, J¼8.2,
7.2, 1.6 Hz, 1H, ArH), 8.04 (dd, J¼8.2, 1.2 Hz, 1H, ArH), 8.39 (dd, J¼8.1,
1.6 Hz, 1H, ArH).
b]quinazoline-13-carboxylate (6i). Yellow powder; 25% yield; mp
1
(DMSO) >220 ꢀC; TLC Rf (EtOAc/Hept 75/25)¼0.4; H NMR: (CDCl3,
200 MHz)
d
ppm: 3.90 (s, 3H, CO2CH3), 6.36 (d, J¼1.2 Hz, 1H,
CHCO2Me), 7.81 (ddd, J¼8.2, 6.9,1.4 Hz,1H, ArH), 7.96 (ddd, J¼8.5, 6.9,
1.6 Hz, 1H, ArH), 8.11 (ddd, J¼8.5, 1.4, 0.7 Hz, 1H, ArH), 8.26 (d,
J¼9.1 Hz, 1H, ArH), 8.48 (ddd, J¼8.2, 1.6, 0.7 Hz, 1H, ArH), 8.68 (dd,
J¼9.1, 2.6 Hz,1H, ArH), 8.70 (br s,1H, ArH), 9.23 (d, J¼2.6 Hz,1H, ArH);
Unambiguous signals corresponding to the enol form 80a (10%)
are listed as follows: 1H NMR: (CDCl3, 200 MHz)
d ppm: 3.82 (s, 3H,
CO2CH3), 5.44 (d, J¼3.0 Hz, 1H, CHCO2CH3), 6.03 (d, J¼3.0 Hz, 1H,
CH]COH). This compound was not analyzed but used directly in
the following step.
IRn
cmꢂ1:1265,1345,1572,1606,1628,1679,1747. HRMS(ESITOF) m/z
calcd for C20H13N4O5 (MþH)þ 389.0886; found 389.0898.
4.3.5. Methyl 6-chloro-3,9-dioxo-1,2,3,9-tetrahydropyrrolo[2,1-b]qui-
4.3. General procedure for the preparation of ketones in
indolizine and pyroloquinazolinone series
nazoline-1-carboxylate (8b). 1H NMR: (CDCl3, 200 MHz)
d ppm: 2.99
(dd, J¼19.9, 3.4 Hz, 1H, CHCH2C]O), 3.33 (dd, J¼19.9, 9.4 Hz, 1H,
CHCH2C]O), 3.86 (s, 3H, CO2CH3), 5.33 (dd, J¼9.4, 3.4 Hz, 1H,
CHCH2C]O), 7.61 (dd, J¼8.6, 2.0 Hz, 1H, ArH), 8.00 (dd, J¼2.0,
0.5 Hz, 1H, ArH), 8.30 (dd, J¼8.6, 0.5 Hz, 1H, ArH). This compound
was not analyzed but used directly in the following step.
To a solution of enamine (1 equiv) in an ethyl acetate/acetoni-
trile 1/1 mixture (200 mL) was added an aqueous solution of so-
dium periodate (70 g/L, 200 mL, >4 equiv) at room temperature.
The resulting biphasic mixture was allowed to stir at room tem-
perature until disappearance of starting material (15e45 min).
Reaction medium was then extracted with dichloromethane
(3ꢁ100 mL). Organic phases were combined and rapidly washed
with water (100 mL). The resulting organic phase was used directly
in the following step without further work-up, except otherwise
specified.
4.3.6. Methyl 7-nitro-3,9-dioxo-1,2,3,9-tetrahydropyrrolo[2,1-b]qui-
nazoline-1-carboxylate (8c). 1H NMR: (CDCl3, 200 MHz)
d ppm:
3.06 (dd, J¼20.0, 3.4 Hz, 1H, CHCH2C]O), 3.38 (dd, J¼20.0, 9.4 Hz,
1H, CHCH2C]O), 3.89 (s, 3H, CO2CH3), 5.39 (dd, J¼9.4, 3.4 Hz, 1H,
CHCH2C]O), 8.17 (d, J¼9.0 Hz, 1H, ArH), 9.23 (d, J¼2.6 Hz, 1H, ArH),
8.67 (dd, J¼9.0, 2.6 Hz, 1H, ArH). This compound was not analyzed
but used directly in the following step.
4.3.1. Methyl 7-[1-(methoxycarbonyl)propyl]-8-nitro-1,5-dioxo-1,2,3,5-
tetrahydroindolizine-3-carboxylate (7d). 1H NMR: (CDCl3, 200 MHz)
4.4. Synthesis of benzaldehyde derivatives
d
ppm: 0.92 and 0.97 (2t, J¼7.4 Hz, 3H, CHCH2CH3), 1.73e1.94 (m,
1H, CHCH2CH3), 2.02e2.24 (m, 1H, CHCH2CH3), 2.79e3.01 (m, 1H,
CH2CH), 3.17e3.34 (m, 1H, CH2CH), 3.57 and 3.58 (2t, J¼7.5 Hz, 1H,
CHCH2CH3), 3.71 and 3.75 (2s, 3H, CO2CH3), 3.86 (s, 3H, CO2CH3),
5.28 (dd, J¼9.2, 3.5 Hz, 1H, CH2CH2CH), 7.04 and 7.08 (2s, 1H, ArH).
4.4.1. 6-Nitro-1,3-benzodioxole-5-carbaldehyde
(12). 1,1-Diacetyl
compound 13 (28.0 g, 94.2 mmol) was dissolved in hot aqueous
ethanol (70/30). Concentrated sulfuric acid (10 mL) was then slowly
added and the reaction medium was refluxed for 10 h. The product

L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
7555
crystallized upon cooling and was isolated by filtration to give
yellow crystals of 6-nitropiperonal (2.5 g, 14%). Filtrate was con-
centrated to an oil, which crystallized upon standing. Yellow crys-
tals were filtered off to give an additional 52% (10.0 g) of
6-nitropiperonal. Yellow crystals; 66% yield; mp (EtOH) 91e93 ꢀC
dropwise added nitric acid (15 mL) at 0 ꢀC. The reaction medium was
stirred at room temperature for 1 h, and then poured into ice. The
resulting white precipitate was filtered, then washed with cold
water, and dried under vacuum (20.8 g, 80%). White crystals; mp
(EtOH) 73e75 ꢀC (lit. 74 ꢀC67); 1H NMR: (CDCl3, 200 MHz)
d ppm:
(lit. 93e94 ꢀC63); 1H NMR: (CDCl3, 200 MHz)
d
ppm: 6.23 (s, 2H,
OCH2O), 7.36 (s, 1H, ArH), 7.55 (s, 1H, ArH), 10.31 (s, 1H, CHO); 13C
NMR: (CDCl3, 50 MHz) ppm: 103.9 (CH2), 105.1 (CH), 107.6 (CH),
7.71 (dd, J¼8.6, 2.3 Hz, ArH), 7.91 (d, J¼2.3 Hz, 1H, ArH), 8.12 (d,
J¼8.3 Hz, 1H, ArH), 10.44 (s, 1H, CHO); 13C NMR: (CDCl3, 50 MHz)
d
d ppm: 125.6 (CH and C), 129.0 (CH), 132.1 (C), 132.8 (CH), 140.7 (C),
128.1 (C), 147.6 (C), 151.6 (C), 152.3 (C), 186.8 (CH); IR
n
cmꢂ1: 1368,
186.2 (CH). Traces of 3-chloro-4-nitrobenzaldehyde 23 were ob-
served in the 1H NMR spectra of the crude mixture, leading to for-
mation of a peak at 9.96 ppm.
1598, 1681. HRMS (ESITOF) m/z calcd for C8H5NO5Na (MþNa)þ
218.0065; found 3218.0075.
4.4.2. 5-(Diacetyloxy)-6-nitro-1,3-benzodioxole (13). To a cold so-
lution of piperonal (5.0 g, 33.3 mmol) in acetic anhydride (50 mL)
was added dropwise nitric acid (7.5 mL, 170 mmol, 5 equiv). The
reaction medium was stirred at 0 ꢀC for 2 h and then allowed to
warm to room temperature. The solution was then evaporated and
the residue was taken in dichloromethane (50 mL). The organic
phase was neutralized with a saturated aqueous NaHCO3 solution,
washed with water (2ꢁ20 mL), dried over magnesium sulfate, and
evaporated. The resulting solid was recrystallized from ethanol to
give acylal 13. Yellowish crystals; 55% yield; mp (EtOH) 141e143 ꢀC
4.4.6. 1-(Diethoxymethyl)-4,5-dimethoxy-2-nitrobenzene
(22). Nitroveratraldehyde was dissolved in hot ethanol and
refluxed for 30 min. The solution was allowed to cool to room
temperature and kept at ꢂ30 ꢀC overnight. The resulting solid was
filtered off to give acetal 22 (0.76 g, 56%). Yellow crystals; mp
(EtOH) 57e59 ꢀC; 1H NMR: (CDCl3, 200 MHz)
d ppm: 1.26 (t,
J¼7.0 Hz, 6H, (OCH2CH3)2), 3.53e3.86 (m, 4H, (OCH2CH3)2), 3.95 (s,
3H, OCH3), 3.99 (s, 3H, OCH3), 6.10 (s, 1H, CH), 7.34 (s, 1H, ArH), 7. 56
(s, 1H, ArH); 13C NMR: (CDCl3, 50 MHz)
d
ppm: 15.1 (2ꢁCH3), 56.3
(2CH3), 63.9 (2CH2), 98.6 (CH), 107.9 (CH), 109.2 (CH), 129.2 (2C),
(lit. 142 ꢀC64); 1H NMR: (CDCl3, 200 MHz)
(OCOCH3)2), 6.17 (s, 2H, OCH2O), 7.13 (s, 1H, ArH), 7.58 (s, 1H, CH
(OCOCH3)2), 8.16 (s, 1H, ArH); 13C NMR: (CDCl3, 50 MHz)
ppm:
20.3 (2ꢁCH3), 85.7 (CH), 103.2 (CH), 105.6 (CH2), 106.5 (CH), 127.3
d
ppm: 2.14 (s, 6H,
148.4 (C), 152.9 (C); IR n
cmꢂ1: 1222, 1274, 1524, 1574, 1687. HRMS
(ESITOF) m/z calcd for C13H19NO6Na (MþNa)þ 308.1110; found
d
308.1106.
(C), 142.0 (C), 148.4 (C), 151.9 (C), 167.9 (2ꢁC); IR
n
cmꢂ1: 1197, 1347,
4.4.7. 3-Formyl methyl carbonate (28). Hydroxybenzaldehyde (60 g,
0.49 mol) was dissolved in pyridine (200 mL) and the resulting
solution was cooled in an ice bath. Methyl chloroformate (65 mL,
0.84 mol) was then added dropwise over 30 min. The reaction
medium was allowed to warm to room temperature and was stirred
for 4 h. Pyridine was evaporated and residue was taken into water
(200 mL). This aqueous layer was extracted with diethyl ether
(3ꢁ75 mL). The organic layers were combined, washed once with
water, once with diluted hydrochloric acid (5%), once with a cold
aqueous solution of sodium hydroxide (5%), and again with water.
The resulting ether layer was dried over magnesium sulfate and
evaporated to dryness to give crude carbonate (147.8 g, 48%).
Aqueous layers could be combined, acidified, and extracted with
ether to recover unreacted hydroxybenzaldehyde (77.3 g, 37%).
White crystals; 76% yield; mp (EtOH) 51e53 ꢀC (lit. 47e49 ꢀC21); 1H
1733, 1770. HRMS (ESITOF) m/z calcd for C12H11NO8Na (MþNa)þ
320.0382; found 320.0385.
4.4.3. 3,4-Dimethoxybenzaldehyde (19). To a solution of vanillin
(3.0 g, 19.7 mmol) in acetone (75 mL) were added potassium car-
bonate (5.5 g, 19.7 mmol, 1 equiv) and methyl sulfate (3.7 mL,
39.4 mmol, 2 equiv) at room temperature. The resulting suspension
was refluxed for 90 min and allowed to cool to room temperature.
Excess of methyl sulfate was neutralized by dropwise addition of
triethylamine and the reaction mixture was concentrated. The
residue was dissolved in dichloromethane (40 mL), washed with
a 10% w/w sodium hydroxide solution (20 mL), and then with water
(2ꢁ15 mL). The organic phase was dried over magnesium sulfate,
filtered, and evaporated to give aldehyde 19 (3.26 g, 99%). White
solid; mp (EtOH) 41e43 ꢀC (lit. 43e45 ꢀC65); 1H NMR: (CDCl3,
NMR: (CDCl3, 200 MHz)
d ppm: 3.94 (s, 3H, CH3OCO), 7.46 (ddd,
200 MHz)
J¼8.2 Hz,1H, ArH), 7.42 (d, J¼1.9 Hz,1H, ArH), 7.47 (dd, J¼8.2,1.9 Hz,
1H, ArH), 9.85 (s, 1H, CHO); 13C NMR: (CDCl3, 50 MHz)
ppm: 55.9
(CH3), 56.1 (CH3), 109.3 (CH), 110.6 (CH), 126.6 (CH), 130.3 (C), 149.7
(C), 154.6 (C), 190.7 (CH); IR
cmꢂ1: 1269, 1587, 1683.
d
ppm: 3.96 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.99 (d,
J¼7.8, 2.4, 1.3 Hz, 1H, ArH), 7.58 (td, J¼7.8, 0.5 Hz, 1H, ArH), 7.72
(ddd, J¼2.4, 1.3, 0.5 Hz, 1H, ArH), 7.79 (dt, J¼7.8, 1.3 Hz, 1H, ArH),
d
10.01 (s, 1H, CHO); 13C NMR: (CDCl3, 50 MHz)
d ppm: 55.6 (CH3),
121.7 (CH), 127.1 (CH), 127.4 (CH), 130.2 (CH), 137.8 (C), 151.6 (C),
n
153.8 (C), 190.9 (CH); IR n
cmꢂ1: 1249, 1691, 1753. HRMS (ESITOF)
m/z calcd for C9H8NO4Na (MþNa)þ 203.0320; found 203.0324.
4.4.4. 4,5-Dimethoxy-2-nitrobenzaldehyde (20). Grinded vera-
traldehyde (5.65 g, 34 mmol) was added portionwise to nitric acid
(35 mL) over 1 h while keeping internal temperature below 20 ꢀC.
Upon complete addition, reaction medium was allowed to stir for
10 min and was then poured into a water/ice mixture (350 mL)
with vigorous stirring and keeping the resulting suspension in dark.
Precipitated crystals were filtered, washed with cold water, and
dried in dark to give nitroveratraldehyde (6.04 g, 84%). Yellowish
crystals; mp (EtOH) 128e130 ꢀC (lit. 132e133 ꢀC66); 1H NMR:
4.4.8. 3-(Diacetoxymethyl)phenyl methyl carbonate (29). 1,1-Diace-
tyl compound 29 was obtained according to the same procedure as
acylal 13. Colorless crystals; 83% yield; mp (EtOH) 62e64 ꢀC; 1H
NMR: (CDCl3, 200 MHz)
d ppm: 2.13 (s, 6H, COCH3), 3.92 (s, 3H,
CO2CH3), 7.20e728 (m, 1H, ArH), 7.34e7.48 (m, 2H, ArH), 7.41 (d,
J¼1.0 Hz, ArH), 7.68 (s, 1H, CH(OCOCH3)2); 13C NMR: (CDCl3,
50 MHz) d ppm: 20.7 (2CH3), 55.3 (CH3), 88.7 (CH), 119.3 (CH), 122.3
(CH),124.3 (CH),129.6 (CH),137.0 (C),151.0 (C),153.9 (C),168.5 (2C);
(CDCl3, 200 MHz)
(s, 1H, ArH), 7.65 (s, 1H, ArH), 10.45 (s, 1H, CHO); 13C NMR: (CDCl3,
50 MHz) ppm: 55.9 (CH3), 56.1 (CH3), 106.9 (CH), 109.5 (CH), 125.2
d
ppm: 4.04 (s, 3H, OCH3), 4.05 (s, 3H, OCH3), 7.42
IR n : 1218, 1743, 1762. HRMS (ESITOF) m/z calcd for
cmꢂ1
C13H14NO7Na (MþNa)þ 305.0637; found 305.0623.
d
(C), 143.5 (C), 152.0 (C), 152.8 (C), 187.2 (CH); IR
n
cmꢂ1: 1336, 1522,
4.4.9. 3-Formyl-4-nitrophenyl methyl carbonate (30). To a solution
of carbonate 28 (50 g, 0.28 mol) in concentrated sulfuric acid
(600 mL) was dropwise added a cold solution of nitric acid (17 mL,
0.31 mol, 1.1 equiv) in sulfuric acid (100 mL) in an ice bath over 1 h.
The resulting solution was stirred at 0 ꢀC for 1 h and was then
carefully poured onto ice (2 kg). The precipitate was filtered off,
1574, 1687. HRMS (ESITOF) m/z calcd for C9H9NO5Na (MþNa)þ
234.0378; found 234.0390.
4.4.5. 5-Chloro-2-nitrobenzaldehyde (21). To a solution of 3-chloro-
benzaldehyde (20 g, 0.14 mol) in sulfuric acid (200 mL) was

7556
L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
vacuum dried, and recrystallized from ethanol to give nitro-
carbonate 30 (47.3 g, 75%). White crystals; mp (EtOH) 80e82 ꢀC (lit.
76e78 ꢀC21); TLC Rf (EtOAc/Hept 75/25)¼0.67; 1H NMR: (CDCl3,
layer was separated, washed with water (3ꢁ15 mL), dried over
magnesium sulfate, and evaporated. The resulting solid was
recrystallized from ethanol to give methoxynitrobenzaldehyde
(7.1 g, 66%). Brown crystals; mp (EtOH) 81e83 ꢀC (lit. 82 ꢀC68); 1H
200 MHz)
d
ppm: 3.97 (s, 3H, CO2CH3), 7.60 (dd, J¼8.8, 2.7 Hz, 1H,
ArH), 7.77 (d,1H, J¼2.7 Hz, ArH), 8.21 (d, J¼8.8 Hz, ArH),10.44 (s,1H,
CHO); 13C NMR: (CDCl3, 50 MHz)
ppm: 56.1 (CH3), 122.0 (CH),
125.7 (CH and C), 126.6 (CH), 152.8 (C), 154.8 (C), 186.9 (C); IR
cmꢂ1: 1226, 1347, 1525, 1585, 1695, 1763.
NMR: (CDCl3, 200 MHz)
d
ppm: 3.96 (s, 3H, OCH3), 7.16 (dd, J¼9.1,
d
2.9 Hz, 1H, ArH), 7.34 (d, J¼2.9 Hz, 1H, ArH), 8.17 (d, J¼9.1 Hz, 1H,
ArH), 10.49 (s, 1H, CHO); 13C NMR: (CDCl3þDMSO-d6, 50 MHz)
n
d ppm: 56.1 (CH3), 113.0 (CH), 118.3 (CH), 126.9 (CH), 134.0 (C), 142.0
(C), 163.7 (C), 188.2 (CH); IR
n
cmꢂ1: 1234, 1288, 1328, 1501, 1581,
4.4.10. 5-Hydroxy-2-nitrobenzaldehyde (31). Carbonate 30 (4.25 g,
20 mmol) was dissolved in concentrated sodium hydroxide (30% w/
w, 30 mL) and the resulting solution was stirred at room temper-
ature for 1 h. Reaction medium was then cooled in an ice bath and
carefully neutralized with acetic acid. Precipitating hydroxyni-
trobenzaldehyde was filtered, dried, and recrystallized from etha-
nol (2.35 g, 70%). Yellow crystals; mp (EtOH) 158e160 ꢀC (lit.
167e169 ꢀC68); TLC Rf (EtOAc/Hept 75/25)¼0.47; 1H NMR: (CDCl3,
1690. HRMS (ESITOF) m/z calcd for C8H8NO4 (MþH)þ 182.0453;
found 182.0453.
4.4.14. 4-Hydroxy-4-(5-methoxy-2-nitrophenyl)butan-2-one (43). To
a solution of hydroxynitrobenzaldehyde 31 (1 g, 6.0 mmol) in ace-
tone (20 mL) was added potassium carbonate (820 mg, 6.0 mmol,
1 equiv) followed by addition of iodomethane (0.3 mL, 6.0 mmol,
1 equiv). The solution was heated to reflux overnight. Solvent was
then evaporated and the residue partitioned between dichloro-
methane (50 mL) and 5% aqueous hydrochloric acid (15 mL). The
organic layer was separated, washed with water (3ꢁ15 mL), dried
over magnesium sulfate, and evaporated. The resulting solid was
recrystallized from acetone to give compound 43 (1.15 g, 80%).
Yellow powder; mp (acetone) 92e94 ꢀC; 1H NMR: (CDCl3,
200 MHz)
ArH), 7.29 (d, J¼2.9 Hz,1H, ArH), 8.16 (d, J¼8.8 Hz, 1H, ArH), 10.48 (s,
1H, CHO); 13C NMR: (DMSO d6, 50 MHz)
ppm: 117.1 (CH), 120.8
(CH), 128.3 (CH), 131.2 (C), 137.9 (C), 174.9 (C), 191.6 (CH); IR
cmꢂ1
d
ppm: 6.16 (br s, 1H, OH), 7.13 (dd, J¼8.8, 2.9 Hz, 1H,
d
n
:
1310, 1332, 1521, 1577, 1668, 3119. HRMS (ESITOF) m/z calcd for
C7H5NO4Na (MþNa)þ 190.0116; found 190.0118.
200 MHz)
d
ppm: 2.24 (s, 3H, COCH3), 2.64 (dd, J¼17.7, 9.2 Hz, 1H,
4.4.11. 2-Nitro-5-[2-(1-piperidinyl)ethoxy]benzaldehyde (34). To a solu-
tion of hydroxynitrobenzaldehyde 31 (3.0 g, 18.0 mmol) in DMF
(30 mL) was added potassium carbonate (9.92 g, 71.8 mmol,
4 equiv) followed by addition of 1-(2-chloroethyl)piperidine hy-
drochloride (3.30 g, 18 mmol, 1 equiv). The solution was heated at
80 ꢀC for 4 h. Solvent was evaporated, and then the residue parti-
tioned between dichloromethane (50 mL) and water (15 mL). The
organic layer was separated, washed with water (3ꢁ15 mL), dried
over magnesium sulfate, and evaporated to give compound 34
(4.75 g, 95%). Dark oil; TLC Rf (EtOAc/Hept 70/30)¼0.23; 1H NMR:
COCH2CHOH), 3.16 (dd, J¼17.7, 1.9 Hz, 1H, COCH2CHOH), 3.71 (br s,
1H, OH), 3.92 (s, 3H, OCH3), 5.82 (dd, J¼9.2, 1.9 Hz, 1H, COCH2
-
CHOH), 6.88 (dd, J¼9.2, 2.8 Hz, 1H, ArH), 7.40 (d, J¼2.8 Hz, 1H, ArH),
8.10 (d, J¼9.2 Hz, 1H, ArH); 13C NMR: (CDCl3, 50 MHz)
d ppm: 30.3
(CH3), 50.8 (CH2), 55.8 (CH3), 65.8 (CH), 112.2 (CH), 113.4 (CH), 127.5
(CH), 142.0 (2C), 164.0 (C), 208.1 (C); IR
n
cmꢂ1: 1226, 1283, 1321,
1500, 1572, 1696, 3406. HRMS (ESITOF) m/z calcd for C11H13NO5Na
(MþNa)þ 262.0691; found 262.0702.
4.4.15. N-(2-Formylphenyl)acetamide (46). Acetylation of com-
pound 44 was carried out under the same conditions as for com-
pound 45. Resulting organic layer was washed three times with
a 5% aqueous hydrochloric acid. The organic layer is then evapo-
rated. The residue was taken in a 50/50 mixture of ethanol/HCl (5%)
and stirred for 4 h. Ethanol was then partially evaporated and the
solution neutralized with a diluted aqueous solution of sodium
hydroxide. The resulting reaction medium was extracted with
dichloromethane (3ꢁ20 mL). The organic layers were combined,
washed with water (3ꢁ15 mL), dried over magnesium sulfate, and
evaporated to give acetylated aminobenzaldehyde 46 (3.80 g, 97%).
Yellow powder; mp (EtOH) 72e74 ꢀC (lit. 66e69 ꢀC69); 1H NMR:
(CDCl3, 200 MHz)
d ppm: 1.39e1.52 (m, 2H, N(CH2CH2)2CH2),
1.52e1.74 (m, 4H, N(CH2CH2)2CH2), 2.44e2.58 (m, 4H,
N
(CH2CH2)2CH2), 2.81 (t, J¼5.9 Hz, 2H, OCH2CH2N), 4.24 (t, J¼5.9 Hz,
2H, OCH2CH2N), 7.16 (dd, J¼9.1, 2.8 Hz, 1H, ArH), 7.34 (d, J¼2.8 Hz,
1H, ArH), 8.15 (d, J¼9.1 Hz, 1H, ArH), 10.48 (s, 1H, CHO). This com-
pound was not analyzed but used directly in the following step.
4.4.12. 3-{(E)-[(4-Methylphenyl)imino]methyl}-4-nitrophenyl acetate
(35). To a solution of phenol 32 (2.0 g, 3.9 mmol) in pyridine
(10 mL) was dropwise added acetic anhydride (1.3 mL, 6.8 mmol,
1.7 equiv) at room temperature, and then the solution was stirred
for 2 h. Solvents were evaporated and the residue was dissolved in
dichloromethane (20 mL). The solution was washed once with 5%
hydrochloric acid, twice with water, and dried over magnesium
sulfate. Solid obtained upon evaporation was recrystallized from
ethanol (1.77 g, 76%). Yellow powder; mp (EtOH) 98e100 ꢀC; 1H
(CDCl3, 200 MHz)
d
ppm: 2.25 (s, 3H, COCH3), 7.20 (t, J¼7.6 Hz, 1H,
ArH), 7.56e7.71 (m, 2H, ArH), 8.74 (d, J¼8.5 Hz, 1H, ArH), 9.92 (s, 1H,
CHO), 11.20 (br s, 1H, NH).
4.4.16. N-(2-Formyl-4-nitrophenyl)acetamide (47). To a solution of
compound 46 (3.5 g, 23.3 mmol) in a 17/3 sulfuric acid/acetic acid
mixture (20 mL) was dropwise added a nitric acid/sulfuric acid
mixture (50/50, 10 mL) at 0 ꢀC. The solution was kept at this tem-
perature for 30 min with stirring, warmed to room temperature,
aged for 4 h, and poured into iced water. Precipitated crystals were
filtered, washed with cold water, dried under reduced pressure, and
recrystallized from ethanol (3.29 g, 74%). Yellow powder; mp
(EtOH) 161e163 ꢀC (lit. 160 ꢀC70); 1H NMR: (CDCl3, 200 MHz)
NMR: (CDCl3, 200 MHz)
d ppm: 2.34 (s, 3H, CH3), 2.36 (s, 3H,
COCH3), 7.19 (s, 4H, ArH), 7.33 (dd, J¼8.9, 2.6 Hz, 1H, ArH), 8.04 (d,
J¼2.6 Hz, 1H, ArH), 8.11 (d, J¼8.9 Hz, 1H, ArH), 8.95 (s, 1H, CH]N);
13C NMR: (CDCl3, 50 MHz)
d ppm: 20.9 (2CH3), 121.1 (2CH2), 122.3
(CH), 124.0 (CH), 126.3 (CH), 129.8 (2CH2), 133.2 (C), 137.2 (C), 146.1
(C), 148.0 (C), 153.7 (CH), 154.1 (C), 168.2 (C); IR n
cmꢂ1: 1192, 1339,
1516, 1574, 1750. HRMS (ESITOF) m/z calcd for C16H15N2O4 (MþH)þ
299.1032; found 299.1047.
d
ppm: 2.33 (s, 3H, COCH3), 8.45 (dd, J¼9.3, 2.7 Hz, 1H, ArH), 8.62 (d,
4.4.13. 5-Methoxy-2-nitrobenzaldehyde (37). To
a
solution of
J¼2.7 Hz, 1H, ArH), 8.96 (d, J¼9.3 Hz, 1H, ArH), 10.02 (d, J¼0.7 Hz,
1H, CHO), 11.40 (br s, 1H, NH).
hydroxynitrobenzaldehyde 31 (10 g, 59.8 mmol) in DMF (20 mL)
was added potassium carbonate (8.4 g, 59.8 mmol, 1 equiv) fol-
lowed by addition of iodomethane (3.8 mL, 59.8 mmol, 1 equiv).
The solution was heated at 80 ꢀC for 4 h. Solvent was then evapo-
rated and the residue partitioned between dichloromethane
(50 mL) and 5% aqueous hydrochloric acid (15 mL). The organic
4.4.17. 2-Amino-5-nitrobenzaldehyde (48). A suspension of com-
pound 47 (3.0 g, 14.4 mmol) in 5% aqueous hydrochloric acid
(20 mL) was heated to reflux overnight. The solution was neutral-
ized with aqueous sodium hydroxide and precipitated crystals

L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
7557
were filtered off, washed with cold water, and vacuum dried (2.16 g,
(CH), 121.2 (2ꢁCH), 127.3 (CH), 129.8 (2CH), 134.1 (C), 136.9 (C),
142.1 (C), 148.4 (C), 155.5 (CH), 162.8 (C); IR
cmꢂ1: 1085, 1205,
90%). Orange powder; mp (EtOH) 150 ꢀC (dec) (lit. 201 ꢀC70); 1H
n
NMR: (CDCl3þDMSO-d6, 200 MHz)
d
ppm: 6.80 (d, J¼9.3 Hz, 1H,
1288, 1328, 1502, 1572, 1612. HRMS (ESITOF) m/z calcd for
C21H26N3O3 (MþH)þ 368.1974; found 368.1987.
ArH), 7.62 (br s, 2H, NH2), 8.12 (dd, J¼9.3, 2.6 Hz, 1H, ArH), 8.47 (d,
J¼2.6 Hz, 1H, ArH), 9.90 (d, J¼0.6 Hz, 1H, CHO); 13C NMR:
(CDCl3þDMSO-d6, 50 MHz)
d
ppm: 116.2 (CH), 129.6 (CH), 132.7
4.5.6. N-[(5-Methoxy-2-nitrophenyl)methylene]-4-methylaniline
(CH),136.7 (C),154.6 (C),167.8 (C),192.4 (CH); IR
1667, 3413.
n
cmꢂ1: 1321,1560,
(40). Yellow powder; 93% yield; mp (EtOH) 110e112 ꢀC; 1H NMR:
(CDCl3, 200 MHz) d ppm: 2.39 (s, 3H, CH3), 3.99 (s, 3H, OCH3), 7.05
(dd, J¼9.1, 2.9 Hz, 1H, ArH), 7.73 (d, J¼2.9 Hz, 1H, ArH), 8.14 (d,
4.5. General procedure for the synthesis of aldimines
J¼9.1 Hz, 1H, ArH), 9.06 (s, 1H, CH]N), 7.23 (s, 4H, ArH); 13C NMR:
(CDCl3, 50 MHz)
d ppm: 20.9 (CH3), 56.1 (CH3), 112.9 (CH), 116.9
To a solution of substituted nitrobenzaldehyde (1 equiv) in
ethanol (3 vol %) was added p-toluidine (1 equiv) and the resulting
solution was heated to reflux for 30 min. The reaction medium was
then cooled to 0 ꢀC and allowed to crystallize overnight. Pre-
cipitated imine was filtered, washed once with cold ethanol, and
dried under reduced pressure.
(CH), 121.2 (2CH), 127.2 (CH), 129.8 (2CH), 134.2 (C), 136.9 (C), 142.2
(C), 148.4 (C), 155.5 (CH), 163.5 (C); IR
n
cmꢂ1: 1293, 1325, 1497,
1575, 1612. HRMS (ESITOF) m/z calcd for C15H15N2O3 (MþH)þ
271.1083; found 271.1096.
4.6. General procedure for the reduction of
nitrobenzaldimines
4.5.1. N-(4-Methylphenyl)-N-[(1E)-(6-nitro-1,3-benzodioxol-5-yl)
methylene]amine (14). Yellow powder; 85% yield; mp (EtOH)
To a solution of protected aminobenzaldehyde derivative
120e122 ꢀC (lit. 121 ꢀC71); 1H NMR: (CDCl3, 200 MHz)
d
ppm: 2.39
(1 equiv) in ethanol (10 vol %) was added anhydrous sodium sul-
fide13 (1.66 equiv), and the resulting solution was heated to reflux
for 5 min in a preheated oil bath. The hot solution was then poured
into iced water (40 vol %). The precipitating reduced imine was
filtered, washed once with cold ethanol, and dried under reduced
pressure.
(s, 3H, CH3), 6.19 (s, 2H, OCH2O), 7.21 (s, 4H, ArH), 7.55 (s, 1H, ArH),
7.74 (s, 1H, ArH), 8.94 (s, 1H, CH]N). HRMS (ESITOF) m/z calcd for
C15H13N2O4 (MþH)þ 285.0875; found 285.0883.
4.5.2. N-[(1E)-(4,5-Dimethoxy-2-nitrophenyl)methylene]-4-methyl-
aniline (24). Yellow foam; 80% yield; mp (EtOH) 130e132 ꢀC (lit.
147 ꢀC72); 1H NMR: (CDCl3, 200 MHz)
d
ppm: 2.39 (s, 3H, CH3), 4.02
4.6.1. N-[(1E)-(6-Amino-1,3-benzodioxol-5-yl)methylene]-N-(4-
methylphenyl)amine (15). Yellow powder; 65% yield; mp (EtOH)
124e126 ꢀC (lit. 134 ꢀC71); 1H NMR: (CDCl3þEt3N,13 200 MHz)
(s, 3H, OCH3), 4.08 (s, 3H, OCH3), 7.22 (s, 4H, ArH), 7.63 (s, 1H, ArH),
7.79 (s, 1H, ArH), 9.05 (s, 1H, CH]N); 13C NMR: (CDCl3, 50 MHz)
d
ppm: 21.0 (CH3), 56.5 (CH3), 56.6 (CH3), 107.2 (CH), 109.8 (CH),
d ppm: 2.36 (s, 3H, CH3), 5.90 (s, 2H, OCH2O), 6.25 (s, 1H, ArH), 6.64
121.1 (2CH), 125.9 (C), 129.8 (2CH), 136.7 (C), 142.4 (C), 148.4 (C),
(br s, 2H, NH2), 6.74 (s, 1H, ArH), 7.07 (d, J¼8.3 Hz, 2H, ArH), 7.18 (d,
150.4 (C), 153.0 (C), 155.1 (CH); IR
n
cmꢂ1: 1219, 1328, 1513, 1574,
J¼8.3 Hz, 2H, ArH), 8.37 (s, 1H, CH]N); 13C NMR: (CDCl3, 50 MHz)
1615. HRMS (ESITOF) m/z calcd for C16H17N2O4 (MþH)þ 301.1188;
d ppm: 20.7 (CH3), 96.2 (CH), 100.8 (CH2), 110.1 (C), 111.3 (CH), 120.5
found 301.1193.
(2CH),129.5 (2CH),134.6 (C), 138.9 (C),146.4 (C),149.3 (C),150.6 (C),
160.9 (CH); IR
n
cmꢂ1: 1211, 1581, 1631, 3444. HRMS (ESITOF) m/z
4.5.3. N-[(5-Chloro-2-nitrophenyl)methylene]-4-methylaniline
calcd for C15H15N2O2 (MþH)þ 255.1134; found 255.1129.
(25). Yellow foam; 31% yield; 1H NMR: (CDCl3, 200 MHz)
d ppm:
2.40 (s, 3H, CH3), 7.23 (s, 4H, ArH), 7.56 (dd, J¼8.9, 2.3 Hz, 1H, ArH),
4.6.2. 4,5-Dimethoxy-2-{[(4-methylphenyl)imino]methyl}aniline
8.05 (d, J¼8.9 Hz, 1H, ArH), 8.32 (d, J¼2.3 Hz, 1H, ArH), 8.96 (s,1H,
(16). Yellow powder; 63% yield; mp (EtOH) 182e184 ꢀC (dec) (lit.
CH]N); 13C NMR: (CDCl3, 50 MHz)
d
ppm: 20.9 (CH3), 121.3 (2CH),
123 ꢀC72); 1H NMR: (CDCl3, 200 MHz)
d ppm: 2.37 (s, 3H, CH3), 3.84
126.1 (CH), 129.5 (CH), 130.0 (2CH), 130.8 (CH), 132.9 (C), 137.5 (2C),
140.3 (C), 147.9 (C), 153.3 (CH). HRMS (ESITOF) m/z calcd for
C14H12ClN2O2 (MþH)þ 275.0587; found 275.0587.
(s, 3H, OCH3), 3.91 (s, 3H, OCH3), 7.22 (s, 4H, ArH), 7.63 (s, 1H, ArH),
7.79 (s, 1H, ArH), 8.44 (s, 1H, CH]N); 13C NMR: (CDCl3þEt3N,13
50 MHz)
d ppm: 20.3 (CH3), 55.4 (CH3), 54.7 (CH3), 101.8 (CH),
110.8 (CH), 119.1 (2CH), 129.4 (2CH), 130.9 (C), 134.3 (C), 143.4 (C),
4.5.4. 3-{(E)-[(4-Methylphenyl)imino]methyl}-4-nitrophenol
144.1 (C), 144.3 (C), 146.1 (C), 149.4 (CH); IR n
cmꢂ1: 1204, 1222,
(32). Yellow foam; 71% yield; mp (EtOH) 185 ꢀC (dec); TLC Rf
1619, 3442. HRMS (ESITOF) m/z calcd for C16H19N2O2 (MþH)þ
(EtOAc/Hept 75/25)¼0.63; 1H NMR: (CDCl3, 200 MHz)
d
ppm: 2.40
271.1447; found 271.1444.
(s, 3H, CH3), 7.00 (dd, J¼9.0, 2.8 Hz, 1H, ArH), 7.25 (s, 4H, ArH), 7.66
(d, J¼2.8 Hz, 1H, ArH), 8.14 (d, J¼9.0 Hz, 1H, ArH), 9.09 (s, 1H, CH]
4.6.3. 4-Chloro-2-{[(4-methylphenyl)imino]methyl}aniline
N); 13C NMR: (CDCl3, 50 MHz)
d
ppm: 20.7 (CH3), 114.8 (CH), 117.8
(17). Yellow powder; 45% yield; 1H NMR: (CDCl3, 200 MHz)
d ppm:
(CH), 121.2 (2CH), 127.8 (CH), 129.9 (2CH), 133.9 (C), 136.3 (C), 140.8
2.38 (s, 3H, CH3), 6.58 (br s, 2H, NH2), 6.65 (dd, J¼8.6, 2.2 Hz, 1H,
ArH), 7.05e7.34 (m, 6H, ArH), 8.46 (s,1H, CH]N). HRMS (ESITOF)
m/z calcd for C14H14ClN2 (MþH)þ 245.0846; found 245.0845.
(C), 148.3 (C), 156.6 (CH), 162.5 (C); IR
n
cmꢂ1: 1252, 1321, 1506,
1586, 1598, 3119. HRMS (ESITOF) m/z calcd for C14H13N2O3 (MþH)þ
257.0926; found 3257.0931.
4.6.4. 4-Amino-3-{(E)-[(4-methylphenyl)imino]methyl}phenyl ace-
4.5.5. 4-Methyl-N-{[2-nitro-5-(2-piperidin-1-ylethoxy)phenyl]meth-
ylene}aniline (38). Purple powder; 61% yield; mp (EtOH) 70e72 ꢀC;
TLC Rf (EtOAc/Hept 75/25)¼0.16; 1H NMR: (CDCl3, 200 MHz)
tate (36). Brown powder; 70% yield; 1H NMR: (CDCl3, 200 MHz)
d
ppm: 2.24 (s, 3H, COCH3), 2.39 (s, 3H, CH3), 6.64 (d, J¼8.0 Hz, 2H,
ArH), 7.22 (dd, J¼9.1, 2.9 Hz, 1H, ArH), 6.97 (d, J¼8.0 Hz, 2H, ArH),
7.43 (d, J¼2.9 Hz, 1H, ArH), 8.03 (d, J¼9.1 Hz, 1H, ArH), 9.00 (s, 1H,
CH]N). This compound was not analyzed but used directly in the
following step.
d
ppm: 1.40e1.55 (m, 2H, N(CH2CH2)2CH2), 1.55e1.72 (m, 4H, N
(CH2CH2)2CH2), 2.39 (s, 3H, CH3), 2.50e2.63 (m, 4H,
N
(CH2CH2)2CH2), 2.85 (t, J¼5.8 Hz, 2H, OCH2CH2N), 4.29 (t, J¼5.8 Hz,
2H, OCH2CH2N), 7.05 (dd, J¼9.1, 2.9 Hz, 1H, ArH), 7.22 (s, 4H, ArH),
7.73 (d, J¼2.9 Hz, 1H, ArH), 8.12 (d, J¼9.1 Hz, 1H, ArH), 9.04 (s, 1H,
4.6.5. 4-Methoxy-2-{(E)-[(4-methylphenyl)imino]methyl}aniline
CH]N); 13C NMR: (CDCl3, 50 MHz)
d
ppm: 21.0 (CH3), 23.9 (CH2),
(41). Yellow powder; 56% yield; mp (EtOH) 190e192 ꢀC; TLC Rf
25.7 (2CH2), 55.0 (2CH2), 57.5 (CH2), 66.8 (CH2), 113.7 (CH), 117.1
(EtOAc/Hept 75/25)¼0.5; 1H NMR: (CDCl3, 200 MHz)
d ppm: 2.37

7558
L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
(s, 3H, CH3), 3.78 (s, 3H, OCH3), 6.21 (br s, 2H, NH2), 6.65e6.72 (m,
1H, ArH), 6.84e6.92 (m, 2H, ArH), 7,11 (dd, J¼8.3, 2.4 Hz, 2H, ArH),
7,20 (dd, J¼8.3, 2.4 Hz, 2H, ArH), 8.50 (s, 1H, CH]N); 13C NMR:
of ethyl acetate in heptane (17 mg, 80%). Yellow oil; 1H NMR:
(CDCl3, 200 MHz) ppm: 3.82 (s, 3H, CO2CH3), 4.73 (s, 2H,
COCH2CO), 7.53 (ddd, J¼8.1, 6.5, 2.0 Hz, ArH), 7.70e7.85 (m, 2H,
ArH), 8.00 (br s, 1H, NH), 8.32 (ddd, J¼8.1, 1.4, 0.7 Hz, 1H, ArH). This
compound was not furthermore analyzed.
d
(CDCl3, 50 MHz)
d ppm: 20.4 (CH3), 55.5 (CH3), 66.0 (CH3), 112.3
(CH),115.2 (CH),118.9 (CH),119.2 (2CH),125.7 (C),129.6 (2CH),131.0
(C), 134.3 (C), 144.4 (C), 153.4 (CH); IR:
n
cmꢂ1 1229, 1572, 3243. This
compound was not analyzed but used directly in the following step.
4.10. Methyl 3-bromo-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]
quinazoline-1-carboxylate (62) and methyl 3,3-dibromo-9-
oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-
carboxylate (63)
4.7. N-(2-{(E)-[(4-Methylphenyl)imino]methyl}phenyl)-
acetamide (45)
To a solution of reduced imine 4413 (0.23 g,1.1 mmol) in pyridine
(5 mL) was dropwise added acetic anhydride (0.2 mL, 2.2 mmol,
2 equiv) at room temperature. The solution was allowed to stand
with stirring overnight. Solvent was then evaporated and the re-
sidual oil partitioned between dichloromethane (50 mL) and cold
water (10 mL). The organic layer was separated, washed with cold
water (2ꢁ10 mL), dried over magnesium sulfate, and evaporated.
The resulting solid was recrystallized from ethanol to give com-
pound 45 (150 mg, 57%). Yellow powder; mp (EtOH) 117e119 ꢀC (lit.
To a solution of compound 51 (0.2 g, 0.7 mmol) in dichloro-
methane (10 mL) was added
gencarbonate (12 mg, 0.14 mmol, 2 equiv) in water (5 mL) then
solution of bromine in dichloromethane (0.05 M, 1.5 mL,
a solution of sodium hydro-
a
1.05 equiv). The resulting biphasic reaction mixture was stirred at
room temperature for 15 h. Water (5 mL) was then added and the
organic layer was separated, washed three times with water, dried
over magnesium sulfate, and evaporated. Yields given in text were
determined by NMR analysis of the residue. Products were isolated
with the same properties as already described.10
146e147 ꢀC73); 1H NMR: (CDCl3, 200 MHz)
d ppm: 2.21 (s, 3H,
COCH3), 2.37 (s, 3H, CH3), 7.10 (dd, J¼7.5, 1.1 Hz, 1H, ArH), 7.14 (d,
J¼8.1 Hz, 2H, ArH), 7.22 (d, J¼8.1 Hz, 2H, ArH), 7.40 (t, J¼7.5 Hz, 2H,
ArH), 8.51 (s, 1H, CH]N), 8.74 (d, J¼7.5 Hz, 1H, ArH), 12.80 (br s, 1H,
4.11. Methyl 3-hydroxy-3-[hydroxy(phenyl)methyl]-9-oxo-
1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylate
(65)
NH); 13C NMR: (CDCl3, 50 MHz)
d ppm: 20.9 (CH3), 25.2 (CH3), 119.8
(CH), 120.7 (2CH), 122.4 (CH), 129.2 (C), 129.9 (2CH), 132.0 (CH),
133.9 (CH), 136.7 (C), 140.1 (C), 146.9 (C), 161.6 (CH), 169.2 (C); IR
Dialcohol 65 was isolated (but not purified) as a by-product of
the oxidation of ethylenic compound 54a, by using the same pro-
cedure as for oxidation of enamines 56, with a catalytic amount of
ruthenium tetroxide (10 mol %). 4% yield; 1H NMR: (CDCl3,
n
cmꢂ1: 1299, 1617, 1678, 2921. HRMS (ESITOF) m/z calcd for
C16H17N2O (MþH)þ 253.1341; found 253.1339.
4.8. Methyl 1-hydroxy-9-oxo-1,9-dihydropyrrolo[2,1-b]
quinazoline-1-carboxylate (58a) and methyl (3Z)-2-oxo-4-(4-
oxo-1,4-dihydro-2-quinazolinyl)-3-butenoate (60a)
200 MHz)
d
ppm: 2.05 (dd, J¼14.7, 2.4 Hz, 1H, CH2CH), 2.80 (dd,
J¼14.7,10.1 Hz,1H, CH2CH), 3.66 (s, 3H, CO2CH3), 4.72 (s, 1H, CHOH),
5.19 (dd, J¼10.1, 2.4 Hz, 1H, CH2CH), 7.28e7.59 (m, 3H, ArH),
7.75e7.85 (m, 4H, ArH), 8.31 (ddd, J¼8.0, 1.3, 0.8 Hz, 2H, ArH).
A stirred mixture of acetate 49 (0.47 g, 1.5 mmol) was solubi-
lized in dry methanol (4 mL) and 30% sodium methylate (0.07 mL,
0.27 mmol) was added. After 4 h, the solution was neutralized by
37% hydrochloric acid and partitioned between dichloromethane
(4 mL) and water (2 mL). The organic layer was washed with water,
and then dried (MgSO4) to give alcohol 58a as a crude oil. 1H NMR
4.12. General procedure for the synthesis of
indolizinoquinolines 66
To a solution of crude compound 7 (100e400 mg, 1 equiv) in
acetic acid (2e5 mL) was added protected aminobenzaldehyde 44
(1.3e1.5 equiv). The solution was heated at 80 ꢀC for 2 h, and then
solvents were evaporated under reduced pressure. The residue was
partitioned between dichloromethane (20 mL) and a 5% aqueous
HCl solution (5 mL). The organic layer was then neutralized with
a saturated NaHCO3 solution (30 mL). The aqueous layers were back
extracted twice with dichloromethane (30 mL). The organic layers
were combined, dried over magnesium sulfate, and evaporated.
The residue was purified by column chromatography on silica gel
with a gradient of ethyl acetate in heptane (0/100 to 100/0).
(CDCl3, 200 MHz)
d
ppm: 3.81 (s, 3H, CO2CH3), 6.80 (d, J¼5.9 Hz,1H,
CH]CHCOH), 6.85 (d, J¼5.9 Hz, 1H, CH]CHCOH), 7.50 (ddd, J¼8.0,
5.6, 2.5 Hz, 1H, ArH), 7.62e7.80 (m, 2H, ArH), 8.27 (ddd, J¼8.0, 1.4,
0.9 Hz, 1H, ArH), 11.49 (br s, 1H, OH).
Alcohol 58a rapidly evolved to give ketone 60a; white crystals;
65% crude yield. This product was characterized only by NMR.
White powder; 1H NMR: (CDCl3, 200 MHz)
d ppm: 3.90 (s, 3H,
CO2CH3), 7.21 (d, J¼16.2 Hz, 1H, CH]CHCO), 7.48 (d, J¼16.2 Hz, 1H,
CH]CHCO), 7.57 (ddd, J¼7.9, 6.0, 2.4 Hz, ArH), 7.77e7.90 (m, 2H,
ArH), 8.35 (ddd, J¼7.9, 1.5, 0.7 Hz, 1H, ArH); 13C NMR: (CDCl3,
50 MHz)
d
ppm: 52.5 (CH3), 121.4 (C), 126.4 (CH), 127.5 (CH), 128.1
4.12.1. Methyl 7-[1-(methoxycarbonyl)propyl]-6-nitro-9-oxo-9,11-di-
hydroindolizino[1,2-b]quinoline-11-carboxylate (66d). This com-
pound was obtained starting from 100 mg of precursor, and was not
subjected to elemental analysis. Yellow oil; 57% yield; TLC Rf
(CH), 128.4 (CH), 135.2 (CH), 136.9 (CH), 148.3 (C), 149.0 (C), 163.1
(C), 165.8 (C), 179.7 (C).
4.9. Methyl 2,4-dioxo-4-(4-oxo-3,4-dihydroquinazolin-2-yl)
butanoate (61)
(EtOAc)¼0.7; 1H NMR: (CDCl3, 200 MHz)
d ppm: 0.99 and 1.04 (2 t,
J¼7.4 Hz, 3H, CHCH2CH3), 1.88e2.09 (m, 1H, CHCH2CH3), 2.15e2.37
(m, 1H, CHCH2CH3), 3.72 (t, J¼7.5 Hz, 1H, CHCH2CH3), 3.74 and 3.79
(2s, 3H, CO2CH3), 3.87 (s, 3H, CO2CH3), 6.14 (s, 1H, CHCO2CH3), 7.43
(d, J¼6.8 Hz, 1H, ArH), 7.67e7.77 (m, 1H, ArH), 7.84e7.94 (m, 1H,
ArH), 7.94e8.01 (m, 1H, ArH), 8.22e8.29 (m, 1H, ArH), 8.49 (br s, 1H,
To a solution of compound 50 (0.2 g, 0.8 mmol) in dichloro-
methane (5 mL) at 0 ꢀC was dropwise added a cold solution of
chromic acid (8 mL). The reaction mixture was allowed to stir at
this temperature for 2 h, then at room temperature for 30 min. The
reaction medium was partitioned between dichloromethane (5 mL)
and water (5 mL). The organic layer was separated, washed once
with a saturated aqueous solution of NaHCO3, twice with water,
dried over magnesium sulfate, and evaporated. The residue was
then purified by silica gel column chromatography using a gradient
ArH); IR n
cmꢂ1: 1209, 1435, 1662, 1718, 1740.
4.12.2. Methyl 8-chloro-7-[1-(methoxycarbonyl)propyl]-9-oxo-9,11-
dihydroindolizino[1,2-b]quinoline-11-carboxylate (66e). This com-
pound was obtained starting from 100 mg of precursor, and was not
subjected to elemental analysis. Yellow powder; 80% yield; mp

L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
7559
(ether) 181e183 ꢀC; TLC Rf (EtOAc)¼0.65; 1H NMR: (CDCl3,
130.7 (CH), 130.8 (CH), 131.2 (C), 142.6 (C), 145.8 (C), 149.0 (C), 150.9
(C), 151.9 (C), 165.1 (C), 170.0 (C); IR
cmꢂ1: 1205, 1437, 1538, 1664,
1740. Anal. Calcd for C19H22N2O10: C, 58.96; H, 5.24; N, 8.09. Found:
C, 58.55; H, 5.02; N, 8.16.
200 MHz)
d
ppm: 0.99 and 1.04 (2t, J¼7.3 and 7.2 Hz, 3H,
n
CHCH2CH3), 1.84e2.35 (m, 2H, CHCH2CH3), 3.74 and 3.75 (2s, 3H,
CO2CH3), 3.85 (s, 3H, CO2CH3), 4.25 (t, J¼7.7 Hz,1H, CHCH2CH3), 6.10
and 6.11 (2d, J¼1.3 Hz, 1H, NCH), 7.36 and 7.39 (2s, 1H, ArH), 7.67 (t,
J¼7.4 Hz, 1H, ArH), 7.85 (t, J¼8 Hz, 1H, ArH), 7.93 (d, J¼7.8 Hz, 1H,
ArH), 8.21 (d, J¼7.4 Hz, 1H, ArH), 8.44 (s, 1H, ArH); 13C NMR: (CDCl3,
4.15. Methyl 3-(4-oxo-3,4-dihydroquinazoline-2-carbonyl)
quinoline-2-carboxylate (74)
50 MHz) d ppm: 11.8 and 11.9 (2s, CH3), 24.9 and 25.2 (2s, CH2), 49.8
(CH), 52.3 (CH3), 53.5 (CH3), 62.9 (CH), 100.0 (CH), 127.0 (CH), 127.8,
128.0 (CH),128.3 (CH),129.6 (CH),131.0 (CH),142.6 (CH),142.7 (CH),
148.7 (CH),149.3 (CH),151.5 (CH),156.7 (CH),166.0 (CH),172.0 (CH);
To a solution of enamine 56a (90 mg, 0.3 mmol) in an ethyl ace-
tate/acetonitrile/dichloromethane mixture (3/3/1, 23 mL) was
added a solution of sodium periodate (0.65 g, 3 mmol, 10 equiv) in
water(5 mL) and ruthenium oxide (8 mg, 0.06 mmol, 0.2 equiv). The
reaction mixture was then stirred at room temperature for 30 min
and separated. The organic layer containing ketone 8a was washed
twice with water. Aminobenzaldehyde 44 (65 mg, 0.3 mmol,
1 equiv) and acetic acid (5 mL) were then added to the organic layer.
The resulting solutionwas partiallyevaporated and additional acetic
acid (5 mL) was introduced. The reaction medium was then refluxed
for 2 h and evaporated. The residue was partitioned between
dichloromethane and a saturated aqueous NaHCO3 solution. The
organic layer was separated, washed twice with water, dried over
magnesium sulfate, and evaporated. The residue was then purified
by column chromatography on silica gel using a gradient of ethyl
acetate in heptane to provide product 74 in a 23% yield as a brown
powder. Recrystallization from acetone led to a degraded product.
IR n
cmꢂ1: 1628, 1661e1495, 1725, 1736.
4.12.3. Methyl 6-bromo-7-[1-(methoxycarbonyl)propyl]-8-nitro-9-
oxo-9,11-dihydroindolizino[1,2-b]quinoline-11-carboxylate
(66f). Yellow powder; 70% yield; mp (EtOAc)¼195e196 ꢀC; TLC Rf
(EtOAc)¼0.6; 1H NMR: (CDCl3, 200 MHz)
d ppm: 1.02 and 1.05 (2t,
J¼7.3 Hz, 3H, CHCH2CH3), 1.98e2.19 (m, 1H, CHCH2CH3), 2.35e2.61
(m, 1H, CHCH2CH3), 3.75 and 3.77 (2s, 3H, CO2CH3), 3.79e3.83 (m,
1H, CHCH2CH3), 3.79 and 3.83 (2s, 3H, CO2CH3), 6.11 (s, 1H,
CHCO2CH3), 7.78e7.79 (m, 1H, ArH), 7.85e7.94 (m, 1H, ArH),
7.95e8.00 (m,1H, ArH), 8.29e8.36 (m,1H, ArH), 8.49 (br s,1H, ArH);
13C NMR: (CDCl3, 50 MHz)
d ppm: 12.3 (CH3), 22.7 (CH2), 49.5 (CH3),
52.7 (CH3), 53.9 (CH), 62.6 (CH), 98.9 (C), 127.8 (C), 127.4 (CH), 127.9
(C), 128.0 (CH), 129.2 (CH), 130.7 (CH), 130.8 (CH), 131.2 (C), 142.6
(C), 145.8 (C), 149.0 (C), 150.9 (C), 151.9 (C), 165.1 (C), 170.0 (C); IR
Brown powder; 1H NMR: (CDCl3, 200 MHz)
d ppm: 3.80 (s, 3H,
n
cmꢂ1: 1210, 1255, 1538, 1670, 1745. Anal. Calcd for C22H18BrN3O7:
CO2CH3), 7.56e7.66 (m, 2H, ArH), 7.72e7.82 (m, 2H, ArH), 7.91e8.01
(m, 2H, ArH), 7.99e8.06 (m, 2H, ArH), 8.58 (d, J¼0.9 Hz, 1H, ArH),
C, 51.18; H, 3.51; N, 8.14. Found: C, 51.04; H, 3.77; N, 8.34.
10.15 (br s, 1H, NH); 13C NMR: (CDCl3, 50 MHz)
d ppm: 53.4 (CH3),
4.13. Methyl 4-bromo-3-ethyl-2,13-dioxo-2,3,11,13-
tetrahydro-1H-pyrrolo[20,30:6,7]indolizino[1,2-b]quinoline-
11-carboxylate (67)
123.2 (C), 127.0 (CH), 127.9 (C), 128.5 (CH), 128.9 (CH), 129.4 (CH),
129.5 (CH), 129.7 (C), 130.5 (CH), 132.3 (CH), 134.9 (CH), 138.8 (CH),
146.6 (C), 147.3 (C), 147.6 (C), 148.2 (C), 160.5 (C), 166.5 (C), 187.8 (C).
To a solution of 66f (500 mg, 0.97 mmol) in glacial acetic acid
was added zinc powder (750 mg) and the resulting suspension was
allowed to stir at room temperature for 2 h prior to filtration. NMR
analysis of filtrate led to the identification of lactam 67, which
rapidly degraded upon attempt of isolation. 1H NMR: (CDCl3,
4.16. Methyl 3-(N,N-dimethylaminomethylidene)-9-oxo-3,9-
dihydropyrrolo[2,1-b]quinazoline-1-carboxylate (76a)
To a stirred solution of compound 56a (200 mg, 0.66 mmol) in
a mixture of H2O (10 mL) and THF (10 mL) was added sodium meta-
periodate (1.4 g, 2 mmol, 3 equiv). The solution was stirred at room
temperature for 5 h and the solid formed was filtered off and washed
with CH2Cl2 (2ꢁ5 mL). The filtrate was extracted with CH2Cl2
(2ꢁ10 mL), dried over MgSO4, filtered, and evaporated under reduced
pressure. The residue was purified by flash chromatography using
a mixture of cyclohexane/EtOAc (2/3) to provide product 76a. Yellow
200 MHz)
d
ppm: 0.85 and 0.88 (2t, J¼7.3 and 5.9 Hz, 3H,
CHCH2CH3), 2.18e2.66 (m, 2H, CHCH2CH3), 3.74e3.86 (m, 1H,
CHCH2CH3), 3.87 (s, 3H, CO2CH3), 6.13 and 6.16 (2s, 1H, CHCO2CH3),
7.61e7.71 (m, 1H, ArH), 7.77e7.95 (m, 2H, ArH), 8.20e8.31 (m, 1H,
ArH), 8.39 (m, 1H, ArH), 8.90 and 9.04 (2br s, 1H, NH).
4.14. Methyl 9-[1-(methoxycarbonyl)propyl]-8-nitro-1,7-
dioxo-2,4,5,7-tetrahydro-1H-pyrrolo[3,2,1-ij]-1,6-
naphthyridine-5-carboxylate (70)
solid; 56% yield; mp¼153e155 ꢀC; 1H NMR (CDCl3, 300 MHz)
d ppm:
3.14 (s, 6H, N(CH3)2), 4.02 (s, 3H, OCH3), 6.51 (s,1H, CH]CCO2Me), 7.54
(t, J¼6.3 Hz, 1H, ArH), 7.82 (dt, J¼7.1, 6.3 Hz, 2H, ArH), 8.31 (d, J¼7.8 Hz,
1H, ArH), 10.15 (s, 1H, CH]C); 13C NMR (CDCl3, 75 MHz)
d ppm: 41.1
To a solution of compound 55c (10 mg, 0.22 mmol) in methanol
(2 mL) was added ammonium formate (100 mg, 2.2 mmol,
10 equiv) and the solution was heated to reflux for 24 h. The re-
action mixture was then evaporated and the residue was parti-
tioned between water and dichloromethane. The aqueous layer was
separated and back extracted with dichloromethane. The organic
layers were combined, dried over magnesium sulfate, and evapo-
rated. The residue was purified by column chromatography on silica
gel with a gradient of ethyl acetate in heptane (0/100 to 100/0).
Yellow powder; 93% yield; mp (EtOAc) >150 ꢀC (dec); TLC Rf
(2CH3), 53.6 (CH3), 88.3 (CH), 123.2 (C), 126.9 (CH), 128.3 (CH), 128.7
(CH),129.4 (C),134.5 (CH),142.9 (CH),148.4 (C),151.6 (C),157.8 (C),165.7
(C), 167.9 (C); IR n
cmꢂ1: 1700, 2994, 3009. Anal. Calcd for C16H15N3O3:
C, 64.64; H, 5,09; N, 14,13. Found: C, 64.49; H, 4.86; N, 14.00.
4.17. Methyl 3-[(dimethylamino)methylene]-7-nitro-9-oxo-
3,9-dihydropyrrolo[2,1-b]quinazoline-1-carboxylate (76c) and
methyl 7-nitro-3,9-dioxo-3,9-dihydropyrrolo[2,1-b]
quinazoline-1-carboxylate (77c)
(EtOAc)¼0.2; 1H NMR: (CDCl3, 200 MHz)
d
ppm: 0.98 and 0.99 (2t,
Nitro esters 76c and 77c were formed whatever the exact con-
ditions, by reacting enamine 56c with oxone in acetone for 1 h at
room temperature, in the presence of potassium hydro-
gencarbonate. It was not possible to isolate these products, which
were identified by NMR of the crude reaction mixture. Partial 1H
NMR spectrum of 76c: 3.11 (s, 6H, N(CH3)2), 6.70 (s, 1H, CH]
CCO2Me); partial 1H NMR spectrum of 77c: 6.21 (s, 1H, CH]
CCO2Me).
J¼7.6 and 7.4 Hz, 3H, CHCH2CH3), 1.76e1.98 (m, 1H, CHCH2CH3),
2.25e2.45 (m, 1H, CHCH2CH3), 2.76e2.85 (m, 2H, CH2CH), 3.71 and
3.72 (2s, 3H, CO2CH3), 3.80 and 3.81 (2s, 3H, CO2CH3), 3.83 (m, 1H,
CHCH2CH3), 4.46 and 4.51 (2br s, H, NH), 5.15 (dd, J¼11.2, 4.3 Hz, 1H,
CH2CH), 8.27 (t, J¼10.8 Hz, 1H, ArH); 13C NMR: (CDCl3, 50 MHz)
d
ppm: 12.3 (CH3), 22.7 (CH2), 49.5 (CH3), 52.7 (CH3), 53.9 (CH), 62.6
(CH), 98.9 (C), 127.8 (C), 127.4 (CH), 127.9 (C), 128.0 (CH), 129.2 (CH),

7560
L. Gavara et al. / Tetrahedron 66 (2010) 7544e7561
4.18. Methyl 7-amino-9-oxo-1,2,3,9-tetrahydropyrrolo[2,1-b]
quinazoline-1-carboxylate (78)
filtered, and evaporated under reduced pressure to provide product
78. Off-white powder; 30% yield; mp¼198e200 ꢀC; 1H NMR (CDCl3,
200 MHz) d: 1.54 (s, 9H, C(CH3)3), 2.27e2.44 (m, 1H, CHCH2CH2),
To a stirred solution of compound 79 (2 g, 6.9 mmol) in MeOH
(100 mL) was added tin chloride dihydrate (14 g, 57.6 mmol,
8 equiv). The solution was refluxed for 2.5 h. After cooling, the
mixture was poured on ice (250 g), neutralized with sodium
hydrogencarbonate, and extracted with EtOAc (3ꢁ50 mL). Organic
phases were washed with water, dried over MgSO4, filtered, and
evaporated under reduced pressure to provide product 78. White
crystals; 90% yield; mp¼198e200 ꢀC; TLC Rf (EtOAc/Hept 40/60)¼
2.47e2.70 (m, 1H, CHCH2CH2), 3.13e3.36 (m, 2H, CHCH2CH2), 3.81
(s, 3H, OCH3), 5.17 (dd, J¼9.4, 2.8 Hz, 1H, CH2CH), 6.72 (br s, 1H,
ArH), 7.62 (d, J¼9.2 Hz, 1H, ArH), 8.00 (s, 1H, ArH), 8.04 (s, NH); 13C
NMR (CDCl3, 50 MHz) d: 24.0 (CH2), 27.7 (2CH3), 30.2 (CH2), 52.5
(CH3), 58.7 (CH), 80.5 (C), 113.7 (CH), 120.1 (C), 125.2 (CH), 127.5
(CH), 136.7 (C), 144.2 (C), 152.0 (C), 156.9 (C), 169.5 (C), 169.9 (C); IR
n
cmꢂ1: 1152, 1212, 1620, 1667, 1721, 1747, 3315. This compound was
not analyzed, but utilized directly in the next syntheses.
0.35; 1H NMR (CDCl3, 200 MHz)
d: 2.26e2.43 (m, 1H, CHCH2CH2),
2.47e2.70 (m, 1H, CHCH2CH2), 3.01e3.36 (m, 2H, CHCH2CH2), 3.51
(br s, 2H, NH2), 3.81 (s, 3H, OCH3), 5.15 (dd, J¼9.5, 3.2 Hz, 1H,
CH2CH), 7.10 (dd, J¼8.7, 2.7 Hz, 1H, ArH), 7.44 (d, J¼2.7 Hz, 1H, ArH),
4.21. Methyl (3E)-7-[(tert-butoxycarbonyl)amino]-3-
[(dimethylamino)methylene]-1,2,3,9-tetrahydropyrrolo[2,1-b]
quinazoline-1-carboxylate (83)
7.50 (d, J¼8.7 Hz, 1H, ArH); 13C NMR (CDCl3, 50 MHz)
d: 24.3 (CH2),
30.5 (CH2), 52.9 (CH3), 58.9 (CH), 108.9 (CH), 121.3 (C), 123.1 (CH),
A stirred mixture of compound 82 (0.2 g, 0.6 mmol) and Bre-
dereck’s reagent (0.1 g, 0.8 mmol) was heated at 110 ꢀC for 2 h. After
cooling at room temperature, CH2Cl2 was added, and then the so-
lution was washed with water. Organic phases were dried over
MgSO4, filtered, and evaporated under reduced pressure to provide
product 83 as black oil, which was only characterized by NMR and
127.9 (CH), 141.8 (C), 145.3 (C), 155.3 (C), 170.3 (2C); IR n
cmꢂ1: 1322,
1612, 1667, 1731, 3357, 3441. HRMS (ESITOF) m/z calcd for
C13H14N3O3 (MþH)þ 260.1035; found 260.1035.
4.19. Methyl 7-amino-1,2,3,9-tetrahydropyrrolo[2,1-b]
quinazoline-1-carboxylate (80) and methyl (3E)-4-(6-amino-
1,4-dihydro-2-quinazolinyl)-2,2-dimethoxy-3-butenoate (81)
IR. 1H NMR (CDCl3, 200 MHz)
d: 1.53 (s, 9H, C(CH3)3), 3.08 (s, 6H, N
(CH3)2), 3.10e3.25 (m, 1H, CHCH2), 3.39e3.61 (m, 1H, CHCH2), 3.78
(s, 3H, OCH3), 5.05 (dd, J¼10.7, 3.9 Hz, 1H, CH2CH), 6.56 (br s, 1H,
ArH), 7.32e7.57 (m, 2H, ArH), 7.75e8.06 (m, 2H, C]CHN, NH); IR
To a stirred solution of compound 79 (1 g, 3.4 mmol) in 48% HBr
(10 mL) was added zinc powder (2 g, 30.6 mmol, 9 equiv). After
5 min, the solution was neutralized with sodium hydro-
gencarbonate, filtered on Celite, and then extracted with CH2Cl2
(3ꢁ50 mL), leading to organic phases A. Water phases were evap-
orated, and MeOH (100 mL), CHCl3 (100 mL), and MeSO3H (0.1 mL)
were added to the residue. The solution was refluxed for 48 h by
n
cmꢂ1: 1092, 1155, 1367, 1563, 1649, 1723, 1750, 3255.
Acknowledgements
The authors gratefully acknowledge the Conseil Régional Nord-
Pas-de-Calais for the L.G.’s and T.B.’s PhD scholarships.
ꢀ
using a Soxhlet filled with 3 A MS. Upon evaporation, the residue
was dissolved in CH2Cl2, and then washed with water. Organic
phases A were added and the combined phases were dried over
MgSO4, filtered, and evaporated under reduced pressure. The res-
idue was purified by flash chromatography using a gradient of
heptane/EtOAc.
Supplementary data
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2010.07.048.
References and notes
4.19.1. Compound 80. Yellow powder; 20% yield; TLC Rf (EtOAc/
MeOH 70/30)¼0.52; 1H NMR (CDCl3, 200 MHz)
d ppm: 2.22e2.42
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(m, 1H, CHCH2CH2), 2.54e2.80 (m, 1H, CHCH2CH2), 3.09e3.50 (m,
2H, CHCH2CH2), 3.85 (s, 3H, OCH3), 4.55 (dd, J¼9.5, 4.3 Hz, 1H,
CH2CH), 4.66 (d, J¼14.6 Hz, 1H, CCH2N), 4.77 (d, J¼14.6 Hz, 1H,
CCH2N), 6.28 (d, J¼2.5 Hz,1H, ArH), 6.53 (dd, J¼8.4, 2.5 Hz,1H, ArH),
7.33 (d, J¼8.4 Hz, 1H, ArH). This compound was not analyzed, but
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4.19.2. Compound 81. Yellow powder; 20% yield; TLC Rf (EtOAc/
MeOH 70/30)¼0.78; 1H NMR (CDCl3, 200 MHz)
d: 3.91 (s, 3H, OCH3),
3.95 (s, 6H, (OCH3)2), 4.08 (br s, 1H, NH), 6.37 (d, J¼12.9 Hz, 1H,
CHCHC(OMe)2), 6.80 (d, J¼8.5 Hz, 1H, ArH), 6.98 (d, J¼12.9 Hz, 1H,
CHCHC(OMe)2), 7.06 (dd, J¼8.5, 2.1 Hz, 1H, ArH), 7.49 (d, J¼2.1 Hz,
1H, ArH); 13C NMR (CDCl3, 50 MHz)
d: 55.0 (2CH3), 55.8 (CH3), 97.0
(C), 109.6 (CH), 116.5 (C), 123.1 (CH), 125.3 (CH), 129.1C,142.1 (CH),
142.3 (C), 144.5 (C), 147.0 (C),172.4 (C), 174.7 (C). HRMS (ESITOF) m/z
calcd for C15H18N3O5 (MþH)þ 320.1246; found 320.1234.
4.20. Methyl 7-[(tert-butoxycarbonyl)amino]-1,2,3,9-
tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylate (82)
To a stirred solution of compound 78 (0.5 g, 1.9 mmol) in MeOH
(10 mL) was added di-tert-butyl dicarbonate (0.53 g, 1.5 mmol) and
Et3N (0.3 mL, 1.9 mmol). The solution was refluxed for 12 h.
Dichloromethane 15 mL was added, and then the solution was
washed with water. Organic phases were dried over MgSO4,
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