Studies on pyrrolidinones. Synthesis of 4,5-fused-3-hydroxypyridinyl-2- propionic acid derivatives

Article abstract of DOI:10.1016/j.tet.2011.11.071

The synthesis of some condensed indolizinediones derived from pyroglutamic acid is described. Treatment of these ketones in HCl, HBr or MeONa/MeOH furnished aryl propionic acid derivatives. During the ketone transformations, two sequential processes could

Full text of DOI:10.1016/j.tet.2011.11.071

Tetrahedron 68 (2012) 1117e1127
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Studies on pyrrolidinones. Synthesis of 4,5-fused-3-hydroxypyridinyl-2-propionic
acid derivatives
a
,
,
c
a
a,
b
,
d
Rufine Akue-Gedu b, Daniel Couturier a , Jean-Pierre Henichart , Benoit Rigo
, Gerard Sanz ,
*
ꢀ
ꢀ
ꢀ
ꢀ
Luc Van Hijfte d, Anne Bourry a
,
b
a Univ Lille Nord de France, F-59000 Lille, France
b UCLille, EA GRIIOT (4481), Laboratoire de pharmacochimie, HEI, 13 rue de Toul, F-59046 Lille, France
c
ꢀ
ꢀ
ꢀ
ꢀ
Laboratoire d’Ingenierie Moleculaire, Universite des Sciences et Technologies de Lille I, 59655 Lille, France
d Janssen Research and Development, 2340 Beerse, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of some condensed indolizinediones derived from pyroglutamic acid is described. Treat-
ment of these ketones in HCl, HBr or MeONa/MeOH furnished aryl propionic acid derivatives. During the
ketone transformations, two sequential processes could take place in competitive manner to provide
heterocyclic systems bearing carboxylic acid or hydroxycarboxylic acid function. Easy synthesis of amides
Received 29 September 2011
Received in revised form 10 November 2011
Accepted 24 November 2011
Available online 1 December 2011
indicates that potential DNA-intercalating heterocyclic systems fused on
nucleus could be obtained from these series.
g-carboline and isoquinoline
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Pyroglutamic acid
Condensed indolizinediones
Aryl propionic acids
Rearrangements
N-Acyliminium
1. Introduction
We have also previously described that treatment of 1 (R¼H,
Me, Cl) in acidic10 or basic11 conditions can lead upon air oxidation
(reaction 1), to retro-pinacol and allylic dehydration (reaction 2) or
to pinacol-like rearrangements and enamide reactions (reaction 3),
which afford a variety of new isoquinolines (3e7, R¼H, Me, Cl)
(Scheme 2). In this context, we report here the studies on the re-
activity of ketones 8e11 (Fig. 2) under both acidic and basic con-
ditions, focusing on their transformation into analogs of quinoline
propionic acids 6 and 7.
The 2-pyrrolidinone ring system is common to many molecules
with great value in medicinal chemistry.1 2-Pyrrolidinone-5-
carboxylic acid (pyroglutamic acid), which has been called ‘the
forgotten amino acid’,2 is a biologically important member of ‘the
chiral pool’.3 Cyclization of N-arylmethylpyroglutamic acid leads to
ketones 1 (Fig. 1).4 The benzo[f]indolizine skeleton5 of derivatives 1
can be converted into naphtoindolizine4d,6 or phenan-
throindolizine4b,7 alkaloids, which have attracted much attention
because they exhibit interesting biological properties.8 1,10a-Dihy-
dropyrrolo[1,2-b]isoquinoline-3,10(2H,5H)-diones1andtheiroximes
are subjects of a variety of skeletal rearrangements under Beck-
mann,9a Schmidt4g,h,9b or SemmlereWolf4c,9c conditions (Scheme 1).
2. Results and discussion
Ketones 8e10 (Fig. 2) have been previously synthesized in good
yields by FriedeleCrafts cyclization of corresponding acids 12aec
(Scheme 3);4i,12 however, due to the sensibility of the 5-
methoxyindole scaffold toward acids, it was necessary to deeply
modify the reaction conditions previously used in order to obtain
ketone 11.
O
O
CO2H
O
N
H
N
Ar
R
Pyroglutamic acid
1
2.1. Synthesis of N-arylmethylpyroglutamic acids 12
precursors of ketones 8e11
Fig. 1. Structure of pyroglutamic acid and ketones 1.
Acids 12aec were previously obtained in good yields by using
reductive amination (NaBH4) of the triethylammonium salt of
* Corresponding author. Tel.: þ33 3 28 38 48 58; fax: þ33 3 28 38 48 04; e-mail
address: benoit.rigo@hei.fr (B. Rigo).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.071

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 1117e1127
1118
O
O
H
N
NOH
NH
Semmler-Wolf
PPA
Beckman
PPA
O
O
O
O
O
N
N
CN
N
N
N
N
O
NH
Cl
S
Ar
S
NC
2
F
Scheme 1. SemmlereWolf and Beckmann reaction of oximes 2.
CO2H
OH
[reaction 1]
air oxidation
[reaction 2]
Allylic dehydration
PPA
O
X
O
O
N
N
N
HCl dil.
or
R
R
R
MeONa/MeOH
7
1
3
[reaction 3]
HCl conc.
enamide reaction
R
R
CO2H
HO2C
N
N
N
N
O
O
N
R
R
R
CO2H
4
5
6
Scheme 2. Examples of transformations of ketones 1 under acidic or basic conditions.
2.2. FriedeleCrafts cyclization of N-arylmethylpyroglutamic
acids 12
O
O
O
O
O
O
O
O
N
N
N
N
OH
NH
NH
Ketones 8e10 (Fig. 2) have been previously synthesized in good
yields by FriedeleCrafts cyclization of acids 12aec.4i,12 In these
reactions, it proved necessary to use 1,2-dichloroethane instead of
dichloromethane as the solvent to avoid a secondary reaction with
the ketone.12 Thus, starting from acid 12d, ketone 11 was not iso-
lated and only decomposition was observed, while acid 12e, in the
presence of AlCl3 at room temperature for 2 h, lead to ketone 21 in
70% yield (Scheme 5). When the reaction time was extended to
36 h, a strong decomposition of the reaction mixture was observed,
and only traces (<1%) of ketones 22 and 23 were isolated and
characterized by NMR study; taking in account that the cleavage of
an aromatic methyl ether by AlCl3 is a common reaction,17 the
formation of phenols 9 or 22 starting from methoxy carboxylic
acids 12b and 12e, respectively, could be explained easily.12 We
thought that reactivity of indole ring of ketone 21 toward haloge-
nating reagents explains the formation of 23 from AlCl3. This re-
activity was confirmed by submitting 11 (Scheme 6) to bromine,
and indeed a good 85% yield of bromoketone 24 was obtained as
the sole isomer formed (the 1H NMR spectrum of 24 show the
presence of two doublets with J¼9.0 Hz, at 7.15 and 7.35 ppm)
(Scheme 5).
OMe
O
O
OMe
MeO
8
9
10
11
Fig. 2. Structure of ketones studied.
glutamic acid (13) with the corresponding aromatic aldehyde
(Scheme 3).13a When these conditions were used for the synthesis
of N-arylmethyl acid 12d substituted by an electron rich 5-
methoxyindolyl group, complete degradation was observed dur-
ing the acidification step of salt (Scheme 3, compound 17), and acid
15d was never isolated (Scheme 3). A similar decomposition of
aminomethylindoles of type 16 has already been described.14
Noteworthy, we already experimented strong dimerization of
electron-rich indole during its Mannich condensation with diethyl
glutamate13b or methyl pyroglutamate,4i,13a and we anticipate
a worse behavior of 5-methoxyindole in similar reactions. It was
thus decided to use the reductive amination of diisopropyl gluta-
mate 18,15 followed by an intramolecular cyclization to give 20,
then saponification of ester 19 to obtain a overall yield of 59% of
acid 12d (Scheme 4). Because pyroglutamic acid derivative 12d also
decomposed during its cyclization to ketone 11 (Scheme 5), a tosyl
withdrawing group was introduced on the 5-methoxyindole ni-
trogen in order to pull down the electronic density on this ring.
Following the standard reaction pathway underlined in Scheme 1,
acid 12e was then easily obtained in a 84% overall yield from N-
tosylindole-3-carbaldehyde.16
We do not have studied the action of BBr3 on ketones 21, which
could favor formation of compounds analogous to 22 and 24,
nevertheless cyclization of acid 12e was also realized in other
conditions (Scheme 6). By using the Eaton reagent (MeSO3H/P2O5,
10/1),18 the cyclization was accompanied by cleavage of the tosyl
group, and ketone 11 was obtained in 80% yield. Alternatively, bo-
ron trifluoride etherate was used as a Lewis acid, leading to a mix-
ture of ketone 11 (40%), hydroxyacid 25 (15%), and heterocycle 26

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 1117e1127
1119
NHR
O
O
N
H
N
16
17
O
(ii)
Ar =
N
H
(i)
(ii)
(iii)
-
-
-
-
O
O2C
CO2
NH2
+
CO2H
Ar CHO
O2C
CO2
HO2C
CO2H
N
NH
NH
Ar
+
2 Et3NH
Ar
2 Et3NH
14
Ar
15
+
12a-c
13
MeO
MeO
Ar =
N
Tos
N
H
N
H
MeO
OMe
O
O
OMe
12a 82%
12b 90%
12c 61%
12d 0%
12e 84%
Scheme 3. Reaction conditions: (i) NaBH4, MeOH, 0 ꢀC, 90 min; (ii) concd HCl (pH 3); (iii) EtOH reflux (12aec) or H2O reflux, 5 h (12e).
H
iPrO2C
O
CO2iPr
NH
O
(i)
iPrO2C
CO2iPr
O
+
NH2
18
N
H
N
H
19
(ii)
(iii)
CO2iPr
CO2H
O
O
N
N
O
O
N
N
H
H
20 61%
12d 96%
Scheme 4. Reaction conditions: (i)(a) CH2Cl2, 3 A MS, CH3SO3H, 20 ꢀC, 12 h; (b) NaBH4, EtOH, 0 ꢀC; 90 min; (ii) AcOH, reflux; (iii) KOH, EtOH, reflux, 3 h then HCl.
ꢁ
(40%). Elimination of carbon monoxide4k,19 from carboxylic acid 12e
gave acyliminium salt 27,19d which upon
-aromatic cyclization
equilibrium via a retro-pinacol transposition. Ring opening of 29c
followed by allylic dehydration in an ultimate step provide car-
boxylic acid 6. Another possibility starts with the opening of the
lactam ring. The amino ketone 30 thus obtained is then oxidized by
the oxygen dissolved in the reaction mixture to give hydrox-
yquinoline 7 (if isolated, the amino ketone 30 can be oxidized by
using hydrogen peroxide). The true pathway depends on the sub-
strate, on the nature and dilution of the acid, and on the temper-
ature of the reaction (Scheme 7).10
With these conditions in hand, ketones 8, 9, and 10 were
studied; they behaved as the derivatives 110 when they were heated
at 60 ꢀC in dilute hydrochloric acid for 9 h. Hydroxyacids 31 (71%)
and 32 (60%) were obtained in good yields, sometimes accompa-
nied by small amounts of quinoline 33 (<5%) and aminoketones 34
(7%), and 35 (10%), which were easily oxidized to the corresponding
hydroxyacid 31 and 32, respectively, in near quantitative yield.
Because of the low solubility of ketone 10 in the reaction medium, it
was necessary to extend the heating period to 36 h. Hydroxyacid 36
p
provided the original fused heterocyclic system 26. Formation of
hydroxyacid 25 was explained by an oxidation process (see Scheme
7) during the neutralization step of the treatment. As for detosy-
lation of compound 21 leading to ketone 11, a mechanism similar to
the demethylation of a methoxy group near an aromatic ketone
explained this reaction: complexation of the Lewis acid on the
ketone group of 21 allowed an easy attack of the halogen atom on
the vicinal sulfonyl group. Salt 28 was thus obtained, which was
later hydrolyzed during the final treatment (Scheme 6).
2.3. Treatment of ketones 8e10 in acidic medium
We have already described that, among others, two different
mechanisms can operate when ketones 1 are treated by hot
aqueous hydrochloric or hydrobromic acid. The protonation of the
ketone group (29a) lead to acyliminium salt 29b and 29c in

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 1117e1127
1120
O
N
(i)
(ii)
O
O
CO2H
N
N
MeO
R
N
R
MeO
(iii)
12d R = H
12e R = Tos
11 R = H 0%
21 R = Tos 70%
(iv)
O
N
O
O
O
O
O
N
N
N
+
Tos
NH
NH
Cl
Br
HO
22 <1%
MeO
23 <1%
MeO
24 85%
Scheme 5. Reaction conditions: (i) (ClCO)2 ClCH2CH2Cl, 30 min, 20 ꢀC; (ii) AlCl3, <10 ꢀC then 2 h, 20 ꢀC; (iii) AlCl3, 36 h, 20 ꢀC; (iv) Br2, NaHCO3, CH2Cl2, 2 h, 20 ꢀC.
(i) 80%
CO2H
OMe
OH
NH
O
O
O
O
CO2H
N
N
N
N
(ii)
+
+
NH
MeO
N
Tos
N
Tos
- CO
MeO
11 40%
MeO
26 40%
12e
25 15%
+
O
N
OMe
N
Tos
27
F
F
+
B
-
O
N
O
O
O
F
N
N
+
Me
SO2F
BF2
N SO2C6H4Me
MeO
BF3 complex of 21
MeO
28
Scheme 6. Reaction conditions: (i) P2O5/MeSO3H, 1/10 w/w, 80 ꢀC, 4 h; (ii) (a) (CF3CO)2O, CH2Cl2, reflux, 30 min; (b) BF3$Et2O, reflux, 10 h; (c) K2CO3/H2O, 2 h.
was thus obtained in 75% yield. Interestingly, when ketone 10 was
refluxed in concd HBr, the reaction produced another heterocyclic
acid 37 in 60% yield (the behavior of ketone 21 with HBr in the same
conditions has not been studied) (Scheme 8).
(80%). Under these conditions, ketone 21 was deprotected, but an
oxidation process also occurred, with the oxygen dissolved in
MeOH as initiator.11 The hydroxyketone 39 being formed from
ketone 21 was not isolated; formation of an N-acyliminium salt 40
during acidification of the reaction mixture, followed ultimately by
the oxidative lactam ring opening, provide hydroxyacid 25 in 95%
yield (Scheme 9). Interestingly, the same reaction took place when
tetrabutylammonium fluoride in THF was used as the deprotecting
agent.
2.4. Treatment of 21 and 26 in basic medium
N-Tosyl deprotection of indole 26 was achieved with sodium
methoxide in refluxing methanol to give the free heterocycle 38

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 1117e1127
1121
CO2H
OH
acyl iminium
+
ring
retro
+
OH
OH
OH
salt
opening
O
pinacol
O
O
N
N
N
N
+
Ar
Ar
Ar
Ar
29d
29a
29b
29c
allylic
dehydration
+
H
CO2H
O
CO2H
OH
CO2H
ring
O
O
opening
enolization
oxidation
N
HN
N
N
Ar
Ar
Ar
Ar
1
30
7
6
Scheme 7. Reaction conditions: aqueous HCl or HBr, 60 ꢀC or reflux.
(ii)
100%
CO2H
CO2H
OH
CO2H
O
O
O
(i)
N
N
HN
N
+
+
O
O
(iii)
O
O
O
O
O
O
8
33 <5%
31 71%
34 7%
(ii)
100%
CO2H
OH
CO2H
O
O
O
N
N
HN
+
(i)
OH
OMe
OH
OMe
OH
OMe
OMe
OMe
OMe
9
32 60%
35 10%
CO2H
CO2H
OH
NH
O
O
N
N
N
(iv)
NH
NH
(iii)
36 75%
37 60%
10
Scheme 8. Reaction conditions: (i) concd HCl, H2O, 60 ꢀC, 9 h; (ii) H2O2, H2O, 20 ꢀC, 5 h; (iii) concd HCl, H2O, 80 ꢀC, 36 h; (iv) concd HBr, reflux, 24 h.
2.5. Reactivity of aryl propionic acids
chlorides (SOCl2/cat. DMF) was tested firstly using 7 (R¼H;
Ar¼benzene, X¼OH).10 Under these conditions, at least three by-
products were observed by TLC. Thus, activation as a methyl ester
was realized by the action of chlorotrimethylsilane in methanol.21
Ester 41 was then isolated in 95% yield, and consequently the use
of the same protocol provided methyl esters 42e46 in excellent
Some tricyclic heterocycles substituted by a lateral amino chain
are DNA-intercalating agents, and possess anti-tumor activity.20 We
thus decided to check the amidification of the propionic acid side
chain of the previous acids (Scheme 10). Activation of acids as acid

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 1117e1127
1122
yields (78e96%) when carboxylic acids 25, 31, 32, 36, and 37 were
OMe
OMe
used as reactants. The free hydroxy group of heterocycles 44 and 46
were also etherified by using dimethyl sulfate, providing esters 47
and 48 in 76e78% yields. Finally, heating esters 42, 44, and 47 with
diethylamine, benzylamine or diethylaminoethylamine led to am-
ides 49e51 in very good yields (72e81%), respectively (Scheme 10).
In ultimate stage, heating a melt of acid 31 in o-phenylenediamine
at 180 ꢀC for 2 min22 furnished 43% of benzimidazole 52.
O
O
O
(i)
N
N
N
NH
N
Tos
26
38 80%
CO2H
OH
NH
O
N
3. Conclusion
(ii)
Tos
N
In this paper, we described the synthesis of some condensed
indolizinediones derived from pyroglutamic acid, and their trans-
formation in novel heterocyclic systems substituted by a propionic
acid side chain. During the ketone transformations, two sequential
processes could take place in competitive manner to provide het-
erocyclic systems bearing carboxylic acid or hydroxycarboxylic acid
function. Noteworthy, easy synthesis of amides indicates that po-
MeO
21
MeO
25 95%
tential DNA-intercalating heterocyclic systems fused on g-carboline
and isoquinoline nucleus could be obtained from these series.
OH
+
O
O
O
O
N
N
Tos
N
NH
4. Experimental
4.1. General
MeO
MeO
40
39
Melting points were determined using an Electrothermal ap-
paratus and are uncorrected. 1H and 13C NMR spectra were ob-
tained on a Varian Gemini 2000 at 200 and 50 MHz, respectively. IR
spectra were obtained in ATR mode on an FTIR Bruker Tensor 27.
Thin layer chromatographies were performed on precoated Kie-
selgel 60F254 plates. Microanalyses were performed by the ‘Service
Scheme 9. Reactions conditions: (i) (a) MeONa, MeOH, reflux, 24 h; (b) HCl; (ii) (a)
MeONa, MeOH, reflux, 2 h; (b) concd HCl.
N
NH
OH
CO2Me
CO2H
O
NR2
OH
X
X
N
N
N
(i)
N
Ar
R
Ar
Ar
O
41 95%
42 96%
43 94%
44 80%
45 96%
46 78%
7
X = OH Ar =
X = OH Ar =
X = OH Ar =
X = OH Ar =
X = H Ar =
X = OH Ar =
O
O
(v)
(iii)
(iv)
O
52 43%
31
32
36
37
25
49 NR2 = NEt2 72%
OH
OMe
OMe
50 NR2 = NHCH2Ph 80%
N
H
N
H
OMe
N
H
H
O
N
NEt2
CO2Me
CO2Me
OMe
NH
OMe
NH
OH
NH
N
N
N
(ii)
(iv)
R
R
44 R = H
47 R = H
78%
51 80%
46 R = OMe
48 R = OMe 76%
Scheme 10. Reaction conditions: (i) MeOH, Me3SiCl, reflux, 4e10 h; (ii) Me2SO4, KHCO3, acetone, reflux, 4 h; (iii) diethylamine, reflux, 1 h; (iv) diethylaminoethylamine or ben-
zylamine, 120 ꢀC, 24 h; (v) o-phenylenediamine, 180 ꢀC, 2 min.

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 1117e1127
1123
ꢀ
de Microanalyses’ of LSEO, Universite de Bourgogne, Dijon, France
solvents was crystallized from ethyl acetate to give 84% of acid 12e as
a white powder, mp (EtOAc) >250 ꢀC; Rf (EtOAc/MeOH,1/1) 0,5; IR:
cmꢁ13250,1731,1646,1530,1482; 1H NMR (CDCl3):
ppm 2.00e2.12
or by the ‘Service Central de Microanalyses’ of CNRS in Vernaison,
France. Methyl pyroglutamate was used as the racemic form.
n
d
(m,1H), 2.20e2.28 (m,1H), 2.30 (s, 3H) 2.45e2.69 (m, 2H), 3.40 (br s,
1H, deuterium oxide exchangeable), 3.75 (s, 3H), 3.88 (dd, J¼8.0,
4.4 Hz,1H), 4.18 (d, J¼15 Hz,1H), 5.10 (d, J¼15 Hz,1H), 6.91 (dd, J¼9.0,
2.5 Hz, 1H), 7.03 (d, J¼2.5 Hz, 1H), 7.17 (d, J¼8.3 Hz, 2H), 7.51 (s, 1H),
4.2. FriedeleCrafts cyclization of acid 12e
4.2.1. 7-Methoxy-5,10-dihydro-1H-indolizino[7,6-b]indol-3,11
(2H,11aH)dione (11) and 1-methoxy-4[(4-methylphenyl)sulfonyl]-
4,9,10,10a-tetrahydrodipyrrolo[2-1-a:4,30,20-de]isoquinolin-8(6H)one
(26). A stirred mixture of acid 12e (10g, 25 mmol) and trifluoro-
acetic anhydride (6.3 mL, 50 mmol) in dry 1,2-dichloroethane
(200 mL) was refluxed for 30 min. Boron trifluoride etherate
(28.4 mL, 230 mmol) was added and the reflux was continued for
10 h under nitrogen atmosphere. After cooling, solvents were
evaporated, then a saturated solution of K2CO3 in water (150 mL)
was added and the mixture was stirred at room temperature for 2 h.
The aqueous phase was extracted with ethyl acetate; the organic
phase was washed with water, dried (Na2SO4), and then evaporated
to give a mixture of 11 and 26, which crystallized from ethyl acetate
in an alternative manner (four times concentration then crystalli-
zation). Acid 25 (15%) can be isolated, with the same properties as
described later, by neutralization of the aqueous phase.
7.70 (d, J¼8.3 Hz, 2H), 7.81 (d, J¼9 Hz, 1H); 13C NMR (CDCl3):
d ppm
21.5 (CH3), 22.6 (CH2), 29.6 (CH2), 36.3 (CH2), 55.6 (CH3), 58.3 (CH),
101.9 (CH), 114.6 (C, CH), 116.7 (CH), 126.5 (CH), 126.7 (2 CH), 129.8
(C), 129.9 (2 CH), 130.6 (C), 134.8 (C), 145.1 (C), 156.6 (C), 175.2 (C),
175.9 (C). Anal. Calcd for C22H22N2O6S, H2O: C, 57.38; H, 5.25; N, 6.08;
S, 6.96. Found: C, 57.31; H, 5.07; N, 6.18; S, 6.63.
4.2.4. N-({5-Methoxy-1-[(4-methylphenyl)sulfonyl]-1H-indol-3-
ylmethyl)glutamic acid (15e). 5-Methoxy-1-(methylphenylsulfonyl)-
1H-indol-3-carbaldehyde (92 g, 280 mmol) was added to a mixture of
glutamic acid (90.4 g, 615 mmol) and triethylamine (171 mL,
1.225 mmol) in methanol (300 mL). The solution was stirred at room
temperature for 3 h then cooledat ꢁ40ꢀC for 12 h NaBH4 powder(4 g,
105 mmol) was slowly added while keeping the temperature below
0 ꢀC, then the stirred solutionwas allowed to raise room temperature.
Solvents were evaporated and the residue was dissolved inwater. The
solution was washed with ethyl acetate (3ꢂ200 mL) then acidified
until pH 3 with 1 M HCl under strong magnetic stirring. The solid
obtained was filtered then recrystallized from water to give 90% of
acid 15e as a white-gray powder, mp (H2O) 160e162 ꢀC; Rf (EtOAc/
Product 11 (white powder): 40%, mp (acetone) >250 ꢀC; Rf
(EtOAc/MeOH, 95/5) 0.6; IR:
(CDCl3):
1H), 4.38e4.46 (m, 1H), 5.50 (d, J¼17.0 Hz, 1H), 6.98 (dt, J¼2.5,
0.7 Hz, 1H), 7.10 (dd, J¼8.9, 2.5 Hz, 1H), 7.34 (dd, J¼8.9, 0.7 Hz, 1H),
8.75 (br s, 1H, deuterium oxide exchangeable); 13C NMR (CDCl3):
n
cmꢁ1 3236, 1682, 1550, 1485; 1H NMR
ppm 2.35e2.65 (m, 4H), 3.85 (s, 3H), 4.38 (d, J¼17.0 Hz,
d
MeOH, 7/3) 0.3; IR:
NaOD):
n
cmꢁ1 1698, 1609, 1572, 1480; 1H NMR (D2O/
ppm 1.63e1.99 (m, 2H), 2.19 (t, J¼8.4 Hz, 2H), 3.16 (dd, J¼7.7,
d
ppm 20.4 (CH2), 29.9 (CH2), 36.8 (CH2), 55.8 (CH3), 60.0 (CH) 100.7
d
(CH), 111.5 (CH), 111.6 (CH), 125.4 (C), 125.6 (C), 129.2 (C), 129.5 (C),
154.2 (C), 173.7 (C), 187.6 (C). Anal. Calcd for C15H14N2O3: C, 66.66;
H, 5.22; N, 10.36. Found: C, 66.43; H, 5.54; N, 10.54.
5.9 Hz, 1H), 3.79 (d, J¼13.1 Hz, 1H), 3.94 (d, J¼13.1 Hz, 1H), 7.18 (t,
J¼6.7 Hz,1H), 7.26 (t, J¼6.7 Hz,1H), 7.33 (s,1H), 7.52 (d, J¼7.4 Hz,1H),
7.94 (d, J¼7.4 Hz, 1H); 13C NMR (D2O/NaOD):
d ppm 21.6 (CH3), 29.7
Product 26 (gray powder): 40%, mp (acetone) 246e248 ꢀC; IR:
n
(CH2), 35.0 (CH2), 45.5 (CH2), 55.7 (CH3), 62.9 (CH), 103.3 (CH), 111.9
(CH),113.7 (C),116.4 (CH),117.8 (CH),126.6 (2 CH), 129.9 (2 CH),130.6
(C), 132.0 (C), 135.2 (C), 144.9 (C), 155.7 (C), 182.0 (C), 182.5 (C). Anal.
Calcd for C22H24N2O7S: C, 57.38; H, 5.25; N, 6.08. Found: C, 57.11; H,
5.44; N, 5.87.
cmꢁ1 1677, 1618, 1500, 1461; 1H NMR (CDCl3):
d ppm 1.88e2.11 (m,
1H), 2.35 (s, 3H), 2.39e2.68 (m, 2H), 2.80e2.98 (m, 1H), 3.86 (s, 3H),
3.96 (dtd, 16.6, 1.7, 0.4 Hz, 1H), 4.92 (dd, J¼9.2, 6.8 Hz, 1H), 5.33 (d,
J¼16.6 Hz, 1H), 6.94 (d, J¼9.0 Hz, 1H), 7.22 (d, J¼8.3 Hz, 2H), 7.23 (s,
1H), 7.73 (dt, J¼8.3, 2.0 Hz, 2H), 7.76 (d, J¼9.0 Hz, 1H); 13C NMR
(CDCl3):
d
ppm 21.6 (CH3), 26.0 (CH2), 31.6 (CH2), 36.4 (CH2), 55.4
4.2.5. Isopropyl N-(5-methoxy-1H-indol-3-yl)pyroglutamate (20). A
mixture of 5-methoxyindole-3-carbaldehyde (6 g, 34.3 mmol),
diisopropyl glutamate15 (15.9 g, 68.7 mmol), acetic acid (20 drops),
(CH), 56.2 (CH3), 110.3 (CH), 113.0 (CH), 115.2 (C), 117.9 (C), 120.1
(CH), 126.7 (2 CH), 128.1 (C), 128.6 (C), 129.9 (2 CH), 135.2 (C), 144.9
(C), 151.2 (C), 174.2 (C). Anal. Calcd for C21H20N2O4S: C, 63.62; H,
5.08; N, 7.07. Found: C, 63.27; H, 5.20; N, 7.08.
ꢁ
and 3 A molecular sieves (15 g) in CH2Cl2 (840 mL) was stirred at
room temperature for 12 h. Upon filtration 1,2-dichloromethane
was evaporated, EtOH (120 mL) was added and the solution was
cooled at 0 ꢀC. While cooling, NaBH4 powder (4 g, 104 mmol) was
added (15 min). The cooling bath was removed and the solution
was stirred for 90 min. Acetic acid (12 mL) was added, and then the
solution was refluxed for 7 h. Upon evaporation the residue was
dissolved in CH2Cl2, and then washed with an aqueous solution of
NaHCO3. The organic phase was dried (Na2SO4) then evaporated.
The residue was purified by chromatography on SiO2 column
(EtOAc/heptane, 70/30) to give ester 20 (61%); mp (acetone)
4.2.2. N-(5-Methoxy-1H-indol-3-yl)pyroglutamic acid (12d). A stir-
red solution of ester 20 (3 g, 9 mmol) and KOH (5.6 g, 100 mmol) in
ethanol (100 mL) was refluxed for 3 h. Upon evaporation of the
solvent, the residue was dissolved in dichloromethane then the
solution was extracted with water. The aqueous phase was acidified
(concd HCl) then extracted with CH2Cl2. The organic phasewas dried
(Na2SO4) then evaporated to give acid 12d (96%); mp (acetone)
138e140 ꢀC; IR:
NaOD): ppm 1.78e1.98 (m, 1H), 2.07e2.30 (m, 1H), 2.34e2.68 (m,
n
cmꢁ1 1734, 1586, 1489, 1436, 1219; 1H NMR (D2O/
d
92e93 ꢀC, Rf (EtOAc/heptane, 70/30) 0.4; IR:
n
cmꢁ1 3245, 1738,
ppm 1.19 (d, J¼6.5 Hz,
2H), 3.75 (dd, J¼8.9, 4.4 Hz, 1H), 3.86 (s, 3H), 4.15 (d, J¼14.8 Hz, 1H),
1661, 1488, 1440, 1211; 1H NMR (CDCl3):
d
5.11 (d, J¼14.8 Hz, 1H), 6.92 (dd, J¼8.8, 2.3 Hz, 1H), 7.08 (d, J¼2.3 Hz,
3H), 1.23 (d, J¼6.5 Hz, 3H), 1.86e2.08 (m, 1H), 2.08e2.25 (m, 1H),
2.25e2.68 (m, 2H), 3.85 (s, 3H), 3.91 (dd, J¼8.9, 3.8 Hz, 1H), 4.17 (d,
J¼14.9 Hz, 1H), 5.02 (hept, J¼6.5 Hz, 1H), 5.21 (d, J¼14.9 Hz, 1H),
6.87 (dd, J¼8.8, 2.4 Hz, 1H) 7.08 (m, 2H), 7.26 (d, J¼8.8 Hz, 1H), 8.0
1H), 7.32 (s,1H), 7.45 (d, J¼8.8 Hz,1H); 13C NMR (D2O/NaOD):
d ppm
25.3 (CH2), 33.0 (CH2), 39.4 (CH2), 58.6 (CH3), 64.4 (CH), 103.0 (CH),
111.9 (C), 114.6 (CH), 115.7(CH), 129.2 (C), 129.5 (CH), 134.4 (C), 155.7
(C), 180.7 (C), 182.1 (C). Anal. Calcd for C15H16N2O4, ¼ H2O: C, 61.53;
H, 5.68; N, 9.57. Found: C, 61.53; H, 5.90; N, 9.65.
(br s, 1H); 13C NMR (CDCl3):
d ppm 21.5 (2 CH3), 22.5 (CH2), 29.9
(CH2), 35.4 (CH2), 55.7 (CH3), 58.7 (CH), 68.9 (CH), 100.3 (CH), 109.8
(C), 111.9 (CH), 112.7 (CH), 124.7 (CH), 127.0 (C), 131.3 (C), 154.1 (C),
171.4 (C), 174.7 (C). Anal. Calcd for C18H22N2O4: C, 65.44; H, 6.71; N,
8.48. Found: C, 65.37; H, 7.07; N, 8.76.
4.2.3. N-[5-Methoxy-1-({(4-methylphenyl)sulfonyl}-1H-indol-3yl]
methyl)pyroglutamic acid (12e). A stirred solution of acid 15e (50 g,
113 mmol) inwater (200 mL) was refluxed for 4 h. The solid obtained
upon cooling was dissolved in ethyl acetate thenwashed with water.
The brown oil obtained upon drying (Na2SO4) and evaporation of the
4.2.6. 7eMethoxy-10-[(4-methylphenyl)sulfonyl]-5,10-dihydro-1H-
indolizino[7,6-b]indol-3,11-(2H,11aH)dione (21). Oxalyl chloride

ꢀ ꢀ
R. Akue-Gedu et al. / Tetrahedron 68 (2012) 1117e1127
1124
(35.9 mL, 410 mmol) was added at 20 ꢀC to a solution of acid 12e
(91 g, 206 mmol) in 1,2-dichloroethane (250 mL). The mixture was
stirred for 30 min, cooled with an ice bath, and then AlCl323 (137 g,
1.03 mol) was added slowly by keeping temperature below 10 ꢀC.
After stirring at 20 ꢀC for 2 h 1,2-dichloromethane was added to
obtain a solution, and then ice and water were added to quench
AlCl3. The phases were separated, and the organic phase was
washed with water. An aqueous saturated solution of K2CO3 was
added to the organic phase and the mixture was stirred at 20 ꢀC for
2 h. The organic phase was washed with water, dried (Na2SO4), and
evaporated. The solid obtained was recrystallized from ethyl ace-
tate to give ketone 21 as a gray powder, mp (EtOAc) 186e188 ꢀC; Rf
(C), 174.8 (C). Anal. Calcd for C15H14N2O4: C, 62.93; H, 4.93; N, 9.78.
Found: C, 62.59; H, 5.30; N, 9.46.
4.2.9. 3-(8-Hydroxy-[1,3]dioxolo[4,5-g]isoquinolin-7-yl)propionic
acid (31), 3-[1,3]dioxolo[4,5-g]isoquinolin-7-yl-propionic acid (33)
and 3-(8-oxo-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolin-7-yl)
propionic acid (34). Ketone 8 (40 g, 163.3 mmol) was strongly
stirred at 60 ꢀC for 9 h in a mixture of 37% HCl (600 mL) and water
(400 mL), in a large beaker opened to the air and equipped with
a big magnetic stirred. Acid 31 (w65%) precipitated upon cooling at
room temperature. The solid was filtered and the solution was
extracted with dichloromethane to remove unreacted ketone 8. The
aqueous phase was concentrated to 350 mL to give a mixture of acid
31 (6%) and amino ketone 34 (7%). Acid 33 can be isolated in less
than 5% by concentration of the filtrate. The mixture of 31 and 34
was added to a solution of 10% w/w H2O2 (30 mL) and water
(120 mL), and then stirred at room temperature for 5 h to give 100%
of acid 31 with a total yield of 78%, mp (D2O, acticarbon) >220 ꢀC;
(EtOAc/MeOH, 9/1) 0,7; IR:
(CDCl3): ppm 2.30e2.60 (m, 4H), 2.42 (s, 3H), 3.88 (s, 3H), 4.30 (d,
n
cmꢁ1 1694, 1530, 1482; 1H NMR
d
J¼18.0 Hz, 1H), 4.22e4.43 (m, 1H), 5.40 (d, J¼18.0 Hz, 1H), 6.96 (d,
J¼2.7 Hz, 1H), 7.23 (dd, J¼9.1, 2.7 Hz, 1H), 7.31 (d, J¼8.3 Hz, 2H), 8.01
(d, J¼8.3 Hz, 2H), 8.30 (d, J¼9.1 Hz, 1H). 13C NMR (CDCl3):
d ppm
20.1 (CH2), 21.5 (CH3), 29.9 (CH2), 37.8 (CH2), 55.8 (CH3), 63.1 (CH),
102.3 (CH), 111.9 (CH), 113.4 (CH), 125.2 (2 CH), 126.8 (C), 127.5 (C),
129.7 (2 CH), 130.0 (C), 130.5 (C), 133.6 (C), 144.7 (C), 156.1 (C), 173.7
(C), 188.7 (C). Anal. Calcd for C22H20N2O5S, 2H2O: C, 57.38; H, 5.25;
N, 6.08; S; 6.96. Found: C, 57.65; H, 4.90; N, 6.44; S, 7.28.
On 1 g scale, and with stirring at room temperature for 36 h, less
than 1% of 22 and 23 were isolated by crystallization and only
characterized by 1H NMR.
IR:
(D2O):
2H), 7.43 (s, 1H), 7.54 (s, 1H), 8.70 (s, 1H); 13C NMR (D2O, NaOD):
ppm 31.8 (CH2), 40.0 (CH2), 101.6 (CH2), 103.9 (CH), 104.8 (CH),
n
cmꢁ1 1695, 1649, 1316, 1548, 1500, 1459, 1193, 1032; 1H NMR
ppm 2.90 (t, J¼6.9 Hz, 2H), 3.32 (t, J¼6.9 Hz, 2H), 6.29 (s,
d
d
129.0 (C), 131.7 (C), 135.7 (CH), 141.2 (C), 149.3 (C), 151.5 (C), 158.4
(C), 186.3 (C). Anal. Calcd for C13H11NO5: C, 59.77; H, 4.24; N, 5.36.
Found: C, 59.51; H, 4.48; N, 5.17.
Product 22: 1H NMR (CDCl3):
d
ppm 2.27e2.65 (m, 4H), 2.41 (s,
Acid 33 was not purified; 1H NMR (D2O, NaOD):
d
ppm 2.54 (t,
2H, J¼7.2 Hz, 2H), 2.95 (t, 2H, J¼7.2 Hz, 2H), 6.01 (s, 2H), 6.70 (s, 1H),
6.82 (s, 1H) 7.10 (s, 1H), 8.42 (s, 1H); 13C NMR (D2O, NaOD):
ppm
3H), 4.31 (d, J¼18.0 Hz, 1H), 4.23e4.45 (m, 1H), 5.37 (d, J¼18.0 Hz,
1H), 7.12 (dd, J¼9.1, 2.5 Hz, 1H), 7.12 (br s, 1H, D20 exchangeable),
7.18 (d, J¼2.5 Hz,1H), 7.30 (d, J¼8.5 Hz, 2H), 8.01 (d, J¼8.5 Hz, 2H), 8,
21 (d, J¼9.1 Hz, 1H).
d
35.9 (CH2), 40.2 (CH2), 104.2 (CH2), 104.4 (CH), 105.1 (CH), 120.4
(CH), 126.1 (C), 137.3 (C), 149.7 (C), 151.0 (CH), 153.0 (C), 154.4 (C),
184.8 (C).
Product 23: 1H NMR (CDCl3):
d ppm: 2.38e2.65 (m, 4H), 3.95 (s,
3H), 4.44 (t, J¼7.0 Hz,1H), 4.60 (d, J¼18.0 Hz,1H), 5.86 (d, J¼18.0 Hz,
1H), 7.18 (d, J¼9.0 Hz, 1H), 7.30 (d, J¼9.0 Hz, 1H), 10.5 (br s, 1H,
deuterium oxide exchangeable).
Amino ketone 34 was not purified but directly oxidized to 31; 1H
NMR (DMSO-d6):
4.07 (d, J¼15.5 Hz,1H), 4.40 (m,1H), 5.98 (s, 2H), 6.70 (s,1H), 7.22 (s,
1H), 7.70 (br s, 1H); 13C NMR (D2O, NaOD):
ppm 28.7 (CH2), 36.7
d
ppm 1.80e2.9 (m, 4H), 4.05 (d, J¼15.5 Hz, 1H),
d
4.2.7. 6-Bromo-7-methoxy-5,10-dihydro-1H-indolizino[7,6,b]indol-
3,11(2H,11aH)dione (24). Bromine (0.6 mL, 11.1 mmol) was added
dropwise at room temperature to a stirred mixture of ketone 11
(2 g, 7.4 mmol) and NaHCO3 (1.25 g,14.8 mmol) in dichloromethane
(50 mL). After stirring for 2 h, a saturated solution of NaHSO3 in
water was added. The organic phase was washed with water, dried
(Na2SO4) then evaporated. Ketone 24 was recrystallized from ethyl
acetate to give a gray powder, mp (EtOAc) >250 ꢀC, Rf (EtOAc) 0.6;
(CH2), 47.7 (CH2), 63.8 (CH), 104.8 (CH2), 107.9 (CH), 108.3 (CH),
126.8 (C), 144.0 (C), 149.6 (C), 155.4 (C), 185.1 (C), 201.3 (C).
4.2.10. 3-(4,5-Dihydroxy-6,7-dimethoxy-isoquinolin-3-yl)propionic
acid (32) and 3-(5-hydroxy-6,7-dimethoxy-4-oxo-1,2,3,4-
tetrahydroisoquinalin-3-yl)propionic acid (35). These compounds
were obtained as for 31 and 34. Amino ketone 35 was not purified
but directly oxidized to 32. Acid 32: yield 60%, mp (D2O):
IR:
n
cmꢁ1 3150, 1667, 1647, 1544, 1485; 1H NMR (CDCl3):
d
ppm
212e214 ꢀC; IR:
NMR (D2O):
ppm 2.90 (t, 2H, J¼6.5 Hz, 2H), 3.25 (t, 2H, J¼6.5 Hz,
2H), 3.93 (s, 3H), 4.00 (s, 3H), 6.95 (s, 1H), 8.47 (s, 1H); NMR (D2O,
NaOD): ppm 29.9 (CH2), 40.0 (CH2), 58.1 (CH3), 63.3 (CH3), 95.6
n
cmꢁ1 1716, 1609, 1552, 1493, 1463, 1237, 1092; 1H
2.37e2.62 (m, 4H), 3.94 (s, 3H), 4.41 (t, J¼6.7 Hz, 1H), 4.60 (d,
J¼18.0 Hz, 1H), 5.94 (d, J¼18.0 Hz, 1H), 7.15 (d, J¼9.0 Hz, 1H), 7.35 (d,
J¼9.0 Hz, 1H), 8.82 (s, 1H, deuterium oxide exchangeable); 13C NMR
d
d
(CDCl3)
d
ppm 20.4 (CH2), 29.9 (CH2), 36.2 (CH2), 57.1 (CH3), 60.0
(CH), 120.6 (C), 129.5 (C), 136.2 (C), 137.4 (C), 140.0 (CH), 155.6 (C),
156.2 (C), 156.6 (C), 185.9 (C). Anal. Calcd for C14H15NO6, ¼ H2O: C,
56.47; H, 5.25; N, 4.70. Found: C, 56.62; H, 5.26; N, 4.67.
(CH), 104.1 (C), 108.7 (CH), 109.1 (CH), 126.5 (C), 130.8 (C), 132.7 (C),
133.3 (C), 151.4 (C), 173.7 (C), 187.6 (C). Anal. Calcd for
C15H13BrN2O3: C, 51.60; H, 3.75; N, 8.02. Found: C, 51.33; H, 3.49; N,
7.78.
Amino ketone 35: yield 10%; 1H NMR (D2O, NaOD):
d ppm
1.81e2.01 (m, 1H), 2.01e2.22 (m, 1H), 2.22e2.38 (m, 2H), 3.28e3.32
(m, 1H), 3.65 (s, 3H), 3.86 (s, 3H), 3.90 (d, J¼15.5 Hz, 1H), 3.94 (d,
4.2.8. 3-(4-Hydroxy-8-methoxy-5H-pyrido[4,3-b]indol-3-yl)pro-
pionic acid (25). A solution of ketone 21 (7 g, 16.5 mmol) and so-
dium methoxide (16.5 mmol) in methanol (100 mL) was refluxed
for 2 h. Upon cooling solvent was evaporated, and then water was
added to the residue. The mixture was acidified with 1 M HCl. The
solid obtained was washed with water to give 95% of acid 25 as
J¼15.5 Hz, 1H), 6.12 (s, 1H); 13C NMR (D2O, NaOD):
d ppm 29.7
(CH2), 36.9 (CH2), 48.3 (CH2), 58.3 (CH3), 62.6 (CH), 65.2 (CH3), 97.5
(CH), 118.4 (C), 140.6 (C), 144.1 (C), 159.3 (C), 169.7 (C), 185.5 (C),
201.0 (C).
4.2.11. 3-(4-Hydroxy-5H-pyrido[4,3-b]indol-3-yl)propionic acid (36).
Ketone 10 (10 g, 41.6 mmol), 37% HCl (120 mL), and water (20 mL)
were placed in a large beaker, opened to the air and equipped with
a big magnetic stirrer, and was heated at 80 ꢀC for 36 h. The in-
termediate ketoaminoacid could be observed by NMR: 1H NMR (D2O,
a gray powder; mp (H2O) 228e229 ꢀC; Rf (MeOH) 0.7; IR:
n
cmꢁ1
3225, 1677, 1613, 1515, 1485; 1H NMR (DMSO-d6):
d
ppm 2.58 (t,
J¼6.8 Hz, 2H), 3.07 (t, J¼6.8 Hz, 2H), 3.88 (s, 3H), 7.04 (dd, J¼9.0,
2.3 Hz, 1H), 7.32 (s, 1H), 7.38 (s, 1H), 7.49 (d, J¼9.0 Hz, 1H), 7.68 (d,
J¼2.3 Hz, 1H), 7.69 (s, 1H); 13C NMR (DMSO-d6):
d
ppm 25.8 (CH2),
NaOD): d ppm 1.86e2.01 (m, 1H), 2.01e2.16 (m, 1H), 2.27e2.40 (m,
34.1 (CH2), 55.5 (CH3), 103.4 (CH), 112.6 (CH), 115.8 (CH), 119.6 (C),
121.8 (C), 130.6 (CH), 133.9 (C), 134.7 (C), 138.7 (C), 138.8 (C), 154.0
2H), 3.60e3.72 (m, 1H), 4.06 (d, J¼16.9 Hz, 1H), 4.27 (d, J¼16.9 Hz,
1H), 7.15 (t, J¼7.5 Hz, 1H), 7.41 (t, J¼8.4 Hz, 1H), 7.51 (d, J¼7.5 Hz, 1H),

ꢀ
ꢀ
R. Akue-Gedu et al. / Tetrahedron 68 (2012) 1117e1127
1125
7.67 (d, J¼8.4 Hz, 1H); 13C NMR (D2O, NaOD):
d
ppm 28.3 (CH2), 36.9
white powder, 96%, mp (MeOH) 194e196 ꢀC; IR:
ppm 3.02 (t,
J¼7.0 Hz, 2H), 3.44 (t, J¼7.0 Hz, 2H), 3.84 (s, 3H), 6.38 (s, 2H), 7.41 (s,
1H), 7.42 (s, 1H), 8.75 (s, 1H); 13C NMR (D2O, 50 ꢀC):
ppm 26.0
(CH2), 34.6 (CH2), 55.3 (CH3), 100.5 (CH), 106.6 (CH, CH2), 127.7 (C),
132.5 (C), 133.8 (C), 137.3 (CH), 150.4 (CH), 153.4 (C), 158.0 (C), 177.9
(C). Anal. Calcd for C14H13NO5: C, 61.09; H, 4.76; N, 5.09. Found: C,
61.15; H, 4.61; N, 5.19.
n
cmꢁ1 2911, 1732,
d
(CH2), 41.4 (CH2), 63.4 (CH), 115.5 (CH), 122.7 (CH), 122.9 (CH), 123.6
(CH), 125.5 (C), 129.8 (C), 131.1 (C), 141.4 (C), 185.0 (C), 195.2 (C). The
solid obtained at the end of the reaction was filtered, and then stirred
in refluxing dichloromethane for 1 h. The solid was washed with
water, and then recrystallized from water to give 75% of acid 36 as
1640, 1620, 1582, 1493, 1455, 1193; 1H NMR (D2O):
d
a light brown powder, mp (H2O) 225e227 ꢀC; Rf (MeOH) 0.7; IR:
n
cmꢁ1 3100, 1658, 1615, 1530, 1482; 1HMR (D2O, NaOD):
d
ppm 2.50 (t,
J¼6.8 Hz, 2H), 3.11 (t, J¼6.8 Hz, 2H), 7.27 (t, J¼7.4 Hz, 1H), 7.47 (t,
J¼7.5 Hz,1H), 7.61 (d, J¼8.2 Hz, 1H), 8.10 (d, J¼7.4 Hz,1H), 8.45 (s,1H);
4.2.16. Methyl
3-(4,5-dihydroxy-6-7-dimethoxy-isoquinolin-3-yl)
13 C NMR (D2O, NaOD):
d
ppm 31.4 (CH2), 40.3 (CH2),114.2 (CH),122.0
propionate (43). This compound was obtained from acid 32 fol-
lowing the procedure for the preparation of ester 41 after hours of
(CH), 122.4 (C), 123.1 (CH), 124.7 (C), 128.7 (CH), 130.3 (CH), 140.9 (C),
142.1 (C), 145.7 (C), 149.3 (C), 188.2 (C). Anal. Calcd for C14H12N2O3,
H2O: C, 61.31; H, 5.14, N; 10.21. Found C: C, 60.77; H, 5.20, N; 10.23.
reflux; white powder, 94%; mp (MeOH) 195e197 ꢀC; IR:
n
cmꢁ1
ppm 2.93 (t,
J¼6.7 Hz, 2H), 3.24 (t, J¼6.7 Hz, 2H), 3.77 (s, 3H), 3.93 (s, 3H), 4.00 (s,
3H), 7.00 (s, 1H), 8.48 (s, 1H); 13C NMR (D2O):
ppm 25.7 (CH2), 34.1
3300, 1730, 1610, 1500, 1460; 1H NMR (D2O):
d
4.2.12. 3-(5H-Pyrido[4,3-b]indol-3-yl)propionic acid (37). Ketone 10
(1 g, 4.17 mmol) was refluxed in concd HBr (25 mL) for 24 h. The
solid obtained was filtered, then recrystallized from water to give
60% of acid 37, as a gray powder; mp (H2O) >250 ꢀC; Rf (MeOH) 0.6;
d
(CH2), 55.3 (CH3), 60.0 (CH3), 63.9 (CH3), 102.7 (CH), 118.5 (C), 127.4
(C), 129.2 (C), 135.4 (C), 142.2 (CH), 147.0 (C), 153.3 (C), 157.9 (C),
177.8 (C). Anal. Calcd for C15H17NO6, H2O: C, 55.38; H, 5.89; N, 4.31.
Found: C, 55.01; H, 6.18; N, 4.32.
IR:
n d ppm 2.74 (t,
cmꢁ1 3100, 1725, 1650; 1H NMR (DMSO-d6):
J¼7.2 Hz, 2H), 3.12 (t, J¼7. 2 Hz, 2H), 7.25 (t, J¼7.5 Hz, 1H), 7.39 (s,
1H), 7.46 (t, J¼7.5 Hz, 1H), 7.57 (d, J¼7.5 Hz, 1H), 8.20 (d, J¼7.5 Hz,
4.2.17. Methyl 3-(4-hydroxy-5H-pyrido[4,3-b]indol-3-yl)propionate
(44). This compound was obtained from acid 36 following the
procedure for the preparation of ester 41 after 4 h of reflux; light
brown powder, 80%; mp (MeOH) 175e176 ꢀC; Rf (EtOAc/MeOH, 1/1)
1H), 9.25 (s, 1H); 13C NMR (D2O):
d ppm 36.6 (CH2), 40.6 (CH2),
106.6 (CH), 113.7 (CH), 120.0 (C), 122.4 (2 CH), 123.1 (C), 128.9 (CH),
142.3 (C), 142.6 (CH), 147.4 (C), 157.5 (C), 185.1 (C). Anal. Calcd for
C14H12N2O2, H2O: C, 65.11; H, 5.46; N, 10.85. Found C: C, 65.29; H,
5.76; N; 10.94.
0.6; IR:
(D2O):
n
cmꢁ1 3400e3100, 1725, 1670, 1600, 1515, 1450; 1H NMR
d
ppm 2.89 (t, J¼6.5 Hz, 2H), 3.24 (t, J¼6.5 Hz, 2H), 3.70 (s,
3H), 7.30 (t, J¼7.8 Hz, 1H), 7.50 (t, J¼6.1 Hz, 1H), 7.52 (d, J¼6.1 Hz,
1H), 7.88 (d, J¼7.8 Hz, 1H), 8.57 (s, 1H). Anal. Calcd for C15H14N2O3:
C, 66.66; H, 5.22; N, 10.36 Found: C, 66.25; H, 5.45; N, 10.24.
4.2.13. 1-Methoxy-4,9,10,10a-tetrahydrodipyrrolo[2,1-a:40,30,20-de]
isoquinolin-8(6H)-one (38). Lactam 26 (2 g, 5 mmol) was refluxed
for 24 h in a solution of sodium methoxide (100 mmol) in methanol
(20 mL). Upon cooling the solvent was evaporated and then the
residue was stirred in water. The mixture was acidified with 1 M
HCl to give 80% of compound 38 as a light brown powder; mp
4.2.18. Methyl 3-3-(5H-pyrido[4,3-b]indol-3-yl)propionate (45).
This compound was obtained from acid 37 following the procedure
for the preparation of ester 41 after 10 h of reflux; white powder,
(EtOAc) 174e176 ꢀC; Rf (EtOAc/MeOH, 9/1) 0.6; IR:
n
cmꢁ1 3166,
96%; mp (MeOH) 146e147 ꢀC; Rf (EtOAc/MeOH, 95/5) 0.3; IR:
n
1657, 1613, 1505, 1471; 1H NMR (CDCl3):
d
ppm 1.98e2.23 (m, 1H),
cmꢁ1 3400, 1725, 1660, 1650, 1620; 1H NMR (D2O):
d ppm 2.96 (t,
2.42e2.70 (m, 2H), 2.87e3.04 (m, 1H), 3.87 (s, 3H), 4.14 (dt, J¼15.8,
1.0 Hz, 1H), 5.07 (dd, J¼9.2, 6.8 Hz, 1H), 5.39 (d, J¼15.8 Hz, 1H), 6.89
(d, J¼9.0 Hz 1H), 6.93 (s, 1H), 7.20 (dd, J¼9.0, 1.0 Hz, 1H), 7.86 (br s,
J¼7.3 Hz, 2H), 3.31 (t, J¼7.3 Hz, 2H), 3.70 (s, 3H), 7.40 (t, J¼7.2 Hz,
1H), 7.53e7.67 (m, 3H), 8.06 (d, J¼8.1 Hz, 1H), 8.97 (s, 1H). 13C NMR
(D2O):
d ppm 27.5 (CH2), 32.2 (CH2), 52.3 (CH3), 105.8 (CH), 111.7
1H, deuterium oxide exchangeable); 13C NMR (CDCl3):
d
ppm 26.1
(CH), 117.5 (C), 118.9 (CH), 120.5 (CH), 122.1 (C), 128.7 (CH), 132.2 (C),
139.9 (CH), 146.1 (C),146.9 (C),174.3 (C). Anal. Calcd for C15H14N2O2:
C, 70.85; H, 5.55; N, 11.02 Found: C, 70.51; H, 5.79; N, 10.81.
(CH2), 31.9 (CH2), 37.1 (CH2), 56.2 (CH), 56.8 (CH3), 108.1 (C),109.6 (2
CH), 116.8 (C), 118.5 (CH), 125.6 (C), 129.2 (C), 148.2 (C), 174.2 (C).
Anal. Calcd for C14H14N2O2, 1/3H2O: C, 67.73; H, 5.95; N, 11.28.
Found: C, 67.66; H, 6.15; N, 10.93.
4.2.19. Methyl 3-(4-hydroxy-8-methoxy-5H-pyrido[4,3-b]indol-3-yl)
propionate (46). This compound was obtained from acid 25 fol-
lowing the procedure for the preparation of ester 41 after 10 h of
reflux; light brown powder, 78%; mp (MeOH) 180e181 ꢀC; Rf
4.2.14. Methyl 3-(4-hydroxy-isoquinolin-3-yl)propionate (41). A
stirred mixture of acid 7 (R¼H) (16 g, 73.7 mmol) and chloro-
trimethylsilane (24 mL, 188 mmol), in methanol (150 mL) was
refluxed for 6 h under nitrogen atmosphere. The solid was filtered
and the filtrate was evaporated. The combined solids obtained were
solubilized in dichloromethane and the solution was washed with
dilute aqueous solution of sodium carbonate, and then with water.
The organic phase was dried (Na2SO4), and then evaporated. Ester
41 was recrystallized from methanol, to give a white powder (95%),
(EtOAc/MeOH, 1/1) 0.6; IR:
n
cmꢁ1 3400, 3175, 1725, 1670, 1515,
ppm 2.84 (t, J¼7.2 Hz, 2H), 3.32 (t,
1450; 1H NMR (DMSO-d6):
d
J¼7.2 Hz, 2H), 3.62 (s, 3H), 3.88 (s, 3H), 7.29 (dd, J¼9.0, 2.4 Hz, 1H),
7.66 (d, J¼9.0 Hz, 1H), 7.98 (d, J¼2.4 Hz, 1H), 9.30 (s, 1H), 9.98 (br s,
1H), 11.15 (br s, 1H). Anal. Calcd for C16H16N2O4: C, 63.99; H, 5.37; N,
9.33. Found: C, 63.61; H, 5.20; N, 9.08.
mp (MeOH) 182e183 ꢀC; IR:
n
cmꢁ1 1729, 1650, 1616, 1500, 1441,
ppm 2.98 (t, J¼7.1 Hz, 2H), 3.41 (t,
4.2.20. Methyl 3-(4-methoxy-5H-pyrido[4,3,b]indol-3-yl)propionate
(47). Dimethyl sulfate (3.15 mL, 33.3 mmol) was added under
reflux to a stirred mixture of ester 44 (4.5 g, 16.6 mmol) and po-
tassium hydrogen carbonate (1.62 g, 16.7 mmol) in anhydrous ac-
etone (100 mL). The mixture was refluxed for 4 h. After cooling,
triethylamine (10 mL) was added and solvents were evaporated.
The residue was washed with water, and then was recrystallized
from methanol to give ester 47 as a white powder, 78%; mp (MeOH)
1413, 1204; 1H NMR (D2O):
d
J¼7.1 Hz, 2H), 3.74 (s, 3H), 7.92 (t, J¼7.6 Hz, 1H), 8.09 (t, J¼8.5 Hz,
1H), 8.24 (d, J¼7.6 Hz, 1H), 8.26 (d, J¼8.5 Hz, 1H), 9.03 (s, 1H); 13C
NMR (D2O):
d ppm 26.2 (CH2), 34.6 (CH2), 55.3 (CH3), 124.0 (CH),
129.7 (C), 132.4 (CH), 132.7 (C), 133.2 (CH), 133.8 (C), 138.2 (CH),
140.4 (CH), 152.1 (C), 177.9 (C). Anal. Calcd for C13H13NO3: C, 67.52;
H, 5.67; N, 6.06. Found: C, 67.18; H, 5.93; N, 5.86.
240e242 ꢀC; Rf (EtOAc/MeOH, 3/7); 0.7; IR:
n
cmꢁ1 3240,1672,1603,
4.2.15. Methyl 3-(8-hydroxy-[1,3]dioxolo[4,5-g]isoquinolin-3-yl)pro-
pionate (42). This compound was obtained from acid 31 following
the procedure for the preparation of ester 41 after 10 h of reflux;
1559, 1485; 1H NMR (CDCl3):
d
ppm 2.98 (t, J¼6.5 Hz, 2H), 3.38 (t,
J¼6.5 Hz, 2H), 3.64 (s, 3H), 4.49 (s, 3H), 7.38 (t, J¼7.8 Hz, 1H), 7.62 (t,
J¼6.1 Hz, 1H), 7.73 (d, J¼6.1 Hz, 1H), 7.97 (d, J¼7.8 Hz, 1H), 8.52 (s,

ꢀ ꢀ
R. Akue-Gedu et al. / Tetrahedron 68 (2012) 1117e1127
1126
1H), 11.91 (s, 1H, deuterium oxide exchangeable); 13C NMR (CDCl3):
ppm 22.3 (CH2), 30.8 (CH2), 46.4 (CH3), 52.0 (CH3), 113.5 (CH),
(s, 3H), 7.35 (t, J¼7.8 Hz, 1H), 7.50e7.67 (m, 2H), 7.97 (d, J¼6.1 Hz,
1H), 8.44 (s, 1H); 13C (D2O):
ppm 7.9 (2 CH3), 21.8 (CH2), 32.6
d
d
119.8 (C), 119.9 (C), 120.7 (CH), 122.5 (CH), 129.4 (CH), 129.9 (CH),
135.3 (C), 136.7 (C), 140.5 (C), 140.7 (C), 173.0 (C). Anal. Calcd for
C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found C, 67.21; H, 6.04; N,
10.05.
(CH2), 34.2 (CH2), 44.4 (CH3), 47.6 (2 CH2), 50.3 (CH2), 111.6 (CH, C),
117.7 (C), 119.9 (C), 120.3 (CH), 121.4 (CH), 127.9 (CH), 129.0 (CH),
135.6 (C), 139.3 (C), 143.2 (C), 175.2 (C). Anal. Calcd for C21H28N4O2,
2H2O: C, 62.35; H, 7.97; N, 13.85. Found: C, 62.04; H, 8.37; N, 13.97.
4.2.21. Methyl
3-(4,8-dimethoxy-5H-pyrido[4,3-b]indol-3-yl)pro-
4.2.25. 7-[2-(1H-Benzimidazol-2-yl)ethyl][1,3]dioxolo[4,5-g]iso-
quinolin-8-ol (52). A melt of acid 31 (0.40 g, 1.53 mmol) and o-
phenylenediamine (0.19 g, 1.76 mmol) was heated at 180 ꢀC until
the end of gas evolution (2 min). The glass obtained was stirred
with ethyl acetate (10 mL) then the solution was filtered then
evaporated. The residue was recrystallized from ethyl acetate to
give 43% of compound 52 as a light brown powder; mp (EtOAc)
pionate (48). This compound was obtained from ester 46 following
the procedure for the preparation of ester 47; white powder (76%),
mp (MeOH) 224e226 ꢀC; Rf (EtOAc/MeOH, 3/7) 0.6; IR:
n
cmꢁ1
d ppm 2.77 (t,
3250, 1677, 1608, 1520, 1485; 1H NMR (DMSO-d6):
J¼7.5 Hz, 2H), 3.42 (t, J¼7.5 Hz, 2H), 3.65 (s, 3H), 3.88 (s, 3H), 4.33 (s,
3H), 7.28 (dd, J¼9.0, 2.5 Hz, 1H), 7.71 (d, J¼9.0 Hz, 1H), 7.80 (d,
J¼2.5 Hz, 1H), 8.30 (s, 1H, deuterium oxide exchangeable), 9.34 (s,
220e224 ꢀC; IR:
ppm 3.44 (s, 4H), 6.21 (s, 2H), 7.25e7.28 (sym m, 2H), 7.42 (s, 1H),
7.53 (s, 1H), 8.62 (s, 1H); 13C (D2O):
ppm 26.7 (CH2), 28.8 (CH2),
n
cmꢁ1 1615, 1503, 1456, 1417; 1H NMR (DMSO-d6):
1H); 13C NMR (DMSO-d6):
d
ppm 21.9 (CH2), 31.1 (CH2), 45.3 (CH3),
d
51.9 (CH3), 56.1 (CH3), 104.2 (CH), 114.0 (CH), 118.5 (CH), 119.2 (C),
121.4 (C), 133.9 (CH), 135.3 (C), 136.6 (C), 137.4 (C), 138.8 (C), 155.6
(C), 172.4 (C). Anal. Calcd for C17H18N2O4: C, 64.96; H, 5.77; N, 8.91.
Found: C, 65.22; H, 5.93; N, 8.64.
d
98.9 (CH), 101.6 (CH2), 102.6 (CH), 114.3 (2 CH), 122.5 (2 CH), 125.7
(C), 129.4 (C), 135.6 (C), 136.9 (2C), 137.9 (CH), 148.1 (C), 148.9 (C),
151.5 (C), 154.6 (C). Anal. Calcd for C19H15N3O3: C, 68.46; H, 4.54; N,
12.61. Found: C, 68.26; H, 4.37; N, 12.96.
4.2.22. N,N-Diethyl-3(8-hydroxy-[1,3]dioxolo[4,5g]isoquinolin-7-yl)
propionamide (49). A mixture of ester 42 (1 g, 3.64 mmol) and
diethylamine (2.6 mL, 1.84 g, 25.18 mmol) was refluxed for 1 h
under nitrogen. Amide 49 obtained as a diethylammonium salt was
crystallized upon cooling. It was filtered, washed with ether, and
then dissolved in dichloromethane. The solution was washed with
1 M HCl, then with water. The organic phase was dried (Na2SO4),
Acknowledgements
The authors gratefully acknowledge the Norbert Segard Foun-
dation for the A.B. and R.A-G.’s scholarships.
Supplementary data
and then evaporated to give 49, 72%; mp (MeOH) 162e163 ꢀC; IR:
cmꢁ1 3069e2878, 1650, 1619, 1593, 1575, 1497, 1451, 1264; 1H NMR:
1H (CDCl3):
n
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2011.11.071. These data
include MOL files and InChiKeys of the most important com-
pounds described in this article.
d
ppm 1.11 (t, J¼7.5 Hz, 3H), 1.18 (t, J¼7.5 Hz, 3H),
3.11e3.19 (m, 2H), 3.36 (q, J¼7.5 Hz, 2H), 3.40 (q, J¼7.5 Hz, 2H),
3.49e3.58 (m, 2H), 6.26 (s, 2H), 7.30 (s, 1H), 7.69 (s, 1H), 8.61 (s, 1H),
12.22 (s, 1H); 13C (CDCl3):
d ppm 12.8 (CH3), 13.7 (CH3), 22.5 (CH2),
33.3 (CH2), 41.2 (CH2), 42.4 (CH2), 99.6 (CH), 102.1 (CH2), 103.5 (CH),
125.0 (C), 129.7 (C), 131.4 (C), 133.1 (CH), 150.1 (C), 151.0 (C), 154.6
(C), 172.6 (C). Anal. Calcd for C17H20N2O4: C, 64.54; H, 6.37; N, 8.85.
Found: C, 64.42; H, 6.76; N, 8.81.
References and notes
1. (a) Psychotropic agents: UCB, S.A., Ger. Patent 2,136,571, 1972; Chem. Abstr.
1972, 76, 113055y; The Organic Chemistry of Drug Synthesis; Lednicer, D.,
Mitscher, L. A., Eds.; Wiley and Sons: New York, NY, 1977; Vol. 1, p 235; Bocchi,
V. G.; Gardini, P.; Pinza, M. Farmaco, Ed. Sci. 1971, 26, 429; (b) Nilsson, B. M.;
Ringdahl, B.; Hacksell, U. J. Med. Chem. 1988, 31, 577 Muscarinic acid agonist:
Lundkvist, J. R. M.; Wistrand, L.-G.; Hacksell, U. Tetrahedron Lett. 1990, 31, 719;
(c) Muscarinic acid antagonist: Nilsson, B. M.; Vargas, H. M.; Ringdahl, B.;
Hacksell, U. J. Med. Chem. 1992, 35, 285; (d) Hypertensive agents: Bergmann, R.;
Gericke, R. J. Med. Chem. 1990, 33, 492; (e) Mimic of peptide derivatives:
Garvey, D. S.; May, P. D.; Nadzan, A. M. J. Org. Chem. 1990, 55, 936; Heffner, R. J.;
4.2.23. N-Benzyl-3-(4-hydroxy-5H-pyrido[4,3-b]indol-3-yl)propio-
namide (50). A mixture of ester 44 (5 g, 18.5 mmol) and benzyl-
amine (20 mL, 185 mmol) was heated at 120 ꢀC for 24 h under
nitrogen atmosphere. After cooling the mixture was washed three
times with water, and then filtered. Amide 50 was recrystallized
from methanol to give 80% of a white powder; mp (MeOH)
ꢀ
Joullie, M. M. Tetrahedron Lett. 1989, 30, 7021; (f) Inhibitors of proteolytic ca-
>250 ꢀC; Rf (EtOAc/MeOH, 10/90) 0.6; IR:
n
cmꢁ1 1635, 1605, 1543,
ppm 2.68 (t, J¼7.3 Hz, 2H), 3.15 (t,
talysis: Corey, E. J.; Li, W.-D. Chem. Pharm. Bull. 1999, 47, 1; (g) Neuraminidase
inhibitors: Brouillette, W. J.; Atigadda, V. R.; Luo, M.; Babu, Y. S. U.S. Patent
6,509,359, 2003; Chem. Abstr. 2003, 138, 106598j; (h) Absorption promoting
agent: Hisamitsu Pharmaceutical Eur. Patent 241,050, 1987; Chem. Abstr. 1988,
108, 167333w; (i) Immunostimulating agent: Poli Industria Chimica S.P.A. PCT
Int. 9,610,036, 1996; Chem. Abstr. 1996, 125, 115132m.
1495, 1439. 1H NMR (DMSO-d6):
d
J¼7.3 Hz, 2H), 4.27 (s, 1H), 4.30 (s, 1H), 7.15e7.29 (m, 5H), 7.42 (t,
J¼8.0 Hz, 1H), 7.55 (d, J¼8.0 Hz, 1H), 8.13 (d, J¼7.8 Hz, 1H), 8.57 (t,
J¼5.6 Hz, 1H), 8.81 (s, 1H), 9.53 (br s, 1H, deuterium oxide ex-
changeable), 11.35 (br s, 1H, deuterium oxide exchangeable); 13C
2. Moret, C.; Briley, M. Trends Pharmacol. Sci. 1988, 9, 278.
3. For complementary reviews covering the main aspects of pyroglutamic acid
chemistry, see: (a) Rigo, B.; Cauliez, P.; Fasseur, D.; Sauvage, F. X. Trends Het-
erocycl. Chem. 1991, 2, 155; (b) Smith, M. B. Alkaloids: Chem. Biol. Perspect. 1998,
12, 229; (c) Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10, 2245.
4. (a) Rigo, B.; Kolocouris, N. J. Heterocycl. Chem. 1983, 20, 893; (b) Buckley, T. F., III;
Rapoport, H. J. Org. Chem. 1983, 48, 4222; (c) Martin, L. L.; Scott, S. J.; Agnew, M.
N.; Setescak, L. L. J. Org. Chem. 1986, 51, 3697; Martin, L. L.; Scott, S. J.; Setescak,
L. L.; Van Engen, D. J. Heterocycl. Chem. 1987, 24, 1541; (d) Lee, G. S.; Cho, Y. S.;
Shim, S. C.; Khim, W. J.; Eibler, E.; Wiegrebe, W. Arch. Pharm. (Weinheim, Ger.)
1989, 322, 607; (e) Marchalin, S.; Decroix, B.; Morel, J. Acta Chem. Scand. 1993,
47, 287; (f) Rigo, B.; Gautret, P.; Legrand, A.; El Ghammarti, S.; Couturier, D.
Synth. Commun. 1994, 24, 2609; (g) Mamouni, A.; Netchitaïlo, P.; Daïch, A.;
Decroix, B. Phosphorus, Sulfur Silicon Relat. Elem. 1996, 119, 169; (h) Daïch, A.;
Decroix, B. J. Heterocycl. Chem. 1996, 33, 873; (i) Al Akoum Ebrik, S.; Legrand, A.;
Rigo, B.; Couturier, D. J. Heterocycl. Chem. 1999, 36, 997; (j) Legrand, A.; Rigo, B.;
NMR (DMSO-d6):
d ppm 26.7 (CH2), 34.4 (CH2), 42.1 (CH2), 111.8
(CH), 119.7 (C), 119.9 (CH), 120.6 (CH), 121.2 (C), 122.3 (CH), 127.1 (2
CH), 128.1 (C, 2CH), 132.3 (2 CH), 137.3(C), 139.4 (C), 139.9 (C), 140.5
(C), 172.5 (C). Anal. Calcd for C21H19N3O2: C, 73.03; H, 5.54; N, 12.17.
Found: C, 73.07; H, 5.90; N, 12.43.
4.2.24. N-[2-(Diethylamino)ethyl]-3-(4-methoxy-5H-pyrido[4,3-b]
indol-3-yl)propionamide (51). A stirred mixture of ester 47 (5.5 g,
19.3 mmol) and diethylaminoethylamine (13.7 mL, 11.3 g,
96.7 mmol) was heated at 120 ꢀC for 24 h. After cooling the mixture
was washed three times with water and then filtered. Amide 51 was
recrystallized from methanol to give 80% of a white powder; mp
ꢀ
Gautret, P.; Henichart, J.-P.; Couturier, D. J. Heterocycl. Chem. 1999, 36, 1263; (k)
ꢀ
(MeOH) 146e148 ꢀC; Rf (Et3N/MeOH, 10/90) 0.6; IR:
1677, 1633, 1598, 1495, 1H NMR (D2O):
ppm 1.80 (t, J¼7.3 Hz, 6H),
2.66 (t, J¼6.5 Hz, 2H), 3.05e3.40 (m, 8H), 3.55 (t, J¼6.5 Hz, 2H), 4.12
n
cmꢁ1 3174,
Legrand, A.; Rigo, B.; Henichart, J.-P.; Norberg, B.; Camus, F.; Durant, F.; Cou-
ꢀ
ꢀ
turier, D. J. Heterocycl. Chem. 2000, 37, 215; (l) Akue-Gedu, R.; Al Akoum Ebrik,
S.; Witczak-Legrand, A.; Fasseur, D.; El Ghammarti, S.; Couturier, D.; Decroix, B.;
Othman, M.; Debacker, M.; Rigo, B. Tetrahedron 2002, 58, 9239.
d

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R. Akue-Gedu et al. / Tetrahedron 68 (2012) 1117e1127
1127
€
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ꢀ
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5. (a) Knefeli, F.; Mayer, K. K.; Poettinger, T.; Stober, G.; Wiegrebe, W. Arch. Pharm.
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tahara, Y.; Saito, N.; Mikami, Y.; Yazawa, K.; Uno, J. Heterocycles 1996, 42, 195.
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WO 2003,070,166, 2003; Chem. Abstr. 2003, 139, 214611 Tylophorine: (c) Khatri,
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cited therein. Tylocrebine: (f) Gellert, E.; Rudzats, R. J. Med. Chem. 1964, 7, 361
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J. Med. Res.1979, 69, 513 For reviews, see: (b) Li, Z.; Jin, Z.; Huang, R. Synthesis 2001,
2365; (c) Govindachari, T. R.; Viswanathan, N. Heterocycles 1978, 11, 587.
9. (a) Beckmann reaction: Marchalin, S.; Decroix, B. J. Heterocycl. Chem. 1993, 30,
ꢀ
ꢀ
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results will be published in due course.
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667; (b) Schmidt reaction: Lebosquain, D.; Decroix, B.; Merour, J.-Y.; Cossais, F.;
20. (a) Vilarem, M.-J.; Charcosset, J.-Y.; Primaux, F.; Gras, M.-P.; Calvo, F.; Larsen, C.-
€
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Piroelle, S. Heterocycles 1993, 36, 2303; Mazeas, D. J. Heterocycl. Chem. 1994, 31,
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SemmlereWolff rearrangements: some benzo[c][1,5]naphthyridines obtained
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quality (99.99%) as catalyst for successful cyclization of N-arylmethylpyro-
glutamic acid chlorides.
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10. Akue-Gedu, R.; Bourry, A.; Camus, F.; Norberg, B.; Durant, F.; Couturier, D.;
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