Intramolecular aldol reaction of N-Acylated (2-Aminophenyl)-α- oxoacetic Acids: Rapid access to Tri- and tetracyclic 1,2-dihydroquinolin-2(1 H)-ones

Article abstract of DOI:10.1021/jo1003339

A four-step synthesis of tri- and tetracyclic 1,2-dihydroquinolin-2(1H)- ones via acylation of various substituted isatins with readily available N-Boc-protected aminoacids followed by an intramolecular aldol reaction and cyclization has been developed. The final products were obtained in moderate to excellent overall yields.

Full text of DOI:10.1021/jo1003339

pubs.acs.org/joc
Intramolecular Aldol Reaction of N-Acylated
(2-Aminophenyl)-r-oxoacetic Acids: Rapid Access to
Tri- and Tetracyclic 1,2-Dihydroquinolin-2(1H)-ones
Malik Hellal and Gregory D. Cuny*
Laboratory for Drug Discovery in Neurodegeneration,
Harvard NeuroDiscovery Center, Brigham & Women’s
Hospital and Harvard Medical School, 65 Landsdowne Street,
Cambridge, Massachusetts 02139
FIGURE 1. Biologically active 4-carboxylquinoline derivatives.
neuroprotective, antistroke, and anticancer activities.3 Quino-
line-4-carboxamides were also described as serotonin 5-HT3
antagonists, as inhibitors of caspase-3 and AChE, and as
antimalarial agents.4 Tri- and tetracyclic quinolines that dis-
play antiproliferative activities, caspase-3 inhibition, or 5-HT3
affinity have also been reported.3a,4 In addition, isaindigoti-
dione, A (Figure 1), is a recently identified tetracyclic 1,2-
dihydroquinolin-2(1H)-one natural product isolated from the
herbaceous plant Isatis indigotica indigenous to China’s
Changjiang river valley.5
gcuny@rics.bwh.harvard.edu
Received February 23, 2010
The synthesis of indolizino[7,6-c]quinoline derivates, such
as A, using an intramolecular aldol reaction of glyoxyla-
mides has been reported.6 Several synthetic strategies for the
preparation of substituted 2-oxo-1,2-dihydroquinoline-4-
carboxamides B have also been described. However, the
synthesis of tricyclic derivatives C has remained less explor-
ed.4a,c Unfortunately, many of the reported methods for the
synthesis of C suffer from several disadvantages, including
requiring large excess of reagents, and are only applicable
to generating fused five-membered rings. Herein is reported
a versatile method for the synthesis of tri- and tetracyclic 1,
2-dihydroquinolin-2(1H)-ones.
A retrosynthetic analysis for 1 is outlined in Scheme 1, where
1is obtained from 2via cyclization. In turn, 2can be prepared by
intramolecular aldolisation of N-acylated (2-aminophenyl)-
R-oxoacetic acids 3, which are obtained from isatins and
N-protected aminoacids 4. tert-Butylcarbamate protection of
the aminoacids was chosen because it could be readily removed
during lactam formation under acidic condition.
A four-step synthesis of tri- and tetracyclic 1,2-dihydro-
quinolin-2(1H)-ones via acylation of various substituted
isatins with readily available N-Boc-protected amino-
acids followed by an intramolecular aldol reaction and
cyclization has been developed. The final products were
obtained in moderate to excellent overall yields.
Heterocycles are among the most prevalent lead molecules
for the discovery of novel therapeutics. For example,
4-carboxyl substituted quinolines are present in an array of
biologically active compounds and have been explored for
potential pharmaceutical applications.1 Many of these com-
pounds have been shown to inhibit therapeutically relevant
enzymes as well as to modulate the activity of various cellular
receptors. For example, substituted 4-carboxyl-quinolines
were reported as potent antagonists of tachykinin NK2 and
NK3 receptors, thus potentially being useful as analgesic or
antiarthritic agents.2 This class of molecules has also displayed
In order to avoid using an excess of acid to affect isatin
acylation,7 the reaction was initially attempted with a mixed
anhydride. However, the desired acylation was followed by
nucleophilic attack of the isobutyl carbonate byproduct to
give 5 in 71% yield (Scheme 2). Presumably this reaction
resulted from the nucleophilic nature of carbonates8 and
(4) (a) Capelli, A.; Anzini, M.; Vomero, S.; Mennuni, L.; Makovec, F.;
Doucet, E.; Hamon, M.; Menziani, C. M.; De Benedetti, P. G.; Giorgi, G.;
Ghelardini, C.; Collina, S. Bioorg. Med. Chem. 2002, 10, 779. (b) Hayashi,
H.; Miwa, Y.; Miki, I.; Ichikawa, S.; Yoda, N.; Ishii, A.; Kono, M.; Suzuki,
F. J. Med. Chem. 1992, 35, 4893. (c) Kravchenko, D. V.; Kuzovkova, Y. A.;
Kysil, V. M.; Tkachenko, S. E.; Maliarchouk, S.; Okun, I. M.; Balakin,
K. V.; Ivachtchenko, A. V. J. Med. Chem. 2005, 48, 3680. (d) Cappelli, A.;
Gallelli, A.; Manini, M.; Anzini, M.; Mennuni, L.; Makovec, F.; Menziani,
M. C.; Alcaro, S.; Ortuso, F.; Vomero, S. J. Med. Chem. 2005, 48, 3564. (e)
Xiao, Z.; Waters, N. C.; Woodard, C. L.; Li, Z.; Li, P. K. Bioorg. Med. Chem.
Lett. 2001, 11, 2875.
(1) (a) Giardina, G. A.; Raveglia, L. F.; Grugni, M.; Sarau, H. M.;
Farina, C.; Medhurst, A. D.; Graziani, D.; Schmidt, D. B.; Rigolio, R.;
Luttmann, M.; Cavagnera, S.; Foley, J. J.; Vecchietti, V.; Hay, D. W. J. Med.
Chem. 1999, 42, 1053. (b) Suzuki, F.; Nakasato, Y.; Tsumuki, H.; Ohmori, K.;
Nakajima, H.; Tamura, T.; Sato, S. U.S. Patent 5371225, 1993; Chem. Abstr.
1994, 120, 217318. (c) Deady, L. W.; Desneves, J.; Kaye, A. J.; Finlay, G. J.;
Baguley, B. C.; Denny, W. A. Bioorg. Med. Chem. 2000, 8, 977. (d) Michael, J. P.
Nat. Prod. Rep. 2005, 22, 627.
(2) (a) Yan, H.; Kerns, J. K.; Jin, Q.; Zhu, C.; Barnette, M. S.; Callahan,
J. F.; Hay, D. W. P.; Jolivette, L. J. Synth. Commun. 2005, 35, 3105. (b) Farina,
C.; Gagliardi, S.; Giardina, G.; Grugni, M.; Martinelli, M.; Nadler, G. WO
0238547, 2002; Der. Abst. C 2002, 454769.
(3) (a) Tseng, C. H.; Chen, Y. L.; Lu, P. J.; Yang, C. N.; Tzeng, C. C.
Bioorg. Med. Chem. 2008, 16, 3153. (b) Ivachtchenko, A. V.; Kobak, V. V.;
Ilyn, A. P.; Khvat, A. V.; Kysil, V. M.; Williams, C. T.; Kuzovkova, J. A.;
Kravchenko, D. V. J. Comb. Chem. 2005, 7, 227.
(5) Wu, X.; Qin, G.; Cheung, K. K.; Cheng, K. F. Tetrahedron 1997, 53,
13323.
(6) Poon, C. Y.; Chiu, P. Tetrahedron Lett. 2004, 45, 2985.
(7) (a) Bursavich, M. G.; Lombardi, S.; Gilbert, A. M. PCT Int. Appl. WO
2007146138, 2007. (b) Rajamanickam, P.; Shanmugam, P. Synthesis 1985, 5,
541.
(8) Verdecchia, M.; Feroci, M.; Palombi, L.; Rossi, L. J. Org. Chem. 2002,
67, 8287.
DOI: 10.1021/jo1003339
r
Published on Web 04/15/2010
J. Org. Chem. 2010, 75, 3465–3468 3465
2010 American Chemical Society

Hellal and Cuny
JOCNote
SCHEME 1. Retrosynthetic Analysis of Tri- or Tetracyclic
1,2-Dihydroquinolin-2(1H)-ones 1
TABLE 1. Optimization of the Aldol Reaction
equiv
of base
temp (oC),
time (h)
yielda
(%)
entry
base
solvent
1
2
3
4
5
6
7
8
NaOH
NEt3
DBU
NaH
t-BuOK
NaH
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
2
2
2
2
2
2
2
2
2
2
1
3
4
3
3
3
H2O
100, 12
80, 4
80, 4
60, 2
60, 2
80, 4
80, 4
80, 4
80, 4
80, 4
80, 4
80, 4
80, 4
rt, 72
60, 4
100, 4
trace
0
0
0
0
DMF
DMF
THF
THF
DMF
DMA
CH3CN
dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
49b
67
53b
33b
77
0
88
53
24
70
81
9
10
11
12
13
14
15
16
SCHEME 2
aIsolated yield. bConversions determined by HPLC.
gave only trace amounts of 2a (Table 1, entry 1). No cyclized
product was obtained with organic bases such as NEt3 or DBU
(entries 2 and 3). Likewise, stronger bases such as NaH or
t-BuOK in THF were not effective (entries 4 and 5). However,
when these bases were used in DMF or DMA, 2a was obtained
(entries 6, 7, and 10). However, in solvents such as 1,4-dioxane
or CH3CN, yields generally were lower (entries 8 and 9).
Next, the quantity of base required for cyclization was
examined. No reaction was observed with 1 equiv of t-BuOK
(entry 11). The highest yield was obtained with 3 equiv of
t-BuOK (entry 12), whereas further increasing the quantity
of base did not improve the yield (entry 13). Finally, the
reaction temperature was also determined to be important
with 80 °C being best (entries 12, 14-16). In summary, the
aldol reaction of 3a to give 2a was optimal with t-BuOK
(3 equiv) in DMF for 4 h at 80 °C.
With the optimized conditions identified, the scope of the
reaction with respect to the aminoacid substrate was exam-
ined. Acylation and aldol reaction of the corresponding
N-acylated isatins showed remarkable tolerance to a range
of aminoacids with markedly different steric and electronic
properties (Table 2, entries 1-13). For example, using
various β-, γ-, δ-, or ε-N-Boc-protected aminoacids resulted
in the generation of 2 in moderate to high yields. With some
N-Boc-protected secondary aminoacids or an anilino acid,
slightly lower yields were obtained (entries 6, 8, 10-12).
Aminoacids containing substituents on the β- or γ-position
of the aliphatic chain were also tolerated in the aldol reaction
(entries 9-12).
N-acylated isatin’s susceptibility to nucleophilic attack.9
Several other acylation strategies were explored, including
use of the corresponding acid chloride or pentafluorophenol
ester,10 or using various coupling agents (i.e., HBTU,
HATU, and BOP), but all failed to give the desired product
6.11 Finally, successful acylation was accomplished with
EDCI. However, the N-acylated isatin 6 was difficult to
purify and therefore was treated with aqueous potassium
carbonate at 100 °C for 1 h, generating 3a in excellent yield
(87%).
Next, the aldol cyclization of 3a to give 2a was studied by
examining various reaction parameters, including the nature
and quantity of base, solvent, and temperature. Utilizing
conditions described in the literature for the synthesis of
3-alkyl-4-carboxyquinolinones (NaOH, H2O, 100 °C, 5 h)12,4b
(9) (a) Bergman, J.; Engqvist, R.; Stalhandske, C.; Wallberg, H. Tetra-
hedron 2003, 59, 1033. (b) Cheah, W. C.; Black, D. StC.; Goh, W. K.; Kumar,
N. Tetrahedron Lett. 2008, 49, 2965.
(10) (a) Luppi, G.; Galeazzi, R.; Garavelli, M.; Formaggio, F.; Tomasini,
C. Org. Biomol. Chem. 2004, 2, 2181. (b) Ramesh, R.; Rajasekaran, S.;
Gupta, R.; Chandrasekaran, S. Org. Lett. 2006, 8, 1933. (c) Gopinath, K. W.;
Govindachari, T. R.; Rajappa, S. Tetrahedron 1960, 8, 291.
(11) For acid chlorides or pentafluorophenol esters only the correspond-
ing hydrolyzed acids were recovered. For the other coupling reagents the
HOBt byproduct formed during acid activation appeared to be more
nucleophilic than isatins leading to acylated HOBt products.
(12) Lyle, R. E.; Portlock, D. E.; Kane, M. J.; Bristol, J. A. J. Org. Chem.
1972, 37, 3967.
The last step for the synthesis of tri- or tetracyclic 1,2-
dihydroquinolin-2(1H)-ones was lactam formation. Three
different methods were used, depending on the substrate.
The first method required an initial deprotection of the
N-protected carbamate with TFA followed by EDCI-mediated
cyclization (Table 2, method A). The other two methods
involved direct one-pot processes. For example, method
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Hellal and Cuny
JOCNote
TABLE 2. Substrate Scope of Aminoacids 4a-l
B simply involved refluxing the substrate in ethanol in the
presence of a catalytic amount of sulfuric acid. In method C the
substrate was heated at 80 °C in neat sulfonyl chloride.
was more efficient for 1g (entry 7). The syntheses of seven- or
eight-membered ring lactams starting from primary amines
were unsuccessful (entries 3 and 4). Nevertheless, when the
terminal nitrogen was substituted with a benzyl group, lactam
formation was performed using method C generating 1h in
73% yield (entry 8). Method C was also useful to synthesize
tetracyclic quinolinones 1j, 1k, and 1l in good yields (entries
10-12).
γ-Lactams 1b, 1f and 1i were obtained in good yields using
method B (entries 2, 6, and 9). In contrast, 1b was obtained in
only 32% yield using method A, and no cyclization was
observed with method C. Surprisingly, when the terminal
nitrogen was substituted with a benzyl group, 1e was obtained
in 89% yield using method C (entry 5). Concerning δ-lactam
synthesis, 1a and 1g were obtained using method A in 57% and
80% yields, respectively (entries 1 and 7). However, method C
To further study the scope of this overall process, the effect
of substituents on the aromatic ring of the isatin was briefly
examined. Both electron-withdrawing and electron-donating
J. Org. Chem. Vol. 75, No. 10, 2010 3467

Hellal and Cuny
JOCNote
TABLE 3. Substrate Scope of Isatins
screening for biological activities. The utilization of this
methodology for the synthesis of additional tri- and tetra-
cyclic quinolin-2(1H)-ones, including A, are currently under
development.
Experimental Section
General Procedure for the Synthesis of 3a-q. Under argon,
isatin (1 equiv) was added to 4a-l (1.2 equiv) in CH2Cl2 (6 mL/
mmol of isatin) at 0 °C, followed by EDCI (1.2 equiv) and
DMAP (0.1 equiv). The reaction was maintained at room
temperature for 3 h. The solvent was removed in vacuo,
and then the mixture was diluted in EtOAc (20 mL/mmol) and
washed with HCl (1 N, 5 mL), satd NaHCO3 (2 ꢀ 5 mL), and
brine (5 mL). The organic layer was dried over Na2SO4, filtered,
evaporated, and concentrated. To this material was added water
(10 mL/mmol) following by K2CO3 (2 equiv), and the mixture
was heated at 100 °C for 1 h. After cooling to 0 °C, the reaction
was acidified with HCl (1 N). The aqueous solution was
extracted with EtOAc (2 ꢀ 20 mL). The organic layers were
combined, washed with brine, dried over Na2SO4, filtered,
and evaporated. The crude product was purified by chromato-
graphy on silica gel (3 to 20% MeOH in CH2Cl2) to yield a
yellow solid.
yielda (%)
entry
R3
3
2
1
1
2
3
4
5
4-Cl
5-Cl
6-Cl
7-Cl
m
n
o
p
q
91
94
90
0
62
73
74
0
80
78
5-OMe
88
58
81
aIsolated yield.
General Procedure for the Synthesis of 2a-q. To a solution
under argon of 3a-q (1 equiv) in DMF (10 mL/mmol) was added
t-BuOK (3 equiv). The mixture was heated to 80 °C for 4 h. After
cooling to 0 °C, HCl (1 N) was added until pH 3. The solution was
extracted with EtOAc (2 ꢀ 20 mL). The organic layers were
combined, washed twice with 10% aqueous LiCl (5 mL) and
brine, dried over Na2SO4, filtered, and evaporated. The crude
product was purified by chromatography on silica gel (5-20%
MeOH in CH2Cl2 þ AcOH 0.5%) to yield a yellow solid.
2,3,4,6-Tetrahydro-benzo[c][2,6]naphthyridine-1,5-dione (1a).
A solution of 2a (0.5 mmol) in CH2Cl2/TFA (1:1 v/v) was stirred
at room temperature for 30 min. The solvent was removed. Then
the crude product was dissolved in DMF (5 mL/mmol), and
EDCI (1.2 equiv) was added, following by NEt3 (2 equiv). The
reaction was stirred at room temperature for 24 h. The solvent
was removed, and the crude product was dissolved in MeOH.
SiO2 (5 g) was added, and then the mixture was evaporated to
dryness before purification by silica gel chromatography (2-5%
MeOH in CH2Cl2 þ AcOH 1%) to yield a white powder (61 mg,
57%). 1H NMR (DMSO-d6) δ: 12.06 (s, 1H), 8.82 (d, J = 8.0
Hz, 1H), 8.33 (s, 1H), 7.47 (t, J = 8.5 Hz, 1H), 7.33 (d, J = 8.5
Hz, 1H), 7.18 (t, J = 8.0 Hz, 1H), 3.23 (t, J = 7.5 Hz, 2H), 2.75
(t, J = 7.5 Hz, 2H); 13C NMR (DMSO-d6) δ: 163.7, 160.5, 137.9,
134.5, 133.1, 129.4, 127.0, 121.8, 116.5, 115.3, 37.7, 22.5; HRMS
(MALDI-TOF) calcd for C12H11N2O2 [M þ H]þ: 215.0815.
Found: 215.0820.
SCHEME 3
substituents in either the 5- or 6-positions of the isatin were
tolerated (Table 3, entries 2, 3, and 5). However, introduction
of a chlorine in the 4-position of the isatin prevented cycliza-
tion to the corresponding γ-lactam (entry 1), whereas intro-
duction of the chlorine at the 7-position of the isatin did not
permit the initial N-acylation (entry 4). Presumably steric
hindrance was responsible for both of these effects.
Interestingly, addition of a catalytic amount of DMF to
the reaction solution during lactamization using method C
gave the expected lactam but also resulted in the concomitant
conversion of the 2-quinolone to the corresponding 2-chloro-
quinoline. For example, treatment of 3k utilizing these
alternate conditions gave 7 in 82% yield (Scheme 3). This
material upon treatment with N-methylpiperazine under-
went a nucleophilic aromatic substitution to generate 8 in
77% yield.
In summary, an efficient approach to the synthesis of tri-
and tetracyclic quinolin-2(1H)-ones has been developed by
exploiting an intramolecular aldol reaction of N-acylated
(2-aminophenyl)-R-oxoacetic acids followed by lactam for-
mation. Substrates for this sequence of reactions are readily
available or can be easily prepared. This methodology
provided access to various substituted tri- and tetracyclic
quinolin-2(1H)-ones, including a bicyclic analogue. These
compounds can be used for various applications, including
Acknowledgment. The authors appreciate financial sup-
port from the Harvard NeuroDiscovery Center. The authors
also thank Dr. Xuechao Xing for insightful discussions
regarding the acylation procedures.
Supporting Information Available: Compound characteri-
zation data. This material is available free of charge via the
Internet at http://pubs.acs.org.
3468 J. Org. Chem. Vol. 75, No. 10, 2010