Modulating the reactivity of heterocyclic ketene aminals in MCR: Selective construction of tetrahydrobenzo[ b ]imidazo[3,2,1- ij ][1,8]naphthyridines

Article abstract of DOI:10.1021/jo101454q

Two new kinds of tetrahydrobenzo[b]imidazo[3,2,1-ij][1,8]naphthyridine derivatives have been successfully synthesized by cascade reactions including Knoevenagel condensation, aza-ene reaction, imine-enamine tautomerization, cyclocondensation, and intramol

Full text of DOI:10.1021/jo101454q

pubs.acs.org/joc
Modulating the Reactivity of Heterocyclic Ketene Aminals in MCR: Selective
Construction of Tetrahydrobenzo[b]imidazo[3,2,1-ij][1,8]naphthyridines
Li-Rong Wen, Chao Liu, Ming Li,* and Li-Juan Wang
State Key Laboratory Base of Eco-Chemical Engineering, College of Chemistry and Molecular Engineering,
Qingdao University of Science and Technology, Qingdao 266042, P. R. China
liming928@qust.edu.cn
Received July 25, 2010
Two new kinds of tetrahydrobenzo[b]imidazo[3,2,1-ij][1,8]naphthyridine derivatives have been successfully
synthesized by cascade reactions including Knoevenagel condensation, aza-ene reaction, imine-enamine
tautomerization, cyclocondensation, and intramolecular SNAr of precursors 2-(2-chloroaroyl)methylene-
imidazolidines with aromatic aldehydes and ethyl acetoacetate or Meldrum’s acid under mild conditions,
respectively. These studies highlighted the concept of a substrate-design approach to the development of
novel multicomponent reactions by simply incorporating an o-halo group into the aryl ring of 2-benzoyl-
methyleneimidazolidine as new synthons. In this domino reaction, at least six different active sites are
involved; two C-C bonds, two C-N bonds, and two new rings are constructed with all reactants efficiently
utilized in the chemical transformation.
Introduction
chemists as a facile means to generate molecular diversity from
multifunctional substrates that react sequentially in an intramo-
lecular fashion. Devising such types of MCRs that achieve the
formation of multiple bonds in a single operation is one of the
major challenges in modern organic synthesis.3
Carbon-carbon and carbon-heteroatom bond-forming re-
actions are central to organic synthesis. The synthesis of hetero-
cycles often involves ene reaction.1 Due to its synthetic potential
in organic chemistry, the ene reaction has received much atten-
tion, and great development has been achieved particularly in
the past three decades.2 Meanwhile, multicomponent coupling
reactions (MCRs) have been frequently used by synthetic
ꢀ
(3) (a) Zhu, J.-P.; Bienayme, H. Multicomponent Reactions; Wiley-VCH:
€
Weinheim, 2005; p 1499. (b) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000,
39, 3168–3210. (c) Domling,A.Chem. Rev. 2006, 106, 17–89. (d) Zhang, M.; Jiang,
€
H.-F.; Liu, H.-L.; Zhu, Q.-H. Org. Lett. 2007, 9, 4111–4113. (e) Zhou, H. Y.;
Zhang, W.; Yan, B. J. Comb. Chem. 2010, 12, 206–214. (f)Liu, A. F.;Zhou, H. Y.;
Su, G. X.;Zhang,W.;Yan,B.J. Comb. Chem. 2009, 11, 1083–1093. (g) Wan, J.-P.;
Gan, S.-F.; Sun, G.-L.; Pan, Y.-J. J. Org. Chem. 2009, 74, 2862–2865. (h) Wan,
J.-P.; Pan, Y.-J. Chem. Commun. 2009, 2768–2770. (i) Ganem, B. Acc. Chem. Res.
2009, 42, 463–472. ( j) Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G.-G. J. Am.
Chem. Soc. 2009, 131, 11660–11661. (k) Jiang, B.; Wang, X.; Shi, F.; Tu, S.-J.; Ai,
T.;Ballew,A.;Li,G.G.J. Org. Chem. 2009,74, 9486–9489. (l) Jiang, B.; Li, C.; Shi,
F.; Tu, S.-J.; Kaur, P.; Wever, W.; Li, G. G. J. Org. Chem. 2010, 75, 2962–2965.
(m) Tu, S.-J.; Li, C.-L.; Li, G.-G.; Cao, L.-J.; Shao, Q.-Q.; Zhou, D.-X.; Jiang, B.;
Zhou, J.-F.; Xi, M. J. Comb. Chem. 2007, 9, 1144–1148. (n) Wei, H.-L.; Yan,
Z.-Y.; Niu, Y.-L.; Li, G.-Q.; Liang, Y.-M. J. Org. Chem. 2007, 72, 8600–8603.
(o)Cui, S.-L.;Lin, X.-F.;Wang, Y.-G.J. Org. Chem. 2005, 70, 2866–2869. ( p) Sun,
J.; Zhang, L.-L.; Xia, E.-Y.; Yan, C.-G. J. Org. Chem. 2009, 74, 3398–3401.
(1) (a) Aider, K.; Pascher, F.; Schmitz, A. Chem. Ber. 1943, 76, 27–53.
(b) Aider, K.; Noble, T. Chem. Ber. 1943, 76, 54–57.
(2) (a) Hoffmman, H. M. R. Angew. Chem., Int. Ed. Engl. 1969, 8, 556–
577. (b) Oppolzer, W.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1978, 17,
476–486. (c) Carruthers, W. Cycloaddition Reactions in Organic Synthesis;
Pergamon: Oxford, 1990; p 241. (d) Mikami, K.; Shimizu, M. Chem. Rev.
1992, 92, 1021–1050. (e) Snider, B. B. Acc. Chem. Res. 1980, 13, 426–432.
(f ) Hoffmman, H. M. R. Angew. Chem., Int. Ed. Eng1. 1969, 8, 556–577.
(g) Borzilleri, R. M.; Weinreb, S. M. Synthesis 1995, 347–360. (h) Clarke,
M. L.; France, M. B. Tetrahedron 2008, 64, 9003–9031. (i) Janine, C.;
Abdelrrahim, B.; Michel, P. J. Org. Chem. 1997, 62, 7106–7113. ( j) Zhang,
J.; Wang, M.; Huang, Z J. Chem. Soc., Perkin Trans. 1 1999, 2087–2094.
DOI: 10.1021/jo101454q
r
Published on Web 10/27/2010
J. Org. Chem. 2010, 75, 7605–7614 7605
2010 American Chemical Society

Wen et al.
JOCArticle
synthetic and medicinal chemists. More than 1000 patents
were located claiming potential pharmaceutical applica-
tions,16 such as antibacterial,17 anti-HIV,18 antischizophrenia,19
antiasthma,20 anti-inflammatory,21 antihypertensive,22 and anti-
cancer23 activities. Therefore, the synthesis of tetrahydroimi-
dazo[3,2,1-ij][1,8]naphthyridine derivatives may be of great sig-
nificance. To the best of our knowledge, very few molecules of
tetrahydroimidazo[3,2,1-ij][1,8]naphthyridines have been syn-
thesized, and there is no general strategy to prepare them.24 In
contrast to these previous approaches which lack scope and
flexibility, our serendipitous route to this class of heterocyclic
system is efficient and fairly general.
On the basis of our progressive endeavors in exploring novel
and practical multicomponent reactions to synthesize useful
heterocyclic compounds,25 by simply incorporating an o-halo
group into the aryl ring of 2-benzoylmethyleneimidazolidine we
could develop two new three-component cascade reactions for
the selective synthesis of tetrahydrobenzo[b]imidazo[3,2,1-ij]-
[1,8]naphthyridine derivatives with 2-(2-chloroaroyl)methyl-
eneimidazolidines 2, aldehydes 3, and ethyl acetoacetate 4 or
Meldrum’s acid 7.
FIGURE 1. Functionalized ketene acetals.
Heterocyclic ketene aminals (HKAs) are powerful and
versatile intermediates in heterocyclic synthesis. Reactions of
cyclic ketene aminals of the general formula 1 with a number of
biselectrophilic reagents such as β-keto ester enol tosylates,4
propiolic acid ester,5 aryl azides,6 polyhaloisophthalonitrile,7
Meldrum’s acid and aldehydes,8 bis(methylthio)methylene
malononitrile,9 itaconic anhydride,10 R-bromo ketones,11 ethyl
2-(bromomethyl)benzoate,12 Baylis-Hillman acetates,13 diethyl
azodicarboxylate,14 and 1,3-dibromopropane15 have been suc-
cessfully used to give five- and six-membered and fused hetero-
cycles during the past years. 2-(2-Chloroaroyl)methyleneimida-
zolidines 2 (Figure 1), as new heterocyclic ketene aminals
(HKAs), show structural features such as the highly polarized
push-pull interaction CdC double bond and use of Cl atom as
leaving group. On one hand, because of the conjugation effect of
the electron-donating amino groups and electron-withdrawing
carbonyl group, the nucleophilicity at the R carbon is greater
than the nitrogen atoms. On the other hand, by simply incor-
porating an o-halo group into the aryl ring of 2-benzoylmethy-
leneimidazolidine, novel heterocyclic ketene aminals 2 would
subject to an intramolecular nucleophilic aryl substitution reac-
tion by attack of nitrogen atom. Therefore, precursors 2 display
a different reactivity profile to that of 2-benzoylmethyleneimi-
dazolidine 1 and could be developed a new strategy for the
synthesis of an unusual tetrahydrobenzo[b]imidazo[3,2,1-ij]-
[1,8]naphthyridine derivatives.
Results and Discussion
Aza-ene reaction and nucleophilic substitution are two
majorreactions in organic chemistry. Inthe initialexperiment,
we explored the three-component aza-ene-type reaction of
novel heterocyclic ketene aminal, 2-(2,4-dichlorobenzoyl)-
methylene imidazolidine 2a, with benzaldehyde 3a and ethyl
acetoacetate 4 as the model substrates for the optimization of
the reaction conditions, such as different solvents, molar ratios,
and catalysts (the results are summarized in Table S1, Support-
ing Information). It was clear from the experiments that the best
conditions could be the use of a molar ratio of 1:1.2:1.2 of
2a:3a:4, Et3N (0.4 equiv) as base and MeCN as solvent at 81 °C.
The subsequent SNAr cyclization requires a suitable base to
enhance the nucleophilicity of the nitrogen atom of imidazole
ring by the capture of HCl during the reaction. Then, we
Functionalized naphthyridines represent an important
class of organic molecules that attract the interest of both
(17) (a) Seefeld, M. A.; Miller, W. H.; Newlander, K. A.; Burgess, W. J.;
DeWolf, W. E., Jr.; Elkins, P. A.; Head, M. S.; Jakas, D. R.; Janson, C. A.;
Keller, P. M.; Manley, P. J.; Moore, T. D.; Payne, D. J.; Pearson, S.; Polizzi,
B. J.; Qiu, X.; Rittenhouse, S. F.; Uzinskas, I. N.; Wallis, N. G.; Huffman,
W. F. J. Med. Chem. 2003, 46, 1627–1635. (b) Davies, D. T.; Jones, G. E.;
Pearson, N. D. WO 006 648, 2008. (c) Gangadhar, L. J. T. R.; Gnanasam,
S. K.; Ramachandran, S.; Sridhar, S. S. K. Bio. Pharm. Bull. 2002, 25, 798–
802.
(4) Yan, S.- J.; Huang, C.; Su, C.- X.; Ni, Y.- F.; Lin, J. J. Comb. Chem.
2010, 12, 91–94.
(5) Schirok, H.; Alonso-Alijia, C.; Benet-Buchnolz, J.; Goller, A. H.;
Grosser, R.; Michels, M.; Paulsen, H. J. Org. Chem. 2005, 70, 9463–9469.
(6) Huang, Z.-T.; Wang, M.-X. J. Org. Chem. 1992, 57, 184–190.
(7) Yan, S.- J.; Niu, Y.- F.; Huang, R.; Lin, J. Synlett 2009, 17, 2821–2824.
(8) Yu, C.-Y.; Yang, P.-H.; Zhao, M.-X.; Huang, Z.-T. Synlett 2006, 12,
1835–1840.
(18) Dress, K. R.; Johnson, T. W.; Plewe, M. B.; Tanis, S. P.; Zhu, H. WO
042 883, 2007; Chem. Abstr. 2006, 146, 441772.
(9) Liao, J.-P.; Zhang, T.; Yu, C.-Y.; Huang, Z.-T. Synlett 2007, 5, 761–
764.
(19) Favor, D. A.; Johnson, D. S.; Repine, J. T.; White, A. D. WO 090
272, 2006; Chem. Abstr. 2006, 145, 293102.
(10) Chakrabarti, S.; Panda, K.; Misra, N. C.; Ila, H.; Junjappa, H.
Synlett 2005, 9, 1437–1441.
(20) Guay, D.; Girard, M.; Hamel, P.; Laliberte, S.; Friesen, R. WO 018
579, 2003; Chem. Abstr. 2003, 138, 205042.
(11) Nie, X.-P.; Wang, M.-X.; Huang, Z.-T. Synthesis 2000, 10, 1439–
1443.
(21) Grossi, G.; Braccio, M. D.; Roma, G.; Ballabeni, V.; Tognolini, M.;
Barocelli, E. Eur. J. Med. Chem. 2005, 40, 155–165.
(12) Xu, Z.-H.; Jie, Y.-F.; Wang, M.-X.; Huang, Z.-T. Synthesis 2002, 4,
523–527.
(13) Yaqub, M.; Yu, C.-Y.; Jia, Y. M.; Huang, Z.-T. Synlett 2008, 9,
1357–1360.
(14) Zhao, M.-X.; Wang, Z.-M.; Wang, M.-X.; Yan, C.-H.; Huang, Z.-T.
Tetrahedron 2002, 58, 7791–7796.
(15) Jones, R. C. F.; Patel, P.; Hirst, S. C.; Turne, I. Tetrahedron 1997, 53,
11781–11790.
(16) (a) Ren, P.; Zhang, G.; You, S.; Sim, T.; Gray, N.; Xie, Y.; Wang, X.;
He, Y. WO 136 465, 2007; Chem. Abstr. 2007, 148, 33755. (b) Cosford,
N. D. P.; Layton, M. E.; Liang, J.; Lindsley, C. W.; Sanderson, P. E.; Zhao,
Z. WO 091 395, 2006; Chem. Abstr. 2006, 145, 293099. (c) Wang, Y.; Mull,
E. S. WO 101 988, 2003; Chem. Abstr. 2006, 140, 16716. (d) Shimamoto, T.;
Inoue, H.; Hayashi, Y. WO 07 704, 1999; Chem. Abstr. 1999, 130, 196577.
(e) Leach, C. A.; Smith, S. A. WO 086 400, 2003; Chem. Abstr. 2003, 139,
337978.
(22) Ferrarini, P. L.; Mori, C.; Calderone, V.; Calzolari, L.; Nieri, P.;
Saccomanni, G.; Martinotti, E. Eur. J. Med. Chem. 1999, 34, 505–513.
(23) Srivastava, S. K.; Jaggi, M.; Singh, A. T.; Madan, A.; Vishnoi,
N. R. M.; Agarwal, S. K.; Mukherjeea, R.; Burman, A. C. Bioorg. Med.
Chem. Lett. 2007, 17, 6660–6664.
(24) (a) Ye, G.-Z.; Zhou, A.-H.; Henry, W. P.; Song, Y.-Q.; Chatterjee, S.;
Beard, D. J.; Pittman, C. U., Jr. J. Org. Chem. 2008, 73, 5170–5172. (b)
Zhang, J.-H.; Wang, M.-X.; Huang, Z.-T. Tetrahedron Lett. 1998, 39, 9237–
9240. (c) Zhang, J.-H.; Wang, M.-X.; Huang, Z.-T. J. Chem. Soc., Perkin
Trans. 1999, 1, 2087–2094.
(25) (a) Wen, L.-R.; Sun, J.-H.; Li, M.; Sun, E.-T.; Zhang, S.-S. J. Org.
Chem. 2008, 73, 1852–1863. (b) Wen, L.-R.; Ji, C.; Li, Y.-F.; Li, M. J. Comb.
Chem. 2009, 11, 799–805. (c) Wen, L.-R.; Ji, C.; Li, M.; Xie, H.-Y. Tetra-
hedron 2009, 65, 1287–1293. (d) Li, M.; Zuo, Z.-Q.; Wen, L.-R.; Wang, S.-W.
J. Comb. Chem. 2008, 10, 436–441. (e) Li, M.; Yang, W.-L.; Wen, L.-R.; Li,
F.-Q. Eur. J. Org .Chem. 2008, 16, 2751–2758.
7606 J. Org. Chem. Vol. 75, No. 22, 2010

Wen et al.
JOCArticle
SCHEME 1. Conversion of 5a to 6a in the Presence of K2CO3
The structural determinations of all products 6a-o were
achieved following their analytical and spectral data. Im-
portantly, this reaction generates one chiral center, but only
one isomer was observed through 1H NMR and 13C NMR
spectra, thin-layer chromatography, and X-ray diffraction
analysis of product 6a (see the Supporting Information).
It is noteworthy that all of the isolated products need only
washing with ethanol rather than column chromatography
or recrystallization. This easy purification makes this meth-
odology facile, practical, and rapid to execute. Significantly,
in this operationally simple domino reaction, at least six
different reactive sites are involved; two C-C bonds, two
C-N bonds, and two new rings are constructed with all
reactants utilized in the chemical transformation. Therefore,
this domino reaction can be extensively employed as an
excellent method for the synthesis of tetrahydrobenzo-
[b]imidazo[3,2,1-ij][1,8]naphthyridine derivatives.
directly explored the use of 5a in the presence of K2CO3 in
DMF at 100 °C for about 12 h monitoring by TLC (Scheme 1).
To our surprise, the reaction conditions did not require any
optimization, and led to the formation of the corresponding
ethyl 10-chloro-4-methyl-7-oxo-6-phenyl-1,2,6,7-tetrahydro-
benzo[b]imidazo[1,2,3-ij] [1,8]naphthyridine-5-carboxylate 6a
in almost quantitative yield.
Encouraged by the efficiency of the two consecutive domino
processes of the aza-ene reaction and nucleophilic substitution,
we set out to explore reaction conditions that would enable its
combination with three-component synthesis of tetrahydro-
benzo[b]imidazo[3,2,1-ij][1,8]naphthyridines 6 in a one-pot
procedure. We performed aza-ene-type reaction of 2-(2,
4-dichlorophenyl)methyleneimidazolidine 2a with benzalde-
hyde 3a and ethyl acetoacetate 4 by simply combining three
components in MeCN employing a molar ratio of 1:1.2:1.2 and
Et3N as base. Stirring the mixture at 81 °C for 8 h readily gave
the expected aza-ene-type adduct 5a, which was not isolated.
After removal of the solvent, the residue was mixed with 1 equiv
of K2CO3 in DMF, and the mixture was heated to 100 °C for
12 h. After completion of the reaction as monitored by TLC,
the mixture was cooled to room temperature, and an amount of
ice-water was added to precipitate the product which was then
collected by filtration and washed with cool water. The dry
solid was then washed with ethanol to afford the expected
product 6a in 87% yield (Table 1, entry 1).
Next, we used Meldrum’s acid 7 instead of ethyl acetoac-
etate 4 in this process. Meldrum’s acid (2,2-dimethyl-1,
3-dioxane-4,6-dione)26 as a class of acylal is a widely useful
methyl derivative.27 It is remarkably acidic (pKa 7.3 in
DMSO at 25 °C) compared to the related dicarbonyl
compounds.28 The high value for C-H acidity and excep-
tional behavior have made it an important candidate for the
design of new practical and facile domino reactions in organic
synthesis.29 Yu and Huang et al.8 reported a novel one-pot
reaction involving HKAs, Meldrum’s acid, and aldehydes to
synthesize tetrahydropyridinone-fused 1,3-diazaheterocycles.
However, to the best of our knowledge, the benzo[b]imidazo-
[3,2,1-ij][1,8]naphthyridines have not been reported before
using 2-(2-chloroaroyl)methyleneimidazolidines 2 as novel N,
N-ketene acetal precursors. Our strategy assumes that precur-
sors 2 might react with Meldrum’s acid and aldehydes to set up
new annulation on the basis of the aza-ene reaction and
nucleophilic substitution.
Under the above optimized conditions, the scope of this
new MCR process was next examined using 2a other 11
aromatic aldehydes 3b-l and ethyl acetoacetate 4 (Table 1,
entries 2-12). The results demonstrated that the reactions went
smoothly, and the yields were all satisfactory. To further
expand the scope of 2-(2-chloroaroyl) methyleneimidazolidine
substrates, we used 2-(2,5-dichlorobenzoyl)methyleneimida-
zolidine 2b, 2-(2,4-dichloro-5-fluorobenzoyl)methyleneimida-
zolidine 2c, and 2-(2-chlorobenzoyl)methyleneimidazolidine 2d
instead of 2a in this process (Table 1, entries 13-15). As can be
seen from Table 2, when aryl aldehydes bearing either electron-
donating or electron-withdrawing groups were used as the
substrates, the reactions could proceed successfully, and the
corresponding products 6 were obtained in excellent yields.
That is, the electronic effects of the substituents on the aromatic
ring have no significant influence on the reaction yields.
Compared to 6m and 6o, for example, the yields of 6a and 6n
are slightly higher and the reaction time is slightly shorter,
which might be attributed to the presence and the site of R
(R = Cl) on the aromatic ring. A 4-chloro group meta to
2-chloro in 2a and 2c only gives an inductive effect with a strong
electron-withdrawing group leading to an increase of electro-
positivity of C2, whereas a 5-chloro group para to 2-chloro in 2b
gives both inductive and conjugate effects leading to a decrease
of electropositivity of C2, so the 2-chloro group is more easily
removed in 2a and 2c as compared to 2b and 2d during the
nucleophilic aromatic substitution reaction.
The above optimized conditions were applied to the reaction
of 2a with 4-bromobenzaldehyde 3b and Meldrum’s acid 7.
Stirring the mixture at 81 °C for about 8 h gave the aza-ene
intermediate, which was not separated, followed by evapora-
tion of the solvent and subsequent addition of K2CO3 in DMF
for about 12 h. Unfortunately, compared with the MCR of 2a,
aromatic aldehydes 3, and ethyl acetoacetate 4, a significant
difference was that 6-(4-bromophenyl)-10-chloro-1,2,5,6-tetra-
hydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-4,7-dione 9b
was found as a major product along with the formation of a
small amount of unidentified byproduct (90b, 17% yield, which
may be oxidation product, it was identified from a singlet at δ
5.96 ppm assigned to the olefinic proton of pyridone moiety).
When improving the purity of 9b, we found that when the reac-
tion time was shortened from 12 to 3 h, the yield of unidentified
byproduct decreased to 2%. To our satisfaction, treatment of
reaction time for 2 h in the second step cleanly afforded only 9b,
with no trace of 90b (Figure 2). Thus, for the second step of
eliminating HCl, controlling the reaction time is especially
important.
Next, a variety of aldehydes 3 also reacted with 2 and 7 under
the optimized conditions as described above. The reactions of 2,
(26) Gaber, A. E. M.; McNab, H. Synthesis 2001, 14, 2059–2074.
(27) Meldrum, A. N. J. Chem. Soc. Trans. 1908, 93, 598–601.
(28) Ivanov, A. S. Chem. Sov. Rev. 2008, 37, 789–811.
(29) Sabitha, G.; Fatima, N.; Reddy, E. V.; Yadav, J. S. Adv. Synth.
Catal. 2005, 347, 1353–1355.
J. Org. Chem. Vol. 75, No. 22, 2010 7607

Wen et al.
JOCArticle
TABLE 1. Synthesis of 6 via a One-Pot Tandem Reaction
7608 J. Org. Chem. Vol. 75, No. 22, 2010

Wen et al.
JOCArticle
TABLE 1. Continued
aThe first step time þ the second step time. bTotal isolated yield.
3, and 7, except 4-nitrobenzaldehyde 3m, proceeded smoothly
with Et3N (0.4 equiv) in refluxing MeCN followed by stirring
the mixture at 81 °C for about 6-8 h, evaporation of the
solvent, and then addition of K2CO3 in DMF for about 1.5-
2 h and led to the formation of tetrahydrobenzo[b]imidazo[3,2,
1-ij][1,8]naphthyridines 9 (Table 2).
The products 9 have been characterized by their IR, H
NMR, 13C NMR, and HRMS spectroscopic data, which are
in agreement with the proposed structures.
When 3m was used in this process, workup of the
reaction mixture did not afford any expected unaroma-
tized compound 9l, but only an unexpected compound 90l,
which is more stable by aerobic oxidation (Scheme 2). In
the 1H NMR spectrum of 90l, the absence of three protons
(δ 2.7-4.6 ppm, CH þ CH2) and existence of olefinic
proton (δ 6.03 ppm) indicate that 6π electron system exists
in the pyridone moiety (see Supporting Information).
From this result, we can deduce that the aldehydes with
strong electron-withdrawing groups and prolonging reac-
tion time of the second step would make the hydrogen
easier to leave in the air.
On the basis of the above experimental results, a plausible
mechanism for the synthesis of tetrahydrobenzo[b]imidazo-
[3,2,1-ij][1,8]naphthyridines 6 or 9 was depicted in Scheme 3.
Take Meldrum’s acid 7, for example; first, aldehydes 3 react
with 7 through Knoevenagel condensation to give intermedi-
ates A. Then, the heterocyclic ketene aminals 2, due to the
two strongly electron-withdrawing groups at the R-position
of the ketene N,N-acetals, acted as heteroene components
react with A to form the intermediates B24b,c,30 which under-
go a rapid imine-enamine tautomerization to give C. Next,
intramolecular cyclization of C with losing a molecule of
acetone and decarboxylation of D led to the formation of
fused heterocyclic imidazo[1,2-a]pyridine motifs 8. Finally,
an intramolecular nucleophilic aryl substitution of the
o-chloro of aryl group (SNAr) by attack of the NH group leads
to new and highly functionalized tetrahydrobenzo[b]imidazo-
[3,2,1-ij][1,8]naphthyridine derivatives 9 with elimination of
HCl. The formation of 90l occurs through an intramolecular
1
(30) Zhao, M.-X.; Wang, M.-X.; Huang, Z.-T. Tetrahedron 2002, 58,
1309–1316.
J. Org. Chem. Vol. 75, No. 22, 2010 7609

Wen et al.
JOCArticle
TABLE 2. Synthesis of 9 via a One-Pot Tandem Reaction
aThe first step time þ the second step time. bTotal isolated yield.
7610 J. Org. Chem. Vol. 75, No. 22, 2010

Wen et al.
JOCArticle
FIGURE 2. Influence of the reaction time for the second step from 1H NMR spectra of 9b: top, 2 h, 9b:90b = 1:0.00; middle, 3 h, 9b:90b =
1:0.02; bottom, 12 h, 9b:90b = 1:0.17.
SCHEME 2. Reaction of 2a with 4-Nitrobenzaldehyde and
Meldrum’s Acid
nucleophilic aryl substitution of the o-chloro of the aryl group
(SNAr) by attack of NH group and quickly undergoing in situ
oxidation by air and subsequent dehydrogenation.
Conclusion
In summary, we have successfully described the application
of 2-(2-chloroaroyl)methyleneimidazolidines 2 to synthesize
tetrahydrobenzo[b]imidazo[3,2,1-ij][1,8]naphthyridines 6 and 9
in a one-pot, two-step sequential process starting from 2,
arylaldehydes 3, and ethyl acetoacetate 4 or Meldrum’s acid 7.
In these reactions, at least six different active sites are involved;
two C-C bonds, two C-N bonds, and two new rings are
constructed with all reactants efficiently utilized in the chemical
transformation. A possible mechanism including Knoevenagel
condensation, aza-ene reaction, intramolecular imine-enamine
tautomerization followed by cyclocondensation and intramole-
cular SNAr was proposed. Undoubtedly, these domino synthetic
strategies open a convenient, effective way to construct the target
molecules from readily available starting materials. The wide
generation of this process suggests its potential in the synthetic
and medicinal importance of this family of compounds and
analogues.
and washed with cool water. The dry solid then was washed with
ethanol.
Ethyl 8-(2,4-dichlorobenzoyl)-5-methyl-7-phenyl-1,2,3,7-tetra-
hydroimidazo[1,2-a]pyridine-6-carboxylate (5a): yellow powder;
mp97-99 °C;IR(KBr, cm-1) 3300, 1691, 1645, 1585, 1554, 1517,
1379, 1225, 838, 769, 705; 1H NMR (CDCl3) δ 1.17 (t, J = 7 Hz,
3H, OCH2CH3), 2.40 (s, 3H, CH3), 3.86-3.99 (m, 6H, 2 ꢀ NCH2
þ OCH2), 4.56 (s, 1H, CH), 6.36-7.49 (m, 8H, ArH), 9.29 (s, 1H,
NH); 13C NMR (CDCl3) δ: 14.2 (pyridine-CH3), 16.4 (OCH2-
CH3), 40.4 (7-CH), 42.8 (NCH2), 45.1(NCH2), 59.9 (OCH2), 89.9
(8-C), 109.2 (6-C), 126.0, 126.7, 127.6, 128.6, 130.0, 134.1, 139.3,
143.0, 147.6 (5-C), 156.5 (9-C), 167.3 (ester CdO), 188.7 (keto
CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for C24H23Cl2N2O3
457.1086, found 457.1097.
Ethyl 10-chloro-4-methyl-7-oxo-6-phenyl-1,2,6,7-tetrahydro-
benzo[b]imidazo[1,2,3-ij] [1,8]naphthyridine-5-carboxylate (6a):
gray powder; mp 263-265 °C; IR (KBr, cm-1) 1687, 1654,
1613, 1576, 1520, 1388, 1325, 1223, 762, 699; 1H NMR (DMSO-
d6) δ 1.11 (t, J = 7 Hz, 3H, OCH2CH3), 2.49 (s, 3H, CH3), 3.98
(q, J = 7 Hz, 2H, OCH2CH3), 4.23-4.47 (m, 4H, 2 ꢀ NCH2),
5.17 (s, 1H, CH), 7.05-7.95 (m, 8H, ArH); 13C NMR (DMSO-
d6) δ 14.5 (CH3), 16.1 (OCH2CH3), 38.3 (6-CH), 45.4 (NCH2),
Experimental Section
General Procedure for the Preparation of Compounds 6 or 9
(6a, for Example). Et3N (0.040 g, 0.4 mmol, 0.4 equiv) was added
to a solution of 2-(2,4-dichlorobenzoyl)methyleneimidazolidine
2a (0.257 g, 1.0 mmol), benzaldehyde 3a (0.127 g, 1.2 mmol), and
ethyl acetoacetate 4 (0.156 g, 1.2 mmol) in 10 mL of MeCN.
The reaction mixture was refluxed for a certain period of time
as indicated by TLC (petroleum ether-EtOAc, 2:1, v/v). The
solvent was removed under vacuum, and the residue together
with potassium carbonate (1 mmol) was heated to 100 °C in
DMF. After completion of the reaction as indicated by TLC
(petroleum ether-EtOAc, 2:3, v/v), the mixture was cooled to
room temperature, and an amount of ice-water was added to
precipitate the products which were then collected by filtration
J. Org. Chem. Vol. 75, No. 22, 2010 7611

Wen et al.
JOCArticle
SCHEME 3. Proposed Mechanism for the Reaction (Meldrum’s Acid, for Example)
45.5 (NCH2), 59.8 (OCH2), 99.1 (6a-C), 105.5 (5-C), 115.1,
122.7, 124.0, 126.3, 127.9, 128.2, 128.2, 136.5, 138.1, 146.2,
147.1, 147.4, 167.2 (ester CdO), 173.1 (keto CdO); HRMS
(ESI-TOF, [M þ H]þ) calcd for C24H22ClN2O3 421.1319, found
421.1329.
Ethyl 6-(4-bromophenyl)-10-chloro-4-methyl-7-oxo-1,2,6,7-tetra-
hydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate (6b):
yellow powder; mp 259-260 °C; IR (KBr, cm-1) 1676, 1654, 1613,
1578, 1520, 1385, 1366, 1326, 1221, 828, 778; 1H NMR (DMSO-d6)
δ 1.10 (t, J = 7 Hz, 3H, OCH2CH3), 2.47 (s, 3H, CH3), 3.99 (q, J =
7 Hz, 2H, OCH2CH3), 4.20-4.47 (m, 4H, 2 ꢀ NCH2), 5.11 (s,
1H, CH), 7.22-7.93 (m, 7H, ArH); 13C NMR (DMSO-d6) δ 14.5
(CH3), 16.2 (OCH2CH3), 38.1 (6-CH), 45.4 (NCH2), 45.5 (NCH2),
59.9 (OCH2), 98.6 (6a-C), 104.8 (5-C), 115.1, 119.3, 122.8, 123.9,
127.8, 130.5, 131.0, 136.6, 138.0, 146.6, 146.8, 146.9, 167.0 (ester
CdO), 173.1 (keto CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for
C24H21BrClN2O3 499.0424, found 499.0404.
Ethyl 10-chloro-6-(4-chlorophenyl)-4-methyl-7-oxo-1,2,6,7-tetra-
hydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate (6c):
yellow powder; mp 266-268 °C; IR (KBr, cm-1) 1676, 1654, 1611,
1575, 1525, 1388, 1369, 1325, 1223, 828, 778; 1H NMR (DMSO-d6)
δ 1.10 (t, J = 7 Hz, 3H, OCH2CH3), 2.49 (s, 3H, CH3), 3.97 (q, J =
7 Hz, 2H, OCH2CH3), 4.23-4.47 (m, 4H, 2 ꢀ NCH2), 5.15 (s,
1H, CH), 7.22-7.95 (m, 7H, ArH); 13C NMR (DMSO-d6) δ 14.5
(CH3), 16.2 (OCH2CH3), 38.0 (6-CH), 45.4 (NCH2), 45.5 (NCH2),
59.9 (OCH2), 98.7 (6a-C), 104.8 (5-C), 115.1, 122.8, 123.9, 127.9,
128.1, 130.1, 130.8, 136.6, 138.1, 146.3, 146.7, 147.0, 167.0 (ester
CdO), 173.1 (keto CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for
C24H21Cl2N2O3 455.0929, found 455.0931.
Ethyl 10-chloro-6-(4-fluorophenyl)-4-methyl-7-oxo-1,2,6,7-tetra-
hydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate (6d):
white powder; mp 267-268 °C; IR (KBr, cm-1) 1690, 1654, 1613,
1575, 1520, 1388, 1328, 1221, 833; 1H NMR (acetone-d6) δ 1.14 (t,
J=7Hz, 3H, OCH2CH3), 2.62(s, 3H, CH3),4.02(q, J= 7 Hz, 2H,
OCH2CH3), 4.45-4.63 (m, 4H, 2 ꢀ NCH2), 5.32 (s, 1H, CH),
6.88-8.06 (m, 7H, ArH); 13C NMR (DMSO-d6) δ 14.6 (CH3), 16.2
(OCH2CH3), 37.8 (6-CH), 45.4 (NCH2), 45.6 (NCH2), 59.9
(OCH2), 99.0 (6a-C), 105.3 (5-C), 114.7, 114.9, 115.2, 122.9,
124.0, 128.0, 130.0, 136.6, 138.1, 143.7, 146.5, 147.0, 161.0 (d,
1J = 240 Hz, F-C couple), 167.2 (ester CdO), 173.2 (keto CdO);
HRMS (ESI-TOF, [M þ H]þ) calcd for C24H21ClFN2O3 439.1225,
found 439.1215.
Ethyl 10-chloro-6-(3-fluorophenyl)-4-methyl-7-oxo-1,2,6,7-tetra-
hydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate (6e):
gray powder; mp 256-258 °C; IR (KBr, cm-1) 1685, 1651, 1611,
1583, 1509, 1388, 1366, 1325, 1221, 803, 776; 1H NMR (DMSO-d6)
δ 1.08 (t, J = 7 Hz, 3H, OCH2CH3), 2.48 (s, 3H, CH3), 3.97 (q, J =
7 Hz, 2H, OCH2CH3), 4.22-4.45 (m, 4H, 2 ꢀ NCH2), 5.16 (s,
1H, CH), 6.87-7.94 (m, 7H, ArH); 13C NMR (DMSO-d6) δ 14.6
(CH3), 16.2 (OCH2CH3), 38.3 (6-CH), 45.5 (NCH2), 45.6 (NCH2),
59.9 (OCH2), 98.5 (6a-C), 104.7 (5-C), 113.2, 115.0, 115.2, 122.9,
124.0, 124.3, 127.9, 130.0, 136.7, 138.1, 146.9, 150.2, 162.4 (d, 1J =
241 Hz, F-C couple), 167.1 (ester CdO), 173.2 (keto CdO); HRMS
(ESI-TOF, [M þ H]þ) calcd for C24H21ClFN2O3 439.1225, found
439.1208.
Ethyl 10-chloro-6-(2-fluorophenyl)-4-methyl-7-oxo-1,2,6,7-tetra-
hydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate (6f ):
gray powder; mp >300 °C; IR (KBr, cm-1) 1685, 1657, 1616, 1580,
1520, 1388, 1328, 1226, 872, 759; 1H NMR (DMSO-d6) δ 1.09
(t, J=7 Hz, 3H, OCH2CH3), 2.47 (s, 3H, CH3), 3.94 (q, J=7 Hz,
2H, OCH2CH3), 4.27-4.43 (m, 4H, 2 ꢀ NCH2), 5.34 (s, 1H,
CH), 6.97-7.89 (m, 7H, ArH); 13C NMR (DMSO-d6) δ 14.4
(CH3), 16.1 (OCH2CH3), 32.7 (6-CH), 45.4 (2C, NCH2), 59.8
(OCH2), 98.4 (6a-C), 104.5 (5-C), 115.1, 122.9, 123.9, 124.29,
127.8, 128.3, 131.5, 134.5, 134.6, 136.6, 138.1, 146.4, 147.2,
159.9 (d, 1J = 245 Hz, F-C couple), 167.1 (ester CdO), 173.0
(keto CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for C24H21-
ClFN2O3 439.1225, found 439.1220.
7612 J. Org. Chem. Vol. 75, No. 22, 2010

Wen et al.
Ethyl 10-chloro-6-(2-chlorophenyl)-4-methyl-7-oxo-1,2,6,7-tetra-
hydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate (6g):
JOCArticle
(DMSO-d6) δ 1.12 (t, J = 7 Hz, 3H, OCH2CH3), 2.50 (s, 3H,
CH3), 4.00 (q, J = 7 Hz, 2H, OCH2CH3), 4.23-4.47 (m, 4H, 2 ꢀ
NCH2), 5.10 (s, 1H, CH), 5.88 (s, 2H, OCH2O), 6.69-7.96 (m, 6H,
ArH); 13C NMR (DMSO-d6) δ 14.7 (CH3), 16.2 (OCH2CH3), 38.0
(6-CH), 45.4 (NCH2), 45.6 (NCH2), 59.9 (OCH2), 99.2 (6a-C),
101.1 (OCH2O), 105.6 (5-C), 108.0, 108.9, 115.1, 121.1, 122.8, 124.0,
128.0, 136.6, 138.1, 141.6, 145.8, 146.0, 147.1, 147.2, 167.3 (ester
CdO), 173.2 (keto CdO), HRMS (ESI-TOF, [M þ H]þ) calcd for
C25H22ClN2O5 465.1217, found 465.1195.
Ethyl 9-chloro-4-methyl-7-oxo-6-phenyl-1,2,6,7-tetrahydro-
benzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate (6m):
gray powder; mp 251-253 °C; IR (KBr, cm-1) 1695, 1659,
1616, 1576, 1540, 1518, 1328, 806, 702; 1H NMR (DMSO-d6) δ
1.11 (t, J = 7 Hz, 3H, OCH2CH3), 2.49 (s, 3H, CH3), 3.98(q, J =
7 Hz, 2H, OCH2CH3), 4.24-4.48 (m, 4H, 2 ꢀ NCH2), 5.19 (s,
1H, CH), 7.06-7.89 (m, 8H, ArH); 13C NMR (DMSO-d6) δ 14.5
(CH3), 16.1 (OCH2CH3), 38.3 (6-CH), 45.4 (NCH2), 45.6
(NCH2), 59.8 (OCH2), 99.2 (6a-C), 105.4 (5-C), 117.8, 125.0,
126.3, 126.5, 127.3, 128.2, 131.6, 135.9, 146.3, 147.1, 147.3, 167.2
(ester CdO), 172.4 (keto CdO); HRMS (ESI-TOF, [M þ H]þ)
calcd for C24H22ClN2O3 421.1319, found 421.1335.
Ethyl 10-chloro-9-fluoro-4-methyl-7-oxo-6-phenyl-1,2,6,7-tetra-
hydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate (6n):
gray powder; mp 249-251 °C; IR (KBr, cm-1) 1687, 1652, 1587,
1522, 1428, 1389, 1328, 1241, 1213, 1108, 975, 835, 698; 1H NMR
(DMSO-d6) δ 1.09 (t, J = 7 Hz, 3H, OCH2CH3), 2.49 (s, 3H, CH3),
3.97 (q, J = 7 Hz, 2H, OCH2CH3), 4.24-4.49 (m, 4H, 2 ꢀ NCH2),
5.16 (s, 1H, CH), 7.05-7.78 (m, 7H, ArH); 13C NMR (DMSO-d6) δ
14.5 (CH3), 16.1 (OCH2CH3), 38.4 (6-CH), 45.6 (NCH2), 45.8
(NCH2), 59.9 (OCH2), 99.9 (6a-C), 105.6 (5-C), 112.2, 112.4, 117.8,
123.9, 124.1, 125.3, 126.4, 128.2, 128.3, 134.2, 146.1, 147.2, 147.3,
153.4 (d, 1J = 242 Hz, F-C couple), 167.2 (esterCdO), 172.3 (keto
CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for C24H21ClFN2O3
439.1225, found 439.1231.
Ethyl 4-methyl-7-oxo-6-phenyl-1,2,6,7-tetrahydrobenzo[b]im-
idazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate (6o): gray powder;
mp 238-240 °C; IR (KBr, cm-1) 1691, 1655, 1616, 1580, 1540,
1522, 1328, 759; 1H NMR (DMSO-d6) δ 1.11 (t, J = 7 Hz, 3H,
OCH2CH3), 2.49 (s, 3H, CH3), 3.98 (q, J = 7 Hz, 2H, OCH2CH3),
4.26-4.47 (m, 4H, 2 ꢀ NCH2), 5.21 (s, 1H, CH), 7.05-7.98 (m,
9H, ArH); 13C NMR (DMSO-d6) δ 14.7 (CH3), 16.2 (OCH2CH3),
38.3 (6-CH), 45.2 (NCH2), 45.6 (NCH2), 59.8 (OCH2), 98.8 (6a-C),
105.3 (5-C), 115.4, 122.6, 125.4, 126.0, 126.3, 128.2, 131.9, 137.2,
146.6, 146.9, 147.7, 167.4 (ester CdO), 173.8 (keto CdO); HRMS
(ESI-TOF, [M þ H]þ) calcd for C24H23N2O3 387.1709, found
387.1700.
8-(2,4-Dichlorobenzoyl)-7-phenyl-2,3,6,7-tetrahydroimidazo-
[1,2-a]pyridine-5-(1H)-one (8a): yellow powder; mp 212-214 °C;
IR (KBr, cm-1) 3284, 1687, 1639, 1583, 1535, 1370, 1321, 843, 729,
703; 1H NMR (CDCl3) δ: 2.74 (dd, J = 1.5 Hz, 16.5 Hz, 1H, C(O)-
CH2), 3.02 (dd, J =7.5 Hz, 16.5 Hz, 1H, C(O)CH2), 3.74-4.16 (m,
5H, 2 ꢀ NCH2 þ CH), 6.63-7.34 (m, 8H, ArH), 9.56 (s, 1H, NH);
13CNMR(CDCl3) δ:37.9(7-CH), 40.4 (6-CH2), 41.9 (NCH2), 42.8
(NCH2), 88.9 (8-C), 126.4, 126.7, 126.80, 128.6, 129.2, 134.5, 138.6,
143.6, 157.1, 167.7 (5-CdO), 188.4 (CdO); HRMS (ESI-TOF,
[M þ H]þ) calcd for C20H17Cl2N2O2 387.0667, found 387.0656.
10-Chloro-6-phenyl-1,2,5,6-tetrahydrobenzo[b]imidazo[1,2,3-ij]-
[1,8]naphthyidine-4,7-dione (9a): yellow powder; mp 252-254 °C;
IR (KBr, cm-1) 1701, 1685, 1652, 1580, 1506, 1366, 1229, 833, 737,
699; 1H NMR (DMSO-d6) δ 2.68 (d, J = 16.5 Hz, 1H, C(O)CH2),
3.16 (dd, J = 8 Hz, 16 Hz, 1H, C(O)CH2), 4.13-4.51 (m, 5H, 2 ꢀ
NCH2 þ CH), 7.18-8.08 (m, 8H, ArH); 13C NMR (DMSO-d6) δ
34.5 (6-CH), 42.9 (NCH2), 45.8 (NCH2), 99.8 (6a-C), 115.7, 123.6,
124.0, 127.1, 128.3, 129.0, 136.8, 138.3, 144.0, 148.4, 168.0 (4-CdO),
173.3 (7-CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for C20H16-
ClN2O2 351.0900, found 351.0914.
yellow powder; mp 257-258 °C; IR (KBr, cm-1) 1685, 1663,
1
1616, 1586, 1509, 1388, 1366, 1328, 1221, 1190, 833, 740; H
NMR (DMSO-d6) δ 1.05 (t, J = 7 Hz, 3H, OCH2CH3), 2.44 (s,
3H, CH3), 3.93 (q, J = 7 Hz, 2H, OCH2CH3), 4.25-4.41 (m,
4H, 2 ꢀ NCH2), 5.40 (s, 1H, CH), 7.05-7.85 (m, 7H, ArH); 13
C
NMR (DMSO-d6) δ 14.4 (CH3), 16.1 (OCH2CH3), 36.9 (6-CH),
45.3 (2C, NCH2), 59.7 (OCH2), 98.6 (6a-C), 104.9 (5-C), 115.0,
122.8, 123.9, 127.1, 127.8, 127.9, 129.3, 132.2, 132.9, 136.6, 138.1,
144.7, 145.8, 147.2, 167.1 (ester CdO), 173.0 (keto CdO); HRMS
(ESI-TOF, [M þ H]þ) calcd for C24H21Cl2N2O3 455.0929, found
455.0946.
Ethyl 10-chloro-6-(2,4-dichlorophenyl)-4-methyl-7-oxo-1,2,6,7-
tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate
(6h): gray powder; mp 258-260 °C; IR (KBr, cm-1) 1678, 1654,
1611, 1578, 1515, 1221, 828, 778; 1H NMR (acetone-d6) δ 1.14 (t,
J= 7 Hz, 3H, OCH2CH3), 2.57 (s, 3H, CH3),4.05(q,J= 7 Hz, 2H,
OCH2CH3), 4.46-4.59 (m, 4H, 2 ꢀ NCH2), 5.54 (s, 1H, CH),
7.12-7.97 (m, 6H, ArH); 13C NMR (DMSO-d6) δ 14.6 (CH3), 16.2
(OCH2CH3), 36.7 (6-CH), 45.4 (2C, NCH2),59.9(OCH2), 98.4 (6a-
C), 104.4 (5-C), 115.2, 123.0, 123.9, 127.3, 128.6, 131.4, 133.5, 134.0,
136.7, 138.2, 144.0, 146.4, 147.1, 167.0 (ester CdO), 173.0 (keto
CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for C24H20Cl3N2O3
489.0540, found 489.0525.
Ethyl 10-chloro-4-methyl-7-oxo-6-(p-tolyl)-1,2,6,7-tetrahydro-
benzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carboxylate (6i): yellow
powder; mp 270-272 °C; IR (KBr, cm-1) 1696, 1654, 1613, 1578,
1520, 1388, 1369, 1325, 1221, 1199, 839, 789; 1H NMR (DMSO-d6) δ
1.13 (t, J=7 Hz, 3H, OCH2CH3), 2.18 (s, 3H, CH3), 2.49 (s, 3H,
CH3), 3.98 (t, J = 7 Hz, 2H, OCH2CH3), 4.21-4.44 (m, 4H, 2 ꢀ
NCH2), 5.12 (s, 1H, CH), 6.96-7.94 (m, 6H, ArH); 13C NMR
(DMSO-d6) δ 14.6 (CH3), 16.1 (OCH2CH3), 21.1 (Ar-CH3), 37.9
(6-CH), 45.4 (NCH2),45.6(NCH2),59.8(OCH2), 99.3 (6a-C), 105.7
(5-C), 115.1, 122.8, 124.1, 128.0, 128.1, 128.8, 135.3, 136.5, 138.1,
144.6, 146.0, 147.1, 167.3 (ester CdO), 173.1 (keto CdO); HRMS
(ESI-TOF, [M þ H]þ) calcd for C25H24ClN2O3 435.1475, found
435.1497.
Ethyl 10-chloro-6-(4-methoxyphenyl)-4-methyl-7-oxo-1,2,6,
7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-carbox-
ylate (6j): yellow powder; mp 264-266 °C; IR (KBr, cm-1) 1701,
1
1654, 1613, 1575, 1525, 1388, 1366, 1328, 1251, 842, 789, 754; H
NMR (DMSO-d6) δ 1.13 (t, J = 7 Hz, 3H, OCH2CH3), 2.49 (s, 3H,
CH3), 3.65 (s, 3H, OCH3), 3.98 (q, J = 7 Hz, 2H, OCH2CH3),
4.19-4.45 (m, 4H, 2 ꢀ NCH2), 5.10 (s, 1H, CH), 6.72-7.94 (m, 7H,
ArH); 13C NMR (DMSO-d6) δ 14.6 (CH3), 16.1 (OCH2CH3), 37.4
(6-CH), 45.3 (NCH2), 45.5 (NCH2), 55.4 (OCH3), 59.8 (OCH2),
99.4 (6a-C), 105.8 (5-C), 113.5, 115.0, 122.7, 123.99, 127.9, 129.1,
136.5, 138.0, 139.7, 145.7, 147.0, 157.9, 167.3 (ester CdO), 173.1
(keto CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for C25H24-
ClN2O4 451.1425, found 451.1425.
Ethyl 10-chloro-6-(3,4-dimethoxyphenyl)-4-methyl-7-oxo-1,2,
6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-5-car-
boxylate (6k): yellow powder; mp 237-239 °C; IR (KBr, cm-1
)
1685, 1660, 1613, 1575, 1520, 1388, 1328, 1265, 1226, 806; 1H NMR
(DMSO-d6) δ:1.15(t, J=7Hz, 3H, OCH2CH3), 2.50 (s, 3H, CH3),
3.65 (s, 3H, OCH3), 3.69 (s, 3H, OCH3), 4.02(q, J = 7 Hz, 2H,
OCH2CH3), 4.23-4.48 (m, 4H, 2 ꢀ NCH2), 5.14 (s, 1H, CH),
6.96-7.98 (m, 6H, ArH); 13C NMR (DMSO-d6) δ 14.7 (CH3), 16.1
(OCH2CH3), 37.7 (6-CH), 45.4 (NCH2), 45.6 (NCH2), 56.0 (2C,
OCH3), 59.8 (OCH2), 99.4 (6a-C), 105.7 (5-C), 112.2, 112.8, 115.1,
120.0, 122.8, 124.1, 128.0, 136.5, 138.1, 140.3, 145.8, 147.1, 147.7,
148.4, 167.4 (ester CdO), 173.3 (keto CdO); HRMS (ESI-TOF,
[M þ H]þ) calcd for C26H26ClN2O5 481.1530, found 481.1521.
Ethyl 6-(benzo[d ][1,3]dioxol-5-yl)-10-chloro-4-methyl-7-oxo-
1,2,6,7-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridine-
5-carboxylate (6l):yellow powder; mp 257-259 °C; IR(KBr, cm-1
1698, 1659, 1616, 1576, 1522, 1339, 1231, 795, 673; 1H NMR
)
6-(4-Bromophenyl)-10-chloro-1,2,5,6-tetrahydrobenzo[b]im-
idazo[1,2,3-ij][1,8]naphthyridine-4,7-dione (9b): yellow powder; mp
J. Org. Chem. Vol. 75, No. 22, 2010 7613

Wen et al.
JOCArticle
239-241 °C; IR (KBr, cm-1) 1687, 1646, 1616, 1583, 1517, 1369,
1229, 839, 781; 1H NMR (DMSO-d6) δ 2.71 (d, J = 17 Hz, 1H,
C(O)CH2), 3.17 (dd, J = 8 Hz, 16.5 Hz, 1H, C(O)CH2), 4.12-4.51
(m, 5H, 2 ꢀ NCH2 þ CH), 7.20-8.07 (m, 7H, ArH); 13C NMR
(DMSO-d6) δ34.1 (6-CH), 39.2 (5-CH2),43.0(NCH2), 46.0 (NCH2),
99.3 (6a-C), 115.8, 123.7, 124.0, 128.3, 129.2, 129.5, 130.8, 137.0,
138.4, 143.5, 148.6, 167.9 (4-CdO), 173.3 (7-CdO); HRMS (ESI-
TOF, [M þ H]þ) calcd for C20H15BrClN2O2 429.0005, found
429.0024.
10-Chloro-6-(4-chlorophenyl)-1,2,5,6-tetrahydrobenzo[b]im-
idazo[1,2,3-ij][1,8]naphthyridine-4,7-dione (9c): yellow powder; mp
223-225 °C; IR (KBr, cm-1) 1701, 1687, 1638, 1616, 1578, 1520,
1369, 1229, 839, 784; 1H NMR (DMSO-d6) δ 2.67 (d, J = 16.5 Hz,
1H, C(O)CH2), 3.16 (dd, J = 9.5 Hz, 17 Hz, 1H, C(O)CH2), 4.12-
4.51 (m, 5H, 2 ꢀ NCH2 þ CH), 7.26-8.07 (m, 7H, ArH); 13CNMR
(DMSO-d6) δ 34.1 (6-CH), 39.2 (5-CH2), 43.0 (NCH2), 46.0
(NCH2), 99.4 (6a-C), 115.8, 123.7, 124.0, 128.3, 128.9, 129.1,
131.7, 137.0, 138.3, 143.0, 148.6, 167.9 (4-CdO), 173.3 (7-CdO);
HRMS (ESI-TOF, [M þ H]þ) calcd for C20H15Cl2N2O2 385.0511,
found 385.0514.
10-Chloro-6-(4-fluorophenyl)-1,2,5,6-tetrahydrobenzo[b]im-
idazo[1,2,3-ij][1,8]naphthyridine-4,7-dione (9d): yellow powder; mp
169-171 °C; IR (KBr, cm-1) 1707, 1638, 1611, 1569, 1534, 1366,
1232, 842, 781, 691; 1H NMR (DMSO-d6) δ 2.67 (d, J = 16.5 Hz,
1H, C(O)CH2), 3.15 (dd, J = 8 Hz, 17 Hz, 1H, C(O)CH2), 4.12-
4.50 (m, 5H, 2 ꢀ NCH2 þ CH), 7.04-8.07 (m, 7H, ArH); 13CNMR
(DMSO-d6) δ 33.9 (6-CH), 43.0 (NCH2), 45.9 (NCH2), 99.8 (6a-C),
115.6, 115.7, 123.6, 124.0, 128.3, 129.0, 129.1, 136.9, 138.3, 140.2,
148.5, 161.5 (d, 1J = 241 Hz, F-C couple), 168.0 (4-CdO), 173.3
(7-CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for C20H15ClFN2O2
369.0806, found 369.0789.
10-Chloro-6-(2-chlorophenyl)-1,2,5,6-tetrahydrobenzo[b]im-
idazo[1,2,3-ij][1,8]naphthyridine-4,7-dione (9e): yellow powder; mp
242-244 °C; IR (KBr, cm-1) 1705, 1648, 1616, 1587, 1540, 1472,
1371, 1277, 961, 784, 748, 677; 1HNMR(DMSO-d6) δ2.52 (dd, J=
8 Hz, 15.5 Hz, 1H, C(O)CH2), 3.24 (dd, J = 9 Hz, 17 Hz, 1H,
C(O)CH2), 4.16-4.80 (m, 5H, 2 ꢀ NCH2 þ CH), 7.04-8.02 (m,
7H, ArH); 13C NMR (DMSO-d6) δ: 32.2 (6-CH), 38.6 (5-CH2), 43.0
(NCH2), 46.1 (NCH2), 97.9 (6a-C), 115.9, 123.7, 124.0, 128.0, 128.2,
129.1, 130.3, 133.0, 137.1, 138.6, 140.5, 149.5, 167.2 (4-CdO), 173.2
(7-CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for C20H15Cl2N2O2
385.0511, found 385.0510.
10-Chloro-6-(4-methoxyphenyl)-1,2,5,6-tetrahydrobenzo[b]im-
idazo[1,2,3-ij][1,8]naphthyridine-4,7-dione (9h): yellow powder;
mp 224-226 °C; IR (KBr, cm-1) 1702, 1685, 1651, 1615, 1588,
1540, 1514, 1373, 1248, 839, 782; 1H NMR (DMSO-d6) δ 2.66 (d,
J = 16 Hz, 1H, C(O)CH2), 3.11 (dd, J = 8 Hz, 17 Hz, 1H, C(O)-
CH2), 3.68 (s, 3H, OCH3), 4.12-4.54 (m, 5H, 2 ꢀ NCH2 þ CH),
6.79-8.08 (m, 7H, ArH); 13C NMR (DMSO-d6) δ 33.7 (6-CH),
42.9 (NCH2), 45.8 (NCH2), 55.5 (OCH3), 100.2 (6a-C), 114.3,
123.5, 124.0, 128.1, 135.9, 136.8, 138.3, 148.3, 158.4, 168.2 (4-CdO),
173.3 (7-CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for C21H18-
ClN2O3 381.1006, found 381.1011.
9-Chloro-6-phenyl-1,2,5,6-tetrahydrobenzo[b]imidazo[1,2,3-ij]-
[1,8]naphthyridine-4,7-dione (9i): yellow powder; mp >300 °C;
IR (KBr, cm-1) 1691, 1641, 1616, 1587, 1547, 1515, 1418, 1382,
1321, 1231, 1166, 907, 705; 1H NMR (DMSO-d6) δ2.70 (d, J= 16.5
Hz, 1H, C(O)CH2), 3.15 (dd, J = 7.5 Hz, 17 Hz, 1H, C(O)CH2),
4.17-4.53 (m, 5H, 2 ꢀ NCH2 þ CH), 7.18-8.01 (m, 8H, ArH); 13
C
NMR (DMSO-d6) δ 34.6 (6-CH), 42.9 (NCH2), 45.9 (NCH2), 99.8
(6a-C), 118.5, 125.3, 126.5, 127.1, 128.1, 129.0, 132.0, 136.1, 144.0,
148.5, 168.1 (4-CdO), 172.7 (7-CdO); HRMS (ESI-TOF, [M þ
H]þ) calcd for C20H16ClN2O2 351.0900, found 351.0887.
10-Chloro-9-fluoro-6-phenyl-1,2,5,6-tetrahydrobenzo[b]im-
idazo[1,2,3-ij][1,8]naphthyridine-4,7-dione (9j): yellow powder; mp
240-242 °C; IR (KBr, cm-1) 1691, 1644, 1594, 1547, 1518, 1421,
1378, 1238, 1015, 950, 795, 768, 698; 1H NMR (DMSO-d6) δ2.70 (d,
J = 15.5 Hz, 1H, C(O)CH2), 3.16 (dd, J = 8 Hz, 16.5 Hz, 1H,
C(O)CH2), 4.14-4.54 (m, 5H, 2 ꢀ NCH2 þ CH), 7.17-7.91 (m,
7H, ArH); 13C NMR (DMSO-d6) δ 34.1 (6-CH), 42.4 (NCH2), 45.7
(NCH2), 99.0 (6a-C), 112.0, 112.2, 118.1, 123.8, 124.0, 124.9, 126.6,
128.5, 133.9, 143.4, 148.2, 153.3 (d, 1J= 242 Hz, F-C couple), 167.6
(4-CdO), 172.0 (7-CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for
C20H15ClFN2O2 369.0806, found 369.0809.
6-Phenyl-1,2,5,6-tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]naph-
thyridine-4,7-dione (9k): yellow powder; mp 254-256 °C; IR
(KBr, cm-1) 1698, 1637, 1616, 1576, 1540, 1522, 1468, 1446,
1310, 1159, 766, 738, 709; 1H NMR (DMSO-d6) δ 2.70 (d, J =
16.5 Hz, 1H, C(O)CH2), 3.15 (dd, J = 8 Hz, 17 Hz, 1H, C(O)CH2),
4.11-4.53 (m, 5H, 2 ꢀ NCH2 þ CH), 7.14-8.10 (m, 9H, ArH); 13
C
NMR (DMSO-d6) δ 34.6 (6-CH), 42.8 (NCH2), 45.6 (NCH2), 99.3
(6a-C), 116.0, 123.3, 125.4, 126.2, 127.0, 127.1, 128.9, 132.1, 137.4,
144.2, 148.0, 168.1 (4-CdO), 173.9 (7-CdO); HRMS (ESI-TOF,
[M þ H]þ) calcd for C20H17N2O2 317.1290, found 317.1282.
10-Chloro-6-(4-nitrophenyl)-1,2-dihydrobenzo[b]imidazo[1,2,3-ij]-
[1,8]naphthyridine-4,7-dione (90l): yellow powder; mp 279-281 °C;
IR(KBr, cm-1) 1665, 1635, 1594, 1564, 1536, 1509, 1347, 1292, 935,
836, 784; 1H NMR (DMSO-d6) δ 4.45 (t, J = 9.5 Hz, 2H, NCH2),
4.61 (t, J = 9.5 Hz, 2H, NCH2), 6.03 (s, 1H, =CH), 7.37-8.24 (m,
7H, ArH); 13C NMR (TFA-d) δ 46.5 (NCH2), 49.5 (NCH2), 102.7
(6a-C), 120.3, 126.1, 129.8, 130.3, 131.3, 139.7, 145.0, 147.8, 150.6,
151.5, 153.8, 172.9 (7-CdO); HRMS (ESI-TOF, [M þ H]þ) calcd
for C20H13ClN3O4 394.0595, found 394.0595.
10-Chloro-6-(2,4-dichlorophenyl)-1,2,5,6-tetrahydrobenzo[b]im-
idazo[1,2,3-ij][1,8]naphthyridine-4,7-dione (9f): yellow powder; mp
182-184 °C; IR (KBr, cm-1) 1697, 1648, 1617, 1584, 1541, 1521,
1
1472, 1373, 1093, 817, 785; H NMR (DMSO-d6) δ 2.54 (1H,
C(O)CH2), 3.26 (dd, J = 9 Hz, 16.5 Hz, 1H, C(O)CH2), 4.15-4.76
(m, 5H, 2 ꢀ NCH2 þ CH), 7.10-8.04 (m, 6H, ArH); 13C NMR
(DMSO-d6) δ 31.9 (6-CH), 38.2 (5-CH2), 43.0 (NCH2), 46.0
(NCH2), 97.4 (6a-C), 115.8, 123.7, 123.8, 127.9, 128.1, 129.6,
129.7, 132.6, 133.9, 137.0, 138.5, 139.7, 149.4, 166.8 (4-CdO),
173.1 (7-CdO); HRMS (ESI-TOF, [M þ H]þ) calcd for C20H14-
N2O2Cl3 419.0121, found 419.0134.
10-Chloro-6-(p-tolyl)-1,2,5,6-tetrahydrobenzo[b]imidazo[1,2,3-ij]-
[1,8]naphthyridine-4,7-dione (9g): yellow powder; mp 196-198 °C;
IR(KBr, cm-1) 1692, 1648, 1617, 1584, 1540, 1519, 1372, 1229, 824,
783; 1H NMR (DMSO-d6) δ 2.21 (s, 3H, CH3), 2.65 (d, J = 16.5
Hz, 1H, C(O)CH2), 3.11 (dd, J = 8 Hz, 16.5 Hz, 1H, C(O)CH2),
Acknowledgment. This work was financially supported by
the National Natural Science Foundation of China (No.
20872074 and 21072110), Natural Science Foundation of
Shandong Province (No. Z2008B03), and the Doctoral Foun-
dation of Qingdao University of Science and Technology.
4.11-4.52 (m, 5H, 2 ꢀ NCH2 þ CH), 7.03-8.07 (m, 7H, ArH); 13
C
NMR (DMSO-d6) δ 21.0 (Ar-CH3), 34.1 (6-CH), 42.9 (NCH2),
45.8 (NCH2), 100.0 (6a-C), 115.7, 123.5, 124.0, 126.9, 128.3, 129.5,
136.1, 136.8, 138.3, 141.0, 148.4, 168.1 (4-CdO), 173.3 (7-CdO);
HRMS (ESI-TOF, [M þ H]þ) calcd for C21H18ClN2O2 365.1057,
found 365.1051.
Supporting Information Available: Experimental proce-
1
dures, copies of H NMR, 13C NMR, and HRMS spectra of
all new compounds, and X-ray data for compound 6a (CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
7614 J. Org. Chem. Vol. 75, No. 22, 2010