Synthesis of hexahydrobenzo[ b ]pyrimido[4,5- h ][1,6]naphthyridines via an intramolecular hetero-diels-alder reaction

Article abstract of DOI:10.1021/cc100018b

Method development was completed for a strategy to access a novel pyrimidine-fused heterocyclic scaffold. The key step for this synthetic route entails an intramolecular inverse electron demand hetero-Diels-Alder reaction of imines or iminiums formed in situ from allylaminopyrimidinealdehydes 3 and anilines. The reactions provided exclusively cis-configuration products 6. Products 6 were readily precipitated in the reaction solution in good to excellent yields. Further transformations of the phenylthio group were demonstrated by an oxidation and subsequent nucleophilic substitution sequence. The synthetic strategy provides an efficient way to access libraries of the tetracyclic pyrimidine-fused heterocycles that can be explored for potential pharmaceutical or biological activities.

Full text of DOI:10.1021/cc100018b

476
J. Comb. Chem. 2010, 12, 476–481
Synthesis of Hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridines via
an Intramolecular Hetero-Diels-Alder Reaction
Fengzhi Yang, Lianyou Zheng, Jinbao Xiang, Qun Dang, and Xu Bai*
The Center for Combinatorial Chemistry and Drug DiscoVery, School of Pharmaceutical Sciences and
College of Chemistry, Jilin UniVersity, 75 Haiwai Street, Changchun, Jilin 130012, P. R. China
ReceiVed February 7, 2010
Method development was completed for a strategy to access a novel pyrimidine-fused heterocyclic scaffold.
The key step for this synthetic route entails an intramolecular inverse electron demand hetero-Diels-Alder
reaction of imines or iminiums formed in situ from allylaminopyrimidinealdehydes 3 and anilines. The
reactions provided exclusively cis-configuration products 6. Products 6 were readily precipitated in the reaction
solution in good to excellent yields. Further transformations of the phenylthio group were demonstrated by
an oxidation and subsequent nucleophilic substitution sequence. The synthetic strategy provides an efficient
way to access libraries of the tetracyclic pyrimidine-fused heterocycles that can be explored for potential
pharmaceutical or biological activities.
Introduction
as described in Scheme 1. Herein, the investigation of the
cascade reactions and preparation of a representative library
are reported.
Access to libraries of novel heterocyclic scaffolds is an
important component of medicinal chemistry and chemical
biology.1 Pyrido[2,3-d]pyrimidine 1 derivatives are reported
to exhibit a variety of biological activities, such as CRF-1
receptor binding and protein tyrosine kinases inhibition
(Figure 1).2 Tetrahydroquinoline derivatives are an important
class of natural products displaying a wide range of interest-
ing biological activities, such as antitumor and antibiotic
activity.3 Octahydrobenzonaphthyridines 2 are pharmacologi-
cally active as central nervous system depressants (Figure
1).4 The tetracyclic ring systems are also found among
compounds with important biological activities, such as
antitumor,5a,b angiogenesis,5c antibiotic,5d and aromatase
inhibition.5e Several methods were reported for the synthesis
of compounds 1 and 2. For example, treatment of lactams
with Viehe’s salt followed by the reaction of the resultant
iminium dichlorides with amidines gives compounds 1.6 A
Dieckmann cyclization of diesters has been used to build
the bicyclic pyridopyrimidine ring.2b The Diels-Alder
reaction of amidines and 1,3,5-triazines has been applied to
prepare analogs of compound 1.7 Compounds 2 were
prepared through condensation of o-carbonyl aniline and
4-piperidone, followed by hydrogenation.4 Our laboratory
has been interested in developing efficient methodologies for
the syntheses of novel pyrimidine-fused heterocycles.8 We
envisioned that a novel hybrid scaffold 6 of structures 1 and
2 with multiple diversification points could be readily
prepared via a cascade reaction: condensation of N-allylami-
nopyrimidinealdehydes 3 and anilines 4 followed by an acid
catalyzed intramolecular inverse electron demand hetero-
Diels-Alder reaction9 should give the desired cis-config-
ured10 tetracycle 6, and 6 could be further transformed8b,h
Results and Discussion
To investigate the proposed cascade reaction shown in
Scheme 1, we initially screened reactions of aniline with
pyrimidines 3, prepared from 4,6-dichloro-5-formylpyrimi-
dine 9a11 (Scheme 2), and results are summarized in Table
1. Trifluoroacetic acid (TFA) was selected as a Brønsted acid
catalyst based on the previous examples of similar reac-
tions.12 No desired product was obtained, and the starting
material 3a was recovered in the absence of TFA in
acetonitrile (CH3CN) (Table 1, entry 1). The reaction of
compound 3a (X ) Cl) and aniline with 0.1 equiv of TFA
in CH3CN after 13 h at 25 °C yielded the desired product
6a (78%) and Cl-hydrolyzed aniline adduct 6′ (8%, Table
1, entry 2). Although increase of TFA to 2.0 equiv resulted
higher yield (82%) and shorter reaction time (2 h), Cl-
hydrolyzed aniline adduct 6′ was still present in the reaction
(Table 1, entry 3). To avoid the Cl-hydrolysis, pyrimidine
3b (X ) pyrrolidinyl) was used instead, but unfortunately,
no desired product was detected by both TLC and HPLC
(Table 1, entry 4). To circumvent these problems and place
a strategic functional group for further transformation,
pyrimidine 3c (X ) PhS) was investigated. The treatment
of 3c with aniline in the similar condition generated the
desired compound 6c in 87% yield without hydrolysis of
the 6-SPh group (Table 1, entry 5). The formation of 6c was
* To whom correspondence should be addressed. Tel: +86-431-
85188955. Fax: +86-431-85188900. E-mail:xbai@jlu.edu.cn.
Figure 1. Hybridization of 1 and 2 into 6.
10.1021/cc100018b  2010 American Chemical Society
Published on Web 06/15/2010

Synthesis of Hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 477
Scheme 1. Strategy for Preparation of Hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridines
Scheme 2. Synthesis of Substrate 3
Table 1. Screening of the Substrates and Optimization of the
Reaction
excellent yields (entries 1, and 3-16). All the products were
determined to be cis-configured by comparison of 1H NMR
spectra with 6c (determined by X-ray analysis) and no trans
isomers were observed in the crude reaction product by LC-
MS. The reactions with aromatic amines containing electron-
withdrawing groups (entries 3-8) were faster than those with
electron-donating groups (entries 9-15), which suggests that
the cycloaddition reactions fall into the category of inverse
electron demand Diels-Alder reactions. When the anilines
had an ortho substituent, the reactions were either sluggish
(entries 7, 9, and 12) or resulted no desired product (entry
2). The reaction of compound 3c with o-nitroaniline under
the current condition did not yield the desired product. This
could be attributed to the combination of steric and strong
electron-withdrawing effects which impeded the formation
of imine or iminium intermediate. It is worth noting that
various functional groups such as carboxyl, hydroxyl, nitro
(except in ortho position), chloro, and fluoro are tolerated.
TFA
(equiv)
yield
(%)
entry
3
X
solvent
CH3CN
time (h)
6
1
2
3
4
5
6
7
8
3a Cl
3a Cl
3a Cl
3b pyrrolidinyl
3c SPh
3c SPh
3c SPh
10
13
2
13
24
4
6a
0.1
2.0
0.1
0.1
1.0
2.0
2.0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN/H2O
(1:1)
6a 78 (8)a
6a 82 (4)a
6b
6c 87
6c 90
6c 91
6c 94
1
11
3c SPh
a Yield of 6′ isolated.
1
Regio isomers were observed by H NMR when meta-Cl
(entry 8) and meta-Me (entry 10) substituted anilines were
used. However, when meta-nitroaniline (entry 3) was used,
only C2-cyclized product was obtained and the employment
of 3,4-(methylenedioxy)aniline (entry 15) resulted the C6-
cyclized product as the sole isomer. When R1 was H, the
reaction stopped at the stage of imine intermediate (entry
17). When R1 was phenyl, no desired product was isolated
(Table 2, entry 18). When R1 was Bn and CH2CO2Et (entries
19 and 20), the reactions were accelerated in comparison to
found to be exclusively cis-selective based on a X-ray
analysis and the1H NMR spectrum (J12a,6a ) 2.4 Hz) (Figure
2).13 This result supported the proposed concerted intramo-
lecular hetero-Diels-Alder mechanism.14 Therefore, com-
pound 3c was selected for further investigation. The increase
of TFA to 1.0 equiv shortened the reaction time to 4 h with
slight increase of product yield (91%, Table 1, entry 6).
Further increase of TFA to 2.0 equiv reduced the reaction
time to 1 h (Table 1, entry 7), and the employment of a 1:1
mixture of CH3CN and H2O as the solvent15 resulted the
precipitation of product 6c, which simplified the reaction
workup (Table 1, entry 8). Therefore, this condition was
chosen as the optimized condition for further studies.
To explore the scope of this reaction, a series of aromatic
amines were reacted with pyrimidines 3 under the optimized
conditions, and the results are reported in Table 2.
As shown in Table 2, various substituted aromatic amines
could react with 3c to give the desired products 6 in good to
Figure 2. X-ray structure of product 6c.

478 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Yang et al.
Table 2. Reaction of Substrates 3 with Substituted Anilines and Analogs

Synthesis of Hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridines
Table 2. Continued
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 479
a Single regio-isomer (cyclized to C2 of aniline). b A mixture of regio-isomers. c Single regio-isomer [cyclized to C6 of 3,4-(methylenedioxy)aniline]. d 92%
yield of imine intermediate was isolated. e Anilines (1.05 equiv), TsOH (0.05 equiv), in refluxing toluene with a Dean-Stark trap.
Table 3. Oxidation and Substitution
entry
products
nucleophile
base
NaH
pyridine
pyridine
solvent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
8a
8b
8c
8d
8e
8f
pyrrolidine
aniline
EtSH
toluene
THF
toluene
toluene
THF
100a
50
7
1
18
14
10
12
98
60
55b
87
80
60
100a
100
r.t.
BnSH
n-BuONac
PhONac
THF
r.t.
a Sealed tube. b 37% yield of 6c was isolated. c Formed in situ by adding sodium to butan-1-ol (or phenol).
Scheme 3. Attempted Reactions of Substrate 3h-i with Aniline
when R1 was Me (entry 1). Despite limited report on the
applications of secondary aryl amines as substrates used to
assemble the iminium diene,16 the reaction of secondary aryl
amines and pyrimidine 3c yielded the desired products under
a modified reaction condition of 0.05 equiv of p-tolunesu-
fonic acid in refluxing toluene with a Dean-Stark trap
(entries 21-23). These results indicated that formation of
the iminium ion could be the key to the cycloaddition
reaction.
To increase the diversity, transformation of the phenylthio
group on the pyrimidine ring to a variety of substituents,
such as alkylamino, alkoxy, and alkylthio groups, was
explored using our previously developed methods.The rep-
resentative 6c was readily oxidized by m-CPBA to sulfoxide
7. When intermediate 7 was treated with nucleophiles, the
desired products 8 were obtained (Table 3). The reaction
proceeded with nearly quantitative yield when pyrrolidine
was used (Table 3, entry 1). On the other hand, aniline led

480 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Yang et al.
to lower yield of the final product 8b (Table 3, entry 2).
The reaction of compound 7 and ethanethiol with pyridine
as base yielded the desired product 8c (55%) and reduction
product 6c (37%) (Table 3, entry 3). The reaction of 7 with
benzyl mercaptan generated compound 8d in 87% yield
without reduction product 6c (Table 3, entry 4). Butan-1-ol
as the nucleophile yielded product 8e in good yield (Table
3, entry 7). The weak nucleophile phenol also gave the
desired product 8f (Table 3, entry 6). These reactions
demonstrated the feasibility of the proposed transformations
of phenylthio group to increase the structural diversity.
In an attempt to expand the scope of this reaction to other
olefins and alkynes, pyrimidines 3h and 3i were synthesized
as depicted in Scheme 3.17 However, neither 3h nor 3i
produced the desired products under the above reaction
conditions. In the reaction with aniline in refluxing CH3CN,
substrate 3h decomposed. Substrate 3i was recovered after
refluxing for 2 h with aniline in CH3CN. These results are
likely due to the lack of reactivity of the dienophiles and
consistent with those of the similar molecular systems
reported in the literature.18
Acknowledgment. This work was supported by Ph.D.
Programs Foundation of Ministry of Education of China
20070183038, National Key Research Program on Drug
Discovery Grants of China 2009ZX09501-010, and
Changchun Discovery Sciences, Ltd.
Supporting Information Available. Detailed experimen-
tal procedures and compound characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
References and Notes
(1) For examples, see: (a) Nefzi, A.; Ostresh, J. M.; Houghten,
R. A. Chem. ReV. 1997, 97, 449–472. (b) Dolle, R. E.;
Bourdonnec, B. L.; Goodman, A. J.; Morales, G. A.; Thomas,
C. J.; Zhang, W. J. Comb. Chem. 2008, 10, 753–802. (c) Dolle,
R. E.; Bourdonnec, B. L.; Goodman, A. J.; Morales, G. A.;
Salvino, J. M.; Zhang, W. J. Comb. Chem. 2007, 9, 855–
902. (d) Dolle, R. E. J. Comb. Chem. 2005, 7, 739–798.
(2) (a) O’Yang, C.; Schoenfeld, R. C. U.S. Patent 7,307,082
(2007). (b) Huang, H.; Hutta, D. A.; Hu, H.; DesJarlais, R. L.;
Schubert, C.; Petrounia, I. P.; Chaikin, M. A.; Manthey, C. L.;
Player, M. R. Bioorg. Med. Chem. Lett. 2008, 18, 2355–2361.
(c) Trumpp-Kallmeyer, S.; Rubin, J. R.; Humblet, C.; Hamby, J. M.;
Showalter, H. D. H. J. Med. Chem. 1998, 41, 1752–1763.
(3) (a) Jaton, J.-C.; Roulin, K.; Rose, K.; Sirotnak, F. M.;
Lewenstein, A.; Brunner, G.; Fankhauser, C. P.; Burger, U.
J. Nat. Prod. 1997, 60, 356–360. (b) Morimoto, Y.; Matsuda,
F.; Shirahama, H. Tetrahedron 1996, 52, 10609–10630.
(4) (a) Wolf, M.; Diebold, J. L. U.S. Patent 3,647,800 (1972).
(b) Wolf, M.; Diebold, J. L. U.S. Patent 3,637,706 (1972).
(c) Wolf, M.; Diebold, J. L. U.S. Patent 3,674,790 (1972).
(5) (a) Wilton, J. H.; Cheney, D. C.; Hokanson, G. C.; French,
J. C.; Cun-heng, H.; Clardy, J. J. Org. Chem. 1985, 50, 3936–
3938. (b) Ku¨nzel, E.; Faust, B.; Oelkers, C.; Weissbach, U.;
Bearden, D. W.; Weitnauer, G.; Westrich, L.; Bechthold, A.;
Rohr, J. J. Am. Chem. Soc. 1999, 121, 11058–11062. (c)
Larsen, D. S.; O’Shea, M. D. J. Org. Chem. 1996, 61, 5681–
5683. (d) Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 9, 103–
137. (e) Ohmori, K.; Mori, K.; Ishikawa, Y.; Tsuruta, H.;
Kuwahara, S.; Harada, N.; Suzuki, K. Angew. Chem., Int. Ed.
2004, 43, 3167–3171.
Conclusion
In conclusion, a novel pyrimidine-fused tetracyclic scaffold
was designed and synthesized by a methodology involving
the intramolecular inverse electron demand hetero-Diels-Alder
reaction of an imine or iminium ion formed in situ from
N-allylaminopyrimidinealdehyde with suitable primary or
secondary aryl amines. The reactions yielded exclusively cis-
configured products in good to excellent yields and are simple
in operation. Further transformations of the phenylthio group
in this tetracyclic scaffold were demonstrated by an oxidation
and subsequent nucleophilic substitution sequence. This
method provides convenient access to a library of structurally
diversified compounds for drug discovery.
Experimental Section
(6) Kiselyov, A. S. Tetrahedron Lett. 2005, 46, 1177–1179.
(7) Boger, D. L.; Kochanny, M. J. J. Org. Chem. 1994, 59, 4950–
4955.
General Procedure for the Synthesis of Hexahydroben-
zo[b]pyrimido[4,5-h][1,6]naphthyridines 6. To a solution
of 3c (143 mg, 0.5 mmol) and aniline (0.048 mL, 0.525
mmol) in CH3CN (2 mL) and water (2 mL) was added a
solution of TFA (0.075 mL, 1.0 mmol). The reaction mixture
was stirred for 11 h at 25 °C. The precipitate was filtered
and washed with ethanol to give the desired product 6c. The
filtrate was diluted with 20 mL of water and extracted with
EtOAc (4 × 8 mL). The organic phase was washed with
brine, dried over anhydrous MgSO4, concentrated in vacuo,
and purified by flash chromatography to give the product
6c. The combined product weighed 169 mg (94% yield). 1H
NMR (CDCl3, δ): 8.28 (s, 1H), 7.56-7.52 (m, 2H),
7.43-7.39 (m, 3H), 7.06-7.00 (m, 2H), 6.68 (t, J ) 7.2
Hz, 1H), 6.51 (d, J ) 7.8 Hz, 1H), 4.75 (d, J ) 2.4 Hz,
1H), 3.92 (s, 1H), 3.56 (t, J ) 12.3 Hz, 1H), 3.30 (dd, J1 )
6.3 Hz, J2 ) 17.1 Hz, 1H), 3.16 (s, 3H), 3.12 (dd, J1 ) 4.8
Hz, J2 ) 12.6 Hz, 1H), 2.62 (d, J ) 17.1 Hz, 1H), 2.47 (m,
1H); 13C NMR (CDCl3, δ): 162.88, 157.66, 157.27, 141.53,
134.84, 129.73, 129.35, 128.99, 127.62, 118.24, 118.12,
114.76, 111.32, 90.60, 49.65, 47.52, 36.30, 29.24, 28.77; MS
(ESI): m/z 361.1 [M + H+].
(8) (a) Yang, J.; Che, X.; Dang, Q.; Wei, Z.; Gao, S.; Bai, X.
Org. Lett. 2005, 7, 1541–1543. (b) Fu, R.; Xu, X.; Dang, Q.;
Bai, X. J. Org. Chem. 2005, 70, 10810–10816. (c) Zheng,
L.; Xiang, J.; Dang, Q.; Guo, S.; Bai, X. J. Comb. Chem.
2005, 7, 813–815. (d) Liu, J.; Dang, Q.; Wei, Z.; Zhang, H.;
Bai, X. J. Comb. Chem. 2005, 7, 627–636. (e) Yang, J.; Dang,
Q.; Liu, J.; Wei, Z.; Wu, J.; Bai, X. J. Comb. Chem. 2005, 7,
474–482. (f) Che, X.; Zheng, L.; Dang, Q.; Bai, X. Tetrahe-
dron 2006, 62, 2563–2568. (g) Xiang, J.; Zheng, L.; Chen,
F.; Dang, Q.; Bai, X. Org. Lett. 2007, 9, 765–767. (h) Zheng,
L.; Yang, F.; Dang, Q.; Bai, X. Org. Lett. 2008, 10, 889–
892. (i) Che, X.; Zheng, L.; Dang, Q.; Bai, X. J. Org. Chem.
2008, 73, 1147–1149.
(9) Reviews: (a) Boger, D. L.; Weinreb, S. M. Hetero Diels-Alder
Methodology in Organic Synthesis; Academic: Orlando, 1987;
Chapters 2 and 9. . (b) Kouznetsov, V. V. Tetrahedron 2009,
65, 2721–2750. (c) Povarov, L. S. Russ. Chem. ReV. 1967,
36, 656–670. (d) Buonora, P.; Olsen, J.-C.; Oh, T. Tetrahe-
dron. 2001, 57, 6099–6138.
(10) (a) Stevenson, G. I.; Leeson, P. D.; Rowley, M.; Sanderson,
I.; Stansfield, I. Bioorg. Med. Chem. Lett. 1992, 2, 371–374.
(b) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc.
2006, 128, 13070–13071. (c) Zhang, W.; Guo, Y.; Liu, Z.;
Jin, X.; Yang, L.; Liu, Z.-L. Tetrahedron 2005, 61, 1325–

Synthesis of Hexahydrobenzo[b]pyrimido[4,5-h][1,6]naphthyridines
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 481
1333. (d) Gaddam, V.; Nagarajan, R. Tetrahedron Lett. 2007,
48, 7335–7338. (e) Kouznetsov, V. V.; Ochoa Puentes, C.;
Boho´rquez Romero, A. R.; Zacchino, S. A.; Sortino, M.;
Gupta, M.; Va´zquez, Y.; Bahsas, A.; Amaro-Luis, J. Lett.
Org. Chem. 2006, 3, 300–304. (f) Damon, D. B.; Dugger,
R. W.; Magnus-Aryitey, G.; Ruggeri, R. B.; Wester, R. T.;
Tu, M.; Abramov, Y. Org. Process. Res. DeV. 2006, 10, 464–
471.
(14) (a) Tietze, L. F.; Brumby, T.; Pretor, M.; Remberg, G. J. Org.
Chem. 1988, 53, 810–820. (b) Iafe, R. G.; Houk, K. N. J.
Org. Chem. 2008, 73, 2679–2686.
(15) (a) Hartikka, A.; Hojabri, L.; Bose, P. P.; Arvidsson, P. I.
Tetrahedron: Asymmetry 2009, 20, 1871–1876. (b) Savitha,
G.; Perumal, P. T. Tetrahedron Lett. 2006, 47, 3589–3593.
(16) Muhuhi, J.; Spaller, M. R. J. Org. Chem. 2006, 71, 5515–
5526.
(11) Gomtsyan, A.; Didomenico, S.; Lee, C.-H.; Matulenko, M. A.;
Kim, K.; Kowaluk, E. A.; Wismer, C. T.; Mikusa, J.; Yu, H.;
Kohlhaas, K.; Jarvis, M. F.; Bhagwat, S. S. J. Med. Chem.
2002, 45, 3639–3648.
(12) Jones, W.; Kiselyov, A. S. Tetrahedron Lett. 2000, 41, 2309–
2312.
(17) See the Supporting Information for the experimental de-
tails.
(18) (a) Jones, W.; Kiselyov, A. S. Tetrahedron Lett. 2000, 41,
2309–2312. (b) Soenen, D. R.; Zimpleman, J. M.; Boger, D. L.
J. Org. Chem. 2003, 68, 3593–3598.
(13) Sabitha, G.; Reddy, E. V.; Maruthi, C.; Yadav, J. S. Tetra-
hedron Lett. 2002, 43, 1573–1575.
CC100018B