Synthesis of novel pyrimidine fused 8-membered heterocycles via iminium ion cyclization reactions

Article abstract of DOI:10.1021/jo7020746

(Chemical Equation Presented) Novel tricyclic pyrimidine-fused 8-membered heterocycles were prepared by an iminium ion cyclization using pyrimidinediamine systems with electron-rich aromatic rings.

Full text of DOI:10.1021/jo7020746

Synthesis of Novel Pyrimidine Fused 8-Membered
Heterocycles via Iminium Ion Cyclization
Reactions
Xin Che, Lianyou Zheng, Qun Dang, and Xu Bai*
The Center for Combinatorial Chemistry and Drug DiscoVery,
Jilin UniVersity, 75 Haiwai Street, Changchun,
Jilin 130012, P. R. China
Pyrimidine is a key structural component in life molecules,
and its derivatives are considered privileged structures in
medicinal chemistry.7 It is therefore logical to explore the
utilities of pyrimidine-fused 8-membered heterocycles in chemi-
cal biology and medicinal chemistry. Recently, we reported a
series of methodologies for the efficient synthesis of various
novel tricyclic and tetracyclic scaffolds consisting of various
pyrimidine-fused heterocycles.8 For example, novel pyrimidine-
fused benzodiazepines are prepared via a Pictet-Spengler-type
cyclization.8a As part of an ongoing endeavor to create novel
heterocyclic scaffolds, we have explored applications of iminium
ion cyclization reactions to the synthesis of pyrimidine-fused
8-membered heterocycles (eq 1). Herein, we report the prelimi-
nary results from studies of this synthetic strategy, which is an
efficient entry to unusual tricyclic systems consisting of an
8-membered heterocyclic ring.
xbai@jlu.edu.cn
ReceiVed September 21, 2007
Novel tricyclic pyrimidine-fused 8-membered heterocycles
were prepared by an iminium ion cyclization using pyrim-
idinediamine systems with electron-rich aromatic rings.
The search for novel compound libraries with potential
biological activities is a major focus for chemical biology and
medicinal chemistry. Therefore, efficient methodologies to
access small molecules of privileged structures are of special
interest.1 Natural products are generated via an evolutionary
selection process and represent the biologically relevant and
prevalidated fractions of chemical spaces explored by nature.
Waldmann et al. conducted a quantitative analysis of natural
product scaffolds and showed that the ones with three rings are
most often found in natural products.2 8-Membered nitrogen-
containing heterocycles are among the natural products that
exhibit important pharmacological effects.3 For example, 9-decyl
benzolactam-V8 was a potent PKC activator similar to the
teleocidins,4 and buflavine is shown to possess interesting
adrenolytic and anti-serotonin activities.5 However, 8-membered
rings are generally more difficult to prepare due to their
associated torsional, transannular, large-angle strain and the high
activation energy needed for the ring closure.6
The pyrimidines (2a,b) required for this study were readily
prepared from commercially available 4,6-dichloro-5-nitropy-
rimidine or 5-amino-4,6-dichloropyrimidine as outlined in
Scheme 1.9
Initially, the cyclization reaction of pyrimidine 2a with
p-nitrobenzaldehyde (eq 1) was investigated under trifluoroacetic
acid (TFA) conditions, which proceeded smoothly to give the
desired product 4-chloropyrimido[b,f][1,5]benzodiazocine 3a in
86% yield (entry 1, Table 1). The structure of compound 3a
was unequivocally assigned through an X-ray diffraction
analysis (details available in the Supporting Information), which
indicates the formation of the 8-membered ring system. The
scope of this cyclization reaction was then explored with other
aldehydes, and the results are summarized in Table 1. In general,
these reactions produced the desired 4-chloropyrimido[b,f][1,5]-
benzodiazocines 3 in moderate to good yields.
(1) (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson,
P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.;
Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235-
2246. (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. ReV. 2003,
103, 893-930.
(2) Koch, M. A.; Schuffenhauer, A.; Scheck, M.; Wetzel, S.; Casaulta,
M.; Odermatt, A.; Ertl, P.; Waldmann, H. Proc. Natl. Acad. Sci. U.S.A.
2005, 102, 17272-17277.
(3) For example, see: (a) Vedejs, E.; Galante, R. J.; Goekjian, P. G. J.
Am. Chem. Soc. 1998, 120, 3613-3622. (b) Basil,B.; Coffee, E. C. J.; Gell,
D. L.; Maxwell, D. R.; Sheffield, D. J.; Wooldridge, K. R. H. J. Med. Chem.
1970, 13, 403-406. (c) Stillings, M. R.; Freeman, S.; Myers, P. L.;
Readhead, M. J.; Welbourn, A. P.; Rance, M. J.; Atkinson, D. C. J. Med.
Chem. 1985, 28, 225-233.
(6) (a) Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Org. Lett. 2005,
7, 2723. (b) Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Chem. Eur.
J. 2007, 13, 6452-6460. (c) Spring, D. R.; Krishnan, S.; Blackwell, H. E.;
Schreiber, S. L. J. Am. Chem. Soc. 2002, 124, 1354-1363. (d) Illuminati,
G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95-102.
(7) For example: (a) Yang, J.; Dang, Q.; Liu, J.; Wei, Z.; Wu, J.; Bai,
X. J. Comb. Chem. 2005, 7, 474-482. (b) Liu, J.; Dang, Q.; Wei, Z.; Zhang,
H.; Bai, X. J. Comb. Chem. 2005, 7, 627-636. (c) Dang, Q.; Gomez-Galeno,
J. E. J. Org. Chem. 2002, 67, 8703-8705. (d) Bhuyan, P.; Boruah, R. C.;
Sandhu, J. S. J. Org. Chem. 1990, 55, 568-571.
(8) (a) Che, X.; Zheng, L.; Dang, Q.; Bai, X. Tetrahedron 2006, 62,
2563-2568. (b) Zheng, L.; Xiang, J.; Dang, Q.; Guo, S.; Bai, X. J. Comb.
Chem. 2005, 7, 813-815. (c) Zheng, L.; Xiang, J.; Dang, Q.; Guo, S.; Bai,
X. J. Comb. Chem. 2006, 8, 381-387.
(9) Yang, J.; Che, X.; Dang, Q.; Wei, Z.; Gao, S.; Bai, X. Org. Lett.
2005, 7, 1541-1543.
(4) Endo, Y.; Ohno, M.; Hirano, M.; Itai, A.; Shudo, K. J. Am. Chem.
Soc. 1996, 118, 1841-1855.
(5) Viladomat, F.; Bastida, J. E.; Codina, C.; Campbell, W. E.; Mathee,
S. Phytochemistry 1995, 40, 307-311.
10.1021/jo7020746 CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/08/2008
J. Org. Chem. 2008, 73, 1147-1149
1147

TABLE 2. Optimization of Reaction Conditions for Conversion of
2b to 4aa
SCHEME 1. Synthesis of Substituted Pyrimidines
entry
TFA (equiv)
[2b] (mmol/mL)
T (°C)
yieldb (%)
1
2
3
4
5
6
7
8
excess
3
1
1
0.066
0.066
0.066
0.066
0.132
0.132
0.33
81
40
40
25
25
25
25
25
0
trace
43
59
61
64
70
81
1
0.1
0.1
0.1
TABLE 1. Synthesis of 4-Chloropyrimido[b,f][1,5]benzodiazocinesa
0.5
a All reactions were conducted under nitrogen with acetonitrile as the
solvent; 0.33 mmol of 2b. b Yields are based on pure products isolated by
flash chromatography.
TABLE 3. Synthesis of Pyrimidine-Fused Indolodiazocines (4a-h)a
entry
product
R
R1
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-Pr
n-Bu
Bn
p-NO2C6H4-
o-NO2C6H4-
m-NO2C6H4-
p-FC6H4-
p-NCC6H4-
Ph-
p-MeC6H4-
p-MeOC6H4-
m-MeOC6H4-
o-MeOC6H4-
3,5-di-MeOC6H4-
n-Pr-
12
12
12
12
12
12
5
7
4.5
7
7.5
1
1
12
2
12
12
12
86
54c
64
72
62
48
48
26d
66
32
64
59
64
72
51
79
73
90
entry
product
R1
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
p-NO2C6H4-
o-NO2C6H4-
m-NO2C6H4-
p-NCC6H4-
p-MeC6H4-
n-Pr-
3
3
3
3
73
73
76
72
71
86
83
80
3
0.33
0.33
2
Et
4g
4h
Et
HOOC-
2-thienyl
HOOC-
p-NO2C6H4-
p-NO2C6H4-
p-NO2C6H4-
a Reaction conditions: 2b (0.75 mmol, 1.0 equiv), R1CHO (1.5 equiv),
and TFA (10 mol %) in acetonitrile (1.5 mL), 25 °C. Yields are based on
pure products isolated by flash chromatography and not optimized.
a Reaction conditions: 2a (1.0 equiv), R1CHO (1.5-2.0 equiv), and TFA
(excess) in acetonitrile, reflux. b Yields are based on pure products isolated
by flash chromatography and unoptimized. c 8% imine intermediate was
also isolated. d 6% imine intermediate was also isolated.
The cyclization was also tested with pyrimidine 2b. When
2b and p-nitrobenzaldehyde were treated under the above
cyclization conditions, surprisingly no desired product was
detected by LC-MS (Table 2, entry 1). Given that indole is an
electron-rich heterocycle and may be liable under strong acidic
conditions, we decided to closely examine the reaction condi-
tions with regard to temperature, concentration, and the amount
of TFA. The results from the optimization of reaction conditions
are summarized in Table 2.
Reducing the amount of TFA to 3 equiv and lowering the
reaction temperature to 40 °C led to generation of the desired
product 4a (entry 2). Reduction of TFA to 1 equiv at 40 °C
increased the yield to 43% (entry 3). Further reducing the TFA
amount, lowering temperature, and increasing the substrate
concentration led to the optimized reaction conditions of 0.1
equiv of TFA, ambient temperature, and 0.5 M 2b (entries 4-8).
The optimized conditions were extended to a variety of
aldehydes, and the results are listed in Table 3. As shown in
Table 3, pyrimidine 2b reacted with various aldehydes to
produce the desired products 4 in excellent yields. When R1
was aliphatic (entries 6-8), the reaction proceeded faster and
the yield was higher compared to the ones with an aromatic
The results in Table 1 could be explained by a previously
proposed mechanism that entailed an intramolecular electrophilic
substitution of the benzene ring by an iminium ion intermediate.8a
The cyclization reaction with an aliphatic aldehyde (R1 ) n-Pr-,
Et-, or -COOH, entries 12, 13, and 15) proceeded faster
compared to those with an aromatic aldehyde (entries 1-11,
14, and 16-18).
When R1 was aromatic, an electron-withdrawing group (e.g.,
p-NO2-) should increase the electron deficiency of the carbonyl,
so to decrease the basicity of imine intermediate, therefore
reducing the capability to form an iminium ion which may in
turn slow down the intramolecular cyclization, while an aliphatic
aldehyde forms a more reactive iminium ion for electrophilic
substitution. This was supported by the fact that the reactions
with aromatic aldehydes bearing an electron-withdrawing group
were slower. Higher yields were obtained when electron-
withdrawing groups were present in aromatic aldehydes (e.g.,
3a, 3c, 3d).
1148 J. Org. Chem., Vol. 73, No. 3, 2008

1
183 °C; H NMR (300 MHz, CDCl3) δ 7.92 (s, 1H), 7.08-7.20
aldehyde (entries 1-5). On the other hand, when an aromatic
aldehyde was employed, the yield and the reaction rate were
not influenced by the electronic properties of its substituents
(entries 1, 4, and 5). In general, the cyclizations of substrate 2b
proceeded faster than those of substrate 2a (Table 3 vs Table
1).
(m, 3H), 7.03 (d, J ) 6.9 Hz, 2H), 6.42 (s, 2H), 6.14 (d, J ) 6.0
Hz, 1H), 5.30(br., 1H), 4.87 (d, J ) 15.6 Hz, 1H), 4.06 (br., 1H),
3.85 (s, 3H), 3.66 (s, 3H), 3.00 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 159.7, 158.5, 151.3, 141.9, 137.9, 128.1, 127.9, 127.2, 124.8,
119.5, 107.1, 98.2, 60.9, 56.0, 55.6, 55.5, 38.1. Anal. Calcd for
C21H21ClN4O2: C, 63.55; H, 5.33; N, 14.12. Found: C, 63.30; H,
5.23; N, 14.30.
General Procedure for 4-Chloropyrimido[b,f][1,5]indolo-
diazocines. Compound 2b (0.75 mmol), the appropriate aldehyde
(1.125 mmol), and TFA (10 mol %) were dissolved in CH3CN (1.5
mL), and the mixture was stirred at room temperature for 0.3-3 h.
After filtration and washing, the pure desired product 4 as a solid
was obtained. The filtrate was concentrated in vacuo, and purifica-
tion by flash chromatography on silica gel gave an additional part
of 4.
In conclusion, a new method was developed for the efficient
preparation of novel tricyclic pyrimidine-fused 8-membered
diazocines. Readily accessible pyrimidine derivatives and vari-
ous aldehydes are within the scope of this new method; an acid-
catalyzed iminium ion cyclization is introduced as the key step
of the synthetic sequence. Two types of diazocines (pyrimidine-
fused benzodiazocines and indolodiazocines) were readily
prepared with a wide variety of substituents being tolerated by
the mild reaction conditions. Application of this new method
to preparation of diverse libraries of new heterocyclic scaffolds
as useful tools in study of chemical biology and medicinal
chemistry is in progress and will be reported in due course.
4-Chloro-15-methyl-6-propylpyrimido[b,f][1,5]indolo-
diazocine (4f): white solid; yield 86% (elution with EtOAc/
petroleum ether ) 1:2); ES-MS 356.1 [(M + 1)+]; mp 178-
1
180 °C; H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.48 (d, J )
8.1 Hz, 1H), 7.20-7.31 (m, 2H), 7.10 (td, J ) 7.4, 1.5 Hz, 1H),
6.74 (d, J ) 15.3 Hz, 1H), 4.84-4.87 (m, 1H), 4.18 (d, J ) 15.6
Hz, 1H), 3.78 (s, 3H), 3.35 (s, 3H), 3.16 (br., 1H), 1.85-1.92 (m,
2H), 1.53-1.61 (m, 2H), 0.99 (t, J ) 7.5 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 161.2, 157.4, 153.3, 137.1, 131.9, 125.9, 124.0,
122.1, 119.3, 118.7, 114.9, 109.5, 57.2, 46.8, 41.0, 40.6, 29.5, 19.0,
14.2. Anal. Calcd for C19H22ClN5: C, 64.13; H, 6.23; N, 19.68.
Found: C, 64.27; H, 6.26; N, 19.76.
Experimental Section
General Procedure for the Synthesis of 4-Chloropyrimido-
[b,f][1,5]benzodiazocines 3. 5-Amino-6-chloro-4-N-methylbenzyl-
aminopyrimidine (2a) (0.65 mmol), the appropriate aldehyde (0.975
mmol), and TFA (0.6 mL) were dissolved in CH3CN (10.0 mL)
and stirred under reflux for 1-12 h. The reaction mixture was
concentrated in vacuo, diluted with EtOAc (15 mL), and washed
with saturated NaHCO3 (3 × 15 mL). The water layer was extracted
with EtOAc (3 × 10 mL). The combined EtOAc layer was washed
with brine, dried over anhydrous Na2SO4, concentrated in vacuo,
and purified by flash chromatography over silica gel to furnish the
cyclized product 3.
Acknowledgment. This work was supported by the National
Natural Science Foundation of China (20572032) and Chang-
chun Discovery Sciences, Ltd.
Supporting Information Available: Analytical data, spectro-
scopic data, copies of LC-MS, 1H and 13C NMR spectra of
products 3 and 4, and CIF files and crystallographic data of 3a
and 3l. This material is available free of charge via the Internet at
http://pubs.acs.org.
4-Chloro-7,9-dimethoxy-12-methyl-6-phenylpyrimido[b,f][1,5]-
benzodiazocine (3f): white solid; yield 48% (elution with EtOAc/
petroleum ether ) 1:2); ES-MS 396.8 [(M + 1)+]; mp 182-
JO7020746
J. Org. Chem, Vol. 73, No. 3, 2008 1149