Photochemical and thermal cyclizations of 4-(2-azidophenyl)-3,4- dihydropyrimidin-2-ones for the synthesis of 4-methylenepyrimidino[5,4-b]indol- 2-ones

Article abstract of DOI:10.1016/j.tetlet.2010.10.176

Photochemical and thermal cyclization of 4-(2-azidophenyl)-3,4- dihydropyrimidin-2-ones could afford fused indoles, such as 1,2,3a,9b- tetrahydro-4-methylenepyrimidino[5,4-b]indol-2-ones and 1,3,5,6,7a,12b- hexahydroquinazolino[9,4-b]indol-2,7-dione in hi

Full text of DOI:10.1016/j.tetlet.2010.10.176

Tetrahedron Letters 52 (2011) 192–195
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Photochemical and thermal cyclizations of 4-(2-azidophenyl)-3,4-dihydropyr-
imidin-2-ones for the synthesis of 4-methylenepyrimidino[5,4-b]indol-2-ones
⇑
Yu-wei Ren, Xuerui Wang, Weixia Wang, Bing Li, Zong-jun Shi, Wei Zhang
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2010
Revised 7 October 2010
Accepted 12 October 2010
Available online 11 November 2010
Photochemical and thermal cyclization of 4-(2-azidophenyl)-3,4-dihydropyrimidin-2-ones could afford
fused indoles, such as 1,2,3a,9b-tetrahydro-4-methylenepyrimidino[5,4-b]indol-2-ones and 1,3,5,6,7a,
12b-hexahydroquinazolino[9,4-b]indol-2,7-dione in high yields via nitrene electrophilic addition and
rearrangement reactions.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Photocyclization
Thermolysis
4-(2-Azidophenyl)-3,4-dihydropyrimidin-2-
ones
4-Methylenepyrimidino[5,4-b]indol-2-ones
The chemistry of organic azides has long attracted the attention
of chemists since their discovery more than a century ago.1 In par-
ticular, an increasing interest could be observed in the past two
decades due to their vast synthetic utility in conjunction with their
easy accessibility via various synthetic routes.2 The photoreaction
of organic azides are well known and are widely used in synthetic
organic chemistry,1–3 photolithography,3a and photoaffinity label-
ing of biopolymers.4 It is commonly believed that photolysis of
the organic azides could afford the very reactive singlet nitrenes
after releasing of molecule nitrogen. The intermolecular insertion
of nitrenes into C–H bonds or addition to double bonds generally
lead to nitrogen-containing heterocycles. For example, photolysis
of o-azidostyrenes afforded mainly indole derivatives via insertion
of a phenylnitrene into the b-carbon–H bond of an adjacent double
bond;1,2,5 and photolysis of o-azidophenyl substituted crotonates
produced aziridino[1,2-a]indoline via the addition of a phenylnit-
rene to double bonds.6 Comparatively, no report was found for
the investigation of photoreaction of 3-(o-azidophenyl)cycloalkene
in the literatures. As a continuance of our studies on the photore-
action of aryl azides with double bonds,7 we report herein a
concise and efficient synthesis of fused indoles, such as 1,2,3a,9b-
tetrahydro-4-methylenepyrimidino[5,4-b]indol-2-ones, 1,3,5,6,7a,
12b-hexahydroquinazolino[9,4-b]indol-2,7-dione by the photo-
chemical or thermal cyclization of 4-(2-azidophenyl)-3,4-dihydro-
pyrimidin-2-ones (1a–j) as shown in Scheme 1.
Pyrimidino[5,4-b]indoles and quinazolino[9,4-b]indoles are well
known for their potential biological and pharmacological activities,8
such as analgesic, anti-allergy, bactericide, anti-infective, antihyper-
tensive, anti-inflammatory, and antitumor activities and can be used
as blood platelet aggregation inhibitors, gastric cancer inhibitors,
HIV-1 RT inhibitors, ulcer inhibitors, virucidal and neoplasm inhib-
itors, and vasodilators. So several other methods have also been
established for the synthesis of the similar fused aromatic com-
pounds. For example, cyclocondensation of N-[3-(2-ethoxycar-
bonyl)indolyl]urea to give pyrimido[5,4-b]indolo-2,4-dione;8a
cyclocondensation of N-[3-(2-ethoxycarbonyl)indolyl] amidines
withaminesto give pyrimido[5,4-b]indolo-2-one.8b Cyclocondensa-
tion of N-[3-(2-ethoxycarbonyl)indolyl]thiourea to give 2-thiopy-
rimido[5,4-b]indolo-2,4-dione.8d
Ten 4-(2-azidophenyl)-3,4-dihydropyrimidin-2-ones (1a–j)
were prepared from 2-azidobenzaldehyde, 1,3-dicarbonyls, and
urea or 1,3-dimethylurea or thiourea by the Biginelli reactions.9
We first investigated the reactions of 4-(2-azidophenyl)-3,4-dihy-
dropyrimidin-2-one (1a) under different conditions (Table 1). The
N3
H
N
NH
COR2
R3
hv, DMDO, rt
R1
X
R1
X
COR2
N
or DMF, reflux
N
R1
CH2R3
N
R1
⇑
Corresponding author. Tel.: +86 931 358 8553; fax: +86 931 891 2582.
E-mail address: zhangwei6275@lzu.edu.cn (W. Zhang).
Scheme 1. Photochemical and thermal cyclizations of 4-(2-azidophenyl)-3,4-
dihydropyrimidin-2-ones 1a–j.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.176

Y. Ren et al. / Tetrahedron Letters 52 (2011) 192–195
193
Table 1
under different conditions. When the thermal reaction was per-
formed in refluxing xylene, the unsatisfactory result was obtained
as listed in Table 1 probably because of the low solubility of 1a in
xylene and low temperature of refluxing xylene. The conversion
and yield could be increased after the addition of DMSO to the xy-
lene and long-time refluxing. Then the thermal reaction was tried
in DMSO at 160 °C, an improved result was obtained. The best
result was obtained from the thermolysis of 1a in refluxing
N,N-dimethylformaide (DMF). So the cyclization reactions of all
other 4-(2-azidophenyl)-3,4-dihydropyrimidin-2-ones were inves-
tigated under both irradiation in DMSO at room temperature and
thermolysis in DMF under refluxing.
Photochemical and thermal cyclizations of 4-(2-azidophenyl)-3,4-dihydropyrimidin-
2-one (1a) under different conditions
N3
hv, rt
or
H
N
NH
CO2Et
H
O
H
O
CO2Et
N
N
N
CH3
H
H
1a
2a
Entry Solvents
Reaction
conditions
t
(h)
Convna
(%)
Yieldb
(%)
The photoreactions of other nine 4-(2-azidophenyl)-3,4-dihy-
dropyrimidin-2-ones (1b–j) were all conducted under selected
reaction conditions for 5–6 h and the expected 1,2,3a,9b-tetrahy-
dro-4-methylenepyrimidino[5,4-b]indol-3-ones or 1,3,5,6,7a,12b-
hexahydroquinazolino[9,4-b]indol-2,7-dione (2b–j) were obtained
as the major products in all cases (Table 2). All products were fully
identified by 1H NMR, 13C NMR and MS,10 and the structure of 2b
was further confirmed by the X-ray crystal analysis as depicted
in Figure 1.11 The thermal reactions of seven selected substrates
were conducted in refluxing DMF, the same products as those ob-
tained in photoreactions were obtained as major products and the
results were also listed in Table 2. Obviously the photolytic process
was a little more facile than the thermal process in yields of
products.
1
2
3
4
5
6
CH3COCH3
CH2Cl2
CH3CN
DMSO
Xylene
Xylene–DMSO (5:1,
v/v)
DMSO
DMF
hv, rt
hv, rt
hv, rt
hv, rt
Reflux
Reflux
5
6
5
6
24
24
92
87
92
98
55
72
46
55
46
82
40
62
7
8
160 °C
Reflux
12
8
87
98
65
78
a
Conversion was calculated on the basis of 1a.
Yield of isolated product based on consumed 1a.
b
photoreactions of 1a in different solvents, such as acetone, dichlo-
romethane, and acetonitrile were examined, but the conversion of
1a was much lower because 1a was difficultly dissolved in these
solvents. When DMSO was used as the solvent instead, it was
found the conversion of 1a was increased greatly under irradiation
at k >300 nm for certain time and 2a was obtained as the sole prod-
uct in high yield. Then, we examined the thermal reaction of 1a
A mechanism is proposed for the transformation of 4-(2-azid-
ophenyl)-3,4-dihydropyrimidin-2-ones (1a) into fused indoles
1,2,3a,9b-tetrahydro-4-methylenepyrimidino[5,4-b]indol-3-one
(2a) under both photolytic and thermal reaction conditions as
Table 2
Photochemical and thermal cyclizations of 4-(2-azidophenyl)-3,4-dihydropyrimidin-2-one (1a–j)
Entry
Reactants
t (h)
Products
Yield (%)
hva
Db
hva
Db
N3
CO2Et
NH
CO Et
1a
2a
1
6
8
82
78
HN
HN
HN
2
N
H
O
N
H
O
N3
NH
COCH3
1b
1c
1d
2b
2c
2d
2
3
6
6
8
8
78
80
75
81
COCH3
HN
O
N
H
N
H
O
N3
NH
COPh
COPh
HN
HN
N
H
O
N
H
O
N3
CO2Et
NH
4
5
5
5
8
8
HN
85
85
72
80
HN
CO Et
2
N
H
O
N
CO2Et
O
H
CO Et
2
N
3
O
NH
O
1e
2e
HN
HN
N
H
N
H
O
O
(continued on next page)

194
Y. Ren et al. / Tetrahedron Letters 52 (2011) 192–195
Table 2 (continued)
Entry
Reactants
t (h)
Products
Yield (%)
hva
Db
hva
Db
N
3
O
NH
1f
O
2f
6
5
—
75
—
HN
HN
N
H
O
N
H
O
N3
NH
1g
1h
2g
2h
7
8
6
6
—
8
76
80
—
CO2Et
HN
HN
CO2Et
N
H
N
H
S
S
N3
O
NH
O
74
HN
HN
N
H
S
N
H
S
N3
CO2Et
NH
2i
2j
9
1i
1j
6
5
—
85
86
—
N
N
CO2Et
N
O
N
O
N
3
O
NH
O
10
8
84
N
N
N
O
N
O
a
Photolysis was carried out under irradiation of 500 W medium pressure Hg lamp in DMSO at room temperatures.
Thermolysis was carried out in DMF under refluxing.
b
_
N3
N:
hv
H
N
CO2Et
HN
CO2Et
HN
+
HN
CO2Et
CH2
N
O
O
N
H
O
N
H
H
H
I
1a
II
H
NH
CO2Et
HN
N
H
O
2a
Scheme 2. Proposed mechanism for the photocyclization of 1a.
Figure 1. X-ray crystal structure of 2b.
[5,4-b]indol-2-ones and 1,3,5,6,7a,12b-hexahydroquinazolino[9,4-
b]indol-2,7-dione in high yields via photochemical or thermal reac-
tion of 4-(2-azidophenyl)-3,4-dihydropyrimidin-2-ones (1a–j) has
been developed. The photolytic process is a little more facile than
the thermal process.
depicted in Scheme 2. Photolysis or thermolysis of 1a expels N2 to
produce a nitrene intermediate, and the cyclization occurs via nit-
rene I electrophilic attacking onto the
a-position of the adjacent
double bond of b-aminoacrylate to form a zwitterion II and subse-
quently the shift of a proton from methyl group to the nitrogen an-
ion to give the product 2a.
Acknowledgment
We thank the National Natural Science Foundation of China
(Grant no. 20872056 and J0730425) for financial support.
In conclusion, an efficient method for the synthesis of fused
indoles, such as 1,2,3a,9b-tetrahydro-4-methylenepyrimidino

Y. Ren et al. / Tetrahedron Letters 52 (2011) 192–195
195
Santagati, M.; Scolaro, L. Monsu; Russo, F. Eur. J. Med. Chem. 1997, 32, 973; (e)
Santagati, N. A.; Caruso, A.; Cutuli, V. M. C.; Caccamo, F. Farmaco 1995, 50, 689;
(f) Monge, A.; Martinez-Crespo, F. J.; Aranzazu Villanueva, M.; Font, M.;
Santiageo, E.; Martinez de Irujo, J. J.; Alberdi, E.; Lopez-Unzu, M. J.;
Cenarruzabeitia, E. Arch. Pharm. 1993, 326, 879; (g) Russo, F.; Romeo, G.;
Guccione, S.; De Blasi, A. J. Med. Chem. 1991, 34, 1850.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.176.
9. (a) Sabitha, G.; Kumar Reddy, G. S. K.; Reddy, Ch. S.; Yadav, J. S. Synlett 2003,
858; (b) Ryabukhin, S. V.; Plaskon, A. S.; Ostapchuk, E. N.; Volochnyuk, D. M.;
Tolmachev, A. A. Synthesis 2007, 417.
References and notes
10. General procedure for the photochemical reactions: to 40 mL DMSO was added
2.0 mmol 1a. The solution was distributed into two 25 mL Pyrex tubes and
1. (a) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36, 1249; (b) Gritsan, N.
P.; Platz, M. S. Chem. Rev. 2006, 106, 3844; (c) Braese, S.; Gil, C.; Knepper, K.;
Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188; (d) Scriven, E. F.;
Turnbull, V. K. Chem. Rev. 1988, 88, 297.
2. (a) Minozzi, M.; Nanni, D.; Spagnolo, P. Chem. Eur. J. 2009, 15, 7830; (b) Lang, S.;
Murphy, J. A. Chem. Soc. Rev. 2005, 35, 146; (c)Organic Azides: Syntheses and
Applications; Bräse, S., Banert, K., Eds.; John Wiley and Sons Ltd: West Sussex,
UK, 2001; (d) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,
40, 2004.
3. (a)Azides and Nitrenes—Reactivity and Utility; Scriven, E. F. V., Ed.; Academic
Press: New York, 1984; (b)The Chemistry of Halides, Pseudo—Halides and Azides,
Part 1and 2; Patai, S., Ed.; John Wiley and Sons, Ltd: Chichester, 1995.
4. Bayley, H. Photogenerated Reagents in Biochemistry and Molecular Biology;
Elsevier: New York, 1983; (b) Wang, J. F.; Downs, W. D.; Cech, T. R. Science
1993, 260, 504.
5. (a) Condie, G. C.; Channon, M. F.; Ivory, A. J.; Kumar, N.; Black, StC. D.
Tetrahedron 2005, 61, 4989; (b) Fresneda, P. M.; Molina, P. J.; Bleda, A.
Tetrahedron 2001, 57, 2355; (c) Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett.
1997, 38, 5603; (d) Fresneda, P. M.; Molina, P. S.; Angeles Saez, M. Synlett 1999,
1651; (e) Kaszynski, P.; Dougherty, D. A. J. Org. Chem. 1993, 58, 5209; (f) Smith,
P. A. S.; Rowe, C. D.; Hansen, D. W. Tetrahedron Lett. 1983, 24, 5169; (g) Garanti,
L.; Zecchi, G. J. Org. Chem. 1980, 45, 4767; (h) Gairns, R. S.; Moody, C. J.; Rees, C.
W. J. Chem. Soc., Perkin Trans. 1 1986, 501.
6. (a) Morimoto, Y.; Matsuda, F.; Shimhama, H. Tetrahedron 1996, 52, 10609; (b)
Morimoto, Y.; Matsuda, F.; Shirahama, H. Tetrahedron Lett. 1990, 31, 6031.
7. Shi, Z.; Ren, Y.; Li, B.; Lu, S.; Zhang, W. Chem. Commun 2010, 46, 3973.
8. (a) Giuseppe, R.; Luisa, M.; Gabriella, M.; Maria, M.; Valeria, P.; Loredana, S.;
Angela, S. M.; Michela, B.; Piero, A.; Kenneth, P. M. Bioorg. Med. Chem. Lett. 2006,
16, 6200; (b) Giuseppe, R.; Luisa, M.; Fabrizio, M.; Alfredo, C.; Tiziana, M.;
Ferdinando, N.; Maurizio, B.; Filippo, R.; Kenneth, P. M. J. Med. Chem. 2003, 46,
2877; (c) Merino, I.; Monge, A.; Font, M.; Martinez de Irujo, J. J.; Alberdi, E.;
Santiago, E.; Prieto, I.; Lasarte, J. J.; Sarobe, P.; Borras, F. Farmaco 1999, 54, 255;
(d) Santagati, A.; Longmore, J.; Guccione, S.; Langer, T.; Tonnel, E.; Modica, M.;
irradiated with
a medium-pressure mercury lamp (500 W) at ambient
temperature for appropriate time. The progree of the reaction was monitored
by TLC at regular intervals. After 1a were disappeared, the solvent removed in
vacuo. The crude product was separated by silica gel column chromatography
eluted with hexane/acetone 5:1 (v/v) to afford 2a and further purified by
recrystallization from ethanol.
Ethyl 4-methylene-2-oxo-2,3,4,4a,5,9b-hexahydro-1H-pyrimido[5,4-b]indole-
4a-1carboxylate (2a): yellow solid; 1H NMR (400 MHz, DMSO-d6): d 1.95 (t, 3H,
J = 7.2 Hz), 4.16 (q, 2H, J = 7.2 Hz), 4.36 (d, 2H, J = 9.6 Hz), 4.89 (d, 1H,
J = 3.2 Hz), 6.61 (d, 1H, J = 8.0 Hz), 6.27–6.67 (t, 1H, J = 7.6 Hz), 6.79 (s, 1H),
7.02 (t, 1H, J = 7.6 Hz), 7.10 (d, 1H, J = 7.2 Hz), 7.49 (s, 1H), 8.97 (s, 1H); 13C NMR
(100.6 MHz, DMSO-d6): d 13.87, 57.4, 61.5, 67.3, 89.8, 109.3, 118.2, 123.7,
128.1, 128.8, 141.7, 148.1, 151.6, 170.8; LC–MS (ESI): m/z requires 273, found
([M+H+], 274); ESI-HRMS: m/z calcd for C14H15N3O3 + H+ (M+H+): 274.1186,
found: 274.1182.
1,3,5,6,7a,12b-Hexahydroquinazolino[9,4-b]indol-2,7-dione (2e) yellow solid;
1H NMR (400 MHz, DMSO-d6): d 2.24–2.31 (m, 1H), 2.32–2.42 (m, 1H), 2.53–
2.61 (m, 1H), 3.14–3.21 (m, 1H), 4.94 (s, 1H), 5.27 (t, 1H, J = 4.4 Hz), 6.48 (d, 1H,
J = 7.6 Hz), 6.63 (t, 1H, J = 7.6 Hz), 7.10 (d, 1H, J = 7.2 Hz), 7.62 (s, 1H), 9.00 (s,
1H); 13C NMR (100.6 MHz, DMSO-d6): d 25.4, 56.3, 72.4, 90.0, 109.36, 118.3,
123.5, 128.5, 128.6, 141.9, 147.9, 151.6, 204.4; LC–MS (ESI): m/z requires 255,
found ([M+H+], 256); ESI-HRMS: m/z calcd for C14H13N3O2 + H+ (M+H+):
256.1081, found: 256.1076.
11. Crystal data for compound 2b (recrystallized from ethanol).
Mr = 243.26. Orthorhombic, a = 7.3985(16) Å, b = 11.859(3) Å, c = 26.749(6) Å,
b = 90.00, V = 2346.9(9) Å3, yellow plates, = 1.377 g cmÀ3, T = 296(2) K, space
group P2 (1)/c, Z = 4, 2hmax = 51.0°, 17008
(Mo K ) = 0.71073 mmÀ1
C13H13N3O2,
q
l
,
a
reflections measured, 4349 unique (Rint = 0.0757) which were used in all
calculation. The final wR(F2) was 0.1543 (for all data), R1 = 0.0676. CCDC file no.
776808.