Regioselective N-nitrosation of dihydropyrimidinones with nitric oxide

Article abstract of DOI:10.1016/j.tetlet.2007.12.035

N-Nitrosation of dihydropyrimidinones with nitric oxide occurred regioselectively, giving the corresponding N(3)-nitrosamides in high yields. The reaction most likely took place by a nucleophilic attack. Aprotic and polar solvents, such as CH₃C

Full text of DOI:10.1016/j.tetlet.2007.12.035

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Tetrahedron Letters 49 (2008) 1220–1222
Regioselective N-nitrosation of dihydropyrimidinones with nitric oxide
Yinglin Shen, Qiang Liu, Guaili Wu, Longmin Wu *
State Key Laboratory of Applied Organic Chemistry, Department of Nuclear Science and Technology, Lanzhou University, Lanzhou 730000, PR China
Received 17 October 2007; revised 5 December 2007; accepted 7 December 2007
Available online 14 December 2007
Abstract
N-Nitrosation of dihydropyrimidinones with nitric oxide occurred regioselectively, giving the corresponding N(3)-nitrosamides in high
yields. The reaction most likely took place by a nucleophilic attack. Aprotic and polar solvents, such as CH3CN and tetrahydrofurane
(THF) greatly favored the reaction, whereas protic solvents with high dielectric constant, such as CH3OH and water, disfavored it.
Ó 2007 Elsevier Ltd. All rights reserved.
N-Nitroso compounds, in general, possess intriguing
properties with an impact on medicine and biochemistry.1
As such, it seems to be important to understand the forma-
tion mechanism for N-nitrosamines/amides. These com-
pounds are traditionally prepared by the reaction of
secondary amines/amides with nitrous acid formed in situ
in aqueous acidic media,2,3 where nitrosonium ion
(H2ONO+, protonated nitrous acid) nitrosates secondary
amines/amides via a series of proton/nitrosonium transfers.
New approaches for the N-nitrosation of secondary and
tertiary amines and amides using the complex
[NO+ꢀCrownꢀH(NO3)ꢁ], a mixture of tin(IV) chloride and
sodium nitrate, and PVP–N2O4 were reported.4
In conjunction with our continuing interest in reactions
of nitric oxide (NO) with various organic molecules,5 we
recently found that NO nitrosated one of the secondary
N-amido groups of dihydropyrimidinones, in which there
were two different kinds of secondary N-amido groups, in
high regioselectivity and in high yield. Itoh et al. studied
the reaction of nitric oxide with amines6 and amides7 and
different products were obtained. The reaction mechanism
was assumed to be an N2O3-mediated hydrogen abstrac-
tion from the NH group. Calculations on the N-nitrosation
of amines by NO2 and NO, respectively, in various media
such as alkaline solution, lipid, and gas phase suggested a
free radical mechanism, in which NO2 abstracted a hydro-
gen atom from the nitrogen of primary/secondary amines
to form an intermediate complex of an aminyl radical
and nitrous acid. The aminyl radical was then quenched
by nitric oxide, leading to the formation of nitrosamine.8
In the present work, yet, the reaction mechanism seems
to take place by a nucleophilic attack of the nitrogen of
an amine on N2O3.
In a typical procedure, 0.25 mmol of 1, which was pre-
pared following the method described in Ref. 9, was dis-
solved in 40 mL of dry CH3CN at ambient temperature.
The resulting solution was then degassed for 20 min. NO
was carried by argon and purified by passing it through a
series of scrubbing flasks containing 4 M NaOH, distilled
water, and CaCl2 in this order. Purified NO was bubbled
through the stirred stock solution. In 3–5 h, after comple-
tion of the reaction, as indicated by TLC, evaporation of
solvent gave almost pure product 2 in high yield (Scheme
1). Product 2 was further purified by column chromato-
graphy on silica gel and characterized by 1H and 13C
NMR, MS, HRMS, and 1D NOE experiments with
comparison to those of the mother molecules.10 No side
product was detected. The results are listed in Table 1.
Table 1 indicates that the nitrosation occurred regiospe-
cifically at N(3). This observation may be rationalized in
terms of the higher nucleophilic strength of N(3) compared
to N(1), owing to a higher electron-withdrawing inductive
effect on N(1) caused by both of a double carbon–carbon
bond and a carbonyl group. This standpoint can be
*
Corresponding author. Tel.: +86 931 8912500; fax: +86 931 8915557.
E-mail address: nlaoc@lzu.edu.cn (L. Wu).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.035

Y. Shen et al. / Tetrahedron Letters 49 (2008) 1220–1222
1221
O
CH3CH2OC
O
R
4
1
R
CH3CH2OC
4
NO
N
3
NO
NH
5
6
3
5
6
2
2
traceO2
1
N
H
H3C
N
O
H3C
O
H
2
1
Scheme 1.
when the system was absolutely protected from air. Pires12
and Lewis13 studied the NO/O2 system in the presence of
phenol and morpholine, respectively, and concluded that
N2O3 was the nitrosating entity. NO is readily oxidized
by oxygen to NO2 and then converted to N2O3.14 Displace-
ment of the good leaving group nitrite (ꢁONO) from N2O3
by the Lewis base N(3) of dihydropyrimidinone with a
stronger nucleophilicity leads to the formation of 3
(Scheme 2). Intermediate 3 then undergoes a deprotonation
to give end product 2.
The solvent effects on product yields were examined
using 1a as a substrate (Table 2) in various solvents, includ-
ing: (a) aprotic and nonpolar solvents such as CCl4,
N(C2H5)3, and benzene; (b) aprotic and polar solvents such
as THF, CH2Cl2, and CH3CN; and (c) protic solvents with
high dielectric constant such as CH3OH and H2O.
Table 1
Reaction of dihydropyrimidinones with NO in CH3CN at ambient
temperature
Substrate
R
Yield of 2 (%)
1a
1b
1c
1d
40-(OMe)–C6H4
40-(Cl)–C6H4
40-(NO2)–C6H4
Ph
95
93
91
93
1e
95
O
1f
1g
1h
1i
iso-Butyl
n-Propyl
iso-Propyl
Ethyl
94
94
95
94
95
0
1j
H
1k
1l
PhCH@CH
(CH3)2C@CH
0
Table 2 indicates that nonpolar solvents such as CCl4
and N(C2H5)3, in which dihydropyrimidinones and NO
may be less soluble, disfavored the nitrosation, whereas
aprotic, polar, and weakly nucleophilic solvents such as
CH3CN and THF, in which dihydropyrimidinones and
NO may be relatively soluble, favored the reaction. Polar
solvents can stabilize ions through a charge dispersion
interaction. The more important role of polar solvents is
to form hydrogen bonds between N-amido hydrogen and
solvent, which will enhance the nucleophilicity of N-
amido.15 Although protic solvents with high dielectric con-
stant such as CH3OH and H2O more favored the hydrogen
bonding, but the reaction did not occur. It may be ratio-
nalized by a stronger hydrogen bonding (Scheme 3), which
blocks N2O3 approaching N(3) of 1. As such, the substrate
molecule most likely undergoes a nucleophilic attack on
N2O3, unlike a free radical mechanism. If not, it
would afford N(1)-nitrosoamides instead of N(3)-nitroso
1
1
supported by H NMR spectra of the substrate. H NMR
peak of N(1)–H of 1a locates downfield at 9.17 ppm,
whereas that of N(3)–H highfield at 5.09 ppm. This reveals
that the reaction proceeds most likely via a nucleophilic
mechanism. Otherwise, the nitrosation proceeded smoothly
when R is aryl or alkyl, whereas no reaction occurred when
R was a vinyl as in the cases of 1k and 1l. The exceptions
may be attributed to the lowering nucleophilicity of N(3)
caused by a vinyl directly linked to C(4). A vinyl will exhi-
bit a stronger electron-withdrawing inductive effect on N(3)
than that of a phenyl. In addition, it is worth pointing out
that the CH–N(NO) protons exhibited no diastereotopic
nature in their H NMR spectra.5e,11
In the reaction using NO as a reagent, there has been
always a problem that the true active species is unidenti-
fied. In our experiments, we found no reaction occurred
1
O
O
O
_
N
N
R
N
O
O
..
R
H
N
H
NO
NO
O
:
EtOOC
H3C
R
N
O
O
N
+
- HONO
NH
NH
N
H
EtOOC
EtOOC
H3C
H3C
3
1
2
Scheme 2.

1222
Y. Shen et al. / Tetrahedron Letters 49 (2008) 1220–1222
3. Zolfigol, M. A. Synth. Commun. 1999, 29, 905.
Table 2
Solvent effects on the reaction of 1a with NOa
4. (a) Zolfigol, M. A.; Zebarjadian, M. H.; Chehardoli, G.; Keypour, H.;
Salehzadeh, S.; Shamsipur, M. J. Org. Chem. 2001, 66, 3619; (b)
Solvent
Conversion (%)
Yield of 2 (%)
´
`
´
´
Celaries, B.; Parkanyi, C. Synthesis 2006, 2371; (c) Iranpoor, N.;
CCl4
0
0
0
0
Firouzabadi, H.; Pourali, A.-R. Synthesis 2003, 1591.
N(C2H5)3
Benzene
THF
CH2Cl2
CH3CN
CH3OH
H2O
5. (a) Yang, D. S.; Lei, L. D.; Liu, Z. Q.; Wu, L. M. Tetrahedron Lett.
2003, 44, 7245; (b) Liu, Z. Q.; Li, R.; Yang, D. S.; Wu, L. M.
Tetrahedron Lett. 2004, 45, 1565; (c) Liu, Z. Q.; Fan, Y.; Li, R.; Zhou,
B.; Wu, L. M. Tetrahedron Lett. 2005, 46, 1023; (d) Liu, Z. Q.; Zhou,
B.; Liu, Z. L.; Wu, L. M. Tetrahedron Lett. 2005, 46, 1095; (e) Peng,
L. J.; Liu, Z. Q.; Wu, L. M. Tetrahedron Lett. 2007, 48, 7418.
6. Itoh, T.; Nagata, K.; Matsuya, Y.; Miyazaki, M.; Ohsawa, A. J. Org.
Chem. 1997, 62, 3582.
75
>99
90
>99
0
73
93
88
94
0
0
0
a
All the reactions were carried out with 0.15 mmol of 1a in 20 mL
7. Itoh, T.; Nagata, K.; Matsuya, Y.; Miyazaki, M.; Ohsawa, A.
Tetrahedron Lett. 1997, 38, 5017.
solvent for 3 h.
8. Zhao, Y. L.; Stephen, L.; Garrison, C. G.; William, D. J. Phys. Chem.
A 2007, 111, 2200.
R
R
9. Ranu, B. C.; Hajra, A.; Dey, S. S. Org. Process Res. Dev. 2002, 6, 817.
H
EtOOC
H3C
EtOOC
H3C
H
O
1
NH
N
N
O
H
Data for 1a: H NMR (300 MHz, CDCl3) d 1.10 (3H, t, J = 7.0 Hz),
O
O
+
+
H
H
H
2.24 (3H, s), 3.71 (3H, s), 3.98 (2H, q, J = 7.0 Hz), 5.09 (1H, s, N(3)–
H), 6.88 (2H, d, J = 8.5 Hz), 7.15 (2H, d, J = 8.6 Hz), 7.68 (1H, s),
9.17 (1H, s, N(1)–H).
N
H
O
N
H
1
10. Data for representative products 2a: Yellow solid, mp 192–193 °C; IR
(KBr) mmax 3256, 3159, 2976, 1741, 1709, 1648, 1510, 1385, 1304, 1243,
1202, 1097, 1026, 835, 792, 653 cmꢁ1; 1H NMR (200 MHz, CDCl3) d
1.22 (3H, t, J = 7.2 Hz), 2.51 (3H, s, CH3), 3.78 (3H, s), 4.13 (2H, q,
J = 7.2 Hz), 6.45 (1H, s), 6.79 (2H, d, J = 8.6 Hz), 7.24 (2H, d,
J = 8.6 Hz), 8.54 (1H, s, N(1)–H); 13C NMR (75 MHz, CDCl3) d
14.05, 18.26, 53.50, 55.19, 60.73, 106.14, 113.93, 128.68, 129.80,
143.93, 150.51, 159.54, 164.19; MS (EI, 70 eV) m/z 319 (M+), 289,
261, 217, 183, 137, 134, 119, 110, 103, 89, 77; HR-ESI-MS m/z calcd
for C15H18N3O5 (M+Na) 342.1060, found: 342.1058. 1D NOE:
Irradiation of CH3 proton at d 2.51 enhanced N(1)–H proton at d 8.54
by 7%. Compound 2f: Yellow solid, mp 150–151 °C; IR (KBr) mmax
3242, 3140, 2967, 2878, 1722, 1646, 1541, 1391, 1310, 1249, 1219,
R
R
CH3
EtOOC
H3C
EtOOC
H3C
H
O
NH
O
H
CH3
N
H
O
N
H
1
Scheme 3.
compounds because N(1)-aminyl radical intermediate com-
plex is more stable than N(3)-aminyl radical intermediate
complex due to a large conjugated system.
In conclusion, we present herein an approach for regio-
selective N-nitrosation of dihydropyrimidinons with NO.
Its main advantages are readily available starting materials,
convenient performance under mild conditions and high
yields.
1086, 1024, 991, 771 cmꢁ1 1H NMR (300 MHz, CDCl3) d 0.87 (3H,
;
d, J = 6.3 Hz), 0.95 (3H, d, J = 6.3 Hz), 1.15 (1H, m), 1.35 (5H, m),
2.45 (3H, s, CH3), 4.23 (2H, m), 5.76 (1H, t, J = 6.9 Hz), 8.94 (1H, s,
N(1)–H); 13C NMR (75 MHz, CDCl3) d 14.14, 18.12, 21.86, 23.07,
24.28, 43.59, 47.80, 60.73, 107.12, 144.91, 151.51, 164.42; MS (EI,
70 eV) m/z 269 (M+), 239, 224, 212, 183, 154, 137, 110, 96, 68; HR-
ESI-MS m/z calcd for
C12H19N3O4 (M+Na) 292.1268, found:
292.1270; 1D NOE: irradiation of N(1)–H proton at d 8.94 enhanced
CH3 proton at d 2.45 by 6.4%.
Acknowledgment
11. Zolfigol, M. A.; Shirini, F.; Choghamarani, A. G.; Taqian-Nasab, A.;
Keypour, H.; Salehzadeh, S. J. Chem. Res. (S) 2000, 420.
12. Pires, M.; Rossi, M. J.; Ross, D. S. Int. J. Chem. Kinet. 1994, 26,
1207.
13. Lewis, R. S.; Tannenbaum, S. R.; Deen, W. M. J. Am. Chem. Soc.
1995, 117, 3933.
Project No. 20572040 was supported by National Natu-
ral Science Foundation of China.
References and notes
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Pergamon Press: Oxford, 1990; Vol. 508, Chapter 11; (c) Upchurch,
G. R.; Welch, G. N.; Loscalzo, J. Adv. Pharmacol. 1995, 34, 343; (d)
von Gratzel, M.; Taniguchi, S.; Henglein, A. Ber. Bunsenges. Phys.
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Org. Chem. 1996, 61, 7986; (b) Darbeau, R. W.; Gibble, R. E.; Pease,
R. S.; Siso, L. M.; Heurtin, D. J. J. Chem. Soc., Perkin Trans. 2 2001,
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15. Ghosh, K. K.; Satnami, M. L.; Sinha, D.; Vaidya, J. J. Mol. Liq.
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2. Williams, D. L. H. Nitrosation Reactions and the Chemistry of Nitric
Oxide; Elsevier: Amsterdam, 2004; Chapter 2.