Chemistry of polyhalogenated nitrobutadienes, 6: A new ring-closure approach to perfunctionalized 5-nitropyrimidines

Article abstract of DOI:10.1055/s-2007-990948

The recently reported capability of pentachloro-2-nitrobutadiene and some closely related derivatives to allow the synthesis of highly substituted acyclic as well as five-membered (hetero)cyclic compounds is herein extended to pyrimidines with an exceptional substitution pattern. Our novel approach starts from a 1,1-diamino-3,4,4-trichloro-2-nitrobuta-1,3-diene and an appropriate amidine. Some of the resulting perfunctionalized pyrimidines were subjected to further transformations to give promising candidates with respect to biological, especially pharmacological, activity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990948

304
PAPER
Chemistry of Polyhalogenated Nitrobutadienes, 6: A New Ring-Closure
Approach to Perfunctionalized 5-Nitropyrimidines
?
??????????
?
iktor A. Zapol’skii,a Jan C. Namyslo,a Cevher Altug,a Mimoza Gjikaj,b Dieter E. Kaufmann*a
a
Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstr. 6, 38678 Clausthal-Zellerfeld, Germany
Fax +49(5323)722834; E-mail: dieter.kaufmann@tu-clausthal.de
b
Institute of Inorganic and Analytical Chemistry, Clausthal University of Technology, Paul-Ernst-Str. 4, 38678 Clausthal-Zellerfeld,
Germany
Received 24 August 2007; revised 18 October 2007
The free amidine is initially generated by the added base.
The ring-closing reaction starts with vinylic nucleophilic
substitution at C1, whereupon the amino group of the ami-
dine acts as the nucleophile and, expectedly, the benzotri-
Abstract: The recently reported capability of pentachloro-2-nitro-
butadiene and some closely related derivatives to allow the synthesis
of highly substituted acyclic as well as five-membered (hetero)cy-
clic compounds is herein extended to pyrimidines with an excep-
tional substitution pattern. Our novel approach starts from a 1,1- azolyl substituent plays the role of leaving group. Then, as
diamino-3,4,4-trichloro-2-nitrobuta-1,3-diene and an appropriate
amidine. Some of the resulting perfunctionalized pyrimidines were
subjected to further transformations to give promising candidates
lecular cyclization reaction. Subsequently, hydrochloric
with respect to biological, especially pharmacological, activity.
the key step, the imino nitrogen within the amidine moiety
of I forms the six-membered heteroring II in an intramo-
acid is eliminated from II by additional base, giving the
Key words: nitro compounds, halides, pyrimidines, ring closure,
exomethylene compound III. Finally, aromatization oc-
nucleophilic substitution
curs that leads to the persubstituted pyrimidines 6–10. As
an example, the structure of 7 was confirmed by X-ray
crystallography (Figure 1).3,4
The electronically remarkable pentachloro-2-nitrobuta-
1,3-diene and similar polysubstituted butadienes are ver-
satile starting materials for a series of synthetic applica-
tions. Among these, we have previously synthesized
thiophenes, developed an unprecedented C4-to-C3 cleav-
age of such a butadiene, and taken advantage of the dieno-
Evidence for the mechanism proposed in Scheme 1 was
obtained by isolating the initial substitution product 11
from the bis(benzotriazole) derivative 1 and benzamidine
and then cyclizing it to the pyrimidine derivative 12 with
base. In conclusion, 1 afforded 11 in 79% yield employing
benzamidine hydrochloride and sodium hydrogen carbon-
philic properties of these electron-deficient molecules. In
ate in acetonitrile. The subsequent ring closure was ac-
addition, we have obtained imidazolidines, oxazolidines,
complished using potassium carbonate in tetrahydrofuran
and related five-membered 1,3-heterocycles from the cor-
to give pyrimidine 12 (43%). In contrast, direct conver-
responding thiolated butadiene derivatives.1
sion of 1, i.e. without isolation of the intermediate 11, re-
Further efforts are underway to explore the entire synthet-
ic potential of this type of compound. In this paper, we
give the first account of the reaction of 1,1-bis(1H-benzo-
triazol-1-yl)-3,4,4-trichloro-2-nitrobuta-1,3-diene (1) or
the 1-amino-1-(benzotriazol-1-yl)-3,4,4-trichloro-2-nitro-
buta-1,3-dienes 2–5 with acetamidine or benzamidine hy-
drochlorides. The latter nitrobutadienes were prepared
from the bis(benzotriazole) derivative 1 in up to 95%
yield in accordance with the procedure of Zapol’skii and
Kaberdin.2 Thus, applying sodium hydride or lithium hy-
dride, aqueous sodium hydroxide, or other bases in tet-
rahydrofuran or dimethyl sulfoxide to 2–5 we obtained the
pyrimidines 6–10 in up to 85% yield (Table 1).
HN
R3
Bzt
NR1R2
NO2
HN
NR1R2
NO2
Cl
Cl
Cl
Cl
Cl
Cl
I
2–5
H
N
R3
NR1R2
NO2
N
Cl
Cl
Cl
II
The optimized procedure includes the application of three
equivalents of the amidine with a fourfold excess of sodi-
um hydride in tetrahydrofuran and requires the reaction
mixture to be initially maintained at –10 °C and then at
room temperature. The proposed mechanism of this novel
ring formation is depicted in Scheme 1.
H
N
R3
NR1R2
NO2
R3
N
NR1R2
N
N
NO2
Cl
Cl
Cl
Cl
6–10
III
SYNTHESIS 2008, No. 2, pp 0304–0310
x
x
.
x
x
.2
0
0
7
Advanced online publication: 07.12.2007
DOI: 10.1055/s-2007-990948; Art ID: T13807SS
Scheme 1 Proposed mechanism of pyrimidine formation
© Georg Thieme Verlag Stuttgart · New York

PAPER
New Ring-Closure Approach to Perfunctionalized 5-Nitropyrimidines
305
Table 1 Synthesis of 4-Amino-6-(dichloromethyl)-5-nitropyrimidines
NH
NR1R2
NO2
Cl
NO2
R3
Bzt
Bzt
Bzt
NR1R2
NH2·HCl
HNR1R2
MeOH
Cl
Cl
Cl
Cl
Cl
NO2
N
N
NaH, THF
Cl
Cl
R3
1
2–5
6–10
Entry
1
NR1R2
2–5
Yield (%)
Base
Solvent
THF
Product
Yield (%)
73
2
88
NaH
6, R3 = Ph
N
O
O
2
NaOH
NaH
DMSO
DMSO
THF
61
3
2
88
7, R3 = Me
56
N
4
NaH
54
5
LiH
THF
22
6
Cs2CO3
NaH
DMSO
THF
21
7
3
4
5
95
95
57
8, R3 = Ph
9, R3 = Me
10, R3 = Me
76
N
8
NaOH
NaH
DMSO
THF
40
9
35
N
N
F
10
11
12
NaOH
NaH
DMSO
THF
32
85
HN
Cl
NaOH
DMSO
30
sulted in the same product, but with lower yield
(Scheme 2).
It is worthwhile to note that syntheses of 5-nitropyrim-
idines are rare in literature. One method, published in
1977, employs the condensation of sodium nitromalonal-
dehyde with amidines.5 The same salt is part of a three-
component ring-closure reaction in combination with 2-
methylisothiourea sulfate and morpholine.6 An alternative
access uses the reaction of 5-nitro-1H-pyrimidine-2,4-di-
one with phosphoryl chloride to obtain 2,4-dichloro-5-ni-
tropyrimidine.7 Another synthesis starts from a mixture of
3-nitrobut-3-en-2-ones, 2-methylisourea, and 2,3-dichlo-
ro-5,6-dicyano-1,4-benzoquinone to afford 2-methoxy-5-
nitropyrimidine.8 In addition, 5-nitropyrimidines have
been obtained by ring opening of a 3-nitrochromen-4-
one.9
Figure 1 X-ray crystal structure of pyrimidine 73,4
HN
Ph
Ph
N
Bzt
HN
Bzt
i
ii
1
N
Cl
Cl
Aside from the viewpoint of an organic chemist, such 5-
nitropyrimidines are interesting due to their structural
similarity to natural compounds, such as bases in nucleo-
sides and nucleotides, and their corresponding physiolog-
ical activity. Various bioactivities of pyrimidines and
other heterocycles are highlighted in a review.10
NO2
NO2
Cl
Cl
Cl
11
12
iii
Among numerous applications, some examples are note-
worthy: antitumor activity is documented11a–c as well as
the potential to inactivate human DNA repair.11d The
broad variety can be illustrated, for example by the activ-
ity against chronic obstructive pulmonary disease,11e ap-
plicability against herpes simplex,11f and other viral
i: benzamidine hydrochloride, NaHCO3, MeCN, 79%
ii: K2CO3, THF, 43%
iii: i, 23%
Scheme 2
Synthesis 2008, No. 2, 304–310 © Thieme Stuttgart · New York

306
V. A. Zapol’skii et al.
PAPER
NO2
To the best of our knowledge, the reduction of a dichlo-
romethyl group attached to a carbo- or hetero-cyclic ring
to a methyl group with tin(II) chloride is unprecedented.
Only a few reactions, somewhat similar to our conversion,
have been previously published.
N
H
N
N
N
N
Cl
NaN3,
DMF, 0 °C
85%
13
NaN3,
DMF, r.t.
74%
Among these, the complete reduction of a dichloroacetyl
substitutent by zinc in acetic acid,13a the reductive elimi-
nation of two chloro atoms during an indium(I) bromide
mediated coupling of a,a-dichloro ketones to 1-arylbu-
tane-1,4-diones,13b and the conversion of a dichloroacetyl
into an acetyl group upon the influence of tributyltin hy-
dride,13c are worthy of note.
10
NaN3,
DMF,
0 °C to r.t.
65%
N
NO2
H
N
N
N
H
N
N
Cl
Interestingly, such 5-aminopyrimidine derivatives exhibit
pharmacological activities, e.g. against anoxia.14
14
Scheme 3
In the course of our own investigations, the exhaustive
acetylation of the amino group in 16 afforded 17 as ex-
pected (76% yield), but in the subsequent reaction with
hydrazine hydrate no triazole was obtained, but one of the
N-acetyl groups was removed reductively. The second
acetyl substituent, in principle remained unaffected, but
tautomerized to a mixture of the Z- and E-isomers (3:1) of
acetimidic acid 18, as evidenced by H NMR spectroscopy.
Obviously, the exclusive presence of these enol tautomers
is caused by the stabilizing conjugation of the enol double
bond with the pyrimidine ring (Scheme 4).
diseases.11g Furthermore, one field of application of 5-ni-
tropyrimidines uses their positive modulating effect of the
GABAB receptor.11h,i
During the course of our synthetic efforts, we obtained in-
teresting derivatives of some of the aforementioned per-
substituted pyrimidines 6–10. Thus, in analogy to a
recently found reaction,12 the cyanopyrimidine 13 was ob-
tained in 85% yield by applying sodium azide at 0 °C,
whereas the same reagent afforded the tetrazole 14 (74%)
at room temperature. Alternatively, 14 is obtained from 10
using an excess of sodium azide at room temperature
(Scheme 3).
In conclusion, we have found a novel synthesis of persub-
stituted 5-nitropyrimidines starting from the easily acces-
sible 1,1-bis(1H-benzotriazol-1-yl)-3,4,4-trichloro-2-nitro-
buta-1,3-diene (1) and an appropriate amidine. Further-
more, we investigated some subsequent conversions. Es-
pecially from a chemical point of view, the latter
syntheses gave some remarkable results, but in addition,
some products should offer interesting biological, in par-
ticular pharmacological properties. Therefore, corre-
sponding tests of these promising compounds are
presently underway.
Moreover, the phenyl group in 6 was selectively nitrated
at the meta-position using fuming nitric acid at 0 °C, to
give 15 (Scheme 4).
Furthermore, treatment of 6 with tin(II) chloride in ace-
tone converted the nitro into an amino group, but also re-
sulted in an unexpected reduction of the dichloromethyl to
a methyl group. Thus, the methylated aminopyrimidine 16
was isolated in 75% yield (Scheme 4), whereupon the as-
sumed intermediate, i.e. the 5-amino-6-(dichloromethyl)
derivative, was not observed.
Melting points were determined with a Büchi apparatus 520 and are
uncorrected. NMR spectra were referenced to the residual solvent
peak: CDCl3, d = 7.26 (1H), d = 77.0 (13C); DMSO-d6, d = 2.50
Cl
NO2
O
NH2
O
N
Me
N
fuming HNO3
SnCl2⋅H2O
Cl
6
N
N
acetone, HCl
r.t. to reflux
75%
N
N
0–10 °C
73%
16
15
Ph
NO2
Ac2O
110 °C
76%
OH
N
Me
Me
N
O
NAc2
O
N
Me
N
hydrazine hydrate
N
N
N
MeOH, 40 °C
93%
17
18
Ph
Ph
Scheme 4
Synthesis 2008, No. 2, 304–310 © Thieme Stuttgart · New York

PAPER
New Ring-Closure Approach to Perfunctionalized 5-Nitropyrimidines
307
(1H), 39.7 (13C); acetone-d6, d = 2.09 (1H), 29.8 (13C). IR spectral
data were obtained on a Bruker Vector 22 FT-IR. Mass spectra were
obtained on a Hewlett Packard MS 5989B spectrometer, usually in
direct mode with EI (70 eV). In the case of chlorinated compounds,
all peak values of molecular ions as well as fragments m/z refer to
the isotope 35Cl. HRMS-ESI were measured with a Bruker APEX
IV 7 Tesla FT ion cyclotron resonance mass spectrometer. TLC was
done on Merck TLC plates (aluminum backed) silica gel 60 F 254.
Column chromatography was carried out on silica gel 60 (Merck).
(CH), 125.0 and 124.5 (CCl=CCl2), 120.8 (CH), 115.0 (CNO2),
110.4 (CH), 51.8 (2 C, NCH2), 25.8 (2 C, NCH2CH2), 23.4
(CH2CCH2).
MS: m/z (%) = 401 [M+] (1), 93 (100).
1-(1H-Benzotriazol-1-yl)-3,4,4-trichloro-1-[4-(4-fluorophe-
nyl)piperazin-1-yl]-2-nitrobuta-1,3-diene (4)
Following the typical procedure for 2 using 4-(4-fluorophenyl)pip-
erazine and recrystallization (MeOH–acetone, 2:1); yield: 95%; mp
177–179 °C.
Benzotriazole derivative 1 was prepared in 72% yield from pen-
tachloro-2-nitrobuta-1,3-diene in Et2O according to Kaberdin et
al.15 Pentachloro-2-nitrobuta-1,3-diene was prepared in 53% yield
(bp 69–71 °C).16
IR (KBr): 3050, 1601, 1562 (NO2), 1504, 1452, 1301 (NO2), 1005,
904, 812, 773, 704, 542 cm–1.
1H NMR (CDCl3): d = 8.17 (d, J = 8.1 Hz, 1 H), 7.40–7.75 (m, 3 H),
6.87–7.05 (m, 4 H), 3.26–3.65 (m, 8 H, NCH2).
1,1-Bis(1H-benzotriazol-1-yl)-3,4,4-trichloro-2-nitrobuta-1,3-
diene (1)
Mp 138–139 °C.
1
13C NMR (CDCl3): d = 158.1 (CF, JC-F = 244 Hz), 147.7, 146.7,
146.4, 132.4, 130.7 (CH), 126.3 (CCl), 126.0 (CH), 124.5 (CCl2),
3
121.1 (CH), 119.3 (2 C, CH, JC-F = 8 Hz), 116.0 (2 C, CH,
IR (KBr): 3099, 3080, 1798, 1650, 1574, 1536 (NO2), 1459, 1426,
1317 (NO2), 1295, 1209, 1173, 1019, 902, 862, 824, 792, 742, 652,
635, 615, 563, 432 cm–1.
1H NMR (CDCl3): d = 8.13–8.26 (m, 2 H), 7.37–7.55 (m, 4 H),
6.71–6.83 (m, 1 H), 6.50–6.57 (m, 1 H).
2JC-F = 22 Hz), 111.8 (CNO2), 110.3 (CH), 50.7 (2 C, NCH2), 50.5
(2 C, NCH2).
MS: m/z (%) = 496 [M+] (3), 479 [M+ – OH] (1), 123 (100).
HRMS (ESI): m/z [M + H]+ calcd for C20H17Cl3FN6O2: 497.04571;
13C NMR (CDCl3): d = 146.2 (Cq,Bzt), 146.1 (Cq,Bzt), 134.1 (CNO2),
132.4 (C1), 131.4 (Cq,Bzt), 131.3 (Cq,Bzt), 130.9 (CH), 130.8 (CH),
130.7 (C3), 126.5 (CH), 126.4 (CH), 121.6 (CH), 121.5 (CH), 119.6
(C4), 109.6 (CH), 109.3 (CH).
MS: m/z (%) = 435 [M+] (1), 316 [M+ – benzotriazole] (2), 198 [M+
– 2 benzotriazole] (4), 51 (100).
found: 497.04565.
1-(1H-Benzotriazol-1-yl)-3,4,4-trichloro-1-(4-chlorophenylami-
no)-2-nitrobuta-1,3-diene (5)
Following the typical procedure for 2 using 4-chloroaniline and re-
crystallization (MeOH–acetone, 2:1); yield: 57%; mp 112–113 °C.
IR (KBr): 3263, 1620, 1578 (NO2), 1488, 1461, 1375 (NO2), 1342,
1188, 1045, 874, 830, 812, 744, 710, 636, 587 cm–1.
1H NMR (CDCl3): d = 11.55 (br s, 1 H, NH), 8.05 (d, J = 8.4 Hz, 1
H, Bzt-H), 7.48 (dd, J = 7.8, 7.6 Hz, 1 H, Bzt-H), 7.40 (dd, J = 8.4,
7.6 Hz, 1 H, Bzt-H), 7.36 (d, J = 7.8 Hz, 1 H, Bzt-H), 7.04 (d,
J = 8.6 Hz, 2 H, CH=CCl), 6.72 (d, J = 8.6 Hz, 2 H, CH=CNH).
13C NMR (CDCl3): d = 146.0, 145.3, 133.6, 133.3, 131.8, 129.9
(CH), 129.8 (2 C, CHCCl), 125.6 (CH), 124.1 (2 C, CHCNH),
120.9 (CH), 120.2 (CNO2), 109.6 (CH). The carbon atoms within
the trichlorovinyl group were not detected.
1-(1H-Benzotriazol-1-yl)-3,4,4-trichloro-1-(morpholin-4-yl)-2-
nitrobuta-1,3-diene (2); Typical Procedure
To a suspension of bisbenzotriazole derivative 1 (5.00 g, 11.45
mmol) in MeOH (70 mL) at 5 °C was added a soln of morpholine
(1.13 g, 13.0 mmol) in MeOH (5 mL) over 3 min. The resulting
mixture was stirred at 10–15 °C for 2 h and at r.t. for 3 h. The pre-
cipitate was filtered off, washed with H2O (2 × 50 mL) and cold
MeOH (20 mL), and dried in vacuo to give 2; yield: 4.07 g (88%);
mp 164–166 °C (MeOH–acetone, 2:1) (Lit.17 mp 163–164 °C).
IR (KBr): 2986, 1599, 1558 (NO2), 1467, 1345, 1283 (NO2), 1230,
1110, 1012, 903, 875, 808, 768, 745, 713, 650, 573, 503 cm–1.
1H NMR (CDCl3): d = 8.16 (d, J = 8.3 Hz, 1 H), 7.44–7.83 (m, 3 H),
3.84–4.19 (m, 4 H, OCH2), 3.17–3.62 (m, 4 H, NCH2).
MS: m/z (%) = 443 [M+] (1), 368 [M+ – Cl] (1), 93 (100).
HRMS (ESI): m/z [M + H]+ calcd for C16H10Cl4N5O2: 443.95831;
found: 443.95845.
1H NMR (acetone-d6): d = 8.24 (d, J = 8.3 Hz, 1 H), 7.53–8.02 (m,
3 H), 3.88–4.17 (m, 4 H, OCH2), 3.31–3.80 (m, 4 H, NCH2).
4-(Dichloromethyl)-6-(morpholin-4-yl)-5-nitro-2-phenylpyrim-
idine (6); Typical Procedures
13C NMR (CDCl3): d = 147.6, 146.3, 132.4, 130.7 (CH), 126.1
(CH), 126.3 and 124.3 (CCl=CCl2), 120.7 (CNO2), 121.1 (CH),
110.3 (CH), 66.4 (2 C, OCH2), 50.4 (2 C, NCH2).
13C NMR (acetone-d6): d = 148.8, 147.2, 133.5, 131.2 (CH), 126.7
(CH), 125.9 and 125.2 (CCl=CCl2), 124.3 (CNO2), 121.4 (CH),
111.6 (CH), 67.0 (2 C, OCH2), 51.1 (2 C, NCH2).
Method I (using aq NaOH, DMSO): To a suspension of 2 (1.00 g,
2.47 mmol) in DMSO (20 mL) at 0 °C was added over 3 min a mix-
ture of benzamidine hydrochloride (1.16 g, 7.41 mmol), 30% aq
NaOH (1.32 g, 9.88 mmol), and DMSO (10 mL). The combined
slurry was stirred at 0–5 °C for 1 h and at r.t. for 3 h. Subsequently,
the mixture was poured into a soln of concd HCl (10 mL) in cold
H2O (100 mL). After 10 min with stirring, the precipitate was fil-
tered off, washed with H2O (2 × 20 mL) and MeOH (2 × 10 mL),
and dried in vacuo to give pyrimidine 6; yield: 0.56 g (61%); mp
167–169 °C (MeOH–CHCl3, 2:1).
MS: m/z (%) = 403 [M+] (1), 368 [M+ – Cl] (1), 93 (100).
1-(1H-Benzotriazol-1-yl)-3,4,4-trichloro-2-nitro-1-(piperidin-1-
yl)buta-1,3-diene (3)
Following the typical procedure for 2 using piperidine and recrys-
tallization (MeOH–acetone, 2:1); yield: 95%; mp 133–134 °C (Lit.3
mp 132–133 °C).
IR (KBr): 3055, 2865, 1590, 1569 (NO2), 1458, 1395, 1345 (NO2),
1221, 1112, 1022, 999, 927, 865, 836, 811, 752, 699, 542 cm–1.
1H NMR (CDCl3): d = 8.40–8.50 (m, 2 H, Ph), 7.40–7.55 (m, 3 H,
Ph), 7.11 (s, 1 H, CHCl2), 3.78–3.86 (m, 4 H, OCH2), 3.63–3.72 (m,
4 H, NCH2).
13C NMR (CDCl3): d = 162.9 (C2), 156.8, 154.6, 135.0 (Cq,Ph),
131.5 (CPh), 128.6 (2 C, CPh), 127.9 (2 C, CPh), 125.5 (CNO2), 65.7
(2 C, OCH2), 65.3 (CHCl2), 46.3 (2 C, NCH2).
IR (KBr): 2946, 1600, 1560 (NO2), 1498, 1453, 1285 (NO2), 1251,
1160, 1025, 931, 918, 895, 803, 765, 751, 708, 665, 573, 461 cm–1.
1H NMR (CDCl3): d = 8.11 (d, J = 8.3 Hz, 1 H), 7.40–7.74 (m, 3 H),
3.00–3.67 (m, 4 H, NCH2), 1.59–2.02 (m, 6 H, CH2).
13C NMR (CDCl3): d = 148.2, 146.2, 132.4, 130.3 (CH), 125.8
Synthesis 2008, No. 2, 304–310 © Thieme Stuttgart · New York

308
V. A. Zapol’skii et al.
PAPER
MS: m/z (%) = 368 [M+] (30), 351 [M+ – OH] (17), 333 [M+ – Cl]
yield, whereas using Method I gave 32% yield; mp 97–98 °C
(MeOH–CHCl3, 2:1).
(31), 322 [M+ – NO2] (12), 295 (68), 105 (100).
HRMS (ESI): m/z [M + H]+ calcd for C15H15Cl2N4O3: 369.05157;
found: 369.05178.
IR (KBr): 3068, 2820, 1568 (NO2), 1510, 1460, 1333 (NO2), 1219,
995, 922, 770, 748, 703, 673, 538 cm–1.
Method II (with NaH in THF): To a suspension of NaH [0.071 g,
2.964 mmol; 0.118 g of 60% NaH in mineral oil washed with anhyd
pentane (2 ×)] in anhyd THF (10 mL) was added benzamidine hy-
drochloride (0.348 g, 2.222 mmol). After cooling this slurry to –10
°C, a soln of 2 (0.300 g, 0.741 mmol) in THF (3 mL) was added
dropwise. The resulting mixture was stirred at –10 °C for 1 h then
at r.t. overnight. Subsequently, the mixture was poured into a soln
of concd HCl (3 mL) in cold H2O (30 mL). The mixture was stirred
for 10 min and the crude product was extracted with CH2Cl2 (3 × 40
mL). The combined organic phases were washed with H2O (2 × 20
mL) and dried in vacuo. Column chromatography (silica gel, petro-
leum ether–EtOAc, 4:1) gave pyrimidine 6; yield: 0.199 g (73%).
1H NMR (CDCl3): d = 6.87–7.05 (m, 4 H, Ph), 6.99 (s, 1 H, CHCl2),
3.70–3.81 (m, 4 H, NCH2), 3.58–3.70 (m, 4 H, NCH2), 2.64 (s, 3 H,
Me).
1
13C NMR (CDCl3): d = 168.7 (C2), 157.9 (CF, JC-F = 241 Hz),
156.7, 154.5, 146.6, 126.2 (CNO2), 118.5 (2 C, 3JC-F = 8 Hz), 115.9
(2JC-F = 22 Hz), 65.2 (CHCl2), 50.1 (2 C, NCH2), 46.3 (2 C, NCH2),
26.1 (Me).
MS: m/z (%) = 399 [M+] (9), 382 [M+ – OH] (1), 364 [M+ – Cl (2),
353 [M+ – NO2] (2), 303 [M+ – PhF] (4), 150 (100).
HRMS (ESI): m/z [M + H]+ calcd for C16H17Cl2FN5O2: 400.07378;
found: 400.07373.
4-(Dichloromethyl)-2-methyl-6-(morpholin-4-yl)-5-nitropyrim-
idine (7)
4-(4-Chlorophenylamino)-6-(dichloromethyl)-2-methyl-
5-nitropyrimidine (10)
Following the typical procedure for 6, Method II using 2 (0.300 g,
0.741 mmol), acetamidine hydrochloride (0.210 g, 2.221 mmol),
and NaH (0.071 g, 2.964 mmol) with purification by column chro-
matography (petroleum ether–EtOAc, 1:1). Subsequent crystalliza-
tion was induced by adding cold MeOH (5 mL) and drying the
resultant precipitate in vacuo to give 7; yield: 0.123 g (54%); mp
95–96 °C (MeOH–CHCl3, 2: 1).
Following the typical procedure for 6, Method II gave 10 in 85%
yield, whereas using Method I gave 30% yield; mp 145–146 °C
(MeOH–CHCl3, 2:1).
IR (KBr): 3320, 1613, 1568 (NO2), 1511, 1407, 1382 (NO2), 1284,
1204, 1097, 1001, 856, 833, 785, 748, 710, 649, 510 cm–1.
1H NMR (CDCl3): d = 9.73 (br s, 1 H, NH), 7.54 (d, J = 8.8 Hz, 2
H, CHCCl), 7.38 (d, J = 8.8 Hz, 2 H, CHCNH), 7.37 (s, 1 H,
CHCl2), 2.68 (s, 3 H, Me).
13C NMR (CDCl3): d = 171.3 (C2), 160.6 (C6), 153.1 (C4), 134.9
(HNCq,Ph), 131.4 (ClCq,Ph), 129.2 (2 C, CHCCl), 128.7 (CNO2),
124.3 (2 C, CHCNH), 66.5 (CHCl2), 26.5 (Me).
IR (KBr): 3031, 2861, 1576 (NO2), 1510, 1405, 1339 (NO2), 1209,
1114, 1064, 995, 874, 838, 826, 778, 741, 672, 532 cm–1.
1H NMR (CDCl3): d = 6.98 (s, 1 H, CHCl2), 3.72–3.78 (m, 4 H,
OCH2), 3.54–3.60 (m, 4 H, NCH2), 2.62 (s, 3 H, Me).
13C NMR (CDCl3): d = 168.7 (C2), 156.7, 154.5, 126.0 (CNO2),
66.2 (2 C, OCH2), 65.2 (CHCl2), 46.6 (2 C, NCH2), 26.1 (Me).
MS: m/z (%) = 306 [M+] (32), 271 [M+ – Cl] (25), 233 (70), 58
(100).
MS: m/z (%) = 346 [M+] (100), 329 [M+ – OH] (4), 311 [M+ – Cl]
(2), 300 [M+ – NO2] (8).
HRMS (ESI): m/z [M + H]+ calcd for C12H10Cl3N4O2: 346.98639;
found: 346.98646.
HRMS (ESI): m/z [M + H]+ calcd for C10H13Cl2N4O3: 307.03592;
N1-[1-(1H-Benzotriazol-1-yl)-3,4,4-trichloro-2-nitrobuta-1,3-
dienyl]benzamidine (11)
found: 307.03593.
For comparison (see Table 1): NaH in DMSO or LiH in THF gave
7 in 56% and 22% yield, respectively. In addition, using Cs2CO3 in
DMSO gave 7 in only 21% yield.
To a suspension of 1 (5.00 g, 11.45 mmol) in MeCN (60 mL) was
added benzamidine hydrochloride (2.07 g, 13.2 mmol) and
NaHCO3 (2.12 g, 25.2 mmol) suspended in MeCN (20 mL). The
mixture was stirred at r.t. for 2 weeks. Subsequently, the precipitate
was filtered off, washed with H2O (2 × 50 mL), and dried in vacuo
to give 11; yield: 3.94 g (79%); mp 131–133 °C (MeOH–acetone,
3:1).
4-(Dichloromethyl)-5-nitro-2-phenyl-6-(piperidin-1-yl)pyrimi-
dine (8)
Following the typical procedure for 6, Method II gave 8 in 76%
yield, whereas using Method I gave only 40% yield; mp 128–129
°C (MeOH–CHCl3, 2:1).
IR (KBr): 3154, 1678, 1558 (NO2), 1449, 1433, 1375 (NO2), 1290,
1255, 1219, 1085, 1020, 940, 854, 785, 711, 644, 612, 551 cm–1.
1H NMR (CDCl3): d = 8.02 (d, J = 8.0 Hz, 1 H, Bzt-H), 7.58–7.68
(m, 3 H), 7.50–7.55 (m, 1 H), 7.40–7.48 (m, 2 H), 7.31–7.39 (m, 2
H), 6.55 (br s, 2 H, NH).
13C NMR (CDCl3): d = 165.1 (C=NH), 147.9 (NHCN), 145.6
(Cq,Bzt), 132.9 (CH, CPh), 132.1 (Cq,Bzt), 131.3 (Cq,Ph), 129.5 (CH,
Bzt), 129.2 (CCl), 129.0 (2 CH, CPh), 127.4 (2 CH, CPh), 126.9
(CCl2), 125.4 (CH, Bzt), 123.4 (CNO2), 120.5 (CH, Bzt), 111.7
(CH, Bzt).
IR (KBr): 3061, 2934, 2852, 1589, 1570 (NO2), 1528, 1395, 1342
(NO2), 1215, 1060, 1028, 921, 832, 771, 746, 705, 663 cm–1.
1H NMR (DMSO-d6): d = 8.34–8.42 (m, 2 H, Ph), 7.53–7.62 (m, 3
H, Ph), 7.50 (s, 1 H), 3.52–3.62 (m, 4 H, NCH2), 1.59–1.71 (m, 6 H,
CH2).
13C NMR (DMSO-d6): d = 162.2 (C2), 156.9, 154.9, 135.7 (Cq,Ph),
132.3 (CPh), 129.0 (2 C, CPh), 128.8 (2 C, CPh), 125.6 (CNO2), 67.6
(CHCl2), 47.8 (2 C, NCH2), 25.2 (2 C, NCH2CH2), 23.5
(CH2CCH2).
MS: m/z (%) = 436 [M+] (2), 401 [M+ – Cl] (2), 78 (100).
HRMS (ESI): m/z [M + H]+ calcd for C17H12Cl3N6O2: 437.00818;
MS: m/z (%) = 366 [M+] (4), 349 [M+ – OH] (7), 294 (14), 105
(100).
HRMS (ESI): m/z [M + H]+ calcd for C16H17Cl2N4O2: 367.07231;
found: 437.00842.
found: 367.07242.
4-(1H-Benzotriazol-1-yl)-6-(dichloromethyl)-5-nitro-2-phenyl-
pyrimidine (12)
Method I (from 1): To a suspension of 1 (5.00 g, 11.45 mmol) in
THF (60 mL) was added over 3 min a suspension of benzamidine
hydrochloride (2.07 g, 13.2 mmol) and K2CO3 (3.48 g, 25.2 mmol)
4-(Dichloromethyl)-6-[4-(4-fluorophenyl)piperazin-1-yl]-
2-methyl-5-nitropyrimidine (9)
Following the typical procedure for 6, Method II gave 9 in 35%
Synthesis 2008, No. 2, 304–310 © Thieme Stuttgart · New York

PAPER
New Ring-Closure Approach to Perfunctionalized 5-Nitropyrimidines
309
in THF (20 mL) at r.t. The mixture was stirred for 2 d and the sol-
vent was removed in vacuo. The residue then was treated with dil
aq 5% HCl (200 mL). Finally, the crude product was extracted with
CH2Cl2 (3 × 50 mL), washed with H2O (2 × 100 mL), and dried
over (anhyd CaCl2). The solvent was removed under reduced pres-
sure and the crude product purified by column chromatography (pe-
troleum ether–EtOAc, 10:1) to give 12; yield: 1.06 g (23%).
HRMS (ESI): m/z [M + H]+ calcd for C12H10ClN8O2: 333.06098;
found: 333.06094.
6-(Dichloromethyl)-4-morpholino-5-nitro-2-(3-nitrophenyl)py-
rimidine (15)
The nitration of pyrimidine 6 was accomplished by adding HNO3 (5
mL) to 6 (0.20 g, 0.54 mmol) at 0 °C over 5 min. The mixture was
stirred for 20 min at this temperature and an additional 10 min at 10
°C. Ice cold H2O was added (50 mL) and the precipitate that formed
was washed successively with H2O (3 × 20 mL) and petroleum
ether (2 × 10 mL). The crude product was dried and recrystallized
(MeOH) to give dinitro compound 15; yield: 0.16 g (73%); mp 162–
163 °C.
Method II (from 11): At r.t., K2CO3 (0.35 g, 2.51 mmol) was added
to a suspension of 11 (1.00 g, 2.28 mmol) in THF (20 mL); the mix-
ture was stirred for 1 d. Workup and purification as described for
Method I gave 12; yield: 0.39 g (43%); mp 179–181 °C (MeOH–
acetone, 3:1).
IR (KBr): 3026, 1597, 1556 (NO2), 1487, 1402, 1356 (NO2), 1212,
1088, 1005, 855, 812, 750, 698, 629 cm–1.
1H NMR (CDCl3): d = 8.54–8.63 (m, 2 H), 8.49 (d, J = 8.3 Hz, 1 H),
8.20 (d, J = 8.3 Hz, 1 H), 7.76–7.87 (m, 1 H), 7.54–7.69 (m, 4 H),
7.07 (s, 1 H, CHCl2).
13C NMR (CDCl3): d = 165.5 (C2), 158.2, 148.5, 146.2 (Cq,Bzt),
134.5 (Cq,Bzt), 133.4 (CH, CPh), 131.1 (Cq,Ph), 130.7 (CH, Bzt), 130.3
(CNO2), 129.5 (2 CH, CPh), 129.2 (2 CH, CPh), 126.5 (CH, Bzt),
121.0 (CH, Bzt), 114.0 (CH, Bzt), 64.9 (CHCl2).
IR (KBr): 2914, 2863, 1593, 1573, 1530 (NO2), 1347 (NO2), 1226,
1116, 1001, 951, 873, 837, 772, 737, 708, 659, 542 cm–1.
1H NMR (CDCl3): d = 9.19 (dd, J = 2.1, 1.6 Hz, 1 H), 8.82 (ddd,
J = 7.9, 1.6, 1.2 Hz, 1 H), 8.39 (ddd, J = 8.2, 2.1, 1.2 Hz, 1 H), 7.70
(dd, J = 8.2, 7.9 Hz, 1 H), 7.08 (s, 1 H, CHCl2), 3.80–3.87 (m, 4 H,
OCH2), 3.68–3.75 (m, 4 H, NCH2).
13C NMR (CDCl3): d = 161.3 (C2), 157.6, 155.1, 148.6 (Cq,PhNO2),
137.4 (Cq,Ph), 134.9 (CH), 129.7 (CH), 126.6 (CNO2), 126.4 (CH),
123.8 (CH), 66.2 (2 C, OCH2), 65.5 (CHCl2), 47.0 (2 C, NCH2).
MS: m/z (%) = 400 [M+] (15), 372 (10), 279 (28), 92 (100).
HRMS (ESI): m/z [M + H]+ calcd for C17H11Cl2N6O2: 401.03151;
MS: m/z (%) = 413 [M+] (11), 396 [M+ – OH] (14), 378 [M+ – Cl]
(10), 322 [M+ – NO2] (8), 234 (100).
found: 401.03148.
HRMS (ESI): m/z [M + H]+ calcd for C15H14Cl2N5O5: 414.03665;
found: 414.03678.
4-(4-Chlorophenylamino)-6-cyano-2-methyl-5-nitropyrimi-
dine (13); Typical Procedure
5-Amino-4-methyl-6-(morpholin-4-yl)-2-phenylpyrimidine (16)
To a soln of 6 (1.00 g, 2.70 mmol) in acetone (50 mL) were added
SnCl2·2 H2O (3.66 g, 16.20 mmol) and concd HCl (10 mL). The
mixture was stirred at reflux for 6 h. The acetone was removed and
then ice cold H2O (200 mL) was added and the mixture was adjusted
to pH 8 with 30% aq NaOH soln. The resulting precipitate was fil-
tered off with suction, washed with H2O (3 × 50 mL) and petroleum
ether–Et2O (5:1, 2 × 20 mL), and the crude product was recrystal-
lized (hexane–EtOAc, 1:1) to give 16; yield: 0.55 g (75%); mp 128–
129 °C.
To a soln of 10 (0.50 g, 1.44 mmol) in DMF (10 mL) at 0 °C was
added NaN3 (0.28 g, 4.31 mmol). The resulting mixture was stirred
at 0 °C for 1 h and at r.t. for 30 min. Then ice cold H2O (70 mL) was
added and the soln was adjusted to pH 7 with 10% HCl soln. The
resulting precipitate was filtered with suction, washed with H2O (2
× 20 mL), dried in vacuo, and recrystallized (hexane–EtOAc, 1:1)
to afford 13; yield: 0.35 g (85%); mp 160–162 °C.
IR (KBr): 3319, 2127 (CN), 1609, 1576 (NO2), 1520, 1494, 1408,
1273, 1215 (NO2), 1090, 998, 857, 839, 788, 686, 510, 439 cm–1.
1H NMR (CDCl3): d = 10.11 (br s, 1 H, NH), 7.53 (d, J = 8.8 Hz, 2
H, CHCCl), 7.41 (d, J = 8.8 Hz, 2 H, CHCNH), 2.65 (s, 3 H, Me).
IR (KBr): 3426, 3327 (NH2), 2957, 2859, 1618, 1583, 1558, 1430,
1287, 1243, 1116, 974, 864, 773, 708, 670, 551, 528 cm–1.
13C NMR (CDCl3): d = 172.2 (C2), 153.1 (C4), 138.6 (C6), 134.0
(HNCq,Ph), 132.1 (ClCq,Ph), 129.3 (2 C, CHCCl), 126.5 (CNO2),
124.6 (2 C, CHCNH), 113.8 (CN), 26.3 (Me).
1H NMR (CDCl3): d = 8.29–8.37 (m, 2 H, Ph), 7.35–7.47 (m, 3 H,
Ph), 3.85–3.92 (m, 4 H, OCH2), 3.52 (br s, 2 H, NH2), 3.34–3.40 (m,
4 H, NCH2), 2.45 (s, 3 H, Me).
13C NMR (CDCl3): d = 154.9, 154.1, 149.5, 138.4 (Cq,Ph), 128.9
(CH, Ph), 128.2 (2 C, CPh), 127.7 (CNH2), 127.1 (2 C, CPh), 66.9 (2
C, OCH2), 48.1 (2 C, NCH2), 19.8 (CH3).
MS: m/z (%) = 289 [M+] (100), 272 [M+ – OH] (9), 254 [M+ – Cl]
(8), 243 [M+ – NO2] (12).
HRMS (ESI): m/z [M + H]+ calcd for C12H9ClN5O2: 290.04393;
found: 290.04391.
MS: m/z (%) = 270 [M+] (100), 225 (48), 213 (82).
HRMS (ESI): m/z [M + H]+ calcd for C15H19N4O: 271.15534;
found: 271.15533.
4-(4-Chlorophenylamino)-2-methyl-5-nitro-6-(1H-tetrazol-5-
yl)pyrimidine (14)
Following the typical procedure for 13 using 13 at r.t. for 10 h;
yield: 74%; mp 155–157 °C (MeOH–acetone, 1:1).
5-(Diacetylamino)-4-methyl-6-(morpholin-4-yl)-2-phenylpyri-
midine (17)
Following the typical procedure for 13 using 10 and NaN3 (5 equiv)
at r.t. for 10 h; yield: 65%.
To Ac2O (50 mL) was added 16 (0.55 g, 2.03 mmol). The resulting
mixture then was stirred at 105–110 °C for 3 h. The mixture was
cooled to r.t. and ice cold H2O (200 mL) was added. The resulting
precipitate was filtered off with suction and treated with H2O
(3 × 50 mL) and petroleum ether (2 × 20 mL) and dried in vacuo to
give 17; yield: 0.55 g (76%); mp 149–150 °C (MeOH–CHCl3, 2:1).
IR (KBr): 3365, 2186, 2126, 1609, 1567 (NO2), 1491, 1343, 1211
(NO2), 1092, 1012, 831, 504 cm–1.
1H NMR (DMSO-d6): d = 9.50 (br s, 1 H, NH-C6H4-Cl), 7.66 (d,
J = 8.8 Hz, 2 H, CHCCl), 7.41 (d, J = 8.8 Hz, 2 H, CHCNH), 2.50
(s, 3 H, Me).
13C NMR (DMSO-d6): d = 167.4 (C2), 156.2, 151.7, 148.5, 137.2
(HNCq,Ph), 134.4 (CNO2), 128.5 (2 C, CHCCl), 128.4 (ClCq,Ph),
125.0 (2 C, CHCNH), 26.0 (Me).
IR (KBr): 2964, 2865, 1716 (C=O), 1550, 1434, 1367, 1239, 1207,
1116, 1090, 983, 855, 776, 716, 586, 539 cm–1.
1H NMR (CDCl3): d = 8.36–8.44 (m, 2 H, Ph), 7.43–7.49 (m, 3 H,
Ph), 3.74–3.80 (m, 4 H, OCH2), 3.52–3.58 (m, 4 H, NCH2), 2.32 (s,
6 H, 2 Ac), 2.31 (s, 3 H, Me).
MS: m/z (%) = 332 [M+] (6), 289 (12), 286 [M+ – NO2] (4), 263 [M+
– CHN4] (10), 75 (100).
Synthesis 2008, No. 2, 304–310 © Thieme Stuttgart · New York

310
V. A. Zapol’skii et al.
PAPER
a = 921.5(3) pm, b = 1230.6(5) pm, c = 1369.6(6) pm,
13C NMR (CDCl3): d = 173.0 (C=O), 165.5, 162.4, 160.8, 137.2
(Cq,Ph), 130.7 (CH, Ph), 128.4 (2 C, CPh), 128.3 (2 C, CPh), 118.3
(C5), 66.7 (2 C, OCH2), 47.7 (2 C, NCH2), 25.8 (2 C, CH3), 20.6
(CH3).
V = 1315.1(9) × 106 pm3, Z = 4, dcalc = 1.551 g cm–3,
F(000) = 632, absorption coefficient = 0.503 mm–1 using
4346 independent reflections and 439 parameters.
R1 = 0.0420, wR2 = 0.1011 [I > 2s(I)], goodness of fit on
F2 = 1.082, residual electronic density = 0.463 and –0.341 e
A–3. Crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-645171. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK (fax: +44(1223)336033, e-
mail: fileserv@ccdc.ac.uk or http://www.ccdc.cam.ac.uk).
(4) Sheldrick, G. M. SHELX-97; University of Göttingen, 1997.
(5) Fanta, P. E.; Hedman, E. A. J. Am. Chem. Soc. 1956, 78,
1434.
MS: m/z (%) = 354 [M+] (92), 311 [M+ – Ac] (68), 268 [M+ – mor-
pholine] (73), 254 [M+ – NAc2] (39), 87 (100).
HRMS (ESI): m/z [M + H]+ calcd for C19H23N4O3: 355.17647;
found: 355.17667.
N-[4-Methyl-6-(morpholin-4-yl)-2-phenylpyrimidin-5-yl]acet-
imidic Acid (18)
To a suspension of 17 (0.20 g, 0.56 mmol) in MeOH (10 mL) was
added 64% hydrazine hydrate (0.084 g, 1.68 mmol) at 20 °C. The
resulting mixture was stirred at 40–45 °C for 6 h and then cooled to
r.t. Subsequently, the solvent was removed under reduced pressure.
The mixture then was treated with ice cold H2O (50 mL) to obtain a
precipitate that was filtered off with suction and washed with H2O
(2 × 50 mL) then dried in vacuo to give 18; yield: 0.16 g (93%);
mixture of E- and Z-isomers, ratio 3:1 (1H NMR); mp 160–161 °C
(MeOH–CHCl3, 1:1).
(6) Hurst, D. T.; Christophides, J. Heterocycles 1977, 6, 1999.
(7) Otzen, T.; Wempe, E.-G.; Kunz, B.; Bartels, R.; Lehwark-
Yvetot, G.; Haensel, W.; Schaper, K.-J.; Seydel, J. K. J.
Med. Chem. 2004, 47, 240.
(8) Remennikov, G. Y.; Boldyrev, I. V.; Kravchenko, S. A.;
Pirozhenko, V. V. Chem. Heterocycl. Compd. (Engl.
Transl.) 1993, 29, 1107.
IR (KBr): 3226, 2847, 1651, 1560, 1438, 1371, 1289, 1224, 1118,
1021, 986, 835, 760, 701, 588, 549 cm–1.
(9) Tanaka, M.; Murakami, Y.; Morita, H.; Takagi, K. Chem.
Pharm. Bull. 1985, 33, 2129.
1H NMR (CDCl3): d = 8.32–8.42 (m, 2.72 H, Ph), 7.40–7.51 (m,
4.08 H, Ph), 6.98 (br s, 0.36 H, OH), 6.70 (br s, 1 H, OH), 3.75–3.83
(m, 5.44 H, OCH2), 3.62–3.73 (m, 1.36 H, NCH2). 3.50–3.59 (m,
4.08 H, NCH2). 2.45 (s, 1.08 H, Me), 2.37 (s, 3 H, Me), 2.15 (s, 3 H,
Me), 1.86 (s, 1.08 H, Me).
13C NMR (CDCl3): d (major isomer) = 168.8, 165.3, 161.4, 161.0,
137.7 (Cq,Ph), 130.3 (1CH, Ph), 128.3 (2 CH, Ph), 128.1 (2 CH, Ph),
115.6 (C5), 66.7 (OCH2), 47.9 (NCH2), 23.2 (CH3), 21.2 (CH3); d
(minor isomer) = 172.9, 165.8, 161.6, 160.9, 137.3 (Cq,Ph), 130.6
(1CH, Ph), 128.4 (2 C, CPh), 128.2 (2 C, CPh), 115.4 (C5), 66.8 (2 C,
OCH2), 47.5 (2 C, NCH2), 21.1 (CH3), 20.2 (CH3).
(10) (a) Bork, J. T.; Lee, J. W.; Chang, Y.-T. QSAR Comb. Sci.
2004, 23, 245. (b) Lagoja, I. M. Chem. Biodiv. 2005, 2, 1.
(11) (a) Otmar, M.; Masojidkova, M.; Votruba, I.; Holy, A.
Bioorg. Med. Chem. 2004, 12, 3187. (b) Thompson, M. D.;
Cupps, T. L.; Wise, D. S.; Wotring, L. L.; Townsend, L. B.
J. Med. Chem. 1997, 40, 766. (c) Grigoryan, L. A.;
Kaldrikyan, M. A.; Srkoyan, L. A.; Arsenyan, F. G.;
Stepanyan, G. M.; Garibdzhanyan, B. T. Pharm. Chem. J.
(Engl. Transl.) 2000, 34, 110. (d) Chae, M.-Y.; Swenn, K.;
Kanugula, S.; Dolan, M. E.; Pegg, A. E.; Moschel, R. C. J.
Med. Chem. 1995, 38, 359. (e) Provins, L.; Christophe, B.;
Danhaive, P.; Dulieu, J.; Durieu, V.; Gillard, M.; Lebon, F.;
Lengele, S.; Quere, L.; van Keulen, B. Bioorg. Med. Chem.
Lett. 2006, 16, 1834. (f) Mikerova, N. I.; Panisheva, E. K.;
Nikolaeva, I. S.; Pushkina, T. V.; Fomina, A. N.; Granik, V.
G. Pharm. Chem. J. (Engl. Transl.) 1991, 25, 391.
(g) Zhang, H.; Schinazi, R. F.; Chu, C. K. Bioorg. Med.
Chem. 2006, 14, 8314. (h) Cryan, J. F.; Kelly, P. H.;
Chaperon, F.; Gentsch, C.; Mombereau, C.; Lingenhoehl,
K.; Froestl, W.; Bettler, B.; Kaupmann, K.; Spooren, W. P.
J. M. J. Pharmacol. Exp. Ther. 2004, 310, 952. (i) Urwyler,
S.; Pozza, M. F.; Lingenhoehl, K.; Mosbacher, J.; Lampert,
C.; Froestl, W.; Koller, M.; Kaupmann, K. J. Pharmacol.
Exp. Ther. 2003, 307, 322.
MS: m/z (%) = 312 [M+] (14), 297 [M+ – Me] (6), 254 [M+
–
(CH3C(OH)=N)] (12), 226 [M+ – morpholine] (8), 78 (100).
HRMS (ESI): m/z [M + H]+ calcd for C17H21N4O2: 313.16590;
found: 313.16587.
Acknowledgment
Financial support of this work by Bayer AG, Leverkusen, is grate-
fully acknowledged. We thank Dr. H. Frauendorf, University of
Göttingen, for high resolution mass spectra and M. Spillner, Claus-
thal University of Technology, for technical assistance.
(12) Zapol’skii, V. A.; Namyslo, J. C.; Gjikaj, M.; Kaufmann, D.
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V. Russ. J. Org. Chem. (Engl. Transl.) 1993, 29, 731.
(16) Potkin, V. I.; Zapol’skii, V. A.; Kaberdin, R. V. Izv. Akad.
Nauk Bel., Ser. Khim. Nauk. 1996, 40, 68.
(b) Zapol’skii, V. A.; Nutz, E.; Namyslo, J. C.; Adam, A. E.
W.; Kaufmann, D. E. Synthesis 2006, 2927. (c) Zapol’skii,
V. A.; Namyslo, J. C.; Blaschkowski, B.; Kaufmann, D. E.
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(2) Zapol’skii, V. A.; Potkin, V. I.; Nechai, N. I.; Kaberdin, R.
V.; Pevzner, M. S. Russ. J. Org. Chem. (Engl. Transl.) 1997,
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(3) All data of C10H12Cl2N4O3 were collected on a Stoe IPDS-II
single-crystal X-ray diffractometer with graphite
(17) Zapol’skii, V. A.; Potkin, V. I.; Nechai, N. I.; Kaberdin, R.
V.; Pevzner, M. S. Russ. J. Org. Chem. (Engl. Transl.) 1997,
33, 1461.
monochromated MoKa radiation (l = 0.71073 Å) at 223 K.
The crystal structure was solved by direct methods and
refined by full matrix least squares on F2 (SHELX-97)4 in
the triclinic space group P1 (Nr. 2), lattice parameters
Synthesis 2008, No. 2, 304–310 © Thieme Stuttgart · New York