Ring cleavage of dihydropyrimidine skeleton

Article abstract of DOI:10.1016/j.tetlet.2011.10.130

The first observation of ring cleavage between positions 1 and 2 of a 1,4-dihydropyrimidine skeleton was reported upon the nucleophilic addition of 4,6-unsubstituted 1,4-dihydropyrimidine with 3 equiv of an aniline derivative or phenylhydrazine in the pre

Full text of DOI:10.1016/j.tetlet.2011.10.130

Tetrahedron Letters 52 (2011) 7185–7188
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Tetrahedron Letters
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Ring cleavage of dihydropyrimidine skeleton
Hidetsura Cho a,b, , Eunsang Kwon a,c, Yoshizumi Yasui d, Satoshi Kobayashi b, Shin-ichiro Yoshida a,c
,
⇑
Yoshio Nishimura b,e, Masahiko Yamaguchi b,d
a Graduate School of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
b Graduate School of Pharmaceutical Sciences, Tohoku University, Japan
c Research and Analytical Center for Giant Molecules, Tohoku University, Japan
d WPI Advanced Institute for Materials Research, Tohoku University, Japan
e Faculty of Pharmacy, Yasuda Women’s University, 6-13-1, Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The first observation of ring cleavage between positions 1 and 2 of a 1,4-dihydropyrimidine skeleton was
reported upon the nucleophic addition of 4,6-unsubstituted 1,4-dihydropyrimidine with 3 equiv of an
aniline derivative or phenylhydrazine in the presence of 0.1 equiv of pyridinium p-toluenesulfonate
(PPTS) in CH2Cl2; the nucleophilic reactions of 4-methyl-6-unsubstituted 1,6(3,4)-dihydropyrimidine
with the same amines gave conventional substituted products at position 2. The effect of this ring open-
ing was found to be due to the electron density of the benzene ring of a nucleophilic amine. On the other
hand, aralkylamines, alkylamines, or heterocyclic amines did not cleave the skeleton. The ring-opening
chemical structure was confirmed by X-ray crystallographic analysis. This characteristically different
phenomenon may be due to the pattern of two C@C double bonds of 1,4-DP and 1,6(3,4)-DP as well as
to the effect of two substituted groups on the DP ring.
Received 27 September 2011
Accepted 21 October 2011
Available online 28 October 2011
Keywords:
Dihydropyrimidine
Ring cleavage
Ring opening
Dihydropyrimidine skeleton
Ó 2011 Elsevier Ltd. All rights reserved.
Dihydropyrimidine (DP) could be theoretically represented as
nine isomers including tautomers when it has different substituted
groups.1 Moreover, DPs in some cases are spontaneously oxidized
during isolation or storage. Therefore, they are unstable and some-
times difficult to handle. The Weis, Cho, Kappe, and Atwal groups
reported the synthesis of a series of 1,4(3,4)-dihydropyrimidines
(tautomeric mixture) (Fig. 1).1,2 Recently, we have disclosed excel-
lent results of nucleophilic substitution at position 2 of 1-tert-butyl
5-ethyl 4-methyl-2-methylsulfanyl-1,6-dihydropyrimidine-1,5-di
carboxylate 1, although substitution at position 2 of DPs has been
difficult because of low reactivity at the position.3 In this Letter, a
variety of DPs a were obtained in excellent yields. (Scheme 1, Eq.
1) In contrast, a series of substitutions at position 2 of 1-tert-butyl
5-ethyl 2-methylsulfanyl-1,4-dihydropyrimidine-1,5-dicarboxyl-
ate 2 did not afford the desired compounds, but provided an unusual
compound whose structure could not be determined at that time.
Since then, we have studied the difference in the reactivity between
DP 1 and 2. In this work, we clarified the surprising result that the
dihydropyrimidine skeleton was cleaved to a linear compound in
good yield instead of giving 2-aminodihydropyrimidine b.
dihydropyrimidine skeleton, although the skeleton is sometimes
oxidized to a pyrimidine skeleton.
Initially, we assumed that the alkoxycarbonylation of com-
pound c with Boc2O occurred at position 3 to provide the
R2
R2
R2
R3
R4
R3
R4
R3
R4
HN
N
N
R1
N
R1
N
R1
N
H
1,4-DP
3,4-DP
R2
4,5-DP
R2
R2
R3
R3
R4
R3
N
N
HN
R1
R1
N
H
R4
R1
N
H
N
R4
1,2-DP
1,6-DP
2,3-DP
R2
R2
R2
Generally, most heterocyclic rings cannot be easily cleaved. 4 No
report has been found on ring-opening reactions of the
R3
R4
R3
R4
R3
R4
HN
N
N
R1
N
R1
N
R1
N
⇑
Corresponding author. Tel.: +81 22 795 5501; fax: +81 22 795 5502.
E-mail addresses: hcho@m.pharm.tohoku.ac.jp, hcho@mail.pharm.tohoku.ac.jp
5,6-DP
2,5-DP
3,6-DP
(H. Cho).
Figure 1. Isomerization and tautomerism of dihydropyrimidines.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.130

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H. Cho et al. / Tetrahedron Letters 52 (2011) 7185–7188
6
the observation of 1.4% NOE between the olefin proton and the t-
Bu protons of the Boc group.
1
Boc
CO2Et
Me
Boc
CO2Et
Me
R1R2NH
N
N
N
5
(eq 1)
(eq 2)
2
PPTS
CH2Cl2
Therefore, the position of the protecting group was proved to be
the other position. Thus, the nucleophilic reaction of DP 2 with
3 equiv of aniline in the presence of 0.1 equiv of pyridinium p-tol-
uenesulfonate (PPTS) in CH2Cl2 was carried out at room tempera-
ture for 9 h to give an unidentified solid compound as the sole
product in a 65% yield.5 The 1H NMR of the product was not what
was expected for b; both methylthio and phenylamino groups
were clearly present. However, this could not be assigned to the
chemical structure of f (Scheme 2). Therefore, X-ray crystallo-
graphic analysis was performed. To our surprise, the ORTEP draw-
ing of the compound revealed the chemical structure of (E)-ethyl
3-tert-butoxycarbonylamino-2-[(Z)-2-methyl-3-phenylisothioure-
ido-methyl]acrylate 3a, the result of the ring cleavage of the dihy-
dropyrimidine skeleton (Fig. 2).6
MeS
R1R2N
N
a
4
N
1
3
6
1
N
Boc
CO2Et
R1R2NH
Boc
CO2Et
5
2
R1R2N
4
MeS
N
2
PPTS
CH2Cl2
N
b
3
Scheme 1. Difference in nucleophilic substitution between dihydropyrimidines.
compound d2a and that the successive nucleophilic addition of an
amine should afford the compound e. However, the NMR
characterization of the chemical structure of the alkoxycarbonylat-
ed compound did not indicate d but rather compound 2 because of
4
5
CO2Et
H
Boc
CO2Et
H
Boc
CO2Et
H
3
N
2
N
NaH
N
6
MeS
N
H
MeS
N
Boc2O
PhHN
N
1
d
e
c
NaH
Boc2O
Y
1
N
CO2Et
Boc
CO2Et
X-C6H3NH2
N
3
MeS
N
Boc
H
MeS
N
PPTS
CH2Cl2
1
3
NOE
2
2
6
5
Boc
CO2Et
N
H
Boc
CO2Et
1
N
3
HN
4
MeS
N
H
2
NH
N
SMe
Y
f
3
X
Y
X
Scheme 2. Unusual ring cleavage of dihydropyrimidine skeleton with amine.
o
1.342(2) A
Boc
CO2Et
N
H
o
HN
1.506(2) A
N
SMe
Ph
3a
Figure 2. ORTEP drawing of 3a with probability ellipsoids drawn at 50% level.

H. Cho et al. / Tetrahedron Letters 52 (2011) 7185–7188
7187
hand, it is assumed that, in the case of reactions of the compound
1 with amines, elimination occurred to afford the compound a
(Scheme 1) so that a product as shown in C in Figure 3 generated
H
b
O+
O+
H
N
b
O
O
a
β
tBu
Et
tBu
Et
O
O
O
N
O
α
a
a,b-and
c,d-conjugated double bonds.
b
N
MeS
MeS
Subsequently, we examined the generality of the ring cleavage
N
NH H
NH H
reaction of a dihydropyrimidine skeleton. Under the same reaction
conditions, a variety of amines and hydrazine were subjected to
the reactions, such as 4-methoxyaniline, 4-nitroaniline, 4-methy-
laniline, 3,4-dimethoxyaniline, benzylamine, n-hexylamine, phen-
ylhydrazine, 2-aminothiazole and 2-aminoimidazole. The results
are shown in Table 1.
Y
Y
X
X
A
B
O
O
tBu
Et
Thus, ethyl 3-tert-butoxycarbonylamino-2-[3-(4-methoxyphen
yl)-2-methylisothioureidomethyl]acrylate 3b and ethyl 3-tert-but-
oxycarbonylamino-2-[3-(3,4-dimethoxyphenyl)-2-methylisothio-
ureidomethyl]acrylate 3e were obtained in 95% and 88% yields,
respectively, without the recovery of the starting material 2 (entries
2 and 5). In contrast to these results, 4-nitroaniline with an electron-
withdrawing group did not cleave the dihydropyrimidine ring, but
the starting material was recovered. Therefore, it was clarified that
the electron density in the benzene ring (nucleophilicity of the
amines) plays a crucial role in the unusual cleavage reaction. The
ring-opening reaction did not proceed to completion using 2-
methylaniline presumably because of the steric hindrance of the
methyl group (entry 4). Aralkylamines or alkylamines, such as
benzylamine or n-hexylamine, as well as heterocyclic amines,
2-aminothiazole or 2-aminoimidazole, were subjected to the reac-
tion. However, they did not furnish the linear compound 3 but led
to the recovery of the compound 2, because the nitrogen atom of
an aralkylamine and an alkylamine may be protonated by PPTS
and have its nucleophilicity diminished. Subsequently, we studied
phenylhydrazine instead of amines as the nucleophile and found
that it also cleaved the dihydropyrimidine ring to afford the
compound 3f in 34% yield, accompanied by the substituted and
cyclized product, ethyl 3-oxo-2-phenyl-2,3,7,8-tetrahydro[1,2,4]
triazolo-[4,3-a]pyrimidine-6-carboxylate 4 in 8% yield and the
recovery of 2 in 32% yield (Scheme 3).
O
N
O
α
MeS
δ
N
H
γ
Me
β
NH
Y
X
C
Figure 3. Elimination by effect of a,b-unsaturated ester group and/or Boc group.
Table 1
Results of ring cleavage of dihydropyrimidine skeleton
Boc
CO2Et
N
H
RNH2 or
PhNHNH2
Boc
CO2Et
N
HN
PPTS
MeS
N
N
R'
SMe
CH2Cl2
2
rt
3
Entry
Amine or hydrazine
Time (h)
Product
Yield (%)
1
2
3
4
5
6
C6H5NH2
9
6
24
24
24
12
3a
3b
3c
3d
3e
3f
65
95
78
24
88
24
4-MeOC6H4NH2
4-MeC6H4NH2
2-MeC6H4NH2
3,4-di(MeO)C6H3NH2
C6H5NHNH2
In summary, nucleophilic reactions of the dihydropyrimidines 1
and 2 with amines or phenylhydrazine provided the markedly
different results described. This result is due to the difference in
pattern between the two C@C double bonds of 1,4-DP and
1,6(3,4)-DP as well as to the effect of two substituted groups on
the DP ring shown in Figure 3. Consequently, a novel cleavage reac-
tion of 1,4-dihydropyrimidine skeleton was observed, although
1,4-DP is usually more stable than 1,6(3,4)-DP. In addition, the ef-
fect of this ring opening was found to be due to the electron den-
sity of the benzene ring of nucleophilic amines. Our findings may
serve future research on dihydroheterocycles as well as on
dihydropyrimidines.
⁄R0 = R or PhNH (in compound 3).
The ORTEP drawing of 3a confirmed that the position of the Boc
group was not N-3 but N-1, and that the location of the double
bond was as shown in Figure 2, determined by comparing two
bond lengths [1.342(2) angstroms (C@C) and 1.506(2) angstroms
(C–C)].
Thus, the reaction proceeded not as in B but as in A (Fig. 3) to
yield the ring-opening compound 3, presumably by the effect of
an
a,b-unsaturated ester group and/or a Boc group. On the other
Boc
CO2Et
N
H
HN
Boc
CO2Et
Boc
CO2Et
N
N
N
SMe
MeS
NHC6H5
N
3f
MeS
N
H
HN
NHC6H5
O
N
2
CO2Et
C6H5
N
N
N
H
4
Scheme 3. Unusual ring cleavage of dihydropyrimidine skeleton with phenylhydrazine and preparation of bicyclic compound 4.

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H. Cho et al. / Tetrahedron Letters 52 (2011) 7185–7188
Takeuchi, Y.; Hamaguchi, M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda, M.;
Acknowledgments
Ishihara, T.; Funahashi, K.; Satoh, F.; Morita, M.; Noguchi, T. J. Med. Chem. 1989,
32, 2399–2406; (m) Atwal, K. S.; Rovnyak, G. C.; Kimball, S. D.; Floyd, D. M.;
Moreland, S.; Swanson, B. N.; Gougoutas, J. Z.; Schwartz, J.; Smillie, K. M.; Malley,
M. F. J. Med. Chem. 1990, 33, 2629–2635; (n) Rovnyak, G. C.; Atwal, K. S.;
Hedberg, A.; Kimball, S. D.; Moreland, S.; Gougoutas, J. Z.; O’Reilly, B. C.;
Schwartz, J.; Malley, M. F. J. Med. Chem. 1992, 35, 3254–3263; (o) Cho, H.; Yasui,
Y.; Kobayashi, S.; Kwon, E.; Arisawa, M.; Yamaguchi, M. Heterocycles 2011, 83,
1807–1818.
We appreciate the financial support of the Tohoku University G-
COE program ‘IREMC’. This work was also supported by the finan-
cial support of Japan Tobacco Inc to H.C.
Supplementary data
3. Cho, H.; Nishimura, Y.; Yasui, Y.; Kobayashi, S.; Yoshida, S.; Kwon, E.; Yamaguchi,
M. Tetrahedron 2011, 67, 2661–2669.
Supplementary data (NMR, IR, MS spectra of products 3 and 4,
and X-ray data of 3a) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.130.
4. Acquadro, F.; Oulyadi, H.; Venturello, P.; Maddaluno, J. Tetrahedron Lett. 2002,
43, 8759–8763.
5. General procedure for the ring cleavage of dihydropyrimidine skeleton:
solution of dihydropyrimidine (15.4 mg, 0.0513 mmol), aniline (13.8
A
L,
2
l
14.1 mg, 0.151 mmol) and pyridinium p-toluenesulfonate (1.31 mg,
0.00522 mmol) in CH2Cl2 (1.0 mL) was stirred for 9 h at rt. The reaction
mixture was quenched with water and the organic materials were extracted
with EtOAc. The combined organic layer was washed with water and brine,
dried over Na2SO4, and evaporated under reduced pressure to leave the residue,
which was purified by silica gel column chromatography (n-
hexane:EtOAc = 10:0 ? 8:2) to give 3a (13.2 mg, 65%) as colorless needles; mp
132.2–133.5 °C (n-hexane); IR (KBr): 3388, 2981, 1731, 1685, 1651, 1566, 1508,
1490, 1234, 1155 cm1; 1H NMR (400 MHz, CDCl3): d 1.31 (9H, s, CMe3), 1.31 (3H,
t, J = 7.2 Hz, CH2CH3), 2.19 (3H, s, SCH3), 4.21 (2H, q, J = 7.2 Hz, CH2CH3), 4.26
(2H, d, J = 6.4 Hz, CH2NH), 5.17 (1H, t, J = 6.4 Hz, CH2NH), 6.94 (2H, d, J = 8.0 Hz,
Ar-o-H), 7.05 (1H, t, J = 8.0 Hz,, Ar-p-H), 7.26 (2H, d, J = 8.0 Hz, Ar-m-H), 7.98 (1H,
d, J = 11.2 Hz, CHNH), 10.48 (1H, d, J = 11.2 Hz, CHNH); 13C NMR (100 MHz,
CDCl3): d 14.0, 14.4, 27.8, 38.0, 60.3, 81.3, 107.7, 123.0, 123.2, 128.6, 139.3,
148.3, 152.8, 155.5, 168.6; LRMS (EI) m/z: 393 (M+); HRMS: calcd for
References and notes
1. (a) Traube, W.; Schwarz, R. Chem. Ber. 1899, 32, 3163–3174; (b) Weis, A. L.
Tetrahedron Lett. 1982, 23, 449–452; (c) Weis, A. L.; van der Plas, H. C.
Heterocycles 1986, 24, 1433–1455; (d) Cho, H.; Iwashita, T.; Ueda, M.; Mizuno,
A.; Mizukawa, K.; Hamaguchi, M. J. Am. Chem. Soc. 1988, 110, 4832–4834; (e)
Wendelin, W.; Schermanz, K. J. Heterocycl. Chem. 1984, 21, 65–69.
2. (a) Cho, H.; Shima, K.; Hayashimatsu, M.; Ohnaka, Y.; Mizuno, A.; Takeuchi, Y. J.
Org. Chem. 1985, 50, 4227–4230; (b) Cho, H.; Ohnaka, Y.; Hayashimatsu, M.;
Ueda, M.; Shima, K. Tetrahedron Lett. 1986, 27, 6377–6380; (c) Cho, H.; Mizuno,
A.; Shima, K.; Ueda, M.; Takeuchi, Y.; Hamaguchi, M.; Taniguchi, N. Heterocycles
1988, 27, 769–774; (d) Weis, A. L. Synthesis 1985, 528–530; (e) Kashima, C.;
Shimizu, M.; Katoh, A.; Omote, Y. Tetrahedron Lett. 1983, 24, 209–212; (f) Cho,
H.; Takeuchi, Y.; Ueda, M.; Mizuno, A. Tetrahedron Lett. 1988, 29, 5405–5408; (g)
Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J. J. Org. Chem. 1989, 54,
5898–5907; (h) Matloobi, M.; Kappe, C. O. J. Comb. Chem. 2007, 9, 275–284; (i)
Kappe, C. O. Tetrahedron 1993, 49, 6937–6963; (j) Kappe, C. O. Eur. J. Med. Chem.
2000, 35, 1043–1052; (k) Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1–116; (l)
Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu, M.; Ohnaka, Y.;
C
19H27N3O4S, 393.1722; found, 393.1727.
6. Crystallographic data for compound 3a has been deposited with the Cambridge
Crystallographic Data Centre (CCDC). The coordinates can be obtained on
request from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. The
CCDC Number of 3a is 842456.