Synthesis of 4-unsubstituted dihydropyrimidines. Nucleophilic substitution at position-2 of dihydropyrimidines

Article abstract of DOI:10.1016/j.tet.2011.01.092

Synthesis of novel 4-unsubstituted dihydropyrimidines (DPs) was performed. Subsequently, a variety of 4-unsubstituted 1,4(3,4)-DPs with amino moieties at position-2 were obtained in excellent yields by activation of position-2 owing to regioselective alkoxycarbonylation at position-3 of the DP skeleton. 3-Oxo-2-phenyl-2,3,5,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine was obtained using phenylhydrazine instead of amines. Individual tautomers of 1,4(3,4)-DP were observed in the ¹H NMR spectra of one derivative depending on temperature and concentration. On the other hand, only 1,4-DP was found in the solid state by single-crystal X-ray crystallography.

Full text of DOI:10.1016/j.tet.2011.01.092

Tetrahedron 67 (2011) 2661e2669
Contents lists available at ScienceDirect
Tetrahedron
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Synthesis of 4-unsubstituted dihydropyrimidines. Nucleophilic substitution
at position-2 of dihydropyrimidines
,
b
,
b
,
,d
Hidetsura Cho a , Yoshio Nishimura e, Yoshizumi Yasui c, Satoshi Kobayashi b, Shin-ichiro Yoshida a
,
*
Eunsang Kwon a d, Masahiko Yamaguchi b
,
,c
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 WPI Advanced Institute for Materials Research, Tohoku University, Japan
d Research and Analytical Center for Giant Molecules, 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:
Synthesis of novel 4-unsubstituted dihydropyrimidines (DPs) was performed. Subsequently, a variety of
4-unsubstituted 1,4(3,4)-DPs with amino moieties at position-2 were obtained in excellent yields by
activation of position-2 owing to regioselective alkoxycarbonylation at position-3 of the DP skeleton.
3-Oxo-2-phenyl-2,3,5,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine was obtained using phenylhydrazine
instead of amines. Individual tautomers of 1,4(3,4)-DP were observed in the 1H NMR spectra of one
derivative depending on temperature and concentration. On the other hand, only 1,4-DP was found in
the solid state by single-crystal X-ray crystallography.
Received 8 December 2010
Received in revised form 28 January 2011
Accepted 28 January 2011
Available online 1 March 2011
Keywords:
Dihydropyrimidine
Tautomerism
Ó 2011 Elsevier Ltd. All rights reserved.
Individual tautomer
X-ray diffraction
Nucleophilic substitution
2,3,5,8-Tetrahydro[1,2,4]triazolo[4,3-a]
pyrimidine
1. Introduction
which have a methylene group at position-4 and an amino group at
position-2 (Fig. 2). Straightforward access to this class of DPs might
Dihydropyrimidine (DP) could be theoretically represented as
nine isomers including tautomers when it bears different
substituted groups.1 Moreover, DPs in some cases were spontane-
ously oxidized during isolation or storage and decomposed under
acidic conditions. Therefore, it is unstable and sometimes difficult to
handle.2 The Cho, Kappe, and Atwal groups reported the synthesis
of a series of 1,4 (3,4)-dihydropyrimidines (tautomeric mixture)
A,2a,3c 4,5-DP B,2b N-substituted 3,4-DP C,2a,c dihydropyrimidin-2-
ones (thiones) D,3a,b,4 N-substituted dihydropyrimidin-2(1H)-ones
(thiones) E,3a,b,5b and N-substituted dihydropyrimidin-2(3H)-ones
F3a (Fig. 1). The classes of the compounds C5a,b and E5b,c have
received significant attention because of their pharmacological ac-
tivity in the cardiovascular system.5 Studies of DPs having the 4-
phenyl group have predominated over those of 4-unsubstituted DPs
owing to their synthetic accessibility2aec,4a,b as well as to their
pharmacological activity. During our studies of the synthesis of HCV
inhibitors,6 we sought to obtain the intermediates DPs 1 and 2,
be through the condensation of guanidine derivatives, formalde-
hyde, and acetoacetate. However, there is no example of this type of
condensation presumably because of the difficulty in controlling
the reaction with highly reactive formaldehyde or its equivalents.
In addition, the difficulty may be due to the instability of the
4-unsubstituted DPs2d,7 to oxidation. In order to obtain novel
4-unsubstituted DPs with an amino moiety, we planned to develop
a method for the nucleophilic substitution of 2-methylthio DP G,
which can be obtained from dihydropyrimidin-2-ones (thiones)
H3,4 (Scheme 1). We thought that it might be useful to provide
a series of 2-amino-4-unsubstituted DPs I not only for our synthetic
interest in HCV inhibitors but also for other studies of medicinal
chemistry.
However, the reactivity at position-2 of dihydropyrimidines
(DP) is quite different from that of pyrimidines. In fact, compared
with well-known nucleophilic substitutions of pyrimidines having
a leaving group at position-2,3c,8 those of DPs are rare because of
low reactivity at position-2. Actually, our theoretical study revealed
that the LUMO energy level of DPs, such as 2-chlorodihydropyr-
imidine-5-carboxylic acid (3,4-DP J and 1,4-DP K) was higher about
11.8e17.5 kcal/mol than that of 2-chloropyrimidine-5-carboxylic
* Corresponding author. Tel.: þ81 22 795 5501; fax: þ81 22 795 5502; e-mail
address: hcho@mail.pharm.tohoku.ac.jp (H. Cho).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.092

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H. Cho et al. / Tetrahedron 67 (2011) 2661e2669
77% yield by aminolysis (NH3/NH4Cl, 70 ꢀC, 12 h, in a sealed tube)
with the DP having a pyrazole moiety at position-2.9
However, the nucleophilic substitution at position-2 of 4-
unsubstituted DPs G was not reported. Herein, we report the syn-
thesis of novel 4-unsubstituted DP I by nucleophilic substitution.
2. Results and discussion
2.1. Synthesis of 4-unsubstituted DPs 4 and 8
Initially, synthesis of 4-unsubstituted DPs 4 and 8 was carried out.
Thus, compound 3 was prepared from thiourea a, ethyl acetoacetate,
and formaldehyde in the presence of 10 mol % TEBA (benzyl-
triethylammonium chloride) at 100 ꢀC for 30 min (Scheme 2).10 The
methylation of 3 with CH3I (10 equiv) afforded DP 4 in 76% yield.
Fig. 1. A variety of dihydropyrimidines.
Scheme 2. Synthesis of dihydropyrimidines with a methylene group and pyrimidine
with an oxo group at position-4.
Fig. 2. Dihydropyrimidines with methylene group at position-4. (In order to simplify
discussion of results, the numbering system as indicated in Figs. 1 and 2 is used
throughout; but, proper nomenclature is assigned to each compound as it appears in
the Experimental section.)
Subsequently, to obtain DPs without a methyl group at position-6,
the cyclization of urea b with ethyl 3-ethoxy-2-methoxymethylene-
propionate 512 was carried out to afford dihydropyrimidin-2-one 6.
Treatment of 6 with P2S5 furnished dihydropyrimidin-2-thione 7 in
57% yield. On the other hand, the direct synthesis of 7 from thiourea
a and 5 gave a complex mixture. The methylation of 7 was performed
with 10 equiv of CH3I in Et3N/CH3OH at 45 ꢀC for 1 h to afford DP 8.
However, the cyclization of 2-methyl-2-thiopseudourea sulfate c
with 5 under similar conditions did not give 8, because compound 8
was very unstable to oxygen and easily decomposed. Therefore,
compound 8 was immediately subjected to next reaction.
The cyclization of 2-methyl-2-thiopseudourea sulfate c and 913
provided pyrimidine 108a with an oxo group at position-4 in the
presence of NaOEt/EtOH at room temperature for 15 h in 81%
yield.
Scheme 1. Nucleophilic substitution at position-2 of dihydropyrimidines.
2.2. Tautomerism of DP 4
acid L. This high lying LUMO energy level of DPs induced a barrier
for attack by the HOMO of the nucleophiles, such as aniline
(Supplementary data).
Generally, individual tautomers of heterocycles are not ob-
served at room temperature in 1H NMR spectra, but a mixture of
two individual tautomers in 1H NMR (CDCl3 and DMSO-d6) was
observed in the case of DP 4 (Fig. 3). In each solvent, the signals of
Thus, only a few reports are limited to substitution at position-2
of 4-phenyl-DPs,1e,3b,c,9 which are more stable and easily isolated
than 4-unsubstituted DP. Moreover, the yields are not always sat-
isfactory. Namely, Atwal reported the construction of 2-amino-4-
phenyl DPs by aminolysis with NH3 or CH3NH2 at position-2 of 1,4
(3,4)-DPs C (R1¼OCH3) in 30e54% yield (Fig. 1).3b Kappe obtained
2-benzylamino-1,4-DP A in 58% yield by the microwave irradiation
of a mixture of the 2-methylthio-1,4-DP TFA salt A and benzylamine
at 120 ꢀC.3c Overman reported the synthesis of 2-amino-DP A in
NH protons (
methylene protons (
d
9.24, 8.19 in DMSO-d6,
d
5.89, 5.16 in CDCl3) and two
4.29, 4.12 in CDCl3)
d
4.10, 3.92 in DMSO-d6,
d
indicated that the two isomers were the 1,4- and 3,4-dihy-
droisomers, and other isomers were ruled out. The major isomer
was assigned to the 1,4-dihydroisomer by HSQC (Heteronuclear
Single Quantum Correlation) and HMBC (Heteronuclear Multiple
Bond Correlation) experiments (Supplementary data). The ratio of

H. Cho et al. / Tetrahedron 67 (2011) 2661e2669
2663
1
Fig. 3. H NMR of the tautomeric mixture of DP 4 (0.100 M, 25 ꢀC) in DMSO-d6.
1,4-DP (major) and 3,4-DP (minor) tautomers of 4 changed in
CDCl3 and DMSO-d6 depending on temperature or concentration
(Tables 1 and 2). Thus, the 1,4-DP major isomer gradually de-
creased in amount and was converted into the 3,4-DP isomer at
elevated temperatures or high concentrations. When a 0.012 M
solution of DP 4 in CDCl3 was heated from 5 ꢀC to 55 ꢀC, the ratio of
1,4-/3,4-DP changed from 5.9 to 3.5. Similarly, the ratio of 1,4-/3,4-
DP changed from 7.5 to 4.2 in DMSO-d6 (0.050 M) when the tem-
perature was changed from 15 ꢀC to 85 ꢀC. At the same temperature
(25 ꢀC), the ratio of 1,4-/3,4-DP (4.7) was observed from 0.012 M to
0.025 M in CDCl3 but not in 0.050 M (average spectrum), or the ratio
of 1,4-/3,4-DP (from 7.0 to 6.5) was observed from 0.012 M to
0.100 M in DMSO-d6. Interestingly, the single-crystal X-ray crystal-
lographic analysis of DP 4 revealed only the 1,4-DP form, because of
Fig. 4. ORTEP drawing of 1,4-DP 4.
ꢀ
its double-bond character: (i) C(2)eN(3) (1.263(3) (A)) (ii) C(2)eN
11
ꢀ
ꢀ
2.3. Regioselective alkoxycarbonylation at position-3 or
position-1
(1) (1.382(3) (A)) (iii) N(1)eC(2) (1.386(3) (A)) (Fig. 4). Therefore,
when a crystal (1,4-form) was dissolved in each solvent, tautom-
erism was initiated and the solution became a mixture of 1,4-DP and
3,4-DP.
The nucleophilic substitution of amine 11 to DPs 4, 8, and py-
rimidine 10 was investigated (Scheme 3). When both DPs 4 and 8
were treated with aromatic amine 11 in n-BuOH at 115 ꢀC for 12 h,
neither of the desired compounds 1 and 2 was obtained and
a complex mixture resulted. On the other hand, the reaction of 11
with pyrimidine 10 furnished 2-amino DP 12 in 67% yield. The
successful result of the reaction from 10 and 11 led us to the as-
sumption that the oxo group at position-4 together with the ester
group activated position-2 through the conjugate double bond
system of 10. Therefore, alkoxycarbonylation of an electron-with-
drawing group (a Boc group) at position-3 of DPs was carried out,
considering that introduction of this group to 4 or 8 may enhance
the activity of position-2 through a conjugated double bond system
by an electron-withdrawing ester group at position-5. Thus, the
reaction of the sodium salt of compound 3 in DMF with 2 equiv of
Table 1
Tautomerization of 4 in 1H NMR in CDCl3
Concentration (M)
Temperature (ꢀC)
Ratio of 1,4-/3,4-DP 4
0.012
0.025
0.050
0.100
0.012
0.012
0.012
0.012
0.012
25
25
25
25
5
15
35
45
55
4.7
4.7
Average spectrum
Average spectrum
5.9
5.3
4.6
4.3
3.5
Table 2
Tautomerization of 4 in 1H NMR in DMSO-d6
Concentration (M)
Temperature (ꢀC)
Ratio of 1,4-/3,4-DP 4
0.012
0.025
0.050
0.100
0.050
0.050
0.050
0.050
0.050
0.050
0.050
0.050
25
25
25
25
15
35
45
55
65
75
85
95
7.0
6.8
6.6
6.5
7.5
6.1
5.9
5.4
4.7
4.4
4.2
Scheme 3. Nucleophilic substitution of amine 11 to dihydropyrimidines 4, 8, and
pyrimidine 10.
Average spectrum

2664
H. Cho et al. / Tetrahedron 67 (2011) 2661e2669
Table 3
di-tert-butyl dicarbonate (Boc2O) occurred regioselectively to give
3-N-substituted DP 13 in 90% yield (Scheme 4).2a,3b The regiose-
lectivity of Boc protection was confirmed by three-bond long-range
coupling (HMBC) between methylene protons at position-4 and
the carbonyl carbon of the Boc group (Supplementary data). The
selectivity of 3 to 13 may be due to more steric hindrance around
position-1 because of the methyl group of 3. The successive
methylation of 13 was carried out with 10 equiv of CH3I in Et3N/
CH3OH at 45 ꢀC for 1 h to afford 3,4-DP 14 in 87% yield. The pro-
tection of 7 under the same reaction conditions gave no protected
compound corresponding to 13 but yielded a mixture. Therefore,
DP 7 was initially converted to 8 by methylation, followed by pro-
tection to selectively furnish a single compound 15 in 44% yield
(two steps). The position of the Boc group was determined to be
position-1 by an NOE experiment (Supplementary data). Thus,
Nucleophilic substitution of amines to dihydropyrimidine 14
Boc
CO2Et
Boc
CO2Et
Me
R5R6NH
CH2Cl2
N
N
MeS
N
14
Me
R5R6N
N
16
Entry
1
R5R6NH
Temp
Time (h)
24
Product
Yield (%)
97
Reflux
16a
16a
16b
16c
NH2
2a
3
rt
6.5
24
89
91
92
NH2
Reflux
Reflux
MeO
NH2
4
24
MeO2C
NH2
when the t-Bu group (
enhancement (1.4%) at H-6 (
sition-1 of the Boc group. On the other hand, when the t-Bu group
¼1.53) of 14 was irradiated, a positive NOE (1.5%) was observed at
H-4 (
¼4.34).
d
¼1.57, in CDCl3) of 15 was irradiated, an NOE
O
d
¼7.78) was observed, indicating po-
5
Reflux
24
16d
84
Me2N
NH2
(d
6a
7a
Reflux
24
1
16e
16f
90
91
NH2
NH2
d
O
rt
NH2
8a
Reflux
Reflux
24
24
16g
16h
76
44
9a
NH
a
With 0.1 equiv of PPTS.
An exceptional result was obtained in the reaction of phenyl-
hydrazine (0.1 equiv of PPTS, room temperature, 2 h) (Scheme 5).
The generation of bicyclic DP 17 lacking the t-Boc group was sug-
gested by 1H NMR and mass spectra. The phenyl group was pre-
sumed to be at position-2 of the bicyclic DP, on the basis of the
reaction mechanism: the primary nitrogen initially attacked the
carbon at position-2 of DP, and then the secondary nitrogen reacted
withthe carbonyl carbon of the t-Boc groupto construct the3-oxo-2-
phenyl-2,3,5,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine skeleton.
The chemical structure of 17 was confirmed by X-ray crystallo-
graphic analysis (Fig. 5 and Supplementary data).11
Scheme 4. Preparation of dihydropyrimidin-2-thione, 3,4- and 1,4-dihydropyrimidine
derivatives.
2.4. Substitution of 4-unsubstituted DP with amines or
phenylhydrazine
Subsequently, the nucleophilic substitution of a wide variety of
aromatic and aliphatic amines was investigated (Table 3).
Initially, the substitution of 14 with 11 was carried out under
the same reaction conditions as those of Scheme 3. However,
N-Boc compound of 1 was not obtained, but a complex mixture
resulted. Therefore, milder reaction conditions were examined.
Thus, a mixture of DP 14 and 3 equiv of aniline in CH2Cl2 was
heated at reflux to provide DP 16a in 97% yield after 24 h (entry 1).
It was found that the addition of 0.1 equiv of pyridinium p-tol-
uenesulfonate (PPTS) resulted in the completion of the reaction
within 6.5 h at room temperature, but in a slightly lower isolated
yield (entry 2). The faster completion may be due to activation by
the protonation on the carbonyl group of the ester or the N-1
atom of DP. Since aromatic amines showed higher reactivity,
conditions without PPTS were evaluated (entries 3e5). Also, the
electronic effect of functional groups on the aromatic ring was
examined using aniline derivatives with an electron-donating
group, OMe or an electron-withdrawing group, COOMe. The
compounds 16b and 16c were obtained in more than 90% yield
without finding any effect by different functional groups at posi-
tion-4. Different from the result of substitution of 4 with 11, de-
sired DP 16d was obtained from the reaction of Boc-protected
compound 14 with 11 in 84% yield under the reaction conditions
(entry 5). In the case of aliphatic amines, it was better to add PPTS
to complete the reaction in a reasonable period (entries 6e8). But
secondary amines were found to react very slowly under these
conditions. For example, Et2NH and piperazine gave no adduct
with the recovery of the starting material. Only a less hindered
pyrrolidine could attack the C-2 position to furnish compound 16h
in moderate yield (entry 9).
Scheme 5. Bicyclic dihydropyrimidine 17.
Fig. 5. ORTEP drawing of 1,4-DP 17 with 30% thermal ellipsoid probability.
1,4(3,4)-DPs 18 without any substitution at position-4 were
isolated after the deprotection of 16 with trifluoroacetic acid (TFA)
at room temperature, as shown in Table 4. Thus, compound 114 was
obtained from 3 in excellent yield as a stable powder. Regarding the

H. Cho et al. / Tetrahedron 67 (2011) 2661e2669
2665
Table 4
Deprotection of 16 with TFA
The synthetic methods and compounds described herein will
likely find use in the field of fine chemistry and medicinal chemistry.
Boc
N
CO2Et
Me
CO2Et
Me
TFA
N
4. Experimental section
4.1. General
R5R6N
CH2Cl2
rt, 1 h
R5R6N
N
16
N
18
R5R6N
Entry
1
Product
Yield (%)
quant.
Unless otherwise noted, reactions were performed under argon.
Melting points were determined on Yanaco micro melting point
apparatus and uncorrected. IR spectra were measured on SHI-
MADZU FTIR-8300 spectrometer. 1H NMR spectra were recorded on
a Varian Mercury (400 MHz) or a Bruker AVANCE III 600 (600 MHz)
with tetramethylsilane (0 ppm), CD3OD (3.30 ppm) or DMSO-d6
(2.49 ppm) as an internal standard. The abbreviations of signal
patterns are follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet; br, broad. 13C NMR spectra were recorded on a Varian
Mercury (400 MHz) or a Bruker AVANCE III 600 (600 MHz) with
CDCl3 (77.0 ppm), CD3OD (49.0 ppm) or DMSO-d6 (39.7 ppm) as an
internal standard. Mass spectra were recorded on a JMS-DX303,
JMS-700 or JMS-T100GC spectrometer. Elemental analyses were
performed by Yanaco CHN CORDER MT-6. Flash column chroma-
tography was performed on silica gel 60 N (Kanto, 40e60 mm)
using indicated solvent. Reactions and fractions of chromatography
were monitored by employing pre-coated silica gel 60 F254 plates
(Merck).
H
N
18a
H
N
2
3
18b
18c
quant.
96
MeO
H
MeO2C
N
O
4
1
quant.
Me2N
N
H
H
5
6
18e
18f
84
84
N
H
O
N
HN
7
8
18g
18h
94
78
N
stability of DPs 18, compounds 18e with an alkyl amino residue and
18f with a benzyloxyamino residue were so unstable as to be par-
tially oxidized to pyrimidine derivatives during SiO2 column chro-
matography or even on standing at room temperature.
On the other hand, the nucleophilic substitution of 6-unsub-
stituted compound 15 with aniline or 4-methoxyaniline gave no
substituted DP under the same reaction conditions for that of 14
with the amines.
Consequently, for nucleophilic substitution at position-2 of
dihydropyrimidines and pyrimidine, we obtained different results
for reactions from 4 to 1 and from 10 to 12 (Scheme 3), and com-
parative results for reactions from 4 to 1 and from 14 to 16d
(Scheme 3 and Table 3). In the case of DP having an electron-with-
drawing group (a Boc group) at position-3, the reactivity at position-
2 of a DP ring was enhanced through a conjugated double bond
system by the ester group at position-5 to afford DPs 16. However,
lower reactivity in the case of DP 4 without the Boc group and in DP
15 with a non-conjugated double bond did not give the desired DPs.
On the other hand, the reaction of pyrimidine 10 with 11 easily oc-
curred because the oxo group at position-4 together with the ester
group activated position-2 through the conjugate double bond
system of 10. Thus, the different reactivities of these compounds
may be due to substitution at positions-1, 3, or 4 of the DP skeleton.
4.1.1. Ethyl 6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-car-
boxylate (3)10. A mixture of thiourea (5.71 g, 75.0 mmol), 37%
formaldehyde solution (50.5 mmol, 4.10 mL), ethyl acetoacetate
(6.51 g, 50.0 mmol), and benzyltriethylammonium chloride (1.14 g,
5.00 mmol) was heated at 100 ꢀC for 30 min, and the formed pre-
cipitate was corrected by filtration. The filtrate was washed with
water and ether, and dried in vacuo to provide the compound 3
(1.45 g, 15%). 1H NMR and IR spectra were identical to those
reported previously.
4.1.2. Ethyl
carboxylate and ethyl 4-methyl-2-methylsulfanyl-1,6-dihydropyr-
imidine-5-carboxylate (4). To solution of the compound
6-methyl-2-methylsulfanyl-1,4-dihydropyrimidine-5-
a
3
(530 mg, 2.65 mmol) and triethylamine (3.80 mL, 27.3 mmol) in
MeOH (10 mL) was added iodomethane (1.70 mL, 27.3 mmol) at
0 ꢀC. The mixture was stirred for 2 h at 45 ꢀC, and water was added.
The organic materials were extracted with EtOAc, and the com-
bined organic extracts were washed with water, brine, dried over
Na2SO4, and concentrated under reduced pressure. The residue was
purified by flash column chromatography (n-hexane/EtOAc¼3:1) to
give the dihydropyrimidine 4 [430 mg, 76%, a mixture of 1,4- and
1,6-dihydro tautomers (6.6:1)] as colorless crystals. Mp 113e115 ꢀC
(n-hexaneꢁCHCl3). IR (KBr) 3318, 1668, 1647, 1497, 1171 cmꢁ1
. dH
(600 MHz, DMSO-d6, 25 ꢀC, 0.1 M) 1.17 (3H, t, J 7.2 Hz, CH2CH3), 2.11
(2.61H, s, C6eCH3), 2.13 (0.39H, s, C4eCH3), 2.26 (2.61H, s, SCH3),
2.34 (0.39H, s, SCH3), 3.92 (0.26H, s, C6eH2), 4.04 (2H, q, J 7.2 Hz,
CH2CH3), 4.10 (1.74H, s, C4eH2), 8.19 (0.13H, s, NH), 9.25 (0.87H, s,
NH). dC (150 MHz, DMSO-d6) 12.7, 14.5, 17.4, 46.6, 59.2, 94.0, 147.8,
151.5, 166.2. LRMS (EI) m/z 214 (Mþ). HRMS (EI): Mþ, found
214.0770. C9H14N2O2S requires 214.0776. The each tautomer of 4 in
1H NMR was assigned by HSQC and HMBC experiments.
3. Conclusions
Novel dihydropyrimidines 14 without any substituted group at
position-4 were synthesized via compound 3 in good yields. Sub-
sequently, a variety of nucleophilic substitutions at position-2 of
a DP skeleton were carried out to provide DP 16 with various amino
moieties in good to excellent yields. The successive deprotection of
the Boc group furnished a variety of novel DPs 1 and 18. Moreover,
novel bicyclic DP 17 was obtained by employing phenylhydrazine
instead of amines. Different reactivity between a protected DP with
a Boc group and a non-protected DP was observed in 4 and 14, as
well as between protected DPs 14 and 15. Interestingly, individual
tautomers of 1,4 (3,4)-DP were observed in the 1H NMR spectra of
DP 4 depending on temperature and concentration. On the other
hand, only 1,4-DP was found in the solid state by single-crystal
X-ray crystallography.
4.1.3. Ethyl 2-ethoxymethyl-3-methoxy-acrylate (5)12. To a suspen-
sion of sodium ethoxide (9.12 g, 134 mmol) in dry toluene (100 mL)
was added a solution of ethyl formate (9.93 g, 134 mmol) and ethyl
3-ethoxypropionate (9.79 g, 67.0 mmol) in dry toluene (40 mL) at
0
ꢀC. After stirring at 0 ꢀC for 2 h, dimethylsulfate (12.8 mL,
135 mmol) was added. The reaction mixture was stirred at 50 ꢀC for
12 h. The mixture was washed with aqueous 2 M NaOH, water and
brine, dried over Na2SO4, and concentrated under reduced pressure.

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H. Cho et al. / Tetrahedron 67 (2011) 2661e2669
The residue was purified by silica gel column chromatography (n-
hexane/EtOAc¼20:1 to 1:2) to give the compound 5 (6.54 g, 52%) as
a mixture of isomers.
14.4, 29.0, 29.8, 45.4, 59.5, 60.5, 68.5, 105.3, 116.2, 119.7, 121.4, 121.6,
123.4, 130.4, 151.2, 156.6, 162.0, 164.4. LRMS (EI) m/z 372 (Mþ).
HRMS (EI): Mþ, found 372.1787. C19H24N4O4 requires 372.1798.
4.1.4. Ethyl 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (6)10. A
mixture of the compound 5 (6.54 g, 34.0 mmol), urea (2.04g,
34.0 mmol), and concentrated HCl (2.5 mL) in ethanol (115 mL) was
heated at reflux for 12 h. After concentrated under reduced pres-
sure, the residue was recrystallized from ethanol to give 6 (1.78 g,
31%) as colorless prisms. Mp 183e185 ꢀC. IR (KBr) 3251, 1720, 1703,
4.1.8. 1-tert-Butyl 5-ethyl 4-methyl-2-thioxo-1,2,3,6-tetrahydropyr-
imidine-1,5-dicarboxylate (13). To a suspension of sodium hydride
(60% dispersion in mineral oil, 752 mg, 18.8 mmol) in DMF (20 mL)
was added compound 3 (1.87 g, 9.34 mmol) in DMF (30 mL) at 0 ꢀC.
After stirring at 0 ꢀC for 10 min, Boc2O (4.10 g, 18.8 mmol) in DMF
(30 mL) was added, and the mixture was stirred at room tempera-
ture for 2 h. Water was added to the reaction mixture, and the or-
ganic materials were extracted with EtOAc. The combined organic
extracts were washed with water and brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (n-hexane/EtOAc¼5:1) to give
the compound 13 (2.52 g, 90%) as pale yellow needles. Mp
121e122 ꢀC (n-hexane/EtOAc). IR (KBr) 2980, 1730, 1657, 1507,
1268 cmꢁ1
. dH (600 MHz, CDCl3) 1.27 (3H, t, J 7.2 Hz, CH2CH3), 4.19
(2H, q, J 7.2 Hz, CH2CH3), 4.20 (2H, s, C4eH2), 5.10e5.35 (1H, br s,
NH), 7.10e7.45 (1H, br s, NH), 7.21 (1H, d, J 5.4 Hz, C6eH). dC
(150 MHz, DMSO-d6) 14.3, 40.1, 59.5, 98.7, 137.0, 152.2, 165.0. LRMS
(EI) m/z 170 (Mþ). HRMS (EI): Mþ, found 170.0694. C7H10N2O3 re-
quires 170.0691.
4.1.5. Ethyl
2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
1230 cmꢁ1
. dH (600 MHz, DMSO-d6) 1.21 (3H, t, J 7.2 Hz, CH2CH3),
(7)15. Phosphorous pentasulfide (1.72 g, 7.74 mmol) was added to
a solution of the compound 6 (1.72 g, 10.1 mmol) in pyridine
(17 mL), and the mixture was heated at reflux for 3 h. After con-
centrated in vacuo, the residue was treated with H2O and cold
ethanol to give a crude solid, which recrystallized from ethanol to
give 7 (1.14 g, 60%) as a pale yellow powder. IR (KBr) 3279, 1698,
1.46 (9H, s, CMe3), 2.21 (3H, s, C4eCH3), 4.11 (2H, q, J 7.2 Hz, CH2CH3),
4.23 (2H, s, C6eH2), 11.18 (1H, s, NH). dC (100 MHz, DMSO-d6) 14.3,
16.3, 27.6, 43.1, 60.2, 83.7, 101.9, 145.3, 152.6, 164.7, 178.2. LRMS (EI)
m/z 300 (Mþ). HRMS (EI): Mþ, found 300.1156. C13H20N2O4S re-
quires 300.1144. The regiochemistry of the Boc group was de-
termined by HMBC experiment.
1657, 1580, 1183 cmꢁ1
. dH (600 MHz, CDCl3) 1.29 (3H, t, J 7.2 Hz,
CH2CH3), 4.19 (2H, t, J 1.2 Hz, C4eH2), 4.21 (2H, q, J 7.2 Hz, CH2CH3),
6.55e6.70 (1H, br s, NH), 7.07 (1H, dt, J 5.4, 1.2 Hz, C6eH), 7.45e7.62
(1H, br s, NH). dC (150 MHz, DMSO-d6) 14.4, 40.4, 60.1, 100.6, 133.4,
164.8, 175.7. LRMS (EI) m/z 186 (Mþ). HRMS (EI): Mþ, found
186.0462. C7H10N2O2S requires 186.0463.
4.1.9. 1-tert-Butyl 5-ethyl 4-methyl-2-methylsulfanyl-1,6-dihy-
dropyrimidine-1,5-dicarboxylate (14). A mixture of the compound
13 (1.46 g, 4.86 mmol), triethylamine (6.80 mL, 48.8 mmol) in dry
MeOH (20 mL) was added iodomethane (3.00 mL, 48.2 mmol) at
0 ꢀC, and the mixture was heated at 45 ꢀC for 1 h. Water was added
to the reaction mixture, and the organic materials were extracted
with EtOAc. The combined organic extracts were washed with
water and brine, dried over Na2SO4, and concentrated under re-
duced pressure. The residue was purified by silica gel column
chromatography (n-hexane/ether¼6:1) to give the compound 14
(1.33 g, 87%) as yellow crystals. Mp 64e67 ꢀC (n-hexane). IR (KBr)
4.1.6. Ethyl 2-methylsulfanyl-6-oxypyrimidine-5-carboxylate (10). To
a solution of sodium ethoxide (1.36 g, 20.0 mmol) in ethanol
(15 mL) was added S-methylisothiourea sulfate (5.57 g, 40.0 mmol)
at 0 ꢀC. After a few minutes, diethyl ethoxymethylenemalonate
(4.00 mL, 19.8 mmol) was added. After stirring at 0 ꢀC for 3 h,
a solution of sodium ethoxide (1.36 g, 20.0 mmol) in ethanol
(15 mL) was added. The resulted solution was stirred at room
temperature overnight. Ethanol was removed under reduced
pressure and the pale yellow residue was dissolved in water. After
filtration, the aqueous filtrate was washed with ether and acidified
with acetic acid (10 mL). The organic materials were extracted with
CHCl3. The combined organic extracts were washed with brine,
dried over MgSO4, and concentrated. Recrystallization of the resi-
due with CHCl3 gave compound 10 (3.44 g, 81%) as colorless nee-
dles. Mp 129e130 ꢀC (CHCl3), lit.16 132e133 ꢀC (benzene/petroleum
2979, 1725, 1621, 1520, 1143 cmꢁ1
. dH (400 MHz, CDCl3) 1.31 (3H, t, J
7.2 Hz, CH2CH3), 1.53 (9H, s, CMe3), 2.32 (3H, s, C4eCH3), 2.42 (3H, s,
SCH3), 4.21 (2H, q, J 7.2 Hz, CH2CH3), 4.34 (2H, s, C6eH2). dC
(150 MHz, CDCl3) 14.3, 15.4, 21.2, 28.0, 42.5, 60.2, 84.1, 106.3, 151.5,
153.0, 159.3, 166.1. LRMS (EI) m/z 314 (Mþ). HRMS (EI): Mþ, found
314.1311. C14H22N2O4S requires 314.1300.
4.1.10. 1-tert-Butyl 5-ethyl 2-methylsulfanyl-1,4-dihydropyrimidine-
1,5-dicarboxylate (15). To a solution of compound 7 (0.770 g,
4.14 mmol) and triethylamine (11.5 mL, 81.8 mmol) in dry MeOH
(50 mL) was added iodomethane (4.90 mL, 81.9 mmol) at 0 ꢀC, and
the mixture was heated at 45 ꢀC for 1 h. After adding water, the
mixture was extracted with EtOAc. The combined organic extracts
were washed with water and brine, dried over Na2SO4, and con-
centrated under reduced pressure. The residue was purified by
silica gel column chromatography (n-hexane/EtOAc¼1.5:1) to give
the unstable dihydropyrimidine 8 (410 mg, 50%), which was im-
mediately subjected to the next reaction. To a suspension of sodium
hydride (60% dispersion in oil, 88.0 mg, 2.20 mmol) in DMF (5 mL)
was added a solution of compound 8 (220 mg, 1.10 mmol) in DMF
(3 mL) at 0 ꢀC. After stirring at 0 ꢀC for 10 min, Boc2O (480 mg,
2.20 mmol) in DMF (3 mL) was added, and the mixture was stirred
at room temperature for 30 min. After adding water, the mixture
was extracted with EtOAc. The combined organic extracts were
washed with water and brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (n-hexane/EtOAc¼15:1) to give the com-
pound 15 (289 mg, 87%) as pale yellow crystals. Mp 74e76 ꢀC (n-
ether). IR (KBr) 3435, 2902, 2805, 1739, 1701, 1529, 1170 cmꢁ1
. dH
(400 MHz, CDCl3) 1.42 (3H, t, J 6.8 Hz, CH2CH3), 2.60 (3H, s, SCH3),
4.43 (2H, q, J 6.8 Hz, CH2CH3), 8.75 (1H, s, C4eH). dC (150 MHz,
DMSO-d6) 13.0, 14.1, 60.2, 111.7, 157.8, 158.9, 163.6, 168.0. LRMS (EI)
m/z 214 (Mþ). HRMS (EI): Mþ, found 214.0458. C8H10N2O3S requires
214.0412.
4.1.7. Ethyl 2-(3-dimethylaminomethyl-chroman-6-ylamino)-6-oxo-
1,6-dihydropyrimidine-5-carboxylate (12). A mixture of amine 11
(200 mg, 0.971 mmol) and dihydropyrimidine 10 (249 mg,
1.16 mmol) in n-butanol (3 mL) was heated at 115 ꢀC for 12 h. After
the solvent was removed under reduced pressure, the residue was
recrystallized from DMF to give 12 (242 mg, 67%) as a colorless
powder. IR (KBr) 1697, 1650, 1498, 1297 cmꢁ1
. dH (600 MHz, DMSO-
d6) 1.24 (3H, t, J 7.2 Hz, CH2CH3), 2.13e2.38 (3H, m, ArCH2CH), 2.25
(6H, s, NMe2), 2.46 (1H, dd, J 16.2, 7.8 Hz, Me2NCHaHb), 2.79 (1H, dd,
J 16.2, 5.4 Hz, Me2NCHaHb), 3.77 (1H, dd, J 10.8, 7.8 Hz, OCHaHb),
4.12 (2H, q, J 7.2 Hz, CH2CH3), 4.16e4.20 (1H, m, OCHaHb), 6.70 (1H,
d, J 8.4 Hz, AreH), 7.26 (1H, d, J 8.4 Hz, AreH), 7.27 (1H, s, Are5-H),
8.40 (1H, s, C6eH), 9.10e10.90 (1H, br s, NH). dC (150 MHz, CDCl3)
hexane). IR (KBr) 1746, 1704, 1328, 1227, 1143 cmꢁ1
CDCl3) 1.30 (3H, t, J 7.2 Hz, CH2CH3), 1.58 (9H, s, CMe3), 2.30 (3H, s,
. dH (600 MHz,

H. Cho et al. / Tetrahedron 67 (2011) 2661e2669
2667
SCH3), 4.22 (2H, q, J 7.2 Hz, CH2CH3), 4.32 (2H, s, C4eH2), 7.78 (1H, s,
C6eH). dC (150 MHz, DMSO-d6) 14.3, 15.7, 27.7, 45.4, 60.6, 85.6,
108.5, 133.4, 148.8, 149.2, 164.5. LRMS (EI) m/z 300 (Mþ). HRMS (EI):
Mþ, found 300.1154. C13H20N2O4S requires 300.1144. The position
of the Boc group was determined by HMBC experiment.
146.7, 151.2, 153.5, 156.8, 166.3. LRMS (EI) m/z 472 (Mþ). HRMS (EI):
Mþ, found 472.2683. C25H36N4O5 requires 472.2686.
4.1.11.5. 1-tert-Butyl 5-ethyl 2-hexylamino-4-methyl-1,6-dihydro-
pyrimidine-1,5-dicarboxylate (16e). Colorless oil. IR (neat) 3339,
2930, 2858, 1699, 1612, 1568, 1303, 1142 cmꢁ1
. dH (600 MHz, CDCl3)
4.1.11. Typical synthetic procedure of 16.
4.1.11.1. 1-tert-Butyl 5-ethyl 4-methyl-2-phenylamino-1,6-dihy-
dropyrimidine-1,5-dicarboxylate (16a). (Method a-1) A mixture of
0.89 (3H, t, J 7.2 Hz, NHCH2CH2CH2CH2CH3), 1.27e1.40 (6H, m,
NHCH2CH2CH2CH2CH2CH3), 1.29 (3H, t, J 7.2 Hz, OCH2CH3), 1.53 (9H,
s, CMe3), 1.55e1.65 (2H, m, NHCH2CH2CH2CH2CH2CH3), 2.29 (3H, s,
C4eCH3), 3.40 (2H, dt, J 4.8, 7.2 Hz, NHCH2CH2CH2CH2CH2CH3), 4.17
(2H, q, J 7.2 Hz, OCH2CH3), 4.37 (2H, s, C6eH2), 7.85e8.20 (1H, br s,
NH). dC (100 MHz, CDCl3) 14.0, 14.4, 22.5, 22.8, 26.6, 27.9, 28.9, 31.4,
41.6, 43.1, 59.3, 83.6, 99.1, 150.1, 153.6, 158.0, 166.6. LRMS (EI) m/z
367 (Mþ). HRMS (EI): Mþ, found 367.2462. C19H33N3O4 requires
367.2471.
13 (63.0 mg, 0.201 mmol) and aniline (54.0 mL, 0.593 mmol) in
CH2Cl2 (2 mL) was heated at reflux for 24 h under Ar. After the
solvent was removed under reduced pressure, the residue was
purified by silica gel column chromatography (n-hexane/Et2O¼5:1)
to give compound 16a (70.0 mg, 97%) as pale yellow needles.
(Method b-1) To a stirred mixture of 14 (31.5 mg, 0.100 mmol)
and aniline (27.5 mM, 0.302 mmol) in CH2Cl2 (1.5 mL) was added
pyridinium p-toluenesulfonate PPTS (2.5 mg, 0.010 mmol) in
CH2Cl2 (0.2 mL). The reaction mixture was stirred at room tem-
perature for 6 h, diluted with water, and extracted with EtOAc.
The combined organic extracts were washed with brine, dried
over Na2SO4, and evaporated under reduced pressure to leave
a residue. Compound 16a (31.9 mg, 89%) was obtained after pu-
rification as mentioned above. Mp 118e119 ꢀC (n-hexane). IR (KBr)
4.1.11.6. 1-tert-Butyl 5-ethyl 2-benzyloxyamino-4-methyl-1,6-di-
hydropyrimidine-1,5-dicarboxylate (16f). Colorless oil. IR (NaCl)
3294, 2983, 1706, 1631, 1367, 1228, 1070 cmꢁ1
. dH (400 MHz, CDCl3)
1.28 (3H, t, J 7.2 Hz, CH2CH3), 1.46 (9H, s, CMe3), 2.29 (3H, s,
C4eCH3), 4.17 (2H, q, J 7.2 Hz, CH2CH3), 4.37 (2H, s, C6eH2), 5.06
(2H, s, CH2Ph), 7.05 (1H, s, NH), 7.31e7.42 (5H, m, AreH). dC
(100 MHz, CDCl3) 14.3, 18.3, 28.0, 41.6, 59.9, 76.4, 82.3, 100.5, 128.1,
128.4, 128.6, 137.2, 142.6, 145.0, 151.8, 165.5. LRMS (EI) m/z 389
(Mþ). HRMS (EI): Mþ, found 389.1936. C20H27N3O5 requires
389.1951.
2979, 2929, 1699, 1604, 1552, 1143 cmꢁ1
. dH (400 MHz, CDCl3) 1.31
(3H, t, J 7.2 Hz, CH2CH3), 1.53 (9H, s, CMe3), 2.35 (3H, s, C4eCH3),
4.21 (2H, q, J 7.2 Hz, CH2CH3), 4.47 (2H, s, C6eH2), 7.09 (1H, t, J
7.2 Hz, Arep-H), 7.32 (2H, t, J 7.2 Hz, Arem-H), 7.65 (2H, d, J 7.2 Hz,
Areo-H). dC (100 MHz, CDCl3) 14.3, 22.2, 27.9, 43.0, 59.6, 84.2,
101.7, 120.9, 123.7, 128.6, 138.3, 146.3, 153.4, 156.3, 166.2. LRMS (EI)
m/z 359 (Mþ). HRMS (EI): Mþ, found 359.1827. C19H25N3O4 re-
quires 359.1845.
4.1.11.7. 1-tert-Butyl 5-ethyl 2-benzylamino-4-methyl-1,6-dihy-
dropyrimidine-1,5-dicarboxylate (16g). Colorless crystals. Mp 72e
73 ꢀC (EtOAc). IR (KBr) 3330, 2975, 1714, 1691, 1558, 1300, 1153,
1115 cmꢁ1
. dH (400 MHz, CDCl3) 1.29 (3H, t, J 7.2 Hz, CH2CH3), 1.50
(9H, s, CMe3), 2.30 (3H, s, C4eCH3), 4.18 (2H, q, J 7.2 Hz, CH2CH3),
4.39 (2H, s, C6eH2), 4.62 (2H, s, CH2Ph), 7.27e7.38 (5H, m, AreH),
8.32 (1H, br s, NH). dC (100 MHz, CDCl3) 14.4, 22.7, 28.0, 43.3, 45.6,
59.5, 83.9, 97.7, 127.4, 128.0, 128.6, 138.3, 150.0, 153.5, 157.7, 166.6.
LRMS (EI) m/z 373 (Mþ). HRMS (EI): Mþ, found 373.1985.
C20H27N3O4 requires 373.2002.
4.1.11.2. 1-tert-Butyl 5-ethyl 2-(4-methoxyphenylamino)-4-methyl-
1,6-dihydropyrimidine-1,5-dicarboxylate (16b). Pale yellow needles.
Mp 119e121 ꢀC (n-hexane). IR (KBr) 2979, 1697, 1617, 1558,
1509 cmꢁ1
. dH (600 MHz, CDCl3) 1.31 (3H, t, J 7.2 Hz, CH2CH3), 1.55
(9H, s, CMe3), 2.32 (3H, s, C4eCH3), 3.80 (3H, s, OCH3), 4.20 (2H, q, J
7.2 Hz, CH2CH3), 4.46 (2H, s, C6eH2), 6.86 (2H, d, J 9.0 Hz, AreH),
7.56 (2H, d, J 9.0 Hz, AreH), 9.60e10.30 (1H, br s, NH). dC (150 MHz,
CDCl3) 14.4, 22.2, 28.0, 29.6, 43.0, 55.4, 59.6, 84.2, 101.3, 113.9, 122.7,
131.5, 146.8, 153.4, 156.1, 166.2. LRMS (EI) m/z 389 (Mþ). HRMS (EI):
Mþ, found 389.1966. C20H27N3O5 requires 389.1951.
4.1.11.8. 1-tert-Butyl 5-ethyl 2-pyrrolidyl-4-methyl-1,6-dihydro-
pyrimidine-1,5-dicarboxylate (16h). Colorless oil. IR (NaCl) 2977,
1720, 1556, 1371, 1298, 1273 cmꢁ1
. dH (400 MHz, CDCl3) 1.29 (3H, t, J
7.2 Hz, CH2CH3), 1.47 (9H, s, CMe3), 1.94 (4H, s, NCH2CH2CH2CH2),
2.34 (3H, s, C4eCH3), 3.46 (2H, br s, NCH2CH2), 3.62 (2H, br s,
NCH2CH2), 4.18 (2H, d, J 7.2 Hz, CH2CH3), 4.78 (2H, br s, C6eH2). dC
(100 MHz, CDCl3) 14.5, 22.1, 24.7, 25.6, 28.1, 43.0, 47.8, 59.3, 82.2,
103.7, 149.3, 151.8, 159.0, 166.5. LRMS (EI) m/z 337 (Mþ). HRMS (EI):
Mþ, found 337.1999. C17H27N3O4 requires 337.2002.
4.1.11.3. 1-tert-Butyl 5-ethyl 2-(4-methoxycarbonylphenylamino)-
4-methyl-1,6-dihydropyrimidine-1,5-dicarboxylate (16c). Pale yel-
low needles. Mp 186e188 ꢀC (n-hexaneeCHCl3). IR (KBr) 2985,
1703, 1638, 1549, 1274 cmꢁ1
. dH (600 MHz, CDCl3) 1.32 (3H, t, J
7.2 Hz, CH2CH3), 1.57 (9H, s, CMe3), 2.36 (3H, s, C4eCH3), 3.90 (3H, s,
OCH3), 4.20 (2H, q, J 7.2 Hz, CH2CH3), 4.47 (2H, s, C6eH2), 7.70e7.85
(2H, m, AreH), 8.00 (2H, d, J 8.4 Hz, AreH), 10.15e10.50 (1H, br s,
NH). dC (100 MHz, CDCl3) 14.3, 22.1, 27.9, 43.0, 51.9, 59.8, 84.6, 102.5,
119.9, 124.7, 130.5, 142.8, 145.8, 153.4, 155.3, 166.0, 166.7. LRMS (EI)
m/z 417 (Mþ). HRMS (EI): Mþ, found 417.1909. C21H27N3O6 requires
417.1900.
4.1.11.9. Ethyl 7-methyl-3-oxo-2-phenyl-2,3,5,8-tetrahydro[1,2,4]-
triazol [4,3-a]pyrimidine-6-carboxylate (17). To a stirred solution of
14 (31.4 mg, 0.100 mmol) in CH2Cl2 (0.5 mL) were added PPTS
(2.5 mg, 0.010 mmol) in CH2Cl2 (1.0 mL) and phenylhydrazine
(30 mM, 0.31 mmol). The mixture was stirred at room temperature
for 2 h, and the reaction mixture was diluted with water and
extracted with EtOAc. The organic layer was dried over Na2SO4 and
evaporated to leave the residue, which was purified with silica gel
column chromatography (toluene/EtOAc¼94:6) to yield compound
17 (25.2 mg, 84%) as colorless crystals. Mp 237e238 ꢀC (EtOAc). IR
4.1.11.4. 1-tert-Butyl 5-ethyl 2-(3-dimethylaminomethyl-chroman-
6-yl-amino)-4-methyl-1,6-dihydropyrimidine-1,5-dicarboxylate
(16d). Pale yellow powder. IR (KBr) 2978, 1698, 1555, 1500,
1217 cmꢁ1
.
dH (600 MHz, CDCl3) 1.30 (3H, t, J 7.2 Hz, CH2CH3), 1.54
(KBr) 3228, 3112, 1704, 1660, 1621, 1263, 1076 cmꢁ1
. dH (400 MHz,
(9H, s, CMe3), 2.20e2.36 (3H, m, ArCH2CH), 2.26 (6H, s, NMe2), 2.31
(3H, s, C4eCH3), 2.52 (1H, dd, J 7.2, 16.2 Hz, Me2NCHaHb), 2.87 (1H,
dd, J 4.2, 16.2 Hz, Me2NCHaHb), 3.82 (1H, dd, J 7.2, 10.2 Hz, OCHaHb),
4.20 (2H, q, J 7.2 Hz, CH2CH3), 4.24e4.30 (1H, m, OCHaHb), 4.45 (2H,
s, C6eH2), 6.76 (1H, d, J 9.0 Hz, AreH), 7.29 (1H, d, J 9.0 Hz, AreH),
7.40 (1H, s, Are5-H). dC (150 MHz, CDCl3) 14.4, 22.3, 28.0, 29.8, 30.4,
43.0, 45.8, 60.0, 61.4, 69.1, 84.1, 101.0, 116.4, 121.0, 121.3, 122.8, 130.9,
DMSO-d6) 1.21 (3H, t, J 7.2 Hz, CH2CH3), 2.29 (3H, s, C7eCH3), 4.09
(2H, q, J 7.2 Hz, CH2CH3), 4.28 (2H, s, C5eH2), 7.14 (1H, t, J 8.0 Hz,
Arep-H), 7.41 (2H, t, J 8.0 Hz, Arem-H), 7.81 (2H, d, J 8.0 Hz, Areo-
H), 10.38 (1H, br s, NH). dC (100 MHz, DMSO-d6) 14.4, 18.3, 39.0,
59.6, 91.7, 117.2, 124.3, 129.2, 138.1, 140.8, 146.4, 149.5, 165.2. LRMS
(EI) m/z 300 (Mþ). HRMS (EI): Mþ, found 300.1214. C15H16N4O3
requires 300.1222.

2668
H. Cho et al. / Tetrahedron 67 (2011) 2661e2669
4.1.12. Typical synthetic procedure of 18
4.1.12.6. Ethyl 2-benzyloxyamino-4-methyl-1,6-dihydropyrimidine-
5-carboxylate (18f). To a solution of 16f (22.7 mg, 0.0584 mmol) in
CH2Cl2 (1 mL) was added trifluoroacetic acid (0.5 mL, 6.7 mmol),
and the mixture was stirred at room temperature for 1 h. The re-
action mixture was concentrated, and added toluene and 4 M HCl
in dioxane. This mixture was concentrated to give colorless powder,
which was recrystallized from hexane/Et2O to give corresponding
HCl salt of 18f: dH (400 MHz, CD3OD) 1.27 (3H, t, J 7.2 Hz, CH2CH3),
2.26 (3H, s, C4eCH3), 4.05 (2H, s, C6eH2), 4.18 (2H, q, J 7.2 Hz,
CH2CH3), 4.92 (2H, s, CH2Ph), 7.39e7.42 (3H, m, AreH), 7.46e7.48
(2H, m, AreH). dC (100 MHz, CD3OD) 14.5, 17.2, 40.3, 61.8, 80.3,
101.3, 129.7, 130.4, 131.0, 135.7, 145.1, 154.1, 165.9. This HCl salt was
suspended in Et2O, and 0.5 M NaOH was added. After separating
the two layers, aqueous layer was extracted with Et2O. Combined
organic extracts was dried over Na2SO4, and concentrated to give
compound 18f (14.2 mg, 84%) as a colorless oil. IR (NaCl) 3332, 3219,
4.1.12.1. Ethyl 2-phenylamino-4-methyl-1,6-dihydropyrimidine-
5-carboxylate (18a). To
a stirred solution of 16a (27.4 mg,
0.0763 mmol) in CH2Cl2 (1 mL) was added trifluoroacetic acid
(0.50 mL, 6.7 mmol) at 0 ꢀC. Stirring was continued at room tem-
perature for 1 h, and the reaction mixture was basified with 0.5 M
aqueous NaOH. The mixture was extracted with EtOAc, and the
combined organic extracts were washed with 0.5 M aqueous NaOH
and brine, dried over Na2SO4, and concentrated under reduced
pressure. The obtained colorless powder was recrystallized from
MeOH to give quantitatively compound 18a (19.6 mg) as colorless
crystals. Mp 171e173 ꢀC (CHCl3). IR (KBr) 3370, 3180, 3056, 2975,
2844, 1681, 1648, 1628, 1265, 1097 cmꢁ1
. dH (400 MHz, CDCl3) 1.24
(3H, t, J 7.2 Hz, CH2CH3), 2.18 (3H, s, C4eCH3), 3.98 (2H, s, C6eCH2),
4.14 (2H, q, J 7.2 Hz, CH2CH3), 6.97 (2H, d, J 7.6 Hz, Areo-H), 7.08 (1H,
t, J 7.6 Hz, Arep-H), 7.34 (2H, t, J 7.6 Hz, Arem-H). dC (100 MHz,
CDCl3) 14.4, 18.5, 40.3, 59.6, 95.6, 123.6, 123.9, 129.7, 146.2, 147.89,
147.94, 166.0. LRMS (EI) m/z 259 (Mþ). HRMS (EI): Mþ, found
259.1303. C14H17N3O2 requires 259.1321.
2981, 2933, 1671, 1496, 1246, 1097 cmꢁ1
. dH (400 MHz, CDCl3) 1.26
(3H, t, J 7.2 Hz, CH2CH3), 2.30 (3H, s, C4eCH3), 3.96 (2H, s, C6eH2),
4.16 (2H, q, J 7.2 Hz, CH2CH3), 4.90 (2H, s, CH2Ph), 5.52 (1H, br s, NH),
7.40 (5H, m, AreH), 9.52 (1H, br s, NH). 13C NMR spectra could not
be obtained due to the instability of the compound 18f. LRMS (EI)
m/z 289 (Mþ). HRMS (EI): Mþ, found 289.1407. C15H19N3O3 requires
289.1426.
4.1.12.2. Ethyl 2-(4-methoxyphenylamino)-4-methyl-1,6-dihydro-
pyrimidine-5-carboxylate (18b). Colorless powder. IR (KBr) 1709,
1687, 1666, 1515, 1203 cmꢁ1
. dH (600 MHz, CDCl3) 1.29 (3H, t, J
7.2 Hz, CH2CH3), 2.44 (3H, s, CH2CH3), 3.83 (3H, s, OCH3), 4.16 (2H, s,
C6eH2), 4.21 (2H, q, J 7.2 Hz, CH2CH3), 6.97 (2H, d, J 9.0 Hz, AreH),
7.18 (2H, d, J 9.0 Hz, AreH). dC (150 MHz, CDCl3) 14.2,17.5, 39.9, 55.6,
60.6, 115.5, 125.2, 127.3, 151.4, 159.7, 163.7, 164.0, 164.6. LRMS (FAB)
m/z 290 (MHþ). HRMS (FAB): MHþ, found 290.1523. C15H20N3O3
requires 290.1505.
4.1.12.7. Ethyl 2-benzylamino-4-methyl-1,6-dihydropyrimidine-
5-carboxylate (18g). Colorless crystals. Mp 220e221 ꢀC (MeOH). IR
(KBr) 3068, 2879, 1704, 1670, 1542, 1279 cmꢁ1
. dH (400 MHz,
CD3OD) 1.28 (3H, t, J 7.2 Hz, CH2CH3), 2.33 (3H, s, C4eCH3), 4.12 (2H,
s, C6eH2), 4.20 (2H, q, J 7.2 Hz, CH2CH3), 4.48 (2H, s, CH2Ph),
7.32e7.35 (3H, m, AreH), 7.40 (2H, s, AreH). dC (100 MHz, CD3OD)
14.6, 17.7, 40.6, 46.2, 61.7, 100.9, 128.4, 129.3, 130.1, 136.8, 146.0,
152.7, 166.2. LRMS (FAB) m/z 274 (MHþ). HRMS (FAB): MHþ, found
274.1562. C15H20N3O2 requires 274.1556.
4.1.12.3. Ethyl 2-(4-methoxycarbonylphenylamino)-4-methyl-1,6-
dihydropyrimidine-5-carboxylate (18c). Colorless needles. Mp ꢁ1199e
200 ꢀC (n-hexane/CHCl3). IR (KBr) 1689, 1633, 1594, 1252 cm
. dH
(600 MHz, CDCl3) 1.28 (3H, t, J 7.2 Hz, CH2CH3), 2.32 (3H, s, C4eCH3),
3.91 (3H, s, OCH3), 4.09 (2H, s, C6eH2), 4.19 (2H, q, J 7.2 Hz, CH2CH3),
7.09 (2H, d, J 8.4 Hz, AreH), 8.04 (2H, d, J 8.4 Hz, AreH). dC (150 MHz,
CDCl3) 14.3,18.2, 40.3, 52.1, 60.1, 97.2,123.6,126.1,131.4,146.4,147.7,
148.3, 165.4, 166.6. LRMS (FAB) m/z 318 (MHþ). HRMS (FAB): MHþ,
found 318.1483. C16H20N3O4 requires 318.1454.
4.1.12.8. Ethyl
2-pyrrolidyl-4-methyl-1,6-dihydropyrimidine-5-
carboxylate (18h). Colorless prisms. Mp 119e121 ꢀC (hexane/
Et2O). IR (KBr) 3504, 3357, 3261, 2977, 2877, 1654, 1590, 1471,
1214, 1078 cmꢁ1
. dH (400 MHz, CDCl3) 1.26 (3H, t, J 7.2 Hz,
CH2CH3), 1.92e1.96 (4H, m, NCH2CH2CH2CH2), 2.31 (3H, s,
C4eCH3), 3.42 (4H, br s, NCH2CH2CH2CH2), 4.14 (2H, q, J 7.2 Hz,
CH2CH3), 4.47 (2H, br s, C6eH2). dC (100 MHz, CDCl3) 14.6, 23.8,
25.3, 41.1, 46.0, 59.0, 93.8, 153.6, 161.1, 167.2. LRMS (EI) m/z 237
(Mþ). HRMS (EI): Mþ, found 237.1493. C12H19N3O2 requires
237.1477.
4.1.12.4. Ethyl 2-(3-dimethylaminomethyl-chroman-6-ylamino)-
4-methyl-1,6-dihydropyrimidine-5-carboxylate (1). Colorless pow-
der. IR (KBr) 1677, 1631, 1492, 1263, 1099 cmꢁ1
. dH (600 MHz, CDCl3)
1.25 (3H, t, J 7.2 Hz, CH2CH3), 2.17e2.30 (3H, m, ArCH2CH), 2.21 (3H,
s, C4eCH3), 2.25 (6H, s, NMe2), 2.48 (1H, dd, J 7.8, 16.2 Hz, Me2N-
CHaHb), 2.82 (1H, dd, J 3.6, 16.2 Hz, Me2NCHaHb), 3.79 (1H, dd, J 7.8,
10.8 Hz, OCHaHb), 3.97 (2H, s, C6eH2), 4.14 (2H, q, J 7.2 Hz, CH2CH3),
4.25e4.30 (1H, m, OCHaHb), 6.64 (1H, s, Are5-H), 6.68 (1H, d, J
8.4 Hz, AreH), 6.76 (1H, d, J 8.4 Hz, AreH). dC (150 MHz, CDCl3) 14.4,
18.8, 29.8, 30.6, 40.3, 45.9, 59.4, 61.6, 69.2, 94.5, 117.2, 122.3, 122.8,
124.9, 138.8, 148.8, 149.2, 150.9, 166.3. LRMS (EI) m/z 372 (Mþ).
HRMS (EI): Mþ, found 372.2148. C20H28N4O3 requires 372.2161.
4.2. Theoretical calculations
The initial geometry of 2-chloro-1,4-dihydropyrimidine-5-
carboxylic acid K was derived from the crystal structure of 4 by
replacing the methylsulfanyl and ethoxy carbonyl groups with
chloro and carboxyl groups. Molecular modeling of 2-chloro-3,4-
dihydropyrimidine-5-carboxylic acid J, 2-chloropyrimidine-5-
carboxylic acid L, and aniline and theoretical conformational
analysis of J, L, and aniline including K was carried out using AM1
semiempirical method incorporated into the Spartan program
(Fig. S3).17 Moreover, the gas phase geometry optimization of the
molecules leading to energy minima was achieved using the
B3LYP hybrid functional with the 6-311þþG(d,p) basis set as
implemented in the Gaussian 03 program package (Fig. S4).18 For
all optimized structures, vibrational normal mode analysis was
carried out to ensure that the obtained structures were corre-
sponding to minimum energy state. The frontier molecular or-
bitals of these compounds were then calculated of each
minimum energy structure employing DFT calculations at the
B3LYP/6-311þþG(d,p) level of theory (Fig. S5). (1 Har-
tree¼627.5095 kcal/mol).
4.1.12.5. Ethyl
boxylate (18e). Colorless crystals.177e178 ꢀC (CHCl3). IR (KBr) 3234,
3155, 3084, 2956, 2929, 2873, 1706, 1608, 1247, 1105 cmꢁ1
dH
2-hexyl-4-methyl-1,6-dihydropyrimidine-5-car-
.
(400 MHz, CDCl3) 0.88 (3H, t, J 7.2 Hz, NHCH2CH2CH2CH2CH3),
1.26e1.30 (7H, m, OCH2CH3, NHCH2CH2CH2CH2CH2CH3), 1.39e1.43
(2H, m, NHCH2CH2CH2CH2CH2CH3), 1.65 (2H, tt, J 6.8, 6.8 Hz,
NHCH2CH2CH2CH2CH2CH3), 2.37 (3H, s, C4eCH3), 3.36 (2H, t, J
6.8 Hz, NHCH2CH2CH2CH2CH2CH3), 4.185 (2H, s, C6eH2), 4.189 (2H,
q, J 7.2 Hz, OCH2CH3). dC (100 MHz, CDCl3) 14.0, 14.3, 17.8, 22.4, 26.3,
28.6, 31.3, 39.5, 42.3, 60.5, 98.6,144.3,151.3,164.7. LRMS (EI) m/z 267
(Mþ). HRMS (EI): Mþ, found 267.1938. C14H25N3O2 requires
267.1947.

H. Cho et al. / Tetrahedron 67 (2011) 2661e2669
2669
6. Seth, P. P.; Miyaji, A.; Jefferson, E. A.; Sannes-Lowery, K. A.; Osgood, S. A.; Propp,
S. S.; Ranken, R.; Massire, C.; Sampath, R.; Ecker, D. J.; Swayze, E. E.; Griffey, R. H.
J. Med. Chem. 2005, 48, 7099e7102.
7. As for unsubstituted DP at position-4, only a few synthetic examples of DPs or/
and tetrahydropyrimidines given by direct reduction of a pyrimidine skeleton
are reported with complex metal hydrides7a or Et3SiH/TFA.7b (a) Shadbolt, R. S.;
Ulbricht, T. L. V. J. Chem. Soc. C 1968, 6, 733e740; (b) Baskaran, S.; Hanan, E.;
Byun, D.; Shen, W. Tetrahedron Lett. 2004, 45, 2107e2111.
8. (a) Ozeki, K.; Ichikawa, T.; Takehara, H.; Tanimura, K.; Sato, M.; Yaginuma, H.
Chem. Pharm. Bull. 1989, 37, 1780e1787; (b) Seto, S.; Kohno, Y. Heterocycles
2009, 78, 2263e2275; (c) Spycha1a, J. Synth. Commun. 1997, 27, 1943e1949; (d)
Waelchli, R.; Bollbuck, B.; Bruns, C.; Buhl, T.; Eder, J.; Feifel, R.; Hersperger, R.;
Janser, P.; Revesz, L.; Zerwes, H.-G.; Schlapbach, A. Bioorg. Med. Chem. Lett. 2006,
16, 108e112.
9. (a) Nilsson, B. L.; Overman, L. E. J. Org. Chem. 2006, 71, 7706e7714; (b) Atwal, K.
S.; Rovnyak, G. C.; Schwartz, J.; Moreland, S.; Hedberg, A.; Gougoutas, J. Z.;
Malley, M. F.; Floyd, D. M. J. Med. Chem. 1990, 33, 1510e1515.
Supplementary data
Characterization data (IR, 1H NMR, 13C NMR, LRMS, HRMS), X-ray
crystallographic data of 4 and 17, and copies of 1H and 13C NMR
spectra of new compounds 1, 2, 4, 7, and 11e18 including HMBC of
4, 13, 15, HSQC of 4, NOE of 14 and 15, the new synthetic procedure
(six steps from o-fluorobenzyl bromide) of 11. Theoretical calcula-
tions of 2-chloro-3,4(1,4)-dihydropyrimidine-5-carboxylic acid J, K,
2-chloropyrimidine-5-carboxylic acid L, and aniline. Supplemen-
tary data related to this article can be found online at doi:10.1016/
j.tet.2011.01.092.
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