Convergent synthesis of 4,6-unsubstituted 5-acyl-2-phenyldihydropyrimidines by substitution reactions of Weinreb amide group of tetrahydropyrimidines

Article abstract of DOI:10.1016/j.tetlet.2016.08.077

A method of convergent and stepwise synthesis of novel 4,6-unsubstituted 5-acyl-2-phenyldihydropyrimidines using the Weinreb amide group is developed. The cyclization of 4-dimethylamino-1,3-diaza-1,3-butadiene having N-protecting groups (Boc) with N-methoxy-N-methylacrylamide gives 6-unsubstituted 4-dimethylamino-2-phenyltetrahydropyrimidine, which is a synthetic intermediate for 4,6-unsubstituted 5-acyl-2-phenyldihydropyrimidines. The transformation of the Weinreb amide group to an acyl group via substitution reaction using organolithium reagents, following the elimination of a dimethylamino group using MeI proceeds smoothly, affording 4,6-unsubstituted 5-acyl-2-phenyldihydropyrimidines in good overall yield. The N-protecting group can be easily removed to obtain N-unsubstituted dihydropyrimidines as a mixture of tautomers, and their tautomeric behaviors were analyzed by¹H NMR spectroscopy.

Full text of DOI:10.1016/j.tetlet.2016.08.077

Tetrahedron Letters 57 (2016) 4492–4495
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Tetrahedron Letters
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Convergent synthesis of 4,6-unsubstituted 5-acyl-2-
phenyldihydropyrimidines by substitution reactions of Weinreb
amide group of tetrahydropyrimidines
a
b
c
Yoshio Nishimura a, , Takanori Kubo , Yasuko Okamoto , Hidetsura Cho
⇑
a Faculty of Pharmacy, Yasuda Women’s University, 6-13-1, Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan
b Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
c Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A method of convergent and stepwise synthesis of novel 4,6-unsubstituted 5-acyl-2-phenyldihydropy-
rimidines using the Weinreb amide group is developed. The cyclization of 4-dimethylamino-1,3-diaza-
1,3-butadiene having N-protecting groups (Boc) with N-methoxy-N-methylacrylamide gives 6-unsubsti-
tuted 4-dimethylamino-2-phenyltetrahydropyrimidine, which is a synthetic intermediate for 4,6-unsub-
stituted 5-acyl-2-phenyldihydropyrimidines. The transformation of the Weinreb amide group to an acyl
group via substitution reaction using organolithium reagents, following the elimination of a dimethy-
lamino group using MeI proceeds smoothly, affording 4,6-unsubstituted 5-acyl-2-phenyldihydropyrim-
idines in good overall yield. The N-protecting group can be easily removed to obtain N-unsubstituted
dihydropyrimidines as a mixture of tautomers, and their tautomeric behaviors were analyzed by 1H
NMR spectroscopy.
Received 13 July 2016
Revised 13 August 2016
Accepted 23 August 2016
Available online 24 August 2016
Keywords:
4,6-Unsubstituted 5-acyl-2-
phenyldihydropyrimidine
1,3-Diaza-1,3-butadiene
Weinreb amide
Ó 2016 Elsevier Ltd. All rights reserved.
Grignard reagent
Organolithium reagent
Dihydropyrimidines have received much attention from syn-
thetic and medicinal chemists owing to their biological activities
and unique physical and chemical characteristics.1 They exhibit a
wide range of activities for medicinal applications, such as antivi-
ral, antitumor, antibacterial, and anti-inflammatory activities. In
whereas the synthesis of less substituted dihydropyrimidines is
problematic. Some reasons for this problem are as follows: it is
difficult to control the high reactivity of formaldehyde (3;
R1 = H), and b-oxoaldehyde (4; R2 = H) is not easily available in
the multicomponent reactions described above. To overcome
these difficulties during the course of our continuous research on
dihydropyrimidines,7 we previously developed a method of step-
wise synthesis of 4,6-unsubstituted 2-phenyldihydropyrimidines
7 having various 5-substituents via the cyclization of 1,3-diaza-
1,3-butadiene 8 and electron-deficient olefins 9 (Scheme 2).7d–f It
addition, they are regarded as calcium channel antagonists,2
a
ROCK1 inhibitor for cardiovascular diseases,3 or a pharmaceutical
agent for anti-hepatitis B virus replication.4 Their anticancer
potential has also been explored recently.5 Therefore, the develop-
ment of versatile synthetic methods for dihydropyrimidines and
the expansion of the structural diversity of these compounds are
important and will contribute to medicinal chemistry.
was
a versatile method to obtain novel 4,6-unsubstituted
dihydropyrimidines 7. Although this method is useful for the
synthesis of some 5-acyl-2-phenyldihydropyrimidine derivatives,
the olefin substrates having ketones such as benzoyl or 4-
chlorobenzoyl groups are not commercially available and need to
be prepared.7d,e In addition, alkyl vinyl ketones such as methyl
vinyl ketone were not applicable. These problems led us to
Dihydropyrimidines 1 have generally been synthesized by the
reactions of (thio)urea 2 with aldehydes 3 and 1,3-dicarbonyl com-
pounds 4, or the reactions of amidines, guanidines, and O(S)-alky-
liso(thio)urea derivatives
5
with a,b-unsaturated carbonyl
compounds
6
(Scheme 1).1a,6 Therefore, the R1 and R2
substituents at the C-4 and C-6 positions of 1 are typically alkyl
or aryl groups, and the COR3 substituent at the 5-position is an
acyl, alkoxycarbonyl, or amide group. Multisubstituted
explore a more efficient route for synthesizing 5-acyl-2-
phenyldihydropyrimidines.
In this study, we utilized the Weinreb amide group (N-meth-
oxy-N-methyl amide group) as an acyl group precursor. The Wein-
reb amide group is a versatile and reliable functional group that is
easily converted to an acyl group via nucleophilic substitution
reaction using Grignard or organolithium reagents.8 Herein, we
dihydropyrimidines
1 are comparatively easy to synthesize,
⇑
Corresponding author. Tel.: +81 82 878 9498; fax: +81 82 878 9540.
E-mail address: nishimura-y@yasuda-u.ac.jp (Y. Nishimura).
http://dx.doi.org/10.1016/j.tetlet.2016.08.077
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

Y. Nishimura et al. / Tetrahedron Letters 57 (2016) 4492–4495
4493
R1
O
O
R1
O
O
6
OMe
Me
Boc
OMe
Me
R1 R3
4
Boc
5
4
O
N
N
2
N
O
H
N
R3
3
N
O
3
R3
5
NH
NH2
NH2
2
N
NMe2
N
NMe2
RLi
O
R2
6
12
R4
R2
N
R2
NH2
1
R5
6
X
O
H
8
13
O
2
4
1
5
4
5
6
X
Boc
5
4
X = O, S
R
5 = alkyl, aryl, OR', SR', NR'2
R1, R2 = alkyl, aryl, R3 = alkyl, aryl, OR, NR2
R4 = O, S, alkyl, aryl, OR', SR', NR'2
MeI
N
2
R
N
2
R
6
N
N
NMe2
10
11
(X = Boc)
(X = H)
14
Scheme 1. Synthesis of dihydropyrimidines by condensation reactions.
Scheme 3. Synthetic strategy for 5-acyl-2-phenyldihydropyrimidines 10 and 11.
describe a convergent synthesis of 4,6-unsubstituted 5-acyl-2-
phenyldihydropyrimidines 10 and 11 from 1,3-diaza-1,3-butadi-
ene
8 and N-methoxy-N-methylacrylamide 12 (Scheme 3).
O
O
OMe
Me
Namely, the cyclization of 8 and 12 provides 6-unsubstituted 4-
dimethylamino-2-phenyltetrahydropyrimidine 13 having the
Weinreb amide at 5-position. Subsequently, the substitution reac-
tion of the Weinreb amide group of 13 with organolithium
reagents gives 6-unsubstituted 5-acyl-4-dimethylamino-2-phenyl-
tetrahydropyrimidine 14, and the subsequent elimination reaction
of the 4-dimethylamino group of 14 with MeI affords 10. The syn-
thesis of dihydropyrimidine 10 is difficult by conventional meth-
ods. In fact, to the best of our knowledge, the general formulae of
10 and N-unsubstituted dihydropyrimidines 11 shown in this
paper have not been reported in the literature.
Boc
Boc
N
N
OMe
Li2CO3 (1.0 eq)
N
N
N
NMe2
Me
4
N
NMe2
mesitylene
100ºC, 48h
12
13
71%
8
O
X
OMe
N
MeI (10 eq)
N
Me
N
CH2Cl2
rt, 2.5 h
TFA (30 eq)
CH2Cl2, rt, 3 h
15
(X = Boc) 74%
(X = H) 89%
16
First, we prepared dihydropyrimidines and related derivatives
having the Weinreb amide. N-methoxy-N-methylacrylamide 12
was synthesized from acryloyl chloride and N-methoxy-N-methy-
lamine hydrochloride under basic condition, and the reaction of
12 with 1,3-diaza-1,3-butadiene 89 was investigated (Scheme 4).
Unlike the optimized reaction conditions in our previous stud-
ies,7d–f the use of large excess amount (30 equiv) of 12 or
solvent-free condition resulted in a low yield of the cyclized
product tetrahydropyrimidine 13, because of polymerization of
12. We eventually found that the reaction proceeded smoothly
using 12 (10 equiv) in mesitylene (0.6 M) in the presence of
Li2CO3 (1.0 equiv) at 100 °C for 48 h to give 13 in 71% yield as a
single stereoisomer. The relative configuration of 13 was
determined to be anti between 4-position and 5-position using
NOE experiments (see; Supplementary Material). Successive
elimination reactions of 13 gave 15 in 74% yield (Scheme 4). The
N-protecting group (Boc) of 15 was removed and N-
unsubstituted dihydropyrimidine 16 was synthesized; 15 was
treated with excess trifluoroacetic acid (TFA) to afford 16 in 89%
yield. Therefore, dihydropyrimidines 15 and 16 could be obtained
as substrates for the synthesis of 4,6-unsubstituted 5-acyl-2-
phenyldihydropyrimidines.
Scheme 4. Synthesis of tetrahydropyrimidine 13 and dihydropyrimidines having
Weinreb amide group 15 and 16.
O
O
OMe
Boc
Boc
N
N
N
R
RMgBr (3.0-6.0 eq)
Me
N
N
THF, 0 ºC, 0.5−2 h
15
10a (R = Me) 82%
10b (R = n-Bu) 9%
10c (R = Ph) 20%
O
Boc
OMe
N
N
RLi (2.0 eq)
Me
N
THF, −70 ºC
15
O
O
Boc
R
OMe
N
Boc
N
N
Me
R
+
N
N
Having secured 15 and 16 in hand, the substitution reactions of
the Weinreb amide group of 15 with nucleophilic reagents were
investigated (Scheme 5). The reaction of 15 with methylmagne-
sium bromide in THF proceeded smoothly to give the 5-acetyl
derivative 10a in 82% yield. However, the reactions with other
Grignard reagents such as n-butylmagnesium chloride or phenyl-
magnesium bromide gave a complex mixture to afford the 5-acyl
products 10b or 10c in low yields even though the starting mate-
rial 15 was consumed. Taking into account of the side reactions
17b (R = n-Bu) 37% (1.1:1.0)
17c (R = Ph) 26% (1.1:1.0)
10b (R = n-Bu) 42%
10c (R = Ph) 54%
Scheme 5. Reactions of dihydropyrimidine 15 with Grignard or organolithium
reagents.
with the Boc group of 15 with Grignard reagents, N-unsubstituted
dihydropyrimidine 16 was used as an alternative substrate. How-
ever, the reactions of 16 also gave similar results giving low yields
of the 5-acyl product. Next, we tested the use of organolithium
reagents in the reaction with 15 instead of Grignard reagents. Both
reactions using n-butyllithium or phenyllithium gave the corre-
sponding 5-acyl derivatives 10 in moderate yields (42% or 54%)
with considerable amounts of side products 17 as a mixture of
stereoisomers (1.1:1.0) derived from the conjugate addition of
organolithium reagents to 15.
Boc
EWG
Boc
N
EWG
N
+
9
N
N
NMe2
heating
7
8
Scheme 2. Synthesis of 4,6-unsubstituted 2-phenyldihydropyrimidines 7 from 1,3-
diaza-1,3-butadiene 8.

4494
Y. Nishimura et al. / Tetrahedron Letters 57 (2016) 4492–4495
O
To prevent the production of 17 in the reaction using organo-
O
OMe
Me
Boc
Boc
lithium reagents, the substrate was changed from dihydropyrim-
idines to tetrahydropyrimidine 13. When 13 was reacted with
butyllithium (3.0 equiv) in THF at 0 °C, the desired 5-pentanoyl
tetrahydropyrimidine 14b (R = n-Bu) was obtained in a quantita-
tive yield without detection of any byproduct (Table 1, entry 1).
When less amount of butyllithium (1.5–2.0 equiv) than 3.0 equiv
was used in the reaction with 13, 14b was obtained but the reac-
tion was not completed by TLC analysis. Therefore, 3.0 equiv of
butyllithium was needed for complete consumption of 13. It is
probably due to the coordination of three nitrogen atoms of 4-
dimethylaminotetrahydropyrimidines 13 to deactivate organo-
lithium reagents. Because 14b was unstable during purification
by silica gel column chromatography, the crude product was trea-
ted with MeI to obtain 10b in 85% isolated yield in two steps from
13 (Table 1, entry 1).10 The reactivity of methylmagnesium bro-
mide with 13 was also tested. However, the reaction was slow even
at 40 °C for 41 h, and 5-acetyl tetrahydropyrimidine was produced
in only 12% yield. Thus, it was found that the use of tetrahydropy-
rimidine 13 as a substrate and organolithiums as alkylating
reagents gives 10 in high yield. Under the optimized reaction con-
ditions, various substrates were subjected to sequential reactions
to form 4,6-unsubstituted 5-acyl-2-phenyldihydropyrimidines 10,
and the results are summarized in Table 1. The reaction using
phenyllithium proceeded smoothly to afford the 5-benzoyl product
10c in 89% yield in two steps (entry 2). In entry 3, (phenylethynyl)
lithium also exhibited good reactivity, affording 10d in 86% yield.
Various aryllithiums, prepared in situ from corresponding aryl bro-
mide and t-butyllithium, reacted smoothly with 13 to give 5-ary-
loyl dihydropyrimidines 10e–h in good yields (entries 4–7). In
the case of entry 8, the reaction using heterocyclic 2-lithiated thio-
phene afforded 5-(2-thiophenecarbonyl)dihydropyrimidine 10i in
65% yield.
1. DIBAL-H (2.1 eq)
THF, 0 ºC, 0.5 h
N
N
N
H
N
NMe2
N
2. MeI (21 eq)
CH2Cl2, rt, 4 h
18
68%
13
O
1
Boc
(EtO)2PCH2CO2Et
CO2Et
(1.5 eq)
N
NaH (2.5 eq)
N
THF, 0 ºC, 0.5 h
19 93%
Scheme 6. Synthesis of 4,6-unsubstituted 5-formyl-2-phenyldihydropyrimidine 18
and Horner–Emmons reaction.
Table 2
Synthesis and 1H NMR analysis of N-unsubstituted dihydropyrimidines 11
O
O
O
TFA
1
HN
4
6
Boc
N
N
R
R
R
CH2Cl2
rt, 4 h
N
N
H
N
1
10
11
11
(1,6-isomer)
(1,4-isomer)
Entry
R
11
Yield %
Ratio of 1,4-/1,6-
tautomers 11
CD3OD
DMSO-d6
1
2
3
4
5
6
7a
n-Bu
Ph
11b
11c
11e
11f
11g
11h
11i
91
91
96
95
100
98
100
Single
Single
Single
Single
Single
Single
Single
Single
Single
Single
Single
1.3:1.0
Single
1.5:1.0
4-MeC6H4
4-MeOC6H4
4-CF3C6H4
2-naphthyl
4-ClC6H4
The synthesis of hitherto unavailable 5-formyl dihydropyrim-
idine 18 was examined (Scheme 6). When 13 was reacted with
diisobutylaluminum hydride (DIBAL-H) and MeI, two-step reac-
tions proceeded smoothly to give 5-formyl dihydropyrimidine 18
in 68% yield. Further transformation of the 5-formyl group of 18
was attempted; the Horner–Emmons reaction using triethyl phos-
phonoacetate and sodium hydride afforded novel dihydropyrim-
idine 19 having the conjugated ester group at 5-position in a
high yield of 93%.
a
Ref. 7e.
afford 11b in 91% yield (entry 1).11 The deprotection reactions of
10c–j with TFA also proceeded to give 11c–j in high yields, respec-
tively (entries 2–7). Subsequently, the tautomeric behaviors of
11b–j were analyzed by 1H NMR spectroscopy. The spectra were
measured in CD3OD and DMSO-d6 at 25 °C (0.01 M, 600 MHz).
While all dihydropyrimidines 11 were observed as a single isomer
(average spectrum of tautomers) in CD3OD, 11g and 11j were
observed as two independent isomers at ratios of 1.3:1.0 and
1.5:1.0 in DMSO-d6, respectively (entries 5 and 7). In the 1H NMR
spectrum of 11g in DMSO-d6, the observed signals of NH protons
[d 9.75 (major), d 9.00 (minor)] and 4-protons [d 4.51 (major), d
4.38 (minor)] indicated that thetwo isomers were 1,4- and 1,6-tau-
tomers. The major tautomer of 11g in DMSO-d6 was assigned to the
1,4-isomer because the 6-H vinyl proton (d 6.94) was observed as a
doublet peak by its coupling (J = 4.2 Hz) with the 1-NH proton (d
9.75). In the 1H NMR spectrum of 11j in DMSO-d6, the major tau-
tomer of 11j was assigned to the 1,4-isomer because the 6-H vinyl
proton (d 6.96) was observed as a doublet peak by its coupling
(J = 4.2 Hz) with the 1-NH proton (d 9.72). Therefore, 5-aryloyl-2-
phenyldihydropyrimidines having electron-withdrawing moieties,
such as trifluoromethyl or chloro groups at para-position, showed
relatively low rates of hydrogen transfer in tautomerism. In our
previous report, 2-phenyldihydropyrimidines having 5-carboxylic
acid ethyl ester or 5-phenylsulfonyl groups also showed similar
behaviors to 11g and 11j; the 1,4-isomers were observed as major
tautomers in DMSO-d6.7e These analytical results showed that the
property of 5-substituents in dihydropyrimidines affected the rate
of hydrogen transfer in tautomerism and the stability of each
tautomer.
The N-protecting group (Boc) was removed and N-unsubsti-
tuted dihydropyrimidines 11 were synthesized (Table 2). 10b
was treated with excess TFA in CH2Cl2 at room temperature to
Table 1
Synthesis of 4,6-unsubstituted 5-acyl-2-phenyldihydropyrimidines 10
O
O
6
OMe
Me
Boc
Boc
1. RLi (3.0 eq)
N
N
N
R
5
4
THF, 0 ºC, 0.5 h
N
NMe2
N
2
2. MeI (21 eq)
CH2Cl2, rt, 4 h
13
10
Entry
R
10
Yield %a
1b
2
3
4
5
6
7
8
n-Bu
Ph
10b
10c
10d
10e
10f
10g
10h
10i
85
89
86
80
79
76
76
65
Phenylethynyl
4-MeC6H4
4-MeOC6H4
4-CF3C6H4
2-Naphthyl
2-Thienyl
a
Yield in two steps from 13.
Reaction time was 1 h.
b

Y. Nishimura et al. / Tetrahedron Letters 57 (2016) 4492–4495
4495
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.
3. Sehon, C. A.; Wang, G. A.; Viet, A. Q.; Goodman, K. B.; Dowdell, S. E.; Elkins, P. A.;
Semus, S. F.; Evans, C.; Jolivette, L. J.; Kirkpatrick, R. B.; Dul, E.; Khandekar, S. S.;
Yi, T.; Wright, L. L.; Smith, G. K.; Behm, D. J.; Benthley, R.; Doe, C. P.; Hu, E.; Lee,
D. J. Med. Chem. 2008, 51, 6631–6634.
4. Deres, K.; Schröder, C. H.; Paessens, A.; Goldmann, S.; Hacker, H. J.; Weber, O.;
Krämer, T.; Niewöhner, U.; Pleiss, U.; Stoltefuss, J.; Graef, E.; Koletzki, D.;
Masantschek, R. N. A.; Reimann, A.; Jaeger, R.; Grob, R.; Beckermann, B.;
Schlemmer, K.-H.; Haebich, D.; Rübsamen-Waigmann, H. Science 2003, 299,
893–896.
O
O
1. TFA
CH2Cl2
rt, 3 h
Boc
N
N
N
CH3
N
CH3
2. KMnO4
acetone
rt, 5 min
10e
20 71% (two steps)
Scheme 7. Synthesis of 5-(4-methylbenzoyl)-2-phenylpyrimidine 20.
5. (a) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.; Schreiber, S. L.;
Mitchison, T. J. Science 1999, 286, 971–974; (b) Zhang, Y.; Xu, W. Anticancer
Agents Med. Chem. 2008, 8, 698–704; (c) Jadhav, J.; Juvekar, A.; Kurane, R.;
Khanapure, S.; Salunkhe, R.; Rashinkar, G. Eur. J. Med. Chem. 2013, 65, 232–239.
6. (a) Weis, A.; Frolow, F.; Zamir, D.; Bernstein, M. Heterocycles 1984, 22, 657–661;
(b) Weis, A. Synthesis 1985, 528–530; (c) Weis, A. L.; van der Plas, H. C.
Heterocycles 1986, 24, 1433–1455; (d) Weis, A.; Zamir, D. J. Org. Chem. 1987, 52,
3421–3425; (e) Cho, H.; Iwashita, T.; Ueda, M.; Mizuno, A.; Mizukawa, K.;
Hamaguchi, M. J. Am. Chem. Soc. 1988, 110, 4832–4834; (f) Cho, H.; Shima, K.;
Hayashimatsu, M.; Ohnaka, Y.; Mizuno, A.; Takeuchi, Y. J. Org. Chem. 1985, 50,
4227–4230; (g) Kappe, C. O. Tetrahedron 1993, 49, 6937–6963; (h) Kappe, C. O.;
Stadler, A. Org. React. 2004, 63, 1–116.
7. (a) Cho, H.; Nishimura, Y.; Yasui, Y.; Kobayashi, S.; Yoshida, S.; Kwon, E.;
Yamaguchi, M. Tetrahedron 2011, 67, 2661–2669; (b) Cho, H.; Yasui, Y.;
Kobayashi, S.; Kwon, E.; Arisawa, M.; Yamaguchi, M. Heterocycles 2011, 83,
1807–1818; (c) Cho, H.; Kwon, E.; Yasui, Y.; Kobayashi, S.; Yoshida, S.;
Nishimura, Y.; Yamaguchi, M. Tetrahedron Lett. 2011, 52, 7185–7188; (d) Cho,
H.; Nishimura, Y.; Yasui, Y.; Yamaguchi, M. Tetrahedron Lett. 2012, 53, 1177–
1179; (e) Nishimura, Y.; Yasui, Y.; Kobayashi, S.; Yamaguchi, M.; Cho, H.
Tetrahedron 2012, 68, 3342–3350; (f) Nishimura, Y.; Cho, H. Tetrahedron Lett.
2014, 55, 411–414; (g) Nishimura, Y.; Cho, H. Synlett 2015, 233–237.
8. (a) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 4171–4174; (b)
Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818; (c)
Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 3707–3738.
The transformation of a dihydropyrimidine to its corresponding
pyrimidine derivative was also examined. Namely, N-unsubsti-
tuted dihydropyrimidine 11e was synthesized by the deprotection
of 10e under acidic condition, and oxidized using KMnO4 to give 2-
phenyl-5-(4-methylphenyl)pyrimidine 20 in 71% yield after
recrystallization in two steps (Scheme 7). This method is useful
for the synthesis of novel 2-phenyl-5-aryloylpyrimidine deriva-
tives because the pyrimidines have not been reported in the
literature.
In summary, it was demonstrated that 4,6-unsubstituted 5-
acyl-2-phenyldihydropyrimidines 10 and 11 were synthesized
using the Weinreb amide group as an acyl precursor. The combina-
tion of tetrahydropyrimidine 13 as a substrate and organolithiums
as alkylating reagents is significant for the effective nucleophilic
substitution reaction of the Weinreb amide group. Given that dihy-
dropyrimidines 10 and 11 were previously unavailable and diffi-
cult to synthesize, the achievement in this study should
contribute largely to the expansion of dihydropyrimidine-based
heterocyclic chemistry and pharmaceutical sciences for drug
development.
9. Preparation of 1,3-diaza-1,3-butadiene 8; see Ref. 7e.
10. Under an atmosphere of argon, to a solution of 13 (39.0 mg, 0.100 mmol) in
THF (0.5 mL) was added butyllithium (1.6 M in hexane, 0.13 mL, 0.208 mmol)
dropwise at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. For
complete consumption of 13, further butyllithium (1.6 M in hexane, 0.06 mL,
0.096 mmol) was added, and the reaction mixture was stirred at 0 °C for 0.5 h.
To the reaction mixture was added saturated NH4Cl aqueous solution (5 mL)
followed by 1 M NaOH solution (8 mL) at 0 °C, and EtOAc (20 mL) was added.
The organic layer was separated, and the aqueous layer was extracted with
EtOAc (15 mL Â 2). The combined organic layers were washed with water
(5 mL), brine (5 mL), dried over anhydrous Na2SO4, and concentrated under
reduced pressure. To the crude mixture in CH2Cl2 (1.0 mL) was added MeI
(0.130 mL, 2.09 mmol) at room temperature and the mixture was stirred at
room temperature for 4 h. After removal of excess MeI under reduced pressure,
to the reaction mixture was added EtOAc (20 mL) followed by 1 M NaOH
aqueous solution (10 mL), and the organic layer was separated. The aqueous
layer was extracted with EtOAc (10 mL Â 2), and the combined organic layers
were washed with water (5 mL), brine (5 mL), dried over anhydrous Na2SO4,
and concentrated under reduced pressure. The residue was purified by flash
column chromatography [hexane-EtOAc-Et3N (200:20:1 to 100:20:1)] to give
10b (29.2 mg, 0.0853 mmol, 85%) as a yellow oil.
11. To a solution of 10b (42.8 mg, 0.125 mmol) in CH2Cl2 (2 mL) was added
trifluoroacetic acid (0.370 mL, 4.98 mmol) at 0 °C. The reaction mixture was
stirred at room temperature for 3 h, and 2 M NaOH aqueous solution (7.5 mL)
and EtOAc (20 mL) were added. The organic layer was separated, and the
aqueous layer was extracted with EtOAc (10 mL Â 2). The combined organic
layers were washed with water (5 mL), brine (5 mL), dried over anhydrous
Na2SO4, and concentrated under reduced pressure. The residue was purified by
flash column chromatography [CH2Cl2-EtOAc-Et3N (50:50:1)] to give 11b
(27.5 mg, 0.113 mmol, 91%) as a yellow solid.
Acknowledgment
This work was financially supported by JSPS KAKENHI Grant
Number 26810095 and 16K08335.
Supplementary data
Supplementary data (synthesis and characterization of com-
pounds, spectroscopic data of IR, NMR, MS) associated with this
article can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetlet.2016.08.077.
References and notes
1. (a) Cho, H. Heterocycles 2013, 87, 1441–1479; (b) Suresh; Sandhu, J. S. ARKIVOC
2012, i, 66–133; (c) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043–1052.
2. (a) Cho, H.; Ueda, M.; Shima, K.; Mizuno, A.; Hayashimatsu, M.; Ohnaka, Y.;
Takeuchi, Y.; Hamaguchi, M.; Aisaka, K.; Hidaka, T.; Kawai, M.; Takeda, M.;
Ishihara, T.; Funahashi, K.; Satoh, F.; Morita, M.; Noguchi, T. J. Med. Chem. 1989,
32, 2399–2406; (b) 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; (c) Rovnyak, G. C.; Atwal, K. S.;