Synthesis of 4,6-unsubstituted 2-aminodihydropyrimidine-5-carboxylates through sequential staudinger/aza-wittig/cyclization reactions

Article abstract of DOI:10.1055/s-0034-1378932

A novel method for constructing the dihydropyrimidine skeleton is developed. The method involves three sequential reactions: (1) the Staudinger reaction of (E)-ethyl 3-azido-2-{[(tert-butoxycarbonyl)amino]methyl}acrylate with triphenylphosphine; (2) aza-W

Full text of DOI:10.1055/s-0034-1378932

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2015, 26, 233–237
letter
233
Y. Nishimura, H. Cho
Letter
Synlett
Synthesis of 4,6-Unsubstituted 2-Aminodihydropyrimidine-5-
carboxylates through Sequential Staudinger/Aza-Wittig/Cycliza-
tion Reactions
Yoshio Nishimura*a
Hidetsura Chob
6
Boc
CO2Et
CO2Et
CO2Et
Ph3P
RNCO
N
2C
BocHN
BocHN
Ph3P
4
RN
H
N
N3
N
a Faculty of Pharmacy, Yasuda Women’s University, 6-13-1,
Yasuhigashi, Asaminami-ku, Hiroshima, 731-0153, Japan
b Graduate School of Pharmaceutical Sciences, Tohoku University,
6-3 Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan
nishimura-y@yasuda-u.ac.jp
R = Ph, 4-ClC6H4, 4-EtO2CC6H4, 4-F3CC6H4,
+
8
1
8
(
2
8
)
7
8
9
5
4
0
4-MeOC6H4, 2-MeC6H4, 1-naphthyl, Bn
Received: 18.09.2014
Accepted after revision: 16.10.2014
Published online: 18.11.2014
tives prepared from aldehydes and 1,3-dicarbonyl com-
pounds.1 Generally, these methods give multisubstituted di-
hydropyrimidines with alkyl or aryl groups at the C-4 and
C-6 positions, and an acyl, alkoxycarbonyl, or amide group
at the C-5 position. Whereas other methods for the synthe-
sis of such multisubstituted derivatives have been report-
ed,7 less substituted dihydropyrimidines are comparatively
difficult to synthesize. To overcome this problem, during
the course of our research on the synthesis of less substitut-
ed dihydropyrimidines,8 we previously reported the
synthesis of 4,6- or 4-unsubstituted 2-phenyldihydropy-
rimidines by a novel [4+2] cyclization of 1,3-diaza-1,3-bu-
tadienes with olefins.8a–c We also developed a nucleophilic
substitution reaction of N1-protected 6-unsubstituted 2-
methylthiodihydropyrimidine 1 with amines as another
approach for synthesizing 6-unsubstituted 2-aminodihy-
dropyrimidines 2 and N-unsubstituted products 3 (Scheme
1).8d However, in the reaction of N1-protected 4,6-unsubsti-
tuted 2-methylthiodihydropyrimidine 4 with amines, 4,6-
DOI: 10.1055/s-0034-1378932; Art ID: st-2014-u0779-l
Abstract A novel method for constructing the dihydropyrimidine skel-
eton is developed. The method involves three sequential reactions: (1)
the Staudinger reaction of (E)-ethyl 3-azido-2-{[(tert-butoxycarbon-
yl)amino]methyl}acrylate with triphenylphosphine; (2) aza-Wittig reac-
tion of the resulting iminophosphorane with isocyanate; (3) intramo-
lecular cyclization of the carbodiimide intermediate to give 4,6-
unsubstituted 2-aminodihydropyrimidine-5-carboxylates in high overall
yield. The method can be applied to various aromatic isocyanates, with
substrates having electron-withdrawing groups showing high reactivi-
ties. In the case of aliphatic benzyl isocyanate, the reaction provides bi-
cyclic dihydropyrimidine as the major product. The N-protecting group
(Boc) can easily be removed to obtain N-unsubstituted dihydropyrimi-
dines. All dihydropyrimidines in this study were previously unavailable
and are difficult to synthesize by conventional methods.
Key words dihydropyrimidine, heterocycles, Staudinger reaction, aza-
Wittig reaction, cyclization
Dihydropyrimidines have received much attention from
synthetic and medicinal chemists because of their biologi-
cal activities as well as their physical and chemical charac-
teristics.1 They exhibit a wide range of biological activities
including antiviral, antitumor, antibacterial, and anti-in-
flammatory properties.1 They are also regarded as pharma-
ceutical agents serving as calcium channel antagonists,2
Ca2+-ATPase inhibitors,3 and ROCK1 inhibitors for cardio-
vascular diseases4 or anti-hepatitis B virus replication.5
Their anticancer potential has recently been explored.6
Therefore, the development of novel methods of synthesiz-
ing dihydropyrimidines and the expansion of their struc-
tural diversity is expected to contribute significantly to me-
dicinal chemistry.
unsubstituted 2-aminodihydropyrimidines 5 were not
formed; instead, only unexpected products 6 were obtained
by ring cleavage of the N1–C2 bonds (Scheme 1).8e These re-
sults led us to explore an alternative route to synthesizing
related dihydropyrimidines.
We designed sequential reactions involving Staudinger
reaction/aza-Wittig reaction/cyclization as a novel method
of constructing the dihydropyrimidine skeleton.9 Herein,
we report the synthesis of 4,6-unsubstituted 2-aminodihy-
dropyrimidine-5-carboxylates by using this strategy, as il-
lustrated in Scheme 2. The Staudinger reaction of prepared
(E)-ethyl
3-azido-2-{[(tert-butoxycarbonyl)amino]meth-
yl}acrylate [(E)-7] with triphenylphosphine, followed by the
aza-Wittig reaction of the resulting iminophosphorane (E)-
8 with isocyanates 9, and intramolecular cyclization of the
carbodiimide intermediates (E)-10 furnished 4,6-unsubsti-
tuted 2-aminodihydropyrimidine-5-carboxylates 11, which
can be converted into N-unsubstituted products 12.
Dihydropyrimidines have conventionally been synthe-
sized by either the three-component condensation of
(thio)urea, aldehydes (RCHO), and 1,3-dicarbonyl com-
pounds or by the two-component cyclization of amidines,
guanidines, or O(S)-alkyliso(thio)urea with enone deriva-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 233–237

234
Y. Nishimura, H. Cho
Letter
Synlett
6
Boc
CO2Et
Me
1N
6
2
MeS
N
Boc
CO2Et
Me
CO2Et
Me
N
HN
1
2
RHN
N
RHN
RHN
N
3
2
RNH2
SMe
4
CO2Et
CO2Et
N
RN
N
H
4
6
CO2Et
2
N
N
HN
Boc
Boc
6
2
MeS
N1
5
6
Boc
not detected
4
Scheme 1 Attempted synthesis of less substituted dihydropyrimidines
CO2Et
CO2Et
RNCO 9
Ph3P
BocHN
BocHN
Ph3P
crude product 14 was converted into ethyl 3-[(tert-butoxy-
carbonyl)amino]-2-hydroxypropanoate (15) in 41% isolated
yield in three steps from 13. The reaction conditions for ox-
idation of 15 were then examined; unfortunately, typical
oxidation conditions using pyridinium dichromate (PDC),
2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), or oxallyl
chloride and dimethylsulfoxide (Swern oxidation) were not
effective, and the reactions either gave a complex mixture
or resulted in the recovery of only 15. However, we found
that Dess–Martin periodinane was a suitable reagent and
its application produced the desired α-keto ester in a high
yield.16 When the crude α-keto ester was subjected to the
Wittig reaction using chloromethyltriphenylphosphonium
chloride and n-butyllithium, ethyl {[(tert-butoxycarbon-
yl)amino]methyl}-3-chloroacrylate (16) was obtained as a
mixture of stereoisomers (1.4:1.0) in 74% yield in two steps
from 15. The treatment of 16 with sodium azide afforded
the two stereoisomers alkenylazide (E)-7 and (Z)-7 (1.0:1.2)
in 65% yield, which were isolated by silica gel column chro-
matography. The structure of the major product (Z)-7 was
determined by NOE experiments. A significant NOE signal
(1.3%) was observed between the methylene protons
(δ 3.83 ppm) and the 3-proton (δ 6.98 ppm). Therefore, its
structure was determined to be that shown as (Z)-7.
A sequential reaction was attempted in which the treat-
ment of (E)-7 with triphenylphosphine (1.2 equiv) in THF at
room temperature for 15 min quantitatively yielded imino-
phosphorane (E)-8,17 to which phenyl isocyanate 9a (1.3
equiv) was added. The reaction mixture was stirred at the
same temperature for 6 h, and the desired 4,6-unsubstitut-
ed 2-phenylaminodihydropyrimidine-5-carboxylate 11a
was obtained in 34% yield (Table 1, entry 1). In the 1H NMR
spectra of the crude reaction mixture, unreacted (E)-8 was
observed in 24% yield. When the amount of 9a was in-
creased to 2.5 equiv, (E)-8 was completely consumed and
the yield was improved to 56% (entry 2). When 5.0 equiv of
9a was used, the reaction proceeded smoothly to give 11a
N3
N
(E)-8
(E)-7
6
CO2Et
X
N
CO2Et
BocHN
4
2
RN
C N
RHN
N
(E)-10
11 (X = Boc)
12 (X = H)
Scheme 2 Synthetic strategy for 4,6-unsubstituted 2-aminodihydro-
pyrimidine-5-carboxylates 11 and 12
In general, multisubstituted 2-aminodihydopyrimidines
have been synthesized by three-component condensation
using guanidines, aldehydes, and β-dicarbonyl com-
pounds,10 by cyclization of guanidines with α,β-unsaturat-
ed carbonyl compounds,11 or by nucleophilic substitution
reaction of 2-alkylthio8d,12a or 2-alkoxydihydropyrimi-
dines12b with amines. For the synthesis of less substituted
2-aminodihydropyrimidines, several methods for providing
5,6-unsubstituted 2-amino-4-oxodihydropyrimidines13 and
only a few examples of reactions proceeding through the
reduction of pyrimidines have been reported so far.14 Our
novel method is useful for synthesizing 4,6-unsubstituted
2-aminodihydropyrimidine-5-carboxylates, which are not
easy to obtain by conventional methods. In fact, to our
knowledge, the general formulae of 11 and 12 have not pre-
viously been reported.
First, ethyl 3-azido-2-{[(tert-butoxycarbonyl)amino]-
methyl}acrylate (7) was prepared from ethyl bromopyru-
vate (13) in six steps, as shown in Scheme 3. As reported
previously,15 the reduction of 13 by using sodium cyanobo-
rohydride and subsequent substitution reaction with sodi-
um azide, afforded ethyl 3-azido-2-hydroxypropanoate
(14). Subsequently, in a hydrogen atmosphere with 10%
palladium on carbon and di-tert-butyl dicarbonate, the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 233–237

235
Y. Nishimura, H. Cho
Letter
Synlett
1. NaBH3CN
MeOH, 0 ºC, 1 h
H2 (1 atm), Pd/C, Boc2O
CO2Et
CO2Et
CO2Et
N3
Br
BocHN
2. NaN3
EtOH–H2O, 75 ºC, 18 h
AcOEt, r.t., 62 h
41% (3 steps)
OH
O
OH
13
15
1. Dess–Martin periodinane
CH2Cl2, r.t., 30 min
H
NaN3
CO2Et
CO2Et
CO2Et
BocHN
BocHN
BocHN
+
DMF, r.t., 3 h
2. Ph3PCH2Cl Cl
n-BuLi, THF
–75 °C to 0 °C, 2 h
74% (2 steps)
Cl
16 (1.4:1.0)
N3
(E)-7
H
N3
65%
(E/Z = 1.0:1.2)
NOE
(Z)-7
Scheme 3 Preparation of substrate 7
in a high yield of 78% (entry 3). The use of an excess amount
of 9a (10 equiv) had no further positive effect and led to the
production of an unidentified byproduct (entry 4). When a
less polar solvent (i.e., dichloromethane or toluene) was
used, the reactions resulted in lower yields of 11a (entries 5
and 6). The use of DMF was also ineffective (entry 7).
Hence, we used the reaction conditions detailed in Table 1,
entry 3 to synthesize 11 from (E)-7.
To determine the effect of the olefin geometry of 7 on
the course of the reaction, (Z)-7 was used as the starting
material (Scheme 4). Under the optimized reaction condi-
tions, 11a was not obtained although nitrogen was generated
during the reaction of (Z)-7 with triphenylphosphine. This
is probably because the carbodiimide intermediate (Z)-17
does not undergo cyclization. Therefore, the olefin geome-
try of 7 is crucial, and only the use of (E)-7 enables the suc-
cessful construction of the dihydropyrimidine skeleton.
Table 1 Optimization of Reaction Conditions
Ph3P
CO2Et
PhNCO
(9a)
Boc
CO2Et
CO2Et
(1.2 equiv)
BocHN
Ph3P
BocHN
N
r.t., 15 min
r.t., 3 h
2
N
N3
(E)-7
PhHN
N
(E)-8
11a
Entry
Solvent
9a (equiv)
Yield (%)
1a
2
3
4
5
6
7
THF
1.3
2.5
5.0
10.0
5.0
5.0
5.0
34
56
78
67
65
64
36
THF
THF
THF
CH2Cl2
toluene
DMF
a Reaction time with 9a was 6 h, and (E)-8 was recovered in 24% yield.
1. Ph3P (1.2 equiv)
CO2Et
CO2Et
THF, r.t., 15 min
BocHN
BocHN
11a
not detected
2. PhNCO (5.0 equiv)
THF, r.t., 3 h
N3
N
C NPh
(Z)-17
(Z)-7
Scheme 4 Use of (Z)-7 as the starting material
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 233–237

236
Y. Nishimura, H. Cho
Letter
Synlett
Table 2 Synthesis of 4,6-Unsubstituted 2-Aminodihydropyrimidines
11
and the subsequent second cyclization by an intramolecu-
lar substitution reaction with a tert-butoxycarbonyl group
afforded 18.
1. Ph3P (1.2 equiv)
THF, r.t., 15 min
CO2Et
Boc
CO2Et
The N-protecting (Boc) group was easily removed to
produce N-unsubstituted dihydropyrimidines 12 (Scheme
6). When 11a was treated with trifluoroacetic acid (TFA) in
dichloromethane at room temperature for 3 h, 12a was ob-
tained in 89% yield.19 The deprotection of 11b also proceed-
ed to give 12b. To analyze the tautomeric behavior of 12a
BocHN
N
2. RNCO 9 (5.0 equiv)
THF, r.t., 3 h
N3
RHN
N
(E)-7
11
Entry
9
R
11
Yield (%)
1
and 12b, H NMR spectra of 12 were measured in CD3OD,
1
2
3
4
5
6a
7
9a
9b
9c
9d
9e
9f
Ph
11a
78
85
92
95
65
47
54
CDCl3, and DMSO-d6 at 25 °C (0.01 M, 600 MHz). In all these
solvents, 12a and 12b were observed as single isomers, the
behaviors of which were the same as those of 2-aminodihy-
dropyrimidines.8d,20 However, in our previous report on the
synthesis of 4,6-unsubstituted 2-phenyl derivatives,8b their
individual tautomers were observed in DMSO-d6. As report-
ed previously by Cho and co-workers,20 it was found that
the nature of the 2-substituents (phenylamino or phenyl
group) on 4,6-unsubstituted dihydropyrimidines affects
the tautomeric behavior.
4-ClC6H4
11b
11c
11d
11e
11f
4-EtO2CC6H4
4-F3CC6H4
4-MeOC6H4
2-MeC6H4
1-naphthyl
9g
11g
a Reaction time with 9f was 12 h.
Under the optimized reaction conditions, aryl isocya-
nates 9 were subjected to sequential reactions with (E)-7 to
assemble 4,6-unsubstituted 2-arylaminodihydropyrimi-
dine-5-carboxylates 11.18 The results are summarized in Ta-
ble 2. Aryl isocyanates 9b–d, with electron-withdrawing
moieties such as 4-chloro, 4-ethoxycarbonyl, and 4-trifluo-
romethyl groups, showed high reactivities, giving 11b, 11c,
and 11d in excellent yields of 85, 92, and 95%, respectively
(entries 2–4). Although isocyanate 9e, with an electron-do-
nating 4-methoxy group, exhibited a relatively low reactivi-
ty, the corresponding product 11e was obtained in an ac-
ceptable yield of 65% (entry 5). Thus, the electrophilic prop-
erties of 9b, 9c, and 9d, with an electron-withdrawing
group at the 4-position, may accelerate their reaction with
nucleophilic iminophosphoranes (E)-8 and the cyclization
of the carbodiimide intermediates (E)-10. Even sterically
hindered 2-tolyl and 1-naphthyl isocyanates 9f–g could be
used in the reactions to obtain 11f–g in moderate yields
(entries 6 and 7).
Boc
CO2Et
CO2Et
TFA
N
HN
CH2Cl2, r.t., 3 h
RHN
N
RHN
N
12
11
12a R = Ph
12b R = 4-ClC6H4
89%
88%
Scheme 6 Deprotection of 11
In summary, a novel method of constructing the dihy-
dropyrimidine skeleton was developed, which involves
Staudinger reaction, aza-Wittig reaction, and cyclization. In
addition to the methods presented in our previous reports,
namely, [4+2] cyclization8a–c and nucleophilic substitution
reaction,8d the one-pot sequential reactions for the synthe-
sis of less substituted dihydropyrimidines were disclosed.
We applied the method to the synthesis of 4,6-unsubstitut-
ed 2-aminodihydropyrimidine-5-carboxylates in this study.
Given that dihydropyrimidines 11 and 12 were previously
unavailable and difficult to synthesize by conventional
methods, this unprecedented achievement should contrib-
ute to an expansion of dihydropyrimidine-based chemistry
and pharmaceutical sciences for drug development.
When aliphatic benzyl isocyanate 9h was reacted with
(E)-7, in addition to dihydropyrimidine 11h (16%), bicyclic
dihydropyrimidine 18 was obtained as the major product in
52% yield (Scheme 5). Owing to the higher nucleophilicity
of the benzyl amine moiety compared with that of the aryl
amine moiety, 11h reacted further with the remaining 9h,
O
1. Ph3P (1.2 equiv)
THF, r.t., 15 min
Boc
CO2Et Bn
CO2Et
CO2Et
N
BocHN
N
N
+
2. BnNCO (9h)
(5.0 equiv)
THF, r.t., 48 h
BnHN
N
N3
(E)-7
O
N
N
11h
16%
Bn
18
52%
Scheme 5 Reaction of (E)-7 with benzyl isocyanate 9h
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 233–237

237
Y. Nishimura, H. Cho
Letter
Synlett
Acknowledgment
(9) (a) Hirota, S.; Sakai, T.; Kitamura, N.; Kubokawa, K.; Kutsumura,
N.; Otani, T.; Saito, T. Tetrahedron 2010, 66, 653. (b) Hirota, S.;
Kato, R.; Suzuki, M.; Soneta, Y.; Otani, T.; Saito, T. Eur. J. Org.
Chem. 2008, 2075.
(10) Eynde, J. J. V.; Hecq, N.; Kataeva, O.; Kappe, C. O. Tetrahedron
2001, 57, 1785.
This work was financially supported by the Sasakawa Scientific Re-
search Grant from The Japan Science Society and JSPS KAKENHI Grant
Number 24790122 and 26810095.
(11) (a) Hamper, B. C.; Gan, K. Z.; Owen, T. J. Tetrahedron Lett. 1999,
40, 4973. (b) Cho, H.; Shima, K.; Hayashimatsu, M.; Ohnaka, Y.;
Mizuno, A.; Takeuchi, Y. J. Org. Chem. 1985, 50, 4227.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378932.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
(13) (a) Li, J.; Kou, J.; Luo, X.; Fan, E. Tetrahedron Lett. 2008, 49, 2761.
(b) Kochubey, V. S.; Blochin, Ya. S.; Rodin, O. G.; Perevalov, V. P.
Chem. Heterocycl. Compd. 2006, 42, 897.
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2004, 45, 2107.
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5498.
(17) Although (E)-8 was not isolated because of its instability under
silica gel column chromatography, its structure was determined
by 1H NMR analysis. The reaction of (E)-7 with triphenylphos-
phine (1.2 equiv) in CDCl3 at r.t. for 15 min quantitatively gave
(E)-8.
(18) Under an argon atmosphere, to a solution of (E)-7 (27.0 mg,
0.100 mmol) in THF (1.5 mL) was added triphenylphosphine
(31.5 mg, 0.120 mmol). The reaction mixture was stirred at r.t.
for 15 min, then phenyl isocyanate 9a (54 μL, 0.499 mmol) was
added, and stirring was continued at the same temperature for
3 h. To the reaction mixture was added EtOAc (20 mL), followed
by sat. aq NaHCO3 (5 mL), and the organic layer was separated.
The aqueous layer was extracted with EtOAc (10 mL), and the
combined organic layers were washed with brine (5 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by flash silica gel column chro-
matography (n-hexane–EtOAc–Et3N, 40:2:1) to give 11a (26.8
mg, 0.0776 mmol, 78%) as pale-yellow crystals [mp 113–114 °C
(n-hexane)].
(19) To a solution of 11a (57.0 mg, 0.165 mmol) in CH2Cl2 (2 mL) was
added trifluoroacetic acid (0.490 mL, 6.60 mmol) at 0 °C. The
reaction mixture was stirred at r.t. for 3 h, and aqueous 2 M
NaOH (5 mL) and EtOAc (20 mL) were added. The organic layer
was separated, and the aqueous layer was extracted with EtOAc
(10 mL). The combined organic layers were washed with water
(5 mL), brine (5 mL), dried over anhydrous Na2SO4, and concen-
trated under reduced pressure. The residue was purified by
recrystallization (n-hexane–EtOAc) to give 12a (35.9 mg, 0.146
mmol, 89%) as colorless crystals (mp 192 °C).
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