Convergent synthesis of 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines using Weinreb amide

Article abstract of DOI:10.1016/j.tetlet.2017.09.064

A method of convergent synthesis of novel 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines 7 is developed. The synthetic intermediate of 7, 4,6-unsubstituted 2-aminodihydropyrimidines 9 having a Weinreb amide at the 5-position, is prepared by the sequen

Full text of DOI:10.1016/j.tetlet.2017.09.064

Accepted Manuscript
Convergent synthesis of 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines
using Weinreb amide
Yoshio Nishimura, Takanori Kubo, Yasuko Okamoto, Hidetsura Cho
PII:
S0040-4039(17)31200-5
https://doi.org/10.1016/j.tetlet.2017.09.064
TETL 49334
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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18 September 2017
21 September 2017
Please cite this article as: Nishimura, Y., Kubo, T., Okamoto, Y., Cho, H., Convergent synthesis of 4,6-unsubstituted
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j.tetlet.2017.09.064
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Tetrahedron Letters
Convergent synthesis of 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines using
Weinreb amide
Yoshio Nishimuraa,*, Takanori Kuboa, Yasuko Okamotob, Hidetsura Choc
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
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A method of convergent synthesis of novel 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines
7 is developed. The synthetic intermediate of 7, 4,6-unsubstituted 2-aminodihydropyrimidines 9
having a Weinreb amide at the 5-position, is prepared by the sequential Staudinger/aza-
Wittig/cyclization
reactions
of
(E)-tert-butyl
{3-azido-2-
Available online
[methoxy(methyl)carbamoyl]allyl}carbamate (E)-10. The transformation of the Weinreb amide
of 9 to an acyl group proceeds smoothly by a substitution reaction using aryllithiums or
alkyllithiums in the presence of a catalytic amount of BF3 etherate, affording 7 in good to high
yield. The N-protecting group of 7 can be easily removed to obtain N-unsubstituted 2-amino-5-
acyldihydropyrimidines 8, and the derivatives are observed as a single isomer in 1H NMR
spectroscopy. All dihydropyrimidines in this study were hitherto unavailable and difficult to
synthesize by conventional methods.
Keywords:
dihydropyrimidine
heterocycles
Staudinger reaction
Aza-Wittig reaction
Weinreb amide
2009 Elsevier Ltd. All rights reserved.
Dihydropyrimidines have received much attention from
synthetic 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 antiviral, antitumor, antibacterial, and anti-inflammatory
activities. In addition, they are regarded as calcium channel
antagonists,2 Rho-associated kinase isoform
1
(ROCK1)
inhibitors for cardiovascular diseases,3 or pharmaceutical agents
for anti-hepatitis B virus replication.4 Their anticancer potential
has also been explored recently.5 Therefore, the development of
versatile synthetic methods for dihydropyrimidines and the
expansion of the structural diversity of these compounds are
important and will contribute to advances in medicinal chemistry.
Dihydropyrimidines 1 have generally been synthesized by the
reactions of (thio)urea 2 with aldehydes 3 and 1,3-dicarbonyl
compounds 4, or the reactions of amidines, guanidines, and O(S)-
alkyliso(thio)urea derivatives 5 with ,-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, whereas the COR3 substituent at the 5-position is
an acyl, alkoxycarbonyl, or amide group. Multisubstituted
dihydropyrimidines 1 are comparatively easy to synthesize,
whereas the synthesis of less substituted dihydropyrimidines is
problematic. Some reasons for this are as follows: it is difficult to
control the high reactivity of formaldehyde (3; R1= H), and
Scheme 1. Synthesis of dihydropyrimidines by condensation
reactions
-oxoaldehyde (4; R2 = H) is not easily available. To overcome
these difficulties during the course of our continuous research on
dihydropyrimidines,7 we previously developed a novel method of
synthesis of 4,6-unsubstituted 2-phenyldihydropyrimidines
having an acyl group at the 5-position, in which a Weinreb amide
was used as an acyl precursor.7h,8 Although this method is useful
for the synthesis of hitherto unavailable 4,6-unsubstituted 5-
acyldihydropyrimidines, the substituent at the 2-position was
limited to only a phenyl group. On the other hand, we previously
developed sequential Staudinger/aza-Wittig/cyclization reactions
for the synthesis of 4,6-unsubstituted 2-aminodihydropyrimidine-
5-carboxylates.7g Using the sequential reactions, we herein
describe a method of convergent synthesis of 4,6-unsubstituted 5-
acyl-2-aminodihydropyrimidines 7 and N-unsubstituted 8 from
dihydropyrimidines 9 (Scheme 2). Namely, the sequential
* Corresponding author. Tel.: +81 82 878 9498; fax: +81 82 878 9540. E-mail
address: nishimura-y@yasuda-u.ac.jp (Y. Nishimura).

2
Tetrahedron Letters
optimal conditions were the same as before, and the reaction
using freshly prepared Dess–Martin periodinane (DMP) worked
well and gave the desired -keto ester in high yield.7g When the
crude -keto ester was subjected to the Wittig reaction using
chloromethyltriphenylphosphonium chloride and n-butyllithium,
chloroalkene 17 was obtained as a single stereoisomer in two
steps in 57% yield. The treatment of 17 with sodium azide
afforded azidoalkene (E)-10 as a single stereoisomer in 63%
yield. The olefin geometries of 17 and 10 were different from
those in our previous report on the synthesis of azidoalkene
bearing an ethyl ester,7g probably because the bulky Weinreb
amide group prevented the production of (Z)-isomers of 17 and
10. The structure of (E)-10 was determined by NOE experiments:
a significant NOE was observed between the methyl protons of
the Weinreb amide and the alkene proton. Therefore, the
structure was determined to be (E)-10 (see Supplementary
Material). After obtaining (E)-10, the sequential reactions for the
synthesis of 9 were attempted. The Staudinger reaction of (E)-10
with triphenylphosphine proceeded smoothly with nitrogen
generation to give the iminophosphorane intermediate (E)-11
quantitatively (shown in Scheme 2), and the aza-Wittig reaction
of (E)-11 with phenylisocyanate following cyclization furnished
Scheme
2.
Synthetic
strategy
for
5-acyl-2-
aminodihydropyrimidines 7 and 8
reactions of alkenyl azide (E)-10 having Weinreb amide provide
9 via iminophosphorane intermediate (E)-11. Subsequently, the
substitution reaction of the Weinreb amide of 9 by organolithium
reagents gives 7. It is difficult to synthesize 7 and 8 by
conventional methods. In fact, the general formulae of 7 and 8
have not as yet been reported. Therefore, our novel method
enables to introduce various 2-amino and 5-acyl groups to the
dihydropyrimidine scaffold.
the
dihydropyrimidine
9a
in
63%
yield.16
4-
(Trifluoromethyl)phenylisocyanate was also successfully applied
to the reaction to provide 9b in 76% yield.
Next, we optimized the reaction conditions of nucleophilic
substitution of 7 (Table 1). When 9a was reacted with
In general, multisubstituted 2-aminodihydopyrimidines have
been synthesized by three-component condensation using
guanidines, aldehydes, and -dicarbonyl compounds,9 by
cyclization of guanidines with ,-unsaturated carbonyl
compounds,6f,10 or by the nucleophilic substitution reactions of 2-
alkylthio7a,11a or 2-alkoxydihydropyrimidines11b with amines. For
the synthesis of less substituted 2-aminodihydropyrimidines,
several methods that provide 5,6-unsubstituted 2-amino-4-oxo-
phenyllithium (3.0 eq) at
0
ºC, the desired 5-
benzoyldihydropyrimidine 7a was obtained in 55% yield with
recovery of 9a at 4% (entry 1). When 2.0 eq of phenyllithium
was used, the reaction was not complete, as determined by TLC
analysis. Therefore, excess phenyllithium was needed for
consumption of 9a, probably because 1.0 eq of phenyllithium
was initially consumed to deprotonate the NH proton of the 2-
phenylamino group of 9a, and the coordination of other nitrogen
atoms in the dihydropyrimidine ring of 9a may deactivate
phenyllithium. In entry 2, decreasing the reaction temperature
(40 ºC) increased the yield of 7a to 68%. The reaction at 80 ºC
was slow and gave 7a in 61% yield, and unreacted 9a (14%) was
dihydropyrimidines12 and
a
few reduction reactions of
pyrimidines have been reported thus far.13
First, the precursor of 9, alkenyl azide (E)-10 with a Weinreb
amide, was prepared from ethyl bromopyruvate 12 in seven steps,
as shown in Scheme 3. The reduction of 12 using sodium
cyanoborohydride and the subsequent substitution reaction with
sodium azide afforded ethyl 3-azido-2-hydroxypropanoate 13 in
two steps in 64% yield.7g,14 Subsequently, 13 was reacted with
N,O-dimethylhydroxylamine hydrochloride in the presence of
trimethylaluminum at room temperature (rt) to give the Weinreb
amide 14 in 78% yield.15 Next, the one-pot reduction of the azide
group to a primary amine and protection of the amine by t-
butoxycarbonyl (Boc) group gave the carbamate 15 in 84% yield.
Although the oxidation reaction of 15 was examined under
several conditions using pyridinium dichromate (PDC), sulfur
trioxide pyridine complex, or 2-iodoxybenzoic acid (IBX), the
reactions resulted in a low yield (<30%) of 16. Eventually the
1
observed in the H NMR spectrum of the crude reaction mixture
(entry 3). Next, we tested the effect of additives on the yield of
7a. Addition of MgCl2 and CeCl3 slightly increased the yields
from 68% to 73% and 75%, respectively (entries 4, 5). When BF3
etherate was added, 9a was obtained in a good yield of 77%
(entry 6). Further optimization revealed that the reaction in the
presence of 0.2 eq of BF3 etherate furnished 9a in high yield of
81% (entry 7).
As reported previously,7h the reaction of 4,6-unsubstituted 2-
phenyldihydropyrimidine 18 having a Weinreb amide at 5-
p os i ti on w it h R Li ( n -C 4 H 9 Li or P h Li ) ga ve 5 -
acyldihydropyrimidines 19 along with side products 20 by
Scheme 3. Preparation of dihydropyrimidine 9.

yield after recrystallization. The deprotection of 7b and 7c also
proceeded to give 8b and 8c, respectively. To analyze their
Table 1. Optimization of reaction conditions for the synthesis of
5-benzoyldihydropyrimidine 7a
Table
2.
Synthesis
of
4,6-unsubstituted
5-acyl-2-
aminodihydropyrimidines 7
conjugate addition (Scheme 4). However, no such side product
was observed in the reaction of 9a shown in Table 1. In the
reaction with 9a, the initial deprotonation of the NH proton of the
2-phenylamino group by PhLi occurred prior to addition to the
Weinreb amide, and conjugate addition of PhLi might not occur
at a -position that is close to the anionic character of nitrogen in
21a (Scheme 4).
1
tautomeric behavior, H NMR spectra were measured in DMSO-
d6 at 25 ºC (0.01 M, 600 MHz). In all spectra, 8 was observed as
a single isomer, the behavior of which was the same as that of 2-
aminodihydropyrimidine-5-esters in our previous report.7g To
compare the stability of dihydropyrimidine tautomers, theoretical
calculation and detailed analysis of 1H NMR measurements are in
progress.18
Scheme 4. Reaction of 2-phenyldihydropyrimidine 18 and 9a
with organolithium reagents
Scheme 5. Synthesis of N-unsubstituted dihydropyrimidine 8
Under the optimized reaction conditions, various organolithium
reagents were subjected to nucleophilic substitution reactions to
form 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines 7, and
the results are summarized in Table 2.17 In addition to
phenyllithium (entry 1), alkyllithium such as butyllithium gave
the 5-pentanoyl product 7b in 59% yield at 80 ºC (entry 2)
while the yield of 7b in the reaction at 40 ºC was 51%.
Although the reaction using (phenylethynyl)lithium at 40 ºC did
not yield the desired product 7c with the recovery of 9a owing to
the low reactivity of the ethynyl anion, the reaction at rt
proceeded smoothly to afford 7c in 80% yield (entry 3). Various
aryllithiums, prepared from corresponding aryl bromides and t-
In summary, it was demonstrated that 4,6-unsubstituted 5-acyl-
2-aminodihydropyrimidines 7 and 8 were synthesized from 9
using the Weinreb amide as an acyl precursor. The substrates 9
were prepared from azidoalkene (E)-10 by sequential
Staudinger/aza-Wittig/cyclization
reactions,
and
the
transformation of the Weinreb amide of 9 to an acyl group
proceeded smoothly in good to high yield by a substitution
reaction using organolithium reagents in the presence of a
catalytic amount of BF3 etherate. Given that dihydropyrimidines
7 and 8 were previously unavailable and difficult to synthesize,
the achievement in this study should contribute considerably to
the expansion of dihydropyrimidine-based heterocyclic chemistry
and pharmaceutical sciences for drug development.
butyllithium,
reacted
with
9a
to
give
5-
aryloyldihydropyrimidines 7d and 7e in good yields (entries 4
and 5). In entries 6 and 7, 9b also exhibited good reactivity with
aryllithiums, affording 7f and 7g in 60% and 59% yields,
respectively.
Acknowledgments
The N-protecting group (Boc) was easily removed to produce
N-unsubstituted dihydropyrimidines 8 (Scheme 5). When 7a was
treated with trifluoroacetic acid (TFA), 8a was obtained in 73%
This work was financially supported by JSPS KAKENHI Grant
Number 16K01939 and 16K08335.

4
Tetrahedron Letters
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Supplementary Material
Supplementary Material (synthesis and characterization of
compounds, spectroscopic data of IR, NMR, MS) associated with
the article can be found, in the online version, at doi:
******/j.tetlet. *********.
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was kept at the temperature for 15 h. To the reaction mixture was
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butyl ether, 0.28 mL, 0.448 mmol) dropwise at 40 ºC, and the
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mixture were added saturated NH4Cl aqueous solution (5 mL) and
EtOAc (20 mL) at 40 ºC. The organic layer was separated, and
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over anhydrous Na2SO4, and concentrated under reduced pressure.
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0.121 mmol, 81%) as a yellow amorphous.
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Highlights
・Novel 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines were synthesized.
・The Staudinger/aza-Wittig/cyclization reactions gave the synthetic intermediate.
・The transformation of the Weinreb amide to an acyl group proceeded smoothly.
・Tautomerization of N-unsubstituted dihydropyrimidines was analyzed by 1H NMR.

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Convergent synthesis of 4,6-unsubstituted 5-
acyl-2-aminodihydropyrimidines using
Weinreb amide
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Yoshio Nishimura,* Takanori Kubo, Yasuko Okamoto, Hidetsura Cho