A mild and practical method for the regioselective synthesis of N-acylated 3,4-dihydropyrimidin-2-ones. New acyl transfer reagents

Article abstract of DOI:10.1016/j.tetlet.2006.09.039

The treatment of 3,4-dihydropyrimidin-2-ones with n-BuLi at -78 °C, followed by quenching with various electrophiles furnished N3-substituted derivatives, regioselectively. Further, N1,N3-diacyl derivatives were found to transfer N1-acyl groups to nucleop

Full text of DOI:10.1016/j.tetlet.2006.09.039

Tetrahedron Letters 47 (2006) 8143–8146
A mild and practical method for the regioselective
synthesis of N-acylated 3,4-dihydropyrimidin-2-ones.
New acyl transfer reagents
Kamaljit Singh* and Sukhdeep Singh
Organic Synthesis Laboratory, Department of Applied Chemical Sciences and Technology, Guru Nanak Dev University,
Amritsar 143 005, India
Received 21 July 2006; revised 29 August 2006; accepted 7 September 2006
Available online 2 October 2006
Abstract—The treatment of 3,4-dihydropyrimidin-2-ones with n-BuLi at À78 °C, followed by quenching with various electrophiles
furnished N3-substituted derivatives, regioselectively. Further, N1,N3-diacyl derivatives were found to transfer N1-acyl groups to
nucleophilic sites.
Ó 2006 Elsevier Ltd. All rights reserved.
4-Aryl-3,4-dihydropyrimidin-2-ones (Biginelli com-
NO2
pounds, DHPMs) represent an azaheterocyclic system
CF3
O
of remarkable pharmacological profile.1 DHPMs are
O
O
O
O
found in natural products and find applications as
calcium channel modulators, a1a-adrenergic receptor
antagonists, mitotic kinesin inhibitors, and hepatitis B
virus replication suppressors. Several marine derived
natural products which are inhibitors of HIV gp-
120CD4, also contain the DHPM core. Although a large
number of DHPM derivatives have been prepared in
single-pot Biginelli multi-component reaction (MCR),
and its variants, a greater number of very interesting
heterocycles have been obtained by the chemical func-
tionalization of the six (N1, C2, N3, C4, C5 and C6)
positions around the DHPM core.2
i-PrO
Me
N
O
i-PrO
Me
N
NH2
N
S
N
H
H
F
N
2
1
F
O
O
MeO
N
NH(CH2)2CH2
F
N
N
O
H
OMe
3
N
Recently, we revealed that Biginelli DHPMs can
be lithiated at the C6 methyl and thus elaborated
regioselectively, with a wide variety of electrophiles.3
Regioselective N3-functionalization (acylation, alkoxy-
carbonylation, and alkylation) of DHPMs is of
considerable importance for the preparation of
N3-substituted DHPMs, related to the biologically
important compounds SQ 32,926 1, SQ 32,547 2, and
L-771,668 3.1a
A survey of the literature revealed a single example of
the direct N3-acylation (DMF/POCl3) of a C-4 aryl-
substituted DHPM, where the N3-formylated product
(12% yield) was attended by a 6H-1,3-thiazine derivative
(47% yield).4 A rather high temperature (100–180 °C)
microwave-aided acylation technique, employing poly-
mer-supported reagents and scavengers provided an
attractive method,5 but lacked the economy and simplic-
ity of a one-pot reaction. In contrast to the acylation,
the alkoxycarbonylation of Biginelli DHPMs with, for
example, ethyl chloroformate and base has proved prob-
lematic leading to mixtures of N1 and N3 substituted
products depending on the substitution pattern around
the DHPM ring.6 Also, N3-monoalkylated DHPMs
Keywords: Biginelli compounds; Calcium channel modulators; Acyl
transfer reagent.
*
Corresponding author. Tel.: +91 0183 2258853/2258802–09x3508;
fax: +91 0183 2258819–20; e-mail: kamaljit19in@yahoo.co.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.039

8144
K. Singh, S. Singh / Tetrahedron Letters 47 (2006) 8143–8146
R1
N1,N3-diacyl derivative 6 formed, was converted into
O
5 (TLC) upon warming the reaction to room tempera-
ture. This finding suggested to us that the diacyl DHPM
derivatives could be used as acyl transfer reagents.
(i) n-BuLi (Table 1)/THF
EtO
Me
NH
N2 atmosphere, -78 oC
N
H
X
(ii) Electrophile (Table 2)
3,4-Dihydropyrimidin-2-ones 4 were prepared according
to the previously described procedures.9 To generate the
lithio anions, a suspension of 4 in dry THF, was treated
with freshly prepared n-BuLi (2.0 N in hexanes,
1.1 equiv) at À78 °C under an atmosphere of dry nitro-
gen, and then the mixture was warmed to room temper-
ature for 0.5 h before cooling back to À78 °C. The pale
yellow colored10 anions were then quenched by drop-
wise addition of the electrophiles (Table 2) in anhydrous
THF at À78 °C. The reaction was allowed to warm to
room temperature and stirred until complete (20–
30 min, TLC) and then quenched with a cooled saturated
solution of ammonium chloride. Some reactions (Table
2, entries 1–5 and 8–10), yielded solid products after the
extractive work-up, which upon re-crystallization from
DCM/hexane (1:1 v/v), furnished the corresponding
pure product 5; for the remaining reactions, chromato-
graphic purification was required. When the reaction
mixtures were treated with saturated ammonium chlo-
ride solution at À78 °C, in addition to product 5, the
N1,N3-diacyl derivatives 6 (Table 2) were also isolated.
However, when the quenching was performed at room
temperature, 5 was exclusively isolated, except entries
4, 12 and 17, where corresponding 6 accompanied the
N3-acyl products, albeit in trace amounts (<5%). In
order to improve the yield of 6, an alternative method
employing 2.5 equiv of potassium tert-butoxide in com-
bination with 18-crown-6 was developed. All products
4 (R1/X) : a, Ph/O; b, Ph/S; c, 4-MeOC6H4/O
d, Et/O; e, H/O; f, 2,4-(MeO)2C6H3/O
R1
O
R1
O
R2
X
R2
X
EtO
Me
N
EtO
Me
N
N
R2
N
H
5
6
R.T. stirring
Scheme 1. Synthesis of N3-acylated DHPMs.
cannot be obtained by the alkylation of unsubstituted
derivatives and when monoalkyl ureas are employed,
only N1-alkylated DHPMs are formed.7 Thus, a flexible,
general, one-pot approach to drug-like DHPM deriva-
tives, avoiding intricate isolation/purification tech-
niques, is required.
In this letter, we report a one-pot and a highly efficient
method that permits the rapid synthesis of N3-acylated
DHPMs 5 which does not rely on the use of any sophis-
ticated technique, but instead allows the use of a number
of acylating agents. Our procedure involves a low tem-
perature (À78 °C) lithiation of DHPMs 4 at N3, using
n-BuLi and subsequent quenching with an acylating
agent (Scheme 1).
1
were characterized by H NMR, 13C NMR, MS and
elemental analysis. In order to eliminate the possibility
that the diacyl compounds were N,O-diacyl derivatives,
the structure of 6b was additionally confirmed by X-ray
crystal structure analysis (Fig. 1).11 We believe that the
regioselectivity arises from the relatively more reactive
and higher proportion of the N3 anionic species, formed
in situ, may produce the products of exclusive function-
During optimization experiments (Table 1), we noted
that when the quantity of the base was greater than
1.1 equiv, the proportion of N3-acetylated DHPMs 5
decreased and, in some cases, C6,N3-diacyl derivatives
were produced.8 Also, under the optimized reaction
conditions, employing a 1.1 equiv of the base, any
Table 1. Optimization of the reaction conditions for N3-acylation of 3,4-dihydropyrimidin-2-ones
O
R'
O
O
O
R'
EtO
N
EtO
Me
NH (i)
n-BuLi /THF/-78 ºC
(ii) propionyl chloride (1.1equiv.)/
THF/-78 ºC-r.t.
Me
N
H
N
H
O
(iii) aqueous NH4Cl (r.t)
4a; R' = Ph
4d; R' = Et
5b; R' = Ph
5j; R' = Et
Entry
Equivalents of n-BuLi
Product
Isolated yield (%)
1
2
3
4
5
6
7
8
1.1
1.1
2.2
2.2
3.1
3.1
4.1
4.1
5b
5j
90
86
52
20
5b
5j
5b
5j
43
0a (<5%)
30
5b
5j
0a (<5%)
a The corresponding N3,C6-diacyl derivative was obtained. Values in parentheses represent the isolated yield of N3,C6-diacyl derivatives.

K. Singh, S. Singh / Tetrahedron Letters 47 (2006) 8143–8146
Table 2. Scope of the regioselective N3-acylation of 3,4-dihydropyrimidin-2-ones
8145
Entry
4
Electrophile
Product
Isolated yields (%) 5
Mp (°C) 5
5a/6b
R1
R2
X
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
MeCOCl
EtCOCl
n-PrCOCl
PhCOCl
p-NO2C6H4COCl
p-MeC6H4SO2Cl
a-C10H7COCl
EtCOCl
EtCOCl
EtCOCl
5a
5b
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
COMe
COEt
COPr-n
COPh
COC6H4ÀpNO2
SO2C6H4–pMe
CO-aC10H7
COEt
COEt
COEt
O
O
O
O
O
O
O
S
O
O
O
O
O
O
O
O
O
O
92
90c
89
91
61
55
71
89
91
86
75
62
30
69
30
65
59
62
170
202
137
151
141
183
140
138
157
134
143
191
209
104
179
222
140
123
5c
5d
5ed
5fd
5gd
5he
5i
9
4-MeOC6H4
Et
H
10
11
12
13
14
15
16
17
18
5j
EtCOCl
EtCOCl
5kd
5l
COEt
COEt
2,4-(MeO)2C6H3
4a
4a
4a
4a
4a
4a
ClCH2COCl
ClCOCOOEt
BrCH2CH2COCl
HCOOEt
BrCH2COOEt
MeCHBrCOOEt
5md
5nd
5od
5pd
5q
Ph
Ph
Ph
Ph
Ph
Ph
COCH2Cl
COCO2Et
COCH@CH2
CHO
CH2COOEtf
MeCHCOOEtf,g
5rd
a Method A: (i) DHPM (1.0 equiv), n-BuLi (1.1 equiv)/À78 °C; (ii) E+ (1.1 equiv)/À78 °C to rt; (iii) aqueous NH4Cl (rt).
b Compounds 6a (10%), 6b (18%), 6c (15%), 6d (22%), 6i (20%), 6j (17%), 6l (23%) and 6q (7%) were formed employing Method B: [(i) DHPM
(1.0 equiv), n-BuLi (1.1 equiv)/À78 °C; (ii) E+ (1.1 equiv)/À78 °C (iii) aqueous NH4Cl (À78 °C)] and 6b (45%) using Method C: [(i) DHPM
(20 mmol), KBuOt (87.5 mmol)/18-C-6 (7.5 mmol)/rt; (ii) E+ (90 mmol)/0 °C to rt (24 h)].
c Formed in 85% yield when propionic anhydride was used as the electrophile.
d Corresponding 6 not formed.
e Corresponding 6h was rapidly converted (TLC) into 5h during work-up.
f N3-alkylated products were formed.
g A mixture of diastereomers (6:4) was obtained. For details, see Supplementary data.
OMe
OMe
N
O
(i)
THF/N2 atmosphere,
-78 o
(ii) 6i/ 6j, 10-15 min
n-BuLi (1.1equiv.)/
O
COEt
O
EtO
Me
NH
EtO
Me
C
N
H
O
N
H
4c
5i
Scheme 2. Acyl transfer from N1,N3-diacyl DHPMs.
The selective monoacylation of amino groups in the
presence of other functional groups has significant util-
ity13 and several reagents have been developed for this
purpose. We envisioned that 6 could be used to effect
acyl transfers to various nucleophiles. As an example,
when 4c was treated with 1.1 equiv of n-BuLi and
quenched with 1.0 equiv of N1,N3-disubstituted DHPM
6i/6j, N3-substituted DHPM 5i was obtained, exclu-
sively, in 96–98% isolated yield (Scheme 2). These
reactions demonstrate the potential of N1,N3-diacyl
DHPM derivatives as acyl transfer reagents. Further
investigations in determining scope and limitation of
this reaction of DHPMs is under investigation.
Figure 1. X-ray crystal structure of 6b showing the stereoview of the
molecule and the numbering scheme used in the structure analysis.
alization at N3. A particularly attractive feature of
this method is its applicability to various electrophiles
(Table 2), a feature lacking in the previous methods.4,5
Further, the substitution pattern around the DHPM
core was not found to influence the yield of 5.
Thus, in summary, we have developed a mild and gen-
eral one-pot protocol for N3-acylation of Biginelli
DHPMs, which tolerates various substituents around
the DHPM nucleus. A facile acyl transfer from
N1,N3-disubstituted DHPMs to give an N3-substituted
DHPM has also been demonstrated.
Acyl transfer to nucleophiles is an important transfor-
mation in organic synthesis. Several enzymes, such as
serine acetyl transferase12 are involved in the direct
transfer of the acyl groups between reactants in biosyn-
thesis in bacteria and plants.

8146
K. Singh, S. Singh / Tetrahedron Letters 47 (2006) 8143–8146
6. (a) Cho, H.; Takeuchi, Y.; Ueda, M.; Mizuno, A.
Acknowledgements
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Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J. J. Org.
Chem. 1989, 54, 5898–5907.
We are thankful to the CSIR (01(1960)/04/EMR-II) and
UGC (F. 31-53/2005 (SR)), New Delhi, for financial
assistance, and National Single Crystal X-ray Diffraction
Facility, IIT Bombay, for X-ray analysis. S.S. thanks the
UGC, New Delhi, for a senior research fellowship.
7. (a) Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1934,
56, 1374–1377; (b) George, T.; Tahilramani, R.; Mehta, D.
V. Synthesis 1975, 405–407.
8. In the case of entries 3, 9 and 10 (Table 2), when 3–4 equiv
of n-BuLi was used, the corresponding N3,C6-diacylated
products were obtained in low yields. However, entry 2
(Table 2) did not yield the corresponding N3,C6-diacy-
lated product, and only N3-acylated product was isolated
in 30% yield.
9. (a) Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1–116;
(b) Kappe, C. O. QSAR Comb. Sci. 2003, 22, 630–645; (c)
Singh, K.; Singh, J.; Deb, P. K.; Singh, H. Tetrahedron
1999, 55, 12873–12880; (d) Ma, Y.; Qian, C.; Wang, L.;
Yang, M. J. Org. Chem. 2000, 65, 3864–3868; (e) Singh,
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Supplementary data
Experimental procedures and spectral data for all
compounds are given in the supplementary data. Sup-
plementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.09.039.
References and notes
10. In our previous investigation,3 on deprotonation of the C6
Me of DHPMs, the trianion generated using LDA was of
a blood red color.
11. Crystallographic data for 6b have been deposited with the
Cambridge Crystallographic Data Centre (CCDC). The
coordinates can be obtained on request from the Director,
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. The
CCDC Number is 614958.
12. Johnson, C. M.; Roderick, S. L.; Cook, P. F. Arch.
Biochem. Biophys. 2005, 433, 85–95.
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