Biginelli reaction beyond three-component limit: Synthesis of functionalized pyrimidinones via a one-pot Biginelli-Pd mediated C-C coupling strategy

Article abstract of DOI:10.1016/j.tetlet.2011.01.015

A new and one-pot synthesis of novel alkynyl/alkenyl/aryl (hetero)aryl substituted 3,4-dihydropyrimidin-2(1H)-one derivatives has been developed via a multi-component reaction involving sequential phosphorus acid-mediated solvent-free Biginelli followed b

Full text of DOI:10.1016/j.tetlet.2011.01.015

Tetrahedron Letters 52 (2011) 1187–1191
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Biginelli reaction beyond three-component limit: synthesis of functionalized
pyrimidinones via a one-pot Biginelli-Pd mediated C–C coupling strategy
P. Mahesh Kumar a,b, K. Siva Kumar a, Srinivas Reddy Poreddy a, Pradeep Kumar Mohakhud a,
K. Mukkanti b, Manojit Pal c,
⇑
a Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Bollaram Road Miyapur, Hyderabad 500 049, India
b Chemistry Division, Institute of Science and Technology, Jawaharlal Nehru Technological University, Hyderabad 500085, Andhra Pradesh, India
c Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and one-pot synthesis of novel alkynyl/alkenyl/aryl (hetero)aryl substituted 3,4-dihydropyrimi-
din-2(1H)-one derivatives has been developed via a multi-component reaction involving sequential
phosphorus acid-mediated solvent-free Biginelli followed by copper-free Sonogashira or Heck or Suzuki
reaction.
Received 22 November 2010
Revised 24 December 2010
Accepted 6 January 2011
Available online 13 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Pyrimidinone
Alkyne
Alkene
Boronic acid
Coupling
Catalysis
Multi-component reactions (MCRs) are powerful strategies for
the quick synthesis of diverse and complex organic molecules of
potential interest particularly in the area of material science and
drug discovery.1 This methodology allows creation of diversity in
addition to molecular complexity by the facile formation of several
new covalent bonds in a one-pot transformation. The search and
discovery of new MCRs, therefore, have gained tremendous impor-
tance.2 One of the widely used MCRs, known as Biginelli reaction3
involves the cyclocondensation of an aldehyde, a b-ketoester, and
urea (or thiourea) to give dihydropyrimidin-2(1H)-ones (or thio
analogues) of pharmacological importances.4,5 The alkynylation
of the (hetero)arene, that is, the Sonogashira reaction6 on the other
hand has been termed as a booming methodology7a in organic syn-
thesis because of its remarkable applications in C–C bond forming
reactions under Pd–Cu catalysis. A Cu-free Sonogashira coupling8 is
of particular value as it reduces the dimerization of reactant al-
kynes significantly, thereby avoiding a cumbersome purification
process. The Heck and Suzuki reactions are other C–C bond forming
reactions that have found wide applications.7b,c While an impres-
sive number of reports are now available on Biginelli reaction9 to
improve the reaction conditions and product yields along with
variations in all the three reactants, its further application beyond
the three component limit has not been explored. The present
communication describes an overall four component reaction
involving a sequential phosphorus acid-mediated Biginelli fol-
lowed by Cu-free Sonogashira or Heck or Suzuki reaction. This
MCR is particularly attractive, because by choosing an appropriate
aldehyde along with an alkyne/alkene/aryl boronic acid partner, a
dihydropyrimidinone can be easily synthesized possessing
functionalized (hetero)arene group of specific interest at C-4
(Scheme 1).
Recently, we have reported a Pd-catalyzed one-pot multi-com-
ponent coupling reaction for the construction of benzene ring
fused with a carbocycle or heterocycle particularly under a Cu-free
CHO
Z
R1O
Ar
I
H3PO3
Ar
heat
O
O
+
R1O2C
NH
R2 or
R3 or
4
[
O
2
1
N
H
O
H2N
NH2
ArB(OH)2 ]
3
5
Pd-cat, heat
Ar = aryl or heteroaryl
Z = alkynyl, akenyl, aryl
⇑
Corresponding author. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail addresses: manojitpal@rediffmail.com, palmanojit@yahoo.co.uk (M. Pal).
Scheme 1. MCR involving Biginelli followed by Pd-catalyzed C–C bond forming
reaction in tandem.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.015

1188
P. M. Kumar et al. / Tetrahedron Letters 52 (2011) 1187–1191
Table 1
alkynes in the absence of Cu-salt. This prompted us to examine
the in situ generation of iodide partner via Biginelli reaction. Our
objective was twofold, for example, (i) identification of a suitable
Biginelli catalyst compatible for subsequent transformation in
the same pot, (ii) to establish an appropriate reaction condition
for efficient Sonogashira/Heck/Suzuki coupling to complete the
procedure. Initially, we focused on Biginelli–Sonogashira reaction.
To our satisfaction, the phosphorus acid9j was found to be a new
and effective catalyst for the Biginelli step whereas the use of
Cu-salt in the Sonogashira step was counter productive. Thus, we
examined the reaction of o-iodobenzaldehyde 1a, the b-ketoester
2a, urea 3 and then terminal alkyne 4a under various conditions
to find the optimum condition for obtaining the MCR product in
good yield (Table 1). Initially, the reaction was carried out using
various amounts of H3PO3 (1–20 mol %) followed by (PPh3)2PdCl2
(2 mol %) (Table 1, entries 1–6). While the expected product 5a
was isolated in all these cases the best result, howeve,r was
achieved when 10.0 mol % of H3PO3 was used in combination with
2 mol % of (PPh3)2PdCl2 (Table 1, entry 5). The use of increased
amount of H3PO3 did not enhance the product yield (Table 1,entry
6) though the reaction was faster, whereas a lower quantity of Pd
catalyst decreased the yield (Table 1,entry 7). The catalyst PdCl2
was found to be equally effective (Table 1,entry 8). Notably, the
Biginelli step was carried out under a solvent-free condition,
whereas pyrrolidine was used as a base as well as a solvent for
the Cu-free Sonogashira coupling step. The use of other bases such
as, Et3N and diisopropylethyl amine was also investigated and was
found to be effective. However, the best yield of the product
was achieved by using pyrrolidine. The compound 5a was well
characterized by IR absorbsions at 2227 (AC„CA), 1700 (C@O)
The reaction of o-iodobenzaldehyde 1a, the b-ketoester 2a, urea 3, and terminal
alkyne 4aa
CHO
H3PO3
100-120 o
2h
I
EtO
C
EtO2C
R
NH
O
O
+
N
H
O
R (4a)
Pd-cat, 80-85 oC
pyrrolidine, 4h
2a
1a
O
H2N
NH2
5a
R = -C6H13-n
3
Entry
H3PO3 (mol %)
Pd-cat (mol %)
%Yieldb
1
2
3
4
5
6
7
8
1.0
2.5
5.0
(PPh3)2PdCl2 (2.0)
(PPh3)2PdCl2 (2.0)
(PPh3)2PdCl2 (2.0)
(PPh3)2PdCl2 (2.0)
(PPh3)2PdCl2 (2.0)
(PPh3)2PdCl2 (2.0)
(PPh3)2PdCl2 (1.0)
PdCl2 (2.0)
35
46
59
68
87
86
64
81
7.5
10.0
20.0
10.0
10.0
a
All the reactions were carried out using 1a (1.0 mmol), 2a (5.0 mmol),
3
(1.25 mmol), and H3PO3 in neat at 100–120 °C followed by the addition of pyrrol-
idine (3.0 mL), Pd-catalyst and 4a (1.2 mmol) at 80–85 °C.
b
Isolated yield.
condition.10 More recently, we have observed that 3,4-dihy-
dropyrimidin-2(1H)-one possessing an iodoarene moiety at C-4
undergoes Pd-mediated smooth coupling reaction with terminal
Table 2
Synthesis of 2-alkynylphenyl substituted dihydropyrimidin-2(1H)-one derivatives (5a–m) using the aldehyde 1aa
Entry
Ester 2;
Alkyne 4;
Product (5)
Timeb (h)
%Yieldc
R1
R2
2a;
Et
4a;
n-Hexyl
1
1.0
87
EtO2C
NH
O
N
H
5a
4b;
n-Pentyl
2
3
4
2a
2a
2a
1.0
1.5
1.5
88
85
83
EtO2C
NH
O
N
H
5b
O
O
4c;
–CH2OH
NH
OH
O
N
H
5c
4d;
–CH(OH)CH3
EtO2C
NH
OH
N
H
O
5d

P. M. Kumar et al. / Tetrahedron Letters 52 (2011) 1187–1191
1189
Table 2 (continued)
Entry
Ester 2;
Alkyne 4;
Product (5)
Timeb (h)
%Yieldc
R1
R2
4e;
–(CH2)2OH
OH
5
2a
1.5
82
EtO2C
NH
O
N
H
5e
OH
4f;
–(CH2)3OH
6
2a
2a
2a
2a
2a
1.5
1.0
1.5
1.5
1.5
1.0
83
89
84
82
84
86
EtO2C
EtO2C
EtO2C
EtO2C
EtO2C
NH
O
N
H
5f
4g;
7
NH
O
N
H
5g
4h;
OH
HO
8
NH
O
N
H
5h
4i;
9
NH
O
N
H
5i
4j;
10
NH
N
H
O
5j
O
O
2b;
t-Bu
11
4b
NH
O
O
O
N
H
5k
12
2b
4g
1.0
85
NH
O
N
H
5l
(continued on next page)

1190
P. M. Kumar et al. / Tetrahedron Letters 52 (2011) 1187–1191
Table 2 (continued)
Entry
Ester 2;
Alkyne 4;
Product (5)
Timeb (h)
%Yieldc
R1
R2
OH
O
13
2b
4h
1.5
83
NH
O
O
N
H
5m
a
All the reactions were carried out using 1a (1.0 mmol), 2 (5.0 mmol), 3 (1.25 mmol) and H3PO3 (10 mol %) in neat at 100–120 °C followed by addition of pyrroli-
dine(3.0 mL), (PPh3)2PdCl2 (2 mol %) and 4 (1.2 mmol) at 80–85 °C.
b
For Sonogashira step.
Isolated yield.
c
and 1650 (C@O) cmÀ1 and the appearance of a peak at 5.6 d corre-
sponding to C-4 hydrogen.11
We were pleased to find that the four-component reaction
provided dihydropyrimidinones with a range of aryl substitu-
tion patterns at C-4 (Table 2). The one-pot Biginelli–Sonogash-
ira reaction proceeded well with a variety of terminal alkynes
to give 5 in good yields (Table 2, entries 1–13). A range of
substituents including alkyl, hydroxyalkyl, cycloalkyl, or aryl
Table 3
Synthesis of alkynyl(hetero)aryl substituted dihydropyrimidin-2(1H)-one derivatives (5n–q) using ester 2a and various aldehydes (1b–e)a
Entry
Aldehyde (1)
Alkyne (4)
Product (5)
Timeb (h)
%Yieldc
HO
I
CHO
1b
1
4h
1.5
80
EtO2C
NH
N
H
O
5n
N
N
I
1c
CHO
2
4a
1.5
80
EtO2C
NH
O
N
5o
H
N
N
I
3
4g
2.0
82
1d
CHO
EtO2C
NH
O
N
H
5p
I
S
OH
CHO
1e
4
4h
2.0
81
S
EtO2C
NH
O
N
H
5q
a
All the reactions were carried out using 1 (1.0 mmol), 2a (5.0 mmol), 3 (1.25 mmol), and H3PO3 (10 mol %) in neat at 100–120 °C followed by addition of pyrrolidine
(3.0 mL), (PPh3)2PdCl2 (2 mol %) and 4 (1.2 mmol) at 80–85 °C.
b
For Sonogashira step.
Isolated yield.
c

P. M. Kumar et al. / Tetrahedron Letters 52 (2011) 1187–1191
1191
(A)
(B)
EtO2C
CONH2
H3PO3
1a
+
H3PO3
100-120 oC
EtO2C
o
100-120 C
NH
EtO2C
2a
+
NH
3-carbamoyl
phenyl boronic
acid
(PPh3)2PdCl2
10%Na2CO3
80-100 oC, 2h
CH2=CHCO2Et
(PPh3)2PdCl2
Et3N
80-100 oC, 3h
N
H
O
3
N
H
O
5r; 88%
5s; 85%
Scheme 2. MCR involving Biginelli–Heck (A) and Biginelli–Suzuki (B) reaction.
present in the alkyne component were found to be well toler-
ated. It is worth mentioning that the present four-component
reaction was carried out in open air under normal atmospheric
pressure.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.015.
We have shown that a variety dihydropyrimidinones can be
prepared via Biginelli–Sonogashira reaction in a single pot. The
optimized condition was used to create further diversity at C-4.
Thus various aryl and heteroaryl aldehydes were used to give the
desired products in good yields (Table 3).
References and notes
1. Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168.
2. Weber, L.; Lllgen, K.; Almstetter, M. Synlett 1999, 366.
3. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
We then focused on combining Biginelli reaction with other
Pd-catalyzed C–C bond forming reactions such as Heck12 or Suzu-
ki13 coupling. Accordingly, ethyl acrylate and 3-carbamoyl phenyl
boronic acid was used in the MCR reaction of 1a, 2a, and 3
(Scheme 2). Under suitable reaction conditions the desired prod-
uct corresponding to Biginelli–Heck (5r) and Biginelli–Suzuki
(5s) was obtained in good yield. Similarly, the use of 1b in Biginel-
li–Suzuki reaction provided the regio-isomer (5t) of 5s (see ESI).
Mechanistically, the MCR described here proceeds via H3PO3-
mediated Biginelli reaction to generate the desired iodopyrimidi-
none intermediate in situ that undergoes C–C bond formation un-
der Pd-catalysis. The H3PO3 perhaps activates the carbonyl
group4,14 of the aldehyde, thereby facilitating the reaction with
urea and ester. Nevertheless, to gain further evidence we con-
ducted the condensation reaction of 1a, 2a, and 3 in the presence
of H3PO3. The corresponding o-iodophenyl substituted 3,4-dihy-
dropyrimidin-2(1H)-one isolated was then treated separately with
the terminal alkyne 4a and (PPh3)2PdCl2 in pyrrolidine under a
Cu-free condition. The desired product 5a was isolated in good
yield indicating that the present single-pot four component reac-
tion proceeds via iodo(hetero)aryl substituted 3,4-dihydropyrimi-
din-2(1H)-one.
In conclusion, we have demonstrated the first multi-component
reaction involving sequential phosphorus acid-mediated solvent-
free Biginelli reaction followed by copper-free Sonogashira/Heck/
Suzuki coupling leading to the formation of novel 3,4-dihydropyr-
imidin-2(1H)-one derivatives in a single pot. Since the quest for
these types of new synthetic concepts is high the methodology,
therefore, would find wide application in combinatorial and diver-
sity-oriented synthesis of dihydropyrimidones of potential phar-
macological interest.
4. For a review, see: (a) Kappe, C. O. Tetrahedron 1993, 49, 6937. and references
cited therein; (b) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
5. (a) 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; (b) Rovnyak, G. C.; Kimball, S. D.; Beyer, B.; Cucinotta, G.;
DiMarco, J. D.; Gougoutas, J. Z.; Hedberg, A.; Malley, M. F.; McCarthy, J. P.;
Zhang, R.; Moreland, S. J. Med. Chem. 1995, 38, 119. and references cited therein.
6. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467.
7. (a) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874; (b) Li, J. J.; Gribble, G. W.
Palladium in Heterocyclic Chemistry A Guide For the Synthetic Chemist, 2nd edn.;
Elsevier: Oxford, 2006; (c) Tsuji, J. Palladium in Organic Synthesis, 1st edn.;
Berlin: Springer, 2005.
8. Pal, M.; Parasuraman, K.; Gupta, S.; Yeleswarapu, K. R. Synlett 2002, 1976.
9. (a) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957; (b)
Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 63, 3454; (c) Kappe, C.
O.; Falsone, S. F. Synlett 1998, 718; (d) Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem.
2000, 65, 6270; (e) Ma, Y.; Qian, C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65,
3864; (f) Lu, J.; Ma, H. Synlett 2000, 63; (g) Bigi, F.; Carloni, S.; Frullanti, B.;
Maggi, R.; Sartori, G. Tetrahedron Lett. 1999, 40, 3465; (h) Reddy, C. V.; Mahesh,
M.; Raju, P. V. K.; Babu, T. R.; Reddy, V. V. N. Tetrahedron Lett. 2002, 43, 2657; (i)
Paraskar, A. S.; Dewkar, G. K.; Sudalai, A. Tetrahedron Lett. 2003, 44, 3305; For
Biginelli reaction using chiral phosphoric acid, see: (j) Chen, X.-H.; Xu, X.-Y.;
Liu, H.; Cun, L.-F.; Gong, L.-Z. J. Am. Chem. Soc. 2006, 128, 14802.
10. Swamy, N. K.; Tatini, L. K.; Babu, J. M.; Annamalai, P.; Pal, M. Chem. Commun.
2007, 1035.
11. A typical procedure for the preparation of 5a: To a mixture of aldehyde 1a
(1.0 mmol), ethyl acetoacetate 2a (5.0 mmol), and urea 3 (1.25 mmol) was
added H3PO3 (10 mol %) at room temperature. After stirring for 5 min, the
reaction flask was fitted with a condenser for cold water circulation and the
mixture was heated to 100–120 °C for 1.0 h and then cooled to 50 °C. To this
was added pyrrolidine (3 mL), PdCl2(PPh3)2 (2 mol %) and the alkyne (4a) with
stirring. The mixture was stirred at 80–85 °C for 1.0 h cooled to room
temperature, poured into water (25 mL), and extracted with ethyl acetate
(3 Â 15 mL). The organic layers were collected, combined, dried over
anhydrous Na2SO4, and concentrated. The residue was purified by column
chromatography using petroleum ether–EtOAc to give the compound 5a as
light brown solid, mp 128–130 °C; 1H NMR (CDCl3, 400 MHz): d 7.87 (bs, 1H,
NH), 7.40 (d, J = 5.5 Hz, 1H, arom H), 7.23-7.14 (m, 3H, arom H), 5.88 (bs, 1H,
NH), 5.6 (s, 1H, CH), 4.02 (q, J = 6.9 Hz, 2H, OCH2), 2.46 (t, J = 6.9 Hz, 2H, CH2),
2.43 (s, 3H, CH3), 1.62-1.31(m, 8H, CH2), 1.05 (t, J = 6.9 Hz, 3H, CH3), 0.90 (t,
J = 6.9 Hz, 3H, CH3); 13CNMR (CDCl3, 50 MHz): d 165.5, 153.3, 148.2, 143.7,
132.6, 128.2, 127.6, 125.7, 122.3, 98.9, 95.5, 78.2, 59.8, 53.2, 31.3, 29.7, 28.7,
22.6, 19.6, 18.2, 14.0; IR (KBr, cmÀ1): 3226, 2931, 2227, 1700, 1650; HRMS
(ESI): calcd for C22H29N2O3 (M+H)+ 369.2178, found 369.2166.
Acknowledgments
12. (a) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320; (b) Mizoroki, T.;
Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581.
13. Miyaura, N.; Suzuki, A. Chem. Commun. 1979, 866.
The authors thank Dr. Vilas Dahanukar, Dr. Madarapu Srinivas
Rao and the analytical group of DRL.
14. Kappe, C. O. J. Org. Chem. 1997, 62, 7201.