Chemo-/regioselective synthesis of 6-unsubstituted dihydropyrimidinones, 1,3-thiazines and chromones via novel variants of Biginelli reaction

Article abstract of DOI:10.1039/b901112a

A novel and facile cascade Biginelli-like assembly employing enaminone, aldehyde and urea/thiourea has been developed, which provides a highly chemo-and regioselective synthesis of new dihydropyrimidinones, 1,3-thiazines and chromones by altering particul

Full text of DOI:10.1039/b901112a

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Chemo-/regioselective synthesis of 6-unsubstituted dihydropyrimidinones,
1,3-thiazines and chromones via novel variants of Biginelli reactionw
Jie-Ping Wan and Yuan-Jiang Pan*
Received (in Cambridge, UK) 19th January 2009, Accepted 10th March 2009
First published as an Advance Article on the web 30th March 2009
DOI: 10.1039/b901112a
A novel and facile cascade Biginelli-like assembly employing
enaminone, aldehyde and urea/thiourea has been developed,
which provides a highly chemo- and regioselective synthesis
of new dihydropyrimidinones, 1,3-thiazines and chromones by
altering particular functional groups in the reactants.
so far have focused on extending its substrate scope. Recently,
Bussolari11a and co-workers developed a protocol for the
synthesis of 5-unsubstituted DHPMs by employing oxalacetic
acid as the active methylene donor, and aromatic ketones have
also been applied as reaction partners to yield 5-unsubstituted
DHPMs in some cases.11b–d However, unlike the success in the
synthesis of 5-unsubstituted DHPMs, few systematic methods
have been established to synthesize 6-unsubstituted DHPMs
The first three-component reaction using aromatic aldehydes,
b-keto esters and urea to synthesize functionalized 3,4-dihydro-
pyrimidinones (DHPMs) was reported by Biginelli over one
century ago.1 Over recent decades, there has been increasing
focus on DHPMs as potential lead structures in drug discovery
based on both simple DHPM molecules and the study of
bioactive natural products.2 Various biological activities
such as antihypertensive,3 antibacterial,4 antiviral5 as well
as calcium channel modulating6 activities etc. have been
discovered in suitably functionalized DHPMs and a large
number of DHPM-based scaffolds have already been developed
into drugs or lead compounds. For instance, monastrol is
the first discovered cell-permeable small molecule which
specifically inhibits mitotic kinesis Eg5.7a Recent research
has demonstrated that (R)-mon-97 has much more potent
antitumor activity than monastrol,7b and (R)-SQ 32, 926 is
an antihypertensive agent with potent oral activity (Fig. 1).2a
The great potential of DHPMs in biological and pharmaceutical
fields has accordingly triggered growing interest in their
synthetic study.8
until Booker-Milburn’s12a recent work on
a
BF3ꢀEt2O
catalyzed three-component reaction involving two aldehydes
and an N- or N,N0-substituted urea (or sulfamide). An
advancement though it is in DHPM synthesis, this methodology
suffers from intolerance to unsubstituted urea and thiourea.
Therefore, searching for more facile and practical synthetic
routes to 6-unsubstituted DHPMs is still a significant task.12b
Multicomponent reaction is now one of the most desirable
methodologies in constructing functional heterocyclic scaffolds
based on its properties of high efficiency and broad product
structural diversity, which caters for the urgent requirement
of building up huge molecule libraries in modern drug
discovery.13
Based on our progressive endeavors in exploring novel
and practical multicomponent reactions to synthesize useful
heterocyclic compounds,14 we present herein the results of
some new three-component cascade reactions for the selective
synthesis of 6-unsubstituted DHPMs and 1,3-thiazines as well
as chromones using enaminone.15
In the last two decades, the work of Kappe’s group has
considerably broadened both the application and understanding
of the classical Biginelli reaction.9 Despite a large body of
work on the Biginelli reaction reported in the literature,
including seminal work by Atwal and Overman,10 few accounts
Initially, enaminone 3a was selected to react with thiourea
and benzaldehyde in the presence of 50 mol% TFA. The target
DHPM 4a was obtained in 80% yield. In order to improve
the reaction efficiency, the reaction conditions were optimized
(Table 1). A study designed to optimize yields showed
TMSCl (1.5 mol eq.) to be superior to TFA. No reaction took
place when acetic acid was used as a promoter. Non-polar
solvents, such as toluene (entry 9), led to an intractable
paste due to issues with low solubility. Conducting the
reaction at a lower temperature (entry 8) resulted in incomplete
conversion.
After screening the reaction parameters, we turned to
examining the reaction scope with the optimized conditions
(entry 5, Table 1). Various aromatic aldehydes, enaminones
and urea/thiourea were subjected to the protocol (Table 2). As
expected, corresponding DHPMs were afforded in satisfactory
yield regardless of the substitution pattern in the arene groups
in both the aldehyde and enaminone substrates with the
exception of 2-OH in enaminone (Table 5). Both urea and
thiourea turned out to be good reaction partners.
Fig. 1 Pharmacologically active DHPMs.
Department of Chemistry, Zhejiang University, Hangzhou, 310027,
P.R. China. E-mail: panyuanjiang@zju.edu.cn;
Fax: 86 571 87951629; Tel: 86 571 87951264
w Electronic supplementary information (ESI) available: Experimental
procedures, analytical data as well as 1H and 13C NMR spectra copies
of all products and intermediates. CCDC 707892. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/b901112a
The structures of the DHPMs were clearly assigned by both
abundant spectral analysis and X-ray single crystal diffraction
ꢁc
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2768 | Chem. Commun., 2009, 2768–2770

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Table 1 Different conditions for the synthesis of DHPMsa
Entry
Catalyst (eq.)
Solvent
T/1C
Yield (%)b
1
2
3
4
5
6
7
8
9
TFA (0.5)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
85
85
85
85
85
85
100
70
80
Fig. 2 X-Ray structure of 4d.
AcOH (0.5)
TMSCl (0.5)
TMSCl (1.0)
TMSCl (1.5)
TMSCl (2.0)
TMSCl (1.5)
TMSCl (1.5)
TMSCl (1.5)
Trace
86
91
Encouraged by the good results acquired from aromatic
aldehydes, we attempted to expand the scope of this three-
component reaction to aliphatic aldehydes. To our delight,
good results were obtained from these reactions although the
DHPMs were afforded in modest yield (Table 3). These
results also highlighted the eminent compatibility of this novel
synthetic system.
95
93
95c
Mixture
Paste
85
a
Reaction condition: 0.3 mmol 1a, 0.35 mmol 2a and 0.3 mmol 3a
c
b
stirred for 10 h. Isolated yield based on aldehyde. Average yield of
two identical run.
The reactions of N-substituted urea and thiourea were
subsequently investigated (Table 4). N1-Methyl DHPMs 7
were isolated exclusively when N-methyl urea was employed;
surprisingly, unprecedented regioselectivity in the classical
Biginelli reaction was observed when N-methyl thiourea was
subjected to the same reaction: instead of DHPM, the isomer
1,3-thiazine 8 was found to be the major product (see ESIw for
Table 2 Synthesis of 6-unsubstituted DHPMs from various aromatic
substratesa
Table
3 Synthesis of 6-unsubstituted DHPMs from aliphatic
aldehydesa
Entry
R1
R2
X
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
H
H
H
H
H
H
H
H
H
H
H
H
H
4-Me
4-Me
4-NO2
4-NO2
H
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
O
O
O
O
O
O
O
O
O
4a
4b
4c
4d
4e
4f
4g
4h
4i
95
91
86
95
89
96
82
93
79
80
77
61
90
92
87
90
89
86
85
86
92
82
93
90
96
4-Me
4-OMe
4-Cl
Entry
R1
R2
X
Product
Yield (%)b
4-Br
4-CF3
4-OH
4-NO2
4-NMe2
2-OMe
2-F
3,4-(OMe)2
4-Cl
4-Me
4-Me
3-NO2
H
4-Me
4-OMe
4-F
4-NO2
3-NO2
H
1
2
3
4
5
6
CH3CH2
H
H
H
H
4-OMe
4-OMe
S
S
S
S
O
O
6a
6b
6c
6d
6e
6f
72
69
74
70
65
62
CH3(CH2)2
CH3(CH2)5
(CH3)2CHCH2
CH3CH2
4j
4k
4l
CH3(CH2)2
a
b
Identical conditions as Table 2. Isolated yield based on aldehyde.
4m
4n
4o
4p
4q
4r
4s
4t
4u
4v
4w
4x
4y
Table 4 Regioselective formation of DHPMs and 1,3-thiazinesa
H
H
H
H
H
4-Me
4-OMe
4-OMe
4-OMe
4-Cl
a
Reaction conditions: 0.3 mmol 1, 0.35 mmol 2 and 0.3 mol 3 mixed
b
Entry
R1
R2
X
Product
Yield (7/8%)b
in 2 mL DMF, 1.5 eq. mol TMSCl, stirred at 85 1C for 10 h. Isolated
yield based on aldehyde.
1
2
3
4
5
4-CH3
4-NO2
H
4-NO2
4-CH3
4-OMe
H
4-OMe
H
O
O
S
S
S
7a
7b
7c/8c
7d/8d
8e
62
66
19/60
20/63
71
on the product 4d (Fig. 2).w It is notable that these DHPMs
bear high structural resemblance to the lead compound
mon-97 as shown in Fig. 1.
H
a
b
Identical conditions as Table 2. Isolated yield based on aldehyde.
ꢁc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 2768–2770 | 2769

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characterization) while corresponding DHPMs were isolated
as minor products.
classical Biginelli reaction in terms of preparing structurally
novel DHPMs and related heterocyclic isomers.
We thank the NSFC of China (20775069), NCET-06-0520
of the National Ministry of Education of China for financial
support on this work.
Unlike the classical Biginelli reaction, the above reactions
plausibly proceeded via the Hofmann elimination of THPM 9.
Therefore, we managed to synthesize 9 under less drastic
catalyst conditions (eqn (1)). Hence, THPM 9 was subjected
to the aforementioned standard conditions, and it was
smoothly converted to DHPM 4b in almost quantitative yield
(98%), which suggested 9 as the key intermediate in the
reaction process.
Notes and references
1 P. Biginelli, Gazz. Chim. Ital., 1893, 23, 360.
2 (a) C. O. Kappe, Eur. J. Med. Chem., 2000, 35, 1043;
(b) A. I. McDonald and L. E. Overman, J. Org. Chem., 1999, 64, 1520.
3 G. C. Rovnyak, K. S. Atwal, A. Hedeberg, S. D. Kimball,
S. Moreland, J. Z. Gougoutas, B. C. O’Reilly, J. Schwart and
M. F. Malley, J. Med. Chem., 1992, 35, 3254.
4 T. Matsuda and I. Hirao, Nippon Kagaku Zasshi, 1965, 86, 1195.
5 E. W. Hurst and R. Hull, J. Med. Pharm. Chem., 1961, 3, 215.
6 (a) V. Kettmann, J. Drimal and J. Svetlik, Pharmazie, 1996, 51,
747; (b) C. O. Kappe, Molecules, 1998, 3, 1; (c) B. Jauk, T. Pernat
and C. O. Kappe, Molecules, 2000, 5, 227.
7 (a) T. M. Mayer, T. M. Kapoor, S. J. Haggarty, R. W. King,
S. L. Schreiber and T. J. Mitchison, Science, 1999, 286, 971;
(b) I. Garcia-Saez, S. DeBonis, R. Lopez, F. Trucco, B. Rousseau,
ð1Þ
P. Thuery and F. Kozielski, J. Biol. Chem., 2007, 282, 9740.
´
8 Recent examples of the Biginelli reaction: (a) B. C. Ranu, A. Hajra
and U. Jana, J. Org. Chem., 2000, 65, 6270; (b) M. J. Lusch and
J. A. Tallarico, Org. Lett., 2004, 6, 3237; (c) X. Y. Han, F. Xu,
Y. Q. Luo and Q. Shen, Eur. J. Org. Chem., 2005, 1500;
(d) J. C. Legeay, J. J. Vanden Eynde and J. P. Bazureau, Tetra-
hedron, 2005, 61, 12386; (e) B. L. Nilsson and L. E. Overman,
J. Org. Chem., 2006, 71, 7706; (f) I. Cepanec, M. F.-L. M. Litvic
and I. Grungold, Tetrahedron, 2007, 63, 11822; (g) M. I. Lannou,
F. Helion and J. L. Namy, Synlett, 2008, 105.
9 For reviews on the Biginelli reaction, see: (a) C. O. Kappe,
Tetrahedron, 1993, 49, 6937; (b) C. O. Kappe, Acc. Chem. Res.,
2000, 33, 879; (c) C. O. Kappe and A. Stadler, Org. React., 2004, 63,
1. For work on the application of the Biginelli reaction:
(d) C. O. Kappe and S. F. Falsone, Synlett, 1998, 718;
(e) C. O. Kappe, Bioorg. Med. Chem. Lett., 2000, 10, 49;
(f) B. Jauk, F. Belaj and C. O. Kappe, J. Chem. Soc., Perkin Trans.
1, 1999, 307; (g) F. S. Falsone and C. O. Kappe, ARKIVOC, 2001, 2,
1111; (h) A. Stadler and C. O. Kappe, J. Comb. Chem., 2001, 3, 624;
(i) C. O. Kappe, QSAR Comb. Sci., 2003, 22, 630; (j) B. Khanetskyy,
D. Dallinger and C. O. Kappe, J. Comb. Chem., 2004, 6, 884. For a
study of mechanism: (k) C. O. Kappe, J. Org. Chem., 1997, 62, 7201.
10 (a) B. C. O’Reilly and K. S. Atwal, Heterocycles, 1987, 26, 1185;
(b) K. S. Atwal, G. C. Rovnyak, B. C. O’Reilly and J. Schwartz,
J. Org. Chem., 1989, 54, 5898; (c) L. E. Overman and
M. H. Rabinowitz, J. Org. Chem., 1993, 58, 3235;
(d) L. E. Overman, M. H. Rabinowitz and P. A. Renhowe,
J. Am. Chem. Soc., 1995, 117, 2657.
The understanding of the reaction process promoted us to
explore the reaction using enaminones with nucleophilic
groups at the ortho position of the benzene ring, which was
expected to trigger the generation of a further fused product.
To our surprise, when 2-hydroxylphenyl enaminone 10 was
used, 3-substituted chromones 11 were selectively furnished
(Table 5), while the dimers 12 were occasionally formed as side
products. The results represent a formally Baylis–Hillman-type
reaction, but what is interesting is that the acidic conditions
in this reaction are significantly different from the basic
conditions in the classical Baylis–Hillman reaction. It is
noteworthy that doubling the amount of aldehyde, enaminone
and the catalyst does not increase the yield of 12, which
demonstrated the good chemoselectivity of this reaction.
In summary, we have developed several new variants of the
Biginelli reaction. In contrast to the traditional Biginelli
reaction, the present method bears specific novelty not only
because of the 6-unsubstituted DHPMs, but also because of
the manipulable synthesis of other important heterocyclic
systems, such as 1,3-thiazines and chromones. A plausible
mechanism has been demonstrated based on the synthesis of
THPM 9 and its transformation to the corresponding DHPM.
The methodology provides an important supplement to the
11 (a) J. C. Bussolari and P. A. McDonnell, J. Org. Chem., 2000, 65,
6777; (b) Z. T. Wang, L. W. Xu, C. G. Xia and H. Q. Wang,
Tetrahedron Lett., 2004, 45, 7951; (c) B. Liang, X. T. Wang,
J. X. Wang and Z. Y. Du, Tetrahedron, 2007, 63, 1981.
12 (a) C. D. Bailey, C. E. Houlden, G. L. J. Bar, G. C. Lloyd-Jones and
K. I. Booker-Milburn, Chem. Commun., 2007, 2932. Also, Kolosov
et al. have developed the synthesis of 6-substituted DHPMs by
applying acetoxy acetaldehyde previously, see: (b) M. A. Kolosov
and V. D. Orlov, Zh. Org. Farm. Khim., 2005, 3, 17.
Table 5 Selective synthesis of 3-substituted chromonesa
13 For recent reviews and practical examples of multicomponent
reactions, see: (a) J. P. Zhu, Eur. J. Org. Chem., 2003, 1133;
(b) A. Domling, Chem. Rev., 2006, 106, 17; (c) V. Nair,
¨
C. Rajesh, A. U. Vinod, S. Bindu, A. R. Sreekanth, J. S. Mathen
and L. Balagopal, Acc. Chem. Res., 2003, 36, 899.
Entry
R1
R2
X
Product
Yield (%)b
14 (a) S. L. Huang, Y. J. Pan, Y. L. Zhu and A. X. Wu, Org. Lett.,
2005, 7, 3797; (b) Y. L. Zhu, S. L. Huang, J. P. Wan, L. Yan,
Y. J. Pan and A. X. Wu, Org. Lett., 2006, 8, 2599; (c) Y. L. Zhu,
S. L. Huang and Y. J. Pan, Eur. J. Org. Chem., 2005, 2354;
(d) J. P. Wan, J. Zhou, H. Mao, Y. J. Pan and A. X. Wu,
Tetrahedron, 2008, 64, 11115.
15 For reviews on the application of enaminones, see: (a) B. Stanovnik
and J. Svete, Chem. Rev., 2004, 104, 2433; (b) A. Z. A. Elassar and
A. A. EI-Khair, Tetrahedron, 2003, 59, 8463; (c) P. Lue and
J. V. Creenhill, Adv. Heterocycl. Chem., 1997, 34, 1347.
1
2
3
4
5
6
7
4-MeC6H4
4-ClC6H4
NH2
NH2
NH2
NH2
NH2
NH2
CH3
S
S
S
S
O
O
O
11a ( 12a)
11b (12b)
11c
11d
11e
61 (16)
70 (13)
83
3-MeOC6H4
(CH3)2CHCH2
4-NO2C6H4
4-MeOC6H4
4-FC6H4
62
77
68
85
11f
11g
a
b
Identical conditions as Table 2. Isolated yield based on aldehyde.
ꢁc
This journal is The Royal Society of Chemistry 2009
2770 | Chem. Commun., 2009, 2768–2770