A chemo- and regio-selective three-component dihydropyrimidinone synthesis

Article abstract of DOI:10.1039/b707361e

A selective three-component coupling, involving co-condensation of aldehyde pairs with substituted ureas under Lewis acid catalysis, provides rapid access to highly functionalised dihydropyrimidinones; sulfamides react analogously. The Royal Society of Ch

Full text of DOI:10.1039/b707361e

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A chemo- and regio-selective three-component dihydropyrimidinone
synthesis{
Chris D. Bailey, Chris E. Houlden, Gre´gory L. J. Bar, Guy C. Lloyd-Jones and Kevin I. Booker-Milburn*
Received (in Cambridge, UK) 16th May 2007, Accepted 4th June 2007
First published as an Advance Article on the web 19th June 2007
DOI: 10.1039/b707361e
generated via an efficient MCR between urea or thiourea with
cyclic ketones and aromatic aldehydes. The reaction requires a full
equivalent of TMSCl as promoter,8 there being no reaction when a
range of other Lewis acids systems, including BF3?Et2O, were
tested. In contrast, the reaction of DMU with phenylacetaldehyde
proceeds efficiently with catalytic quantities of BF3?Et2O in
toluene,9 Scheme 1. We thus sought to examine the scope of the
condensation with a range of aliphatic aldehydes and found that,
in general, the homocoupling was complete within 2–5 h, Table 1.
Generally, yields were slightly higher (y10%) when molecular
sieves were employed, suggesting potential reversibility due to
hydrolysis of intermediates, although once formed, the dihydro-
pyrimidinone products were stable. Use of N,N9-dimethylsulfa-
mide led to the corresponding cyclic sulfamide, entries 11–13.
In the reaction of DMU with phenylacetaldehyde the formation
of enamide 1 could clearly be seen by TLC, thus confirming 1 as
an early intermediate in the overall sequence to the pyrimidinone 2.
Significantly, subjecting a pure sample of 1 (prepared from Pd(II)
sequence) to the BF3?Et2O conditions results in the formation of 2
(60%) plus the formation of DMU. We suggest that the generation
of the pyrimidinones proceeds by initial formation of the enamide
3 through an aldehyde/DMU condensation, Scheme 2. Enamide 3
can react further with another equivalent of aldehyde by two
A selective three-component coupling, involving co-condensa-
tion of aldehyde pairs with substituted ureas under Lewis acid
catalysis, provides rapid access to highly functionalised
dihydropyrimidinones; sulfamides react analogously.
In 1933 Folkers and Johnson1 reported that urea (H2NCONH2)
reacts with phenylacetaldehyde in ethanol at reflux, catalysed by
hydrochloric acid, to give 4-benzyl-5-phenyl-dihydropyrimidinone.
In the context of modern efforts towards developing multi
component reactions (MCRs) it is surprising that no further work
appears to have been reported on the extension of this potentially
useful reaction. During recent studies involving the development of
Pd(II)-catalysed methods for diamination of alkenes,2 we noted
that N,N9-dimethyl urea (DMU) added to styrene to produce the
enamide 1 (Scheme 1),3 and, over longer periods of time, the
dihydropyrimidinone 2 (16%, 72 h). It was subsequently found
that simply heating two equivalents of phenylacetaldehyde with
DMU in the presence of BF3?Et2O (10%) as a catalyst afforded 2
in 92% yield. Herein we report on the development of this reaction
sequence to facilitate condensation of a range of N- and N,N9-
substituted ureas with aldehydes. Intriguingly, the reaction
proceeds with high chemo- and regio-selectivity when pairs of
aldehydes are co-reacted, to generate the hetero-condensation
products in good yield.
The reaction between two molecules of aldehyde and one of
urea has similarities to the well-established three-component
Biginelli reaction4,5 (aldehyde, b-ketoester and urea/thiourea),
where research is now focused on development of milder
conditions and asymmetric modifications.6 Recently Pan et al.7
reported that bicyclic and spirocyclic fused pyrimidinones are
Table 1 Homocoupling of aldehydes with DMU and sulfamides
Entry
X
R
Pyrimidinone yield (%)
1
2
3
4
5
6
7
8
9
10
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
–Ph
–CH2Ph
–CH3
–CH2CH3
–CH2CH2CH3
–CH(CH3)2
–CH2(CH2)2CH3
–CH2(CH2)3CH3
–CH2CHLCH2
92
86
74a
70
87
62
88a
86a
76a
25
Scheme 1 Discovery and optimization of a novel dihydropyrimidinone
synthesis.
11
12
13
a
SO2
SO2
SO2
–Ph
–CH2Ph
–CH3
51
53
52
School of Chemistry, University of Bristol, Cantock’s Close, Bristol,
UK BS8 1TS. E-mail: k.booker-milburn@bristol.ac.uk
{ Electronic supplementary information (ESI) available: experimental
details. See DOI: 10.1039/b707361e
3 eq. of aldehyde added to urea solution at reflux.
2932 | Chem. Commun., 2007, 2932–2934
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Table 3 Selective homocoupling of aldehydes with mono-substituted
ureas
Entry
R1
R2
11 Yield (%)
1
2
3
4
–Me
–Me
–Ph
–Ph
–CH2CH2CH3
–Ph
–Ph
67
59
56
62
–CH2CH2CH3
increased the 9 : 10 ratio slightly but at the expense of overall yield
due to the competing formation (23%) of the phenylpropionalde-
hyde homocoupled product (Entry 3).
We then explored the reaction of monosubstituted ureas with
aldehydes in a homocoupling sequence. Initially it was speculated
that the most nucleophilic nitrogen would be likely to influence the
enamide formation and thus control the ultimate regiochemistry of
the overall coupling. In the four examples studied only one
regioisomer of the pyrimidinone was observed which indicated
that the substituted urea nitrogen is the most nucleophilic and
forms the enamide, Table 3. For entries 3 and 4, however, we were
surprised to observe that the product was formed from an enamide
which itself was formed from apparent attack of the N-phenylurea
on the aldehyde by the inherently much less nucleophilic aniline
nitrogen. We suggest that this high degree of chemoselectivity can
be attributed to attack by the unsubstituted nitrogen, which would
lead to unproductive and reversible imine rather than enamide
formation.10
Scheme 2 Possible mechanisms for condensation.
pathways. Firstly, further reaction with the secondary nitrogen
would lead to the iminium ion 4 (Path A). This could then undergo
cyclisation to the iminium ion 5 followed by proton loss to the
afford the product 6. It is equally plausible that the reaction
involves attack of the b-carbon in 3 on the aldehyde to generate
the iminium ion 7 (Path B). This species can then undergo proton
loss and dehydration to generate the a,b-unsaturated iminium ion
8, which then undergoes cyclisation to 6.
We then explored the possibility of developing this sequence into
a 3-component heterocoupling by studying the reaction of DMU
with phenylacetaldehyde and other aldehydes, Table 2. Simply
heating equimolar mixtures of the two aldehydes generated the
hetero 9 and homo-coupled pyrimidinone 10 in a ratio of 3.8 : 1
(Entry 1). This surprisingly selective result (4 possible products)
indicates that phenylacetaldehyde reacts first because it results in a
conjugated enamide. Use of two equivalents of phenylpropional-
dehyde gave an improved ratio of 6.25 : 1 in an impressive 89%
yield (Entry 2). Further equivalents of phenylpropionaldehyde
Further elaboration of this principle with mono-substituted
ureas allowed the realisation of a selective three component
coupling with two different aldehydes to yield the single
pyrimidinones 13 in reasonable yields (Table 4). Key to the
success of this was the use of aryl aldehydes. According to the
mechanisms outlined in Scheme 2, these cannot form an enamide
and thus selectivity is assured in a heterocoupling sequence.
Table 4 Selective three-component coupling of mono-substituted
ureas with aliphatic and aromatic aldehydes
Table 2 Heterocoupling of aldehydes with DMU
Entry
R1
R2
13 Yield (%)
Entry
R (eq.)
9 : 10
Yield (%)
1
2
3
4
–CH2CH2CH3
–CH2CH2CH3
–CH2CH2CH3
–CH2Ph
–H
–Cl
–OMe
–H
60
59
51
60
1
2
3
4
5
a
–CH2Ph (1)
–CH2Ph (2)
–CH2Ph (3)
–CH2CH3 (2)
–CH(CH3)2 (2)
3.8 : 1
6.25 : 1
7.5 : 1a
4.3 : 1b
3 : 0c
68
89
77
67
45
In summary, we have demonstrated that ureas and sulfamides
undergo a useful three-component coupling sequence to provide
pyrimidinones in moderate to high yields. The reaction has proved
to be of broad scope, reproducible, operationally simple and
allows the rapid assembly of dihydropyrimidinones containing
Homocoupling product of phenylpropionaldehyde observed as side
Homocoupling product of propionaldehyde
c
b
product (23%);
observed as side product (10%); No 10 formed but 15% of other
isomeric product of 9 observed.
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functionality suitable for further elaboration (e.g. 14 to 15).11 This
methodology produces complimentary products to those obtained
by the well known Biginelli reaction and as such should prove to
be useful in the synthesis of potentially pharmacologically
important molecules.
B. Boumoud, M. Amimour, A. Belfaitah, S. Rhouati and B. Carboni,
Tetrahedron Lett., 2006, 47, 5697–5699.
7 Y.-L. Zhu, S.-L. Huang and Y.-J. Pan, Eur. J. Org. Chem., 2005,
2354–2367.
8 In addition to ketone–benzaldehyde coupling, these authors observed
homocoupling of a few aliphatic aldehydes with urea to give
pyrimidinones analogous to those reported in this study. Interestingly,
under our conditions (BF3?Et2O catalysis) the only reactions observed
between, for example, phenylacetaldehyde and acetone were those of
homocoupling of the more reactive aldehyde with the DMU (60%).
9 Reactions with TsOH gave pyrimidinones but were very sluggish and
did not proceed to completion. Reactions without any acid catalyst gave
no product.
10 For example, initial condensation via the primary nitrogen would yield
the imine 12 rather than the enamide. This imine would be unlikely to
condense with another aldehyde and thus be succeptible to hydrolysis
back to the urea and the aldehyde.
We are grateful to EPSRC and AstraZeneca for generous
studentship funding and Gair J. Ford (AZ, Macclesfield) for useful
discussion.
Notes and references
1 K. Folkers and T. B. Johnson, J. Am. Chem. Soc., 1933, 55, 3361–3368.
2 G. L. J. Bar, G. C. Lloyd-Jones and K. I. Booker-Milburn, J. Am.
Chem. Soc., 2005, 127, 7308–7309.
3 V. I. Timokhin and S. S. Stahl, J. Am. Chem. Soc., 2005, 127,
17888–17893.
4 (a) C. O. Kappe, Tetrahedron, 1993, 49, 6937–7963; (b) C. O. Kappe,
Acc. Chem. Res., 2000, 33, 879–888; (c) C. O. Kappe and A. Stadler,
Org. React., 2004, 68, 1–116.
5 For recent reviews, see: (a) Multicomponent Reactions, ed. J. Zhu and
H. Bienayme´, Wiley-VCH, Weinheim, 2005; (b) G. Guillena,
D. J. Ramo´n and M. Yus, Tetrahedron: Asymmetry, 2007, 18,
693–700; (c) V. Nair, R. S. Menon and V. Sreekumar, Pure Appl.
Chem., 2005, 77, 1191–1198; (d) A. Do¨mling, Chem. Rev., 2006, 106,
17–89; (e) M. A. Mironov, QSAR Comb. Sci., 2006, 25, 423–431; (f)
A. Dondoni and A. Massi, Acc. Chem. Res., 2006, 39, 451–463.
6 (a) Y. Huang, F. Yang and C. J. Zhu, J. Am. Chem. Soc., 2005, 127,
16386–16387; (b) X.-Y. Chen, X.-Y. Xu, H. Liu, L.-F. Cun and
L.-Z. Gong, J. Am. Chem. Soc., 2006, 128, 14802–14803; (c) A. Debache,
11 For example, rapid assembly of the 7,6-fused pyrimidinone 15 was
achieved in two steps from DMU and 4-pentenal followed by RCM of
the resulting pyrimidinone diene 14 with Grubbs I catalyst.
2934 | Chem. Commun., 2007, 2932–2934
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