Modified multicomponent Biginelli-Atwal reaction towards a straightforward construction of 5,6-dihydropyrimidin-4-ones

Article abstract of DOI:10.1039/c5ra08792a

A straightforward access to 5,6-dihydropyrimidin-4-ones as racemic mixtures or enantiopure diastereoisomers was achieved thanks to a multicomponent Knoevenagel-aza-Michael-Cyclocondensation reaction involving Meldrum's acid and isourea derivatives. This constitutes not only a novel MCR of the original Biginelli-Atwal condensation but allows the construction of dihydrouracyl derivatives known as biorelevant diazole architectures. This journal is

Full text of DOI:10.1039/c5ra08792a

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Modified multicomponent Biginelli–Atwal reaction
towards a straightforward construction of 5,6-
dihydropyrimidin-4-ones†
Cite this: RSC Adv., 2015, 5, 46267
*
Etienne Pair, Vincent Levacher and Jean-François Briere
`
A
straightforward access to 5,6-dihydropyrimidin-4-ones as racemic mixtures or enantiopure
Received 20th April 2015
Accepted 18th May 2015
diastereoisomers was achieved thanks to a multicomponent Knoevenagel-aza-Michael-Cyclocondensation
reaction involving Meldrum's acid and isourea derivatives. This constitutes not only a novel MCR of the
original Biginelli–Atwal condensation but allows the construction of dihydrouracyl derivatives known as
biorelevant diazole architectures.
DOI: 10.1039/c5ra08792a
www.rsc.org/advances
backbones or precursors of naturally occurring and bioactive
compounds,8 b-amino acids and nucleobases.9
Introduction
A literature survey pointed out that interesting multicom-
ponent, likely KaMC reactions, between Meldrum's acid 4 and
aldehydes were reported with urea component in reuxing
AcOH,10 heterocycles-embedded guanidine motif,11 and guani-
dines itself,12 although signicant heating conditions are
usually required and limit the scope of these approaches.7 In
one case,12b Balalaie performed a MCR with guanidinium
carbonate in reuxing EtOH with aromatic aldehydes. Very
recently, an encouraging perspective towards diversication
was achieved using the benzamidine nucleophile allowing the
use of a larger array of aldehydes such as some aliphatic ones in
the presence of Et3N in reuxing EtOH.13
We are pleased to report hereby on an innovative modied
multicomponent Biginelli–Atwal reaction between Meldrum's
acid 4, isourea derivatives 1 and various type of aldehydes 5
upon smooth basic conditions (<40 ꢀC). This eventually opens a
straightforward access to 5,6-dihydropyrimidin-4-ones 7 both in
A great deal of methodological investigations have been driven
by the elaboration of 3,4-dihydropyrimidines, a signicant core
structure of medicinal ingredients. In that context, the Biginelli
condensation,
a robust multicomponent reaction (MCR),
stands out.1 Involving a mixture of aldehyde, urea and aceto-
acetic ester derivative, this sequence, mostly promoted by acid
additives, led to various substituted 3,4-dihydropyrimidines. In
1987, Atwal and colleagues proposed
a complementary
approach upon orthogonal basic conditions, allowed by the use
of isourea ammonium salts derivatives 1 and enones 2, pre-
synthesized Michael-acceptors (Scheme 1a).2 This alternative
strategy not only extended the scope of the original Biginelli
condensation – i.e., larger tolerance of both aliphatic and more
hindered aldehydes – but allowed the synthesis of new bioactive
1,4-dihydropyrimidines architectures 3 such as antihyperten-
sive agents.3 Unfortunately, despite Kappe's contribution in
solid phase synthesis,4 the MCR of Biginelli–Atwal's condensa-
tion is still challenging.1a–e We reasoned that a modied but
multicomponent Biginelli–Atwal reaction could be feasible by
starting from Meldrum's acid 4 in the presence of aldehydes 5
as precursors of reactive alkylidene derivatives 6 upon basic
conditions,5 ready to be engaged along a domino Knoevenagel-
aza-Michael-Cyclocondensation (KaMC) reaction (Scheme 1b).6
This approach would not only extend the scope of Meldrum's
acid 4 connected to MCR6,7 but also open a straightforward
access to 5,6-dihydropyrimidin-4-ones 7. Derivatives 7, or
dihydrouracyl derived thereof, are indeed representative
Normandie Univ, COBRA, UMR 6014 et FR 3038, Univ Rouen, INSA Rouen, CNRS,
`
1 rue Tesniere, 76821 Mont Saint Aignan cedex, France. E-mail:
IRCOF,
jean-francois.briere@insa-rouen.fr
† Electronic supplementary information (ESI) available: Further experimental
optimizations, procedures and compound characterization data (1H, 13C NMR,
HPLC, mass). See DOI: 10.1039/c5ra08792a
Scheme 1 Modified multicomponent Biginelli–Atwal reaction.
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a racemic and unprecedented diastereoselective fashion toward
enantiopure compounds.
Results and discussion
Towards a proof of principle, we carried out the MCR by mixing
the commercially available ammonium salt of O-methylisourea
1a, benzaldehyde 5a and a stoichiometric amount of cesium
carbonate in MeCN/H2O mixture at 40 ꢀC (Table 1). The desired
dihydropyrimidin-4-ones 7aa product was obtained with 59% of
NMR yield (entry 1). The product 7aa was observable as a
Scheme 2 Mechanistic proposal.
1
mixture of tautomers 7aa0 (D1,2) and 7aa00 (D2,3) by H NMR in
the formation of ammonium salt 8 (Scheme 2). Then, the
species 8 undergoes a Knoevenagel condensation to give very
reactive Meldrum acid alkylidene 6,5,6 subsequently engaged
into the domino aza-Michael-cyclocondensation reaction with
the liberated isourea 9 en route to the elaboration of diazole 7aa
through a multicomponent KaMC reaction. Importantly, the
synthesis of dihydropyrimidin-4-one 7aa was also achieved in
70% yield by mixing pre-formed benzylidene Meldrum's acid 6a
(R1 ¼ Ph) and O-methylisourea isourea 9 as free-base, showing
this multicomponent reaction likely takes place through an aza-
Michael key step (versus a Mannich type process). As a practical
issue, it is more convenient to use isoureas 1 as ammonium
salts (usually the commercially and/or available form) rather
than the hydroscopic free base counterpart 9. First of all, this
strategy minimizes the use of strong bases or high temperatures
in order to liberate isourea 9. Next, the rather facile addition
CDCl3 (7aa0/7aa00 ¼ 86/14). On the other hand, the domino
sequence did not proceed without any mineral base to liberate
the isourea free-base (entry 2). It was found that the reaction
could be carried out by means of various bases with a potassium
cation (entries 3) along with their sodium homologues (entries
4–6); the best result was obtained with sodium carbonate at 40
ꢀC furnishing product 7aa with 87% yield (entry 6). However, a
sluggish reaction took place at 20 ꢀC (entry 7). A solvent
screening revealed this MCR could be carried out in EtOH or
MeCN/H2O solvents preferentially,14 otherwise precipitation
events were observed and led to erratic outcomes. Interestingly,
the MCR sequence was also feasible with a stoichiometric
amount of pre-formed Meldrum's acid enolate 4ꢁNa+ as a
sodium salt without extra mineral base to provide uneventfully
the dihydropyrimidinone 7aa with 75% NMR yield in nearly
neutral conditions (entry 8).
ꢀ
reaction of isourea 9 in so conditions (40 C) is a welcomed
issue of this KaMC sequence with respect to literature
guanidine-based procedures generally requiring higher
temperature to occur (vide infra).7
Accordingly, as far as the mechanism is concerned, we
anticipate that a facile deprotonation of Meldrum's acid 4 (pKa
¼ 4.93 in water versus pKa ¼ 9 for the O-methylisourea ammo-
nium salt 1a)6 would furnish the corresponding Meldrum's acid
enolate 4ꢁNa+ allowing an ion-metathesis process giving rise to
We were pleased to observe that these reaction conditions
are not only compatible with ammonium salts of O-methyl-
isourea 1a (79% isolated yield), but also with thioisourea 1b and
pyrazole carboxamidine 1c furnishing the corresponding diaz-
oles 7aa–7ca with isolated yields ranging from 79% to 95% aer
column chromatography (Scheme 3).14 This last example
constitutes a novel extension of the Overman approach of the
Biginelli–Atwal reaction making use of carboxamidine
Table 1 Proof of principlea
Entry
Base (1.1 equiv.)
Temp.
Yieldb (%)
1
2
3
4
5
6
7
8
Cs2CO3
—
40 ꢀ
40 ꢀ
40 ꢀ
40 ꢀ
40 ꢀ
40 ꢀ
20 ꢀ
40 ꢀ
C
C
C
C
C
C
C
C
59
2
K2CO3
NaOH
NaHCO3
Na2CO3
Na2CO3
4ꢁNa+c
79
79
83
87
7
75
a
Reaction performed at 0.1 M on 0.10 mmol scale with 1 equiv. of each
b
components and 1.1 equiv. of base in MeCN/H2O (9/1). NMR yield
c
determined by an internal standard. Reaction performed with pre-
synthesized sodium salt of 4 (4ꢁNa+, 1 equiv.) without extra base.
Scheme 3 Scope and limitation of isourea type nucleophiles.
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derivatives 1c.15 Interestingly, the guanidinium salt 1d led to an glyceraldehyde 5m developed by Ley's group to provide dihy-
interrupted MCR affording the zwitterionic aza-Michael adduct dropyrimidinone 7am with >95 : 5 dr and 51% yield aer
10. Obviously, the subsequent proton transfer event is inhibited column chromatography (minor isomer hardly seen on 1H
due to the high basicity of the guanidine part versus the 1,3- NMR).16,17 In this case, the best result was obtained starting
dioxanone moiety. Therefore, the lower pKa of the isourea from Meldrum's acid enolate 4ꢁNa+, otherwise a more complex
nucleophiles 1a–c is key for the success of our multicomponent crude mixture was obtained. Although not identied aer
KaMC reaction in so conditions.
column, we cannot fully rule out the presence of the other
The scope of this multicomponent KaMC reaction with diastereoisomers on the crude reaction mixture due to the
regard to various aldehydes 5 was investigated with O-methyl- presence of side products and tautomers. In the literature, the
isourea derivative 1a (Table 2). Aromatic and heteroaromatic scope of multicomponent KaMC reactions with Meldrum's acid
aldehydes (entries 1–4) were successfully transformed into the 4 mainly focused on aromatic aldehydes with very few
corresponding dihydropyrimidinones 7ab–7ae with isolated successful examples involving aliphatic aldehydes; none of
yields ranging from 34% to 85%. Worthy of note, the 3-car- them displayed acid sensitive functional groups.12a,12c,10,13
boxyladehyde indole 5g gave the diazole 7ag in 62% isolated Pleasingly, this modied Biginelli–Atwal reaction shows an
yield as soon as an N-Boc protected derivative was used (entry 5 expended scope with regard to aldehyde component thanks to
versus 6). This outcome highlights electronic requirements of the smooth conditions developed.
transient alkylidene Meldrum's acid 6 from which the ones
displaying a push–pull effect tend to be reluctant to react. conditions would tolerate
Next, we were curious to see whether this MCR in so
diastereoselective sequence,
a
Importantly, this MCR sequence turned out to be compatible involving chiral isourea derivatives 11,12, towards the forma-
with a variety of aliphatic aldehydes either linear (5h,5i, 75– tion of non-racemic products 13. Furthermore, this would give a
81%, entries 7 and 8), a-branched (5j,5k, 88–90%, entries 9 and unique opportunity of exploring extra-molecular space
10) or possessing acidic-sensitive NHBoc functional group (5l) (Table 3). Accordingly, we intended to capitalize on the readily
albeit with a slight decreased in yield in the last case (45%, entry availability of 12 (one-step from (R)-2-phenylglycinol) which was
11). Moreover, a diastereoselective reaction was also demon- developed as useful chiral auxiliary by Dechoux and
strated starting from readily available protected chiral colleagues.18,19 Following our optimized conditions (entry 1),
using an equivalent of Na2CO3 and benzaldehyde 5a, the MCR
proceeded smoothly but furnished
a 1 : 1 mixture of
Table 2 Scope and limitation with various aldehydesa
regioisomers 13a and 14a versus 15a and 16a from which the
known anti-dihydropyrimidin-4-one 13a was the major diaste-
reomer.18 We were delighted to see that base-free conditions,
making use of enolate 4ꢁNa+ and ammonium salt 11, not only
favored regioisomers 13a and 14a (13a,14a/15a,16a ¼ 66/34) but
Table 3 Diastereoselective approacha
Entry
Base (1.1 equiv.)
Yieldb (%)
1
2
3
4
5
6
7
8
4-MeOC6H4 (5b)
4-CF3C6H4 (5c)
2-BrC6H4 (5d)
3-pyridine (5e)
3-N-MeIndole (5f)
3-N-BocIndole (5g)
(CH2)2Ph (5h)
i-Bu (5i)
74 (7ab)
79 (7ac)
85 (7ad)
34 (7ae)
0 (7af)
62 (7ag)
81 (7ah)
75 (7ai)
90 (7aj)
88 (7ak)
45 (7al)
9
10
11
i-Pr (5j)
Cy (5k)
(CH2)2NHBoc (5l)
Entry Isourea Conditions
Product (13/14/15/16)b Yieldc (%)
1
2
3
4
5
6
11
11
12
12
12
12
Na2CO3, 40 ꢀ
C
45/5/43/7
61/5/29/5
64/6/25/5
61/7/26/6
62/8/22/8
69/5/17/9
—
—
4ꢁNa+, d40 ꢀC
40 ꢀ
40 ꢀ
40 ꢀ
40 ꢀ
C
C
C
C
55% (13a)
52% (13b)
46% (13c)
53% (13n)
12
51 (7am)c
(5m)
a
a
Reaction conditions: Meldrum's acid 4 (0.50 mmol) in MeCN/H2O (9/
Optimized reaction conditions: Meldrum's acid 4 (0.50 mmol) in
1) at 0.25 M at 40 ꢀC for 24 hours with aldehyde 5 (1 equiv.) and isourea
MeCN/H2O (9/1) at 0.25 M at 40 ꢀC for 24 hours with aldehydes 5 (1.0
equiv.) and chiral isourea 12 (1.0 equiv.). Ratio determined by NMR
b
b
salt 1a (1 equiv.). Isolated yield aer column chromatography of 7
observable by 1H NMR as a mixture of D1,2 : D2,3 tautomers (72 : 28 to
c
on the crude product. Isolated yield of pure 13 aer silica gel
c
column chromatography. Sodium salt 4ꢁNa+ of Meldrum's acid (1
d
98 : 2). Reaction performed with Meldrum's acid sodium salt of
4ꢁNa+ (1 equiv.) without extra base giving 7al with >95 : 5 dr aer
equiv.) was used without extra-base.
column.
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revealed a good diastereoisomeric ratio of 92 : 8 (13a : 14a,
entry 2).20 Eventually, to prevent the detrimental effect of an
external base, the multicomponent KaMC reaction was effected
by chiral isourea 12 and native Meldrum's acid 4 to give similar
outcomes (entry 3). Importantly, product 13a was easily isolated
by column chromatography with 55% yield as a sole diaste-
reoisomer (entry 3). These reaction conditions were competent
to synthesize the corresponding anti-diastereopure 5,6-
dihydropyrimidin-4-ones 13b–13n anked by electron-rich and
electron-poor aromatic rings (13b,13c) or an aliphatic chain
(13n) pendants with isolated yields ranging from 46% to 53%
with similar stereoselectivities as testify on the crude reaction
mixture (entries 4–6). Although the regioselectivity issue of this
sequence would deserve to be improved, this unprecedented
Scheme 5 Towards an enantiopure dihydrouracyl.
Eventually, in order to exploit the full potential of the dia-
stereoselective MCR strategy (Scheme 5), the possibility to
cleave the chiral auxiliary of 13a was demonstrated to provide a
readily access to enantiopure dihydrouracyl 17.18,23
diastereoselective modied Biginelli–Atwal MCR allows
straightforward access to enantioisomerically pure diazoles 13
in a one-step operation.
a
Conclusions
In summary, we have developed a straightforward access to 5,6-
dihydropyrimidin-4(3H)ones 7 through an original multicom-
ponent KaMC reaction involving Meldrum's acid 4, various
aldehydes 5 and isourea derivatives 1 upon smooth basic-
conditions. The possibility to perform a diastereoselective
approach from readily available enantiopure Dechoux's chiral
isourea 12 was demonstrated. Eventually, chemoselective
transformations were achieved onto this useful heterocyclic
platforms en route to the construction of bio-pertinent
architectures.
In order to highlight the usefulness of this synthetic
sequence, we turned our attention to chemoselective trans-
formations of these readily available heterocyclic platforms 7
(Scheme 4). In parallel to known a-alkylation and reduction
reactions of the ketone moiety,19,20 the methoxy-precursor 7aa
was easily hydrolyzed in high 92% yield into the dihydrouracyl
17, following an improved literature procedure.9a Complete
regioselective N1-Boc-introduction (vide infra) was successfully
performed to furnish products 18,19 in 85% to 99% yields
respectively. This shows a similar behavior with Atwal's 1,4-
dihydropyrimidine architectures allowing a chemoselective
substitution towards specic structure modulation.21 Although
precursors 7aa, 7ba and 7ca were reluctant to aminolysis
condensation, the Boc-derivatives 18,19 were smoothly trans-
formed into the corresponding guanidine-heterocycle 20 in
more than 81% yield.15 Interestingly, a smooth reduction of N-
Boc dihydropyrimidin-4-ones 18 was achieved with NaBH4 to
furnish the corresponding tetrahydropyrimidinone 21 in 85%
yield.22 The position of the Boc-group was proven by 1H NMR on
this compound 21, thanks to COSY experiment showing an
exclusive cross-peak between NHCO and AB-system (NCH2N).14
Acknowledgements
This work has been partially supported by INSA Rouen, Rouen
University, CNRS, EFRD and Labex SynOrg (ANR-11-LABX-0029)
and region Haute-Normandie (CRUNCh network).
Notes and references
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