Probing the mode of asymmetric induction of biginelli reaction using proline ester salts

Article abstract of DOI:10.1002/ejoc.200900455

Described are the studies on the mechanism of the asymmetric Biginelli reaction using proline ester salt catalyst to explain the enantioselectivity of the 3,4-dihydropyrimidin2(1H)-one (DHPM) formation. Of the three possible activation methods by the cata

Full text of DOI:10.1002/ejoc.200900455

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900455
Probing the Mode of Asymmetric Induction of Biginelli Reaction Using Proline
Ester Salts
Jeong-Hun Sohn,*[a] Hyun-Moo Choi,[b] Sunjung Lee,[b] Seewon Joung,[b] and
Hee-Yoon Lee*[b]
Keywords: Asymmetric Biginelli reaction / Organocatalysis / Proline / Multicomponent reactions
Described are the studies on the mechanism of the asymmet- the catalyst is most responsible for the enantioselectivity.
ric Biginelli reaction using proline ester salt catalyst to ex-
plain the enantioselectivity of the 3,4-dihydropyrimidin-
2(1H)-one (DHPM) formation. Of the three possible acti-
vation methods by the catalyst that could provide asymmetric
induction we revealed that the steric environment of the chi-
ral enamine formed by the condensation of β-keto ester with
This assumption is supported by experiments with the N-
methylated catalyst, and the combination sets of - or -pro-
line ester catalyst with racemic or chiral BINOL-derived
phosphoric acid as counter acid.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
L
D
complexes, BINOL-derived phosphoric acids, or chiral sec-
ondary amines was employed, have been described.[11,12] Al-
though success has been achieved in these works, the design
and synthesis of new catalysts remains an interesting chal-
lenge mostly due to ambiguity of the exact mechanism of
the Biginelli reaction and the mode of chiral induction.
During the development of enantioselective Biginelli reac-
tions with organocatalysts, we realized that the understand-
ing of the mode of chirality transfer is essential. To reach
this goal, well designed experiments that offer pivotal evi-
dence for characterizing the reaction mechanism are re-
quired.[13] Herein, we report on the asymmetric induction
of the Biginelli reaction catalyzed by chiral secondary
amine salts. Such salts have been applied to many asymmet-
ric reactions as organocatalysts, and these applications have
resulted in a number of successful asymmetric reactions
through the formation of enamine-type intermediates.[14,15]
However, in the Biginelli reactions for the synthesis of race-
mic mixture of DHPMs, Brønstead- or Lewis acids have
been employed as catalysts to activate either the aldehyde
or acylimine intermediate.[16] Furthermore, a recent report
on the asymmetric Biginelli reaction suggested that proline-
derived secondary amine and a Brønsted acid as the com-
bined catalyst made the reaction proceed through a dual-
activation route.[11e]
Introduction
Multifunctionalized
3,4-dihydropyrimidin-2(1H)-one
(DHPM) derivatives are of great importance in the field of
medicinal chemistry ever since compounds possessing this
DHPM privileged structure were identified as drug candi-
dates or lead scaffolds. The DHPM derivatives have been
found to possess antihypertensive, antiviral, antitumor, an-
tibacterial, and antiinflammatory properties.[1] These com-
pounds have also emerged as calcium channel blockers,[1a]
Rho kinase inhibitors,[2] inhibitors of the fatty acid trans-
[3]
porter,
α
receptor antagonists,[4] antioxidant,[5] and neu-
1a
ropeptide Y (NPY) antagonists.[1] Due to the chirality of
these compounds, pharmacological studies concerning the
absolute configuration at the C(4) stereogenic center are
well documented and, in some cases, individual enantio-
mers show more different biological properties. For in-
stance, only the enantiomer, (R)-SQ 32,926 exhibits an anti-
hypertensive effect,[6] and only (S)-Monastrol[7] and (R)-
Mon-97[8] present potential anticancer activity.
The Biginelli reaction,[9] one of the most useful and well
known multicomponent reactions, allows straightforward
access to multifunctionalized DHPM compounds.[10] Re-
cently, several examples of enantioselective Biginelli reac-
tions in which asymmetric catalysis with either chiral metal
In the case of the asymmetric Biginelli reaction catalyzed
by chiral secondary amine salts, there are three possible
modes of activation methods which allow for asymmetric
induction. These pathways are outlined in Figure 1: 1) the cat-
alyst acts as chiral Brønstead acid to activate the acylimine
generated by the condensation of aldehyde and urea (A);[17]
2) chiral enamine, which is produced by the reaction be-
tween the catalyst and β-keto ester, attacks stereoselectively
onto the acylimine (B);[18] or 3) dual activation property
[a] Institut Pasteur Korea,
Seoungnam 463-400, Korea
Fax: +82-31-8018-8013
E-mail: sohnjh@ip-korea.org
[b] Department of Chemistry, KAIST,
Daejeon 305-701, Korea
E-mail: leehy@kaist.ac.kr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900455.
3858
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3858–3862

Biginelli Reaction Using Proline Ester Salts
(C).[11e] In order to get deeper insight into the mode of residue. Table 1 exhibits the final results of the Biginelli re-
stereoinduction of the enantioselective reaction we em- action using three ester salts. The enantioselectivity depends
ployed a proline ester salt as organocatalyst.
on the bulkiness of the ester group in the catalyst (entries
1–3). The enantiomeric ratio for tert-butyl ester 7 was 70:30
which is higher than either for methyl ester 5 (58:42) or
isopropyl ester 6 (61:39), and the loading amount of cata-
lyst insignificantly affected the enatioselectivity (entries 3–
5). The N-tert-butyl amide 8 afforded lower enantio-
selectivity (e.r. = 58:42, entry 6). This result was quite unex-
pected but indicates that, along with the result from iso-
propylamide (e.r. ≈ 1:1), amides that are more rigid than
esters, could not influence the enantioselectivity as much as
esters. The enantiomeric ratio (70:30), generated by the tert-
butyl ester salt 7, is thought to provide a good starting
point for mechanistic studies on the mode of asymmetric
activation.
Table 1. Biginelli reaction catalyzed by the -proline ester·HCl.
Figure 1. Three possible activation protocols leading to enantio-
selectivity with chiral secondary amine salt catalyst.
Results and Discussion
Since the proline ester or its salt, to the best of our
knowledge, has not been reported to be used in the enantio-
selective Biginelli reaction, we needed to investigate the eli-
gibility of the proline ester or its salt for our purpose. The
Biginelli reaction is not at all successful with proline ester
catalyst but proceeds well with its hydrochloride salt. We
carried out the reaction using HCl salts of methyl, isopro-
pyl, and tert-butyl -proline esters. The reaction mixture of
m-nitrobenzaldehyde (1), urea (2), β-keto ester (3) and each
catalyst in THF was allowed to stir at 70 °C for 24 h to
afford an enantiomeric mixture of DHPM 4.
While we were setting up the reaction protocol, we found
out that the solubilities of the pure enantiomers and race-
mic mixtures of the products in organic solvents were dra-
matically different. For example, when the resulting reac-
tion mixture was filtered and washed with diethyl ether af-
ter addition of water, the isolated product was a racemate
(e.r. = 53:47) whereas the product solution in the diethyl
ether filtrate was highly enantiomerically pure (e.r. = 99:1).
When the extraction of products with organic solvents like
diethyl ether or ethyl acetate was performed after the ad-
dition of water, low product yields with relatively high enan-
tiomeric ratio (Ͼ90:10) were observed. Afterwards, it was
confirmed that the racemic mixture was nearly insoluble in
diethyl ether or ethyl acetate but the pure enantiomer was
soluble in such solvents.[19] This finding is very important
for the determination of enantiomeric ratios since the solu-
bility differences among enantiomers, racemates, and mix-
tures of enantiomers can lead to false conclusions. The cor-
rect e.r. value without loss of either enantiomer was mea-
sured by dilution of the resulting reaction mixture with
iPrOH, which converted the heterogeneous mixture to a
Entry XR
% Loading[a] Ratio (R/S)[b] % Yield[c]
1
2
3
4
5
6
MeO (5)
10
10
10
20
30
10
58:42
61:39
70:30
71:29
70:30
58:42
82
85
87
83
83
80
iPrO (6)
tBuO (7)
tBuO (7)
tBuO (7)
tBuNH (8)
[a] mol-% of catalyst. [b] Ratio of crude product. Absolute configu-
ration was determined by the comparison of the characteristic CD
spectrum with DHPMs of known absolute configuration.[21] [c] Iso-
lated yield.
At first, we carried out the Biginelli reaction with a C2-
symmetric proline derivative to provide the symmetric envi-
ronment around the chiral amine catalyst.[20] To our sur-
prise, the reaction did not proceed well and there was no
enantioselectivity observed (Scheme 1). This result could
mean that the 1,5-disubstituted pyrrolidine is not able to
bind to the substrate effectively and thus did not provide
any enantioinduction.
Scheme 1. Biginelli reaction catalyzed by proline derivative with C2
symmetry.
To further probe the asymmetric induction, the N-meth-
homogeneous solution. The reaction yield was obtained by ylated catalysts 9 and 10 were employed. If the proline ester
removal of the solvent from the diluted reaction mixture salt catalysts act as Brønstead acids for the asymmetric in-
followed by the column chromatographic purification of the duction with the activation of the acylimine, it was expected
Eur. J. Org. Chem. 2009, 3858–3862
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J.-H. Sohn, H.-M. Choi, S. Lee, S. Joung, H.-Y. Lee
SHORT COMMUNICATION
that their N-methylated forms could give e.r. values ranging sponsible for the asymmetric induction, the Biginelli reac-
from racemic mixture to higher than that for catalyst 7. On tions would afford e.r. values comparable to 70:30 for all
the other hand, if the enantioselectivity is generated due to cases of the combinations. If the Brønstead acid affects the
the steric environment of chiral enamine species which at- asymmetric induction or the dual activation operates the
tacks stereoselectively onto the acylimine, the reaction reaction would result in unpredictable e.r. values (Figure 2).
product should be racemic mixture since tert-amine cannot
produce an enamine or iminium ion. The catalysts were
each prepared by reductive amination of methyl or tert-
butyl proline ester using NaOAc, paraformaldehyde and
Pd/C under H2 in MeOH, followed by formation of the
hydrochloride salt.[22] When the mixture of m-nitrobenzal-
dehyde (1), urea (2), β-keto ester (3) was treated with cata-
lyst 9 or 10 (10 mol-%) in THF and allowed to stir at 70 °C
for 60 h, the DHPM obtained from the reaction was com-
pletely racemic in each case (Table 2). These results indicate
that, for the asymmetric induction, the formation of an en-
amine species might be crucial; methylated proline deriva-
tives cannot form enamine intermediates. Another observa-
tion from the reactions using N-methylated catalysts was
that the reaction proceeded even without making enamine
intermediates though slower than those using the corre-
sponding secondary amine salts and could not provide the
environment for asymmetric induction. This result also sup-
ports the findings for the C2-symmetric catalyst which is
not able to form an enamine species with 3.
Figure 2. ,-proline ester and BINOL-phosphoric acid for com-
bined catalysts.
With the necessary elements for the combined catalysts
in hand, we made five combination sets of proline deriva-
tives and BINOL-phosphoric acids, and carried out the Bi-
ginelli reaction. The reaction mixture of m-nitrobenzalde-
hyde (1), urea (2), β-keto ester (3) was treated with catalyst
(10 mol-%) in THF and allowed to stir at 70 °C for 48 h to
afford DHPM 4 in good yield (Ն80%). Table 3 displays the
results. BINOL-phosphoric acid 13 alone gave e.r. = 58:42,
and this lower value, compared to those reported, is pre-
sumably caused by the higher reaction temperature (entry
1). As anticipated, the hydrochloride of -proline ester,
12·HCl, afforded an e.r. opposite to that produced by its
enantiomer (entry 2). The results, showing that catalysts
11·rac-13 or 11·13 provided a similar e.r. to catalyst 7 (e.r.
= 7:3), obviously indicate that the enantioselectivity in the
Biginelli reaction stems from the steric environment of the
chiral enamine species, while also ruling out the role of the
catalyst as chiral Brønstead acid or the dual activation
pathway (entries 3 and 4). This fact was confirmed by an-
other experiment using the -proline-based catalyst 12·13,
which gave the e.r. value that is the same value but opposite
sign to that for catalysts 7 or 11·13.
Table 2. The Biginelli reaction catalyzed by N-methylated proline
ester salt.
Entry
R
% Loading[a] Ratio (R/S)[b]
% Yield[c]
1
2
Me (9)
tBu (10)
10
10
49.8:50.2
49.3:50.7
n.d.[d]
63%
Table 3. Biginelli reaction using catalysts consisting of - or -pro-
line ester and BINOL-phosphoric acid.
[a] mol-% of catalyst. [b] Ratio of crude product. [c] Isolated yield,
reactions incomplete. [d] n.d.: not determined.
We next investigated the effect of the counter acid of the
proline ester to confirm the asymmetric induction through
the formation of enamine species. At first, the effect of vari-
ous acid salts of proline was investigated. It turned out that
acids with pKa values ranging from 0 to –8 (CF3CO2H to
HCl) show similar enantioselelctivities. The reaction did not
proceed at all with weak acids like AcOH. These results
support the enamine-mediated asymmetric induction since
salts of weak acids would react too sluggish and salts of
strong acids could compete with an acid-catalyzed reaction.
Since chiral BINOL-derived phosphoric acids were re-
ported to afford high enantioselectivity in Biginelli reac-
tion,[11c] we employed this acid as the counter acid of pro-
line derivatives. We designed experiments that would ac-
complish with catalysts consisting of combinations of - or
Entry
Combina-
tion
% Loading[a] Ratio (R/S) % Yield[c]
[b]
1
2
3
4
5
13
10
10
10
10
10
58:42
32:68
67:33
69:31
32:68
Ͼ 80
Ͼ 80
80
Ͼ 80
Ͼ 80
12·HCl
11·rac-13
11·13
12·13
[a] mol-% of catalyst. [b] Ratio of crude product. [c] Isolated yield.
Based on the results exhibited in Tables 2 and 3, we as-
-proline ester (11 or 12) and racemic or chiral BINOL sume that the reaction promoted by the proline ester salt
phosphoric acid 13.[11c] If only the enamine species are re- that act as Brønstead acids is a rather slow background
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Eur. J. Org. Chem. 2009, 3858–3862

Biginelli Reaction Using Proline Ester Salts
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Conclusions
Studies on the mechanism of the asymmetric Biginelli
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Experimental Section
General Procedure for the Biginelli Reaction: A microreactor was
charged with
a mixture of aldehyde 1 (0.2 mmol), urea 2
(1.2 equiv.), acetoacetate 3 (1.0 equiv.) and -proline-based catalyst
(10 mol-%) in THF (0.5 mL), and sealed. After stirring for 24 h at
70 °C, the resulting suspension was diluted with iPrOH until it
turned to homogeneous solution. The e.r. value was determined by
HPLC (Daicel Chirapak AD-H, n-hexane/iPrOH = 80:20, flow rate
1.0 mL/min): tR = 10.26 {R form, [α]2D5 = –154.0 (c = 0.105,
MeOH)}, tR = 13.46 (S form). The mixture was concentrated under
reduced pressure and purified by silica gel column chromatography
to afford DHPM 4. 1H NMR (400 MHz, [D6]DMSO): δ = 9.35 (s,
1 H, 1-H), 8.13 (dd, J = 1.4, 7.8 Hz, 1 H, 4Ј-H), 8.07 (s, 1 H, 2Ј-
H), 7.88 (s, 1 H, 3-H), 7.70–7.62 (m, 2 H, 5Ј-H and 6Ј-H), 5.29 (d,
J = 3.3 Hz, 2 H, 4-H), 3.99 (m, 2 H, OCH2Me), 2.26 (s, 3 H, 7-H),
1.08 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 165.0, 151.8, 149.4, 147.7, 147.0, 133.0, 130.2,
122.3, 121.0, 98.3, 59.4, 53.5, 17.8, 14.0 ppm.
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J.-H. Sohn, H.-M. Choi, S. Lee, S. Joung, H.-Y. Lee
SHORT COMMUNICATION
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Eur. J. Org. Chem. 2009, 3858–3862