Enantioselective organocatalytic Biginelli reaction: Dependence of the catalyst on sterics, hydrogen bonding, and reinforced chirality

Article abstract of DOI:10.1021/jo101717m

From a systematic investigation involving the synthesis of a series of catalysts and screening studies, the organocatalyst 16, which is sterically hindered, contains a strong hydrogen-bonding site, and is endowed with reinforced chirality, is shown to pro

Full text of DOI:10.1021/jo101717m

pubs.acs.org/joc
Enantioselective Organocatalytic Biginelli Reaction: Dependence of the
Catalyst on Sterics, Hydrogen Bonding, and Reinforced Chirality†
Satyajit Saha and Jarugu Narasimha Moorthy*
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
moorthy@iitk.ac.in
Received August 31, 2010
From a systematic investigation involving the synthesis of a series of catalysts and screening studies,
the organocatalyst 16, which is sterically hindered, contains a strong hydrogen-bonding site, and is
endowed with reinforced chirality, is shown to promote the Biginelli cyclocondensation of aromatic
as well as aliphatic aldehydes with ethyl acetoacetate and urea in a remarkably high enantioselectivity
(ee ca. 94-99%).
Introduction
The Biginelli reaction is an important one such multicompo-
nent one-pot domino reaction, which allows easy access to
dihydropyrimidinones (DHPMs) in one step starting from
an aldehyde, urea, and a β-ketoester (eq 1).2 The heterocyclic
pyrimidinone products, i.e., DHPMs, are known to exhibit a
While catalysis by nonhazardous and environmentally
benign organic molecules is a major breakthrough, rapid
construction of structurally complex molecules from simple
and readily available precursors in one operation, referred to
as a domino reaction, is an exciting prospect.1 Domino
reactions, a new direction in organocatalysis, preclude formation
of waste products and increase the efficiencies of reactions.
† Dedicated to Prof. Yashwant D. Vankar on the occasion of his 60th birthday.
(1) (a) Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed.
2007, 46, 1570. (b) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.
1993, 32, 131. (c) Tietze, L. F. Chem. Rev. 1996, 96, 115. (d) Tietze, L. F.;
Haunert, F. In Stimulating Concepts in Chemistry; Vogtle, F., Stoddart, J. F.,
Shibasaki, M., Eds.; Wiley-VCH: Weinheim, Germany, 2000; p 39. (e)
Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551.
(f) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005,
105, 1001. (g) Ramkn, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602.
(h) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354. (i) Pellissier,
H. Tetrahedron 2006, 62, 1619. (h) Pellisier, H. Tetrahedron 2006, 62, 2143. (i)
Tietze, L. F.; Brasche, G.; Gerike, K. Domino Reactions in Organic Chem-
istry; Wiley-VCH: Weinheim, Germany, 2006.
wide range of important pharmacological properties and make
up a large family of medicinally relevant compounds.3 In-
deed, both enantiomers of DHPMs have been found to show
396 J. Org. Chem. 2011, 76, 396–402
Published on Web 12/30/2010
DOI: 10.1021/jo101717m
r
2010 American Chemical Society

Saha and Moorthy
JOCArticle
CHART 1. Structures of Catalysts Explored for the Asymmetric Biginelli Reaction in the Present Investigation
distinct or opposite pharmacological activities.4 Thus, the
asymmetric version of the Biginelli reaction is of significant
contempo-
rary interest. In general, optically pure DHPMs are accessed
via resolution5 and chiral auxiliary methods.6 We are aware
of only a few reports so far in the literature for the synthesis
of optically pure DHPMs by employing organocatalysts.7 In
continuation of our recent forays into organocatalysis focus-
ing on catalyst design for enantioselective transformations,8
we targeted the asymmetric Biginelli reaction based on ratio-
nally designed prolinamides. Herein, we report that sterically
hindered N-arylprolinamides augmented by reinforced chi-
rality and acidic hydrogen bond donors promote the Biginelli
reaction in a very high enantioselectivity (ee ca. 94-99%),
albeit in the presence of some additives.
Results and Discussion
(2) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360. (b) Dondoni, D.;
Massi, A. Acc. Chem. Res. 2006, 39, 451. (c) Kappe, C. O. In Multicomponent
Reactions; Zhu, J., Bienaymq, H., Eds.; Wiley-VCH: Weinheim, Germany,
2005; p 95. (d) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879. (e) Simon, C.;
Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957. (e) Taylor,
M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (f) Connon,
S. J. Angew. Chem., Int. Ed. 2006, 45, 3909.
Our journey in pursuit of the highly enantioselective
Biginelli reaction with organocatalysts began with prolina-
mides 1-4 (Chart 1), which either contain an acidic NH or
exhibit the potential for double hydrogen bonding. The
Biginelli reaction between p-methoxybenzaldehyde (a repre-
sentative case), urea, and ethyl acetoacetate did proceed with
these catalysts, but the DHPM was formed with each catalyst
in a low enantioselectivity (ee ca. 18%; cf. Table 1). The
modified catalysts 5-7 that contain a sterically hindered
amide site (cf. Chart 1) were no better in terms of enantio-
selectivity under a variety of solvents and additive screening
conditions; cf. Table 1. A recourse, at this stage, to the literature-
reported catalysts (Chart 2) that modulate the Biginelli
reaction in moderate enantioselectivity suggested that rein-
forcement of chirality by way of additional stereogenic
(3) Hurst, E. W. Ann. N. Y. Acad. Sci. 1962, 98, 275.
(4) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
(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) Atwal, K. S.; Swanson,
B. N.; Unger, S. E.; Floyd, D. M.; Moreland, S.; Hedberg, A.; Orreilly, B. C.
J. Med. Chem. 1991, 34, 806. (c) Dondoni, A.; Massi, A.; Sabbatini, S.
Tetrahedron Lett. 2002, 43, 5913. (d) Kappe, C. O.; Uray, G.; Roschger, P.;
Lindner, W.; Kratky, C.; Keller, W. Tetrahedron 1992, 48, 5473. (e) Sidler,
D. R.; Barta, N.; Li, W.; Hu, E.; Matty, L.; Ikemoto, N.; Campbell, J. S.;
Chartrain, M.; Gbewonyo, K.; Boyd, R.; Corley, E. G.; Ball, R. G.; Larsen,
R. D.; Reider, P. J. Can. J. Chem. 2002, 80, 646.
(6) Kappe, C. O.; Uray, G.; Roschger, P.; Lindner, W.; Kratky, C.;
Keller, W. Tetrahedron 1992, 48, 5473.
(7) (a) Xin, J. G.; Chang, L.; Hou, Z. R.; Shang, D. J.; Liu, X. H.; Feng,
X. M. Chem.;Eur. J. 2008, 14, 3177. (b) Wu, Y.-Y.; Chai, Z.; Liu, X.-Y.;
Zhao, G.; Wang, S.-W. Eur. J. Org. Chem. 2009, 904. (c) Wang, Y.; Yang, H.;
Yu, J.; Miao, Z.; Chen, R. Adv. Synth. Catal. 2009, 351, 3057. (d) Olvera,
R. D.; Demare, P.; Regla, I.; Juaristi, E. ARKIVOC 2008, 61.
(8) (a) Moorthy, J. N.; Saha, S. Eur. J. Org. Chem. 2009, 739. (b) Saha, S.;
Moorthy, J. N. Tetrahedron Lett. 2010, 51, 912. (c) Saha, S.; Seth, S.;
Moorthy, J. N. Tetrahedron Lett. 2010, 51, 5281. (d) Moorthy, J. N.; Saha,
S. Eur. J. Org. Chem. 2010, 6359.
J. Org. Chem. Vol. 76, No. 2, 2011 397

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JOCArticle
TABLE 1. Screening of the Catalysts 1-7 for the Enantioselective
Biginelli Reaction between p-Methoxybenzaldehyde, Urea, and Ethyl
Acetoacetatea
CHART 2. Structures of Catalysts Reported in the Literature
for the Enantioselective Biginelli Reaction
entry catalyst
solvent
DCM
THF
IPA
DCM
THF
IPA
acidb time (h) yield (%)c ee (%)d
1
2
3
4
5
6
7
8
1
1
1
2
2
2
3
4
TFA
TFA
TFA
p-TSA
TFA
TFA
48
48
48
48
48
48
72
48
45
58
55
66
60
62
25
58
9
5
8
9
10
12
4
THF/dioxane TFA
DCM
tartaric
acid
TFA
TFA
7
9
10
11
12
13
14
15
16
17
4
4
5
6
6
6
7
7
7
THF
IPA
48
48
72
72
72
72
72
72
72
54
40
45
48
44
60
45
38
48
6
9
mides 1-7 were synthesized starting from Cbz-protected
L-proline, which was treated with ethyl chloroformate in THF
in the presence of Et3N at 0 °C to afford the mixed anhydride.
The latter was reacted with substituted amines to yield
Cbz-protected N-aryl-L-prolinamides, the deprotection of
which under catalytic hydrogenation using 10% Pd/C led to
N-aryl-L-prolinamides 1-7 in respectable overall yields; cf.
Scheme 1. Catalyst 3 was prepared by following the literature
reported procedure.9
The catalysts 8-14 were synthesized starting from Cbz-
protected trans-4-hydroxy-L-proline following the same pro-
tocol described above in Scheme 1. The catalysts 15 and 16
were prepared starting from Boc-protected trans-4-hydroxy-
L-prolinamide. Mesylation of the Boc-protected trans-
4-hydroxy-L-prolinamide, followed by nucleophilic substitu-
tion with sodium azide, led to the azide derivative with an
inverted configuration at the C4 position. Catalytic hydro-
genation of the azide derivative yielded the corresponding
amine, which on tosylation followed by deprotection of the
Boc group, led to catalysts 15 and 16 in respectable yields.
Screening of the Enantioselective Biginelli Reaction with
Catalysts 8-16. The efficacy of catalysts 8-14 in regulating
the stereochemical outcome of the Biginelli reaction was
explored for the reaction between p-methoxybenzaldehyde,
urea, and ethyl acetoacetate in the presence of each of the
catalysts in a variety of solvents with or without additives.
The results are summarized in Table 2.
THF/dioxane TFA
14
15
14
18
12
14
15
THF TFA
dioxane TFA
THF/dioxane TFA
THF
TFA
TFA
THF/dioxane TFA
dioxane
aAll reactions were run on ca. 0.5 mmol of p-methoxybenzaldehyde at rt
(25 °C) using 2 equiv of urea, 10 equiv of ethyl acetoacetate, and 10 mol %
of catalyst. b10 mol % of additive was used; p-TSA = p-toluenesulphonic
acid. cIsolated yields based on p-methoxybenzaldehyde. dThe enantiomeric
excess was determined from chiral HPLC using an OD-H column.
centers is advantageous.7 In particular, the trans-4-hydroxy-
L-proline based catalysts by Feng et al. (Chart 2)7a as applied
to the multicomponent Biginelli reaction spurred us to de-
sign and synthesize catalysts 8-14 that contain an additional
chiral center suitably disposed at the C4 position of L-proline
with sterics built at the C2 position. Buoyed by respectable
enantioselectivities observed with catalysts 13 and 14 for the
Biginelli reaction, further improvisation was accomplished
through catalysts 15 and 16 that contain a better hydrogen
bond donating sulfonamide group. The catalyst 16 was
found to work well with uniformly high enantioselectivity
for cyclocondensation of aliphatic as well as aromatic alde-
hydes with urea and ethyl acetoacetate.
Synthesis of Catalysts 1-16. The synthetic routes for all
the catalysts 1-7 are shown in Scheme 1. All arylprolina-
SCHEME 1. Synthesis of Organocatalysts 1-16 for the Asymmetric Biginelli Reaction
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TABLE 2. Screening of the Catalysts 8-16 for the Enantioselective Biginelli Reaction between p-Methoxybenzaldehyde, Urea, and Ethyl
Acetoacetatea
entry
catalyst
solventb
acidc
time (h)
yield (%)d
ee (%)e
1
2
3
4
5
6
7
8
9
8
8
9
9
9
9
9
9
9
THF/dioxane
THF/dioxanef
THF/dioxane
THF/dioxane
THF/dioxane
DCM
p-TSA
PFBA
p-TSA
(þ)-CSA
o-NBA
PhCOOH
PhCOOH
PhCOOH
PFBA
72
72
72
72
72
72
72
72
72
72
98
98
98
72
96
72
72
72
72
72
72
96
72
72
72
72
72
72
96
98
98
72
72
72
72
88
96
88
96
40
30
46
30
58
57
65
66
62
ndh
ndh
ndh
75
50
ndh
50
70
78
30
55
60
60
82
48
84
68
90
88
97
95
30
32
65
90
65
77
76
60
95
78
95
76
99
35
trace
trace
trace
25
IPA
hexane
THF/dioxanef
IPA
DCM
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
10
10
10
10
10
11
11
11
11
11
12
12
13
13
13
13
13
13
13
14
14
14
14
14
14
14
15
15
16
16
TFA
48
trace
30
44
34
60
55
38
46
28
35
30
70
30
30
40
42
30
38
72
24
57
52
44
40
42
68
60
65
66
THF/dioxane
THF/dioxane
THF/dioxanef
IPA
THF/dioxane
CHCl3
PhCOOH
p-TSA
PFBA
TFA
p-TSA
(þ)-CSA
o-NBA
PFBA
TFA
THF/dioxane
THF/dioxanef
THF/dioxane
THF/dioxanef
THF/dioxane
THF/dioxane
THF/dioxane
THF/dioxanef
THF/dioxaneg
pet etherf
PFBA
TFA
PhCOOH
p-TSA
PFBA
PFBA
TFA
PhCOOH
TFA
PhCOOH
p-TSA
TFA
TFA
TFA
PFBA
TFA
PFBA
TFA
PFBA
DCMg
THF/dioxane
THF/dioxane
THF/dioxane
THF
DCM
IPA
THF/dioxanef
THF/dioxane
THF/dioxanef
THF/dioxane
THF/dioxanef
aAll the reactions were run on ca. 0.5 mmol of p-methoxybenzaldehyde at rt (25 °C) using 2 equiv of urea, 10 equiv of ethyl acetoacetate, and 10 mol %
of the catalyst. bTHF/dioxane (1:1). c20 mol % of acid additive was used. Abbreviations: p-TSA=p-toluenesulphonic acid, PFBA=pentafluorobenzoic
acid, TFA=trifluoroacetic acid, o-NBA =o-nitrobenzoic acid, and (þ)-CSA=(þ)-camphorsulfonic acid. dIsolated yields based on p-methoxyben-
zaldehyde. eThe enantiomeric excess was determined from chiral HPLC using an OD-H column. f20 mol % of Ph3CNH3þCF3COO-. g20 mol % of
iPrNH3þCF3COO-. hnd=not determined.
A perusal of Table 2 suggests the following:
tivity, the two catalysts were screened in a variety of solvents and
in the presence of acids such as benzoic acid, TFA, p-tol-
uenesulphonic acid and pentafluorobenzoic acid (entries 22-24
and 27-34, Table 2). Significantly high enantioselectivities were
observed for both catalysts 13 and 14 in the THF/dioxane mixture
with an additive such as tritylammonium trifluoroacetate (entries
25 and 35, Table 2); the ee’s were typically 95-97%. It should be
noted that the additive, such as iso-propylammonium trifluor-
oacetate, also exhibited a similar, but less pronounced effect
on the enantioselectivity. These catalysts were further im-
proved by increasing the acidity of the hydrogen donor at C4
by converting the hydroxy functionality in 13 and 14 to that of
p-toluenesulfonamide as in 15 and 16; cf. Chart 2.
(i) Acids such as TFA, o-nitrobenzoic acid, (þ)-camphor-
sulfonic acid, etc. afford different results (yields and ees) in
different solvent conditions.
(ii) Yields are moderate with added acids, but the enan-
tiomeric excess increases to as high as 90% with additives
such as PhCOOH (entry 23).
(iii) Addition of organic salt has a dramatic effect, as found
by Feng et al.,7a leading to ees that are pronouncedly increased
at the expense of relatively low yields, when the acid employed
is pentafluorobenzoic acid (entries 25 and 35).
On the basis of the encouraging results with catalysts 13
and 14 that lead to the DHPM in a respectable enantioselec-
The Biginelli reaction between p-methoxybenzaldeyde,
urea, and ethyl acetoacetate with catalyst 16, under identical
(9) Dahlin, N.; Bogevig, A.; Adolfsson, H. Adv. Synth. Catal. 2004, 346, 1101.
J. Org. Chem. Vol. 76, No. 2, 2011 399

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TABLE 3. Results of the Enantioselective Biginelli Reaction Using Catalyst 16a
aAll the reactions were run on ca. 0.5 mmol of the aldehyde at rt (25 °C) using 2 equiv of urea, 10 equiv of ethyl acetoacetate, 10 mol % of the catalyst
16, 20 mol % of PFBA, and 20 mol % of Ph3CNH3þCF3COO-. bIsolated yields based on aldehyde.
conditions as those employed for 13 and 14, i.e., with penta-
fluorobenzoic acid and tritylammonium trifluoroacetate as an
additive, led to the DHPM with an optical purity of 99% and in
a respectable isolated yield of 66% (entry 39, Table 2). It is
noteworthy that the catalysts 15 and 16 exhibited better
solubility than 13 and 14 in the THF/dioxane (1:1) mixture.
Enantioselective Biginelli Reactions of Diverse Aldehydes
with Catalyst 16. With the conditions established above, the
Biginelli reactions of a variety of aromatic as well as aliphatic
aldehydes with urea and ethyl acetoacetate were investigated
with the catalyst 16 specifically. The results of enantioselective
multicomponent Biginelli condensation reactions are collected
in Table 3. As can be readily seen, the reaction works very
well with almost all aliphatic and aromatic aldehydes, yielding
chiral DHPMs in respectable yields (44-68%), but in a
remarkably high enantioselectivity (94-99%).
in Table 3 are in the range of 94-99% regardless of the
nature of the aldehyde. Aliphatic aldehydes such as isobu-
tyraldehyde and cyclohexanecarbaldehyde also afforded the
DHPMs in moderate yields, but in high enantioselectivities
(entries 16 and 17, Table 3). Clearly, the nature of the aldehyde,
i.e., aromatic/aliphatic, has no discernible influence on the
stereoselectivity of the reaction other than that of the reaction
yield. The enantioselectivity in all cases was determined by
chiral HPLC analysis using an OD-H column. The stereo-
chemistry in the products was assigned “R” based on com-
parison of the HPLC profiles reported in the literature,7
which was also complemented by optical rotation values.
Mechanistic Considerations. Although the catalyst 16 seem-
ingly constitutes a modification of the catalysts reported by
Feng and co-workers,7a it works remarkably well with high
enantioselectivities for the diverse carbonyl compounds in-
vestigated. Indeed, the uniformly high ees observed with
In general, e-rich aldehydes were found to afford DHPMs
in a relatively higher yield (60-66%, entries 1-6, Table 3)
than the e-poor aldehydes (44-54%, entries 10-14, Table 3).
The enantioselectivities observed for the DHPMs collected
(10) Chen, X.-H.; Xu, X.-Y.; Liu, H.; Cun, L.-F.; Gong, L.-Z. J. Am.
Chem. Soc. 2006, 128, 14802.
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FIGURE 1. Mechanism of the Biginelli reaction and the plausible transition-state structures responsible for enantioselectivity with both trans
(left) and cis (right) configured catalysts 14 and 16, respectively.
catalyst 16 for aliphatic as well as aromatic aldehydes are not
replicated with any other catalyst type reported thus far for
the asymmetric Biginelli reaction.2e,f,10 Indeed, the enantio-
selectivities observed with catalyst 16 in the present investi-
gation constitute the best so far for Biginelli reactions
mediated by organocatalysts based on enamine chemistry.
What is the role of tritylammonium trifluoracetate? We
believe that the trifluoroacetate salt of the trityl amine
somehow constricts the chiral environment of the developing
transition state. The role of the acid additive, i.e., pentafluo-
robenzoic acid, is likely to be in the early stages in catalyzing
the imine formation between aldehyde and urea as well as in
the enamine formation between catalyst and ethyl acetoace-
tate (Figure 1). Given the observation in the screening studies
that strong acids such as TFA enhance the reaction rate, but
depreciate the enantioselectivity of the Biginelli reaction
product (Tables 1 and 2), it is also likely that the added
trifluoroacetate salt of the trityl amine also acts as a buffer in
controlling the acidity of the medium.
Wang et al. reported that proline-derived catalysts with a
binding group at C4 in a trans orientation with respect to the
group at C2 performs better from the point of view of
enantioselectivity as compared with the cis isomer.7b Our
results reveal no such dependence of the stereochemical
outcome on the disposition of the group at the C4 position
(entries 35 and 39, Table 2). In other words, the configura-
tional inversion at the C4 position in going from catalysts 13/
14 to those of the sulfonamides 15/16 has no influence on the
stereochemical outcome in the product. A perusal of the
results in Table 2 on a broad spectrum of catalysts is quite
instructive: (i) the fact that one observes a significant rise in
ees with catalysts 8-14 (Table 2) as compared with those
with 1-7 (Table 1) suggests that the reinforced chirality at
C4 is important, and (ii) a comparison of the results with
catalyst 11 (entries 16 and 19, Table 2) with those of 13 and 14
(entries 24, 25, 31, and 35) shows that enhanced acidity of the
prolinamide NH at C2 is less important. Rather, sterics as in
13 and 14 improve the enanatioselectivity; enhanced acidity
at C4, however, has a pronounced effect on the optical yields,
as suggested from a comparison of the results with catalysts
13/14 (entries 22 and 29, Table 2) and 15/16 (entries 36 and
38). Thus, one may conclude that sterics at the C2 carbox-
amide, reinforced chirality, and enhanced acidity for hydro-
gen bonding at the C4 substituent are important for high
optical yields in the Biginelli cyclocondensation. In light of
these considerations, let us now consider how the cis and
trans relationship between the substitutuents at C2 and C4
lead to the products of the same configuration.
In Figure 1 is shown the overall mechanism of the Biginelli
reaction.7a-c The crucial step responsible for stereoinduction
constitutes the attack of the (E)-enamino-ester derived from
proline and the β-ketoester on to the re-face of the imino-
amide formed between the carbonyl compound and urea.
The plausible transition states for organocatalysis with
catalysts 13/14 (trans relationship between C2 and C4
substituents) and 15/16 (cis relationship between C2 and
C4 substituents) are shown separately in Figure 1; the enamine
nitrogen is considered to be sp2-hybridized due to possible
conjugation. As mentioned earlier, hydrogen bonding via the
substituent at the C4 position, i.e., OH or NHTs, crucially
controls the optical yield. Thus, the imino-amide is likely to
be attacked at the bottom and top faces of the enamines
J. Org. Chem. Vol. 76, No. 2, 2011 401

Saha and Moorthy
JOCArticle
formed with the catalysts 13/14 and 15/16, respectively as
shown in Figure 1. In the case of 13/14, the role of the
sterically bulky substituent at C2 appears to merely block the
approach of the imino-amide from the top face. In contrast,
it is likely that it constricts the transition state through sterics
in the case of 15/16. In the case of the latter, the transition
state may be further stabilized via hydrogen-bonding inter-
actions, as shown in the Figure 1.
6 h. Subsequently, it was quenched with addition of water and
extracted with CHCl3, dried, and concentrated to obtain the crude
product, which was further purified by a short pad silica gel column
chromatography to obtain the Boc-protected tosyl amide (1.1 g,
85% yield).
The Boc amide (1.0 g, 1.8 mmol) obtained from the above
step, was dissolved in 20 mL of dry DCM and cooled to 0 °C.
TFA (5.0 mL) was slowly added to this solution at 0 °C and
stirred for 3 h at room temperature. The reaction mixture was
evaporated in vacuo and washed thoroughly with petroleum ether.
The oil was dissolved in a minimum amount of water and basified
with NH4OH, extracted with chloroform, washed thoroughly
with water, dried over anhyd Na2SO4, and concentrated to
obtain the pure (2S,4R)-4-tosylamido-N-(2,4,6-triethylphenyl)-
pyrrolidine-2-carboxamide, 15 (0.76 g, 94% yield).
Conclusions
From a systematic investigation involving the synthesis of
a series of catalysts and screening studies, the catalyst 16,
which is sterically hindered, yet contains a strong hydrogen-
bonding site, is shown to promote the Biginelli cycloconden-
sation of ethyl acetoacetate with aromatic as well as aliphatic
aldehydes and urea in a high enantioselectivity. The remark-
able ees observed in these reactions demonstrate the fact
that chiral prolinamides with reinforced chirality and enhanced
hydrogen acidity at the C4 position and sterics built at the C2
position are excellent organocatalysts in asymmetric synthesis.
The novel prolinamide catalyst 16 and analogous compounds
with readily tunable sterics and hydrogen-bonding attributes
are likely to further expand the scope of various other
organocatalytic reactions.
A similar procedure was followed for the preparation of
(2S,4R)-4-hydroxy-N-(2,4,6-triphenylbenzene)pyrrolidine-2-carbox-
amide, 16.
(2S,4R)-4-Tosylamido-N-(2,4,6-triethylphenyl)pyrrolidine-2-
carboxamide, 15: yield 65%; mp 120 °C; [R]27D=-4.0° (c=0.5,
EtOH); IR (KBr) cm-1 1160, 1329, 1660, 2965, 3273; 1H NMR
(CDCl3, 500 MHz) δ 1.10 (t, 6H, J=7.3 Hz), 1.20 (t, 3H, J=
7.3 Hz), 1.78-1.82 (m, 1H), 2.34-2.42 (m, 1H), 2.40 (s, 3H),
2.48 (q, 4H, J=7.3 Hz), 2.58 (q, 2H, J=7.3 Hz), 2.83-2.89 (m,
1H), 3.19-3.22 (m, 1H), 3.72-3.75 (m, 1H), 3.93-3.94 (m, 1H),
6.90 (s, 2H), 7.26 (d, 2H, J=9.2 Hz), 7.71 (d, 2H, J = 8.2 Hz),
8.80 (s, 1H); 13C NMR (CDCl3, 125 MHz) δ 14.5, 15.5, 21.5,
24.9, 28.6, 36.7, 53.1, 54.2, 59.5, 125.8, 127.0, 129.5, 129.8, 137.3,
140.8, 143.5, 143.7, 172.6; ESI-MSþ m/z calcd for C24H33N3O3S
444.2320 [M þ H], found 444.2321.
Experimental Section
Preparation of Catalysts 15 and 16. The Boc-protected (2S,4R)-
4-hydroxy-N-(2,4,6-triethylphenyl)-pyrrolidine-2-carboxamide
(4.0 g, 10.2 mmol) was dissolved in dry DCM and cooled to 0 °C,
and Et3N (1.2 g, 12.2 mmol) was added. The reaction mixture was
then stirred for 15 min, and methanesulphonyl chloride (1.4 g, 12.2
mmol) was added dropwise. The reaction mixture was then stirred
at rt for 16 h and then quenched with the addition of water. The
organic matter was and extracted with CHCl3, washed with brine,
dried, and concentrated to obtain the product (4.4 g, 92%), which
was used as such for the next step.
The mesylate (4.4 g, 9.4 mmol) obtained from the above
reaction was dissolved in 15 mL of dry DMF, and sodium azide
(1.2 g, 18.8 mmol) was added under a N2 atmosphere. The
reaction mixture was heated at 65-70 °C for 16 h. The reaction
mixture was cooled and the solvent evaporated under reduced
pressure. The residue was extracted with CHCl3, dried, and
concentrated to obtain the crude product, which was finally
purified by a short pad column chromatography to obtain the
azide (3.5 g, 90%).
To the solution of the azide derivative (3.0 g, 7.2 mmol),
obtained from the above step, in 25 mL of MeOH was added a
catalytic amount of 10% Pd/C. The container was evacuated by
applying vacuum and filled subsequently with a H2 gas. The
reaction mixture was stirred at room temperature for 6 h and
was filtered through a Celite pad. The residue obtained, after
removing the solvent in vacuo, was purified by a silica gel column
chromatography to afford the desired amine (2.7 g, 98% yield).
The amine (2.5 g, 6.4 mmol) thus obtained from the above
step was dissolved in 25 mL of dry DCM. The reaction mixture
was cooled to 0 °C, and Et3N (0.77 g, 7.6 mmol) was added,
followed by p-toluenesulphonyl chloride (1.4 g, 7.6 mmol). The
reaction mixture was stirred at 0 °C for 30 min and then at rt for
(2S,4R)-4-Tosylamido-N-(2,4,6-triphenylbenzene)pyrrolidine-
2-carboxamide, 16: yield 60%; mp 178-180 °C; [R]27D=-12.8°
(c=0.08, EtOH); IR (KBr) cm-1 1158, 1327, 1493, 1674, 3304,
3505; 1H NMR (CDCl3, 500 MHz) δ 2.00-2.06 (m, 1H), 2.16-
2.19 (m, 1H), 2.41 (s, 3H), 2.89 (dd, 1H, J1=11.4 Hz, J2=6.5 Hz),
3.34 (dd, 1H, J1=9.2 Hz, J2=6.5 Hz), 3.48-3.52 (m, 1H), 4.12
(d, 1H, J=6.1 Hz), 7.24-7.72 (m, 21 H), 8.69 (s, 1H); 13C NMR
(CDCl3, 125 MHz) δ 21.6, 27.0, 36.0, 52.7, 54.1, 59.2, 127.0, 127.3,
127.5, 127.7, 128.3, 128.6, 128.9, 129.1, 129.9, 130.3, 140.0, 140.2,
140.5, 141.3, 143.7, 172.8; ESI-MSþ m/z calcd for C36H33N3O3S
588.2320 [M þ H], found 588.2325.
Typical Procedure for the Enantioselective Biginelli Reaction
Using Catalyst 16. A mixture of p-methoxybenzaldehyde (0.1 g,
0.73 mmol), urea (0.86 g, 1.46 mmol), pentafluorobenzoic acid
(0.03 g, 0.14 mmol), and Ph3CNH3þCF3COO- (0.05 g, 0.14
mmol) in 0.8 mL of THF/dioxane (1:1) was stirred in a small
round-bottom flask at rt for 45 min. Subsequently, the catalyst
16 (0.04 g, 0.07 mmol) was added, followed by ethyl acetoacetate
(0.95 g, 7.3 mmol). The reaction mixture was stirred for 96 h. A
white solid that formed was filtered, washed with chilled EtOAc,
and dried to obtain 5-ethoxycarbonyl-6-methyl-4-(4-methoxy-
phenyl)-3,4-dihydropyrimidin-2(1H)-one.
Acknowledgment. J.N.M. is thankful to DST, India, for
funding through the Ramanna fellowship, and S.S. is grate-
ful to CSIR, India, for a senior research fellowship.
Supporting Information Available: Synthesis and character-
ization data of all the catalysts and HPLC profiles for the
products of organocatalytic reactions. This material is available
free of charge via the Internet at http://pubs.acs.org.
402 J. Org. Chem. Vol. 76, No. 2, 2011