Highly diastereo- And enantioselective aldol reactions in common organic solvents using N-arylprolinamides as organocatalysts with enhanced acidity

Article abstract of DOI:10.1002/ejoc.200800960

A broad set of N-arylprolinamides 1-8 with increasing NH acidity and steric crowding has been synthesized and its catalytic activity explored for enantioselective aldol reactions. In DMF containing 10 mol-% of TFA, all arylamides are found to catalyze the reaction between cyclohexanone and a variety of electrophilic aldehydes leading to aldols in excess of 90% yield and >95 % enantioselectivity. The per-fluorophenyl catalyst 8 is found to perform best with a broad substrate scope as compared to all other N-arylamides 1-7. It is shown that 8 can indeed be employed in highly nonpolar as well as polar solvents including brine to afford high yields of aldols with excellent diastereo- as well as enantio-selectivity. The results observed for 8 are amongst the best reported so far for prolinamides that do not contain additional stereogenic center(s) and hydrogen-bonding site(s). The molecular structures of 7 and 8, determined by X-ray crystallography and presumed to reflect the most stable conformations, reveal a notable difference in the conformations of the N-aryl rings; the aryl ring exhibits tendency to lie coplanar with the amide functionality in the case of 7, while the per- fluorophenyl ring twists almost orthogonally with respect to the plane of the amide of functionality in 8. The superior performance of the latter is attributed to, in addition to the enhanced NH acidity, the tendency of the perfluorophenyl ring to lie orthogonally to the amide group, which may facilitate a stronger binding of the electrophilic aldehyde via hydrogen bonding in the transition state.

Full text of DOI:10.1002/ejoc.200800960

FULL PAPER
DOI: 10.1002/ejoc.200800960
Highly Diastereo- and Enantioselective Aldol Reactions in Common Organic
Solvents Using N-Arylprolinamides as Organocatalysts with Enhanced Acidity
Jarugu Narasimha Moorthy*[a] and Satyajit Saha[a]
Keywords: Asymmetric synthesis / Aldol reactions / Organocatalysis / Proline / Amides / C–C bond formation
A broad set of N-arylprolinamides 1–8 with increasing NH
acidity and steric crowding has been synthesized and its
catalytic activity explored for enantioselective aldol reac-
tions. In DMF containing 10 mol-% of TFA, all arylamides
are found to catalyze the reaction between cyclohexanone
and a variety of electrophilic aldehydes leading to aldols in
excess of 90% yield and Ͼ95% enantioselectivity. The per-
fluorophenyl catalyst 8 is found to perform best with a broad
substrate scope as compared to all other N-arylamides 1–7.
It is shown that 8 can indeed be employed in highly nonpolar
as well as polar solvents including brine to afford high yields
of aldols with excellent diastereo- as well as enantio-
selectivity. The results observed for 8 are amongst the best
reported so far for prolinamides that do not contain additional
stereogenic center(s) and hydrogen-bonding site(s). The mo-
lecular structures of 7 and 8, determined by X-ray crystal-
lography and presumed to reflect the most stable conforma-
tions, reveal a notable difference in the conformations of the
N-aryl rings; the aryl ring exhibits tendency to lie coplanar
with the amide functionality in the case of 7, while the per-
fluorophenyl ring twists almost orthogonally with respect to
the plane of the amide of functionality in 8. The superior per-
formance of the latter is attributed to, in addition to the en-
hanced NH acidity, the tendency of the perfluorophenyl ring
to lie orthogonally to the amide group, which may facilitate
a stronger binding of the electrophilic aldehyde via hydrogen
bonding in the transition state.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
that function based on the principle of the so-called “en-
amine catalysis” have been reported.[5] Although the acidic
proton of the carboxylic group of proline is responsible for
enantioselectivity in aldol reactions, it is sufficiently clear
that the carboxylic acid group is not indispensable for catal-
ysis. A variety of pyrrolidine-based organocatalysts that are
devoid of carboxyl groups have been designed and shown
to be efficient.[6] The underpinning requirement in these cat-
alysts is that they must possess functional groups or molec-
ular moieties,[1] which may involve in hydrogen bonding in-
teractions.[7] Of course, highly acidic hydrogen atoms,[8] ad-
ditional hydrogen bonding sites[9] and additional stereo-
genic centres[10] contribute to high differentiation in the dia-
stereomeric transition states.
In the course of our studies on hydrogen bond-mediated
molecular self-assembly and hydrogen bond-controlled
photochemical Norrish Type II processes,[11] our interest
was drawn toward exploiting hydrogen bonding in organo-
catalysis. With organocatalytic enantioselective photochem-
ical reactions as our primary goal, we designed a broad
set of N-aryl--prolinamides with graded NH acidity and
varying magnitudes of steric crowding around the amide
functionality. The initial studies by Gong et al.[12] on enan-
tioselective aldol reactions using N-arylprolinamides as or-
ganocatalysts prompted us to examine the extent to which
the various catalysts in Figure 1 catalyze the aldol reaction
enantioselectively. Motivations for these investigations
were:
There is a growing interest at the current time in organo-
catalytic reactions to accomplish enantioselective C–C
bond forming reactions,[1] as the environmentally-benign
organocatalysts obviate the use of copious amounts of or-
ganometallic hazardous and scarce counterparts. A wide
variety of catalysts are constantly being developed to pro-
vide a facile and atom economic access to optically pure
compounds.[2] Insofar as the C–C bond forming enantiose-
lective reactions are concerned, asymmetric aldol reaction
holds a special significance from the following points of
view: i) the reaction may be catalyzed by a base as well as
an acid, ii) it affords 1,3-dioxygenated products, which may
be further structurally elaborated, and iii) the reaction of-
fers a challenge, with appropriate reaction partners, to con-
trol diastereochemistry as well as enantioselectivity at the
same time.[3] Not surprisingly, this reaction constitutes one
of the immensely investigated amongst C–C bond forming
reactions in the realm of organocatalysis. Since the pioneer-
ing work of List et al.,[4] who demonstrated the use of -
proline in catalyzing the direct aldol reaction of p-ni-
trobenzaldehyde with acetone, a number of organocatalysts
[a] Department of Chemistry, Indian Institute of Technology,
Kanpur 208016, India
E-mail: moorthy@iitk.ac.in
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 739–748
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. N. Moorthy, S. Saha
FULL PAPER
stereo- and enantioselectivity (Ͼ96%) and in significantly
reduced reaction times (20–36 h); the enhancement of
amide NH acidity and careful screening of reaction condi-
tions are the basis for observed stereoselectivities.
Results and Discussion
Synthesis of N-Aryl-L-prolinamides 1–8
All arylprolinamides 1–8 were synthesized starting from
Boc-protected -proline, which was treated with ethyl chlo-
roformate in THF in the presence of Et3N at 0 °C to afford
the mixed anhydride (Scheme 1). The latter was treated with
substituted amines to afford Boc-protected N-aryl--prolin-
amides, the deprotection of which under standard condi-
tions involving 30% TFA in DCM at 0 °C led to N-aryl--
prolinamides 1–8 in respectable overall yields.
Figure 1. Structures of various prolinamides 1–8 examined for
enantioselective aldol reactions.
(i) The enantioselectivities observed by Gong et al.[12] are
not significantly high with simple prolinamides, e.g., ee ca.
50% for the aldol product of p-nitrobenzaldehyde and ace-
tone, which leaves ample scope for further improvement.
Screening of the Catalytic Activity of N-Arylamides in
Various Solvents
To establish the solvent and temperature conditions that
(ii) Very simple proline derivatives are rarely reported to promote the reactivity as well high enantioselection, the ar-
yield aldol products with high (Ͼ90%) enantioselectivity as ylamide 6 with a moderate steric influence as well as acidity
well as diastereoselectivity.[13] It is the bifunctional proline was considered as a representative case. The catalytic reac-
derivatives or those that contain additional stereogenic tivity of 6 was examined for the aldol reaction between p-
centre(s) that are often found to catalyze aldol reactions nitrobenzaldehyde and cyclohexanone in a variety of sol-
leading to products with enantioselectivity in excess of vents with or without an additive as shown in Table 1. In a
95%.[14] Thus, the catalytic activity of simple proline deriva- typical experiment, 0.3–0.4 mmol of p-nitrobenzaldehyde
tives was deemed still underexplored.
was treated with cyclohexanone in the presence of 20 mol-
(iii) The aryl rings of N-aryl--prolinamides could be an- % of the catalyst. After monitoring the reaction at various
ticipated in some way to interfere with the diastereomeric temperatures, 3Ϯ1 °C was uniformly maintained for the re-
transition states of the aldol reaction such that it manifests action in various solvents and/or additives as shown in
in enantio- as well as diastereocontrol.
Table 1. The progress of reaction in each case was moni-
Herein, we report facile synthesis of N-aryl--prolin- tored by TLC as well as HPLC analyses.
amides 1–8 and results of enantioselective aldol reactions
A perusal of the results in Table 1 shows that the reaction
catalyzed by them. It is shown that all arylamides 1–8 enan- occurs in a variety of solvents, but faster in DMF contain-
tioselectively catalyze the aldol reactions. In particular, the ing 10 mol-% of TFA; in the latter, the reaction also leads
reactions proceed with catalyst 8 in a variety of common to a high enantioselectivity. The aldol product was isolated,
organic solvents to afford aldol products in a high dia- after 36 h, in Ͼ90% yield with the anti product being
Scheme 1.
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Selective Aldol Reactions in Common Organic Solvents
formed in ca. 96% ee (entry 9); although similar enantio- aldehyde and 20 equiv. of cyclohexanone in DMF. Subse-
selectivity was observed in THF and dioxane, the reaction quent to a routine work-up, the crude product was analyzed
1
times were found to be much longer. Surprisingly, the reac- by H NMR analysis. For analysis of the enantiomeric ex-
tion was found to be slower with 20 mol-% TFA in DMF cess, the crude product was rapidly filtered through a short
in addition to the fact that the enantioselectivity was com- pad of silica gel and the product mixture was submitted to
parably lower (entry 8). This critical dependence of reaction HPLC. Thus, the diastereomeric ratio (anti/syn) and ee (for
as well as enantioselectivity on the mol-% of TFA employed the major diastereomer) in each case were determined by
is quite inexplicable. What is otherwise noteworthy is that 1H NMR (see Supporting Information) and HPLC analy-
the catalyst works in a variety of solvents and solvent com- ses, respectively. The values given in Table 2 are based on
binations, with the exception of DMF/H2O (entry 14), lead- two or more independent determinations. As can be seen
ing to the aldol product with Ն 80% ee for the anti dia- from Table 2, the aldol product was obtained in 75% yield
stereomer. Although high diastereo- and enantioselectivities with an ee of 77% for N-phenylprolinamide 1 (entry 1,
were observed in dioxane and THF solvents, the reaction Table 2). The reaction progressed sluggishly with the steri-
times were much longer (entries 5 and 10, Table 1). Thus, cally hindered 2,6-dimethylphenylprolinamide 2 leading to
the solvent-additive combination involving DMF-TFA a mere 20% yield of the product (entry 2). Otherwise, all
(10 mol-%) was considered singularly exceptional for exam- other catalysts, i.e., p-(nitrophenyl)prolinamide 3, m-(ni-
ining the organocatalytic activity of all other N-arylprolin- trophenyl)prolinamide 5, 3,5-dinitrophenylprolinamide 7,
amides in Figure 1 for performing aldol reactions.
N-(perfluorophenyl)prolinamide 8 and sterically hindered
2,6-dimethyl-4-nitrophenylprolinamide 4 were found to cat-
alyze the reaction and afford the aldols in 95–97% ee (en-
tries 3–8). A comparison of the results with catalyst 1, 2
and 4 clearly shows that steric hindrance retards the reac-
tion, while enhancement of the acidity through substitution
of nitro group(s) overrides the steric factor. A similar sce-
nario was uniformly observed for the reaction of cyclohexa-
none in the presence of catalysts 3–8 with a variety of alde-
hydes that include m- and o-nitrobenzaldehydes, m-chloro-
benzaldehyde, p-bromobenzaldehyde, p-fluorobenzaldehyde
and p-(trifluoromethyl)benzaldehyde (entries 9–20 and SI);
in view of better results with 7 and 8 only the results for
these catalysts are shown in Table 2. With the exception of
p-bromo and p-fluorobenzaldehydes, the yields of aldols in
all cases were in excess of ca. 72%; for bromo- and fluoro-
benzaldehydes, the isolated yields were in the range of 40–
64% (entries 15–18). Remarkably, the enantioselectivity for
most cases was found to be Ͼ95%. In particular, with (3,5-
dinitrophenyl)- (7) and (perfluorophenyl)prolinamide (8)
catalysts, both diastereo- and enantioselectivities (Ͼ95%)
were found to be higher for all aldols of cyclohexanones
with diverse aldehydes. Indeed, 7 and 8 were found to cata-
lyze the reactions of cyclohexanone with heteroaromatic al-
dehydes, viz., pyridine-3-carboxaldehyde and pyridine-4-
carboxaldehyde, quite rapidly leading to the formation of
aldols in 70–90% isolated yields within 3–4 h; of course, the
enantioselectivity in each case was found to be in excess of
Ͼ85% (entries 21–24).
Table 1. Results of N-arylprolinamide 6-catalyzed aldol reaction
between cyclohexanone and p-nitrobenzaldehyde in various sol-
vents with/without an additive.[a]
Entry
Solvent
Additive
Time Yield dr[b]
[h]
ee
[%] [anti/syn] [%][c]
1
2
3
4
5
6
7
8
9
10
none
H2O
–
–
–
–
–
–
–
74
76
76
76
76
76
74
74
36
76
94
85
70
70
62
68
62
71
92
75
82:18
80:20
90:10
84:16
97:3
90:10
82:18
87:13
97:3
87
87
92
85
93
83
87
90
96
93
DCM
DMSO
dioxane
toluene
DMF
DMF
DMF
THF
TFA(20 mol-%)[d]
TFA(10 mol-%)[d]
–
96:4
PhCOOH (10%)
11
12
13
14
DCM
76
76
76
76
90
87
84
90
85:15
68:32
84:16
84:16
83
79
80
67
[d]
DME
2-propa-
nol
–
–
DMF
H2O[e]
[a] The reactions in all solvents were run under identical conditions
by employing 20 mol-% of the catalyst 6 (relative to the aldehyde).
The reactions were run on 0.3–0.4 mmol of p-nitrobenzaldehyde,
and the reaction temperature was maintained at 3Ϯ1 °C. [b] From
400-MHz 1H NMR spectroscopy. [c] Based on chiral HPLC analy-
ses for the major diastereomer. [d] Based on p-nitrobenzaldehyde.
[e] DMF/H2O = 1:1.
The reaction of cyclopentanone with p-nitrobenzalde-
hyde in the presence of catalysts 1–8 over a period of 36 h,
under similar conditions as described above, led to compar-
atively lower yields of aldols. As for cyclohexanone, a high
enantioselectivity was observed with the perfluorophen-
ylprolinamide 8 (entry 26). A similar trend was observed
for the reaction of cyclopentanone with m-nitrobenzalde-
Results of Enantioselective Aldol Reactions Catalyzed by
N-Arylamides 1–8
To begin with, the reaction between cyclohexanone and hyde as well (entries 27 and 28).
p-nitrobenzaldehyde with N-arylprolinamides 1–8 was ex-
The encouraging results described above for the aldol re-
amined with 20 mol-% of the catalyst in DMF/TFA action of cyclopentanone and cyclohexanone spurred us to
(10 mol-%) at 3Ϯ1 °C. Typically, the reactions were con- test the catalytic activity of 3–8 in mediating the aldol reac-
ducted for 36 h by employing ca. 0.5 mmol of p-nitrobenz- tion between acyclic acetone and p- and m-nitrobenzalde-
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J. N. Moorthy, S. Saha
FULL PAPER
Table 2. Results of enantio- and diastereoselective aldol reactions catalyzed by N-arylprolinamides 1–8 in DMF containing 10 mol-% of
TFA.[a]
[a] All reactions were run on a 0.5–0.7 mmol scale with 20 mol-% of the catalyst in 0.8–1.5 mL of DMF containing 10 mol-% of TFA.
The temperature was uniformly maintained at 3Ϯ1 °C. [b] The diastereomeric ratios were calculated based on integrations of the diagnos-
tic signals of the syn and anti diastereomers in the 1H NMR spectra of the crude reaction mixture. [c] The ee values were calculated from
HPLC profiles of the reaction mixtures, see text; the ee values reported are for the major enantiomer.
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Selective Aldol Reactions in Common Organic Solvents
hydes. Under similar reaction conditions, i.e., DMF-TFA for 36 and 20 h, respectively, Table 3; it should be noted
(10 mol-%) at 3Ϯ1 °C and 20 mol-% of catalyst loading, that TFA as an additive was mandatory, lest the reactions
the aldols were obtained in 68–80% isolated yields (entries were found to occur slowly. The results collected in Table 3
29–35). With the exception of catalyst 8, the ee values for show that the catalyst works in all solvents, but in varying
all other catalysts, i.e., 3–7, were found to be 71–73%. The isolated yields of the products and enantio- and diastereo-
fact that the enantioselectivity does not vary significantly selectivities. In particular, the aldols were isolated in Ͼ95%
in spite of varying magnitudes of steric factors associated
with 3–6 indicates that NH acidity plays a pivotal role. For
catalyst 8, a remarkably high enantioselectivity was ob-
Table 3. Results of N-(perfluorophenyl)prolinamide-catalyzed aldol
served (entry 35). While further enhancement of acidity is
definitely one reason for the increase in enantioselectivity,
the conformational factors associated with the perfluo-
rophenyl ring in 8 vis-à-vis nitro-substituted phenyl rings in
3–7 may also contribute to the observed difference in the
enantioselectivities, vide infra. Similar to the reaction of
acetone with p-nitrobenzaldehdye, a high enantioselectivity
was observed in the presence of 8, for the reaction with m-
nitrobenzaldehyde as well (entry 36).[15]
reaction between cyclohexanone and p-nitrobenzaldehyde in vari-
ous solvents.[a]
Entry
Solvent
Temp. Time
Yield
[%][d]
dr[b]
ee
[°C]
[h]
[%][c]
1
2
3
4
5
6
7
8
cyclohexane
3
22
3
22
22
3
36
22
36
22
22
20
20
20
22
24
40
22
40
22
88
95
86
92
88
76
79
75
97
96
72
82
80
95
98:2
95:5
98:2
93:7
95:5
98:2
98:2
99:1
99:1
96:4
99:1
95:5
98:2
95:5
95
94
95
93
93
93
96
97
96
94
95
96
94
93
dichloromethane
acetonitrile
toluene
water
3
3
brine
9
22
33
3
22
3
N-(Perfluorophenyl)prolinamide Reactions in Nonpolar as
well as Polar Solvents
10
11
12
13
14
methanol
We were encouraged by the high diastereo- and enantio-
differentiation observed with perfluorophenylprolinamide 8
to explore its potential in common organic solvents. Thus,
the catalytic behavior of 8 was examined for the reaction of
cyclohexanone and p-nitrobenzaldehyde in diverse solvents
that include nonpolar hexane/toluene, polar aprotic aceto-
nitrile and polar protic solvents such as methanol, water,
ethyl formate
22
[a] The reactions in all solvents were run under identical conditions
by employing 20 mol-% of the catalyst 8 (relative to the aldehyde)
with 10 mol-% TFA as an additive. The reactions were run on
0.4 mmol of p-nitrobenzaldehyde at the temperature shown. [b]
anti/syn was determined by 400-MHz 1H NMR spectroscopy. [c]
Based on HPLC analyses using chiral column; the ee values are for
etc. at two different temperatures, i.e., 3Ϯ1 and 22Ϯ1 °C, the major enantiomer. [d] Isolated yields of both diastereomers.
Table 4. Results of aldol reactions catalyzed by N-(perfluorophenyl)prolinamide 8 at room temp. (22Ϯ1 °C) in cyclohexane and brine.[a]
[a] The reactions were run under identical conditions on 0.4 mmol of the aldehyde by employing 20 mol-% of the catalyst 8 (relative to
1
the aldehyde) and10 mol-% TFA as an additive. [b] Isolated yields of both diastereomers. [c] anti/syn was determined by 400 MHz H
NMR spectroscopy. [d] Based on HPLC analyses using chiral AD-H column; the ee values are for the major enantiomer. [e] At 3Ϯ1 °C.
For reactions at 22Ϯ1 °C, poor yield was due to the formation of elimination product at the employed conditions of the reaction.
Eur. J. Org. Chem. 2009, 739–748
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J. N. Moorthy, S. Saha
FULL PAPER
within 20 h in cyclohexane and brine at 22 °C (entries 2, 9 amide moiety (–CONH–) moiety in the case of 7 (6.58°),
and 10); it should be noted that the reaction in brine was while the perfluorophenyl ring is twisted by ca. 76.15° in 8.
biphasic.[16] The loss of enantio- and diastereoselectivity Except for this feature, all other geometrical parameters are
was found to be only marginal for a considerable reduction unexceptional. Given that fluorine is isosteric with hydro-
in the duration of the reaction. Hence, the aldol reactions gen,[17] it is intriguing that the conformation of perfluo-
of a select few ketones and aldehydes were conducted at rophenyl ring in 8 differs so drastically as compared to the
room temp. (22Ϯ1 °C) with 20 mol-% of 8 and 10 mol-% conformation of 3,5-dinitrophenyl ring in 7.
of TFA in cyclohexane and brine, cf. Table 4.
The aldol products of the reaction of cyclohexanone with
m- and p-nitrobenzaldehydes were obtained in Ͼ95% iso-
Mechanistic Rationalization of Enantioselectivity
lated yields in 20 h with impressive optical purities (entries
As mentioned at the outset, Gong et al. first showed that
1–4, Table 4). Even for a poor substrate such as p-fluoro- the stereoselectivity in aldol reactions increases as the elec-
benzaldehyde, the aldol product was obtained in 74% iso- tron-withdrawing nature of the substituent in N-arylprolin-
lated yield with Ͼ94% ee in both cyclohexane and brine amide increases.[12] They also showed that prolinamide de-
(entries 5 and 6, Table 4). Under the employed conditions rivatives that contain additional stereogenic centre(s) and
of the reaction, the reaction of acetone with p-nitrobenzal- hydrogen bonding site(s) lead to a very high stereocontrol
dehyde was found to lead to significant amounts of elimi- in aldol reactions.[12] Subsequent to these findings, simple
nation product (entries 7 and 8). The aldol was obtained in N-arylprolinamides have been further modified and their
ca. 40–45% yield in both cyclohexane and brine with ca. catalytic activity has been explored in aldol reactions.[8]
76–79% ee; indeed, no respectable improvement was ob- While our investigations with N-arylamides were in pro-
served when the reactions were run for the two solvents at gress, Shirai et al. reported N-arylamides as organocatalysts
3 °C (entries 7 and 8). Clearly, the novelty of catalyst 8 is with enhanced acidity for enantioselective aldol reac-
evident from its enhanced reactivity as well as solubility in tions.[18] Indeed, Shirai et al. also examined the catalytic
a range of solvents; while the former facilitates occurrence behavior of catalysts 3 and 8 in addition to 2,4,6-trinitro
of reactions rapidly at room temp., the latter renders, in derivative of 1.[18] However, we note that the results re-
appropriate solvents, the work-up quite simple.
ported by them suffer from several drawbacks. First of all,
the solvent employed for demonstrating high stereocontrol
is hazardous HMPA. Second, the reaction durations are
considerably longer, Ͼ90 h. Third, their investigations are
limited to branched acyclic ketones, and broad substrate
scope was not illustrated. Finally, the potential of N-(per-
fluorophenyl)prolinamide was explored only little, if any. In
contrast, the results described herein, which hinge on a
careful screening of solvent and reactions conditions, high-
light several following advantages of N-arylamides as or-
ganocatalysts for aldol reactions:
X-ray Crystal Structure Determinations of N-Arylprolin-
amides 7 and 8
We determined the crystal structures of N-arylamides 7
and 8 to gauge variations in the structures of the two cata-
lysts; the crystals were readily grown by slow evaporation
of their solutions in MeOH and diethyl ether, and the X-
ray intensity data were collected, cf. SI. In Figure 2 are
shown the X-ray determined molecular structures of 7 and
8. A striking difference between the two structures is that
the 3,5-dinitrophenyl ring is virtually coplanar with the
(i) The ease of synthesis starting from Boc--proline and
arylamines makes N-arylamides particularly attractive or-
ganocatalysts.
(ii) All N-arylamides 1–8 function as catalysts, and those
with high NH acidity, i.e., 7 and 8 effect high diastereo- and
enantiodiscrimination (Ͼ95%). Indeed, the results observed
for 8 surpass those reported so far for simple prolinamide
derivatives and are comparable to those of the organocata-
lysts of much more structural complexity.[8,9,14]
(iii) The catalyst 8, in particular, can be employed in both
nonpolar as well as polar common organic solvents. The
reactions in solvents such as cyclohexane/brine obviate the
tedious work-up leading to facile isolation of the aldol
products.
(iv) For heteroaromatic aldehydes as electrophilic coun-
terparts, the reactions go to completion in such short dura-
tions as 3–4 h.
(v) The catalyst 8 works efficiently at room temp.
(22Ϯ1 °C) with only a marginal sacrifice of the enantio-
and diasteroselectivity. Only very few catalysts are known
that work at room temp. to afford aldol products with
Ͼ90% enantiopurity.[10a,10e,16a]
Figure 2. Perspective views of the structures of N-prolinamides 7
(top) and 8 (bottom). Notice that the 3,5-dinitrophenyl ring in 7 is
coplanar with the amide functionality, while the perfluorophenyl
ring is nearly orthogonal in 8.
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Selective Aldol Reactions in Common Organic Solvents
Why is it that (perfluorophenyl)prolinamide performs actions due to the perfluorophenyl ring (C–H···F, π···π,
best of all N-arylprolinamides investigated in the present etc.)[21] in 8 also abet the transition state structure in some
study? Aside from the enhanced acidity, we believe, as men- way.
tioned earlier, that the differences in the conformations of
the aryl rings in 3–7 and 8 may also contribute to the ob-
served outcome. The structural attributes available from X-
ray single crystal structure determinations may shed some
light on the enamine catalysis. More often than not, the
conformationally-flexible molecules are found to exist in
the solid state in or near lowest-energy conformations.[19]
Based on this premise, one observes a perceptible difference
in the conformations of 7, a representative case for sterically
reactions with catalysts 7 (left) and 8 (right).
Figure 3. The proposed transition state geometries for the aldol
unhindered 1, 3, 5–7 and 8, for which the X-ray structures
were determined. As can be seen in Figure 2, the 3,5-dini-
trophenyl ring is almost coplanar with the amide function-
Conclusions
ality in 7, while the perfluorophenyl ring is twisted almost
orthogonally with respect to the amide group in the case of
8. We have analyzed the crystal structures of compounds
that contain acyclic N-phenylcarboxamide moiety de-
posited in the Cambridge Structural Database (CSD). In
several N-arylamides that are closely related to 7 and 8 and
do not contain any alkyl groups at ortho positions, the aryl
ring is found to be near coplanar with the amide moiety;
of course, for N-arylamides that contain 2,6-dimethyl sub-
stituents, the aryl ring is found to be nearly orthogonal. The
angles between the plane comprised of the amide moiety
(CON atoms) and the aryl ring are found to vary within 0–
40°, see Supporting Information. Clearly, the aryl rings in
secondary N-arylamides tend to exploit conjugative stabili-
zation via overlap with the p-orbitals of the amide function-
ality. In contrast, the near orthogonality (ca. 76.15°) ob-
served in 8 suggests that the loss of stability through ex-
tended conjugation of the perfluorophenyl ring with the
amide group is not significant in this case. Presumably, the
highly electron-withdrawing nature of fluorine renders loss
of conjugation with the nitrogen p-orbital, which is already
involved in a primary electronic effect with the carbonyl of
the amide group, less meaningful.[20] This difference in the
geometries of the aryl rings around the amide functionali-
ties in 1, 3, 5–7 vis-à-vis 8 presumably translates into the
corresponding transition state geometries for the aldol reac-
tions. The fact that the reactions of all substrates proceed
with comparatively higher stereoselectivities with 8, when
compared to 7, suggests that the perfluorophenyl ring may
exhibit conformational flexibility to facilitate better binding
of the electrophilic aldehyde via hydrogen bonding with the
amide NH group; of course, the enhanced acidity is defi-
nitely a chief factor. Presumably, the twisting of the perfluo-
rophenyl ring allows the aromatic aldehyde to be castled
in the transition state via N–H···O hydrogen bond more
comfortably around N-arylamide functionality (Figure 3);
notice the anti geometry for the enamine in the presumed
transition state structures.[4c] For all other arylamides, i.e.,
1–7, the varying amounts of steric crowding between the
aldehyde and the coplanar aryl ring of the catalyst may not
permit such strong binding as in 8 leading to manifest in
considerable reduction in the stereocontrol for some sub-
A broad set of secondary N-arylprolinamides 1–8 with
increasing NH acidity and steric crowding has been synthe-
sized in a facile manner and its catalytic activity explored
for enantioselective aldol reactions. It is shown from that
in DMF containing 10 mol-% of TFA, all catalysts with
moderate to high NH acidity catalyze the reaction between
cyclohexanone and a variety of electrophilic aldehydes lead-
ing to aldols in excess of 90% yield and Ͼ95% enantio-
selectivity. However, catalyst 8 performs best with a broad
substrate scope as compared to all other N-arylamides 1–7.
Indeed, the simple and readily accessible catalyst 8 can be
employed in highly nonpolar as well as polar solvents in-
cluding brine to afford high yields of aldols with excellent
diastereo- as well as enantioselectivity, and the results un-
covered for 8 are among the best reported so far for prolina-
mides.[13,16] The X-ray determined molecular structures of
7 and 8, which are presumed to reflect the most stable con-
formations, reveal a notable difference in the conformations
of the N-aryl rings in that the aryl ring exhibits tendency
to lie coplanar with the amide functionality in the case of
7, while the perfluorophenyl ring twists almost orthogonally
with respect to the plane of the amide of functionality in 8.
The superior performance of the latter is attributed to, in
addition to the enhanced NH acidity, the tendency of the
perfluorophenyl ring to lie orthogonal to the amide group,
which may facilitate a stronger binding of the electrophilic
aldehyde via hydrogen bonding in the transition state.
Experimental Section
General: 2,6-Dimethylaniline, 2,6-dimethyl-4-nitroaniline, and 3,5-
dinitroaniline were prepared by following the literature-reported
procedures. Other arylamines like aniline, 4-nitroaniline, perfluo-
roaniline, 2-methyl-5-nitroaniline, and 3-nitroaniline are commer-
cially available and were used as such.
General Procedure for the Preparation of Catalysts 1–8: To a two-
necked round-bottomed flask containing Boc--proline (2.54 g,
11.8 mmol) in 30 mL dry THF was added TEA (1.19 g, 11.8 mmol)
under N2 atmosphere. The resultant solution was cooled to 0 °C.
Subsequently, ethyl chloroformate (1.27 g, 11.8 mmol) was intro-
duced dropwise over a period of 30 min. After the solution was
strates, cf. Figure 3. Further, it is also likely that weak inter- stirred at this temperature for 1 h, aniline (1.0 g, 10.7 mmol) was
Eur. J. Org. Chem. 2009, 739–748
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
745

J. N. Moorthy, S. Saha
FULL PAPER
added, under N2 atmosphere, in small portions. The reaction mix-
ture was stirred at 0 °C for 1 h, at room temp. for 2 h, and heated
at reflux for 6–48 h (6 h for aniline and 48 h for perfluoroaniline);
the reaction was continually monitored by TLC analyses. At the
end of the reaction as judged by TLC analysis, the reaction mixture
was cooled to room temp. and filtered. The filtrate was concen-
trated to get hold of the crude product, which was further purified
by silica-gel cloumn chromatography.
δ = 1.73–1.80 (m, 2 H), 2.02–2.10 (m, 1 H), 2.18–2.27 (m, 1 H),
2.33 (s, 3 H), 2.95–3.01 (m, 1 H), 3.08–3.14 (m, 1 H), 3.92 (dd, J1
= 9.2, J2 = 4.8 Hz, 1 H), 7.23–7.28 (m, 1 H), 7.80 (dd, J1 = 8.4, J2
= 2.2 Hz, 1 H), 9.02 (d, J = 2.2 Hz) ppm. 13C NMR (CDCl3,
100 MHz): δ = 17.8, 26.3, 30.7, 47.4, 61.2, 115.2, 118.5, 130.5,
134.4, 136.8, 146.9, 173.5 ppm. ESI-MS+ m/z calcd. for
C12H15N3O3 250.1190 [M + H]; found 250.1151.
(S)-N-(3,5-Dinitrophenyl)pyrrolidine-2-carboxamide (7): Yield 60%;
m.p. 174–176 °C. [α]2D7 = –39.06 (c = 0.5, EtOH). IR (KBr): ν =
The above product was dissolved in dry 25 mL of DCM and cooled
to 0 °C. TFA (7.5 mL) was slowly added to this solution at 0 °C
and stirred for 3 h at room temp. The reaction mixture was evapo-
rated 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 with anhydrous Na2SO4 and concentrated to get hold
of the pure carboxamide (1.67 g, 82% overall yield for catalyst 1).
˜
1
1347, 1674, 2960, 3105, 3202 cm–1. H NMR (CDCl3, 500 MHz):
δ = 1.80–1.85 (m, 2 H), 2.02–2.09 (m, 1 H), 2.25–2.33 (m, 1 H),
3.03–3.07 (m, 1 H), 3.14–3.18 (m, 1 H), 4.02 (dd, J1 = 9.1, J2
=
5.3 Hz, 1 H), 8.71 (d, J = 2.3 Hz, 1 H), 8.82 (d, J = 2.3 Hz, 1 H)
ppm. 13C NMR(CDCl3, 100 MHz) δ = 26.3, 30.7, 47.4, 60.9, 113.1,
118.7, 140.2, 148.8, 174.3 ppm. ESI-MS+ m/z calcd. for
C11H12N4O5 281.0885 [M + H]; found 281.0885.
(S)-N-Phenyl-pyrrolidine-2-carboxamide (1):[12] Yield 82%; m.p.
(S)-N-(Perfluorophenyl)pyrrolidine-2-carboxamide (8):[18] Yield
72 °C. [α]2D7 = –43.95 (c = 0.5, EtOH). IR (KBr): ν = 1668, 2873,
67%; m.p. 82–84 °C. [α]2D7 = –36.46 (c = 0.5, EtOH). IR (KBr): ν
˜
˜
2967, 3225, 3351 cm–1. 1H NMR (CDCl3, 500 MHz): δ = 1.70–1.79
(m, 2 H), 2.00–2.06 (m, 1 H), 2.15–2.24 (m, 1 H), 2.95–3.00 (m, 1
H), 3.05–3.10 (m, 1 H), 3.87 (dd, 1 H, J1 = 9.1 Hz, J2 = 5.1 Hz),
7.07 (t, 1 H, J = 7.3 Hz), 7.30 (t, 2 H, J = 7.3 Hz), 7.58–7.60 (m,
2 H) 9.74 (br. s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 26.2,
30.7, 47.2, 61.0, 119.2, 123.8, 128.8, 137.8, 173.2 ppm.
= 1668, 2873, 2967, 3225, 3351 cm–1. 1H NMR (CDCl3, 500 MHz):
δ = 1.76–1.85 (m, 2 H), 2.04–2.07 (m, 1 H), 2.19–2.26 (m, 1 H),
2.99–3.04 (m, 1 H), 3.08–3.13 (m, 1 H), 3.96–3.97 (m, 1 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 26.2, 30.9, 47.4, 60.7, 112.0,
112.1, 112.2, 136.8, 138.7, 141.8, 143.8, 174.0 ppm. ESI-MS+ m/z
calcd. for C11H9N2OF5 281.0713 [M + H]; found 281.0712.
(S)-N-(2,6-Dimethylphenyl)pyrrolidine-2-carboxamide (2):[12] Yield
74%; m.p. 78 °C. [α]2D7 = –27.89 (c = 0.5, CHCl3). IR (KBr) 1637,
3044, 3215. H NMR (CDCl3, 400 MHz): δ = 1.92–1.98 (m, 2 H),
2.04–2.22 (m, 1 H), 2.08 (s, 6 H), 2.41–2.46 (m, 1 H), 2.8 (br. s, 1
H), 3.25–3.34 (m, 2 H), 4.96 (br. s, 1 H), 6.94–7.06 (m, 3 H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 17.9, 24.3, 30.1, 46.1, 59.9,
127.6, 128.1, 132.8, 135.1, 167.5 ppm.
General Procedure for Aldol Reaction: A mixture of catalyst 3
(0.031 g, 0.13 mmol), ketone (1.21 g, 13.2 mmol) and TFA
(0.0075 g, 0.066 mmol) contained in 1.0 mL of DMF (1.0 mL) was
stirred at room temp. for 45 min. Subsequently, the temperature
was brought down to 3 °C and the aldehyde (0.1 g, 0.66 mmol) was
introduced. The reaction mixture was stirred at 3 °C until the reac-
tion was judged to be complete based on TLC analysis. The reac-
tion was quenched by adding saturated NH4Cl solution, and the
organic material was extracted with ethyl acetate (2ϫ20 mL). The
combined organic extract was dried with Na2SO4 and concentrated
in vacuo. The crude product was purified by silica gel column
chromatography to give the pure aldol adduct.
1
(S)-N-(4-Nitrophenyl)pyrrolidine-2-carboxamide (3):[12] Yield 66%;
m.p. 88–90 °C. [α]2D7 = –49.41 (c = 0.5, EtOH). IR (KBr): ν = 1345,
˜
1690, 2875, 3214, 3373 cm–1. 1H NMR (CDCl3, 500 MHz): δ =
1.73–1.78 (m, 2 H), 2.00–2.06 (m, 1 H), 2.19–2.25 (m, 1 H), 2.95–
2.99 (m, 1 H), 3.07–3.12 (m, 1 H), 3.88 (dd, J1 = 9.4, J2 = 5.4 Hz,
1 H), 7.76 (d, J = 9.7 Hz, 2 H), 8.18 (d, J = 9.2 Hz, 2 H), 10.17
(br. s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 26.5, 30.8,
47.5, 61.1, 118.8, 125.1, 143.3, 143.7, 174.3 ppm.
The crude product before SiO2 chromatography was submitted to
1H NMR analysis to determine diastereomeric ratio. The product
after SiO2 chromatography was analyzed by HPLC to determine
the enantiomeric as well as the diastereomeric ratios; the latter
matched, within allowable limits, the values determined by 1H
NMR analysis. The syn and anti diastereomers of the aldols were
readily distinguished in 1H NMR spectroscopy by the diagnostic
chemical shifts of –CHOH– proton, cf. SI for the chemical shift
data.
(S)-N-(2,6-Dimethyl-4-nitrophenyl)pyrrolidine-2-carboxamide (4):
Yield 60%; m.p. 110–112 °C. [α]2D7 = –31.67 (c = 0.5, EtOH). IR
(KBr): ν = 1346, 1676, 2850, 2924, 3234, 3365, 3434 cm–1. 1H NMR
˜
(CDCl3, 500 MHz): δ = 1.82–1.87 (m, 2 H), 2.06–2.12 (m, 1 H),
2.25–2.34 (m, 4 H), 3.05–3.09 (m, 1 H), 3.13–3.21 (m, 1 H), 4.07
(br. s, 1 H), 7.94 (s, 2 H), 9.55 (br. s, 1 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 18.8, 26.3, 30.9, 47.5, 60.8, 123.0, 136.1, 140.4,
145.7, 173.1 ppm. ESI-MS+ m/z calcd. for C13H17N3O3 264.1348
[M + H]; found 264.1348.
CCDC-697386 (for 7) and -697387 (for 8) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(S)-N-(3-Nitrophenyl)pyrrolidine-2-carboxamide (5): Yield 64%;
gummy liquid. [α]2D7 = –40.71 (c = 0.57, EtOH). IR (KBr) 1352,
1681, 2874, 2971, 3092, 3258. 1H NMR (CDCl3, 500 MHz): δ =
1.72–1.80 (m, 2 H), 1.95–2.03 (m, 1 H), 2.16–2.26 (m, 1 H), 2.97–
3.03 (m, 1 H), 3.06–3.12 (m, 1 H), 3.38 (br. s, 1 H), 3.96 (dd, J1 =
11.6, J2 = 6.7 Hz), 7.38 (t, J = 10.4 Hz, 1 H), 7.83 (dd, J1 = 9.9, J2
= 2.4 Hz), 8.35 (t, J = 2.4 Hz), 10.14 (br. s, 1 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 26.3, 30.7, 47.3, 60.9, 113.9, 118.4, 124.9,
129.7, 138.9, 148.5, 174.0 ppm. ESI-MS+ m/z calcd. for
C11H13N3O3 236.1035 [M + H]; found 236.1035.
Supporting Information (see also the footnote on the first page of
1
this article): Details of synthesis, H and 13C NMR spectral repro-
ductions of all the catalysts 1–8, 1H NMR diagnostic chemical shift
data for syn and anti aldols, HPLC profiles for all results in Tables 2
and 4, crystal data for 7 and 8, and the results of CSD search for
N-arylamides.
Acknowledgments
(S)-N-(2-Methyl-5-nitrophenyl)pyrrolidine-2-carboxamide (6): Yield
63%; m.p. 92–94 °C. [α]2D7 = –57.79 (c = 0.5, EtOH). IR (KBr): ν
J. N. M. is thankful to Department of Science and Technology
˜
= 1686, 2847, 2980, 3129, 3370 cm–1. 1H NMR (CDCl3, 400 MHz): (DST), New Delhi for generous financial support. S. S. is grateful
746
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 739–748

Selective Aldol Reactions in Common Organic Solvents
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The catalytic activity of N-arylprolinamide 8, in particular, was
tested for the reaction of cyclohexanone with less electrophilic
aldehydes such as benzaldehyde, p-methoxybenzaldehyde, etc.
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sluggish leading to Ͻ20% of the products even after 48 h.
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Eur. J. Org. Chem. 2009, 739–748
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
747

J. N. Moorthy, S. Saha
FULL PAPER
[20] The observed near-orthogonality of the perfluorphenyl ring
with respect to the amide functionality is unlikely to be a result
of crystal packing. We are currently carrying out structural
studies of a number of perfluorophenylamides and other re-
lated systems to establish the conformational preference ob-
served for 8.
[21] G. R. Desiraju, T. Steiner, The Weak Hydrogen Bond in Struc-
tural Chemistry and Biology, Oxford University Press, New
York, 1999, pp. 202–224.
Received: October 1, 2008
Published Online: December 29, 2008
748
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 739–748