Systematic evaluation of a few proline derivatives as catalysts for a direct aldol reaction

Article abstract of DOI:10.1016/j.tetasy.2012.11.018

A series of pyrrolidine derivatives were prepared and examined as catalysts for an aldol reaction. Structural variations in these molecules involved altering the sterics at the α-position, the position of the carbonyl group, and the acidities of the hydrogen bonding sites. The effect of these factors on catalytic activity and enantioselectivity was studied. The experimental results revealed that additional sterics at the α-position were detrimental. However, no correlation was found between the catalytic activity and N-H acidity.

Full text of DOI:10.1016/j.tetasy.2012.11.018

Tetrahedron: Asymmetry 24 (2013) 43–49
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Systematic evaluation of a few proline derivatives as catalysts for a direct
aldol reaction
⇑
Revannath L. Sutar, Navalkishore N. Joshi
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 October 2012
Accepted 23 November 2012
A series of pyrrolidine derivatives were prepared and examined as catalysts for an aldol reaction. Struc-
tural variations in these molecules involved altering the sterics at the
bonyl group, and the acidities of the hydrogen bonding sites. The effect of these factors on catalytic activity
and enantioselectivity was studied. The experimental results revealed that additional sterics at the -posi-
a-position, the position of the car-
a
tion were detrimental. However, no correlation was found between the catalytic activity and N–H acidity.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
design and synthesis of efficient enamine catalysts still receives
considerable attention.11
Since the discovery of
L
-proline catalyzed intermolecular aldol
Most of the successful enamine catalysts reported for direct al-
dol-type reactions are based on the amide derivatives of proline or
diamines with or without additional hydrogen bonding sites12 or
derivatives of 4-hydroxy proline.13 Recently, catalysts with modifi-
cations at both sites, that are the 4-hydroxy and carboxylate
groups of 4-hydroxy proline, have also been reported.14 The strat-
egies used for their modification mainly focus on variations in the
electronic and/or steric properties of the groups in the side chains.
Despite the recently reported kinetic studies and theoretical
calculations on the mechanistic investigations and the comparison
of various organocatalysts for this reaction,15 there is still a need
for systematic and practical screenings of simple proline deriva-
tives based on the transition states shown in Figure 1. Such infor-
mation could explain the effect of sterics at the stereogenic center,
the effect of the position of the carbonyl group in the amide con-
taining the catalysts, and the effect of the acidities of the hydrogen
bonding sites. Herein we report a series of chiral bifunctional sec-
ondary amines and their catalytic behavior in a direct aldol reac-
tion (See Figs. 2–4).
reactions,1 asymmetric organocatalysis has received growing
attention.2 Although the direct use of free
a
-amino acids1,3 and
easily accessible chiral amines4 as catalysts is much preferable,
the rather narrow applicability, unsatisfactory catalytic activities,
formation of various side products and, low reaction rates restricts
their generality.5 To overcome these limitations, simple modifica-
tions of amino acids and chiral amines have become an expedient
choice.6 Therefore various primary and secondary amines have
been continuously developed as new organocatalysts based on
the principles of enamine, iminium and hydrogen bonding, cataly-
sis etc.7
For an amine to act as an efficient catalyst,8 Lewis or Brønsted
acidic additives are needed to assist enamine formation. The enam-
ine generated reacts readily with reactive electrophiles, which con-
trol its approach through steric interactions.9a However for
relatively unreactive electrophiles such as aldehydes, ketones and
imines, additional assistance for the catalysis is required, which
is generally provided by suitably positioned hydrogen bond donors
in the catalyst.9b,c This results in the simultaneous activation of
both nucleophiles and electrophiles. If these hydrogen bonding
sites are sufficiently acidic as the carboxylic acid groups of amino
acids, then they also assist the enamine formation. Thus, for enan-
tioselective enamine catalysis, the presence of a properly posi-
tioned steric bulk or a substituent carrying at least one hydrogen
bonding site, is essential. A catalytic system containing all these
factors together as a combination of two chiral organocatalysts,
has recently been reported.10 Although a number of bi- and poly-
functional catalysts have been already developed, the rational
2. Results and discussion
There are only a few reports on
as catalysts for this reaction; -methyl proline, thiazolidinium
derivatives,3a and a0-disubstituted imidazolidinone.16 It has
been reported that when the reaction is catalyzed by -methyl
proline 1b, it gives a lower yield and enantioselectivity of the aldol
product than that catalyzed by
-proline (Table 1, entries 1 vs 3).3a
-substituent, the
a,a-disubstituted pyrrolidines
a
a-
a
L
To further study the effect of sterics of the
a
methyl group in 1b was replaced by a benzyl group 1c.17a A few
easily accessible proline derivatives 2a–3b17b–d with and without
a substituent at the stereogenic carbon were prepared and exam-
⇑
Corresponding author. Tel.: +91 20 25902055; fax: +91 20 25902629.
E-mail address: nn.joshi@ncl.res.in (N.N. Joshi).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.018

44
R. L. Sutar, N. N. Joshi / Tetrahedron: Asymmetry 24 (2013) 43–49
present study
mechanisms of enamine catalysis
H
H
H
H
H
X
H
N
N
X
H
N
X
N
X
N
N
X
Y
H
H
O
O
O
H
Z
Y
Z
Y
X
Z
Y
X
H
H
Y
Ar
X = N, O
effect of sterics
H
Ar
H
Ar
H
steric control
hydrogen bonding control
X = N, Y = COR
effect of the positon of the amide carbonyl
and acidities of the hydrogen bonding sites
Figure 1. Transition states for enamine catalysis.
R
R
O
O
O
R
O
4
5
3
3
N
4
N
H
N
H
N
H
N
5
NH2
OH
OH
6
N
2
N
2
H
H
1O
O
1 O
O
O 6
7
H
H
1a:
2a: R = H
2b: R = Bn
R = H
3a: R = H
3b: R = Bn
7
8
H
R
1b: R = Me
1c: R = Bn
R
H
Figure 2. Selected pyrrolidine derivatives used to study the effect of sterics at the
a-position.
(R)-aldol
(S)-aldol
Figure 5. Stereochemical outcome and ring size of the transition state.
O
O
N
H
N
H
O
N
H
HN
HN
HN
R
Ph
R
tions, 1c could not catalyze the reaction while 1a gave a moderate
yield and enantioselectivity (Table 1, entries 5 vs 2). To rule out the
possiblility of oxazolidinone formation as the side reaction,15d
aqueous DMF was examined as the solvent. However similar re-
sults were realized (Table 1, entry 6). Therefore, for the rest of
our study, neat reaction conditions were employed. The catalytic
reactivity pattern of prolinamides 2a and 2b was similar to proline
derivatives 1a and 1c. Further evidence for the detrimental effect
5a: R = Ph
5b: R = t-Bu
6a: R = Ph
7
6b: R = t- Bu
Figure 3. Selected chiral amides used to study the effect of the position of the
carbonyl group.
of the
a-substituent was provided by the proline derivatives 3a
ined as catalysts for a direct aldol reaction. For the sake of compar-
ison, acetone and p-nitrobenzaldehyde were used as substrates
(See Scheme 1).
It was observed that the rate as well as enantioselectivity de-
creased considerably with an increase in steric hindrance from
1a–1c (Table 1, entries 1, 3, and 4). However, under neat condi-
and 3b. Acetone was replaced with cyclopentanone to rule out
the possibility of imidazolidinone formation from the reaction with
an amino alcohol. However, similar results were obtained. The
reaction of cyclopentanone with benzaldehyde was catalyzed by
3a, but not by 3b, as can be seen in Table 1 (entries 9 and 10).
O
O
O
N
H
N
H
N
H
O
O
O
HN
HN
HN
O
HN
HN
R
Ph
9a
9b
8a: R = Ph
8b:
Ph
R = t-Bu
O
O
N
H
N
H
HN
HN
HOOC
HO
10
11
Figure 4. Organocatalysts for comparison of increased acidities and hydrogen bonding.

R. L. Sutar, N. N. Joshi / Tetrahedron: Asymmetry 24 (2013) 43–49
45
Table 1
Table 2
Screening of pyrrolidine derivatives to study the effect of
a
-sterics
Yielda (%)
68
Pyrrolidine derivatives with different positions of the amide carbonyla
No
Catalyst
Solvent
Time (h)
eeb (%)
No
Catalyst
Time (h)
Yieldb (%)
eec (%)
1c
1a
1a
1b
1c
1c
1c
2a
2b
3a
3b
DMSO
Neat
2
24
2
72
96
48
24
72
15
18
76
67
61
36
—
1
2
5a
5b
6a
6b
7
60
60
24
24
24
65
68
88
55
82
10
5
37
15
21
2c
3c
4
60
26
57
Trace
Trace
81
DMSO
DMSO
Neat
3d
4d
5d
5
6
aq DMFd
Neat
—
a
b
c
7e
8
33
—
All reactions run under neat conditions at a concentration of 1.0 M solution.
Isolated yield of aldol product (A).
Neat
Neat
Neat
Trace
9f
10f
89g
36h
—
The ee of the (R)-enantiomer determined by chiral HPLC analysis.
d
Reported18a using 20 mol % of catalyst.
No reaction
a
b
c
Isolated yield of aldol product A.
used for Michael reactions.17e Herein we prepared carboxamides
5a and 5b from a chiral amine (S)-benzyl 2-(aminomethyl)pyrrol-
idine-1-carboxylate17e (Scheme 2).
The behavior of these catalysts was then examined in direct al-
dol reactions under neat conditions and the results compared with
those reported for analogous catalysts 6a, 6b. and 717a (Table 2).
It was observed that both the rate as well as the enantioselec-
tivity decreased considerably (Table 2, entry 3 vs 1 and entry 4
vs 2) as the carbonyl group moves away from the pyrrolidine ring.
It can thus be concluded that for pyrrolidine derived amide organ-
ocatalysts, the carbonyl part should derive from proline.
It is generally accepted that the strength of hydrogen bonding
interactions increases with increasing acidity of the heteroatom–
hydrogen bond involved. Unlike other pyrrolidine derivatives, the
carboxamide N–H of prolinamides are weak hydrogen bond donors
and in the majority of cases provide extra hydrogen bonding,12 the
addition of water or external acids19 is used to obtain better selec-
tivities. However, the effect of the acidity of these different hydro-
gen bond donors on the catalytic activity and stereoselectivity in
this reaction has not been investigated in detail.20 Therefore to
study the effect of increased acidity of the carboxamide NH, imides
8a and 8b17f were chosen as catalysts. To evaluate the effect of
additional hydrogen bonding, urea derivatives 9a and 9b were se-
lected. Amide derivatives 10 and 11 would provide information
about the more acidic functionality. All the required organocata-
lysts were prepared from N-Cbz proline as shown in Scheme 3.
These catalysts were then used in the direct aldol reaction and
the results were compared with those of analogous catalysts 6a,
6b,18a and 1018b (Table 3).
The ee of the (R)-enantiomer was determined by chiral HPLC analysis.
Reported3a using 20 mol % of catalyst.
3 vol % water in DMF.
d
e
f
Reported18a using 20 mol % of catalyst.
Cyclopentanone and benzaldehyde were used as reactants.
syn:anti (80:20).
g
h
The ee of the major syn-diastereoisomer.
Our results indicated that in proline derivatives, substitution of
the a-hydrogen with an alkyl group adversely affects the outcome
of the direct aldol reaction. It retards the initial reaction of the pyr-
rolidine nitrogen with acetone as the bulk increases from methyl to
benzyl. When the reaction was carried out with catalysts with large
a
-sterics, the reactivity vanishes completely under neat conditions.
These results are in accordance with the theoretical calculations by
Boyd et al.,15a which indicate that the initial complexation between
proline and acetone requires substantial energy and would inhibit
further progress of the reaction. This was also reported by Maruoka
et al. as one of the reasons for the increased reactivity of their
bifunctional-binaphthyl based secondary amine catalyst.11a In this
case, the absence of a substituent a- to the secondary amine group
decreases steric repulsion in the enamine intermediate. It has been
reported that the rate determining step of the proline catalyzed al-
dol reaction is the C–C bond formation and not the enamine forma-
tion.15e Our results indicate that with sterically hindered catalysts,
the enamine formation is sufficiently slowed down and thus it be-
comes the rate determining step.
The majority of enamine organocatalysts containing an amide
group are derived from proline carboxylate due to their ease of
synthesis for example 6a, 6b, and 7.18a For this reason, prolinamide
organocatalysts are of contemporary interest. We were interested
to know the behavior of amides derived from chiral pyrrolidine
methylamine and achiral acids. One such sulfonamide has been
It was observed that imide 8a, even with a higher acidity, does
not catalyze the reaction while the corresponding amide 6a gave
good yields (Table 3, entry 3 vs 1). The reaction rate as well as
enantioselectivity decreased considerably from 6b to 8b (Table 3,
organocatalyst
O
O
OH
*
O
(10 mol%)
+
H
solvent, rt
NO2
NO2
A
Scheme 1. Representative example of a direct aldol reaction used herein.
lit.17b,17e
O
b
a
N
N
N
H
N
O
O
NH2
HN
OH
HN
Cbz
Cbz
Cbz
R
R
4a:
4b:
R = Ph
5a: R = Ph
5b:
R = t- Bu
R = t- Bu
Scheme 2. Preparation of the amides. Reagents and conditions: (a) (i) RCOCl, pyridine, CHCl3, 0 °C; (b) H2-Pd/C, MeOH.

46
R. L. Sutar, N. N. Joshi / Tetrahedron: Asymmetry 24 (2013) 43–49
O
O
O
d
c
N
N
N
H
O
O
NH2
HN
HN
Cbz
Cbz
HN
HN
R
R
9a: R = Ph
ref.17b
9b:
R = Bz
O
O
COOH
a
b
N
N
HN
MeOOC
N
H
HN
c
Cbz
Cbz
HOOC
11
Scheme 3. Preparation of organocatalysts. Reagents and conditions: (a) (i) EtOCOCl, Et3N, CHCl3, 0 °C; (ii) methyl 2-aminobenzoate; (b) LiOH, MeOH, 25 °C; (c) H2-Pd/C,
MeOH; (d) RNCO, toluene, reflux.
Table 3
various simple proline derivatives, we have observed that sterics
at the -position had an adverse effect on the outcome of the direct
Comparison of catalysts with varying acidities of the hydrogen bonding sites
a
No
Catalyst
Solvent
Time (h)
Yielda (%)
eeb (%) (conf.)
aldol reaction, which is in accordance with the results of Maruoka
et al.11a and theoretical calculations by Boyd et al.15a Herein we have
reported that with sterically hindered catalysts, the rate determin-
ing step shifts from C–C bond formation to enamine formation. The
position of the carbonyl group in the pyrrolidine derived amides is
also important and easily accessible prolinamides were found to
be better than the amides of (S)-pyrrolidin-2-yl-methanamine. In
contrast to the sulfonamide17f and N-sulfinyl prolinamides;17g in-
creased acidity of the N–H of carboxamides and urea derivatives
had an adverse effect on either the yield or selectivity. Our findings
support the report20 that the effect of hydrogen bond donors in the
organocatalytic reactions is possibly dependent on the substrates
and the reaction conditions. These results provide useful informa-
tion for the development of the next generation of organocatalysts.
1c
2c
3
4
5
6
7
8
6a
6b
8a
8b
9a
9a
9b
9b
10
11
11
Neat
Neat
Neat
Neat
24
24
120
36
24
72
48
48
48
48
28
88
55
37 (R)
15 (R)
—
<5 (R)
31 (R)
39 (R)
—
No reaction
59
89
Neat
aq DMFd
Neat
79
No reaction
No reaction
21
aq DMFd
Neat
—
9d
10
11
62 (R)
52 (S)
32 (S)
Neat
48
53
aq DMFe
a
b
c
Isolated yield of aldol product A.
Determined by chiral HPLC analysis.
Reported18a using 20 mol % of catalyst.
Reported18b using 20 mol % of catalyst.
3 vol % water in DMF.
d
e
4. Experimental
4.1. General
entry 2 vs 4). This finding is contradictory to the common under-
standing that the more acidic N–H bond in the imides should pro-
vide better catalytic efficiency than in the corresponding amides.
This may be due to the complete delocalization of the imide proton
forming a stable six membered intramolecular hydrogen bond
with the carbonyl groups. Such an arrangement would lead to a
loss in the catalytic activity. However, the good yield of the aldol
product obtained in the reaction catalyzed by monoacyl urea 9a
(Table 3, entry 5 and 6) rules out this possibility. The correspond-
ing diacyl derivative 9b did not catalyze the reaction (Table 3, entry
7 and 8). These results support the conclusion that the effect of the
hydrogen bond donors in the organocatalytic reactions is depen-
dent on the substrates and the reaction conditions, as observed
by Yan et al.20 A few of these organoctalysts were also used
employing aqueous DMF as the solvent, which leads to only a mar-
ginal improvement in the enantioselectivity (e.g. Table 3, entry 6).
With catalysts 10 and 11, which possess a more acidic proton
for hydrogen bonding, the results did not provide any convincing
information. It is noteworthy that as the ring size of the hydrogen
bonding interactions in the transition state increases from 7 to 8,
the absolute configuration of the product changes from (R) to (S).
All reagents and solvents were purified and dried according to
the literature.21 Organocatalysts 1c,17a 2a,17b 2b,17c 3a,17d 8a,
8b,17f N-Cbz-prolinamide,17b and (S)-benzyl 2-(aminomethyl)pyr-
rolidine-1-carboxylate17e were prepared according to the reported
procedures. The reactions were monitored by TLC using silica gel
60 F254 pre-coated plates and were visualized with UV, in an io-
dine chamber or with a phosphomolybdic acid spray. The products
were purified by column chromatography on silica gel (100–200 or
230–400 mesh) and characterized by IR, 1H NMR, 13C NMR and ele-
mental analysis or HRMS. The data of the aldol products were
found to be in good agreement with the reported values.18a,c All
melting points were recorded on a Büchi B-540 electro thermal
melting point apparatus and are uncorrected. Optical rotations
were measured on Bellimheam + Standley ADP220 digital polarim-
eter and IR spectra were recorded on a Shimadzu FTIR-8400 spec-
trophotometer. 1H spectra were recorded at 200 MHz with TMS as
the internal standard and 13C NMR spectra were recorded at
50 MHz with CDCl3 (d 77) or MeOH (d 49) as the reference. Micro-
analysis was performed using a Carlo-Erba CHNS-0 EA 1108 ele-
mental analyzer. HRMS were recorded on Thermoscientific Q
EXACTIVE mass spectrometer. The enantiomeric excess was deter-
mined using a chiral column on HPLC. The absolute configuration
3. Conclusion
The design and synthesis of a nearly ideal organocatalyst in-
volved modifications based on the original design. After screening
of the aldol products was assigned from [
a]
D
values and HPLC
retention times as reported in the literature.18a

R. L. Sutar, N. N. Joshi / Tetrahedron: Asymmetry 24 (2013) 43–49
47
4.2. Preparation of organocatalysts
4.2.3. Preparation of (S)-N-(pyrrolidin-2-ylmethyl)pivalamide
5b
4.2.3.1. (S)-Benzyl-2-(pivalamidomethyl)pyrrolidine-1-carbox-
ylate 4b. The procedure described above for the preparation
4.2.1. Preparation of (R)-(2-benzylpyrrolidin-2-yl)methanol 3b
In an oven dried 25 mL side armed flask equipped with a reflux
condenser, LiAlH4 (230 mg, 5 mmol) was taken. It was then cooled
to 0 °C and freshly distilled anhydrous tetrahydrofuran (10 mL)
was added under an argon atmosphere. To the resulting suspen-
sion, (R)-2-benzylpyrrolidine-2-carboxylic acid17a (615 mg,
3 mmol) was added portionwise through a solid addition funnel.
The mixture was then heated at reflux. After completion of the
reaction (5 h) as indicated by TLC, it was cooled to 0 °C, diluted
with tetrahydrofuran (10 mL) and quenched by the dropwise addi-
tion of 1 M NaOH (2 mL). The white solid was then removed by fil-
tration. The filtrate and THF washings were combined together,
dried over anhydrous Na2SO4, and concentrated to give a crude
product. The residue was purified by column chromatography
using methanol/dichloromethane (1:9) as the eluent to obtain 3b
(530 mg, 92%) as a white hygroscopic solid. Mp 110–112 °C; Rf
of 4a was followed using (S)-benzyl 2-(aminomethyl) pyrrolidine-
1-carboxylate (470 mg, 2 mmol) and pivaloyl chloride (0.28 mL,
2.2 mmol). The usual work-up gave a crude product, which was
purified by column chromatography using ethyl acetate: petroleum
ether (1:3) as eluent to give 4b (550 mg, 86%) as a sticky mass. Rf
(40% EtOAc/hexane): 0.4; ½a D25
¼ ꢁ53:7 (c 1.34, CHCl3); IR (Neat)
ꢀ
v
(cmꢁ1): 3359, 2963, 1697, 1659, 1528, 1412, 1106; 1H NMR
(CDCl3) d: 1.15 (s, 9H), 1.60–2.15 (m, 4H), 3.07–3.60 (m, 4H),
4.00–4.20 (m, 1H), 5.14 (ABq, J = 12.38, 6.19 Hz, 2H), 7.27–7.50
(m, 6H); 13C NMR (CDCl3) d: 23.9, 27.5, 29.5, 38.5, 46.0, 46.9, 56.9,
67.1, 127.8, 128.0, 128.5, 136.5, 156.9, 179.2; HRMS (ESI+) for
C
18H26N2O3; Calculated: 319.2016 [M+H]+. Found: 319.2010.
4.2.3.2. (S)-N-(Pyrrolidin-2-ylmethyl)pivalamide 5b.
The
(10% methanol/dichloromethane): 0.3;
½
a 2D5
ꢀ
¼ þ20:5 (c 1.27,
procedure described above for Cbz-deprotection of 4a was followed
for 4b (510 mg, 1.6 mmol). After stirring for 10 h, the usual work-up
and purification by column chromatography using methanol/
dichloromethane (1:3) as eluent gave 5b (250 mg, 85%) as a sticky
CHCl3); IR (Nujol)
v
(cmꢁ1): 3325, 2956, 2871, 1604, 1056; 1H
NMR (CDCl3) d: 1.40–1.86 (m, 4H), 2.46 (br s, 1H), 2.54 (br s, 1H),
2.67–3.05 (m, 4H), 3.20–3.34 (m, 2H), 7.14–7.36 (m, 5H); 13C
NMR (CDCl3) d: 25.6, 32.2, 42.3, 45.7, 65.5, 65.9, 126.4, 128.2,
130.2, 137.6; HRMS (ESI+) for C12H17NO; Calculated: 192.1383
[M+H]+. Found: 192.1384.
mass. Rf (methanol): 0.2; ½a D25
¼ þ8:85 (c 1.21, CHCl3); IR (Neat)
ꢀ
v
(cmꢁ1): 3338, 2956, 2873, 1640, 1535, 1402, 1212; 1H NMR
(CDCl3) d: 1.20 (s, 9H), 1.29–1.53 (m, 1H), 1.59–1.98 (m, 3H), 2.76
(br s, 1H), 2.92 (t, J = 6.44 Hz, 2H), 3.00–3.16 (m, 1H), 3.22–3.47
(m, 2H), 6.35 (br s, 1H); 13C NMR (CDCl3) d: 25.6, 27.5, 28.7, 38.6,
42.9, 43.0, 46.1, 57.9, 179.0; Analysis for: C10H20N2O; Calculated:
C, 65.18; H, 10.94; N, 15.20. Found: C, 65.40, H, 10.63, N, 15.42.
4.2.2. Preparation of (S)-N-(pyrrolidin-2-ylmethyl)benzamide
5a
4.2.2.1. (S)-Benzyl 2-(benzamidomethyl)pyrrolidine-1-carboxyl-
ate 4a.
A solution of (S)-benzyl 2-(aminomethyl)pyrrolidine-
1-carboxylate (470 mg, 2 mmol) and pyridine (1.62 mL, 20 mmol)
in anhydrous CHCl3 (4 mL) was cooled to 0 °C. Freshly distilled
benzoyl chloride (0.27 mL, 2.2 mmol) was added dropwise and
stirring continued. After completion of the reaction (30 min) as
indicated by TLC, 1 M HCl (20 mL) was added. The organic layer
was separated and the aqueous layer was extracted with dichloro-
methane (2 ꢂ 10 mL). The combined organic layer was succes-
sively washed with aqueous NaHCO3 (10 mL) followed by brine
(10 mL) and dried over anhydrous Na2SO4. It was then concen-
trated and the residue was purified by column chromatography
using ethyl acetate: petroleum ether (1:3) as the eluent to obtain
4a (580 mg, 86%) as a sticky mass. Rf (30% EtOAc/hexane): 0.4;
4.2.4. Preparation of (S)-N-(phenylcarbamoyl)pyrrolidine-2-
carboxamide 9a
4.2.4.1. (S)-Benzyl 2-((phenylcarbamoyl)pyrrolidine-1-carboxyl-
ate.
In an oven dried 10 mL side armed flask equipped with a
reflux condenser, N-Cbz prolinamide (496 mg, 2 mmol) was sus-
pended in anhydrous toluene (4 mL). Phenyl isocyanate (0.22 mL,
2 mmol) was then added under an argon atmosphere and the solu-
tion was refluxed. After completion of the reaction (40 h) as indi-
cated by TLC, the solvent was evaporated to give a white residue,
which was purified by column chromatography using ethyl acetate:
petroleum ether (1:4) as eluent to give the desired product (600 mg,
82%) as a white solid. Mp 173–174 °C; Rf (25% EtOAc/PE): 0.2;
½
a 2D5
ꢀ
¼ þ27:9 (c 1.22, CHCl3); IR (Neat)
v
(cmꢁ1): 3334, 3065,
½
a 2D5
ꢀ
¼ ꢁ105:3 (c 1.11, CHCl3); IR (KBr) v
(cmꢁ1): 3242, 3188,
2953, 2883, 1697, 1659, 1538, 1414, 1104; 1H NMR (CDCl3) d:
1.70–2.22 (m, 4H), 3.31–3.72 (m, 4H), 4.09–4.34 (m, 1H), 5.05–
5.32 (m, 2H), 7.22–7.55 (m, 8H), 7.84 (d, J = 6.32 Hz, 2H), 8.25 (br
s, 1H); 13C NMR (CDCl3) d: 23.9, 29.6, 46.6, 47.0, 56.9, 67.2, 127.0,
127.7, 128.0, 128.3, 128.4, 131.1, 134.0, 136.3, 157.2, 167.4; LCMS
for: C20H22N2O3; Calculated: 338.16 [M+H]+. Found: 339.19.
1728, 1702, 1667, 1603, 1553, 1218, 1183; 1H NMR (CDCl3) d:
1.86–2.42 (m, 4H), 3.40–3.71 (m, 2H), 4.30–4.58 (m, 1H), 5.17
(ABq, J = 12.26, 10.73 Hz, 2H), 7.05–7.55 (m, 10H), 8.71 and 9.21
(br s, 1H, rotamers), 10.36 (br s, 1H); 13C NMR (CDCl3) d: 23.7,
24.4, 29.3, 31.2, 47.0, 47.4, 61.1, 67.5, 120.3, 124.3, 128.0, 128.1,
128.4, 128.9, 136.0, 137.0, 151.1, 154.4, 155.8, 174.1, 174.8; Analy-
sis for: C20H21N3O4; Calculated: C, 65.38; H, 5.76; N, 11.44. Found:
C, 65.67; H, 5.48; N, 11.60.
4.2.2.2. (S)-N-(Pyrrolidin-2-ylmethyl)benzamide 5a.
To a
solution of 4a (545 mg, 1.6 mmol) in methanol (10 mL), 10% Pd/C
(80 mg) was added and stirred vigorously under the balloon-pres-
sure of hydrogen. After completion of the reaction (8 h) as indicated
by TLC, argon was bubbled through the reaction mixture and fil-
tered through a small pad of Celite. The filtrate and the washings
were concentrated and the resulting crude product was purified
by filtration column chromatography using methanol/dichloro-
methane (1:4) as the eluent to obtain 5a (300 mg, 92%) as a sticky
4.2.4.2.
9a.
(S)-N-(Phenylcarbamoyl)pyrrolidine-2-carboxamide
The procedure described above for the Cbz-deprotection
of 4a was followed for (S)-benzyl 2-((phenylcarbamoyl) carbamoyl)
pyrrolidine-1-carboxylate (368 mg, 1 mmol). After stirring for 8 h
and the usual work-up, 9a (210 mg, 90%) was obtained as a white
solid. Mp 78–79 °C; Rf (40% ethyl acetate/hexane): 0.2;
½
a 2D5
ꢀ
¼ ꢁ72:5 (c 1.09, CHCl3); IR (Nujol) v
(cmꢁ1): 3344, 3234,
mass. Rf (MeOH): 0.3; ½a D25
ꢀ
¼ þ29:0 (c 1.0, CHCl3); IR (Neat)
2954, 2926, 2859, 1702, 1690, 1600, 1222; 1H NMR (CDCl3) d:
1.65–2.35 (m, 5H), 2.91–3.15 (m, 2H), 3.87 (dd, J = 9.35, 5.95 Hz,
1H), 7.10 (tt, J = 7.32, 1.33 Hz, 1H), 7.25–7.37 (m, 2H), 7.47–7.57
(m, 2H), 9.86 (br s, 1H), 10.44 (br s, 1H); 13C NMR (CDCl3) d: 26.0,
30.7, 47.1, 60.5, 120.1, 124.0, 128.8, 137.2, 150.2, 177.4; Analysis
for C12H15N3O2: Calculated: C, 61.79; H, 6.48; N, 18.01. Found: C,
61.73; H, 6.49; N, 18.04.
v
(cmꢁ1): 3303, 3060, 2958, 2871, 1639, 1603, 1538, 1303; 1H
NMR (CDCl3) d: 1.35–2.05 (m, 4H), 2.94 (t, J = 6.69 Hz, 2H), 3.19–
3.52 (m, 3H), 3.55–3.70 (m, 1H), 7.24 (br s, 1H), 7.35–7.55 (m,
3H), 7.83 (dd, J = 6.66, 1.64 Hz, 2H); 13C NMR (CDCl3) d: 25.6, 28.9,
43.5, 46.1, 57.9, 127.0, 128.3, 131.3, 134.3, 167.6; HRMS (ESI+) for
C
12H16N2O; Calculated: 205.1335 [M+H]+. Found: 205.1334.

48
R. L. Sutar, N. N. Joshi / Tetrahedron: Asymmetry 24 (2013) 43–49
4.2.5. (S)-N-(Benzoylcarbamoyl)pyrrolidine-2-carboxamide 9b
4.2.5.1. (S)-Benzyl2-((benzoylcarbamoyl)carbamoyl)pyrroli-
dine-1-carboxylate. The procedure described above was fol-
carbonyl)phenyl)carbanoyl)pyrrolidene-1-carboxylate
(1.45 g,
3.8 mmol) in methanol (8 mL), lithium hydroxide monohydrate
(319 mg, 7.6 mmol) was added and the solution was stirred at
room temperature. After completion of the reaction (15 h) as indi-
cated by TLC, the solvent was removed on a rotavapour and the
residue was acidified to pH 4 using 2 M HCl. It was then extracted
with ethyl acetate (3 ꢂ 10 mL). The organic layer was washed with
brine (10 mL), dried over anhydrous Na2SO4, and concentrated to
obtain a crude product. Purification of the product was carried
out via column chromatography using ethyl acetate as the eluent
to afford the desired product (1.3 g, 93%) as a white solid. Mp 62–
lowed using N-Cbz prolinamide (496 mg, 2 mmol) and benzoyl
isocyanate22a (0.25 mL, 2 mmol). After refluxing for 2 h and the
usual work-up followed by column chromatography using ethyl
acetate: petroleum ether (1:2) as the eluent, gave the desired prod-
uct (700 mg, 89%) as a white solid. Mp 63–66 °C; Rf (35% EtOAc/hex-
ane): 0.2; ½a 2D5 (cmꢁ1): 3189,
¼ ꢁ81:7 (c 1.05, CHCl3); IR (Nujol) v
ꢀ
2947, 2922, 2852, 1774, 1703, 1675, 1599, 1181; 1H NMR (CDCl3)
d: 1.87–2.45 (m, 4H), 3.42–3.80 (m, 2H), 4.44–4.69 (m, 1H), 4.98–
5.28 (m, 2H), 7.09–7.70 (m, 8H), 7.77–8.00 (m, 2H), 10.40 (br s,
1H), 10.79 (br s, 1H); 13C NMR (CDCl3) d: 24.4, 29.4, 29.6, 31.1,
47.0, 47.40, 61.6, 67.5, 127.3, 127.9, 128.1, 128.4, 128.9, 132.0,
133.5, 136.1, 149.4, 155.8, 166.1, 173.7; Analysis for: C21H21N3O5;
Calculated: C, 63.79; H, 5.35; N, 10.63. Found: C, 63.94; H, 5.48; N,
10.25.
64 °C; Rf (EtOAc): 0.3; ½a D25
¼ ꢁ126:4 (c 1.25, CHCl3); IR (Nujol)
ꢀ
v
(cmꢁ1): 3186, 2928, 2857, 1689, 1603; 1H NMR (CDCl3) d: 1.85–
2.40 (m, 4H), 3.50–3.87 (m, 2H), 4.40–4.80 (m, 2H), 4.97–5.39 (m,
2H), 6.90–7.33 (m, 6H), 7.34–7.67 (m, 1H), 7.87 and 8.06 (d,
J = 7.71, 1H, rotamers), 8.75 (dd, J = 8.34, 4.17 Hz, 1H), 11.58 (d,
J = 7.57 Hz, 1H); 13C NMR (CDCl3) d: 23.5, 24.2, 29.6, 30.6, 31.4,
47.0, 47.4, 62.3, 67.4, 67.6, 114.5, 115.0, 120.0, 122.8, 122.9,
127.8, 128.0, 128.2, 128.4, 131.6, 131.7, 135.0, 135.9, 136.2, 141.0,
141.3, 155.1, 155.9, 170.9, 171.1, 171.2, 171.4, 171.7; HRMS (ESI+)
for C20H20N2O5; Calculated: 369.1445 [M+H]+. Found: 369.1442.
4.2.5.2.
9b.
(S)-N-(Benzoylcarbamoyl)pyrrolidine-2-carboxamide
The procedure described for the Cbz-deprotection of 4a
was followed for (S)-benzyl 2-((benzoylcarbamoyl) carbamoyl)
pyrrolidine-1-carboxylate (617 mg, 1.7 mmol). After completion
of the reaction (6 h) and the usual work-up followed by column
chromatographic purification using ethyl acetate/petroleum ether
(1:2) as eluent, 9b (380 mg, 86%) was obtained as a white solid.
4.2.6.3.
11.
(S)-2-(Pyrrolidine-2-carboxamido)benzoic
The procedure described above for the Cbz-deprotection
acid
of 4a was followed for (S)-2-(1-((benzyloxy)carbonyl pyrrolidine-
2-carboxamido)benzoic acid (1.29 g, 3.5 mmol). After stirring vig-
orously under a balloon pressure of hydrogen for 6 h, the usual
work-up afforded the crude product, which was purified by a filtra-
tion column using methanol/dichloromethane (1:4) as the eluent to
yield 11 (750 mg, 92%) as a white solid. Mp 240–242 °C (Lit.22b 225–
Mp 94–96 °C; Rf (40% EtOAc/PE):0.2; ½a D25
¼ ꢁ76:4 (c 1.27, CHCl3);
ꢀ
IR (Neat)
v
(cmꢁ1): 3373, 3175, 3061, 2951, 2922, 2857, 1758,
1728, 1710, 1658, 1624, 1230, 1112, 1080; 1H NMR (CDCl3) d:
1.65–2.34 (m, 4H), 3.15–3.30 (m, 1H), 3.62–3.77 (m, 1H), 4.14
(dd, J = 9.10, 7.45 Hz, 1H), 6.29 (br s, 2H), 7.40–7.60 (m, 3H), 7.78–
7.88 (m, 2H), 8.93 (br s, 1H); 13C NMR (CDCl3) d: 27.0, 27.2, 45.1,
64.6, 127.3, 128.4, 131.8, 133.2, 161.0, 170.1, 175.1; Analysis for:
227 °C); Rf (20% methanol/dichloromethane): 0.3; ½a D25
¼ ꢁ84:5 (c
ꢀ
1.04, H2O); IR (Nujol)
v
(cmꢁ1): 3359, 2948, 2923, 2857, 1690,
C13H15N3O3; Calculated: C, 59.76; H, 5.79; N, 16.08. Found: C,
1626, 1041, 1020; 1H NMR (D2O) d: 2.01–2.30 (m, 3H), 2.42–2.65
(m, 1H), 3.35–3.51 (m, 2H), 4.55 (t, J = 7.20 Hz, 1H), 7.23 (dt,
J = 7.58, 0.88 Hz, 1H), 7.48 (dt, J = 7.58, 1.52 Hz, 1H), 7.86 (dd,
J = 7.84, 1.39 Hz, 1H), 8.02 (d, J = 7.83 Hz, 1H); 13C NMR (D2O) d:
24.0, 29.3, 46.5, 60.9, 122.0, 125.2, 131.2, 133.5, 137.2, 167.5,
171.7; Analysis for: C12H14N2O3; Calculated: C, 61.53; H, 6.02; N,
11.96. Found: C, 61.47; H, 6.16; N, 11.86.
59.88; H, 6.09; N, 16.04.
4.2.6. Preparation of (S)-2-(pyrrolidine-2-carboxamido)benzoic
acid 11
4.2.6.1. (S)-Benzyl 2-((2-(methoxycarbonyl)phenyl)carbamoyl)
pyrrolidine-1-carboxylate.
A solution of N-benzyloxycar-
bonyl- -proline (1.25 g, 5 mmol) and triethylamine (0.7 mL,
L
5 mmol) in anhydrous CHCl3 (5 mL) was cooled to 0 °C. Ethyl chloro-
formate (0.48 mL, 5 mmol) was then added dropwise and the result-
ing white suspension was stirred at 0 °C for 0.5 h. Methyl
anthranilate (0.65 mL, 5 mmol) was then added and stirring was
continued for 0.5 h at the same temperature. The reaction mixture
was gradually warmed to room temperature and monitored by
TLC. After completion of the reaction (1 h), it was diluted with
dichloromethane (20 mL). The organic layer was washed succes-
sively with 1 M HCl (10 mL), saturated aqueous NaHCO3 (10 mL),
and water (10 mL). The organic layer was dried over anhydrous
Na2SO4 and concentrated. The residue was purified by column chro-
matography using ethyl acetate: petroleum ether (1:5) as the eluent
to obtain the desired product (1.5 g, 78%) as a sticky mass. Rf (20%
4.3. Representative procedure for direct aldol reactions
A 10 mL round bottomed flask was charged with the catalyst
(0.2 mmol), appropriate solvent, and acetone (0.4 mL) followed
by 4-nitrobenzaldehyde (302 mg, 2 mmol). The reaction mixture
was stirred at room temperature and monitored by TLC. After
completion of the reaction, the solvent was evaporated on a rota-
vapor and the residue was redissolved in 10 mL of ethyl acetate.
The organic layer was washed with water (5 mL) and brine
(5 mL), dried over anhydrous Na2SO4, concentrated, and the result-
ing product was purified by column chromatography using ethyl
acetate/pet ether (1:3) as the eluent. Characterization of the puri-
fied product was carried out by IR and 1H NMR. The spectroscopic
data were found to be in good agreement with the reported val-
ues.18a,c The enantiomeric excess was determined by HPLC using
a Chiralcel OJ-H column and iso-propanol/hexane (30:70) as the
mobile phase.
EtOAc/PE): 0.2; ½a 2D5 (cmꢁ1):
¼ ꢁ133:3 (c 1.23, CHCl3); IR (Neat) v
ꢀ
3268, 2953, 2882, 1699, 1603, 1586, 1525, 1267, 1156, 1090; 1H
NMR (CDCl3) d: 1.85–2.40 (m, 4H), 3.50–3.90 (m, 5H), 4.37–4.59
(m, 1H), 4.95–5.31 (m, 2H), 6.99–7.60 (m, 7H), 8.01 (d, J = 7.83 Hz,
1H), 8.74 (t, J = 8.46 Hz, 1H), 11.48 and 11.61 (s,1H, rotamers); 13
C
NMR (CDCl3) d: 23.6, 24.2, 30.3, 31.4, 46.9, 47.3, 52.2, 62.3, 67.0,
67.1, 115.3, 120.0, 120.1, 122.6, 127.7, 128.0, 128.3, 130.7, 134.4,
136.2, 136.6, 140.7, 140.9, 154.6, 155.4, 168.0, 168.4, 171.3, 171.7;
HRMS (ESI+) for C21H22N2O5; Calculated: 383.1601 [M+H]+. Found:
383.1606.
Acknowledgments
Financial support for this work was provided by the National
Chemical Laboratory (CSIR) through an ‘in house’ program. One
of us (R.L.S.) thanks the CSIR, New Delhi, for a research scholarship.
We are thankful to Mrs. S. Kunte for chiral HPLC analysis.
4.2.6.2.
(S)-2-(1-((Benzyloxy)carbonyl)pyrrolidine-2-carboxa-
mido)benzoic acid. To a solution of (S)-benzyl 2-((2-(methoxy-

R. L. Sutar, N. N. Joshi / Tetrahedron: Asymmetry 24 (2013) 43–49
49
13. (a) Fu, Y.-Q.; An, Y.-J.; Liu, W.-M.; Li, Z.-C.; Zhang, G.; Tao, J.-C. Catal. Lett. 2008,
124, 397–404; (b) Giacalone, F.; Gruttadauria, M.; Meo, P. L.; Riela, S.; Noto, R.
Adv. Synth. Catal. 2008, 350, 2747–2760; (c) An, Y.-J.; Zhang, Y.-X.; Wu, Y.; Liu,
Z.-M.; Pi, C.; Tao, J.-C. Tetrahedron: Asymmetry 2010, 21, 688–694.
14. (a) Zhang, S.; Fu, X.; Fu, S. Tetrahedron Lett. 2009, 50, 1173–1176; (b) Siyutkin,
D. E.; Kucherenko, A. S.; Zlotin, S. G. Tetrahedron 2010, 66, 513–518. and
references cited therein.
15. (a) Rankin, K. N.; Gauld, J. W.; Boyd, R. J. J. Phys. Chem. A 2002, 106, 5155–5159;
(b) Shinisha, C. B.; Sunoj, R. B. Org. Biomol. Chem. 2007, 5, 1287–1294; For
recent reviews see: (c) Houk, K. N.; Cheong, P. H.-Y. Nature 2008, 455, 309–313;
(d) Zotova, N.; Franzke, A.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc.
2007, 129, 15100–15101; (e) Zotova, N.; Broadbelt, L. J.; Armstrong, A.;
Blackmond, D. G. Bioorg. Med. Chem. Lett. 2009, 19, 3934–3937; (f) Allemann,
C.; Um, J. M.; Houk, K. N. J. Mol. Catal. A: Chem. 2010, 324, 31–38. and references
cited therein.
References
1. List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396.
2. Recent entire issue devoted to this topic see: (a) List, B. Chem. Rev. 2007, 107,
5413–5883; (b) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2011, 50, 8492–8509.
3. (a) Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123,
5260–5267; (b) Córdova, A.; Zou, W.; Ibrahem, I.; Reyes, E.; Engqvist, M.; Liao,
W.-W. Chem. Commun. 2005, 3586–3588; (c) Xu, L.-W.; Lu, Y. Org. Biomol. Chem.
2008, 6, 2047–2053.
4. For recent reviews on primary amine catalysis, see: (a) Peng, F.; Shao, Z. J. Mol.
Catal. A: Chem. 2008, 285, 1–13; (b) Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun.
2009, 1807–1821.
5. For examples of the variety of reactions that aldehyde acceptors can undergo
with proline, see: (a) Rizzi, G. P. J. Org. Chem. 1970, 35, 2069–2072; (b) Seebach,
D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am. Chem. Soc. 1983, 105, 5390–5398;
(c) Orsini, F.; Pelizzoni, F.; Forte, M.; Destro, R.; Gariboldi, P. Tetrahedron 1988,
44, 519–541; (d) Orsini, F.; Pelizzoni, F.; Forte, M.; Sisti, M.; Bombieri, G.;
16. Mangion, I. K.; Northrup, A. B.; MacMillan, D. W. C. Angew. Chem., Int. Ed. 2004,
43, 6722–6724.
17. (a) Genin, M. J.; Baures, P. W.; Johnson, R. L. Tetrahedron Lett. 1994, 35, 4967–
4968; (b) Matsushita, H.; Tsujino, Y.; Noguchi, M.; Saburi, M.; Yoshikawa, S.
Bull. Chem. Soc. Jpn. 1978, 51, 201–204; (c) Holladay, M. W.; Nadzan, A. M. J. Org.
Chem. 1991, 56, 3900–3905; (d) Enders, D.; Fey, P.; Kipphardt, H. Org. Synth.
1993, Coll. vol. 8, 26; (e) Wang, J.; Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem.
Eur. J. 2006, 12, 4321–4332; (f) Tang, G.; Hu, X.; Altenbach, H. J. Tetrahedron
Lett. 2011, 52, 7034–7037; (g) Robak, M. T.; Herbage, M. A.; Ellman, J. A.
Tetrahedron 2011, 67, 4412–4416.
18. (a) Tang, Z.; Jiang, F.; Cui, X.; Gong, L.-Z.; Mi, A.-Q.; Jiang, Y.-Z.; Wu, Y.-D. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5755–5760; (b) Fu, Y.-Q.; Li, Z.-C.; Ding, L.-N.;
Tao, J.-C.; Zhang, S.-H.; Tang, M.-S. Tetrahedron: Asymmetry 2006, 17, 3351–
3357; (c) Wu, C.; Long, X.; Li, S.; Fu, X. Tetrahedron: Asymmetry 2012, 23, 315–
328.
19. Chimni, S. S.; Singh, S.; Kumar, A. Tetrahedron: Asymmetry 2009, 20, 1722–1724.
and references cited therein.
20. For a similar study on conjugate addition reactions see: Lao, J.; Zhang, X.;
Wang, J.; Li, X.; Yan, M.; Luo, H. Tetrahedron: Asymmetry 2009, 20, 2818–2822.
21. Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed.;
Pergamon: Oxford, New York, 1988.
Benetollo, F. J. Heterocycl. Chem. 1989, 26, 837–841; For
a discussion of
oxazolidinone formation in proline-catalyzed aldol reactions and equilibrium
constants with different ketones, see: (e) List, B.; Hoang, L.; Martin, H. J. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5839–5842.
6. For recent reviews see: (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B.
Chem. Rev. 2007, 107, 5471–5569; (b) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev.
2010, 39, 1600–1632.
7. Macmillan, D. W. C. Nature 2008, 455, 304–308.
8. Pihko, P. M.; Majander, I.; Erkkilä, A. Top. Curr. Chem. 2010, 291, 29–75.
9. (a) Bure´s, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2012, 134, 6741–
6750. and references cited therein; (b) Bahmanyar, S.; Houk, K. N.; Martin, H. J.;
List, B. J. Am. Chem. Soc. 2003, 125, 2475–2479; (c) Doyle, A. G.; Jacobsen, E. N.
Chem. Rev. 2007, 107, 5713–5743.
10. Rahaman, H.; Madarász, Á.; Pápai, I.; Pihko, P. M. Angew. Chem., Int. Ed. 2011,
50, 6123–6127.
11. For recent reviews on bifunctional enamine catalysts see: (a) Kano, T.; Maruoka,
K. Chem. Commun. 2008, 5465–5473; (b) Lattanzi, A. Chem. Commun. 2009,
1452–1463; (c) Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2009, 6145–6158.
12. For a recent review on the role of double hydrogen bond donors in enamine
catalysis see: Chen, X.-H.; Yu, J.; Gong, L.-Z. Chem. Commun. 2010, 46, 6437–
6448.
22. (a) Speziale, A. J.; Smith, L. R. J. Org. Chem. 1962, 27, 3742–3743; (b) Pearson, A.
J.; Panda, S. Tetrahedron 2011, 67, 3969–3975.