Design, synthesis and catalytic property of L-proline derivatives as organocatalysts for direct aldol reaction

Article abstract of DOI:10.5012/jkcs.2013.57.5.591

A series of chiral prolinamide compounds with pyridine-2, 6-dicarboxylic acid moieties derived from L-proline have been designed and synthesized, their catalytic properties for direct asymmetric aldol reactions were also studied in this article. These catalysts gave the aldol product in high yield (87%) and high enantioselectivity, up to 85%, of the anti-structure at room temperature but gave disappointing results at a lower temperature or when additive was added. Conditions, including solvents, temperature and additives were screened for the reactions. Moreover, the influence of presence of water on yield and stereoselectivity was also discussed. Copyright

Full text of DOI:10.5012/jkcs.2013.57.5.591

Journal of the Korean Chemical Society
2013, Vol. 57, No. 5
Printed in the Republic of Korea
http://dx.doi.org/10.5012/jkcs.2013.57.5.591
Design, Synthesis and Catalytic Property of L-Proline Derivatives
as Organocatalysts for Direct Aldol Reaction
Lei Wang, Ruiren Tang*, and Hua Yang
School of Chemistry and Chemical Engineering, Central South University, Changsha, 410083, P. R. China.
*
E-mail: trr@csu.edu.cn
(Received June 2, 2013; Accepted August 28, 2013)
ABSTRACT. A series of chiral prolinamide compounds with pyridine-2, 6-dicarboxylic acid moieties derived from L-proline have
been designed and synthesized, their catalytic properties for direct asymmetric aldol reactions were also studied in this article.
These catalysts gave the aldol product in high yield (87%) and high enantioselectivity, up to 85%, of the anti-structure at room
temperature but gave disappointing results at a lower temperature or when additive was added. Conditions, including solvents, tem-
perature and additives were screened for the reactions. Moreover, the influence of presence of water on yield and stereoselec-
tivity was also discussed.
Key words: Amides, Asymmetric catalysis, Asymmetric synthesis, Stereoselectivity, Stereoselective synthesis
Proline has attracted significant attention in this area −
INTRODUCTION
8,9
particularly in the role of catalyzing aldol reactions.
Aldol reactions play an important role in the develop-
ment of organic synthesis-owing to their critical importance
for the forming of carbon-carbon bond while concur-
rently one or two chiral centers come into beings. The first
aldol reaction catalyzed by non-metal catalyst: Hajos-Par-
Despite the utility of proline in facilitating aldol reactions,
13
it’s not without its shortcomings : the reactivity and selec-
tivity of some of these proline-catalyzed aldol reactions
have serious limitations because of the difficulty in struc-
turally modifying proline; a substoichiometric amount of
proline is often necessary to achieve reasonable yields in
the direct aldol reaction; proline is known to react with
electron-deficient aromatic aldehydes to form iminium salts,
which undergo decarboxylation, even at room tempera-
ture. Consequently, many organocatalysts (Fig. 1)derived
from proline were discovered or synthetized, they have
been created to provide an improved reactivity profile and
are widely used in Aldol reaction, Mannich reaction and
Michael reaction. Two commonly employed classes are
1
rish-Eder-Sauer-Wiechert reaction discovered by Hajos,
Parrish, etc. in 1970s, claimed the generation of organo-
catalyst for enantioselective aldol reaction. They took achiral-
ity triketone as substrate, which was treated with 30 mol%
2
loading (S)-(−)-proline as catalyst, and got exciting results.
The discovery that proline is a successful catalyst for
aldol reaction lighted the interest in organocatalyst and it
also has allowed previously difficult reactions to be suc-
cessfully accomplished in a stereoselective manner. More-
over, the widespread presence of this functionality in natural
products has made their construction a central focus of
10
11
12
the tetrazole a and sulfonamides b1−b3 , c1−c3. Deriv-
atives of 4-trans-hydroxyproline (e.g., Fig. 1, b1−b3) have
3
4,5
organic chemistry. In 2000, List and Barbas etc. performed
direct aldol reaction between acetone and p-nitrobenzal-
dehyde, catalyzed by (S)-proline, resulting in 68% yield
14
been utilized in organocatalysis; however, in actual syn-
thesis of these organocatalysis, only one enantiomer of
trans-hydroxyproline is readily available. It's also worth
noting that most processes employed DMF or DMSO as
reaction solvents, this obviously added the difficulty for
6
and 76% ee . This reaction was called List-Barbas aldol
reaction (Scheme 1), which is regarded as the real start of
7
resurgence of organocatalysis.
Figure 1. Examples of proline-derived organocatalysts.
Scheme 1. List-Barbas aldol reaction.
-591-

592
Lei Wang, Ruiren Tang, and Hua Yang
o
KOH pellets in methanol at 0 C to provide 8, filtration
procedure is avoided by an improved postprocedure com-
22
paring with the literature method. The condensation reaction
between 8 and corresponding amide provided 9a−c. The
other key intermidate 10a−c was got by the hydrolysis of
the remained ether function of 9a−c. Combine 6 and 10a−c
by condensation reaction, then deprotect the N-Boc group
of the resulted 11a−c, the organocatalysts 12a−c were finally
obtained.
Aldol reaction between acetone or cyclohexanone and
p-nitrobenzaldehyde is widely taken as template reaction
23
to test the catalytic effects of catalyst newly synthetized.
Herein, we tested this series of catalysts in the reactions
between p-nitrobenzaldehyde and cyclohexanone. The affec-
tion of catalyst, solvent, additive and the presence of water
was respectively detected so as to optimize reaction con-
dition and thus to get the best results. In view of the sim-
ilarity of 12a−c, only 12a was taken to screen the factors
in the experiments followed.
Scheme 2. General synthesis route of designed organocatalysts
12a−c.
product isolation. In response to these challenges, we
designed and synthetized a series of organocatalysts 12a−c
(Scheme 2), and we hoped that they could provide improved
results in the following test of catalytic performance.
The structures of designed catalysts 12a−c are shown in
Scheme 2. N-methylpicolinamide and N-sulfonyl amide
groups were introduced because of the previous reports,
N-methylpicolinamide was found to be a suitable group to
RESULTS AND DISCUSSIONS
Solvent employed in reaction was primary screened
(Table 1) in order to simplify the following procedure.
As is shown in Table 1, variety of solvents resulted in
enormous variation in yield and enantioselectivity: the
adduct obtained in DCM, DCE, and solvent-free systems
presented better results both in terms of diastereoselec-
tivity and enantioselectivity than others, especially the
value of dr in DCE, it’s obviously higher than the others.
Interestingly, enantiomeric excess for syn-diastereomer was
remarkable when MeOH or water was used as reaction
solvent, this phenomenon has been previously observed
15,16
bind a carboxyl molecule; and the hydrogen bond between
the aldehyde C–H and the sulfonamide S–O was consid-
ered as the key to the increased diastereoselectivity in “hua
17,18
cat”.
Their presence would theoretical possibly bring
improvement in both reactivity and stereoselectivity. The
introduction of alkyl group connecting with phenyl is
expected to improve the solubility of the catalysts in com-
monly used organic solvents. Designed in this way, extra
active sites were created; catalysts were estimated to per-
form in an enzyme-catalyzed manner. Catalytic effects of
the catalysts that enhanced binding effects and improved
stereoselectivity and solubility with small catalyst loading
are aspired to acquire.
24
and reported, so MeOH and water were also tested as
solvents in the following experiments hoping to get higher
enantiomeric excess for syn-diastereomer under optimized
conditions. Lower temperature didn’t lead to higher yield
or enantioselecetivity as many workgroups reported. In
view of these results, DCM, DCE, MeOH and water were
taken as solvents in the following experiments (Table 2, 3)
Dimethyl 2,6-pyridinedicarboxylate, a kind of inexpen-
sive industrial product, is easily modified to bifunctional
compound, so it’s taken as the carrier of 2-N-methylpicolina-
mide and N-sulfonyl groups. Detailed procedures for pre-
paring organocatalysts 12a–c are outlined in Scheme 2.
Catalysts 12a−c were synthesized in several steps start-
ing from commercially available L-proline and Dimethyl
2,6-pyridinedicarboxylate. First, L-proline was reduced to
o
at 20 C in which we would screen the best conditions for
this system.
Addition of any of these additives didn’t lead to higher
yield or stereoselectivity, on the contrary, it lowered ste-
reoselectivity by a great extent. The reaction process in MeOH
or DCE was even restrained when ZnCl2 was added, how-
ever, accelerated in DCM. The presence of water didn’t
bring any obvious alteration on both yield and stereose-
lectivity, so it’s not considered as the affecting factors for
N-Boc-(S)-2-aminomethyl-pyrrolidine, 6 through a very
20,21
mature route.
The dimethyl ester was hydrolyzed selec-
tively at only one of its two ester functions by 1.0 equiv
Journal of the Korean Chemical Society

Design, Synthesis and Catalytic Property of L-Proline Derivatives as Organocatalysts for Direct Aldol Reaction
593
a
Table 1. Primary selection of solvent employed in aldol reaction.
b
Yield (%)
c
Dr (anti/syn)
c
Ee (%) (anti)
Entry
Solvent
MeOH
DCM
Time (h)
72
Temperature (°C)
d
1
2
20
20
20
20
20
20
20
20
20
0
22
76
62:38
72:28
74:26
68:32
87:13
54:46
63:37
49:51
−
21(84)
72
85
48
28
68
3
CHCl3
DMF
72
26
4
72
19
5
DCE
72
54
d
6
Water
Neat
72
30
13(62)
7
72
84
76
47
−
8
DMSO
n-hexane
DCM
72
43
9
72
Trace
57
10
11
120
120
69:31
80
DCE
0
44
66:34
75
a
o
All the reactions were performed with 1.0 mmol of p-nitrobenzaldehyde, 1.0 mL of cyclohexanone, 10 mol.% catalyst 12a, at 0 C or 20 C.
o
b
Isolated yield.
c
Determined by chiral HPLC for anti-diastereomer.
d
Enantiomeric excess determined by chiral HPLC for syn-diastereomer.
a
Table 2. Screening of various solvents and additives using catalyst 12a.
b
Yield (%)
c
Dr (anti/syn)
d
Ee (%)
Entry
Additive
Benzyl acid
Benzyl acid
Benzyl acid
Benzyl acid
Benzyl acid
ZnCl2
Solvent
Neat
Time (h)
72
1
2
99
53
68:32
72:28
72:28
43
e
Water
DCM
MeOH
DCE
72
33(66)
3
72
78
84
4
72
Trace
71
5
72
60:40
55:45
21
14
6
DCM
MeOH
DCE
72
99
7
ZnCl2
72
Trace
Trace
75
8
ZnCl2
72
9
Acetic acid
o-nitrobenzoic acid
DCM
DCM
72
50:50
83:17
43
10
72
87
45
a
o
All the reactions were performed with 1.0 mmol of p-nitrobenzaldehyde, 1.0 mL of cyclohexanone, 10 mol % catalyst 12a, 20 C.
b
Isolated yield.
c
Determined by chiral HPLC.
d
Determined by chiral HPLC for anti-diastereomer.
e
Determined by chiral HPLC for syn-diastereomer.
this series of catalysts. What’s disappointing, desired higher
enantiomeric excess for syn-diastereomer reactions in MeOH
or water by the addition of additives and (or) water was
not observed.
tion with its own regularity was discovered that for any of
the three catalysts, products obtained in DCM have gen-
eral higher yield and enantioselectivity than that obtained
in DCE. However, products obtained under the same con-
ditions have general higher diastereoselectivity when DCE
was employed as solvents. The variation of R-group didn’t
change the reaction mechanism, so the enantioselectivity
of the products in Table 4 was similar to each other.
The results for catalysts 12a−c are presented in Table 4,
moderate yield and high stereoselectivity (up to 85% ee
and 72:28 dr for 12a in DCM, up to 90:10 dr and 83% ee
for 12c in DCE) were obtained. Some exciting informa-
2013, Vol. 57, No. 5

594
Lei Wang, Ruiren Tang, and Hua Yang
a
Table 3. Effect of presence of water using catalyst 12a.
b
Yield (%)
c
Dr (anti/syn)
d
Ee (%)
Entry
Additive
Benzyl acid
Benzyl acid
Benzyl acid
Benzyl acid
ZnCl2
Solvent
Neat/H2O
DCM/H2O
MeOH/H2O
DCE/H2O
DCM/H2O
MeOH/H2O
DCE/H2O
DCM/H2O
DCM/H2O
Time (h)
72
1
2
3
4
5
6
7
8
9
99
92
66:34
72:28
62:38
60:40
63:37
76
30
72
e
72
18
18(31)
72
73
2
72
99
−44
ZnCl2
72
Trace
Trace
59
ZnCl2
72
Acetic acid
o-nitrobenzoic acid
72
88:12
74:26
11
57
72
66
a
All the reactions were performed with 1.0 mmol of p-nitrobenzaldehyde, 1.0 mL of cyclohexanone, 10 mol % catalyst 12a, 4 equiv H2O,
o
20 C.
b
Isolated yield.
c
Determined by chiral HPLC.
d
Determined by chiral HPLC for anti-diastereomer.
e
Determined by chiral HPLC for syn-diastereomer.
a
Table 4. Screening of various catalysts.
b
Yield (%)
c
Dr (anti/syn)
d
Ee (%)
Entry
Cat
12a
12a
12b
12b
12c
12c
Solvent
DCM
DCE
Time (h)
72
1
2
3
4
5
6
76
54
81
67
87
59
72:28
87:13
66:34
71:29
82:18
90:10
85
68
81
78
83
72
72
DCM
DCE
72
72
DCM
DCE
72
72
a
All the reactions were performed with 1.0 mmol of p-nitrobenzaldehyde, 1.0 mL of cyclohexanone, 10 mol.% catalyst 12a−c, without addi-
o
tive or water, 20 C.
b
Isolated yield.
c
Determined by chiral HPLC.
dDetermined by chiral HPLC for anti-diastereomer.
Synthesis Section
= doublet; dd = doublet of doublets; q = quartet; t = triplet;
br = broad; m = multiplet, coupling constant expressed in
Hertz, integration, assignment of peak. FTIR spectra were
recorded on a Varian 660-IR FTIR spectrometer and KBr
discs were produced using a KBr press. Melting points
were measured on a digital melting point apparatus. Opti-
cal rotations were measured on an AA series polAAr 20
automatic polarimeter. Analytical high performance liq-
uid chromatography (HPLC) was carried out on Agilent
1200 instrument equipped with a diode array ultra-violet
(UV) detector using Chiralpak AD (4.6 mm×250 mm).
General
All reagents were commercial products. The reactions
were monitored by TLC (thin layer chromatography). The
column and preparative TLC purification were carried out
using silica gel. Flash column chromatography was per-
formed on silica gel (200–300 mesh). NMR spectra were
recorded on a Bruker Avance 400 spectrometer at ambient
temperature using CDCl3 or DMSO-d6 as solvents with tet-
ramethylsilane (TMS) as an internal standard. Chemical
shifts (δ) are given in ppm relative to TMS as the internal
reference. Spectral patterns are designated as s = singlet; d
Journal of the Korean Chemical Society

Design, Synthesis and Catalytic Property of L-Proline Derivatives as Organocatalysts for Direct Aldol Reaction
595
Preparation and Characterization Data of Compounds
Then, the organic layer was dried with anhydrous sodium
20,21
sulphate, filtered and concentrated under reduced pres-
sure, affording a colorless oil. The crude product was puri-
fied by flash chromatography through deactivated silica,
eluting with 15:1 dichloromethane-ethyl acetate mixture.
After evaporation of the solvents, the title product was
obtained as colorless oil (16.6 g, 47mmol, 97% yield).
2−6
Preparation of L-prolinol, 2.
Lithium aluminium hydride (7.6 g, 200 mmol) was placed
in a 1 L reactor equipped with magnetic stirring, cooled to
o
0 C. Then, dry, newly distilled THF (200 mL) was added
o
and, after the temperature became stable again at 0 C, L–
20
[α] = −39.7 (c = 1.08, CHCl3) The H NMR was identical
D
1
proline (15 g, 130 mmol) was introduced portionwise as a
solid, controlling the temperature to keep the system stay
boiling without extra heat. The resulting mixture was refluxed
for an hour and a half. After this time, the mixture was
cooled to room temperature then 20% aqueous KOH solu-
tion (30 mL) was carefully added, and the mixture was fil-
tered through Buchner funnel. The residue was refluxed
with another 200 mL dry THF for 30 mins, then filtered
through Buchner funnel. Filtrate was combined and con-
centrated under vacuum to afford clear oil (12.6 g, 127 mmol,
97% yield). The product was stored in the refrigerator
without further purified until it was used.
17
1
to the previously reported data : H NMR (400 MHz,
CDCl3): δ 1.37 to 1.41 (br, 9H), 1.80 to 1.92 (m, 4H), 2.44
(s, 3H), 3.27 to 3.35 (m, 2H), 3.89 to 4.15 (m, 3H), 7.34
(br, 2H), 7.78 (d, 2H).
Preparation of (S)-tert-Butyl-2-(azidomethyl)pyrro-
lidine-1-carboxylate, 5.
(S)-tert-Butyl-2-(tosyloxymethyl)pyrrolidine-1-carbox-
ylate (6.3 g, 17.7 mmol) was dissolved in dry DMSO (150
mL) and sodium azide (5.8 g, 90 mmol) was added. The
o
reaction mixture was heated to 64 C and stirred at this
temperature for 27 h. After this time, the mixture was allowed
to cool down to room temperature and it was diluted with
diethyl ether (150 mL). The organic layer was washed
with 3×80 mL water and 2×80 mL brine, dried with anhy-
drous sodium sulphate and concentrated under reduced
pressure, to obtain the title product as a colorless oil (3.8 g,
16.8 mmol, 89% yield). The product was not further puri-
fied and was stored in the refrigerator until it was used.
Preparation of N-Boc-L-prolinol, 3.
L-prolinol (12.6 g, 127 mmol) was diluted with dry
THF (160 mL) in a 400 mL flask and then a solution con-
taining Boc2O (27.3 g, 127 mmol) in THF (80 mL) was
slowly added. The resulting mixture was stirred for 19 h at
room temperature and then 20% aqueous citric acid solu-
tion (100 mL) was added. The layers were separated; the
organic one was washed with saturated NaCl solvent (3×50
mL), dried with anhydrous sodium sulphate, filtered and
concentrated under vacuum to afford a clear oil. The prod-
uct was purified by flash chromatography through deac-
tivated silica, eluting with methanol-dichloromethane (1:19)
mixtures to obtain, after removal of the solvents, the title
product as a faint yellow oil (23.3 g, 115 mmol, 91% yield).
20 1
[α] = −45.4 (c = 1.18, CHCl3) The H NMR was iden-
D
18
1
tical to the previously reported data : H NMR (400 MHz,
d6-DMSO): δ 1.45 (s, 9H), 1.74 to 1.82 (m, 2H), 1.86 to 1.93
(m, 1H), 1.98 to 2.05 (m, 1H), 3.26 (m, 1H), 3.36 to 3.41
(m, 2H), 3.49 (dd, 1H), 3.88 to 3.91 (m, 1H);
Preparation of N-Boc-(S)-2-aminomethylpyrrolidine, 6.
N-Boc-(S)-2-azidomethylpyrrolidine, 5 (3.2 g, 14 mmol)
was dissolved in anhydrous tetrahydrofuran (100 mL),
triphenylphosphine (8.0 g, 30.5 mmol) and H2O (0.5 mL)
were added to it. The reaction mixture was heated to
reflux temperature for 22 h until all starting material had
been consumed (TLC monitoring). The organic solvent
was then removed under reduced pressure and the remain-
ing oil was dissolved in diethyl ether (200 mL). The pH of
solution was adjusted to around 2 by using 1.0 mol/L HCl
solution with vigorous stirring, and the aqueous phase was
washed with diethyl ether (2×40 ml). The pH of the aque-
ous phase was adjusted to 13 by using 2.0 mol/L NaOH
solution and extracted with CH2Cl2 (6×30 mL). The organic
phase was dried with anhydrous sodium sulphate and con-
centrated under reduced pressure to afford the crude prod-
20 1
[α] = −39.7 (c = 1.2, CHCl3) The H NMR was identical
D
17
1
to the previously reported data : H NMR (400 MHz,
CDCl3): δ1.48 (s, 9H), 1.53 to 1.60 (m, 1H), 1.73 to 1.90
(m, 2H), 1.98 to 2.06 (m, 1H), 3.29 to 3.35 (m, 2H), 3.44
to 3.49 (m, 1H), 3.57 to 3.67 (m, 2H), 3.89 to 3.98 (br,
1H).
Preparation of (S)-tert-Butyl 2-(tosyloxymethyl)pyrro-
lidine-1-carboxylate, 4.
N-Boc-L-prolinol (9.7 g, 48 mmol) was dissolved in the
mixture of 100 mL dichloromethane and 5 mL pyridine,
o
cooled down to 0 C. Then, p-toluenesulphonyl chloride
(9.2 g, 48 mmol) was added, the mixture was stirred at room
temperature for 16 h. After this time, the reaction mixture
was diluted with diethyl ether (150 mL) and washed with
1 M hydrochloric acid (3×100 mL), saturated sodium bicar-
bonate solution (3×100 mL) and, finally, water (2×100 mL).
uct 6 (2.3 g, 11.5 mmol, 82% yield) as colorless oil, which
20
was not further purified for the further procedure. [α] = −56.2
D
2013, Vol. 57, No. 5

596
Lei Wang, Ruiren Tang, and Hua Yang
1
(c = 1.2, CHCl3) The H NMR was identical to the pre-
1
H NMR (400 MHz, CDCl3) δ 0.63 to 0.79 (m, 6H) 0.97
to 1.17 (m, 13H) 1.51 to 1.57 (m, 4H) 2.45 to 2.47 (t, 2H)
3.95 (s, 3H) 7.17 to 7.20 (b, 2H) 7.38 to 7.40 (b, 2H) 7.94
to 7.98 (t, 1H) 8.18 to 8.19 (b, 1H) 8.35 to 8.36 (b, 1H).
(S)-tert-butyl 2-((6-(tosylcarbamoyl)picolinamido)methyl)
pyrrolidine-1-carboxylate, 11a.
18
1
viously reported data : H NMR (400 MHz, CDCl3): δ
1.40 (s, 9H), 1.49 (m, 2H), 1.75 (m, 4H), 2.62(m, 1H),
2.77 (b, 1H), 3.26 (m, 2H), 3.75 (m, 2H).
Synthesis of 6-(methoxycarbonyl)pyridine-2-carbox-
22
ylic acid, 8.
o 20
White solid, melting point 96−99 C, 59% yield, [α] =
Dimethyl 2,6-pyridinedicarboxylate (7.0 g, 36.0 mmol)
was dissolved in methanol (150 mL), then the mixture was
D
1
−27.2 (c = 1.0, CHCl3). H NMR δ 1.45 (s, 9 H), 1.88 to
o
cooled to 0 C and KOH (2.1 g, 36.0 mmol) was slowly
1.91 (m, 4H), 1.97 to 2.05(m, 2H), 2.47 (s, 3H) 3.37 to
3.50 (m, 1H), 3.51 to 3.57 (m, 1H), 3.91 to 4.11 (m, 2H),
7.25 to 7.30 (b, 2H), 7.97 to 8.01 (t, 1H) 8.08 to 8.11(b,
o
added, the reaction mixture was stirred at 0 C for 2 h and
then at room temperature for 24 h. After that the solvent
was removed under reduced pressure, and the residue was
suspended in H2O (100 mL), extracted with ethyl acetate
(3×30 mL). The pH of aqueous layer was adjusted to about
2 with 1M HCl solution and extracted with chloroform
(5×30 mL). The combined organic layers were dried over
anhydrous sodium sulphate and concentrated under reduced
pressure to provide the desired product 8 (4.3 g, 24 mmol,
−1
2H), 8.19 to 8.21 (b, 1H), 8.36 to 8.38 (b, 1H); IR (KBr), v/cm :
3595−3390,2974, 1708, 1658, 1186.
(S)-tert-butyl 2-((6-((mesitylsulfonyl)carbamoyl)picolina-
mido)methyl)pyrrolidine-1-carboxylate, 11b.
o
White solid, melting point 127−129 C, 61% yield,
20 1
[α] = −23.5 (c = 1.0, CHCl3). H NMR δ 1.48 (s, 9H), 1.87
D
to 1.90 (m, 4H), 1.98 to 2.16 (m, 2H), 2.31 (s, 3H), 2.74 (s,
6H), 3.38 to 3.51 (m, 1H), 3.53 to 3.58 (m, 1H), 4.43 to
4.45 (m, 2H), 6.94 (s, 2H), 7.95 to 8.00 (t, 1H), 8.18 to
8.21 (b, 1H), 8.35 to 8.36 (b, 1H).
o 1
66.5% yield) as a white solid: m.p. 144−146 C. The H
1
NMR was identical to the previously reported data: H NMR
(400 MHz, DMSO-d6): δ8.12 to 8.24 (m, 3H), 3.93 (s, 3H); IR
−1
(KBr), v/cm : 3670-3073, 2964, 2852, 1725, 1581, 1325.
(S)-tert-butyl 2-((6-(((4-dodecylphenyl)sulfonyl)car-
bamoyl)picolinamido)methyl)pyrrolidine-1-carboxy-
late, 11c.
26
General synthesis of compounds 9a−c, 11a−c
o 20
White solid, melting point 58−60 C, 52% yield, [α] =
6-(methoxycarbonyl)pyridine-2-carboxylic acid, 8 was
dissolved in dichloromethane, 1 equivalent of corresponding
amine (for 11a−c) or R-sulfamide (for 9a−c), EDCI, DMAP
was added consecutively. The reaction mixture was stirred at
room temperature for 72 h. After that the solution was
washed with 10% HCl solution and distilled water, the
organic layer was dried over anhydrous sodium sulphate
and concentrated under reduced pressure to provide an orange
red oil, the crude product was purified by flash chroma-
tography through deactivated silica, eluting with 19:1 dichlo-
romethane-methanolmixture. Afterevaporationof thesolvents,
the title product was obtained as white solid.
D
1
−19.7 (c = 1.0, CHCl3). H NMR δ 0.61 to 0.77 (m, 6H)
0.95 to 1.15 (m, 13H), 1.48 (s, 9H), 1.52 to 1.59 (m, 4H),
1.76 to 1.85 (m, 2H), 1.96 to 2.23 (m, 4H), 3.38 to 3.51 (m,
1H), 3.53 to 3.58 (m, 1H), 3.84 to 4.05 (m, 2H), 7.17 to
7.19 (b, 2H), 7.22 to 7.24 (b, 2H), 7.95 to 7.97 (t, 1H), 8.17
to 8.19 (b, 1H), 8.33 to 8.35 (b, 1H).
25
General synthesis of compounds 10a−c
9a−c in mixed solvent (dichloromethane:methanol = 3:2)
o
was cooled to 0 C, 2equipment of 3M NaOH aqueous
solution was added dropwise. The reaction mixture was
o
stirred at 0 C for 2 h, and then at room temperature for 12 h.
Methyl 6-(tosylcarbamoyl)picolinate, 9a.
o
1
White solid, melting point 229−231 C, 65% yield. H
NMR (400 MHz, DMSO-d6): δ 2.32 (s, 3H), 3.94 (s, 3H),
7.18 to 7.20 (b, 2H), 7.70 to 7.71(b, 2H), 8.05 to 8.19 (m,
The organic solvent was removed under reduced pressure
and the residual was distilled with water. The aqueous
solution was washed with ethyl acetate, after that pH of
the aqueous layer was acided to 2 by 3M HCl solution, the
resulted solvent was extracted repeatedly with dichlo-
romethane, after that the organic layers were dried over
anhydrous sodium sulphate and concentrated under reduced
pressure to provide the titled product as white solid.
6-(tosylcarbamoyl)picolinic acid, 10a.
−1
2H), 8.17 to 8.19 (b, 1H); IR (KBr), v/cm : 3471−3267,
2924, 1754, 1596, 1340.
Methyl 6-((mesitylsulfonyl)carbamoyl)picolinate, 9b.
o
1
White solid, melting point 230−231 C, 71% yield. H
NMR (400 MHz, CDCl3) δ 2.31 (s, 3H) 2.73 (s, 6H) 7.06 (s,
2H) 7.94 to 7.98 (t, 1H) 8.18 to 8.20 (b,1H) 8.35 to 8.37 (b, 1H).
Methyl 6-(((4-dodecylphenyl)sulfonyl)carbamoyl)picoli-
nate, 9c.
o
1
White solid, melting point 234−235 C, 92% yield. H NMR
δ 2.45 (s, 3H), 7.38 to 7.40 (b, 2H), 8.10 to 8.12 (t, 1H),
8.13 to 8.15 (b, 2H), 8.38 to 8.40 (b, 1H), 8.42 to 8.45 (b,
o
White solid, melting point 189−191 C, 69% yield.
Journal of the Korean Chemical Society

Design, Synthesis and Catalytic Property of L-Proline Derivatives as Organocatalysts for Direct Aldol Reaction
597
−1
1H); IR (KBr), v/cm : 3466, 2956, 1711, 1580, 1331.
2 6
(S)-N -(pyrrolidin-2-ylmethyl)-N -tosylpyridine-2,
6-((mesitylsulfonyl)carbamoyl)picolinic acid, 10b.
6-dicarboxamide, 12a.
o
1
o
White solid, melting point 147−150 C, 99% yield,
White solid, melting point 229−231 C, 91% yield. H
NMR δ2.30 (s, 3H), 2.75 (s, 6H), 7.08 (s, 2H), 8.08 to 8.10 (t,
1H), 8.27 to 8.30 (b, 1H), 8.41 to 8.43 (b, 1H).
6-(((4-dodecylphenyl)sulfonyl)carbamoyl)picolinic acid,
10c.
20 1
[α] = −27.1 (c = 1.0, CHCl3). H NMR δ 1.85 to 1.88 (m,
D
4H), 2.08 to 2.15 (m, 2H), 2.32 (s, 3H), 3.42 to 3.45 (m,
1H), 3.62 to 3.67 (m, 1H), 4.01 to 4.09 (m, 2H), 7.12 to
7.25 (b, 2H), 7.78 to 7.90 (t, 1H) 8.18 to 8.21(b, 2H), 8.24
o
1
−1
White solid, melting point 195−197 C, 82% yield. H
NMR δ 0.60 to 0.76 (m, 6H), 0.96 to 1.15 (m, 13H), 1.53
to 1.59 (m, 4H), 2.46 to 2.47 (t, 2H), 7.21 to 7.24 (b, 2H),
7.76 to 7.78 (b, 2H), 8.14 to 8.16 (t, 1H), 8.35 to 8.37 (b,
1H), 8.43 to 8.45 (b, 1H).
to 8.25 (b, 1H), 8.33 to 8.35 (b, 1H); IR (KBr), v/cm :
3243, 2976, 2750 ,1708, 1670.
2
6
(S)-N -(mesitylsulfonyl)-N -(pyrrolidin-2-ylmethyl)
pyridine-2,6-dicarboxamide, 12b.
o
White solid, melting point 165−167 C, 99% yield,
20 1
[α] = −21.4 (c = 1.0, CHCl3). H NMR δ 1.88 to 1.90 (m,
D
4H), 1.90 to 2.14 (m, 2H), 2.30 (s, 3H), 2.77 (s, 6H), 3.42
to 3.44 (m, 1H), 3.64 to 3.68 (m, 1H), 4.01 to 4.04 (m,
2H), 7.12 to 7.24 (b, 2H), 7.78 to 7.91 (t, 1H) 8.17 to 8.21
(b, 2H), 8.24 to 8.25 (b, 1H), 8.34 to 8.35 (b, 1H).
General Procedure of Aldol Reaction Between of p-
22,23
nitrobenzaldehyde and Cyclohexanone
1.51 g (1.0 mmol) p-nitrobenzaldehyde and 1.0 mL (9.6
mmol) cyclohexanone in 5 mL selected solvent was mixed in
a 10 mL reaction flask, then 0.10 mmol catalyst (and 4 equiv
water when needed) was added. The mixture was stirred
for 72 h at given temperature. After that, solvent was removed
under reduced pressure, the resulted residual was purified
by flash chromatography through deactivated silica, elut-
ing with 3:2 ethyl acetate-petroleum ether mixture. After
evaporation of the solvents, the resulted adduct was obtained
2
6
(S)-N -((4-dodecylphenyl)sulfonyl)-N -(pyrrolidin-
2-ylmethyl)pyridine-2,6-dicarboxamide, 12c.
o
White solid, melting point 128−130 C, 99% yield,
20 1
[α] = −19.9 (c = 1.0, CHCl3). H NMR δ 0.62 to 0.77 (m,
D
6H) 0.96 to 1.16 (m, 13H), 1.53 to 1.59 (m, 4H), 1.76 to
1.85 (m, 2H), 1.99 to 2.43 (m, 4H), 3.24 to 3.26 (m, 1H),
3.36 to 3.40 (m, 1H), 3.82 to 4.04 (m, 2H),7.18 to 7.19 (b,
2H), 7.22 to 7.24 (b, 2H), 7.95 to 7.97 (t, 1H), 8.18 to 8.19
(b, 1H), 8.34 to 8.35 (b, 1H).
o
1
as white solid, melting point 147−149 C. H NMR for
anti, δ1.31 to 1.45 (m, 1H), 1.51 to 1.67 (m, 3H), 1.78 to 1.87
(m, 1H), 2.06 to 2.17 (m, 1H), 2.36 (m, 1H), 2.45 to 2.65
(m, 2H), 4.09 (d, J=3.0 Hz, 1H, OH), 4.90 (br s, 1H,
CHOH), 7.51(d, 2H), 8.21 (d, 2H); for syn, 3.20 (br, 1H,
CONCLUSION
−1
OH), 5.48 (br s, 1H, CHOH); IR (KBr), v/cm : 3730−
Generally, attempts to improve the enantioselectivity of
catalyst 12a by varying additive, water and temperature
proved rewardless, for the best results were acquired under
the original given condition. However the solvents were found
to have significant effect on yield and stereoselectivity of
the products.
3300, 2924, 1699, 1519, 1346, 854; Enantiomeric excess
was determined by HPLC with a Chiralpak AD column
o
(hexane/2-propanol = 70:30), 20 C, 254 nm,0.5 mL/min,
tR (syn isomer) = 10.08 min (minor), 10.70 min (major); tR
(anti isomer) = 11.44 min (minor), 14.28 min (mayor).
The stereochemistry of the aldol reaction can be ratio-
nalized through the proposed transition state (Fig. 2). Here
the carbonyl group of the aldehyde is activated by hydro-
22
General procedure of deprotection of 11a–c for 12a−c
o
11a−c dissolved in dichloromethane was cooled to 0 C,
10 equiv of concentrated hydrochloric acid was added.
The resulted mixture was stirred for 9 h, then the organic
layer was removed under reduced pressure. The residual
was diluted with dichloromethane and methanol (3:1),
the pH of the solution was basified by ammonia to
around 10. The mixture was concentrated under reduced
pressure to obtain dry white solid, this crude product was
purified by flash chromatography through deactivated
silica, eluting with 15:5 dichloromethane-methanol mix-
ture. After evaporation of the solvents, the title product
was obtained.
Figure 2. Proposed transition state models for the aldol reaction
catalyzed by 12a−c.
2013, Vol. 57, No. 5

598
Lei Wang, Ruiren Tang, and Hua Yang
Tetrahedron 2003, 59, 10105−10146.
gen-bonding with the amide N−H or sulfamide N−H, the
enamine attacks the aldehyde on their face and leads to the
formation of the favored anti-diastereomer as the major
product. It’s suggest that N−H of pyrrolidine and at least
one of that between 2-N-methylpicolinamide and N-sul-
fonyl amide are vitally necessary to obtain desired enan-
tioselectivity, the hydrogen bond between sulfonamide S–O
and the aldehyde C–H along with the remained N−H pro-
moted the improvement of enantioselectivity and assured
high yield. It could be because that the pyrrolidin-2-ylm-
ethyl moiety played a role of electron-donating group which
possibly brought down the reactivity of the N−H of 2-N-
methylpicolinamide, thus the reactivity of entire catalysts
was lessened to some extent. Catalysts with unreduced proline
moiety or introduction of electrophilic substituent groups in the
α-position of (S)-pyrrolidin-2-ylmethanamine are being under
consideration in order to increase the reactivity of target catalysts.
In conclusion, we have designed and synthesized a series
of proline-derived compounds with Pyridine-2,6-dicarboxylic
acid moieties 12a−c as organocatalysts for asymmetric
aldol reaction, bearing both N-methylpicolinamin and N-
sulfonyl. These catalysts gave the aldol adduct in high
yield (up to 87%) and high enantioselectivity (up to 85% ee)
under mild conditions, they were also proved to have better
solubility in most of commonly used solvents. Conditions,
including temperature, additives and solvents were screened;
however original given condition was finally proved to be
most suitable for these catalysts. Conditions needed in this
system that room temperature and absence of additive
could be considered as an improvement since in several
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o
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Acknowledgments. Financial support from the National
Natural Science Foundation of China (No.21071152) is
gratefully acknowledged. And the publication cost of this
paper was supported by the Korean Chemical Society.
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Journal of the Korean Chemical Society