Monofunctional primary amine: A new class of organocatalyst for asymmetric Aldol reaction

Article abstract of DOI:10.1007/s12039-017-1237-y

A new class of organocatalysts involving a primary amine as the only functional group is developed for catalytic asymmetric aldol reaction of cyclohexanone/cyclopentanone with various aryl aldehydes in the presence of benzoic acid as an additive at ?10

Full text of DOI:10.1007/s12039-017-1237-y

c
J. Chem. Sci. Vol. 129, No. 3, March 2017, pp. 301–312. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-017-1237-y
REGULAR ARTICLE
Monofunctional primary amine: A new class of organocatalyst
for asymmetric Aldol reaction
KHIANGTE VANLALDINPUIA, PORAG BORA and GHANASHYAM BEZ∗
Department of Chemistry, North Eastern Hill University, Shillong, Meghalaya 793 022, India
Email: ghanashyabez@yahoo.com
MS received 7 September 2016; accepted 13 January 2017
Abstract. A new class of organocatalysts involving a primary amine as the only functional group is developed
for catalytic asymmetric aldol reaction of cyclohexanone/cyclopentanone with various aryl aldehydes in the
presence of benzoic acid as an additive at −10◦C. In an unexpected observation, the primary amine catalyzed
reactions gave excellent yield and good to excellent stereoselectivity, while secondary amines were found to
have little or no reactivity under similar reaction conditions.
Keywords. D-Fructose; primary amine; monofunctional organocatalyst; asymmetric aldol.
1. Introduction
Moreover, the β-hydroxy carbonyl moiety that formed
as a result of aldol reaction, is found in many bio-
logically active compounds10 such as carbohydrates,
antibodies, alkaloids, and terpenes.
Recently, chiral primary amines1 have shown tremen-
dous synthetic potential in asymmetric functional-
ization of sterically hindered carbonyl compounds,
which cannot be functionalized using either secondary
amines or metal-based catalyst. As a result, organo-
catalysis using bifunctional/multifunctional primary
amines derived from amino acids,2 chincona,3 and
carbohydrates4 have emerged. Interestingly, most of
the asymmetric organocatalysts involving amine are
bifunctional or multifunctional in nature. In contrast,
only a few L-proline derived pyrrolidine based mono-
functional amine organocatalysts are reported for asym-
metric organocatalysis.5 Unlike the bifunctional amines
where the functional groups are involved in activa-
tion of both the donor and acceptor by forming highly
organized transition state that controls overall stereo-
chemical outcome of the product, controlling stereo-
chemical outcome employing only one functional group
remains a huge challenge. More so in case of the pri-
mary amine where it reacts with carbonyl compound to
form a less nucleophilic and unstable iminium ion6 that
have unfavorable imine-enamine equilibrium.7 To the
best of our knowledge, monofunctional primary amine
catalyzed asymmetric aminocatalysis has never been
reported (Figure 1).
Although numerous methods involving metal
enolates11 were developed to control the stereochemical
outcome of the aldol reaction, the use of L-proline as a
catalyst by List et al.,12 opened up an interesting new
field of oragnocatalysis. Since then, various organocat-
alysts bearing secondary amine,13 amides,14 chiral
bifunctional-thioureas,15 and diamines16 have been
applied for the said synthesis. Very recently, Ricci and
co-workers4a used chitosan aerogel as a heterogeneous
organocatalyst for asymmetric direct aldol reaction
in water. Zhang et al.,4b also reported D-glucosamine
derived amino alcohols catalyzed enantioselective aldol
reaction of isatins with ketones in dichloromethane.
Along the similar line, Peddinti et al.,4c reported the
use of glucosamine derived amino alcohol to achieve
organocatalytic aldol reaction. Here, we report a highly
selective asymmetric aldol reaction between aryl alde-
hydes and cyclohexanone/cyclopentanone catalyzed by
D-fructose derived monofunctional primary amine 1a
(Scheme 1).
2. Experimental
Since its discovery back in 18728 by Charles-
Aldolphe Wurtz, aldol reaction has evolved as one
of the most important and powerful carbon-carbon
bond forming reactions in modern organic chemistry.9
2.1 General remarks
Chemicals and reagents were purchased from commercial
sources and used without further purification. IR spectra
were recorded on a Perkin–Elmer Spectrum One FTIR spec-
1
∗For correspondence
trometer. H NMR (400 MHz) and 13C NMR (100 MHz)
301

302
Khiangte Vanlaldinpuia et al.
−
−
Figure 1. Schematic presentation of aminocatalysis.
−
Scheme 1. Asymmetric aldol reaction catalyzed by fructose-derived amines.
1
1478, 1325, 1210, 1130, 1070, 825 cm−1; HNMR (400
spectra were obtained on a Bruker AC-400 using CDCl3
as solvent and TMS as internal standard, unless otherwise
stated. Mass spectra were obtained from Waters ZQ 4000
mass spectrometer by the ESI method, while the elemen-
tal analyses of the complexes were performed on a Perkin–
Elmer-2400 CHN/S analyzer. Reactions were monitored by
thin layer chromatography (TLC). The melting points of
the compounds were recorded by open capillary method
and were uncorrected. HPLC analysis was carried out on a
Waters M515 equipped with Chiracel OD-H, Chiralcel AD-
H, and Chiral OJ columns using n-hexane and 2-propanol as
mobile phase at room temperature.
MHz, CDCl3): δ 4.17–4.05 (5H, m), 3.93 (1H, d, J = 8.8
Hz), 3.61 (1H, t, J = 7.6, 7.6 Hz), 2.11 (1H, d, J = 8.0
Hz), 1.49 (3H, s), 1.46 (3H, s), 1.39 (3H, s), 1.32 (3H, s);
13CNMR (100 MHz, CDCl3): δ 112.0, 109.6, 104.7, 28.13,
26.62, 26.46, 26.14 ppm. ESI-MS (m/z): 283.2 (M++Na);
Elemental analysis for C12H20O6: Calculated (%) C 55.37, H
7.74; Found (%) C 55.62, H 7.89.
2.3 Synthesis
2.3a 1,2:4,5-Di-O-isopropylidene-3-amino-3-deoxy-α-D-
fructopyranose (1a) and 1,2:4,5-Di-O-isopropylidene-3-
amino-3-deoxy-β-D-fructopyranose (2a): To a solution
of NiCl2.6H2O (9.50 g, 40 mmol) in MeOH (200 mL) was
added NaBH4 (1.5 g, 40 mmol) portion wise at 0◦C. The
2.2 Synthesis of 1,2:4,5-Di-O-isopropylidene-β-D-
fructo-pyranose (3)
To a suspension of D-fructose (36 g, 200 mmol) and 2, 2- reaction mixture was stirred at 0◦C for 30 min and then
dimethoxy propane (400 mmol) in dry acetone (200 mL) was sugar oxime (3, 10.96 g, 40 mmol) dissolved in MeOH
added 5 mol% of phosphotungstic acid and was stirred at was added portion-wise along with NaBH4 (9 equiv.) for
room temperature under nitrogen atmosphere for 4 h. After over a period of 8 h. After completion of the reaction,
completion of the reaction, the solvent was removed un- the reaction mixture was run through a celite and washed
der reduced pressure. Water was added to the residue and with ethyl acetate. The organic portion collected was con-
extracted with dichloromethane (3 × 20 mL). The combined centrated under reduced pressure to get the crude product
organic layer was dried over Na2SO4 and concentrated under which was purified by column chromatography using 50%
vacuum to get the crude product, which was recrystallized ethyl acetate in hexane as an eluent to achieve 1,2:4,5-
by dissolving in boiling ether (5 mL/g), cooling, and adding di-O-isopropylidene-3-amino-3-deoxy-β-D-fructopyranose
hexane (5 mL/g) to give 1,2:4,5-di-O-isopropylidene-β-D- (2a, 2.18 g, 21%), followed by 1,2:4,5-di-O-isopropylidene-
fructopyranose (37 g, 71%). IR (KBr): 3547, 2983, 2839, 3-amino-3-deoxy-α-D-fructo-pyranose (1a, 6.42 g, 62%).

Monofunctional primary amine in asymmetric catalysis
303
2.3b 1,2:4,5-Di-O-isopropylidene-3-amino-3-deoxy-α-D-
fructopyranose (1a): Colourless oil, IR (KBr): 3410, 3328,
2928, 2839, 1652, 1475, 1425, 1327, 1211, 1110, 1070,
2.5 Synthesis of 1,2:4,5-di-O-isopropylidene-3-(N-ben-
zyl) amino-3-deoxy-β-D-fructopyranose (2c)
1
845 cm−1; HNMR (400 MHz, CDCl3): δ 4.42 (dd, 1H, J
Compound 2c was synthesized from 1,2:4,5-di-O-
isopropylidene-3-amino-3-deoxy-α-D-fructopyranose (1.3
g, 5 mmol) by the procedure similar to that of 1c. Pale
yellow solid (1.47 g, 87%); IR (KBr): 3328, 3025, 2983,
= 3.2, 3.6 Hz), 4.21 (d, 2H, J = 9.6 Hz), 3.92–3.76 (m,
4H), 3.03 (d, 1H, J = 2.8 Hz), 1.46 (s, 3H), 1.45 (s, 3H),
1.39 (s, 3H), 1.31 (s, 3H); 13CNMR (125 MHz, CDCl3):
δ 109.34, 109.10, 106.27, 73.73, 73.03, 71.88, 61.93,
52.19, 26.60, 26.12, 25.49, 24.59 ppm. ESI-MS (m/z):
260 (M+); Elemental analysis for C12H21NO5: Calculated
(%) C 55.58, H 8.16, N 5.40; Found (%) C 55.81, H 8.29,
N 5.31.
2873, 1621, 1540, 1443, 1324, 1297, 1210, 1108, 847 cm−1
;
1HNMR (400 MHz, CDCl3): δ 7.30–7.15 (m, 5H), 4.39
(dd, 1H, J = 2.4, 2.4 Hz), 3.40 (d, 1H, J = 9.2 Hz), 4.11
(d, 1H, J = 7.6 Hz), 3.94–3.82 (m, 3H), 3.69-3.59 (m,
3H), 2.92 (d, 1H, J = 2.0 Hz), 1.41 (s, 3H), 1.38 (s, 3H),
1.38 (s, 3H), 1.23 (s, 3H); 13CNMR (125 MHz, CDCl3):
δ 139.85, 128.51, 128.44, 128.12, 127.14, 126.95, 109.37,
109.03, 106.20, 73.47, 72.31, 72.06, 62.33, 56.77, 52.08,
26.68, 26.28, 25.73, 24.74 ppm. ESI-MS (m/z): 373.1
(M++Na); Elemental analysis for C19H27NO5: Calculated
(%) C 65.31, H 7.79, N 4.01; Found (%) C 65.81, H 7.61,
N 4.37.
2.3c 1,2:4,5-Di-O-isopropylidene-3-amino-3-deoxy-β-D-
fruc-topyranose (2a): White solid, IR (KBr): 3410, 3328,
2928, 2839, 1652, 1475, 1425, 1327, 1211, 1110, 1070,
1
845 cm−1; HNMR (400 MHz, CDCl3): δ 4.25 (d, 1H, J =
8.4 Hz), 4.14–4.03 (m, 3H), 3.95 (d, 1H, J = 8.4 Hz), 3.88
(dd, 2H, J = 1.6, 1.6 Hz), 2.78 (d, 1H, J = 8.4 Hz), 1.51
(s, 3H), 1.49 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H); 13CNMR
(125 MHz, CDCl3): δ 111.70, 109.02, 105.82, 79.39, 73.02,
72.30, 60.27, 53.87, 28.39, 26.35, 26.29, 26.14 ppm. ESI-
MS (m/z): 260 (M+); Elemental analysis for C12H21NO5:
Calculated (%) C 55.58, H 8.16, N 5.40; Found (%) C 55.73,
H 8.26, N 5.31.
2.6 Synthesis of N-Cbz-1,2:4,5-di-O-isopropylidene-
3-amino-3-deoxy-α − D-fructopyranose (6)3
To a mixture of phosphotungstic acid hydrate (0.05 mmol)
and benzylchloroformate (1.1 mmol) was added a solution
of the amine 1a (0.260 g, 1.0 mmol) in dichloromethane
(4 mL). After stirring for 10 min, the reaction mixture was
filtered through ordinary filter paper and the filtrate was
concentrated by distillation under reduced pressure. The
resulting crude product was then purified by flash chromatog-
raphy using 40% ethyl acetate in hexane as eluent to get
the pure product (6). White solid, 0.362 g, 92% yield. IR
(CHCl3): 3327, 3101, 2928, 2875, 1710, 1600, 1537, 1456,
1372, 1230, 1088, 967 cm−1; 1HNMR (400MHz, CDCl3): δ
7.22–7.12 (m, 5H); 5.02–4.94 (m, 1H); 4.98 (s, 2H); 4.33 (dd,
J = 5.6, 4.8 Hz, 1H); 4.07 (dd, J = 2.4, 2.0 Hz, 1H); 3.97–
3.79 (m, 4H); 1.32 (s, 3H); 1.29 (s, 3H); 1.20 (s, 3H); 1.17 (s,
3H); 13C NMR (100MHz, CDCl3): δ 156.14, 136.20, 128.50,
128.30, 128.20, 111.50, 109.20, 104.45, 73.31, 71.72, 71.70,
67.09, 61.34, 51.85, 26.29, 26.09, 25.73, 24.98 ppm. ESI-MS
(m/z): 416.3 (M++Na); Elemental analysis for C20H27NO7:
Calculated (%) C 61.06, H 6.92, N 3.56; Found (%) C 61.33,
H 7.21, N 3.87.
2.4 Synthesis of 1,2:4,5-di-O-isopropylidene-3-(N-
benzyl) amino-3-deoxy-α-D-fructopyranose (1c)
A
mixture of 1,2:4,5-di-O-isopropylidene-3-amino-3-
deoxy-α-D-fructo-pyranose (1.3 g, 5 mmol) and benzalde-
hyde (530 mg, 5 mmol) was ground with a glass rod for
about 10 min by which time, a slightly yellow solid (8)
was formed. Dry dichloromethane (20 mL) was then added
to dissolve the compound (8) followed by the addition of
sodium cyanoborohydride (378 mg, 6 mmol). Upon stirring
at room temperature for 6 h, the reaction mixture was passed
through celite and washed with ethyl acetate. The combined
organic layers were washed with water, dried with Na2SO4
and concentrated under reduced pressure to give the crude
product. The crude product so obtained was purified by col-
umn chromatography on silica gel using 30% ethyl acetate in
hexane as an eluent to obtain 1,2:4,5:di-O-isopropylidene-
3-(N-benzyl)amino-3-deoxy-α-D-fructopyranose as a pale
yellow solid (1.48 g, 88%). IR (KBr): 3328, 3025, 2983,
2873, 1621, 1540, 1443, 1324, 1297, 1210, 1108, 847 cm−1
;
2.7 Synthesis of 1,2:4,5-Di-O-isopropylidene-3-(N-
methyl) amino-3-deoxy-α-D-fructopyranose (1b)
1HNMR (400 MHz, CDCl3): δ 7.37–7.25 (m, 5H), 4.47 (dd,
1H, J = 2.4, 2.4 Hz), 4.42 (d, 1H, J = 9.2 Hz), 4.20 (d,
1H, J = 8.0 Hz), 4.03–3.90 (m, 3H), 3.78-3.68 (m, 3H), To a solution of N-Cbz-1,2:4,5-di-O-isopropylidene-3-
3.00 (d, 1H, J = 2.4 Hz), 1.49 (s, 3H), 1.47 (s, 3H), 1.31 (s, amino-3-deoxy-α-D-fructopyranose (0.787 g, 2 mmol) in dry
3H), 1.25 (s, 3H); 13CNMR (125 MHz, CDCl3): δ 138.98, DMF (5 mL) was added NaH (0.053 g, 2.2 mmol) at 0◦C
128.31, 128.22, 127.98, 127.79, 127.56, 110.12, 109.87, and stirred for 10 min. Freshly distilled MeI (0.296 g, 2.1
106.71, 75.28, 73.02, 72.89, 65.16, 58.56, 53.34, 26.54, mmol) was then added and the reaction was allowed to run
26.42, 26.27, 26.14 ppm. ESI-MS (m/z): 373.1 (M++Na); for 2 h. After completion of the reaction, ice-cooled water
Elemental analysis for C19H27NO5: Calculated (%) C 65.31, (20 mL) was added and the compound was extracted with
H 7.79, N 4.01; Found (%) C 65.79, H 7.63, N 4.23.
ethyl acetate (20 mL × 3). The combined organic layer was

304
Khiangte Vanlaldinpuia et al.
washed with brine, dried over anhydrous Na2SO4 and con-
centrated under vacuum to get the crude product, which was
purified using column chromatography to obtain the prod-
uct (7) as an oily liquid in 92% yield. IR (KBr): 3018, 2991,
2980, 2892, 1712, 1600, 1550, 1455, 1382, 1240, 1087, 968
2.9 Synthesis of 1,2:4,5-di-O-isopropylidene-3-(N-
methyl) amino-3-deoxy-β-D-fructopyranose (2b)
The compound (2b) was synthesized from N-Cbz-1,2:4,5-di-
O-isopropylidene-3-amino-3-deoxy-β-D-fructopyranose (8)
via the compound (9) following similar procedure adopted
for the synthesis of the compound (1b).
1
cm−1; HNMR (400 MHz, CDCl3): δ 7.38–7.29 (m, 5H),
5.16 (d, 2H, J = 12.0 Hz), 4.48 (dd, 1H, J = 1.6, 1.2 Hz),
4.33–4.29 (m, 1H), 4.20 (d, 1H, J = 9.2 Hz), 3.99–3.87 (m,
3H), 3.72 (d, 1H, J = 13.6 Hz), 3.15 (s, 3H), 1.49 (s, 3H),
1.44 (s, 3H), 1.32 (s, 3H), 1.25 (s, 3H); 13CNMR (125 MHz,
CDCl3): δ 157.54, 136.57, 128.83, 128.45, 128.21, 128.08,
110.10, 109.24, 105.45, 75.23, 73.90, 71.63, 67.64, 63.20,
54.91, 29.70, 26.34, 26.01, 25.86, 25.19 ppm; ESI-MS (m/z):
296.3 (M++Na); Elemental analysis for C13H23NO5: Calcu-
lated (%) C 57.13, H 8.48, N 5.12; Found (%) C 56.81, H
8.43, N 5.23.
Compound (9): Colourless gum in 95% yield. IR (KBr):
3025, 2989, 2982, 2876, 1715, 1602, 1537, 1455, 1382,
1235, 1088, 968 cm−1; 1HNMR (400 MHz, CDCl3): δ 7.36–
7.29 (m, 5H), 5.15 (d, 2H, J = 2.0 Hz), 4.53 (d, 1H, J =
10.0 Hz), 4.48–4.44 (m, 1H), 4.30–4.22 (m, 2H), 4.11–3.87
(m, 3H), 3.02 (d, 3H, J = 2.8 Hz), 1.56 (s, 3H), 1.46 (s
3H), 1.39 (s, 3H), 1.33 (s, 3H); 13CNMR (125 MHz, CDCl3):
δ 156.84, 136.08, 128.54, 128.46, 128.32, 127.95, 127.62,
112.09, 109.63, 105.46, 73.28, 72.22, 71.11, 67.51, 69.82,
56.14, 30.21, 28.02, 26.53, 26.37, 26.26 ppm; ESI-MS (m/z):
429.3 (M++Na); Elemental analysis for C21H29NO7: Calcu-
lated C (%) 61.90, H 7.17, N 3.44, O 27.49; Found (%) C
62.01, H 7.21, N 3.58, O 27.76.
To a solution of 7 (0.407 g, 1 mmol) in ethyl acetate
(5 mL) was added Pd/C (15 mg/mmol) and the reaction
mixture was stirred at room temperature under hydrogen
atmosphere (1 atm) for 24 h. The solution was filtered
and the residue was washed thoroughly with ethyl acetate.
The combined filtrate was concentrated to get the crude
product which was purified by column chromatography
using 30% ethyl acetate in hexane as an eluent. The pure
product, 1,2:4,5-Di-O-isopropylidene-3-(N-methyl)amino-
3-deoxy-β-D-fructopyranose (1b) was obtained as a colour-
less oily liquid with 87% yield (0.237 g). IR (KBr): 3344,
2989, 2893, 1640, 1541, 1487, 1345, 1321, 1248, 1180,
Compound (2b): White solid in 90% yield (0.245 g). IR
(KBr): 3340, 2989, 2893, 1642, 1541, 1487, 1348, 1321,
1
1248, 1180, 1087, 874 cm−1; HNMR (400 MHz, CDCl3):
δ 4.61–4.57 (m, 1H), 4.36 (d, 1H, J = 8.0 Hz), 4.19 (m,
1H), 4.08–3.99 (m, 3H), 3.90 (d, 1H, J = 8.0 Hz), 2.72 (d,
1H, J = 9.2 Hz), 2.52 (s, 3H), 1.55 (s, 3H), 1.47 (s, 3H),
1.42 (s, 3H), 1.37 (s, 3H); 13CNMR (125 MHz, CDCl3): δ
111.82, 108.88, 107.04, 73.68, 72.56, 72.04, 63.46, 59.79,
43.62, 28.54, 26.58, 26.49, 26.12 ppm. ESI-MS (m/z): 296.3
(M++Na); Elemental analysis for C13H23NO5: Calculated
(%) C 57.13, H 8.48, N 5.12; Found (%) C 56.79, H 8.35, N
5.24.
1
1087, 874 cm−1; HNMR (400 MHz, CDCl3): δ 4.55 (dd,
1H, J = 1.2, 0.8 Hz), 4.36 (d, 1H, J = 8.8 Hz), 4.15 (m, 1H),
3.83 (d, 1H, J = 8.8 Hz), 3.69 (dd, 2H, J = 1.6, 1.6 Hz),
3.55 (d, 1H, J = 13.2 Hz), 2.61 (s, 1H), 2.42 (s, 3H), 1.42 (s,
3H), 1.41 (s, 3H), 1.37 (s, 3H), 1.25 (s, 3H); 13CNMR (125
MHz, CDCl3): δ 109.60, 108.97, 106.94, 74.65, 72.29, 70.82,
63.70, 62.62, 44.96, 26.59, 26.42, 26.36, 25.15 ppm. ESI-MS
(m/z): 296.3 (M++Na); Elemental analysis for C13H23NO5:
Calculated (%) C 57.13, H 8.48, N 5.12; Found (%) C 56.83,
H 8.36, N 5.22.
2.10 Typical procedure for aldol reaction
D-Fructose derived amine 4 (39 mg, 0.15 mmol), benzoic
acid (18 mg, 0.15 mmol) and cyclohexanone (392 mg, 4
mmol) were stirred at −10◦C for 30 min. Then, the p-
nitrobenzaldehyde (151 mg, 1 mmol) was added and the mix-
ture was stirred for the specified time as shown in Table 3.
After completion of the reaction, the mixture was stirred
vigorously with aqueous 2.0 N HCl solution (10 mL) and
extracted with ethyl acetate (10 mL × 3). The organic layer
was washed with water, dried (Na2SO4), filtered and concen-
trated to get the crude product which was subjected to HPLC
analysis. The product was purified through flash column
chromatography on silica gel (hexane/ethyl acetate) to obtain
the pure aldol product, 5a in 92% (229 mg, 0.92 mmol) yield.
2.8 Synthesis of N-Cbz-1,2:4,5-di-O-isopropylidene-
3-amino-3-deoxy-β-D-fructopyranose (8)
The compound 8 was synthesized from the amine 2a fol-
lowing similar procedure adopted for the synthesis of the
compound 6. White solid, 0.358 g, 91% yield. IR (CHCl3):
3328, 3100, 2928, 2876, 1712, 1601, 1537, 1456, 1372,
1230, 1088, 967 cm−1; 1HNMR (400MHz, CDCl3): δ 7.28–
7.19 (m, 5H); 5.08 (d, J = 3.2 Hz, 1H); 5.05 and 5.03
(both singlet, 2H, C6H5CH2−); 4.77 (m, 1H); 4.08−3.76
(m, 5H); 1.53 (s, 3H); 1.40 (s, 3H); 1.31 (s, 3H); 1.30
(s, 3H); 13C NMR (100MHz, CDCl3): δ 156.51, 136.16, 2.10a 2-[Hydroxy-(4-nitro-phenyl)-methyl]-cyclohexanone
128.58, 128.53, 128.44, 128.30, 128.19, 128.05, 111.79, (5a)17: Yield 92%; Syn/anti: 3/1; IR (KBr): 3435, 3330,
109.58, 105.10, 75.94, 72.88, 72.37, 72.11, 67.16, 60.13, 3025, 2889, 2789, 1720, 1602, 1547, 1440, 1320, 1284,
52.87, 28.04, 26.44, 26.37, 26.04 ppm. ESI-MS (m/z): 416.3 1220, 1180 cm−1; HNMR (400 MHz, CDCl3): δ 8.13 (d,
1
(M++Na); Elemental analysis for C20H27NO7: Calculated J = 1.2 Hz, 1H), 8.12 (d, J = 2.4 Hz, 1H), 7.42 (t, J =
(%) C 61.06, H 6.92, N 3.56; Found (%) C 61.39, H 7.25, 8.8, 8.0 Hz, 2H), 5.44 (d, J = 2.0 Hz, 1H for syn), 4.83
N 3.84.
(d, J = 8.4 Hz, 1H for anti), 2.53−1.29 (m, 9H); 13CNMR

Monofunctional primary amine in asymmetric catalysis
305
(100 MHz, CDCl3): δ 214.77 (anti), 214.05 (syn), 149.14, HPLC analysis Chiralcel OD-H (Hexane/ i-PrOH = 95/5,
148.53, 127.87, 126.60, 123.55, 73.97 (anti), 70.08 (syn), 0.5 mL/min, 220 nm, 20◦C): syn product tR (major) 15.20
57.16 (anti), 56.77 (syn), 42.66, 30.73, 27.63, 25.88, 24.74 min, tR (minor) 16.24 min, ee: 33%, anti product tR (minor)
ppm; ESI-MS (m/z): 272.9 (M++Na); Elemental analysis 18.58 min tR (major) 25.51 min, ee: 44%.
for C13H15NO4: Calculated (%) C 62.64, H 6.07, N 5.62;
Found (%) C 62.71, H 6.12, N 5.68. HPLC analysis Chiral-
2.10e 2-[Hydroxy-(4-chloro-phenyl)-methyl]-cyclohexanone
cel OD-H (Hexane/ i-PrOH = 95/5, 0.5 mL/min, 254 nm,
20◦C): syn product tR (minor) 56.31 min, tR (major) 64.62
min, ee: 86%, anti product tR (minor) 71.71 min tR (major)
103.06 min, ee: 62%.
(5e)19: Yield 90%; Syn/anti: 2.7/1; IR (KBr): 3440, 3353,
3025, 2885, 2789, 1727, 1610, 1541, 1452, 1324, 1284,
1220, 1186, 1121 cm−1 1HNMR (400 MHz, CDCl3): δ
;
7.36–7.17 (m, 4H), 5.34 (d, J = 2.4 Hz, 1H for syn), 4.76 (d,
J = 8.0 Hz, 1H for anti); 2.64−1.14 (m, 9H); 13CNMR (100
2.10b 2-[Hydroxy-(3-nitro-phenyl)-methyl]-cyclohexanone, MHz, CDCl3): δ 215.23 (anti), 214.37 (syn), 139.95, 139.71,
(5b)17: Yield 94%; Syn/anti: 1.6/1; IR (KBr): 3440, 3331, 133.49, 132.86, 129.98, 129.78, 128.41, 128.20, 74.07
3020, 2889, 2878, 1725, 1605, 1550, 1432, 1328, 1220, 1120 (anti), 70.04 (syn), 57.32 (anti), 57.05 (syn), 42.69, 42.53,
1
cm−1; HNMR (400 MHz, CDCl3): δ 8.17–7.49 (m, 4H), 30.18, 27.86, 27.78, 25.81, 24.87, 24.73 ppm; ESI-MS
5.48 (d, J = 2.0 Hz, 1H for syn), 4.88 (d, J = 8.4 Hz, 1H for (m/z): 261.7 (M++Na); Elemental analysis for C13H15ClO2:
anti), 2.66–1.17 (m, 9H); 13CNMR (100 MHz, CDCl3): δ Calculated (%) C 65.41, H 6.33; Found (%) C 65.23, H 5.99.
214.79 (anti), 214.03 (syn), 148.17, 143.91, 143.25, 133.94, HPLC analysis Chiralcel OD-H (Hexane/ i-PrOH = 90/10,
129.08, 121.06, 120.82, 73.88 (anti), 69.75 (syn), 57.07 0.5 mL/min, 220 nm, 20◦C): syn product tR (major) 12.80
(anti), 56.6 (syn), 42.43, 27.72, 25.86, 24.68 ppm; ESI-MS min, tR (minor) 15.32 min, ee: 81%, anti product tR (major)
(m/z): 272.6 (M++Na); Elemental analysis for C13H15NO4: 20.07 min tR (minor) 22.85 min, ee: 40%.
Calculated (%) C 62.64, H 6.07, N 5.62; Found (%) C 62.69,
H 6.17, N 5.68. HPLC analysis Chiralcel OD-H (Hexane/i-
2.10f 2-[Hydroxy-(2-chloro-phenyl)-methyl]-cyclohexanone
PrOH = 95/5, 0.5 mL/min, 254 nm, 20◦C): syn product
(5f)17: Yield 87%; Syn/anti: 19/1; IR (KBr): 3441, 3325,
tR (minor) 26.30 min, tR (major) 28.20 min, ee: 53%, anti
3018, 2889, 2877, 1721, 1602, 1541, 1423, 1320, 1248,
product tR (minor) 31.13 min tR (major) 45.12 min, ee: 46%.
1185, 1120 cm−1; 1HNMR (400 MHz, CDCl3): δ 7.53–7.23
(m, 4H), 5.70 (d, J = 2.0 Hz, 1H for syn), 5.34 (d, J = 8.4
2.10c 2-[Hydroxy-(4-bromo-phenyl)-methyl]-cyclohexanone Hz, 1H for anti), 2.83–1.32 (m, 9H); 13CNMR (100 MHz,
(5c)17: Yield 96%; Syn/anti: 2.6/1; IR (KBr): 3445, 3320, CDCl3): δ 215.17 (anti), 214.58 (syn), 139.00, 138.91,
3018, 2889, 2877, 1725, 1602, 1540, 1423, 1322, 1240, 132.65, 131.17, 130.49, 130.45, 129.03, 128.73, 127.01,
1184, 1120 cm−1; 1HNMR (400 MHz, CDCl3): δ 7.40 (d, J 126.74, 70.38 (anti), 67.57 (syn), 57.84 (anti), 53.53 (syn),
= 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 5.27 (d, J = 2.4 42.61, 42.55, 30.31, 27.89, 27.74, 25.86, 24.89, 24.71 ppm;
Hz, 1H for syn), 4.68 (d, J = 8.4 Hz, 1H), 2.48–1.18 (m, ESI-MS (m/z): 261.8 (M++Na); Elemental analysis for
9H); 13CNMR (100 MHz, CDCl3): δ 215.16 (anti), 214.43 C13H15ClO2: Calculated (%) C 65.41, H 6.33; Found (%)
(syn), 140.51, 140.29, 131.19, 131.06, 127.72, 127.54, C 65.32, H 6.11. HPLC analysis Chiralcel OD-H (Hexane/
121.01, 120.64, 74.03 (anti), 70.07 (syn), 57.25 (anti), 56.93 i-PrOH = 94/6, 0.5 mL/min, 220 nm, 20◦C): syn product
(syn), 42.98, 42.21, 27.82, 27.10, 25.87, 24.76, 24.72 ppm; tR (minor) 8.64 min, tR (major) 12.32 min, ee: 99%, anti
ESI-MS (m/z): 307.1 (M++Na); Elemental analysis for product tR (major) 19.50 min tR (minor) 24.43 min, ee:
C13H15BrO2: Calculated (%) C 55.14, H 5.34; Found (%) 44%.
C 55.27, H 5.43. HPLC analysis Chiralcel OD-H (Hexane/
i-PrOH = 95/5, 0.5 mL/min, 220 nm, 20◦C): syn product
2.10g 2-[Hydroxy-(2-nitro-phenyl)-methyl]-cyclohexanone
tR (minor) 24.40 min, tR (major) 25.86 min, ee: 77%, anti
(5g)17: Yield 89%; Syn/anti: 1/2.1; IR (KBr): 3430, 3334,
product tR (minor) 35.79 min tR (major) 51.10 min, ee: 30%.
3018, 2898, 2789, 1732, 1541, 1432, 1328, 1284, 1187,
1
1121 cm−1; HNMR (400 MHz, CDCl3): δ 7.93–7.37 (m,
2.10d 2-[Hydroxy-(3-bromo-phenyl)-methyl]-cyclohexa-
4H), 5.92 (d, J = 2.4 Hz, 1H for syn), 5.39 (d, J = 8.0
none, (5d)18: Yield 91%; Syn/anti: 1.8/1; IR (KBr): 3440, Hz, 1H for anti), 2.78–1.35 (m, 9H); 13CNMR (100 MHz,
3331, 3018, 2889, 2878, 1721, 1600, 1543, 1421, 1323, CDCl3): δ 214.56 (anti), 213.77 (syn), 149.54, 148.65,
1280, 1220, 1185, 1123 cm−1; 1HNMR (400 MHz, CDCl3): 137.98, 134.03, 129.94, 127.67, 124.56, 69.83 (anti), 66.36
δ 7.49–7.40 (m, 2H), 7.24–7.17 (m, 2H), 5.32 (d, J = 2.0 Hz, (syn), 57.21 (anti), 54.78 (syn), 42.38, 42.37, 27.32, 26.42,
1H for syn), 4.75 (d, J = 8.4 Hz, 1H for anti), 2.60–1.22 (m, 24.67 ppm; ESI-MS (m/z): 272.6 (M++Na); Elemental
9H); 13CNMR (100 MHz, CDCl3): δ 215.28 (anti), 214.73 analysis for C13H15NO4: Calculated (%) C 62.64, H 6.07, N
(syn), 143.85, 143.32, 131.84, 130.01, 129.88, 128.77, 5.62; Found (%) C 62.76, H 6.17, N 5.76. HPLC analysis
125.75, 122.56, 122.45, 74.29 (anti), 70.64 (syn), 57.21, Chiralcel OD-H (Hexane/i-PrOH = 94/6, 0.5 mL/min, 254
42.62, 30.74, 27.76, 25.88, 24.67, 24.56 ppm; ESI-MS nm, 20◦C): syn product tR (major) 19.54 min, tR (minor)
(m/z): 307.3 (M++Na); Elemental analysis for C13H15BrO2: 22.77 min, ee: 65%, anti product tR (major) 26.97 min tR
Calculated (%) C 55.14, H 5.34; Found (%) C 55.22, H 5.39. (minor) 35.31 min, ee: 95%.

306
Khiangte Vanlaldinpuia et al.
1
1182, 827 cm−1; HNMR (400 MHz, CDCl3): δ 7.53–7.10
2.10h 2-[Hydroxy-(2-hydroxyphenyl)-methyl]-cyclohexa-
none (5h): Yield 87%; Syn/anti: 2/1; IR (KBr): 3441,
3332, 3025, 2879, 1712, 1600, 1545, 1432, 1421, 1384,
1220, 1184 cm−1; 1HNMR (400 MHz, CDCl3): δ 7.54−6.83
(m, 4H), 5.36 (d, J = 2.4 Hz, 1H for syn), 4.86 (d, J = 9.2
Hz, 1H for anti), 2.18–0.81 (m, 9H); 13CNMR (100 MHz,
CDCl3): δ 229.12, 161.16, 160.01, 132.96, 1321.71, 130.08,
128.42, 118.79, 118.47, 117.34, 109.94, 109.89, 109.44,
109.37, 67.85, 63.02, 61.97, 51.93, 26.51, 26.32, 26.20,
26.07, 25.77, 25.44 ppm; ESI-MS (m/z): 243.4 (M++Na);
Elemental analysis for C13H16O3: Calculated (%) C 70.89,
H 7.32, O 21.79; Found (%) C 70.91, H 7.42, O 21.86.
HPLC analysis Chiralcel OD-H (Hexane/ i-PrOH = 90/10,
0.5 mL/min, 220 nm, 20◦C): syn product tR (major) 12.53
min, tR (minor) 19.83, ee: 92%; anti product tR (minor)
23.57 min, tR (major) 26.47 min, ee: 2%.
(m, 4H), 5.60 (d, J = 2.4 Hz, 1H for syn), 5.22 (d, J =
9.2 Hz, 1H for anti), 2.61−1.18 (m, 7H); 13CNMR (100
MHz, CDCl3): δ 222.99, 220.24, 140.14, 139.09, 133.53,
132.41, 130.99, 130.12, 130.11, 129.99, 129.94, 129.32,
129.25, 129.93, 128.43, 128.36, 128.34, 128.31, 127.46,
127.37, 126.85, 126.55, 75.86, 70.34, 67.88, 55.52, 53.54,
39.05, 38.67, 37.91, 29.64, 29.26, 26.41, 22.48, 20.53, 20.34
ppm; ESI-MS (m/z): 247.6 (M++Na); Elemental analysis
for C12H13ClO2: Calculated (%) C 64.15, H 5.83, Cl 15.78,
O 14.24; Found (%) C 63.89, H 5.91, Cl 15.65, O 14.41.
HPLC analysis Chiralcel OD-H (Hexane/ i-PrOH = 47/3,
0.5 mL/min, 220 nm, 20◦C): syn product tR (major) 20.45
min, tR (minor) 27.53 min, ee: 82%, anti product tR (major)
36.82 min tR (minor) 43.17 min, ee: 78%.
2.10l 2-[Hydroxy(2-nitrophenyl)methyl]cyclopentanone
(5l)20: Yield 91%; Syn/anti: 1.5/1; IR (KBr): 3441, 3342,
3098, 2893, 2787, 1735, 1601, 1526, 1473, 1346, 1280,
2.10i 2-(Hydroxy-phenyl-methyl)-cyclohexanone
Yield 89%; Syn/anti: 2.7/1; IR (KBr): 3440, 3330, 3018,
2879, 1710, 1600, 1540, 1430, 1384, 1220, 1184 cm−1
(5i)17:
1
1189, 907 cm−1; HNMR (400 MHz, CDCl3): δ 7.84–7.24
;
1HNMR (400 MHz, CDCl3): δ 7.29–7.19 (m, 4H), 5.31 (d, J
= 2.4 Hz, 1H for syn), 4.71 (d, J = 8.8 Hz, 1H for anti), 3.90
(s, 1H), 2.55–1.18 (m, 9H); 13CNMR (100 MHz, CDCl3): δ
215.55 (anti), 214.84 (syn), 140.95, 139.72, 127.89, 126.79,
126.23, 126.13, 74.74 (anti), 70.67 (syn), 57.41 (anti), 57.14
(syn), 42.62, 30.88, 27.85, 27.67, 25.88, 24.71, 24.63 ppm;
ESI-MS (m/z): 227.4 (M++Na); Elemental analysis for
C13H16O2: Calculated (%) C 76.44, H 7.90; Found (%) C
76.39, H 7.82. HPLC analysis Chiralcel OD-H (Hexane/
i-PrOH = 90/10, 0.5 mL/min, 220 nm, 20◦C): syn product tR
(major) 15.12 min, tR (minor) 16.29, ee: 56%; anti product
tR (minor) 18.82 min, tR (major) 30.07 min, ee: 34%.
(m, 4H), 5.92 (d, J = 2.0 Hz, 1H for syn), 5.44 (d, J = 8.4
Hz, 1H for anti), 2.84−1.46 (m, 7H); 13CNMR (100 MHz,
CDCl3): δ 221.59, 219.33, 148.34, 147.73, 137.03, 136.11,
132.59, 132.31, 128.81, 128.73, 128.23, 128.04, 123.85,
123.76, 69.08, 65.13, 56.01, 51.69, 39.16, 38.29, 26.92,
26.83, 21.05, 20.25 ppm; ESI-MS (m/z): 258.3 (M++Na);
Elemental analysis for C12H13NO4: Calculated (%) C 61.27,
H 5.57, N 5.95, O 27.21; Found (%) C 61.19, H 5.54, N 5.87,
O 27.14. HPLC analysis Chiralcel OD-H (Hexane/i-PrOH
= 47/3, 0.5 mL/min, 220 nm, 20◦C): syn product tR (major)
22.21 min, tR (minor) 28.57 min, ee: 20%, anti product tR
(major) 33.80 min tR (minor) 43.08 min, ee: 94%.
2.10m 2-[Hydroxy(p-tolyl)methyl]cyclopentanone (5m)21:
Yield 88%; Syn/anti: 1.3/1; IR (KBr): 3340, 3100, 2989,
2898, 2789, 1745, 1601, 1535, 1482, 1397, 1324, 1280,
2.10j 2-[Hydroxy-(pyridin-2-yl)-methyl]-cyclohexanone
(5j): Yield 88%; Syn/anti: 6/1; IR (KBr): 3450, 3343,
3100, 2898, 2789, 1724, 1600, 1537, 1474, 1398, 1321,
1286, 1224, 1189, 1121 cm−1; 1HNMR (400 MHz, CDCl3):
δ 8.21–8.08 (m, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.55–7.50
(m, 2H), 7.26 (s, 1H), 5.48 (d, J = 2.0 Hz, 1H for syn), 4.89
(d, J = 8.4 Hz, 1H for anti), 3.19 (s, 1H), 2.65–1.52 (m, 9H);
13CNMR (100 MHz, CDCl3): δ 214.76 (anti), 214.21 (syn),
143.74, 143.21, 133.19, 131.94, 129.31, 129.15, 122.89,
122.10, 122.02, 120.86, 74.06 (anti), 69.90 (syn), 57.13,
56.75, 42.67, 42.62, 30.74, 27.88, 27.62, 25.89, 24.75, 24.66
ppm; ESI-MS (m/z): 229.0 (M++Na); Elemental analysis
for C12H15NO2: Calculated (%) C 70.22, H 7.37, N 6.82;
Found (%) C 70.38, H 7.58, N 7.03. HPLC analysis Chiral-
cel OD-H (Hexane/ i-PrOH = 47/3, 0.5 mL/min, 220 nm,
20◦C): syn product tR (major) 24.51 min, tR (minor) 27.90
min, ee: 32%, anti product tR (minor) 32.47 min tR (major)
37.84 min, ee: 98%.
1222, 1189, 1120 cm−1 1HNMR (400 MHz, CDCl3): δ
;
7.43–7.13 (m, 4H), 5.13 (d, J = 2.0 Hz, 1H for syn), 4.62
(d, J = 9.2 Hz, 1H for syn), 3.00 (s, 1H), 2.88 (m, 1H),
2.48–1.17 (m, 9H); 13CNMR (100 MHz, CDCl3): δ 222.55,
221.74, 133.65, 133.12, 132.72, 132.54, 130.82, 130.60,
130.23, 130.16, 129.88, 129.72, 129.54, 129.47, 129.20,
129.04, 128.45, 75.04, 71.53, 56.12, 55.30, 39.27, 38.77,
27.00, 26.55, 21.51, 20.17, 14.13 ppm; ESI-MS (m/z): 227.8
(M++ Na); Elemental analysis for C13H16O2: Calculated
(%) C 76.44, H 7.90, O 15.67; Found (%) C 76.79, H 8.11,
O 15.94. HPLC analysis Chiralcel OD-H (Hexane/ i-PrOH
= 47/3, 0.5 mL/min, 220 nm, 20◦C): syn product tR (major)
10.54 min, tR (minor) 13.63 min, ee: 80%, anti product tR
(major) 15.46 min tR (minor) 25.31 min, ee: 78%.
3. Results and Discussion
2.10k 2-[(2-Chlorophenyl)(hydroxy)methyl]cyclopentanone,
(5k): Yield 92%; Syn/anti: 4.9/1; IR (KBr): 3330, 3025,
To start with, we synthesized the catalyst 1a fol-
2887, 2784, 1742, 1600, 1472, 1380, 1322, 1286, 1224, lowing the Scheme 2. The acetonation of D-fructose

Monofunctional primary amine in asymmetric catalysis
307
−
−
Scheme 2. Synthesis of the catalyst 1a and 2a.
was accomplished by stirring D-fructose in 2,2-
dimethoxypropane (DMP)/acetone in the presence of
a catalytic amount of phosophotungstic acid (PTA).22
The product, so obtained, was converted to oxime via
Shi’s ketone following literature protocol.23 The con-
version of the oxime to amine by literature procedure18
hardly gave any yield (reported yield 11%). Therefore,
we developed a new protocol to synthesize the amine
by treatment of the oxime 4 with a mixture of NaBH4
(10 equiv), NiCl2.6H2O (1 equiv) in methanol at −10 to
0◦C to achieve the corresponding amines in 73% yield.
The yield of the amine derivative 1a was three times
higher than that of its enantiomer 2a.
Scheme 3. Synthesis of D-fructose derived monofunc-
tional secondary amines.
In our bid to evaluate the catalytic activity of 1a, we
chose the aldol reaction between p-nitrobenzaldehyde
and cyclohexanone as our pilot reaction. To begin with,
a mixture of the amine catalyst 1a (15 mol%), benzoic
acid (15 mol%) and cyclohexanone (1 mmol) in water
(1 mL) was stirred at room temperature for 30 min.
To this reaction mixture, p-nitrobenzaldehyde (1 mmol)
was added and the reaction was allowed to stir at room
temperature for 30 h. Ironically, the reaction resulted in
very poor yield (17%) and diastereoselectivity (syn:anti
= 59:41). Assuming that the reactants might not have
mixed properly in water, we screened a series of sol-
vents, viz. ethanol, acetonitrile, methylene chloride,
DMF, DMSO, and THF to observe that the reaction was
insignificant in terms of yield and selectivity in most
of these solvents (See Table S1 in the Supplementary
Information). Interestingly, when the reaction was car-
ried out as neat with excess amount of cyclohexanone (4
mmol), the reaction was complete within 12 h to gener-
ate the desired product in 92% yield. HPLC analysis of
the crude product indicated much improved selectivity;
diastereoselectivity (syn/anti) ratio of 2.6:1 and enantio-
meric excess of 21% and 15% for syn- and anti-product,
respectively. Studies on the role of different acid additives
to increase the yield and selectivity of the pilot reaction
confirmed that benzoic acid as the best choice (Table 1).
To improve upon the selectivity, the reaction was car-
ried out by lowering the temperature while keeping the
other parameters unchanged (entries 1–5, Table 2). The
diastereomeric ratio of the syn- and anti-products and
their enantioselectivities were found optimum at −10◦C
(entry 4). Keeping in mind that the catalyst loading has
a big role to play in organocatalytic reactions,18 cat-
alytic efficiency at optimum temperature in different
catalyst loading (entries 6–8) were studied to find 15
mol% of 1a (entry 4) as the optimum loading.
Given the fact that many secondary amines have been
proven as organocatalysts for various asymmetric trans-
formations, we synthesized some secondary amines
such as 1b, 2b, 1c, and 2c (Figure 2) starting from their
corresponding primary amines.
For the synthesis of monomethylated amines 1b and
2b, the primary amines 1a and 2a were first protected
with benzylchloroformate in the presence of a catalytic
amount of phosphotungstic acid (1 mol%).24 The Cbz
derivatives, so obtained, were methylated with MeI and

308
Khiangte Vanlaldinpuia et al.
Table 1. Effect of additives.
Cyclohexanone (4 equiv)
Catalyst 1a (15 mol%)
Additive (15 mol%)
OH
O
O
Neat, RT
O2N
O2N
Entry
additives
t/h
% yielda
syn/antib
%eeb
1
2
3
4
5
6
None
PhCOOH
TFA
72
12
36
36
36
36
67
92
70
65
20
20
1.2/1
2.6/1
1.1/1
1/1
19
21
8
CH3COOH
CSA
3
nd
–
–
p-TsOH
nd
aIsolated yields.
bStereoselectivity was determined by HPLC analysis of the crude mixture using
Chiralcel OD-H columns.
Table 2. Effect of temperature and catalyst loading.
O
Cyclohexanone (4 equiv)
Catalyst 1a
OH
O
Benzoic acid (15 mol%)
−10oC to +10oC
O2N
Entry
O2N
% yielda
1a (mol%)
T/◦C
t/h
syn/anti
%eeb
1
2
3
4
5
6
7
8
15
15
15
15
15
10
5
10
0
30
36
36
36
48
60
72
36
91
89
89
92
71
77
54
94
1.6 : 1
2.6 : 1
2.4 : 1
3.0 : 1
2.8 : 1
3.0 : 1
2.8 : 1
2.6 : 1
45
70
72
86
84
86
85
84
−5
−10
−20
−10
−10
−10
20
aIsolated yields.
bStereoselectivity was determined by HPLC analysis of the crude mixture using
Chiralcel OD-H columns.
Figure 2. Fructose derived monofunctional secondary amines.
NaH in DMF and the resulting compounds (7 and 9, the same pilot reaction was carried out under optimized
Scheme 3) were deprotected by hydrogenation on 10% reaction conditions by varying the amine catalysts.
Pd/C to achieve the desired products, 1b and 2b. The Catalyst 2a gave excellent yield (91%) and good enan-
synthesis of benzylamines, 1c and 2c were accom- tioselectivity for syn (67%) and anti (71%) prod-
plished by reducing a ground mixture of benzaldehyde ucts, but almost no diastereoselectivity was observed
and the primary amine in dichloromethane with sodium (Table 3). The same reaction in the presence of
cyanoborohydride at room temperature.
N-methyl amine derivatives 1b and 2b gave the aldol
To study the catalytic efficiency of newly synthesized products in less than 10% yield. The pilot reaction did
monofunctional amines for asymmetric aldol reaction, not proceed at all in the presence of catalysts 1c and

Monofunctional primary amine in asymmetric catalysis
309
Table 3. Screening of various amine catalysts for Aldol reaction.
−
Entry
Catalysts
T/h
% yielda
syn: anti
% ee (syn)
% ee (anti)
1
2
3
4
5
6
1a
1b
1c
2a
2b
2c
36
92
<10
–
91
<10
–
3.2 : 1
86
–
–
67
–
–
62
–
–
71
–
–
120
120
36
120
120
–
–
1 : 1.2
–
–
aIsolated yields.
bStereoselectivity was determined by HPLC analysis of the crude mixture using
Chiralcel OD-H columns.
Table 4. Asymmetric aldol reaction catalyzed by organocatalyst 1a.a
ketone (4 equiv)
catalyst 1a
O
OH
O
(15 mol%)
benzoic acid (15 mol%)
R
R
Neat, −10oC
n
X
X
sy n
5a−m
Entry
R
X
n
5
t/h
% yieldb
syn/antic
% eec,d
1
2
3
4
5
6
7
8
p-NO2
m-NO2
p-Br
m-Br
p-Cl
o-Cl
o-NO2
o-OH
H
H
o-Cl
o-NO2
p-Me
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
2
2
2
2
2
2
2
2
2
2
1
1
1
a
b
c
d
e
f
g
h
i
36
36
36
36
24
36
36
24
32
36
24
24
24
92
94
96
91
90
87
89
85
89
88
92
91
88
3 : 1
1.6 : 1
2.6 : 1
1.8 : 1
2.7 : 1
19 : 1
1: 2.2
2 : 1
2.7 : 1
6 : 1
4.9 : 1
1.5 : 1
1.3 : 1
86
53
77
33
81
99
95e
92
56
32
82
20
88
9
10
11
12
13
j
k
l
CH
CH
CH
m
aReaction conditions: aldehyde (1 mmol), catalyst (15 mol%), benzoic acid (15
mol%) and ketone (4 mmol).
bIsolated yields.
cDetermined by HPLC analysis of the crude products using Chiralcel OD-H and
AD-H columns.
d%ee of the major diastereomer.
2c. Such results might be attributed to the fact that asymmetric aldol reaction of cyclohexanone with a
steric hindrance caused by introduction of the bulky variety of aromatic aldehydes in the presence of benzoic
substituents such as methyl and benzyl groups on the acid (Table 4, entries 1–10). The reaction gave excel-
primary amine which might have blocked the initial lent yields in all the cases with moderate to excellent
formation of enamine with cyclohexanone.
enantioselectivity for both syn- and anti- products.
After optimizing the reaction conditions such as sol- Especially, the aldehydes having ortho-substituents
vent, temperature, acid additive, and catalyst loading, (entries 6–7, Table 4) gave very good enantioselectiv-
the substrate scope of our method was explored for ities (up to 99%), while those with meta-substituents

310
Khiangte Vanlaldinpuia et al.
derived secondary amines (1b, 1c, 2b, and 2c) were
found to be ineffective.
Acknowledgements
Authors acknowledge the Council of Scientific and Indus-
trial Research (CSIR), New Delhi, India for financial support
(Scheme no. 1 (1992)/05/EMR-II). The analytical services
provided by Sophisticated Analytical Instrumentation Facil-
ity, North Eastern Hill University, Shillong are gratefully
acknowledged.
Figure 3. Plausible mechanism of syn-selectivity.
Supporting Information (SI)
1H and 13C NMR spectra of new compounds and HPLC data
are available free of charge at www.ias.ac.in/chemsci.
(entries 2, 4) gave poorer enantioselectivity. Inter-
estingly, diastereoselectivity of o-nitrobenzaldehyde
derived aldol product (5 g) was found to be oppo-
site to all other aldehydes where syn- diastereomer
was formed as the major product. Given the fact
that cyclopentanone forms enamine faster than that
of cyclohexanone,25 we screened aminocatalysis of
cyclopentanone with aryl aldehydes to synthesize cor-
responding β-hydroxy ketones. In all the three cases,
reaction time was found to be reduced substantially
to give comparable diastereoselectivity with similar
starting aldehydes.
The plausible mechanism to account for the stere-
oselectivity might be the formation of the transition
states TS-1 and TS-2 wherein the catalyst 1a could
catalyze the aldol reaction as shown in Figure 3. The
aldehyde might be activated by hydrogen-bonding with
NH group of cyclohexenylamine via formation of the
six-membered transition states. In TS-2, the plane of
aryl group might experience substantial steric hindrance
due to cyclohexane ring making the transition state less
favorable than TS-1. Therefore, the approach of the
enamine carbon from re-face of aldehyde in TS-1 led to
syn-selective aldol product.
References
1. For review, see: (a) Xu L-W, Luo J and Lu Y 2009
Asymmetric catalysis with chiral primary amine-based
organocatalysts Chem. Commun. 1807; (b) Peng F and
Shao Z 2008 Advances in asymmetric organocatalytic
reactions catalyzed by chiral primary amines J. Mol.
Catal. A: Chem. 285 1; (c) Uehara H and Barbas III
C F 2009 anti-Selective Asymmetric Michael Reactions
of Aldehydes and Nitroolefins Catalyzed by a Primary
Amine/Thiourea Angew. Chem. Int. Ed. 48 9848; (d)
Bhanushali M and Zhao C-G 2011 Developing Novel
Organocatalyzed Aldol Reactions for the Enantioselec-
tive Synthesis of Biologically Active Molecules Syn-
thesis 1815; (e) Wu C, Long X, Li S and Fu X 2012
Simple and inexpensive threonine-based organocata-
lysts as highly active and recoverable catalysts for large-
scale asymmetric direct stoichiometric aldol reactions
on water Tetrahedron: Asymm. 23 315; (f) Umehara A,
Kanemitsu T, Nagata K and Itoh T 2012 Stereoselec-
tive Synthesis of vic-Halohydrins via L-tert-Leucine-
Catalyzed syn-Selective Aldol Reaction Synlett 453; (g)
Jiang L and Chen Y-C 2011 Asymmetric organocatal-
ysis mediated by primary amines derived from cin-
chona alkaloids: Recent advances Catal. Sci. Technol.
354; (h) Bartoli G and Melchiorre P 2008 A Novel
Organocatalytic Tool for the Iminium Activation of α,
β-Unsaturated Ketones Synlett 1759
4. Conclusions
2. (a) Pizzarello S and Weber A L 2004 Prebiotic Amino
Acids as Asymmetric Catalysts Science 303 1151; (b)
Ramasastry S S V, Zhang H, Tanaka F and Barbas III C F
2007 Direct Catalytic Asymmetric Synthesis of anti-1,2-
Amino Alcohols and syn-1,2-Diols through Organocat-
alytic anti-Mannich and syn-Aldol Reactions J. Am.
Chem. Soc. 129 288
3. (a) Zhou J, Wakchaure V, Kraft P and List B 2008
Primary-Amine-Catalyzed Enantioselective Intramolec-
ular Aldolizations Angew. Chem. Int. Ed. 47 7656; (b)
Zheng B-L, Liu Q-Z, Guo C-S, Wang X-L and He
L 2007 Highly enantioselective direct aldol reaction
catalyzed by cinchona derived primary amines Org.
Biomol. Chem. 5 2913; (c) Li P, Zhao J, Li F, Chan A S C
In conclusion, we have established monofunctional
primary amine, 1,2:4,5-di-O-isopropylidene-3-amino-
3-deoxy-α-D-fructopyranose (1a) as an efficient
aminocatalyst for stereoselective synthesis of β-
hydroxy ketones by aldol reaction. Under optimal
conditions, very high diastereoselectivities (up to 95%)
and enantioselectivities (up to 99%) were achieved. It
may be noted that this is the first report on any stere-
oselective organocatalysis employing monofunctional
primary amine, albeit monofunctional secondary amine
catalysis exist in literature. Interestingly, the fructose

Monofunctional primary amine in asymmetric catalysis
311
and Kwong F Y 2010 Highly Enantioselective and Effi-
cient Organocatalytic Aldol Reaction of Acetone and
β, γ -Unsaturated α-Keto Ester Org. Lett. 12 5616; For
review, see: (d) Melchiorre P 2012 Cinchona-based Pri-
mary Amine Catalysis in the Asymmetric Functionaliza-
tion of Carbonyl Compounds Angew. Chem. Int. Ed. 51
9748
Tetrahedron 41 3569; (d) Masamune S, Bates G S and
Corcoran J W 1977 Electrocyclic Ring Opening Reac-
tions of Ethylene Oxides Angew. Chem. Int. Ed. 16 585;
For reviews on asymmetric aldol reaction, see: (e) Trost
B M and Brindle C S 2010 The direct catalytic asym-
metric aldol reaction Chem. Soc. Rev. 39 1600; (f) Geary
L M and Hultin P G 2009 The State of the Art in asym-
metric induction: The aldol reaction as a case study
Tetrahedron: Asymm. 20 131; (g) Saito S and Yamamoto
H 2004 Design of Acid−Base Catalysis for the Asym-
metric Direct Aldol Reaction Acc. Chem. Res. 37 570;
(h) Machajewski T D and Wong C-H 2000 The Catalytic
Asymmetric Aldol Reaction Angew. Chem. Int. Ed. 39
1352
4. (a) Ricci A, Bernardi L, Gioia C, Vierucci S, Robitzer M
and Quignard F 2010 Chem. Commun. 6288; (b) Shen C,
Shen F, Xia H, Zhang P and Chen X 2011 Tetrahedron:
Asymm. 22 708; (c) Agarwal J and Peddinti R K 2011 J.
Org. Chem. 76 3502
5. (a) Bertelsen S, Halland N, Bachmann S, Marigo M,
Braunton A and Jorgensen K A 2005 Organocatalytic
asymmetric α-bromination of aldehydes and ketones
Chem. Commun. 4821; (b) Jensen K L, Franke P T,
Nielsen L T, Daasbjerg K and Jørgensen K A 2010
Anodic Oxidation and Organocatalysis: Direct Regio-
and Stereoselective Access to meta-Substituted Anilines
by α-Arylation of Aldehydes Angew. Chem. Int. Ed.
49 129; (c) Alba A, Company X, Moyano A and Rios
R 2009 Formal Highly Enantioselective Organocat-
alytic Addition of Alkyl Anions to α, β-Unsaturated
Aldehydes: Application to the Synthesis of Isotope-
Enantiomers Chem. Eur. J. 15 11095; (d) Kano T, Mii H
and Maruoka K 2009 Direct Asymmetric Benzoyloxy-
lation of Aldehydes Catalyzed by 2-Tritylpyrrolidine J.
Am. Chem. Soc. 131 3450; (e) Aggarwal V K, Lopin
C and Sandrinelli F 2003 New insights in the mecha-
nism of amine catalyzed epoxidation: Dual role of pro-
tonated ammonium salts as both phase transfer catalysts
and activators of oxone J. Am. Chem. Soc. 125 7596
6. (a) Hickmott P W 1982 Enamines: Recent advances in
synthetic, spectroscopic, mechanistic, and stereochem-
ical aspects-i Tetrahedron 38 1920; (b) Rappaport Z
1994 In Chemistry of Enamines (Chichester: Wiley); (c)
Hine J and Evangelista R A 1980 Iminium-ion forma-
tion and deuterium exchange by acetone in the presence
of pyrrolidine, pyrazolidine, Isoxazolidine, and their
acyclic analogs J. Am. Chem. Soc. 102 1649
11. For review, see: (a) Mahrwald R 1999 Diastereoselec-
tion in Lewis-Acid-Mediated Aldol Additions Chem.
Rev. 99 1095; (b) Johnson J S, Evans D A 2000
Chiral Bis(oxazoline) Copper(II) Complexes: Versatile
Catalysts for Enantioselective Cycloaddition, Aldol,
Michael, and Carbonyl Ene Reactions Acc. Chem. Res.
33 325; (c) Casiraghi G, Battistini L, Curti C, Rassu G
and Zanardi F 2011 The Vinylogous Aldol and Related
Addition Reactions: Ten Years of Progress Chem. Rev.
111 3076
12. List B, Lerner R A and Barbas III C F 2000 Proline-
Catalyzed Direct Asymmetric Aldol Reactions J. Am.
Chem. Soc. 122 2395
13. (a) Tong S T, Harris P W R, Barker D and Brimble
M A 2008 Use of (S)-5-(2-Methylpyrrolidin-2-yl)-1H-
tetrazole as a Novel and Enantioselective Organocata-
lyst for the Aldol Reaction Eur. J. Org. Chem. 164; (b)
Zheng J F, Li Y X, Zhang S Q, Yang S T, Wang X M,
Wang Y Z, Bai J and Liu F A 2006 New N-terminal
prolyl-dipeptide derivatives as organocatalysts for direct
asymmetric aldol reaction Tetrahedron Lett. 47 7793; (c)
Moorthy J N and Saha S 2009 Highly Diastereo- and
Enantioselective Aldol Reactions in Common Organic
Solvents Using N-Arylprolinamides as Organocatalysts
with Enhanced Acidity Eur. J. Org. Chem. 739; (d)
Pedrosa R, Andrés J M, Manzano R and Rodríguez P
2010 L-Prolinamides Derived from Chiral and Achi-
ral 1,2-Diamines as Useful Bifunctional Organocata-
lysts for Direct Diastereo- and Enantioselective Aldol
7. (a) Witkop B 1956 Imine-Enamine Systems and the
Mechanism of their Oxidation J. Am. Chem. Soc. 78
2873; (b) Clark R A and Parker D C 1971 Imine-
enamine tautomerism. I. 2-(N-Cyclohexylimino)-1,3-
diphenylpropane J. Am. Chem. Soc. 93 7257; (c)
Boyd D R, Jennings W B and Waring L C 1986
Dynamic stereochemistry of imines and derivatives. 19.
Mutarotation and E-Z isomerization of chiral imines in
[2H4]methanol solution J. Org. Chem. 51 992
Reaction Eur
. J. Org. Chem. 5310; (e) Gruttadauria
M, Giacalone F, Marculescu A M, Meo P L, Riela
S and Noto R 2007 Hydrophobically Directed Aldol
Reactions: Polystyrene-Supported L-Proline as a Recy-
clable Catalyst for Direct Asymmetric Aldol Reactions
in the Presence of Water Eur. J. Org. Chem. 4688; (f)
J Huang, Zhang X and Armstrong D W 2007 Highly
Efficient Asymmetric Direct Stoichiometric Aldol Reac-
tions on/in Water Angew. Chem. Int. Ed. 46 9073 and
the references cited therein; (g) Melchiorre P, Marigo M,
Carlone A and Bartoli G 2008 Angew. Chem. Int. Ed.
47 6138; (h) Dondoni A and Massi A 2008 Asymmetric
Organocatalysis: From Infancy to Adolescence Angew.
Chem. Int. Ed. 47 4638
8. Wurtz A 1872 On an aldehyde-alcohol Bull. Soc. Chim.
Fr. 17 436
9. (a) Smith M B and March J 2001 In Advanced Organic
Chemistry 5th
ed. (New York: Wiley Interscience)
p.1218; (b) Wade L G 2005 Organic Chemistry 6th ed.
(NewJersey: Prentice Hall) p.1056; (c) Mahrwald R 2004
In Modern Aldol Reactions Vol. 1 and 2 (Weinheim,
Germany: Wiley-VCH Verlag) p.1218
10. (a) Li J J 2004 In Contemporary Drug Synthesis (New
Jersey: Wiley-Interscience) 118; (b) Schetter B and
Mahrwald R 2006 Modern Aldol Methods for the Total 14. (a) Agarwal J and Peddinti R K 2010 Highly effi-
Synthesis of Polyketides Angew. Chem. Int. Ed. 45 7506;
(c) Paterson I and Mansuri M M 1985 Recent devel-
opments in the total synthesis of macrolide antibiotic
cient and solvent-free direct aldol reaction catalyzed by
glucosamine-derived prolinamide Tetrahedron: Asymm.
21 1906; (b) Guillena G, Hita M C and Nájera C

312
Khiangte Vanlaldinpuia et al.
2007 α-Chloroacetone as a donor in the BINAM-l- 19. Tang H and Carter R G 2008 N-(p-Dodecylphenyl-
prolinamide organocatalyzed aldol reaction: Applica-
tion to the enantioselective synthesis of α, β-epoxy
ketones Tetrahedron: Asymm. 18 1272; (c) Viozquez S F,
sulfonyl)-2-pyrrolidinecarboxamide: A Practical Proline
Mimetic for Facilitating Enantioselective Aldol Reac-
tions Org. Lett. 10 4649
Banon-Caballero A, Guillena G, Najera C and Gomez- 20. Inoue H, Kikuchi M, Ito J and Nishiyama H 2008 Chiral
Bengoa E 2012 Enantioselective direct aldol reaction
of α-keto esters catalyzed by (Sa)-binam-D-prolinamide
Phebox–rhodium complexes as catalysts for asymmetric
direct aldol reaction Tetrahedron 64 493
under quasi solvent-free conditions Org. Biomol. Chem. 21. Giacalone F, Gruttadauria M, Meo P L, Riela S and Noto
10 4029
R 2008 New Simple Hydrophobic Proline Derivatives
as Highly Active and Stereoselective Catalysts for the
Direct Asymmetric Aldol Reaction in Aqueous Medium
Adv. Synth. Catal. 350 2747
15. Nie J, Li X-J, Zheng D-H, Zhang F-G, Cui S and Ma
J-A 2011 Chiral bifunctional thiourea-catalyzed enan-
tioselective aldol reaction of trifluoroacetaldehyde
hemiacetal with aromatic ketones J. Fluorine Chem. 132 22. Vanlaldinpuia K and Bez G 2011 Useful methods for the
468
synthesis of isopropylidenes and their chemoselective
cleavage Tetrahedron Lett. 52 3759
16. Vincent J-M, Margottin C, Berlande M, Cavagnat D,
Buffeteau T and Landais Y 2007 A concise organocat- 23. Guo J and Frost J W 2002 Biosynthesis of 1-Deoxy-1-
alytic and enantioselective synthesis of isotetronic acids
Chem. Commun. 4782
17. Chen J R, Lu H H, Li X Y, Cheng L, Wan J
imino-D-erythrose 4-Phosphate:A Defining Metabolite
in the Aminoshikimate Pathway J. Am. Chem. Soc. 124
528
and Xiao W 2005 Readily Tunable and Bifunctional 24. Vanladinpuia K, Sema H A, Rokum L and Bez G
L-Prolinamide Derivatives: Design and Application in
the Direct Enantioselective Aldol Reactions Org. Lett. 7
4543
2010 An excellent method for Cbz protection of amines
Chem. Lett. 228
25. Rulli G, Duangdee N, Baer K, Hummel W, Berkessel
A and Groger H 2011 Direction of Kinetically ver-
sus Thermodynamically Controlled Organocatalysis and
Its Application in Chemoenzymatic Synthesis Angew.
Chem. Int. Ed. 50 7944
18. Hernández J G and Juaristi E 2011 Asymmetric Aldol
Reaction Organocatalyzed by (S)-Proline-Containing
Dipeptides: Improved Stereoinduction under Solvent-
Free Conditions J. Org. Chem 76 1464