Effect of ligand N,N-substituents on the reactivity of chiral copper(II) salalen, salan, and salalan complexes toward asymmetric nitroaldol reactions

Article abstract of DOI:10.1016/j.tetasy.2014.07.013

The synthesis and effect of ligand N,N-substituents on the reactivity of chiral copper(II) salalen, salan, and salalan complexes toward nitroaldol reactions of nitromethane with various aldehydes have been described. The salan complexes exhibit superior results compared to the salalen and salalan complexes; the nature of the N,N-substituents is crucial for the enantioselectivity of the target nitroaldol products.

Full text of DOI:10.1016/j.tetasy.2014.07.013

Tetrahedron: Asymmetry 25 (2014) 1331–1339
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Tetrahedron: Asymmetry
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Effect of ligand N,N-substituents on the reactivity of chiral copper(II)
salalen, salan, and salalan complexes toward asymmetric nitroaldol
reactions
⇑
Masanam Kannan, Tharmalingam Punniyamurthy
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and effect of ligand N,N-substituents on the reactivity of chiral copper(II) salalen, salan, and
salalan complexes toward nitroaldol reactions of nitromethane with various aldehydes have been
described. The salan complexes exhibit superior results compared to the salalen and salalan complexes;
the nature of the N,N-substituents is crucial for the enantioselectivity of the target nitroaldol products.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 18 July 2014
Accepted 31 July 2014
Available online 10 September 2014
1. Introduction
1 with phthalic anhydride 2 using hydrated p-toluenesulfonic acid
gave imide 3 in 95% yield which could then be reacted with trieth-
Enantioenriched nitroaldols are versatile synthetic intermedi-
ates for the asymmetric synthesis of numerous pharmaceutically
important compounds.1,2 Furthermore, optically active b-nitro
alcohols can be readily transformed into valuable chiral b-amino
ylamine (Et3N) to afford 4 in 87% yield.8 The condensation of 4 with
3,5-di-tert-butyl-2-hydroxybenzaldehyde 5 gave the Schiff base 6
in 85% yield that could be readily reduced utilizing NaBH4 to fur-
nish amine 7a in high yield. The latter was reacted with formalde-
hyde followed by NaCNBH3 to provide the N-methylated amine 7b
in 88% yield. Treatment of 7a and 7b with hydrazine hydrate affor-
ded the respective amines, which could be reacted with 5 to pro-
duce salalens 8a and 8b in 60% and 64% yields, respectively. The
reduction of salalen 8b using NaBH4 furnished salalen 9a in high
yield.
Chiral salen 10 was prepared by condensation of diamine 1 with
aldehyde 5 in high yield.9 Treatment of 10 with NaBH4 in methanol
furnished the salan 9b in 96% yield. The latter was reacted with
formaldehyde and acetaldehyde to afford the corresponding imi-
nes, which could be reduced using NaBH4 to produce N,N-dialky-
lated salans 9c–d in high yields (Scheme 2).10
alcohols by reduction and into
a-hydroxy acids by the Nef reac-
tion.3,4 The development of effective methods for their asymmetric
synthesis has thus received much attention.5
Chiral salalen and salans have attracted significant recent inter-
est as effective ligands for metal catalyzed asymmetric synthesis
because they are more flexible and can be readily modified com-
pared to a salen ligand.6 In addition, metal salalen and salan com-
plexes have a greater tendency to adopt the cis-b-configuration
that might produce strong asymmetric induction in some reac-
tions.7 Herein we report the synthesis and the effect of ligand
N,N-substituents on the reactivity of chiral copper(II) salalen
11a–b, salan 12a–c, and salalan 13 toward nitroaldol reaction of
nitromethane with aldehydes at room temperature. Chiral salan
complexes 12a–c exhibited superior results compared to the sala-
len and salalan complexes, while the nature of the N,N-substitu-
The reaction of chiral ligands 8–10 with Cu(OAc)2ꢀH2O in etha-
nol afforded the corresponding chiral copper(II) complexes 11–14
in high yields (Scheme 3).11 Since the copper(II) complexes are
effective Lewis acids for 1,2-addition reactions,12 the catalytic
activity of complexes 11–14 was studied toward the nitroaldol
reaction.
ents plays
a crucial role on the enantioselectivity of the
nitroaldol products.
First, the optimization of the reaction was performed using 4-
nitrobenzaldehyde 15a as a model substrate with nitromethane
(Table 1). The reaction occurred readily to give the nitroaldol prod-
uct with 21% ee when the substrates were stirred with 10 mol % of
the salalen complex 11a in toluene at room temperature (entry 1).
Similar results were obtained using the N-methylated salalen
complex 11b as the catalyst. However, the use of the chiral salan
2. Results and discussion
The synthesis of the chiral salalen 8a–b and salan 9a ligands is
shown in Scheme 1. The reaction of (R,R)-1,2-diaminocyclohexane
⇑
Corresponding author.
E-mail address: tpunni@iitg.ernet.in (T. Punniyamurthy).
http://dx.doi.org/10.1016/j.tetasy.2014.07.013
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1332
M. Kannan, T. Punniyamurthy / Tetrahedron: Asymmetry 25 (2014) 1331–1339
O
N
N
O
O
O
O
O
TsO H3N
N
H2N
N
O
ii
iii
i
t-Bu
OH
O
O
H2N
NH2
t-Bu
1
2
3
4
6
iv
R
Me
R
O
N
N
N
N
N
HN
OH HO
t-Bu t-Bu
vii
vi
O
t-Bu
OH HO
t-Bu
t-Bu
OH
t-Bu
t-Bu
t-Bu
t-Bu
8a R = H
t-Bu
7a R = H
9a
8b R = Me
v
7b
R = Me
Scheme 1. Reagents and conditions: (i) p-TsOHꢀH2O (1 equiv), xylene, reflux, 5 h, 95%; (ii) Et3N (1.2 equiv), CH2Cl2/MeOH (1:1), rt, 3 h, 87%; (iii) 3,5-di-tert-butyl-2-
hydroxybenzaldehyde 5 (1 equiv), MeOH, 50 °C, 8 h, 85%; (iv) NaCNBH3 (2.1 equiv), MeOH/CH3CN (1:4), rt, 3 h, 97%; (v) HCHO solution (37–41% w/v) (5 equiv), AcOH
(11 equiv), MeOH, rt, 0.5 h, NaCNBH3 (3 equiv), rt, 12 h, 88%; (vi) N2 H4ꢀH2O (10 equiv), THF, reflux, 4 h, 5 (1 equiv), MeOH, 50 °C, 8 h, (R = H, 60%; R = Me, 64%); (vii) NaBH4
(1.2 equiv), MeOH/THF (3:1), rt, 3 h, 95%.
N
N
NH HN
OH HO
t-Bu
OH HO
t-Bu t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
10
9b
R
R
N
N
i. 11 equiv AcOH
CH3CN, rt, 0.5 h
t-Bu
OH HO
t-Bu
5 RCHO
9b
+
ii. 3 equiv NaBH4
rt, 12 h
t-Bu
t-Bu
9c
9d
R = Me, 84%
R = Et, 86%
Scheme 2. Reagents and conditions: (i) RCHO (5 equiv), AcOH (11 equiv), CH3CN, rt, 0.5 h; (ii) NaBH4 (3 equiv), rt, 12 h.
complexes 12a–c led to an improvement in the enantioselectivity
to an acceleration of the reaction with high yield but led to a
decrease in the enantioselectivity, which may be due to the base
catalyzed reactions (entries 10–16).
of 16a, and the best result was observed using the N,N-dimethylat-
ed 12b with 69% ee, whereas 12a afforded 41% ee. In contrast, com-
plex 12c with bulkier N,N-diethyl substituents yielded 54% ee.
Furthermore, the N-methyl salalen complex 13 gave the product
with 38% ee. In addition, the catalytic activity of the chiral salen
complex 14 was examined; however, it was less effective and
afforded inferior results.
The effect of reaction temperature, solvent, and base was exam-
ined next (Table 2). Decreasing the reaction temperature to ꢁ40 °C
led to an increase in the enantioselectivity to 76% (entry 1). Tolu-
ene was found to be the solvent of choice in affording the best
results. In contrast, CH2Cl2, EtOAc, CH3CN, EtOH, Et2O, THF, xylene,
and chlorobenzene were less effective and afforded 16a with <67%
ee (entries 2–9). The use of a base such as Et3N, diisopropylethyl-
amine (DIPEA), morpholine, N-methylmorpholine, N-methylimid-
azole, N,N-dimethylamino-pyriridine (DMAP), or 2,6-lutidine led
With the optimal conditions in hand, the substrate scope of this
protocol was examined for the reaction of various aldehydes
(Table 3). The substrates with electron withdrawing groups exhib-
ited a greater reactivity compared to those bearing electron donat-
ing groups. For examples, benzaldehyde 15b underwent reaction
with 64% yield and 78% ee at room temperature, while the more
reactive 2-nitrobenzaldehyde 15c proceeded readily at ꢁ40 °C to
give the product with 86% yield and 90% ee. Likewise, 3-bromobenz-
aldehyde 15d proceeded with 61% yield and 80% ee at room temper-
ature, whereas the highly reactive 3-nitrobenzaldehyde 15e
underwent reaction at ꢁ40 °C with 76% yield and 81% ee. Further-
more, 4-bromo-, 4-chloro-, 4-methoxy-, and 4-methylbenzaldehd-
yes 15f–i underwent reaction with 54–89% yields and 65–82%
ee. In addition, 2-naphthyl 15j, 2-furyl 15k, and 2-thiophene 15l

M. Kannan, T. Punniyamurthy / Tetrahedron: Asymmetry 25 (2014) 1331–1339
1333
8a-b 9a-d 10
and
chiral ligands
,
Cu(OAc)2.H2O
11-14
chiral copper(II) complexes
EtOH, rt, 12 h,
R
N
R'
R''
N
O
N
O
N
O
Cu
Cu
t-Bu
O
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
11a
11b
R = H, 96%
12a R', R'' = H, 94%
12b R', R''= Me, 85%
R = Me, 87%
12c R', R'' = Et, 86%
Me
N
O
N
H
N
O
N
O
Cu
Cu
t-Bu
O
t-Bu
t-Bu
t-Bu
t-Bu
13
t-Bu
t-Bu
t-Bu
92%
14
, 94%
Scheme 3. Synthesis of chiral copper(II) salalen 11a–b, salan 12a–c, salalan 13, and salen 14 complexes.
Table 1
Screening of the chiral copper(II) complexes 11–14a
OH
*
CHO
NO2
10 mol % CuL*
CH3NO2
+
toluene
rt, 13 h
O2N
O2N
15a
16a
Entry
1
CuL*
Yieldb (%)
95
eec (%)
21
11a R = H
R
N
O
N
O
99
21
Cu
11b R = Me
2
t-Bu
t-Bu
t-Bu
t-Bu
86
95
41
69
12a
R', R'' = H
12b R', R'' = Me
12c
3
4
5
R'
R''
90
99
54
38
N
O
N
O
R', R''= Et
Cu
t-Bu
t-Bu
13 R '= Me, R'' = H
6
t-Bu
t-Bu
58
19
N
O
N
Cu
14
7
t-Bu
O
t-Bu
t-Bu
t-Bu
b Isolated yield.
c Determined by HPLC analysis with chiralcel OJ column using n-hexane/2-propanol (8:2).
a
Reaction conditions: 4-nitrobenzaldehyde 15a (0.25 mmol), nitromethane (2.5 mmol), catalyst (10 mol %), toluene
(0.75 mL), 13 h, rt, N2.

1334
M. Kannan, T. Punniyamurthy / Tetrahedron: Asymmetry 25 (2014) 1331–1339
Table 2
aldehydes proceeded with 34–71% yields and 71–77% ee, whereas n-
heptyl aldehyde 15m underwent reaction with 67% yield and 90% ee.
These results suggest that the protocol is general and that reaction of
aryl, heteroaryl, and alkyl aldehydes can be accomplished with good
to high enantioselectivities at room temperature.
A proposed catalytic cycle is shown in Scheme 4. Coordination
of nitromethane with a copper(II) salan complex may lead to the
formation of the nitronate intermediate a that could undergo reac-
tion with aldehyde to give intermediate b. An intramolecular reac-
tion of the nitronate to the chelated aldehyde can give the
nitroaldol product and the catalyst to complete the catalytic cycle.
Figure 1 shows the proposed transition state for the formation of
the nitroaldol with an (R)-configuration.
Screening of solvents, temperature, and basea
OH
*
CHO
NO2
12b
10 mol %
solvent, -40 oC
CH3NO2
+
O2N
O2N
13 h
15a
Solvent
16a
Entry
Baseb
Yieldc (%)
eed (%)
1
2
3
4
5
Toluene
CH2Cl2
EtOAc
CH3CN
EtOH
—
—
—
—
85e, 72f, 56
70, 73, 76
43
46
15
35
60
32
—
69e 12
6
7
8
9
10
11
12
13
14
15
16
Et2O
THF
Xylene
Chlorobenzene
Toluene
Toluene
Toluene
Toluene
Toluene
—
—
—
—
34
52
72
75
87
85
91
79
81
84
14
67
55
53
35
47
39
09
21
17
15
64
R
O2N
CuL*
CH3NO2
(R) OH
Et3N
DIPEA
Morpholine
N-Methylmorpholine
N-Methylimidazole
DMAP
CH3NO2
R
H
O
OH
N
L*Cu
L*Cu
Toluene
Toluene
O
O
N
2,6-Lutidine
a
H
O
b
a
Reaction conditions: 4-nitrobenzaldehyde 15a (0.25 mmol), nitromethane
(2.5 mmol), 12b (10 mol %), solvent (0.75 mL), 13 h, ꢁ40 °C, N2.
b
RCHO
Base (0.5 equiv) used.
c
Isolated yield.
d
Scheme 4. Proposed catalytic cycle.
Determined by HPLC analysis with Chiralcel OJ column using 80:20 n-hexane/2-
propanol.
e
Reaction temperature 0 °C.
Reaction temperature at ꢁ20 °C.
f
R
to use by standard procedure.13a Compounds 3, 4,8 9b,10 and 1013b
were prepared according to the literature procedure. Column chro-
matography was carried out with Rankem 60–120 mesh silica gel.
Analytical TLC was performed with Rankem silica gel G and GF 254
plates. NMR spectra were recorded using a DRX-400 Varian spec-
trometer (400 MHz for 1H and 100 MHz for 13C) and a Bruker
Avance III 600 MHz spectrometer (600 MHz for 1H and 150 MHz
for 13C) using CDCl3 as the solvent and Me4Si as the internal stan-
dard. Melting points were determined using Buchi B-540 melting
point apparatus and are uncorrected. FT-IR spectra were obtained
using a Perkin–Elmer spectrum one spectrometer. Optical rotations
were measured with a Rudolph Autpol II automatic polarimeter in
the solvent indicated. HRMS mass was analyzed with an Agilent Q-
TOF 6500. UV–vis spectra were recorded using Perkin–Elmer
Lambda 25 UV/vis spectrometer. EPR spectra were measured on
X-Band Microwave unit, JESFA200 ESR spectrometer. HPLC analysis
was carried out using a Waters-2489 with Daicel Chiralcel OD-H,
OJ-H, AD-H and OJ columns.
H
O
N
(R)-product
O
N
N
H
O
Cu
O
O
Figure 1. Proposed transition state.
3. Conclusions
In conclusion, the synthesis and the effect of ligand N,N-substit-
uents on the reactivity of chiral copper(II) salalen, salalan, and
salan complexes toward the nitroaldol reaction have been
described. The protocol is general and the reaction of aryl, hetero-
aryl, naphthyl, and alkyl aldehydes can be accomplished with
nitromethane in high enantioselectivities at room temperature
under additive free conditions. The salan complexes exhibit supe-
rior results, and the N,N-substituents play a crucial role on the
enantioselectivity of the nitroaldol products.
4.2. Synthesis of ligands
4.2.1. 2-((1R,2R)-2-((E)-(3,5-Di-tert-butyl-2-hydroxybenzylidene)
amino)cyclohexyl)isoindoline-1,3-dione 6
4. Experimental section
4.1. General
2-((1R,2R)-2-Aminocyclohexyl)isoindoline-1,3-dione 4 (4 mmol,
976 mg) and 3,5-di-tert-butylsalicylaldehyde 5 (4 mmol, 937 mg)
were stirred in MeOH (15 mL) for 8 h at 50 °C. The progress of the
reaction was monitored by TLC using ethyl acetate and hexane.
After completion, the solvent was evaporated under reduced pres-
sure and the residue was treated with water (10 mL), and extracted
with CH2Cl2 (3 ꢂ 10 mL). Drying (Na2SO4) and evaporation of the
solvent on a rotary evaporator gave a residue, which was purified
on a silica gel column chromatography using ethyl acetate and hex-
ane (3:17) as eluent to give 6 as a pale yellow solid; yield (1.566 g,
All reactions involving air- or moisture-sensitive reagents or
intermediates were carried out in an oven-dried glassware under
a nitrogen atmosphere. CH3NO2 (96%), aldehydes, and 2,4-di-tert-
butyl phenol (99%) were purchased from Aldrich, NaBH4 (95%),
HCHO solution (37–41% w/v), phthalic anhydride (98%), N2H4ꢀH2O
(99%), and Cu(OAc)2ꢀ1H2O (>98%) were purchased from Merck, and
NaCNBH3 (>96%) was purchased from Spectrochem and used as
received. Solvents were purchased from Rankem and purified prior
85%); mp 141.9–143.3 °C; [a D
(400 MHz, CDCl3): d = 13.27 (s, 1H), 8.30 (s, 1H), 7.75–7.73 (m,
]
29 = ꢁ130.7 (c 1.02, CHCl3); 1H NMR

M. Kannan, T. Punniyamurthy / Tetrahedron: Asymmetry 25 (2014) 1331–1339
1335
Table 3
Chiral copper(II) salan 12b catalyzed asymmetric nitroaldol reactiona
ee (%)
78
Configuration
Product
OH
Yield (%)
64
Entry
Substrate
Time (h)
CHO
NO2
NO2
(R)
1
48
15b
15c
OH
16b
16c
CHO
NO2
90
80
86
61
2
3
(R)
(R)
96
48
NO2
OH
Br
CHO
Br
NO2
15d
16d
OH
OH
OH
O2N
CHO
CHO
CHO
O2N
NO2
NO2
NO2
4
5
81
82
65
76
65
89
(R)
(R)
(R)
96
24
48
15e
15f
16e
16f
Br
Cl
Br
Cl
6
15g
OH
16g
CHO
CHO
NO2
70
54
(R)
7
8
96
MeO
Me
MeO
Me
16h
OH
OH
15h
NO2
NO2
79
77
68
43
(R)
(R)
72
48
16i
16j
15i
15j
CHO
9
76
71
71
34
(R)
10
11
48
NO2
O
CHO
O
OH
16k
15k
(R)
(R)
48
72
NO2
NO2
S
CHO
S
OH
OH
16l
15l
CHO
67
12
90
15m
16m
b Isolated yield.
c Determined by HPLC analysis with Chiralcel OD-H for 16d, 16f, 16g, and 16l, Chiralpak AD-H for 16c and 16e, Chiralcel OJ for 16a,
16j–k, and 16m and Chiralcel OJ-H for 16b and 16h–i using n-hexane/2-propanol.
d Determined from the sign of the specific rotation.
a
Reaction conditions: aldehyde 15 (0.25 mmol), nitromethane (2.5 mmol), and catalyst 12b (10 mol %) were stirred in toluene (0.75 mL)
for the appropriate time at room temperature (28 °C) under N2 atmosphere.
2H), 7.65 (dd, J = 12.4, 4.0 Hz, 2H), 7.30 (s, 1H), 6.95 (s, 2H), 4.42–
4.37 (m, 1H), 4.16–4.109 (m, 1H), 2.23–2.18 (m, 1H), 1.94–1.83
(m, 3 H), 1.75–1.66 (m, 1H), 1.61–1.45 (m, 2H), 1.34 (s, 9H), 1.23
(s, 9H); 13C NMR (100 MHz, CDCl3): d = 168.3, 165.9, 158.0, 139.7,
136.6, 133.8, 131.7, 126.8, 125.9, 123.1, 117.6, 67.8, 55.6, 34.9,
34.8, 34.0, 31.4, 29.3, 29.0, 25.4, 24.2; FT-IR (KBr) 3464, 2952,
2864, 1769, 1713, 1627, 1595, 1468, 1440, 1390, 1362, 1330,
1273, 1255, 1244, 1202, 1173, 1156, 1133, 1099, 1066, 1052,
1016, 1000, 981, 948, 932, 906, 869, 860, 843, 868, 804, 773, 719,
698, 639, 531, 474 cmꢁ1; HRMS (ESI, pos.): Calcd for C29H37N2O3
[M+H]+: 461.2799, found: 461.2812.
4.2.2. 2-((1R,2R)-2-((3,5-Di-tert-butyl-2-hydroxybenzyl)amino)-
cyclohexyl)isoindoline-1,3-dione 7a
To a stirred solution of 2-((1R,2R)-2-((E)-(3,5-di-tert-butyl-2-
hydroxybenzylidene)amino) cyclohexyl)isoindoline-1,3-dione
6

1336
M. Kannan, T. Punniyamurthy / Tetrahedron: Asymmetry 25 (2014) 1331–1339
(3.5 mmol, 1.612 g) in a 1:4 mixture of MeOH and CH3CN (25 mL)
was added NaCNBH3 (7.35 mmol, 461 mg) at an ice-cool tempera-
ture. After complete consumption of the starting material, the sol-
vents were evaporated under reduced pressure, and the residue
was dissolved in water (10 mL), and extracted with CH2Cl2
(3 ꢂ 10 mL). Drying (Na2SO4) and evaporation of the solvent on a
rotary evaporator afforded a residue that was purified on a silica
gel column chromatography using ethyl acetate and hexane
(3:17) as eluent to give 7a as a white solid; yield (1.570 g, 97%);
which was reacted with 5 in MeOH (15 mL) at 50 °C for 8 h to give
a pale yellow solid, which was filtered and washed with cold meth-
anol to yield analytically pure compounds 8a and 8b.
4.2.4.1. 2,4-Di-tert-butyl-6-((E)-((1R,2R)-2-(3,5-di-tert-butyl-2-
hydroxybenzylamino)cyclohexylimino)methyl)phenol 8a. Pale
yellow solid; yield (494 mg, 60%); mp 146.8–148.6 °C;
[a]
29 = ꢁ103.7 (c 1.34, CHCl3); 1H NMR (400 MHz, CDCl3):
D
d = 13.47 (s, 1H), 11.63 (s, 1H), 8.40 (s, 1H), 7.37 (d, J = 2.0 Hz,
1H), 7.16 (d, J = 2.0 Hz, 1H), 7.05 (d, J = 2.4 Hz, 2H), 6.8 (d,
J = 2.0 Hz, 1H), 4.04 (d, J = 13.2 Hz, 1H), 3.81 (d, J = 13.44 Hz, 1H),
3.06 (td, J = 10.8, 2.8 Hz, 1H), 2.83 (td, J = 10.8, 3.2 Hz, 1H), 2.25
(d, J = 12.8 Hz, 1H), 1.82–1.81 (m, 3H), 1.43 (s, 9H), 1.33 (s, 9H),
1.27 (s, 9H), 1.23 (s, 9H). 13C NMR (100 MHz, CDCl3): d = 166.7,
158.1, 154.7, 140.5, 140.3, 136.7, 136.0, 127.3, 126.3, 123.2,
123.0, 122.9, 117.9, 74.1, 61.2, 50.9, 35.2, 35.0, 34.2, 34.1, 31.8,
31.6, 29.8, 29.7, 24.7, 24.6. FT-IR (KBr) 3490, 2955, 2863, 1734,
1648, 1627, 1479, 1467, 1440, 1391, 1361, 1301, 1273, 1251,
1202, 1172, 1125, 1080, 1025, 981, 931, 877, 827, 801, 772, 738,
713, 645, 535, 510 cmꢁ1. HRMS (ESI, pos.): Calcd for C36H57N2O2
[M+H]+: 549.4415, found: 549.4426.
mp 172.9–174.8 °C;
[a
]
D
29 = ꢁ7.6 (c 0.99, CHCl3); 1H NMR
(400 MHz, CDCl3): d = 7.84 (dd, J = 5.2, 3.2 Hz, 2H), 7.71 (dd,
J = 5.2, 3.2 Hz, 2H), 7.10 (d, J = 1.6 Hz, 1H), 6.78 (d, J = 1.2 Hz, 1H),
4.04–3.96 (m, 2H), 3.77 (d, J = 13.2 Hz, 1H), 3.51 (td, J = 11.1,
3.6 Hz, 1H), 2.42–2.28 (m, 2H), 1.86 (br s, 3H), 1.22 (s, 9H), 1.09
(s, 9H); 13C NMR (100 MHz, CDCl3): d = 168.9, 154.9, 140.3, 135.9,
133.9, 132.1, 123.3, 122.9, 122.9, 121.9, 56.8, 50.6, 34.7, 34.2,
31.8, 29.6, 29.5, 25.6, 24.8; FT-IR (KBr) 3462, 3305, 2954, 1947,
1767, 1717, 1699, 1683, 1612, 1546, 1480, 1393 1331, 1330,
1236, 1155, 1116, 1084, 1047, 1017, 1002, 978, 955, 926, 903,
871, 859, 843, 823, 798, 719, 700, 677, 667, 648, 639, 530, 509,
.
454 cmꢁ1 HRMS (ESI, pos.): Calcd for C29H39N2O3 [M+H]+:
463.2955, found: 463.2951.
4.2.4.2. 2,4-Di-tert-butyl-6-((E)-(((1R,2R)-2-((3,5-di-tert-butyl-2-
4.2.3. 2-((1R,2R)-2-((3,5-Di-tert-butyl-2-hydroxybenzyl)(methyl)-
amino)cyclohexyl)isoindo-line-1,3-dione 7b
To a stirred solution of 2-((1R,2R)-2-((3,5-di-tert-butyl-2-hydro-
xybenzyl)amino)cyclohexyl)iso-indoline-1,3-dione 7a (1.5 mmol,
693.9 mg) in a 3:1 mixture of CH3CN and MeOH (15 mL) was added
hydroxybenzyl)(methyl)amino)cyclohexyl)imino)methyl)phe-
nol 8b.
116.4 °C; [
Pale yellow solid; yield (540 mg, 64%); mp 114.3–
a]
29 = ꢁ97.0 (c 0.88, CHCl3); 1H NMR (400 MHz, CDCl3):
D
d = 13.57 (s, 1H), 10.59 (s, 1H), 8.37 (s, 1H), 7.38 (d, J = 2.0 Hz, 1H),
7.10 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 2.0 Hz,
1H), 3.83–3.70 (m, 2H), 3.27–3.25 (m, 1H), 2.98–2.91 (m, 1H),
2.22 (s, 3H), 1.99–1.63 (m, 6H), 1.47 (s, 9H), 1.44–1.32 (m, 2H),
1.28 (s, 9H), 1.24 (s, 9H), 1.12 (s, 9H). 13C NMR (100 MHz, CDCl3):
d = 165.9, 158.3, 154.9, 139.9, 139.9, 136.7, 135.5, 127.0, 125.9,
123.4, 122.6, 121.1, 118.3, 70.4, 66.8, 58.5, 35.4, 35.2, 34.8, 34.2,
31.9, 31.7, 31.5, 29.8, 29.6, 25.3, 24.8, 23.92; FT-IR (KBr) 3472,
2954, 2863, 1678, 1630, 1479, 1467, 1455, 1441, 1390, 1361,
1302, 1273, 1245, 1234, 1203, 1173, 1113, 1073, 1025, 982, 948,
938, 878, 825, 801, 772, 763, 738, 714, 695, 645, 566, 538,
dropwise CH3COOH (3.5 mL) followed by HCHO solution (650 lL)
at room temperature. The reaction mixture was stirred for 0.5 h,
after which NaCNBH3 (4.5 mmol, 282 mg) was added portionwise
at 0 °C. The reaction mixture was then stirred at room temperature
for 12 h. The progress of the reaction was monitored by TLC using
ethyl acetate and hexane. After completion, the solvent was evap-
orated under reduced pressure, and the residue was treated with
saturated NaHCO3 solution followed by water (5 mL). The mixture
was extracted with CH2Cl2 (3 ꢂ 10 mL), dried (Na2SO4), and evap-
orated on a rotary evaporator to give a residue, which was purified
on a silica gel column chromatograph using ethyl acetate and
hexane (3:17) as eluent to give 7b as a colorless solid; yield
.
509 cmꢁ1 HRMS (ESI, pos.): Calcd for C37H59N2O2 [M+H]+:
563.4571, found: 563.4579.
(714 mg, 88%); mp 183.9–185.5 °C; [
a
]
29 = ꢁ24.8 (c 0.76, CHCl3);
4.2.5. 2,4-Di-tert-butyl-6-((((1R,2R)-2-((3,5-di-tert-butyl-2-hyd-
roxybenzyl)(methyl)amino) cyclohexyl)amino)methyl)phenol
9a
D
1H NMR (400 MHz, CDCl3): d = 11.32 (s, 1H), 7.82 (dd, J = 4.5,
2.4 Hz, 2H), 7.70 (dd, J = 5.0, 2.8 Hz, 2H), 7.02 (d, J = 1.4 Hz, 1H),
6.71 (d, J = 2.2 Hz, 1H), 4.32 (td, J = 11.6, 3.4 Hz, 1H), 3.76–3.66
(m, 3H), 2.36–2.28 (m, 1H), 2.15 (s, 3H), 2.06 (d, J = 9.1, 1H),
1.92–1.84 (m, 3H), 1.49–1.31 (m, 3H), 1.21 (s, 9H), 0.90 (s, 9H);
13C NMR (100 MHz, CDCl3): d = 168.9, 154.8, 139.9, 135.0, 133.7,
123.2, 123.0, 122.5, 120.2, 110.1, 63.2, 51.7, 34.5, 34.2, 31.8, 30.1,
29.2, 25.7, 24.9, 23.5; FT-IR (KBr) 3372, 2955, 2867, 1766, 1703,
1659, 1606, 1482, 1468, 1390, 1361, 1302, 1233, 1202, 1163,
1125, 1027, 1012, 937, 905, 876, 822, 797, 763, 720, 668, 648,
530, 510 cmꢁ1. HRMS (ESI, pos.): Calcd for C30H41N2O3 [M+H]+:
477.3112, found: 477.3118.
To a stirred solution of 2,4-di-tert-butyl-6-((E)-(((1R,2R)-2-
((3,5-di-tert-butyl-2-hydroxybenzyl)-(methyl)amino)cyclohexyl)-
imino)methyl)phenol 8b (0.75 mmol, 422 mg) in a 1:3 mixture of
THF/MeOH at 0 °C, NaBH4 (0.9 mmol, 30.2 mg) was added, and
the resultant mixture was stirred for 12 h at room temperature.
The progress of the reaction was monitored by TLC using ethyl ace-
tate and hexane. After completion, the solvent was evaporated
under reduced pressure and the residue was neutralized with a
saturated NaHCO3 solution. The mixture was then treated with
water (5 mL) and extracted with CH2Cl2 (3 ꢂ 10 mL). Drying
(Na2SO4) and evaporation of the solvent on a rotary evaporator
provided a residue, which was purified by silica gel column
chromatography using ethyl acetate and hexane (3:17) as eluent
to give 9a as a colorless viscous liquid; yield (382 mg, 95%);
4.2.4. General procedure for the synthesis of compounds 8a and
8b
To a stirred solution of 7 (1.5 mmol) in dry THF (10 mL), N2H4
ꢀH2O (2.25 mL) was added. After refluxing for 4 h, the reaction
mixture was cooled to room temperature and diluted with Et2O
(20 mL) to precipitate out phthaloyl hydrazide. After filtering the
solid, the filtrate was concentrated under reduced pressure to give
a residue, which was dissolved in ethyl acetate (5 mL) and
extracted with dilute HCl (2 ꢂ 5 mL). The solution was then neu-
tralized using a saturated NaHCO3 solution and extracted using
dichloromethane (3 ꢂ 10 mL). Drying (Na2SO4) and evaporation
of the solvent on a rotary evaporator furnished a colorless solid,
[a]
29 = ꢁ5.0 (c 1.38, CHCl3); 1H NMR (600 MHz, CDCl3): d = 7.22
D
(d, J = 2.4 Hz, 2H), 6.88 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H),
4.08 (d, J = 13.2 Hz, 1H), 3.98 (d, J = 13.2 Hz, 1H), 3.90 (d,
J = 13.2 Hz, 1H), 3.77 (d, J = 13.2 Hz, 1H), 2.67 (td, J = 10.8, 4.2 Hz,
1H), 2.52 (td, J = 10.8, 3 Hz), 2.28 (s, 3H), 1.98 (d, J = 13.2 Hz, 1H),
1.82–1.81 (m, 1H), 1.73–1.72 (m, 1H), 1.42 (s, 9H), 1.37 (s, 9H),
1.29 (s, 19H), 1.20–1.13 (m, 4H); 13C NMR (150 MHz, CDCl3):
d = 154.7, 154.3, 140.8, 140.5, 135.9, 135.8, 123.6, 123.3, 123.1,
123.0, 122.6, 121.2, 65.3, 58.7, 56.8, 50.4, 35.7, 35.0, 34.3, 32.2,

M. Kannan, T. Punniyamurthy / Tetrahedron: Asymmetry 25 (2014) 1331–1339
1337
31.9, 29.9, 29.9, 29.8, 25.2, 25.0, 22.5, 14.4; FT-IR (neat) 3503, 2954,
2860, 2071, 1634, 1480, 1390, 1361, 1302, 1235, 1202, 1165, 1124,
1526, 1467, 1435, 1409, 1383, 1360, 1349, 1301, 1286, 1254,
1236, 1201, 1167, 1134, 1092, 1025, 970, 927, 877, 858, 830,
807, 789, 741, 639, 624, 535, 503, 467 cmꢁ1; UV–vis (CH2Cl2):
1096, 1018, 977, 878, 822, 799, 758, 724, 695, 667, 648, 509 cmꢁ1
.
HRMS (ESI, pos.): Calcd for C37H61N2O2 [M+H]+: 565.4728, found:
565.4732.
kmax(e) = 586 (4655), 382 (37355), 275 (124897), 246 nm
(186347 molꢁ1 dm3 cmꢁ1); EPR (THF): liquid N2 temp; gII = 2.333,
g\ = 2.019, AII = 21.19 mT; HRMS (ESI, pos.): Calcd for C36H55N2O2
Cu [M+H]+: 610.3554, Found: 610.3561.
4.2.6. General procedure for the synthesis of compounds 9c–d
To
a
solution of 6,60-(1R,2R)-cyclohexane-1,2-diylbis(aza-
nediyl)bis(methylene)bis(2,4-di-tert-butylphenol) 9b (2 mmol,
1.101 g) in CH3CN (25 mL) were added dropwise CH3COOH
(5 mL) and HCHO solution (2 mL) at room temperature. The resul-
tant mixture was stirred for 0.5 h, and then treated with NaBH4
(10 mmol, 378 mg) at 0 °C. After stirring at room temperature for
12 h, the solvent was evaporated under reduced pressure and the
residue was dissolved in CH2Cl2 (10 mL) and neutralized with sat-
urated NaHCO3 solution. The aqueous layer was extracted with
CH2Cl2 (2 ꢂ 10 mL), and the combined organic layer was washed
with water, dried (Na2SO4), and evaporated on a rotary evaporator
to give a residue, which was purified on silica gel column chroma-
tography using ethyl acetate and hexane as eluent to give com-
pounds 9c–d.
4.3.2. Complex 11b
Green solid; yield (271 mg, 87%); [
a
]
29 = ꢁ1828.6 (c 0.028,
D
CHCl3); FT-IR (KBr): 2950, 2905, 2866, 1726, 1674, 1617, 1527,
1474, 1433, 1412, 1386, 1360, 1333, 1303, 1254, 1235, 1202,
1167, 1133, 1090, 1004, 973, 931, 874, 831, 809, 790, 778, 742,
658, 639, 534, 480 cmꢁ1; UV–vis (CH2Cl2): kmax
(e) = 594 (5024),
402 (37346), 276 (133740), 251 nm (191144 molꢁ1 dm3 cmꢁ1);
EPR (THF): liquid N2 temp; gII = 2.333, g\ = 2.009, AII = 21.71 mT;
HRMS (ESI, pos.): Calcd for C37H57N2O2Cu [M+H]+: 624.3711,
Found: 624.3715.
4.3.3. Complex 12a
Green solid; yield (287 mg, 94%); [
CHCl3); FT-IR (KBr): 3428, 3188, 2950, 2865, 1773, 1665, 1623,
a
]
D
29 = ꢁ558.8 (c 0.068,
4.2.6.1. 6,60-(((1R,2R)-Cyclohexane-1,2-diylbis(methylazanediyl))
1527, 1469, 1439, 1411, 1388, 13,611, 1299, 1254, 1235, 1201,
bis(methylene))bis(2,4-di-tert-butylphenol) 9c10
.
Colorless
1166, 1094, 1059, 876, 827, 805, 783, 738, 668, 536, 460 cmꢁ1
;
viscous liquid; yield (995 mg, 84%); [a D
]
29 = +37.3 (c 0.54, CHCl3);
UV–vis (CH2Cl2): kmax
246 nm (21776 molꢁ1 dm3 cmꢁ1); HRMS (ESI, pos.): Calcd for
36H57N2O2Cu [M+H]+: 612.3711, Found: 612.3715.
(e) = 623 (894), 423 (2406), 290 (13752),
1H NMR (400 MHz, CDCl3): d = 7.17 (d, J = 2.0 Hz, 2H), 6.80 (d,
J = 2.0 Hz, 2H), 7.73 (dd, J = 5.6, 2.8 Hz, 2H), 3.82–3.72 (m, 4H),
2.67 (m, 2H), 2.19 (s, 6H), 2.00–1.97 (m, 2H), 1.78–1.76 (m, 2H),
1.35 (s, 18H), 1.26 (s, 18H), 1.12–1.16 (m, 4H); 13C NMR
(100 MHz, CDCl3): d = 154.6, 140.3, 135.7, 123.7, 122.9, 121.5,
61.5, 58.8, 35.0, 34.3, 31.9, 29.8, 27.1, 25.5, 22.7; FT-IR (neat):
3451, 2950, 2899, 2866, 1603, 1559, 1469, 1437, 1412, 1389,
1381, 1362, 1349, 1293, 1279, 1264, 1238, 1204, 1166, 1134,
1102, 1012, 994, 968, 879, 873, 831, 812, 777, 739, 668, 639,
C
4.3.4. Complex 12b
Green solid; yield (272 mg, 85%); [
a]
29 = ꢁ1981.4 (c 0.022,
D
CHCl3); FT-IR (KBr): 3418, 2948, 2899, 2866, 1761, 1604, 1539
1469, 1437, 1412, 1380, 1360, 1349, 1326, 1295, 1238, 1203,
1166, 1134, 1102, 1012, 994, 969, 876, 831, 812, 776, 739, 640,
538, 488 cmꢁ1
; UV–vis (CH2Cl2): kmax(e) = 641 (5396), 445
538 cmꢁ1
.
HRMS (ESI, pos.): Calcd for C38H63N2O2 [M+H]+:
(8110), 299 (62478), 254 nm (80632 molꢁ1 dm3 cmꢁ1); EPR
(THF): liquid N2 temp; gII = 2.341, g\ = 2.016, AII = 20.52 mT; HRMS
(ESI, pos.): Calcd for C38H61N2O2Cu [M+H]+: 640.4024, Found: 640.
4020.
579.4884, found: 579.4906.
4.2.6.2. 6,60-(((1R,2R)-Cyclohexane-1,2-diylbis(ethylazanediyl))bis
(methylene))bis(2,4-di-tert-butyl phenol) 9d.
Colorless solid;
yield (1.068 g, 86%); mp 170.6–173.1 °C; [a D
]
29 = +11.0 (c 0.40, CHCl3).
4.3.5. Complex 12c
1H NMR (400 MHz, CDCl3): d = 7.14 (d, J = 2.4 Hz, 4H), 6.77 (s, 4H),
3.96 (s, 2H), 3.50 (q, J = 7.2 Hz, 4H), 3.29 (s, 2H), 2.43–2.35 (m, 4H),
2.04 (s, 4H), 1.76 (d = 7.2 Hz, 4H), 1.25 (s, 36H), 1.22 (t, J = 7.2 Hz,
6H); 13C NMR (150 MHz, CDCl3): d = 153.8, 140.4, 135.9, 124.2,
122.6, 122.2, 58.6, 52.7, 42.6, 34.9, 34.2, 31.9, 29.7, 25.9, 23.4, 13.0;
FT-IR (KBr): 3387, 2952, 2863, 1739, 1605, 1481, 1470, 1390, 1361,
1285, 1262, 1240, 1216, 1201, 1164, 1123, 1109, 1069, 1055, 1033,
993, 971, 946, 928, 877, 865, 820, 800, 772, 759, 740, 726, 695,
Green solid; yield (287 mg, 86%); [
a
]
29 = ꢁ33.33 (c 0.024,
D
CHCl3); FT-IR (KBr): 3414, 2951, 2901, 2867, 1731, 1674, 1469,
1438, 1412, 1388, 1360, 1300, 1242, 1203, 1167, 1132, 1094,
969, 874, 831, 770, 741, 685, 669, 650, 538, 492 cmꢁ1; UV–vis
(CH2Cl2): kmax(e) = 669 (5968), 457 (8888), 300 (82100), 253 nm
(104388 molꢁ1 dm3 cmꢁ1); EPR (THF): liquid N2 temp; gII = 2.345,
g\ = 2.026, AII = 20.57 mT; HRMS (ESI, pos.): Calcd for C40H65N2O2
Cu [M+H]+: 668.4337, Found: 668.4346.
672, 649, 605, 566, 540 cmꢁ1
. HRMS (ESI, pos.): Calcd for
C40H67N2O2 [M+H]+: 607.5197, found: 607.5205.
4.3.6. Complex 13
Green solid; yield (288 mg, 92%); [
a]
29 = ꢁ3422.2 (c 0.090,
D
4.3. General procedure for the synthesis of copper(II) complexes
CHCl3); FT-IR (KBr): 2949, 2864, 1726, 1661, 1619, 1602, 1467,
1439, 1412, 1389, 1361, 1299, 1287, 1253, 1237, 1203, 1166,
1132, 998, 877, 828, 807, 778, 661, 642, 535 cmꢁ1; UV–vis
To a stirred solution of ligand (0.5 mmol) in EtOH (5 mL) was
added Cu(OAc)2ꢀ1H2O (0.5 mmol) in EtOH (2 mL). After stirring at
room temperature under air for 12 h, the solvent was evaporated
under reduced pressure, and the residue was extracted with ethyl
acetate (3 ꢂ 5 mL) and washed with water (1 ꢂ 5 mL). Drying
(Na2SO4) and evaporation of the solvent on a rotary evaporator
gave a residue, which was purified on a silica gel column chroma-
tography using hexane and ethyl acetate (2:3) as eluent to give the
respective complex as a green solid.
(CH2Cl2): kmax(e) = 622 (4933), 436 (8425), 298 (53208), 250 nm
(71646 molꢁ1 dm3 cmꢁ1); EPR (THF): liquid N2 temp; gII = 2.329,
g\ = 2.010, AII = 21.87 mT; HRMS (ESI, pos.): Calcd for C37H59N2O2
Cu [M+H]+: 626.3867, Found: 626.3872.
4.3.7. Complex 14
Green solid; yield (285 mg, 94%); [
a
]
D
29 = ꢁ331.2 (c 0.046,
CHCl3); FT-IR (KBr): 3313, 2954, 2905, 2867, 1726, 1621, 1527,
1463, 1431 1383, 1362, 1348, 1323, 1254, 1200, 1167, 1132,
1097, 968, 877, 832, 788, 743, 556, 537, 476 cmꢁ1; UV–vis (CH2
4.3.1. Complex 11a
Green solid; yield (292 mg, 96%); [
CHCl3); FT-IR (KBr): 3505, 3226, 2950, 2865, 1728, 1658, 1622,
a
]
D
29 = ꢁ1471.4 (c 0.028,
Cl2): kmax
(e) = 569 (940), 378 (14452), 281 (40276), 256 nm
(43531 molꢁ1 dm3 cmꢁ1); EPR (THF): liquid N2 temp; gII = 2.333,

1338
M. Kannan, T. Punniyamurthy / Tetrahedron: Asymmetry 25 (2014) 1331–1339
g\ = 2.008, AII = 22.24 mT; HRMS (ESI, pos.): Calcd for C36H53N2O2
4.4.6. (R)-(ꢁ)-1-(4-Bromophenyl)-2-nitroethanol 16f15
Cu [M+H]+: 608.3398, Found: 608.3394.
Yellow oil, yield 65%; 1H NMR (400 MHz, CDCl3): d = 7.53 (dd,
J = 9.0, 4.2 Hz, 2H), 7.28 (d, J = 10.2 Hz, 2H), 5.43–5.40 (m, 1H),
4.57–4.46 (m, 2H), 2.86 (s, 1H); 13C NMR (100 MHz, CDCl3):
d = 137.2, 132.3, 127.8, 123.0, 81.0, 70.4; FT-IR (neat): 3404,
1553, 1381 cmꢁ1; ee: 82%, determined by HPLC (Daicel Chiralcel
OD-H, hexane/iPrOH (17:3), flow rate 0.9 mL/min, k = 215 nm):
4.4. General procedure for enantioselective nitroaldol reactions
To a stirred solution of catalyst 12b (16 mg, 0.025 mmol) and
aldehyde (0.25 mmol) in dry toluene (0.75 mL), nitromethane
(2.5 mmol) was added at the appropriate temperature. After the
indicated time, the reaction mixture was treated with saturated
NH4Cl solution (1 mL) followed by water (3 mL). The mixture
was extracted using ethyl acetate (3 ꢂ 5 mL). Drying (Na2SO4)
and evaporation of the solvent gave a residue, which was purified
on a silica gel column chromatography using hexane and ethyl ace-
tate (4:1) as eluent to afford the analytically pure nitroaldol
product.
tR = 12.5 min (minor), tR = 15.9 min (major); [
CHCl3).
a
]
D
29 = ꢁ22.1 (c 0.83,
4.4.7. (R)-(ꢁ)-1-(4-Chlorophenyl)-2-nitroethanol 16g15
Yellow oil, yield 89%; 1H NMR (400 MHz, CDCl3): d = 7.40–7.34
(m, 4H), 5.48–5.44 (m, 1H), 4.60–4.47 (m, 2H), 2.89 (d, J = 3.2 Hz,
1H); 13C NMR (100 MHz, CDCl3): d = 136.7, 134.7, 129.2, 127.4,
81.0, 70.3; FT-IR (neat): 3528, 1553, 1380 cmꢁ1; ee: 65%, deter-
mined by HPLC (Daicel Chiralcel OD-H, hexane/iPrOH (17:3), flow
rate 0.9 mL/min, k = 215 nm): tR = 11.3 min (minor), tR = 12.5 min
4.4.1. (R)-(ꢁ)-2-Nitro-1-(4-nitrophenyl)ethanol 16a14
(major); [
a
]
D
29 = ꢁ27.0 (c 0.61, CHCl3).
Yellow oil, yield 56%; 1H NMR (400 MHz, CDCl3): d = 8.28 (dd,
J = 6.4, 1.2 Hz, 2H), 7.63 (d, J = 9.2 Hz, 2H), 5.62–5.58 (m, 1H),
4.63–4.55 (m, 2H), 3.21 (d, J = 4.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d = 148.2, 145.3, 127.1, 124.3, 80.8, 70.1; FT-IR (neat):
3528, 1557, 1520, 1350 cmꢁ1; ee: 76%, determined by HPLC (Daicel
4.4.8. (R)-(ꢁ)-1-(4-Methoxyphenyl)-2-nitroethanol 16h15
Yellow oil, yield 54%; 1H NMR (400 MHz, CDCl3): d = 7.33 (d,
J = 8.8 Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 5.44–5.39 (m, 1H), 4.63–
4.46 (m, 2H), 3.81 (s, 3H), 2.72 (t, J = 3.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d = 156.2, 130.0, 127.4, 126.1, 121.4, 110.7,
80.0, 68.0, 55.6; FT-IR (neat): 3472, 1553, 1379 cmꢁ1; ee: 70%,
determined by HPLC (Daicel Chiralcel OJ-H, hexane/iPrOH
(9:1), flow rate 0.6 mL/min, k = 215 nm): tR = 42.4 min (minor),
Chiralcel OJ, hexane/iPrOH (4:1), flow rate 1.0 mL/min,
29
k = 215 nm): tR = 11.5 min (minor), tR = 14.9 min (major); [
ꢁ29.6 (c 0.52, CHCl3).
a]
=
D
4.4.2. (R)-(ꢁ)-2-Nitro-1-phenylethanol 16b15
tR = 50.1 min (major); [
a]
29 = ꢁ18 (c 1.80, CHCl3).
Yellow oil, yield 64%; 1H NMR (400 MHz, CDCl3): d = 7.41–7.36
(m, 5H), 5.49–5.45 (m, 1H), 4.64–4.49 (m, 2H), 2.84 (d, J = 3.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): d = 138.3, 129.0, 129.0, 126.0,
81.3, 71.0; FT-IR (neat): 3548, 1553, 1379 cmꢁ1; ee: 78%, deter-
mined by HPLC (Daicel Chiralcel OJ-H, hexane/iPrOH (17:3), flow
rate 0.8 mL/min, k = 215 nm): tR = 21.6 min (minor), tR = 26.1 min
D
4.4.9. (R)-(ꢁ)-2-Nitro-1-(p-tolyl)ethanol 16i15
Yellow oil, yield 68%; 1H NMR (400 MHz, CDCl3): d = 7.30 (d,
J = 8 Hz, 2H), 7.22 (d, J = 8 Hz, 2H), 5.45–5.41 (m, 1H), 4.63–4.47
(m, 2H), 2.75 (d, J = 4 Hz, 1H), 2.36 (s, 3H); 13C NMR (100 MHz,
CDCl3): d = 138.9, 135.3, 129.7, 126.0, 81.3, 70.9, 21.2; FT-IR (neat):
3551, 1554, 1378 cmꢁ1; ee: 79%, determined by HPLC (Daicel
Chiralcel OJ-H, hexane/iPrOH (17:3), flow rate 0.8 mL/min,
k = 215 nm): tR = 18.7 min (minor), tR = 21.7 min (major);
(major); [
a]
D
29 = ꢁ33.1 (c 0.24, CHCl3).
4.4.3. (R)-(+)-2-Nitro-1-(2-nitrophenyl)ethanol 16c2a
Yellow oil, yield 86%; 1H NMR (400 MHz, CDCl3): d = 8.08 (dd,
J = 8, 1.2 Hz, 1H), 7.96 (dd, J = 7.6, 0.8 Hz, 1H), 7.76 (td, J = 7.6,
0.8 Hz, 1H), 7.57 (td, J = 8.4, 0.8 Hz, 1H), 6.05–6.02 (m, 1H), 4.88–
4.84 (m, 1H), 4.58–4.52 (m, 1H), 3.29 (s, 1H); 13C NMR (100 MHz,
CDCl3): d = 147.2, 134.5, 134.3, 129.7, 128.8, 125.0, 80.2, 66.9; FT-
IR (neat): 3529, 1555, 1525, 1346 cmꢁ1; ee: 90%, determined by
HPLC (Daicel Chiralcel AD-H, hexane/iPrOH 90/10, flow rate 1 mL/
min, k = 215 nm): tR = 14.3 min (major), tR = 15.7 min (minor);
[a]
29 = ꢁ24.3 (c 1.24, CHCl3).
D
4.4.10. (R)-(ꢁ)-1-(Naphthalen-2-yl)-2-nitroethanol 16j15
Colorless solid, mp 80.9–81.8 °C, yield 43%, 1H NMR (400 MHz,
CDCl3): d = 7.90–7.84 (m, 4H), 7.54–7.46 (m, 3H), 5.66–5.62 (m,
1H), 4.72–4.58 (m, 2H), 2.94 (d, J = 3.6 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d = 138.9, 135.3, 129.7, 126.0, 81.3, 70.9; FT-IR
(KBr): 3547, 1553, 1377 cmꢁ1; ee: 77%, determined by HPLC
[a]
20 = +185 (c 0.59, CHCl3).
D
(Daicel Chiralcel OJ, hexane/iPrOH (8:2), flow rate 1 mL/min,
4.4.4. (R)-(ꢁ)-1-(3-Bromophenyl)-2-nitroethanol 16d15
29
k = 215 nm): tR = 18.2 min (minor), tR = 25.9 min (major); [
ꢁ35.6 (c 0.38, CHCl3).
a]
=
D
Yellow oil, yield 61%; 1H NMR (400 MHz, CDCl3): d = 7.59 (s,
1H), 7.50 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.30 (d,
J = 7.6 Hz, 1H), 5.47–5.43 (m, 1H), 4.61–4.49 (m, 2H), 2.91 (d,
J = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d = 140.4, 132.0,
130.7, 129.2, 124.7, 123.1, 81.0, 70.2; FT-IR (neat): 3542,
1556, 1377 cmꢁ1; ee: 80%, determined by HPLC (Daicel Chiralcel
OD-H, hexane/iPrOH (17:3), flow rate 0.8 mL/min, k = 215 nm):
4.4.11. (R)-(ꢁ)-1-(Furan-2-yl)-2-nitroethanol 16k14
Yellow oil, yield 71%; 1H NMR (400 MHz, CDCl3): d = 7.40 (s,
1H), 6.38 (d, J = 3.6 Hz, 1H), 6.36 (dd, J = 3.0, 1.8 Hz, 1H), 5.46–
5.45 (m, 1H), 4.78–4.74 (m, 1H), 4.67–4.64 (m, 1H), 2.84 (s, 1H);
13C NMR (100 MHz, CDCl3): d = 150.8, 143.3, 110.8, 108.4, 78.5,
65.0; FT-IR (neat): 3418, 1555, 1380 cmꢁ1; ee: 76%, determined
by HPLC (Daicel Chiralcel OJ, hexane/iPrOH (17:3), flow rate
0.9 mL/min, k = 215 nm): tR = 15.9 min (minor), tR = 18.6 min
tR = 11.7 min (minor), tR = 14.5 min; [
a]
20 = ꢁ23.2 (c 1.50, CHCl3).
D
4.4.5. (R)-(ꢁ)-2-Nitro-1-(3-nitrophenyl)ethanol 16e15
Yellow oil, yield 76%; 1H NMR (400 MHz, CDCl3): d = 8.32 (s, 1H),
8.23 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 8.4 Hz, 1H),
5.63–5.59 (m, 1H), 4.66–4.56 (m, 2H), 3.23 (d, J = 4.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3): d = 148.6, 140.4, 132.2, 130.3, 123.9,
121.3, 80.8. 70.0; FT-IR (neat): 3546, 1557, 1538, 1347 cmꢁ1; ee:
81%, determined by HPLC (Daicel Chiralcel AD-H, hexane/iPrOH
(9:1), flow rate 1 mL/min, k = 215 nm): tR = 16.1 min (major),
(major); [
a
]
D
29 = ꢁ32.8 (c 0.22, CHCl3).
4.4.12. (R)-(ꢁ)-2-Nitro-1-(thiophen-2-yl)ethanol 16l16a
Yellow oil, yield 34%; 1H NMR (400 MHz, CDCl3): d = 7.33–7.31
(m, 1H), 7.06–7.04 (m, 1H), 7.01–6.99 (m, 1H), 5.72–5.70 (m, 1H),
4.73–4.57 (m, 2H), 3.00 (d, J = 4.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d = 141.5, 127.3, 126.2, 125.1, 81.0, 67.2; FT-IR (neat):
3416, 1618, 1557, 1380 cmꢁ1; ee: 71%, determined by HPLC (Daicel
tR = 18.5 min (minor); [
a
]
D
29 = ꢁ28.8 (c 0.13, CHCl3).

M. Kannan, T. Punniyamurthy / Tetrahedron: Asymmetry 25 (2014) 1331–1339
1339
Chiralcel OD-H, hexane/iPrOH (17:3), flow rate 0.9 mL/min,
Angew. Chem., Int. Ed. 1981, 20, 397; (c) Barrett, A. G. M.; Spiling, C. D.
Tetrahedron Lett. 1988, 29, 5733; (d) Wehner, V.; Jager, V. Angew. Chem., Int. Ed.
1990, 29, 1169; (e) Kiess, F.-M.; Poggendorf, P.; Picasso, S.; Jager, V. Chem.
Commun. 1998, 119; (f) Ballini, R.; Palmieri, A.; Righi, P. Tetrahedron 2007, 63,
12099.
k = 215 nm): tR = 10.1 min (minor), tR = 11.5 min (major);
[
a]
D
29 = ꢁ16 (c 0.25, CHCl3).
4.4.13. (R)-(ꢁ)-1-Nitrononan-2-ol 16m16b
5. For some selected examples, see: (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.;
Shibasaki, M. J. Am. Chem. Soc. 1992, 114, 4418; (b) Trost, B. M.; Yeh, V. S. C.
Angew. Chem., Int. Ed. 2002, 114, 889; (c) Evans, D. A.; Seidel, D.; Rueping, M.;
Lam, H. W.; Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125, 12692; (d)
Palmo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem., Int. Ed. 2004, 43, 5442; (e)
Palomo, C.; Oiarbide, M.; Halder, R.; Laso, A.; Lopez, R. Angew. Chem., Int. Ed.
2006, 45, 117; (f) Park, J.; Lang, K.; Abboud, K. A.; Hong, S. J. Am. Chem. Soc.
2008, 130, 16484; (g) Sanjeevkumar, N.; Periasamy, M. Tetrahedron: Asymmetry
2009, 20, 1842; (h) Zulauf, A.; Mellah, M.; Schulz, E. J. Org. Chem. 2009, 74,
2242; (i) Constable, E. C.; Zhang, G.; Housecroft, C. E.; Neuburger, M.; Schaffner,
S.; Woggon, W. D. New J. Chem. 2009, 33, 1064; (j) Kureshy, R. I.; Das, A.; Khan,
N. H.; Abdi, S. H. R.; Bajaj, H. C. ACS Catal. 2011, 1, 1529; (k) Dhahagani, K.;
Rajesh, J.; Kannan, R.; Rajagopal, G. Tetrahedron: Asymmetry 2011, 22, 857; (l)
Kanagaraj, K.; Suresh, P.; Pitchumani, K. Org. Lett. 2010, 12, 4070; (m) Ibrahim,
F.; Jaber, N.; Guerineau, V.; Hachem, A.; Ibrahim, G.; Mellah, M.; Schulz, E.
Tetrahedron: Asymmetry 2013, 24, 1395; (n) Didier, D.; Schulz, E. Tetrahedron:
Asymmetry 2013, 24, 769; (o) Ni, B.; He, J. Tetrahedron: Asymmetry 2013, 54,
462; (p) Wolinska, E. Tetrahedron 2013, 69, 7269.
6. For selected examples, see: (a) Gao, J.; Reibenpies, J. H.; Martell, A. E. Angew.
Chem., Int. Ed. 2003, 42, 6008; (b) Saito, B.; Katsuki, T. Angew. Chem., Int. Ed.
2005, 44, 4600; (c) Yang, H.; Wang, J.; Zhu, C. J. Org. Chem. 2007, 72, 10029; (d)
Suyama, K.; Sakai, Y.; Matsumoto, K.; Saito, B.; Katsuki, T. Angew. Chem., Int. Ed.
2010, 49, 797; (e) Fujisaki, J.; Matsumoto, K.; Matsumoto, K.; Katsuki, T. J. Am.
Chem. Soc. 2011, 133, 56; (f) Xuan, W.; Zhang, M.; Liu, Y.; Chen, Z.; Cui, Y. J. Am.
Chem. Soc. 2012, 134, 6904; (g) North, M.; Stewart, E. L.; Young, C. Tetrahedron:
Asymmetry 2012, 23, 1218.
Yellow oil, yield 67%; 1H NMR (400 MHz, CDCl3): d = 7.38–7.34
(m, 2H), 7.0–6.93 (m, 2H), 5.52 (d, J = 10.4 Hz, 1H), 4.2–4.14 (m,
2H), 3.63 (d, J = 9.2 Hz, 1H), 1.49 (t, J = 7 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d = 80.8, 68.8, 33.9, 31.8, 29.4, 29.2, 25.3, 22.7;
FT-IR (neat): 3418, 1555, 1382 cmꢁ1; ee: 90%, determined by HPLC
(Daicel Chiralcel OJ, hexane/iPrOH (17:3), flow rate 0.8 mL/min,
29
k = 215 nm): tR = 12.2 min (minor), tR = 16.0 min (major); [
ꢁ15.1 (c 1.0, CHCl3).
a]
=
D
Acknowledgments
We thank the Council of Scientific and Industrial Research, New
Delhi for financial support. M.K. thanks the Council of scientific and
Industrial Research, New Delhi, for SRF fellowship. We thank the
Central Instruments Facility, IIT Guwahati for the NMR and EPR
analyses.
References
7. Matsumoto, K.; Saito, B.; Katsuki, T. Chem. Commun. 2007, 3619.
8. Kaik, M.; Gawronski, J. Tetrahedron: Asymmetry 2003, 14, 1559.
9. Jacobsen, E. N.; Zhang, W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc.
1991, 113, 7063.
1. Henry, L. Bull. Soc. Chim. Fr. 1895, 13, 999.
2. For selected examples, see: (a) Xiong, Y.; Wang, F.; Huang, X.; Wen, Y.; Feng, X.
Chem. Eur. J. 2007, 13, 829; (b) Blay, G.; Domingo, L. R.; Hernandez-Olmos, V.;
Pedro, J. R. Chem.-Eur. J. 2008, 14, 4725; (c) Kureshy, R. I.; Anjan Das, B. D.; Khan,
N. H.; Abdi, S. H. R.; Bajaj, H. C. Appl. Catal., A Gen. 2012, 439–440, 74; (d)
Niabaru, T.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2012, 51, 1644; (e)
Lang, K.; Park, J.; Hong, S. Angew. Chem., Int. Ed. 2012, 51, 1620; (f) White, J. D.;
Shaw, S. Org. Lett. 2012, 14, 6270.
3. (a) Rosini, G. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; ;
Pergamon: New York, 1991; Vol. 2, p 321; (b) Shibasaki, M.; Groer, H. In
Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; ; Springer: Berlin, 1991; Vol. III, p 1075; (c) Ono, N. The Nitro Group in
Organic Synthesis; Wiley-VCH: New York, 2001; (d) Wolf, J. P. In Name Reactions
for Functional Group Transformations; Li, J. J., Corey, E. J., Eds.; ; Wiley: New
Jersey, 2007; Vol. III, p 645.
10. (a) Balsells, J.; Carroll, P. J.; Walsh, J. J. Inorg. Chem. 2001, 40, 5568; (b) Sakthivel,
S.; Jammi, S.; Punniyamurthy, T. Tetrahedron: Asymmetry 2012, 23, 101.
11. Velusamy, S.; Punniyamurthy, T. Eur. J. Org. Chem. 2003, 3919.
12. (a) Jammi, S.; Punniyamurthy, T. Eur. J. Inorg. Chem. 2009, 2508; (b) Jammi, S.;
Ali, M. A.; Sakthivel, S.; Rout, L.; Punniyamurthy, T. Chem. Asian J. 2009, 4, 314.
13. (a) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. In Vogel’s Textbook
of Practical Organic Chemistry; Pearson Education Pte Ltd: Indian Branch, Delhi,
2004; p 395; (b) Larrow, J. F.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 1939.
14. Jin, W.; Li, X.; Huang, Y.; Wu, F.; Wan, B. Chem. Eur. J. 2010, 16, 8259.
15. Jammi, S.; Saha, P.; Sanyashi, S.; Sakthivel, S.; Punniyamurthy, T. Tetrahedron
2008, 64, 11724.
16. (a) Bandini, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem.
Commun. 2007, 616; (b) Boobalan, R.; Lee, G.-H.; Chen, C. Adv. Synth. Catal.
2012, 354, 2511.
4. For examples, see: (a) Colvin, E. W.; Beck, A. K.; Seeback, D. Helv. Chim. Acta
1981, 64, 2264; (b) Seebach, D.; Beck, A. K.; Lehr, F.; Weller, T.; Colvin, E. W.