A highly diastereo-and enantioselective copper(I)-catalyzed henry reaction using a bis(sulfonamide)-diamine ligand

Article abstract of DOI:10.1021/jo101932a

A series of bis(sulfonamide)-diamine (BSDA) ligands were synthesized from commercially available chiral α-amino alcohols and diamines. The chiral BSDA ligand 3a, coordinated with Cu(I), catalyzes the enantioselective Henry reaction with excellent enantios

Full text of DOI:10.1021/jo101932a

pubs.acs.org/joc
A Highly Diastereo- and Enantioselective Copper(I)-Catalyzed Henry
Reaction Using a Bis(sulfonamide)-Diamine Ligand
Wei Jin, Xincheng Li, and Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
bswan@dicp.ac.cn
Received September 30, 2010
A series of bis(sulfonamide)-diamine (BSDA) ligands were synthesized from commercially available
chiral R-amino alcohols and diamines. The chiral BSDA ligand 3a, coordinated with Cu(I), catalyzes
the enantioselective Henry reaction with excellent enantioselectivity (up to 99%). Moreover, with the
assistance of pyridine, a CuBr-3a system promotes the diastereoselective Henry reaction with
various aldehyde substrates and gives the corresponding syn-selective adduct with up to a 99% yield
and 32.3:1 syn/anti selectivity. The enantiomeric excess of the syn adduct was 97%.
Introduction
obtained with a copper-based catalyst system. The design
and development of the ligand plays a pivotal role in the
development of efficient metal-catalyzed asymmetric reac-
tions. In a recent communication, we developed a chiral
The nitroaldol (Henry) reaction is one of the most atom-
economic C-C bond-forming reactions.1 The resulting pro-
ducts, β-nitroalcohols, are widely used organic intermediates
because of the many possible transformations of the nitro
group into other functional groups.2 Thus, the development
of catalytic, asymmetric protocols for this reaction has gain-
ed particular attention. Efforts aimed at achieving an asym-
metric version of the process by using chiral, metallic (such as
rare-metal,3 Cu,4 Zn,5 Co,6 Cr,7 Mg8) and organic catalysts9
as well as biocatalysts10 have been extensively explored in
recent years, and the most prominent results have been
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Yanagisaka, A. Org. Lett. 2007, 9, 3595–3597. (i) Blay, G.; Climent, E.;
(1) For reviews on the asymmetric Henry reaction, see: (a) Luzzio, F. A.
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Barua, N. C. Tetrahedron: Asymmetry 2006, 17, 3315–3326. (c) Palomo, C.;
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2046–2049. (j) Blay, G.; Climent, E.; Fernandez, I.; Hernandez, V.; Pedro,
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Kanai, M. In Comprehensive Asymmetric Catalysis, Supplement 1; Jacobsen,
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Published on Web 12/21/2010
DOI: 10.1021/jo101932a
r
2010 American Chemical Society

Jin et al.
JOCArticle
SCHEME 1. Synthesis of BSDA Ligands
TABLE 1. Screening of Central Metals and BSDA Ligand Structuresa
bis(sulfonamide)-diamine (BSDA) skeleton for the Cu(OAc)2-
catalyzed enantioselective Henry reaction.11 Although a high
yield and high enantioselectivity were observed when nitro-
methane was used as the nucleophile, the diastereo- and
enantioselective Henry reactions of nitroethane or other
nitroalkanes remain less explored. Even after the Shibasaki
group reported the first syn-selective Henry reaction using
modified heterometallic complexes,12 examples of effective
reactions are still quite limited.13,14 Moreover, limitations,
such as low reaction temperature and a multistep synthetic
procedure for ligand preparation, still need to be addressed.
Therefore, in this paper, we fully delineate the details of our
findings on the highly diastereo- and enantioselective Henry
reaction using the BSDA-CuBr system as the catalyst.
entry
ligand
CuX
CuI
yield (%)
ee (%)b
1
2
3a
3a
3a
3a
3a
3b
3c
3d
4
76
95
55
84
84
54
59
48
33
99
99
78
94
89
20
83
11
77
87
87
rac
rac
CuBr
CuCl
CuCN
CuOAc
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
3
4
5
6
7
8
9
10
11
(6) (a) Kogami, Y.; Nakajima, T.; Ashizawa, T.; Kezuka, S.; Ikeno, T.;
Yamada, T. Chem. Lett. 2004, 33, 614–615. (b) Kogami, Y.; Nakajima, T.;
Ikeno, T.; Yamada, T. Synthesis 2004, 1947–1950.
1a
1b
(7) (a) Kowalczyk, R.; Kwiatkowski, P.; Skarzewski, J.; Jurczak, J. J.
Org. Chem. 2009, 74, 753–756. (b) Zulauf, A.; Mellah, M.; Schulz, E. J. Org.
Chem. 2009, 74, 2242–2245.
(8) Choudary, B. M.; Ranganath, K. V. S.; Pal, U.; Kantam, M. L.;
Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 13167–13171.
aReactions were carried out using 0.25 mmol of p-nitrobenzaldehyde,
ethanol (1 mL), and nitromethane (10 equiv) at room temperature.
bEnantiomeric excesses were determined by HPLC analysis on a chiral
OD-H column.
(9) (a) Corey, E. J.; Zhang, F. Y. Angew. Chem., Int. Ed. 1999, 38, 1931–
1934. (b) Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054–
2055. (c) Li, H. M.; Wang, B. M.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732–
733. (d) Marcelli, T.; nan der Haas, R. N. S.; van Maarseveen, J. H.;
Hiemstra, H. Angew. Chem., Int. Ed. 2006, 45, 929–931. (e) Sohtome, Y.;
Hashimoto, Y.; Nagasawa, K. Eur. J. Org. Chem. 2006, 2894–2897. (f)
Mandal, T.; Samanta, S.; Zhao, C. G. Org. Lett. 2007, 9, 943–945. (g)
Bandini, M.; Sinisi, R.; Umani-Ronchi, A. Chem. Commun. 2008, 4360–
4362. (h) Sohtome, Y.; Hashimato, Y.; Nagasawa, K. Adv. Synth. Catal.
2005, 347, 1643–1648.
(10) For the first biocatalytic asymmetric nitroaldol reaction: (a) Pur-
karthofer, T.; Gruber, K.; Gruber-Khadjawi, M.; Waich, K.; Skrane, W.;
Mink, D.; Griengl, H. Angew. Chem., Int. Ed. 2006, 45, 3454–3456. (b)
Gruber-Khadjawi, M.; Purkarthofer, T.; Skrane, W.; Griengl, H. Adv.
Synth. Catal. 2007, 349, 1445–1450.
Results and Discussion
Ligands 3 and 4 were prepared via a one-step reaction
between commercially available chiral diamines 1 and the
corresponding aziridines 215 (Scheme 1).16 Pure products
were obtained with satisfactory yields. These ligands are
stable for months in air.
Before examining the diastereoselective Henry reaction, it
is reasonable to test the potential of the BSDA ligands in an
enantioselective nitroaldol model reaction using p-nitroben-
zaldehyde and nitromethane. The results are summarized in
Table 1. At the outset, a series of Cu(I) catalysts, such as CuI,
CuCl, CuCN, and CuOAc, were screened in the presence of
ligand 3a in ethanol (Table 1, entries 1-5), and the corre-
sponding products of the Henry reaction were obtained with
relatively low yields and moderate ee values (Table 1, entries
1 and 3-5). CuBr turned out to be the best copper catalyst
for the reaction (Table 1, entry 2). The sequential investiga-
tions on the steric and electronic effects of the BSDA ligands
showed that the reactivity and enantioselectivity were closely
related to the chiral backbone and the substituents of the
(11) Jin, W.; Li, X. C.; Huang, Y. B.; Wu, F.; Wan, B. S. Chem.;Eur. J.
2010, 16, 8259–8261.
(12) Sasai, H.; Tokunaga, T.; Watanabe, S.; Suzuki, T.; Itoh, N.; Shiba-
saki, M. J. Org. Chem. 1995, 60, 7388–7389.
(13) For syn-selective direct nitroaldol reactions, see: (a) Sohtome, Y.;
Hashimoto, Y.; Nagasawa, K. Eur. J. Org. Chem. 2006, 2894–2897. (b)
Sohtome, Y.; Takemura, N.; Takada, K.; Takagi, R.; Iguichi, T.; Nagasawa,
K. Chem.;Asian J. 2007, 2, 1150–1160. (c) Arai, T.; Takashita, R.; Endo, Y.;
Watanabe, M.; Yanagisawa, A. J. Org. Chem. 2008, 73, 4903–4906. (d)
Toussaint, A.; Pfaltz, A. Eur. J. Org. Chem. 2008, 4591–4597. (e) Cheng, L.;
Dong, J. X.; You, J. S.; Gao, G.; Lan, J. B. Chem.;Eur. J. 2010, 16, 6761–
6765.
(14) For anti-selective direct nitroaldol reactions, see: (a) Uraguchi, D.;
Sakaki, S.; Ooi, T. J. Am. Chem. Soc. 2007, 129, 12392–12393. (b) Pur-
karthofer, T.; Gruber, K.; Gruber-Khadjawi, M.; Waich, K.; Skranc, W.;
Mink, D.; Griengl, H. Angew. Chem., Int. Ed. 2006, 45, 3454–3456. (c)
Nitabaru, T.; Nojiri, A.; Kobayashi, M.; Kumagai, N.; Shibasaki, M. J. Am.
ꢀ
Chem. Soc. 2009, 131, 13860–13869. (d) Blay, G.; Domingo, L. R.; Hernan-
(15) Chiral aziridines 2 were easily synthesized from corresponding
commercially available R-amino alcohols in one step: Mao, J. C.; Wan,
B. S.; Wang, R. L.; Wu, F.; Lu, S. W. J. Org. Chem. 2004, 69, 9123–9127.
(16) (a) Trost, B. M. Science 1991, 254, 1471–1477. (b) Trost, B. M.; Jiang,
C. H. J. Am. Chem. Soc. 2001, 123, 12907–12908. (c) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259–281.
dez-Olmos, V.; Pedro, J. R. Chem.;Eur. J. 2008, 14, 4725–4730. (e) Handa,
S.; Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2008, 47, 3230–3233. (f) Selvakumar, S.; Sivasankaran, D.; Singh,
V. K. Org. Biomol. Chem. 2009, 7, 3156–3162. (g) Noole, A.; Lippur, K.;
Metsala, A.; Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75, 1313–1316.
J. Org. Chem. Vol. 76, No. 2, 2011 485

Jin et al.
JOCArticle
TABLE 2. Effect of Solvents on the Asymmetric Henry Reactiona
TABLE 3. Henry Reaction of Various Aromatic and Aliphatic
Aldehydesa
ee (%)b
entry
R
product
time (h)
yield (%)
ee (%)b
entry
solvent
ethanol
methanol
acetonitrile
dichloromethane
toluene
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4-NO2-C6H4
Ph
6a
6b
6c
6d
6e
6f
6g
6h
6i
24
48
48
60
48
60
36
36
24
24
24
36
30
36
48
36
36
36
36
36
98
93
92
75
77
74
85
80
85
70
83
83
99
99
99
99
93
99
97
99
95 (R)
96 (R)
97 (R)
96 (R)
94 (R)
92 (R)
95 (R)
95 (R)
93 (R)
95 (R)
96 (R)
99 (R)
98 (R)
98 (R)
97 (R)
97 (R)
97 (R)
98 (R)
99 (R)
98 (R)
1
2
3
4
5
6
7
95
98
36
27
32
79
70
94
95
77
66
61
79
90
2-Me-C6H4
2-MeO-C6H4
3-MeO-C6H4
4-MeO-C6H4
4-Cl-C6H4
4-Br-C6H4
1-naphthyl
2-naphthyl
PhCH2CH2
(CH3)2CH
CH3(CH2)4
c-hexyl
THF
2-propanol
aReactions were carried out using 0.25 mmol of p-nitrobenzaldehyde,
CuBr (10 mol %), 3a (10 mol %), and nitromethane (10 equiv) in solvent
(1 mL) at room temperature for 24 h. bEnantiomeric excesses were
determined by HPLC analysis on a chiral OD-H column.
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
6t
ligand moiety. The result obtained with ligand 3a was super-
ior to that with ligands 3d and 4 in terms of yield and
enantioselectivity (Table 1, entries 2, 8, and 9). The R2
substituent of the sulfonamide moiety of the BSDA ligand
significantly affected the yield and enantioselectivity (Table 1,
entries 2, 6, and 7). In control experiments, the known chiral
diamines 1a and 1b were also tested in the reaction.4k In terms
of ee values, ligands 1a and 1b produced inferior results com-
pared with those of ligand 3a. Therefore, we conclude that the
weak coordination of the additional sulfonamide fragment is
necessary for further acceleration and stereocontrol in the
addition reaction as compared to reactions with the chiral
diamines.
PhCH2
(CH3)2CHCH2
CH3(CH2)3
CH3(CH2)8
(CH3CH2)2CH
c-C5H9
aReactions were carried out using 0.25 mmol of aldehyde, CuBr (10
mol %), 3a (10 mol %), and nitromethane (10 equiv) in methanol (1 mL)
at room temperature. bEnantiomeric excesses were determined by HPLC
analysis, and the absolute configuration was assigned by comparison to
literature values.17
isobutyraldehyde and 2-ethylbutyraldehyde. In the most
successful reactions, up to a 99% ee was obtained (Table 3,
entries 12 and 19).
The solvent effects on enantioselectivity were examined in
the presence of 10 mmol % CuBr-3a, and the results are
shown in Table 2. Among the screened solvents, ethanol,
methanol, and 2-propanol were superior in terms of enan-
tioselectivity (Table 2, entries 1, 2, and 7). The best enantios-
electivity, as well as an excellent yield, was observed when the
reaction was performed in methanol (Table 2, entry 2).
Given the above-mentioned optimal results, the complex
of CuBr-3a was used in the asymmetric addition of nitro-
methane to a variety of other aldehydes (Table 3). The
reactions worked well to generate the Henry adduct in high
yields with excellent enantioselectivities. For aromatic alde-
hydes, the present system tolerated both electron-withdraw-
ing and electron-donating substituents (Table 3, entries
3-8). Interestingly, the position of the substituent on the
phenyl ring had a limited effect on the enantioselectivity
(Table 3, entries 4-6). Aldehydes with a large sterical
hindrance, such as 1-naphthaldehyde and 2-naphthalde-
hyde, could also give the corresponding adducts with good
yield and high enantioselectivity (Table 3, entries 9 and 10).
Aliphatic aldehydes were found to be good substrates,
affording the corresponding adducts with excellent selectiv-
ities. High yields and excellent enantioselectivities were
achieved with the addition of nitromethane to linear and
branched aldehydes. For linear aldehydes, the length of the
alkyl carbon chain had little effect on the enantioselectivity
(Table 3, entries 13, 17, and 18), and the size of the alkyl
group also had no effect on the enantioselectivity (Table 3,
entries 14 and 20). Excellent reactivity and enantioselectivity
were observed with R-branched aliphatic aldehydes, such as
Finally, the optimized catalyst system was applied to the
diastereoselective Henry reaction. The initial results indi-
cated that the reaction between the benzaldehyde (5b) and
nitroethane required an extended reaction time (Table 4,
entry 1) to reach completion. Because the Henry reaction is
considered to employ basicity to generate the nitronate, base
was added to the reaction system to increase the reactivity of
the catalyst.13c A series of bases were tested in a model reac-
tion between nitroethane and benzaldehyde (5b) in the
presence of ligand 3a and CuBr. The results are summarized
in Table 4. As expected, the reactivity of the catalyst and the
yield of the nitroaldol products were significantly improved
when a series of bases were added (Table 1, entries 2-9).
Variation of the base slightly affected the syn/anti ratio while
greatly influencing the yield and enantioselectivity. Among
the screened bases, morpholine gave a negative result
(Table 4, entry 7). Bulky amines, such as Et3N, DIPEA,
and DBU, gave the nitroaldol adduct in moderate to good
yields with low enantioselectivities (Table 4, entries 1, 2, and
4). The strong coordinating bases DMAP and 2,6-diamino-
pyridine gave poor enantioselectivities (Table 4, entries 3
and 5). In contrast to morpholine, N-methylmorpholine ex-
hibited good reactivity and moderate enantioselectivity for
the syn product (Table 4, entry 8). When pyridine was
employed, the enantioselectivity of the syn diastereomer
improved substantially to 87% (Table 4, entry 9).
After the optimal base was determined, the scope of the
catalytic diastereoselective Henry reaction was evaluated,
and the results are summarized in Table 5. When nitroethane
486 J. Org. Chem. Vol. 76, No. 2, 2011

Jin et al.
JOCArticle
TABLE 4. Effect of Bases on the Diastereoselective Henry Reactiona
FIGURE 1. Ligand 8.
entry
base
yield (%) syn/antib ee of syn (%)c
1d
2
3
4
5
6
7
8
9
no
Et3N
DIPEA
DMAP
DBU
2,6-diaminopyridine
morpholine
N-methylmorpholine
pyridine
55
77
91
87
88
30
0
2.0:1
1.9:1
1.9:1
2.1:1
1.8:1
2.0:1
80
<1
5
13
17
19
86
95
2.1:1
2.2:1
25
87
aReactions were carried out using 0.25 mmol of benzaldehyde, CuBr
(10 mol %), 3a (10 mol %), base (1 equiv), and nitroethane (10 equiv) in
methanol (1 mL) at room temperature for 24 h. bDetermined by NMR
c
d
analysis. Determined by HPLC analysis of the crude product. Reac-
tion was run for 7 days.
FIGURE 2. Plausible transition state for the diastereoselective
Henry reaction.
TABLE 5. Asymmetric Henry Reaction of Nitroalkanes and Aldehydes
Catalyzed by CuBr-3aa
diastereoselectivity 13.3:1 (Table 5, entry 5). In general,
diastereoselectivity was dramatically improved when 1-ni-
tropropane was used. 4-Chlorobenzaldehyde reacted with
1-nitropropane to afford the corresponding product in good
diastereoselectivity (15.7:1). In contrast, the reaction be-
tween 4-chlorobenzaldehyde and nitroethane only gave a
ratio of 2.2:1 (Table 5, entries 4 and 10). Moreover, the
addition of 1-nitropropane and cyclohexanecarboxaldehyde
gave the corresponding adduct with a 97:3 syn selectivity.
The enantioselectivity of the syn product was 97% (Table 5,
entry 12). Furthermore, we found that the catalyst system of
CuBr-3a-pyridine was also effective for the diastereoselec-
tive Henry reaction between (nitromethyl)benzene and cy-
clohexanecarboxaldehyde. The syn adduct was furnished
with a good syn/anti ratio of 5.7:1, and the ee value of the
syn diastereomer was 77% (Table 5, entry 13).
To investigate the function of the sulfonamide moiety,
ligand 8 was synthesized and explored in the Henry reaction
(Figure 1). Ligand 8 turned out to be inefficient in the
copper-catalyzed Henry reaction. This result suggests that
the nitrogen atom from the sulfonamide serves as a weak
coordinating site in the molecule because it is a poor electron
donor.18 On the basis of the observed syn selectivity of the
reaction, a possible transition state model of Cu with 3a is
depicted in Figure 2. After accounting for the steric hin-
drance of the Cu-containing transition state, the structure
TS-I is most favored and results in a syn adduct.
yield
(%)
syn/
antib
ee of syn
(%)c
entry
R
R0
product
1
Ph
Me
7a
7b
7c
7d
7e
7f
7g
7h
7i
95
86
99
98
88
81
71
88
82
57
90
72
90
2.2:1
8.1:1
3.9:1
2.2:1
13.3:1
4.3:1
8.1:1
4.3:1
24:1
15.1:1
2.1:1
32.3:1
5.7:1
87
92
77
72
82
93
94
80
94
81
98
97
77
2d
3d
4
2-MeO-C6H4 Me
4-MeO-C6H4 Me
4-Cl-C6H4
1-naphthyl
PhCH2CH2
c-hexyl
Me
Me
Me
Me
Et
5
6
7
8
Ph
9
2-MeO-C6H4 Et
10
11
12
13e
4-Cl-C6H4
PhCH2CH2
c-hexyl
Et
Et
Et
Ph
7j
7k
7l
c-hexyl
7m
aReactions were carried out using 0.25 mmol of aldehyde, CuBr (10
mol %), 3a (10 mol %), pyridine (1 equiv), and nitroalkane (10 equiv) in
methanol (1 mL) at room temperature. bDetermined by HPLC analysis.
cEnantiomeric excesses were determined by HPLC analysis of the crude
product. dThe reaction was run for 60 h. eThe reaction was run for 36 h.
was used, the reaction of aromatic and aliphatic aldehydes
proceeded well to afford the desired product in moderate to
good yields, accompanied by the predominant syn diaster-
eomer, and good to excellent enantioselectivities. Interest-
ingly, the reaction with an ortho-substituted benzaldehyde as
the substrate provided much higher diastereoselectivity than
that with a para-substituted benzaldehyde. For instance, the
reaction with 2-methoxybenzaldehyde afforded the corre-
sponding product with a syn/anti diastereoselectivity of
8.1:1, while the reaction with 4-methoxybenzaldehyde gave
a ratio of 3.3:1 (Table 5, entries 2 and 3). Interestingly, use of
a bulky aldehyde, such as 1-naphthaldehyde, resulted in high
Conclusion
The bis(sulfonamide)-diamine ligand 3a, containing both
diamine and bis-sulfonamide moieties, together with CuBr,
was able to promote a highly enantioselective Henry reaction
between nitromethane and a wide range of aromatic and
aliphatic aldehydes, providing high yields and excellent
enantioselectivities. Notably, with the assistance of pyridine,
(17) The absolute configuration was assigned by comparison to literature
values; see the Experimental Section.
(18) Pritchett, S.; Gantzel, P.; Walsh, P. J. Organometallics 1997, 16,
5130–5132.
J. Org. Chem. Vol. 76, No. 2, 2011 487

Jin et al.
JOCArticle
this catalyst system was able to promote a highly syn-
selective Henry reaction of an aldehyde with nitroalkanes
with up to a 97% ee of the syn adduct in 99% yield. The
effectiveness of this catalyst system and the simplicity of
the reaction procedure make our catalyst widely applic-
able. Further work is in progress with the aim of expanding
the applications of these inexpensive chiral ligands to
other enantioselective catalytic processes.
128.3, 127.4, 127.2, 127.1, 60.8, 60.5, 57.8, 52.5, 49.4, 32.6, 31.1,
25.0, 24.6, 20.7; HRMS (APCI) calculated for C36H44N4O4S2
(M þ Hþ) 661.2882, found 661.2865.
General Procedure for the Addition of Nitromethane to Alde-
hydes. Under an argon atmosphere, the ligand 3a (16.5 mg, 0.025
mmol, 10 mmol %) and CuBr (3.6 mg, 0.025 mmol, 10 mmol %)
were suspended in anhydrous methanol (1.0 mL). After stirring
for 1 h at room temperature, nitromethane (0.27 mL, 10 mmol)
and the aldehyde (0.025 mmol) were added and the reaction was
stirred for a specified amount of time at room temperature. The
volatile components were then removed under reduced pressure,
and the crude product was purified by flash column chroma-
tography on silica gel (petroleum ether/ethyl acetate=5:1) to
give the pure product. The enantiomeric purity of the product
was determined by HPLC analysis. The absolute configurations
of the products were assigned by comparison to literature
values.
Experimental Section
General Procedure for the Preparation of the Bis(sulfonamide)-
Diamines 3 and 4. Chiral diamines 1a or 1b and the corresponding
aziridines 25 were dissolved in dry acetonitrile, and the mixture
was stirred under reflux for 3 days. The solvent was evaporated
under reduced pressure. The crude product was purified by flash
column chromatography on a silica gel using petroleum ether and
ethyl acetate as eluent.
Characterization of 3a: white solid; 70% yield; mp 74-76 °C;
[R]25D = -12.9 (c 1.06, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
7.78-7.76 (m, 2H), 7.59-7.57 (m, 2H), 7.28-7.20 (m, 5H),
7.22-7.05 (m, 9H), 4.39 (t, J = 7.44 Hz, 1H), 3.81-3.78 (m,
1H), 3.06-3.03 (m, 1H), 2.91-2.87 (m, 2H), 2.68 (m, 1H), 2.39
(s, 1H), 2.31 (s, 3H), 2.29 (m, 1H), 1.85-1.84 (m, 2H), 1.57-1.54
(m, 2H), 0.89-0.83 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
143.5, 143.1, 141.2, 139.6, 137.9, 137.2, 129.9, 129.4, 128.9,
128.5, 127.9, 127.6, 127.4, 127.2, 126.98, 126.7, 61.7, 58.4,
58.1, 57.7, 52.5, 49.8, 31.95, 31.4, 24.97, 24.8, 21.7, 21.6; HRMS
(APCI) calculated for C36H44N4O4S2 (M þ Hþ) 661.2882,
found 661.2862.
Characterization of the Enantioselective Henry Products. (R)-
(-)-2-Nitro-1-(4-nitrophenyl)ethanol (6a).4e 98% yield; 95% ee;
yellow solid; HPLC (Chiralcel OD-H, 85/15 n-hexane/i-PrOH,
0.8 mL/min, 20 °C, 215 nm): tr (major)=22.00 min, tr (minor) =
27.69 min; [R]25D = -39.1 (c 0.98, CH2Cl2, 95% ee); 1H NMR
(400 MHz, CDCl3) δ 8.28 (dd, J1=2.4 Hz, J2=9.2 Hz, 2H), 7.65
(d, J = 2.4 Hz, 2H), 5.62 (dd, J1 = 4 Hz, J2 = 8 Hz, 1H), 4.56-
4.64 (m, 2H), 3.15 (b, 1H); 13C NMR (100 MHz, CDCl3) δ 148.4,
145.1, 127.2, 124.4, 80.8, 70.2.
(R)-(-)-2-Nitro-1-phenylethanol (6b).4e 93% yield; 96% ee;
yellow oil; HPLC (Chiralcel OD-H, 85/15 n-hexane/i-PrOH,
0.8 mL/min, 20 °C, 215 nm): tr (major)=13.24 min, tr (minor) =
16.33 min; [R]25D=-53.1 (c 1.01, CH2Cl2, 96% ee); 1H NMR
(400 MHz, CDCl3) δ 7.32-7.40 (m, 5H), 5.39 (dd, J1 = 2.86 Hz,
J2 = 9.6 Hz, 1H), 4.55 (dd, J1 = 9.6 Hz, J2 = 13.2 Hz, 1H), 4.44
(dd, J1 = 2.86 Hz, J2 = 13.2 Hz, 1H), 3.20 (b, 1H); 13C NMR
(100 MHz, CDCl3) δ 138.3, 129.1, 129.0, 126.1, 81.3, 71.1.
(R)-(-)-2-Nitro-o-tolylethanol (6c).4e 92% yield; 97% ee; col-
orless oil; HPLC (Chiralcel OD-H, 85/15 n-hexane/i-PrOH, 0.8
mL/min, 20 °C, 215 nm): tr (major) = 11.27 min, tr (minor)=
16.33 min; [R]25D = -48.4 (c 1.10, CH2Cl2, 97% ee); 1H NMR
(400 MHz, CDCl3) δ 7.46-7.49 (m, 1H), 7.21-7.25 (m, 2H),
7.17-7.15 (m, 1H), 5.62 (dd, J1 = 2.4 Hz, J2 = 9.68 Hz, 1H),
4.49 (dd, J1=9.68 Hz, J2 = 13.28 Hz, 1H), 4.39 (dd, J1=2.4 Hz,
J2 = 13.28 Hz, 1H), 3.02 (b, 1H); 13C NMR (100 MHz, CDCl3)
δ 136.4, 134.6, 130.98, 128.8, 126.9, 125.8, 80.4, 68.1, 18.98.
(R)-(-)-2-Nitro-1-(2-methoxyphenyl)ethanol (6d).14d 75% yield;
96% ee; colorless oil; HPLC (Chiralcel OD-H, 90/10 n-hexane/
i-PrOH, 0.8 mL/min, 20 °C, 215 nm): tr (major) = 15.84 min, tr
(minor)=19.20 min; [R]25D = -48.9 (c 0.99, CH2Cl2, 96% ee); 1H
NMR (400 MHz, CDCl3) δ 7.42 (dd, J1 = 1.6 Hz, J2=7.2 Hz,
1H), 7.32 (td, J1=1.6 Hz, J2 = 8 Hz, 1H), 7.02 (dd, J1 = J2 = 8
Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 5.61 (dd, J1 = 3.2 Hz, J2=9.2
Hz, 1H), 4.63 (dd, J1 = 3.2 Hz, J2 = 12.8 Hz, 1H), 4.55 (dd, J1=
9.2 Hz, J2 = 12.8 Hz, 1H), 3.87 (s, 3H), 3.26 (b, 1H); 13C NMR
(100 MHz, CDCl3) δ 156.2, 129.95, 127.3, 126.1, 121.3, 110.7,
80.0, 67.96, 55.6.
Characterization of 3b: yellow oil; 35% yield; [R]25D = -31.0
(c 0.91, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.81-7.79 (m,
4H), 7.29-7.27 (m, 4H), 3.40-3.36 (m, 2H), 2.75-2.71 (m, 2H),
2.40-2.36 (m, 8H), 2.10-2.08 (m, 2H), 2.04 (b, 2H), 1.84-1.80
(m, 2H), 1.63-1.61 (m, 2H), 1.12-1.09 (m, 2H), 0.99-0.91 (m,
8H); 13C NMR (100 MHz, CDCl3) δ 143.0, 138.5, 129.6, 127.0,
61.1, 51.7, 50.2, 31.8, 24.9, 21.5, 19.1; HRMS (APCI) calculated
for C26H40N4O4S2 (M þ Hþ) 537.2569, found 537.2567.
Characterization of 3c: white solid; 44% yield; mp 128-
1
129 °C; [R]25D=-53.9 (c 1.06, CH2Cl2); H NMR (400 MHz,
CDCl3) δ 7.61-7.59 (m, 4H), 7.16-7.12 (m, 10H), 6.99-6.97 (m,
4H), 3.62 (m, 2H), 2.85-2.82 (m, 2H), 2.70-2.62 (m, 4H), 2.54-
2.30 (m, 8H), 1.83 (m, 2H), 1.65 (m, 2H), 1.15-1.14 (m, 4H); 13
C
NMR (100 MHz, CDCl3) δ 143.0, 138.3, 137.8, 129.8, 129.4,
128.7, 127.0, 126.5, 59.8, 56.1, 48.5, 39.5, 31.7, 25.2, 21.7; HRMS
(APCI) calculated for C38H48N4O4S2 (M þ Hþ) 689.3195, found
689.3178.
Characterization of 3d: white solid; 74% yield; mp 83-85 °C;
[R]25D = þ18.4 (c 0.63, CH2Cl2); 1H NMR (400 MHz, CDCl3) δ
7.60-7.58 (m, 2H), 7.44-7.42 (m, 2H), 7.41-7.20 (m, 10H),
7.18-7.12 (m, 3H), 7.09-7.00 (m, 5H), 6.83 (m, 4H), 6.74-6.72
(m, 2H), 5.74 (b, 1H), 5.07 (b, 1H), 4.33 (m, 1H), 3.43-3.41 (m,
1H), 3.21-3.19 (m, 2H), 2.97-2.86 (m, 2H), 2.67-2.63 (m, 1H),
2.52-δ 2.36 (m, 1H), 2.31 (s, 3H), 2.26 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 143.4, 143.0, 140.8, 140.4, 140.2, 139.6, 129.8,
129.5, 128.9, 128.6, 128.3, 128.2, 128.0, 127.8, 127.6, 127.4,
127.3, 127.2, 126.9, 69.2, 65.4, 58.8, 57.4, 52.6, 49.6, 21.7, 21.6;
HRMS (APCI) calculated for C44H46N4O4S2 (M þ Hþ)
759.3039, found 759.3010.
(R)-(-)-2-Nitro-1-(3-methoxyphenyl)ethanol (6e).4e 77% yield;
94% ee; colorless oil; HPLC (Chiralcel OD-H, 85/15 n-hexane/
i-PrOH, 0.8 mL/min, 20 °C, 215 nm): tr (major) = 20.03 min, tr
(minor) = 29.22 min; [R]25D = -38.8 (c 0.99, CH2Cl2, 94% ee);
1H NMR (400 MHz, CDCl3) δ 7.30 (t, J = 8 Hz, 1H), 6.95-6.94
(m, 2H), 6.88 (dd, J1 = 2.4 Hz, J2 = 9.2 Hz, 1H), 5.41 (dd, J1 =
2.4 Hz, J2 = 9.6 Hz, 1H), 4.58 (dd, J1 = 9.6 Hz, J2 = 13.2 Hz,
1H), 4.49 (dd, J1 = 2.4 Hz, J2 = 13.2 Hz, 1H), 3.81 (s, 3H), 3.05
(b, 1H); 13C NMR (100 MHz, CDCl3) δ 160.2, 139.96, 130.3,
118.3, 114.6, 111.7, 81.4, 71.1, 55.5.
Characterization of 4: white solid; 42% yield; mp 69-71 °C;
1
[R]25D = þ51.9 (c 0.86, CH2Cl2); H NMR (400 MHz, CD3-
COCD3) δ 7.78-7.76 (m, 2H), 7.65-7.63 (m, 2H), 7.40-7.38
(m, 2H), 7.29-7.18 (m, 12H), 4.43 (t, J = 7.88 Hz, 1H), 3.74 (t,
J = 6 Hz, 1H), 3.00-2.85 (m, 3H), 2.65 (m, 1H), 2.41 (s, 3H),
2.33 (s, 3H), 2.06-1.99 (m, 2H), 1.89-1.55 (m, 2H), 1.07-1.05
(m, 2H), 0.85-0.83 (m, 2H); 13C NMR (100 MHz, CD3COCD3)
δ 144.0, 143.1, 142.8, 140.9, 138.9, 138.3, 129.8, 129.4, 128.9,
(R)-(-)-2-Nitro-1-(4-methoxyphenyl)ethanol (6f).14d 74% yield;
92% ee; colorless oil; HPLC (Chiralcel OD-H, 85/15 n-hexane/
i-PrOH, 0.8 mL/min, 20 °C, 215 nm): tr (major) = 17.77 min, tr
(minor) = 22.15 min; [R]25D = -47.1 (c 1.00, CH2Cl2, 92% ee);
488 J. Org. Chem. Vol. 76, No. 2, 2011

Jin et al.
JOCArticle
1H NMR (400 MHz, CDCl3) δ 7.33-7.30 (m, 2H), 6.94-6.90 (m,
2H), 5.40 (dd, J1 = 3 Hz, J2 = 9.6 Hz, 1H), 4.60 (dd, J1 = 9.6 Hz,
J2 = 13.6 Hz, 1H), 4.47 (dd, J1 = 3 Hz, J2 = 13.6 Hz, 1H), 3.81 (s,
3H), 2.79 (b, 1H); 13C NMR (100 MHz, CDCl3) δ 160.2, 130.4,
127.5, 114.6, 81.4, 70.7, 55.6.
1H NMR (400 MHz, CDCl3) δ 4.51-4.40 (m, 2H), 4.12-4.07
(m, 1H), 2.55 (b, 1H), 1.82-1.77 (m, 3H), 1.69-1.68 (m, 2H),
1.52-1.43 (m, 1H), 1.25-1.08 (m, 5H); 13C NMR (100 MHz,
CDCl3) δ 79.5, 73.0, 41.6, 28.98, 28.1, 26.3, 26.1, 25.9.
(R)-(þ)-1-Nitro-3-phenyl-2-propanol (6o).4n 99% yield; 97%
ee; colorless oil; HPLC (Chiralcel OD-H, 90/10 n-hexane/
i-PrOH, 0.5 mL/min, 20 °C, 220 nm): tr (major) = 39.20 min,
tr (minor) = 51.70 min; [R]25D = þ15.7 (c 1.05, CH2Cl2, 97%
ee); 1H NMR (400 MHz, CDCl3) δ 7.35-7.20 (m, 5H), 4.53 (b,
1H), 4.43-4.33 (m, 2H), 2.90-2.78 (m, 2H), 2.63-2.62 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 136.0, 129.5, 129.1, 127.5, 79.9,
69.7, 40.5.
(R)-(-)-2-Nitro-1-(4-chlorophenyl)ethanol (6g).4e 85% yield;
95% ee; colorless oil; HPLC (Chiralcel OD-H, 85/15 n-hexane/
i-PrOH, 0.8 mL/min, 20 °C, 215 nm): tr (major) = 14.40 min, tr
(minor) = 18.74 min; [R]25D = -48.1 (c 1.01, CH2Cl2, 95% ee);
1H NMR (400 MHz, CDCl3) δ 7.37-7.30 (m, 4H), 5.41 (dd, J1 =
3.24 Hz, J2 =9.36 Hz, 1H), 4.55(dd, J1 = 9.36Hz, J2 = 13.28Hz,
1H), 4.47 (dd, J1 = 3.24 Hz, J2 = 13.28 Hz, 1H), 3.30 (b, 1H); 13
C
NMR (100 MHz, CDCl3) δ 136.7, 134.9, 129.3, 127.5, 81.1, 70.4.
(R)-(-)-2-Nitro-1-(4-bromophenyl)ethanol (6h).5d 80% yield;
95% ee; colorless oil; HPLC (Chiralcel OD-H, 85/15 n-hexane/
i-PrOH, 0.8 mL/min, 20 °C, 215 nm): tr (major) = 14.54 min, tr
(minor) = 18.97 min; [R]25D = -48.0 (c 0.95, CH2Cl2, 95% ee);
1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8.36 Hz, 2H), 7.26
(d, J = 8.36 Hz, 2H), 5.41-5.38 (m, 1H), 4.55 (dd, J1 = 9.36 Hz,
J2 = 13.32 Hz, 1H), 4.47 (dd, J1 = 3.2 Hz, J2 = 13.32 Hz, 1H),
3.23 (b, 1H); 13C NMR (100 MHz, CDCl3) δ 137.3, 132.3, 127.8,
123.1, 81.1, 70.5.
(R)-(þ)-4-Methyl-1-nitro-2-pentanol (6p).4h 99% yield; 97%
ee; colorless oil; HPLC (Chiralcel OJ-H, 97/3 n-hexane/i-PrOH,
0.8 mL/min, 20 °C, 215 nm): tr (major) = 21.82 min, tr (minor)
D
1
= 23.85 min; [R]25 = -2.62 (c 0.99, CH2Cl2, 97% ee); H
NMR (400 MHz, CDCl3) δ 4.43-4.33 (m, 3H), 1.85-1.82 (m,
1H), 1.52-1.49 (m, 1H), 1.27-1.20 (m, 1H), 0.96 (t, J = 6.36
Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 81.9, 67.2, 42.6, 24.5,
23.4, 21.9.
(R)-(-)-1-Nitro-2-pentanol (6q).4h 93% yield; 97% ee; color-
less oil; HPLC (Chiralcel OJ-H, 97/3 n-hexane/i-PrOH, 0.6 mL/
min, 20 °C, 215 nm): tr (major)=38.21 min, tr (minor) = 40.12 min;
(R)-(-)-2-Nitro-1-(1-naphthyl)ethanol (6i).4e 85% yield; 93%
ee; yellow oil; HPLC (Chiralcel OD-H, 85/15 n-hexane/i-PrOH,
0.8 mL/min, 20 °C, 215 nm): tr (major)=16.53 min, tr (minor)=
27.01 min; [R]25D=-30.6 (c 1.01, CH2Cl2, 93% ee); 1H NMR
(400 MHz, CDCl3) δ 8.02 (d, J = 8.4 Hz, 1H), 7.90 (d, J=8.4 Hz,
1H), 7.85 (d, J = 8.4 Hz, 1H), 7.75 (d, J=7.2 Hz, 1H), 7.49-7.61
(m, 3H), 6.24 (t, J = 4 Hz, 1H), 4.66-4.64 (m, 2H), 2.93 (d, J =
3.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 133.9, 133.7, 129.6,
129.5, 127.3, 126.3, 125.7, 124.1, 122.0, 80.97, 68.5.
1
[R]25D=-9.04 (c 1.04, CH2Cl2, 97% ee); H NMR (400 MHz,
CDCl3) δ 4.46-4.37 (m, 2H), 4.35-4.30 (m, 1H), 2.78 (b, 1H),
1.59-1.46 (m, 3H), 1.45-1.35 (m, 3H), 0.92 (t, J=7.2 Hz, 3H); 13
NMR (100 MHz, CDCl3) δ 80.9, 68.9, 33.6, 27.4, 22.6, 14.0.
C
(R)-(-)-1-Nitro-2-decanol (6r).14d 99% yield; 98% ee; colorless
oil; HPLC (Chiralcel AD-H, 95/5 n-hexane/i-PrOH, 1.0 mL/
min, 20 °C, 220 nm): tr (major) = 11.02 min, tr (minor) = 16.23
D
1
min; [R]25 = -5.5 (c 1.01, CH2Cl2, 98% ee); H NMR (400
(R)-(-)-2-Nitro-1-(2-naphthyl)ethanol (6j).4e 70% yield; 95%
ee; yellow solid; HPLC (Chiralcel OD-H, 80/20 n-hexane/
i-PrOH, 1.0 mL/min, 20 °C, 215 nm): tr (major) = 22.71 min,
tr (minor) = 32.29 min; [R]25D=-51.5 (c 1.11, CH2Cl2, 95% ee);
1H NMR (400 MHz, CDCl3) δ 7.89-7.83 (m, 4H), 7.55-7.45
(m, 3H), 5.63 (dd, J1 = 3.2 Hz, J2 = 9.6 Hz, 1H), 4.69 (dd, J1 =
9.6 Hz, J2=13.6 Hz, 1H), 4.59 (dd, J1 = 3.2 Hz, J2=13.6 Hz,
1H), 2.90 (b, 1H); 13C NMR (100 MHz, CDCl3) δ 135.6, 133.6,
133.4, 129.3, 128.3, 128.0, 126.9, 125.6, 123.4, 81.4, 71.4.
(R)-(þ)-1-Nitro-4-phenyl-2-butanol (6k).4g 83% yield; 96%
ee; off-white solid; HPLC (Chiralcel AD-H, 90/10 n-hexane/
i-PrOH, 1.0 mL/min, 20 °C, 215 nm): tr (major) = 11.69 min, tr
(minor) = 14.88 min; [R]25D = þ15.8 (c 0.89, CH2Cl2, 96% ee);
1H NMR (400 MHz, CDCl3) δ 7.32-7.28 (m, 2H), 7.25-7.19
(m, 3H), 4.40-4.27 (m, 3H), 2.85-2.82 (m, 1H), 2.78-2.69 (m,
2H), 1.87-1.77 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 140.8,
128.8, 128.6, 126.5, 80.7, 67.95, 35.3, 34.5.
MHz, CDCl3) δ 4.45-4.29 (m, 2H), 2.77 (b, 1H), 1.58-1.47 (m,
3H), 1.38-1.27 (m, 13H), 0.88 (t, J = 7 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 80.9, 68.9, 33.9, 33.0, 29.6, 29.6, 29.5, 29.4, 25.3,
22.8, 14.3.
(R)-(-)-3-Ethyl-1-nitro-2-pentanol (6s).14c 97% yield; 99% ee;
colorless oil; HPLC (Chiralcel AD-H, 99/1 n-hexane/i-PrOH,
0.5 mL/min, 20 °C, 220 nm): tr (major)=62.53 min, tr (minor) =
70.29 min; [R]25D = -18.9 (c 0.88, CH2Cl2, 99% ee); 1H NMR
(400 MHz, CDCl3) δ 4.46-4.42 (m, 2H), 4.37 (m, 1H), 2.51 (b,
1H), 1.52-1.27 (m, 5H), 0.94 (t, J = 7.2 Hz, 6H); 13C NMR (100
MHz, CDCl3) δ 79.7, 70.4, 44.9, 21.99, 21.5, 11.6, 11.6.
(R)-(-)-2-Nitro-(1-cyclopentan)ethanol (6t).9h 93% yield; 97%
ee; colorless oil; HPLC (Chiralcel OD-H, 98/2 n-hexane/
i-PrOH, 1.0 mL/min, 20 °C, 215 nm): tr (major) = 24.88 min,
tr (minor) = 26.85 min; [R]25D=-3.18 (c 1.02, CH2Cl2, 97% ee);
1H NMR (400 MHz, CDCl3) δ 4.49 (dd, J1=12.8 Hz, J2 = 2.4
Hz, 1H), 4.39 (dd, J1=8.8 Hz, J2 = 12.8 Hz, 1H), 4.13 (t, J =7.6
Hz, 1H), 2.72 (b, 1H), 1.95-1.90 (m, 2H), 1.71-1.57 (m, 5H),
1.28-1.27 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 80.5, 72.9,
43.3, 29.1, 28.7, 25.8, 25.5.
(R)-(-)-3-Methyl-1-nitro-2-butanol (6l).4c 83% yield; 99% ee;
yellow oil; HPLC (Chiralcel OD-H, 98/2 n-hexane/i-PrOH, 0.2
mL/min, 20 °C, 215 nm): tr (major) = 100.40 min, tr (minor) =
112.97 min; [R]25D = -29.9 (c 0.57, CH2Cl2, 99% ee); 1H NMR
(400 MHz, CDCl3) δ 4.50 (dd, J1 = 2.88 Hz, J2 = 12.72 Hz, 1H),
4.41 (dd, J1 = 9.36 Hz, J2=12.72 Hz, 1H), 4.10-4.06 (m, 1H),
3.42 (b, 1H), 1.79 (td, J1 = 6.72 Hz, J2 = 13.4 Hz, 1H), 0.97 (t,
J = 6.72 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 79.4, 73.5,
31.7, 18.2, 17.3.
General Procedure for the Diastereoselective Henry Reaction.
A solution of 3a (0.025 mmol, 16.5 mg, 10 mol %) and CuBr
(0.025 mmol, 3.6 mg, 10 mol %) in methanol (1.0 mL) was
stirred for 1 h at room temperature to generate the catalyst. The
nitroalkane (2.5 mmol, 10 equiv), pyridine (0.25 mmol, 20 μL,
1 equiv), and the aldehyde (0.25 mmol) were then added. After
the reaction was stirred for a specified amount of time at room
temperature, the volatile components were removed under
reduced pressure and the residue was purified by column
chromatography (using neutral silica gel, petroleum ether/
ethyl acetate = 6:1) to afford the corresponding adduct as the
product. The diastereoselectivity was determined by NMR
analysis. The enantiomeric excess was determined by HPLC
analysis.
(R)-(-)-1-Nitro-2-heptanol (6m).4h 99% yield; 97% ee; color-
less oil; HPLC (Chiralcel AD-H, 97/3 n-hexane/i-PrOH, 1.0 mL/
min, 20 °C, 215 nm): tr (major) = 20.29 min, tr (minor) = 29.66
1
min; [R]25D=-10.0 (c 1.01, CH2Cl2, 97% ee); H NMR (400
MHz, CDCl3) δ 4.46-4.28 (m, 3H), 2.68 (b, 1H), 1.57-1.47 (m,
3H), 1.39-1.31 (m, 5H), 0.90 (t, J = 6.72 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 80.9, 68.9, 33.9, 31.6, 25.0, 22.6, 14.0.
(R)-(-)-2-Nitro-(1-cyclohexyl)ethanol (6n).4c 99% yield; 98%
ee; colorless oil; HPLC (Chiralcel AD-H, 97/3 n-hexane/
i-PrOH, 1.0 mL/min, 20 °C, 215 nm): tr (major)=30.16 min, tr
(minor) = 32.90 min; [R]25D = -19.0 (c 0.66, CH2Cl2, 98% ee);
Characterization of the Diastereoselective Henry Products.
(1R,2R)-2-Nitro-1-phenyl-1-propanol (7a).14d colorless oil; 99%
yield; 1H NMR (400 MHz, CDCl3) δ 7.42-7.26 (m, 5H), 5.38 (d,
J. Org. Chem. Vol. 76, No. 2, 2011 489

Jin et al.
JOCArticle
J = 3.6 Hz, 0.31H) (anti), 5.02 (d, J = 8.8 Hz, 0.69H) (syn),
4.80-4.68 (m, 1H), 2.73 (b, 0.31H) (anti), 2.62 (b, 0.69H) (syn),
1.49 (d, J = 6.8 Hz, 0.93H) (anti), 1.31 (d, J = 6.8 Hz, 2.07H)
(syn); 13C NMR (100 MHz, CDCl3) δ 138.5, 129.4, 129.2, 128.9,
128.7, 127.1, 126.2, 88.6, 87.6, 76.5, 74.1, 16.7, 12.3. The ee
(87%) was determined by chiral HPLC analysis on a DAICEL
Chiralcel AD-H column, 95/5 n-hexane/i-PrOH, 1.0 mL/min,
20 °C, 220 nm: tr (syn, major) = 22.75 min, tr (syn, minor) =
20.21 min, tr (anti, major)=16.27 min, tr (anti, minor) =14.50
min. syn isomer [R]25D=-25.9 (c 0.89, CH2Cl2, 87% ee); anti
isomer [R]25D=-0.2 (c 0.22, CH2Cl2, 65% ee).
(1R,2R)-1-Cyclohexyl-2-nitro-1-propanol (7g).13c colorless
oil; 71% yield; H NMR (400 MHz, CDCl3) δ 4.75-4.63 (m,
1
1H), 3.95 (dd, J1=3.0 Hz, J2 = 8.2 Hz, 0.11H) (anti), 3.65 (dd,
J1=J2 = 5.3 Hz, 0.89H) (syn), 2.43 (b, 1H), 1.78-1.16 (m, 14H);
13C NMR (100 MHz, CDCl3) δ 85.7, 84.5, 76.9, 76.5, 40.4, 30.1,
29.1, 26.4, 26.3, 26.0, 25.8, 16.7. The ee (94%) was determined
by chiral HPLC analysis on a DAICEL Chiralcel AD-H col-
umn, 97/3 n-hexane/i-PrOH, 1.0 mL/min, 20 °C, 220 nm: tr (syn,
major) = 25.96 min, tr (syn, minor)=17.65 min, tr (anti, major) =
16.42 min, tr (anti, minor) = 19.19 min.
(1R,2R)-2-Nitro-1-phenyl-1-butanol (7h).14d colorless oil;
88% yield; 1H NMR (400 MHz, CDCl3) δ 7.43-7.32 (m, 5H),
5.16 (dd, J1 = J2 = 2.0 Hz, 0.19H) (anti), 5.02 (dd, J1 = 9.0 Hz,
J2 = 3.1 Hz, 0.81H) (syn), 4.64-4.56 (m, 1H), 2.76-2.75 (b,
0.19H) (anti), 2.58-2.57 (b, 0.81H) (syn), 1.89-1.81 (m, 1H),
1.44-1.39 (m, 1H), 0.93 (t, J = 7.4 Hz, 0.57H) (anti), 0.87 (t, J =
7.4 Hz, 2.43H) (syn); 13C NMR (100 MHz, CDCl3) δ 138.9,
129.4, 129.2, 128.9, 127.1, 126.4, 95.4, 94.9, 75.7, 74.4, 24.1, 21.5,
10.6, 10.3. The ee (80%) was determined by chiral HPLC
analysis on a DAICEL Chiralcel OD-H þ AD-H column, 95/5
n-hexane/i-PrOH, 1.0 mL/min, 20 °C, 220 nm: tr (syn, major) =
38.57 min, tr (syn, minor)=34.48min, tr (anti, major) = 26.31 min,
tr (anti, minor) = 22.19 min.
(1R,2R)-1-(2-Methoxyphenyl)-2-nitro-1-propanol (7b).14d col-
orless oil; 86% yield; 1H NMR (400 MHz, CDCl3) δ 7.36-7.27
(m, 2H), 7.02-6.92 (m, 2H), 5.15-5.14 (m, 1H), 5.04-4.99 (m,
1H), 3.90 (s, 3H), 3.28-3.26 (b, 1H), 1.34 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 156.9, 130.3, 129.2, 126.1, 121.4,
110.2, 87.8, 74.5, 55.6, 16.8. The ee (92%) was determined
by chiral HPLC analysis on a DAICEL Chiralcel AD-H
column, 95/5 n-hexane/i-PrOH, 1.0 mL/min, 20 °C, 220 nm: tr
(syn, major) = 32.16 min, tr (syn, minor) = 30.44 min, tr (anti,
major) = 22.28 min, tr (anti, minor) = 16.05 min.
(1R,2R)-1-(4-Methoxyphenyl)-2-nitro-1-propanol (7c).14d col-
orless oil; 99% yield; 1H NMR (400 MHz, CDCl3) δ 7.30-7.28
(m, 2H), 6.93-6.89 (m, 2H), 5.30 (d, J = 3.6 Hz, 0.21H) (anti),
4.98 (d, J = 9.2 Hz, 0.79H) (syn), 3.82 (s, 3H), 2.65 (b, 0.21H)
(anti), 2.53 (b, 0.79H) (syn), 1.52 (d, J = 6.4 Hz, 0.63H) (anti),
1.30 (d, J = 6.8 Hz, 2.37H) (syn); 13C NMR (100 MHz, CDCl3)
δ 160.4, 130.6, 128.4, 127.5, 114.6, 114.4, 88.7, 87.8, 76.1, 55.6,
16.7, 12.7. The ee (77%) was determined by chiral HPLC
analysis on a DAICEL Chiralcel AD-H column, 90/10 n-hexane/
i-PrOH, 1.0 mL/min, 20 °C, 215 nm: tr (syn, major) = 19.89 min, tr
(syn, minor) = 17.15 min, tr (anti, major) = 13.70 min, tr (anti,
minor) = 11.97 min.
(1R,2R)-1-(2-Methoxyphenyl)-2-nitro-1-butanol (7i).14d col-
orless oil; 82% yield; 1H NMR (400 MHz, CDCl3) δ 7.36-
7.31 (m, 1H), 7.27-7.25, (m, 1H), 7.01-6.92 (m, 2H), 5.14 (dd,
J1 = J2 = 8.5 Hz, 1H), 4.87-4.81 (m, 1H), 3.90 (s, 3H), 3.29-
3.20 (b, 1H), 1.96-1.88 (m, 1H), 1.45-1.39 (m, 1H), 0.87 (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 156.9, 130.3, 129.1,
126.4, 121.4, 111.2, 94.6, 73.7, 55.7, 24.3, 10.4. The ee (94%) was
determined by chiral HPLC analysis on a DAICEL Chiralcel
AD-H column, 95/5 n-hexane/i-PrOH, 1.0 mL/min, 20 °C, 220
nm: tr (syn, major) = 43.81 min, tr (syn, minor) = 40.88 min, tr
(anti, major) = 27.82 min, tr (anti, minor) = 24.81 min.
(1R,2R)-1-(4-Chlorophenyl)-2-nitro-1-butanol (7j).14d color-
(1R,2R)-1-(4-Chlorophenyl)-2-nitro-1-propanol (7d).14d color-
less oil; 98% yield; 1H NMR (400 MHz, CDCl3) δ 7.39-7.33 (m,
2H), 7.32-7.30 (m, 2H), 5.38 (d, J = 8.8 Hz, 0.31H) (anti), 5.02
(d, J = 8.8 Hz, 0.69H) (syn), 4.74-4.72 (m, 0.69H) (syn), 4.71-
4.64 (m, 0.93H) (syn), 2.79 (b, 0.31H) (anti), 2.70 (b, 0.69H)
(syn), 1.49 (d, J = 8.4 Hz, 0.63H) (anti), 1.33 (d, J = 6.8 Hz,
2.07H) (syn); 13C NMR (100 MHz, CDCl3) δ 137.1, 136.96,
135.3, 134.6, 129.4, 129.2, 128.5, 127.6, 88.4, 87.4, 75.7, 73.4,
16.6, 12.2. The ee (72%) was determined by chiral HPLC
analysis on a DAICEL Chiralcel AD-H column, 95/5 n-hex-
ane/i-PrOH, 1.0 mL/min, 20 °C, 220 nm: tr (syn, major) = 22.85
min, tr (syn, minor) = 25.64 min, tr (anti, major) = 17.26 min, tr
(anti, minor) = 15.64 min.
1
less oil; 57% yield; H NMR (400 MHz, CDCl3) δ 7.39-7.26
(m, 4H), 5.18 (d, J = 4.8 Hz, 0.94H) (syn), 5.03 (d, J = 8.8 Hz,
0.06H) (anti), 4.56-4.51 (m, 1H), 3.02-3.00 (b, 0.06H) (anti),
2.77 (b, 0.94H) (syn), 2.46 (m, 0.06H) (anti), 2.17-2.11 (m,
0.94H) (syn), 1.91-1.85 (m, 1H), 0.98-0.89 (m, 3H); 13C NMR
(100 MHz, CDCl3) δ 137.2, 134.8, 129.2, 127.8, 94.7, 73.8, 21.5,
10.6. The ee (81%) was determined by chiral HPLC analysis on a
DAICEL Chiralcel AD-H column, 95/5 n-hexane/i-PrOH, 1.0
mL/min, 20 °C, 220 nm: tr (syn, major) = 18.38 min, tr (syn,
minor)=23.21 min, tr (anti, major) = 13.85 min, tr (anti, minor) =
12.66 min.
(1R,2R)-1-(Naphthalen-1-yl)-2-nitro-1-propanol (7e).14g col-
orless oil; 88% yield; H NMR (400 MHz, CDCl3) δ 8.29 (d,
(3R,4R)-4-Nitro-1-phenyl-3-hexanol (7k).14b colorless oil; 90%
yield; 1H NMR (400 MHz, CDCl3) δ 7.31-7.18 (m, 5H), 4.41-
4.35 (m, 1H), 3.89 (m, 1H), 2.88-2.85 (m, 1H), 2.75-2.73 (m,
1H), 2.03-2.00 (b, 1H), 1.87-1.82 (m, 1H), 1.81-1.74 (m, 3H),
0.99-0.93 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 141.0, 128.8,
128.6, 126.4, 94.5, 94.0, 71.6, 71.2, 35.6, 34.9, 31.96, 31.7, 24.0,
21.7, 10.7, 10.3. The ee (98%) was determined by chiral HPLC
analysis on a DAICEL Chiralcel AD-H column, 95/5 n-hexane/
i-PrOH, 1.0 mL/min, 20 °C,220 nm: tr (syn, major)=18.80 min, tr
(syn, minor)=18.01 min, tr (anti, major)=13.83 min, tr (anti,
minor) = 12.98 min.
1
J = 8.4 Hz, 1H), 7.92-7.87 (m, 2H), 7.61-7.48 (m, 4H), 5.81
(dd, J1 = 9.2 Hz, J2=3.2 Hz, 1H), 5.17-5.10 (m, 1H), 2.68-
2.67 (b, 1H), 1.44 (d, J=6.8 Hz, 0.21H) (anti), 1.28 (d, J=6.8 Hz,
2.79 H) (syn); 13C NMR (100 MHz, CDCl3) δ 134.2, 131.0,
130.0, 129.4, 127.1, 126.3, 125.9, 123.4, 88.7, 73.97, 17.1. The ee
(82%) was determined by chiral HPLC analysis on a DAICEL
Chiralcel AS-H column, 98/2 n-hexane/i-PrOH, 1.0 mL/min,
20 °C, 215 nm: tr (syn, major) = 53.92 min, tr (syn, minor) = 46.70
min, tr (anti, major)=33.95 min, tr (anti, minor)=32.11 min.
(3R,4R)-4-Nitro-1-phenyl-3-pentanol (7f).13a,b colorless oil;
81% yield; 1H NMR (400 MHz, CDCl3) δ 7.32-7.19 (m, 5H),
4.56-4.50 (m, 1H), 3.91-3.89 (m, 1H), 2.89-2.84 (m, 1H),
2.78-2.72 (m, 1H), 2.44-2.42 (b, 1H), 1.84-1.68 (m, 2H), 1.55
(d, J = 5 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 141.0, 128.8,
128.6, 126.5, 87.9, 86.6, 72.3, 71.4, 34.9, 34.8, 32.1, 31.6, 16.4,
12.7. The ee (93%) was determined by chiral HPLC analysis on a
DAICEL Chiralcel AD-H column, 95/5 n-hexane/i-PrOH, 1.0
mL/min, 20 °C, 220 nm: tr (syn, major) = 20.07 min, tr (syn,
minor)=21.90 min, tr (anti, major)= 16.07 min, tr (anti, minor) =
15.02 min.
(1R,2R)-1-Cyclohexyl-2-nitro-1-butanol (7l).4h colorless oil;
72% yield; 1H NMR (400 MHz, CDCl3) δ 4.60-4.50 (m, 1H),
3.80 (dd, J1 = J2 = 5.6 Hz, 0.03H), 3.63 (m, 0.97H), 2.18 (b,
1H), 2.09-2.04 (m, 1H), 1.89-1.86 (m, 1H), 1.85-1.66 (m, 5H),
1.24-1.13 (m, 6H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 92.1, 76.2, 40.5, 30.0, 27.1, 26.3, 26.2, 25.97,
24.3, 10.4. The ee (97%) was determined by chiral HPLC analysis
on a DAICEL Chiralcel OJ-H column, 99/1 n-hexane/i-PrOH,
0.3 mL/min, 20 °C, 220 nm: tr (syn, major) = 60.83 min, tr (syn,
minor) = 58.31 min, tr (anti, major) = 44.74 min, tr (anti, minor) =
47.10 min.
490 J. Org. Chem. Vol. 76, No. 2, 2011

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(1R,2R)-1-Cyclohexyl-2-nitro-2-phenylethanol (7m).13a,13h
JOCArticle
and concentrated under vacuum. The residue was purified by
flash column chromatography to give 8 as a yellow oil with 73%
colorless oil; 90% yield; 1H NMR (400 MHz, CDCl3) δ 7.58-
7.26 (m, 5H), 5.53 (d, J = 9.9 Hz, 1H), 4.43 (dd, J1 = 10 Hz,
J2 = 1.5 Hz, 0.85H) (syn), 4.33 (dd, J = 6 Hz, 0.15H) (anti), 2.17
(b, 1H), 1.71-0.95 (m, 11H); 13C NMR (100 MHz, CDCl3) δ
132.2, 130.4, 129.6, 129.4, 129.2, 128.3, 94.96, 91.8, 76.4, 39.9,
38.7, 30.5, 29.8, 26.96, 26.3, 26.2, 25.9, 24.9. The ee (77%) was
determined by chiral HPLC analysis on a DAICEL Chiralcel
AD-H column, 97/3 n-hexane/i-PrOH, 1.0 mL/min, 20 °C, 220 nm:
tr (syn, major) = 32.67 min, tr (syn, minor) = 28.58 min, tr (anti,
major) = 38.40 min, tr (anti, minor) = 24.35 min.
1
yield: [R]25 = þ17.0 (c 0.96, MeOH); H NMR (400 MHz,
D
CDCl3) δ 7.40-7.27 (m, 10H), 4.11-4.08 (m, 2H), 3.84 (b, 4H),
3.12-3.09 (m, 2H), 2.69-2.66 (m, 4H), 2.40-2.38 (m, 2H),
2.06-2.04 (m, 2H), 1.15-1.12 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 143.0, 128.9, 127.8, 126.7, 63.92, 61.81, 55.74, 53.75,
46.28, 30.97, 24.82; HRMS (APCI) calculated for C22H32N4
(M þ Hþ) 353.2700, found 353.2699.
Acknowledgment. Financial support from the National
Basic Research Program of China (2010CB833300) is grate-
fully acknowledged.
General Procedure for Preparation of 8. A mixture of bis-
(sulfonamide)-diamine 3a (661 mg, 1 mmol), phenol (1.93 mg,
6.4 mmol), and HBr (8.39 mL, 48% in water) was refluxed for 48
h. Water (37 mL) and 2 M NaOH (16 mL) were carefully added
at room temperature to adjust the pH to about 1. The aqueous
phase was washed with EtOAc (3 ꢀ 21 mL), and its pH was then
adjusted to 13 with 2 M NaOH (about 148 mL). The aqueous
phase was then extracted with CH2Cl2 (5 ꢀ 42 mL). The
combined organic phases were dried over Na2SO4, filtered,
Supporting Information Available: General experimental
methods as well as 1H NMR, 13C NMR, and HRMS spectra for
the characterization of compounds are reported. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 491