Henry reaction in aqueous media at neutral pH

Article abstract of DOI:10.1002/ejoc.201201682

An efficient method for the synthesis of β-nitro alcohols from nitro alkanes and aldehydes in aqueous phosphate buffer under neutral pH conditions at room temperature is reported. In the case of higher nitro alkanes, the reaction showed very good diastereoselectivity to give syn β-nitro alcohols in preference to their anti products. Copyright

Full text of DOI:10.1002/ejoc.201201682

Job/Unit: O21682
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Date: 21-03-13 15:20:45
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FULL PAPER
DOI: 10.1002/ejoc.201201682
Henry Reaction in Aqueous Media at Neutral pH
Pranjal P. Bora[a] and Ghanashyam Bez*[a]
Keywords: Henry reaction / C–C coupling / β-Nitro alcohols / Asymmetric synthesis / Diastereoselectivity
An efficient method for the synthesis of β-nitro alcohols from
nitro alkanes and aldehydes in aqueous phosphate buffer un-
der neutral pH conditions at room temperature is reported.
In the case of higher nitro alkanes, the reaction showed very
good diastereoselectivity to give syn β-nitro alcohols in pref-
erence to their anti products.
Introduction
Among carbon–carbon bond-forming reactions, the syn-
thesis of β-nitro alcohols[1] by the nitro aldol (Henry) reac-
tion is one of the most extensively studied reactions in or-
ganic synthesis and has been the subject of continuous ef-
fort to develop better synthetic protocols over the years.
Because of the presence of two versatile functionalities in
the form of nitro and hydroxy groups, nitro alcohols can be
the synthetic precursors to many important organic bifunc-
tional derivatives, including 2-hydroxycarboxylic acids, 2-
nitro ketones, 2-amino alcohols, and nitro alkenes, which in
turn are precursors to a diverse range of pharmaceutically
important compounds.[2] The majority of the procedures for
the synthesis of β-nitro alcohols focus on the use of organic
and inorganic bases as catalysts for the reaction of alde-
hydes with nitro alkanes, which leads to the generation of
many undesired side products resulting from competitive
base-catalyzed transformations,[3] such as the aldol reac-
tion, the Michael reaction, the Cannizaro reaction, and de-
hydration reactions (Figure 1). Therefore, control of the re-
action conditions is important in nitro aldol reactions, and
this point needs attention so that these competitive side re-
actions can be avoided. Recently, nitro aldol reactions cata-
lyzed by organocatalysts[4] and enzymes[5] have gained tre-
mendous attention, and these reactions are considered to
work under mild reaction conditions.
Figure 1. Side products in the base-catalyzed Henry reaction.
essential ingredient in biological processes,[7] study of any
organic reaction in aqueous media is considered to be help-
ful in understanding the mechanism of biological processes.
Although there are a large number of methods[8] available
to synthesize β-nitro alcohols through the nitro aldol reac-
tion in organic media, only a few reports exist for the nitro
aldol reaction in aqueous media. The most notable method
is the NaOH-catalyzed nitro aldol reaction reported by Bal-
lini et al.,[9] which is effective for both aliphatic and aro-
matic aldehydes. However, the yields for the Henry reac-
tions of aromatic aldehydes were comparatively low, proba-
bly owing to the formation of side products. Additionally,
the use of the strong base NaOH may not be compatible
with base-sensitive functionalities in multistep syntheses.
Wang et al.[10] reported the use of Et3N as a catalyst for the
same transformation in aqueous media, but the reaction
was not effective for aromatic aldehydes having electron-
donating substituents on the phenyl ring. A few biocata-
lysts, such as DNA[11] and hydroxynitrile lyase,[5b,5c] were
also used as catalysts, but these enzymes are costly. Re-
cently, Lai et al.[12] reported the use of CuII complexes for
nitro aldol reactions in water, in which the preparation of
the catalyst is required before use. In other interesting work,
Pitchumani et al.[13] reported a highly stereoselective nitro
aldol reaction in water/acetonitrile by using per-6-amino-β-
cyclodextrin.
Given the current emphasis on the development of green
synthetic protocols, organic reactions in water have become
highly desirable for process development in both industry
and academia.[6] Water is cheap, harmless, and very easy to
handle; organic reactions performed in water are important
in many acid- and base-catalyzed reactions. As water is an
[a] Department of Chemistry, North Eastern Hill University,
Shillong 793022, India
Fax: +91-3642558014
E-mail: ghanashyambez@yahoo.com
Homepage: http://www.nehu.ac.in/Schools/
Physical%20Sciences/Chemistry/GB.php
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201682.
Given that the role of a base is to generate the nitronate
anion to enable nucleophilic attack on the carbonyl moiety
to generate β-nitro alcohols in the Henry reaction, careful
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FULL PAPER
control of the experimental conditions is necessary to avoid the question as to whether the reaction could be simply
competitive side reactions. We were intrigued by the pos- accomplished in water. To that end, we vigorously stirred
sibility of carrying out the reaction without the addition of the same reaction mixture in water (2 mL) for 24 h at room
any base catalyst or enzyme, in which case the formation of temperature, but the formation of the product was not de-
the side products could be avoided. Therefore, we wanted tected.
to carry out the Henry reaction under neutral conditions
To optimize the volume of the buffer solution, we carried
by maintaining the pH at 7.0 with an aqueous phosphate out the model reaction with different volumes of the phos-
buffer. Carrying out this reaction in the laboratory under phate buffer at pH 7.0 (Table 1). As is evident from Table 1,
physiological pH in aqueous media would be advantageous the optimal reaction conditions included the use of 1.0 mL
in terms of procedural simplification, and it would poten- of phosphate buffer solution (Table 1, entry 2). Reduction
tially provide higher functional group compatibility in of the volume of the buffer to 0.5 mL (Table 1, entry 1) af-
multistep syntheses, in addition to reducing the cost and fected the overall reaction time, and this suggests that the
environmental impact. To the best of our knowledge, the amount of phosphate affected the overall yield and time.
nitro aldol (Henry) reaction in aqueous media under neu- Likewise, an increase in the volume of the buffer (Table 1,
tral pH conditions has not been reported. Herein, we wish entries 3 and 4) reduced the reaction time, although this
to report our findings that resulted in the development of had very little effect on the reaction yield. The amount of
a very efficient method for the synthesis of β-nitro alcohols phosphate present in solution changes with the volume of
in aqueous phosphate buffer at pH 7.0 (Scheme 1).
buffer added, and thus, the amount of phosphate ions in
solution may affect the reaction time and yield. As the rate
of a catalytic reaction depends on the catalyst loading, we
concluded that phosphate ions in the buffer might be in-
volved as a catalyst in the reaction.
Table 1. Effect of the volume of the buffer on the Henry reaction.[a]
Entry Buffer volume [mL]
t [h]
% Yield[b]
Scheme 1. Synthesis of β-nitro alcohols.
1
2
3
4
0.5
1.0
1.5
2.0
36
18
16
14
56
78
80
78
Results and Discussion
[a] Reaction conditions: aldehyde (0.25 mmol)/nitromethane = 1:3,
r.t. [b] Yield of isolated product.
Efficient methods for the synthesis of β-nitro alcohols
starting from aromatic aldehydes through the base-cata-
lyzed nitro aldol reaction are very few because of the in-
We wanted to explore the general applicability of our
stantaneous formation of β-nitro alkenes.[9] We presumed method for the nitro aldol reactions of various aromatic
that if the nitro aldol reaction of aromatic aldehydes could aldehydes with nitromethane (Table 2). Aryl aldehydes with
be carried out at neutral pH, subsequent formation of the a large negative inductive effect or a small positive reso-
nitro alkenes may be minimized. Notably, in many enzy- nance effect (Table 2, entries 1–5) underwent the reaction
matic[14] and enamine-based asymmetric organocatalytic re- more quickly than aryl aldehydes with a large positive reso-
actions,[15] aqueous buffer solution (pH 7–8) is used to nance effect (Table 2, entries 6–12). The position of the elec-
avoid general base catalysis[16] that is possible in nonbuff- tron-withdrawing group, for example, the nitro group on
ered solution. However, no effort has been made to under- the phenyl ring, hardly affected the rate and the yield of the
stand whether (1) the buffer itself can perform any catalytic reaction.
role in those reactions and (2) the buffer can contribute to
We also employed this protocol in the nitro aldol (Henry)
the overall stereochemical outcome of the products. To ad- reaction of nitromethane with ketones. The reaction of
dress these issues, we planned to carry out the Henry reac- acetophenone (Scheme 2) with nitromethane in phosphate
tion in aqueous phosphate buffer at pH 7.0. To that effect, buffer at pH 7.0 did not take place at room temperature
a mixture of benzaldehyde (1 mmol) and nitromethane even after 120 h. When a more electrophilic ketone such
(3 mmol) in water at neutral pH, which was maintained by as p-nitro acetophenone was treated under similar reaction
using a pH 7.0 phosphate buffer solution (2 mL), was conditions, the reaction failed to show any conversion after
stirred vigorously at room temperature. After 24 h, com- the same reaction time.
plete conversion of the starting benzaldehyde was observed,
When we tried to extend the same protocol to the nitro
and the corresponding β-nitro alcohol was obtained in 78% aldol reaction of aliphatic aldehydes, we observed that the
yield. Optimization of the reaction conditions revealed that reaction of hexanal (Table 3, entry 3) with nitromethane did
the reaction was complete within 18 h at room temperature. not give any yield upon stirring at room temperature even
The fact that pure water is also pH neutral inevitably led to after 96 h. We suspected that the hydrophobicity of the hy-
2
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Henry Reaction in Aqueous Media at Neutral pH
Table 2. Reaction of aromatic aldehydes with nitromethane.[a]
Table 3. Nitro aldol reaction of nitromethane with aliphatic alde-
hyde at room temperature.[a]
Entry
R
Product
t [h]
% Yield[b]
Entry
R
t [h]
Product
% Yield[b]
70
1
2
3
4
5
6
7
8
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
4-ClC6H4
4-BrC6H4
C6H5
4-CH3OC6H4
3,4-(CH3O)2C6H3
3,4-(OCH2O)C6H3
4-HOC6H4
4-OH,3-MeOC6H3
4-(NMe2)C6H4
2-pyridyl
1a
1b
1c
1d
1e
1f
14
15
14
18
16
18
19
22
24
28
30
40
12
95
92
96
87
90
78
85
87
68
78
80
61
90
1
2
3
4
5
6
7
8
9
10
n-C3H7
40
40
96
40
40
40
40
40
40
20
2a
2b
2c
2c
2d
2e
2f
2g
2h
2i
n-C5H11
n-C6H13
n-C6H13
n-C7H15
n-C8H17
n-C9H19
n-C11H23
PhCH2CH2
EtO2C
82
0[c]
82
85
65
75
72
60
90
1g
1h
1i
9
10
11
12
13
1j
1k
1l
[a] Reaction conditions: aldehyde/nitromethane/CTAB = 1:3:0.1,
r.t. [b] Yield of isolated product. [c] Without CTAB.
1m
[a] Reaction conditions: aldehyde/nitromethane = 1:3, r.t. [b] Yield
of isolated product.
our knowledge, this is the first report on the diastereoselec-
tive synthesis of β-nitro alcohols under catalyst-free condi-
tions. Upon generalization, it was observed that the syn
product was formed preferentially to the anti nitro aldol
product (Table 4) in all cases. In general, aromatic alde-
hydes having electron-donating substituents (Table 4, en-
tries 1–4) showed higher diastereoselectivity relative to
more electrophilic aromatic aldehydes (Table 4, entries 6–8).
For example, the reaction of nitroethane with p-anisal-
dehyde gave extremely good diastereoselectivity (syn/anti =
94:6). Likewise, very good selectivities were observed for
less electrophilic aldehydes (Table 4, entries 2 and 3) such
as 3,4-methylenedioxybenzaldehyde (dr = 91:9) and 3,4,5-
trimethoxybenzaldehyde (dr = 86:14). Given the diastereo-
selectivity pattern and the reaction time for completion, we
were led to believe that a slower reaction rate might yield
Scheme 2. Henry reaction with ketone.
drocarbon chain might have caused solubility problems in
the aqueous solution, so that it could not react with nitro-
methane, and it could be that under our reaction condi-
tions, the nitro aldol reaction takes place only in the aque-
ous phase. To test our assumption, the phase transfer rea-
gent N,N,N,N-cetyltrimethylammonium bromide (CTAB)
was added to a mixture of hexanal and nitromethane in
aqueous phosphate buffer at pH 7.0, and the mixture was
allowed to stir. The reaction proceeded and was complete
within 40 h to give the desired product in 82% isolated
yield. When other aliphatic aldehydes (Table 3, entries 1, 2,
and 5–10) and nitromethane were treated under similar re-
action conditions, good to excellent yields of the desired
products were obtained.
Table 4. Diastereoselective synthesis of β-nitro alcohols.[a]
Then we turned our attention to the reaction of alde-
hydes with nitroethane at room temperature. Under similar
reaction conditions, the reactions with nitroethane gave ex-
cellent yields of the β-nitro alcohols, although longer reac-
tion times were required for completion. The longer reac-
tion time with higher nitro alkanes suggested that the reac-
tion rate might be controlled by the solubility of the nitro
alkanes in the water (buffer) solution. Given that the solu-
bility of nitromethane[17] (10 g/100 mL) in water is higher
than that of nitroethane[17] (4.6 g/100 mL), the reaction of
aldehydes with nitromethane is comparatively fast. This
finding led us to define this Henry reaction in phosphate
buffer at pH 7.0 as a reaction in water.[18] Interestingly, the
reaction of aromatic aldehydes with nitroethane in phos-
phate buffer at pH 7.0 resulted in moderate to excellent dia-
Entry
R
R1 t [h] Product % Yield[b] syn/anti[c]
1
2
3
4
5
6
7
8
4-MeOC6H4
3,4-(OCH2O)C6H3 Me 30
3,4,5-(OMe)3C6H2 Me 60
4-MeC6H4
C6H5
4-NO2C6H4
3-NO2C6H4
4-BrC6H4
4-ClC6H4
4-NO2C6H4
4-ClC6H4
4-MeC6H4
Me 30
3a
3b
3c
3d
3e
3f
94
94
72
87
86
85
92
90
81
87
82
70
94:6
91:9
86:14
74:26
73:27
67:33
78:22
62:38
75:25
88:12
94:6
Me 30
Me 50
Me 30
Me 30
Me 30
Me 30
Et 50
Et 72
Et 72
3g
3h
3i
3j
3k
3l
9
10
11
12
67:33
[a] Reactions were carried out at r.t. with aldehyde/nitro alkane
(1:3) in aqueous phosphate buffer. [b] Calculated on the basis of
isolated pure product. [c] Diastereoselectivity determined by HPLC
stereoselectivity in favor of the syn product. To the best of by using Chiralcel OD-H and Chiralpak AD-H columns.
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better selectivity. Keeping that in mind, we chose 1-nitro-
propane, which was expected to be less reactive than its
lower homologue, nitroethane, because of the high pKa of
the α-hydrogen atoms of 1-nitropropane. Interestingly, the
selectivities of more electrophilic aldehydes were found to
be comparatively higher with 1-nitropropane (Table 4, en-
tries 10 and 11). The diastereoselectivity for the reaction of
p-chlorobenzaldehyde with 1-nitropropane was significantly
higher (syn/anti = 94:6; Table 4, entry 11) than that for the
reaction of p-chlorobenzaldehyde with nitroethane (syn/anti
= 75:25; Table 4, entry 9). These observations confirmed
our assumption that the overall diastereoselectivity is de-
pendent on the reactivity of the aldehydes and nitro alk-
anes.
Figure 3. Preferential formation of the syn diastereomer.
Butanal, heptanal, nonanal, and dodecanal also gave excel-
lent yields of the corresponding β-nitro alcohols under
these conditions, but lower diastereoselectivities were ob-
tained for these aldehydes.
A plausible mechanism for buffer catalysis at pH 7.0 may
be due to the presence of an equilibrium mixture of the
Brønsted acid (dihydrogen phosphate anion) and its conju-
gate base (phosphate dianion) in the phosphate buffer at
pH 7.0. Likely, these species would form a complex with the
nitro alkane, in which the required tautomerization occurs.
The phosphate ions might accelerate the initial formation
of the nitronic acid (aci–nitro tautomer) through abstrac-
tion of the acidic αCH proton by the phosphate dianion to
generate the resonance-stabilized nitronate dianion species
followed by proton transfer to the oxygen ion (Figure 2).
The resulting nitronic acid[19] might react with the alde-
hydes to afford the corresponding β-nitro alcohols.
Table 5. Synthesis of β-nitro alcohols of aliphatic aldehydes with
nitroethane.[a]
Entry
R
Product
% Yield[b]
syn/anti[c]
1
2
3
4
5
butanal
3-methylbutanal
heptanal
nonanal
dodecanal
4a
4b
4c
4d
4e
70
72
78
75
68
57:43
61:39
51:49
54:46
59:41
[a] The reactions were carried out at r.t. for 60 h. [b] Isolated yield.
[c] Diastereoselectivity determined by HPLC by using Chiralcel
OD-H and Chiralpak AD-H columns.
Figure 2. Plausible catalytic role of the phosphate buffer at pH 7.0
with nitro alkane species (likely as phosphate complexes).
Mechanistically, the preferential formation of the syn-ni-
tro aldol product for the aromatic aldehydes might be at-
tributed to the formation of water-assisted cyclic transition
Conclusions
In conclusion, the nitro aldol (Henry) reaction of alde-
states TS-I and TS-II, which are formed by H-bonding be- hydes with nitro alkanes in aqueous phosphate buffer at
tween the oxygen atom of the aldehyde and the hydrogen neutral pH is reported for the first time. The reaction works
atom of the nitronic acid, that is, the aci–nitro tautomer of excellently at room temperature without the formation of
nitroethane (Figure 3). The orientation of the aryl group in side products. Unlike base-catalyzed Henry reactions, no in-
the equatorial position of TS-I might be preferred to the stantaneous formation of the olefin was observed for the
axial position of the aryl group in TS-II, which results in Henry reaction with aromatic aldehydes. For higher nitro
the preferential formation of the syn diastereomer. In con- alkanes, the reaction was diastereoselective and gave syn-β-
trast, aliphatic aldehydes cannot form the water-assisted nitro alcohols in preference to anti-β-nitro alcohols. With
transition state with the nitronic acid because of the pos- nitroethane, the syn selectivity was excellent for less electro-
sible micellar nature of the solvent after the addition of philic aromatic aldehydes, but more electrophilic aromatic
CTAB, and hence, no diastereoselectivity was observed.
aldehydes and aliphatic aldehydes showed marginal dia-
As for aliphatic aldehydes, the reaction of butanal with stereoselectivity. Interestingly, a slight increase in the selec-
nitroethane (Table 5, entry 1) in aqueous phosphate buffer tivity was observed in the reaction of aldehydes with 1-ni-
at pH 7.0 did not give any product upon stirring at room tropropane. No added base catalyst or hazardous solvents,
temperature for 50 h. However, the addition of CTAB to the use of an aqueous reaction medium, easy workup, the
the reaction mixture resulted in almost complete conversion simplicity of the method, excellent yields of the products,
after 72 h. Under these conditions, we investigated the and excellent diastereoselectivities are some of the high-
scope of the reaction with a variety of aldehydes (Table 5). lights of this method.
4
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Henry Reaction in Aqueous Media at Neutral pH
H), 4.47–4.60 (m, 2 H), 5.44 (dd, J = 2.8, 9.2 Hz, 1 H), 7.24–7.30
(m, 2 H), 7.54 (d, J = 8 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 70.34, 80.90, 122.99, 127.62, 132.20, 137.00 ppm. MS
(ESI): m/z = 269 [M + Na]+.
Experimental Section
General Information: All chemicals and reagents are commercially
available and were used without further purification. All the prod-
ucts were characterized by 1H NMR, 13C NMR, and IR spec-
2-Nitro-1-phenylethanol (1f):[13] Colorless oil: 32.5 mg, 78% yield.
1H NMR (400 MHz, CDCl3): δ = 3.36 (s, 1 H), 4.48 (dd, J = 2.8,
13.2 Hz, 1 H), 4.58 (dd, J = 9.6, 13.2 Hz, 1 H), 5.42 (dd, J = 2.8,
9.6 Hz, 1 H), 7.33–7.41 (m, 5 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 70.98, 81.35, 125.96, 128.90, 129.00, 129.18, 129.41,
132.19 ppm.
1
troscopy. H NMR (400 MHz) and 13C NMR (100 MHz) spectra
were recorded in CDCl3 by using tetramethylsilane as an internal
standard. LRMS and HRMS data were recorded by using the elec-
trospray ionization (ESI) method. HPLC analyses were carried out
with the help of Diacel chiral columns (Chiralcel OD-H and Chi-
ralpak AD-H) by using mixtures of n-hexane/2-propanol as mobile
phase at 25 °C.
1-(4-Methoxyphenyl)-2-nitroethanol (1g):[13] Yellow oil: 42 mg, 85%
yield. 1H NMR (400 MHz, CDCl3): δ = 2.81 (s, 1 H), 3.74 (s, 3 H),
4.40 (dd, J = 2.8, 13.2 Hz, 1 H), 4.53 (dd, J = 10, 13.2 Hz, 1 H),
5.33 (dd, J = 2.4, 9.6 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 2 H), 7.24 (d,
J = 8.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.55,
70.67, 81.27, 114.39, 127.29, 130.19, 160.03 ppm.
Preparation of Phosphate Buffer: One buffer tablet (pH 7.0) con-
taining chlorides, potassium phosphates, and sodium phosphates
(product no. 43155, batch no. 0198/Mfg/6385/81), purchased from
s.d. Fine Chemicals, Ltd., India, was dissolved in Millipore water
in a 100 mL volumetric flask. The pH of the solution was ascer-
tained by using a digital pH meter and was used for the nitro aldol
(Henry) reaction.
1-(3,4-Dimethoxyphenyl)-2-nitroethanol (1h):[20] Yellow solid:
1
49 mg, 87% yield; m.p. 95–96 °C. H NMR (400 MHz, CDCl3): δ
= 3.88 (s, 3 H), 3.90 (s, 3 H), 4.50 (dd, J = 3.2, 13.2 Hz, 1 H), 4.62
(dd, J = 9.6, 13.2 Hz, 1 H), 5.42 (dd, J = 2.8, 9.6 Hz, 1 H), 6.86–
6.94 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.95, 55.97,
70.88, 81.33, 108.73, 111.23, 118.34, 130.61, 149.40 ppm.
C10H13NO5 (227.22): calcd. C 52.86, H 5.77, N 6.16; found C
52.81, H 5.68, N 6.21.
Synthesis of 2-Nitro-1-phenylethanol (1f) as a Representative Pro-
cedure: The aqueous phosphate buffer solution (pH 7.0, 1.0 mL)
was added to a round-bottomed flask containing a mixture of
benzaldehyde (0.027 g, 0.25 mmol) and nitromethane (0.046 g,
0.75 mmol). [For aliphatic aldehydes, CTAB (10 mol-%) was also
added]. Upon vigorous stirring at room temperature for the speci-
fied time, the reaction was complete. The reaction mixture was ex-
tracted with ethyl acetate (3ϫ 15 mL), and the combined organic
layer was dried with anhydrous sodium sulfate, concentrated under
vacuum, and purified by column chromatography (ethyl acetate/
hexane) to obtain the pure product (0.033 g, 00197 mmol, 78%).
1-(Benzo[d][1,3]dioxol-5-yl)-2-nitroethanol (1i): White solid: 38 mg,
1
72% yield; m.p. 90–91 °C. H NMR (400 MHz, CDCl3): δ = 2.82
(s, 1 H), 4.47 (dd, J = 2.8, 13.2 Hz, 1 H), 4.58 (dd, J = 9.6, 13.2 Hz,
1 H), 5.37 (d, J = 8.8 Hz, 1 H), 5.99 (s, 2 H), 6.85 (m, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 70.82, 81.23, 101.39, 106.35,
108.62, 119.61, 131.97, 148.08, 148.24 ppm. MS (ESI): m/z = 234.1
[M + Na]+. C9H9NO5 (211.17): calcd. C 51.19, H 4.30, N 6.63;
found C 51.22, H 4.33, N 6.43.
2-Nitro-1-(4-nitrophenyl)ethanol (1a):[13] Pale yellow solid: 53.3 mg,
1
95% yield; m.p. 38–39 °C. H NMR (400 MHz, CDCl3): δ = 3.38
(s, 1 H), 4.56–4.65 (m, 2 H), 5.60–5.64 (m, 1 H), 7.63 (d, J = 8.8 Hz,
2 H), 8.24 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 69.98, 80.63, 124.17, 126.99, 145.15, 148.04 ppm. MS (ESI):
m/z = 235.2 [M + Na]+. C8H8N2O5 (212.16): calcd. C 45.29, H
3.80, N 13.20; found C 45.27, H 3.78, N 13.22.
4-(1-Hydroxy-2-nitroethyl)phenol (1j):[13] Colorless oil: 35.7 mg,
78% yield. 1H NMR (300 MHz, CDCl3): δ = 2.76 (s, 1 H), 4.48
(dd, J = 3.3, 13.5 Hz, 1 H), 4.61 (dd, J = 8.7, 12.6 Hz, 1 H), 5.12
(s, 1 H), 5.41 (d, J = 9.9 Hz, 1 H), 6.87 (d, J = 7.2 Hz, 2 H), 7.28
(d, J = 9.9 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 70.65,
81.23, 115.86, 127.54, 130.31, 156.13 ppm.
2-Nitro-1-(3-nitrophenyl)ethanol (1b):[13] Pale yellow solid: 48.7 mg,
1
92% yield; m.p. 70–71 °C. H NMR (400 MHz, CDCl3): δ = 3.26
(d, J = 4 Hz, 1 H), 4.55–4.67 (m, 2 H), 5.60–5.64 (m, 1 H), 7.62 (t, 4-(1-Hydroxy-2-nitroethyl)-2-methoxyphenol (1k):[13] Colorless oil:
J = 8 Hz, 1 H), 7.78 (d, J = 7.2 Hz, 1 H), 8.23 (d, J = 8 Hz, 1 H), 42.6 mg, 80% yield. 1H NMR (400 MHz, CDCl3): δ = 2.82 (s, 1
8.33 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 69.83, 80.68, H), 3.92 (s, 3 H), 4.49 (dd, J = 2.8, 12.8 Hz, 1 H), 4.61 (dd, J =
121.14, 124.22, 130.14, 132.03, 140.22, 148.53 ppm. C8H8N2O5 9.6, 13.2 Hz, 1 H), 5.70 (s, 1 H), 6.87 (dd, J = 1.2, 8 Hz, 1 H), 6.93
(212.16): calcd. C 45.29, H 3.80, N 13.20; found C 45.25, H 3.76,
N 13.21.
(d, J = 8.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 56.01,
70.94, 81.37, 108.22, 114.69, 119.03, 130.06, 146.11, 146.93 ppm.
MS (ESI): m/z = 214 [M + 1]+.
2-Nitro-1-(2-nitrophenyl)ethanol (1c):[13] Yellow solid: 51 mg, 96%
1
yield. H NMR (400 MHz, CDCl3): δ = 3.07 (s, 1 H), 4.37 (dd, J
1-[4-(Dimethylamino)phenyl]-2-nitroethanol (1l):[13] Yellowish oil:
1
= 9.2, 13.6 Hz, 1 H), 4.67 (dd, J = 2, 13.6 Hz, 1 H), 5.85 (dd, J =
1.6, 9.2 Hz, 1 H), 7.37 (t, J = 8 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H),
7.76 (d, J = 8 Hz, 1 H), 7.88 (d, J = 8.4 Hz, 1 H) ppm. 13C NMR
32 mg, 61% yield. H NMR (300 MHz, CDCl3): δ = 2. 97 (s, 6 H),
4.46 (dd, J = 1.2, 9.9 Hz, 1 H), 4.63 (dd, J = 10.5, 13.8 Hz, 1 H),
5.36 (dd, J = 3, 10.5 Hz, 1 H), 6.72 (d, J = 8.4 Hz, 2 H), 7.25 (d,
(75 MHz, CDCl3): δ = 66.78, 80.13, 124.99, 128.72, 129.68, 134.15, J = 8.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.46,
134.45, 147.11 ppm. C8H8N2O5 (212.16): calcd. C 45.29, H 3.80, N
13.20; found C 45.26, H 3.77, N 13.23.
70.98, 81.33, 112.51, 125.46, 127.01, 150.92 ppm.
2-Nitro-1-(pyridin-2-yl)ethanol (1m):[13] Yellow gum: 37.8 mg, 90%
1-(4-Chlorophenyl)-2-nitroethanol (1d):[13] White solid: 43.7 mg,
yield. H NMR (400 MHz, CDCl3/[D6]DMSO): δ = 4.52–4.55 (m,
1
1
87% yield; m.p. 34–35 °C. H NMR (400 MHz, CDCl3): δ = 1.79 1 H), 4.88 (dd, J = 2, 12.8 Hz, 1 H), 5.37 (d, J = 8.8 Hz, 1 H), 7.18
(s, 1 H), 4.39–4.52 (m, 1 H), 5.36 (d, J = 9.2 Hz, 2 H), 7.19–7.31 (d, J = 4.8 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.70 (d, J = 6 Hz,
(m, 5 H) ppm. 13C NMR (100 Hz, CDCl3): δ = 70.29, 81.03, 1 H), 8.43 (d, J = 4.8 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3/
127.35, 129.21, 134.78, 136.61 ppm. C8H8ClNO3 (201.61): calcd. C
47.66, H 4.00, N 6.95; found C 47.64, H 4.01, N 6.96.
[D6]DMSO): δ = 70.60, 80.65, 120.77, 122.82, 137.23, 148.15,
158.69 ppm.
1-(4-Bromophenyl)-2-nitroethanol (1e):[13] White solid: 55 mg, 90%
yield; m.p. 64–66 °C. H NMR (400 MHz, CDCl3): δ = 2.99 (s, 1 NMR (400 MHz, CDCl3): δ = 0.96 (t, J = 6.8 Hz, 3 H), 1.38–1.57
1-Nitropentan-2-ol (2a):[21] Colorless oil: 23.3 mg, 70% yield. 1H
1
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O21682
/KAP1
Date: 21-03-13 15:20:45
Pages: 9
P. P. Bora , G. B e z
(3b): Colorless
FULL PAPER
(m, 4 H), 2.68 (br., 1 H), 4.33–4.45 (m, 3 H) ppm. 13C NMR 1-(Benzo[d][1,3]dioxol-5-yl)-2-nitropropan-1-ol
1
(75 MHz, CDCl3): δ = 14.04, 18.43, 35.73, 68.41, 80.70 ppm. MS
gummy liquid: 52.9 mg, 94% yield. H NMR (400 MHz, CDCl3):
δ = 1.24 (d, J = 6.4 Hz, 3 H), 1.45 (d, J = 6.8 Hz, 3 H), 2.09 (br.
s, 1 H), 4.55–4.67 (m, 1 H), 4.87 (d, J = 8.8 Hz, 1 H), 5.20 (d, J =
4.0 Hz, 1 H), 5.94 (s, 2 H), 6.7–6.8 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 16.50 (12.47), 76.10 (73.82), 88.42 (87.55),
101.42 (101.29), 106.88 (106.46), 108.53 (108.37), 120.83 (119.58),
132.10 (132.34), 148.27 ppm. HRMS (ESI): calcd. for C10H11NO5
[M – H]– 224.0559; found 224.0550. HPLC (Chiralpak OD-H, 2-
propanol/n-hexane = 6:94, flow rate = 0.5 mLmin–1, λ = 220 nm):
tR = 46.2, 47.4 min (anti), 50.3, 54.8 min (syn); syn/anti = 90:10.
(ESI): m/z = 156 [M + Na]+.
1-Nitroheptan-2-ol (2b):[21] Colorless oil: 33 mg, 82% yield. 1H
NMR (300 MHz, CDCl3): δ = 0.88 (t, J = 6.3 Hz, 3 H), 1.31–
149 (m, 8 H), 2.95 (br., 1 H), 4.32–4.45 (m, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 13.91, 22.44, 24.83, 31.44, 33.71, 68.73,
80.73 ppm.
1-Nitrooctan-2-ol (2c):[22] Colorless oil: 35.9 mg, 82% yield. 1H
NMR (400 MHz, CDCl3): δ = 0.82 (t, J = 6.8 Hz, 3 H), 1.19–1.32
(m, 8 H), 1.41–1.5 (m, 2 H), 2.51 (br., 1 H), 4.22–4.39 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.01, 22.51, 25.12,
28.96, 31.60, 33.72, 68.68, 80.66 ppm. MS (ESI): m/z = 198 [M +
Na]+.
2-Nitro-1-(3,4,5-trimethoxyphenyl)propan-1-ol (3c): White solid:
65 mg, 96% yield; m.p. 85–87 °C. H NMR (400 MHz, CDCl3): δ
1
= 1.25 (d, J = 6.8 Hz, 3 H), 1.44 (d, J = 6.4 Hz, 3 H), 2.50 (br. s,
1 H), 3.73 (s, 3 H), 3.74 (s, 6 H), 3.77 (s, 3 H), 3.78 (s, 6 H), 4.60
(m, 1 H), 4.67 (m, 1 H), 4.86 (d, J = 9.6 Hz, 1 H), 5.23 (d, J =
3.6 Hz, 1 H), 6.49 (d, J = 3.2 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 11.30 (15.50), 55.12, 59.83, 72.94 (75.47), 86.47 (87.37),
101.81, 102.69, 133.09, 133.38, 152.34, 152.47 ppm. MS (ESI): m/z
= 294.1 [M + Na]+. C12H17NO6 (271.27): calcd. C 53.13, H 6.32,
N 5.16; found C 53.28, H 6.40, N 5.07. HPLC (Chiralpak AD-H,
2-propanol/n-hexane = 14:86, flow rate = 0.5 mLmin–1, λ =
220 nm): tR = 12.0, 19.9 min (anti); 22.0, 23.5 min (syn); syn/anti =
86:14.
2-Nitro-1-(p-tolyl)propan-1-ol (3d):[21] Colorless gummy liquid:
42.4 mg, 87% yield. 1H NMR (300 MHz, CDCl3): δ = 1.30 (d, J =
7.2 Hz, 3 H), 1.48 (d, J = 6.6 Hz, 3 H), 2.35 (s, 3 H), 2.36 (s, 3 H),
2.72 (br., 1 H), 2.82 (br., 1 H), 4.66–4.80 (m, 2 H), 4.97 (d, J =
9.2 Hz, 1 H), 5.33 (s, 1 H), 7.17–7.27 (m, 5 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 16.47 (21.14), 21.20 (23.39), 76.14 (73.92),
88.48 (87.53), 126.84 (125.89), 129.68 (129.40), 135.53 (135.37),
139.13 (138.36) ppm. HPLC (Chiralpak AD-H, 2-propanol/n-hex-
ane = 10:90, flow rate = 0.5 mLmin–1, λ = 220 nm): tR = 21.7,
23.5 min (anti); 28.7, 32.5 min (syn); syn/anti = 74:26.
1-Nitrononan-2-ol (2d):[22] Colorless oil: 40 mg, 85% yield. 1H
NMR (300 MHz, CDCl3): δ = 0.87 (t, J = 6.9 Hz, 3 H), 1.22–1.29
(m, 10 H), 1.45–1.55 (m, 2 H) 2.91 (br., 1 H), 4.24–4.45 (m, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.03, 22.58, 25.16,
29.08, 29.25, 31.70, 33.75, 68.72, 80.72 ppm.
1-Nitrodecan-2-ol (2e):[21,22] Colorless oil: 33 mg, 65% yield. 1H
NMR (400 MHz, CDCl3): δ = 0.64 (t, J = 6.8 Hz, 3 H), 1.05–1.08
(m, 12 H), 1.19–1.35 (m, 2 H), 2.00 (br., 1 H), 4.05–4.22 (m, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 14.07, 22.63, 25.16,
29.16, 29.30, 29.38, 31.80, 33.72, 68.66, 80.64 ppm. MS (ESI): m/z
= 204 [M + H]+.
1-Nitroundecan-2-ol (2f):[23] Colorless liquid: 40.7 mg, 75% yield.
1H NMR (400 MHz, CDCl3): δ = 0.86 (t, J = 6.9 Hz, 3 H), 1.25
(m, 14 H), 1.45–1.56 (m, 2 H) 2.92 (br., 1 H), 4.27–4.45 (m, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.08, 22.65, 25.17,
29.26, 29.30, 29.43, 29.47, 31.84, 33.75, 68.72, 80.72 ppm.
1-Nitrotridecan-2-ol (2g): White solid: 44.1 mg, 72% yield; m.p. 45–
1
47 °C. H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.4 Hz, 3 H),
1.17–1.36 (m, 18 H), 1.47–152 (m, 2 H), 2.69 (d, J = 2.8 Hz, 1 H),
4.31–4.33 (m, 1 H), 4.35–4.46 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 14.13, 22.69, 25.17, 29.31, 29.33, 29.44, 29.51, 29.61,
31.90, 33.70, 68.66, 80.63 ppm. MS (ESI): m/z = 245.1 [M]+.
C13H27NO3 (245.36): calcd. C 63.64, H 11.09, N 5.71; found C
63.68, H 11.12, N 5.57.
2-Nitro-1-phenylpropan-1-ol (3e):[13] Colorless oil: 38.9 mg, 86%
yield. H NMR (400 MHz, CDCl3): δ = 1.25 (d, J = 6.8 Hz, 3 H),
1
1.44 (d, J = 6.8 Hz, 3 H), 2.95 (br., 1 H), 4.62–4.67 (m, 1 H), 4.68–
4.76 (m, 1 H), 4.95 (d, J = 9.2 Hz, 1 H), 5.31 (d, J = 4 Hz, 1 H)
7.28–7.37 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.41
(12.10), 76.22 (73.98), 88.49 (87.47), 127.00 (126.01), 128.71
(128.47), 128.98 (129.05), 138.39 (138.64) ppm. HPLC (Chiralpak
AD-H, 2-propanol/n-hexane = 12:88, flow rate = 0.5 mLmin–1, λ
= 220 nm): tR = 21.8, 23.8 min (anti); 29, 33 min (syn); syn/anti =
73:27.
1-Nitro-4-phenylbutan-2-ol (2h):[22,23] Colorless gummy liquid:
42.4 mg, 87% yield. 1H NMR (300 MHz, CDCl3): δ = 1.78–192
(m, 2 H), 2.7–2.92 (m, 2 H), 4.27–4.41 (m, 3 H), 7.20–7.27 (m, 3
H), 7.3–7.35 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 31.33,
35.14, 67.79, 80.60, 126.34, 128.44, 128.66, 140.65 ppm. MS (ESI):
m/z = 196 [M + H]+.
2-Nitro-1-(4-nitrophenyl)propan-1-ol (3f):[13] Yellow gummy liquid:
1
48 mg, 85% yield. H NMR (300 MHz, CDCl3): δ = 1.36 (d, J =
Ethyl 2-Hydroxy-3-nitropropanoate (2i):[24] Colorless gummy liquid:
6.6 Hz, 3 H), 1.48 (d, J = 6.6 Hz, 3 H), 2.74 (s, 1 H), 4.70–4.82 (m,
2 H), 5.19 (d, J = 8.4 Hz, 1 H), 5.56 (d, J = 4.4 Hz, 1 H), 7.56–7.61
(m, 2 H), 8.22–8.24 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 16.24 (11.84), 75.04 (72.87), 87.78 (86.78), 124.11 (123.96), 127.93
(127.02), 145.26 (145.51), 148.26 (147.87) ppm. HPLC (Chiralpak
AD-H, 2-propanol/n-hexane = 14:86, flow rate = 0.5 mLmin–1, λ
= 254 nm): tR = 23.4 (anti); 32.9, 38.8 min (syn); syn/anti = 67:33.
1
36.7 mg, 90% yield. H NMR (400 MHz, CDCl3): δ = 1.26 (t, J =
7.2 Hz, 3 H), 4.27 (m, 2 H), 4.58 (t, J = 4 Hz, 1 H), 4.71 (d, J =
4 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.01, 62.08,
66.54, 75.73, 169.73 ppm.
1-(4-Methoxyphenyl)-2-nitropropan-1-ol (3a):[13] Yellow gummy li-
1
quid: 49.6 mg, 94% yield. H NMR (400 MHz, CDCl3): δ = 1.30
(d, J = 6.8 Hz, 3 H), 1.52 (d, J = 6.8 Hz, 3 H), 2.51 (br., 1 H), 3.82
(s, 3 H), 3.89 (s, 3 H), 4.62–4.67 (m, 1 H), 4.71–4.78 (m, 1 H), 4.98 52 mg, 92% yield. H NMR (400 MHz, CDCl3): δ = 1.34 (d, J =
2-Nitro-1-(3-nitrophenyl)propan-1-ol (3g):[13] Yellow gummy liquid:
1
(d, J = 9.2 Hz, 1 H), 5.27 (d, J = 4 Hz, 1 H) 6.92 (d, J = 8.4 Hz,
7.2 Hz, 3 H), 1.45 (d, J = 6.8 Hz, 3 H), 2.87 (d, J = 3.6 Hz, 1 H),
2 H), 7.29 (d, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): 2.94 (d, J = 4 Hz, 1 H), 4.63–4.76 (m, 2 H), 5.13 (dd, J = 3.6,
δ = 16.47 (12.47), 55.34 (55.31), 75.89 (73.79), 88.53 (87.57), 114.35 8.4 Hz, 1 H), 5.48 (s, 1 H), 7.54 (q, J = 8, 16 Hz, 1 H), 7.67 (d, J
(114.09), 128.19 (127.27), 130.41 (130.57), 160.11 (159.64) ppm.
HPLC (Chiralpak AD-H, 2-propanol/n-hexane = 10:90, flow rate
= 0.5 mLmin–1, λ = 220 nm): tR = 21.4, 23.6 min (anti); 29,
33.1 min (syn); syn/anti = 94:6.
= 7.6 Hz, 1 H), 8.14–8.24 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 15.26 (10.94), 73.99 (71.70), 86.78 (85.84), 120.95
(120.16), 123.03 (122.49), 128.97 (128.85), 131.91 (131.07), 139.43
(139.59), 147.47 ppm. HPLC (Chiralpak AD-H, 2-propanol/n-hex-
6
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21682
/KAP1
Date: 21-03-13 15:20:45
Pages: 9
Henry Reaction in Aqueous Media at Neutral pH
ane = 6:74, flow rate = 0.8 mLmin–1, λ = 254 nm): tR = 21.8,
23.5 min (anti); 26, 40 min (syn); syn/anti = 78:22.
5-Methyl-2-nitrohexan-3-ol (4b):[21] Colorless oil: 29 mg, 72% yield.
1H NMR (400 MHz, CDCl3): δ = 0.79–0.96 (m, 12 H), 1.08–1.26
(m, 2 H), 1.37–1.41 (m, 2 H), 1.46–152 (m, 6 H), 1.69–2.01 (m, 2
H), 2.85 (br., s, 1 H), 3.85–3.94 (m, 1 H), 4.21 (m, 1 H), 4.38–4.50
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 16.09 (16.02),
21.58 (21.24), 23.56 (23.25) 24.47 (24.16), 41.83 (41.75), 72.43
(71.24), 86.75 (88.37) ppm. HPLC (Chiralpak AD-H, 2-propanol/
n-hexane = 2:98, flow rate = 0.5 mLmin–1, λ = 210 nm): tR = 30.6,
33.3 min (anti); 39.7, 44.3 min (syn); syn/anti = 61:39.
1-(4-Bromophenyl)-2-nitropropan-1-ol (3h):[25] Colorless oil:
58.5 mg, 90% yield. 1H NMR (400 MHz, CDCl3): δ = 1.31 (d, J =
6.4 Hz, 3 H), 1.47 (d, J = 6.8 Hz, 3 H), 3.01 (br., 1 H), 4.62–4.66
(m, 1 H), 4.67–4.75 (m, 1 H), 4.99 (d, J = 9.2 Hz, 1 H), 5.35 (d, J
= 3.2 Hz, 1 H), 7.25 (t, J = 5.2 Hz, 2 H), 7.52 (t, J = 8 Hz, 2
H) ppm. HPLC (Chiralpak AD-H, 2-propanol/n-hexane = 10:90,
flow rate = 0.5 mLmin–1, λ = 220 nm): tR = 16.8, 17.8 min (anti);
22.4, 25.3 min (syn); syn/anti = 62:38.
2-Nitrononan-3-ol (4c): Colorless oil, 36.8 mg, 78% yield. 1H NMR
(400 MHz, CDCl3): δ = 0.89 (t, J = 6.4 Hz, 6 H), 1.29–1.61 (m, 26
H), 2.21 (d, J = 7.2 Hz, 1 H), 2.31 (d, J = 4.4 Hz, 1 H), 3.90 (d, J
= 5.6 Hz, 1 H), 4.19 (t, J = 4 Hz, 1 H), 4.48–4.56 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 12.37, 14.04, 16.27, 22.54, 25.11,
25.69, 29.03, 29.66, 31.64, 31.65, 33.01, 33.04, 72.04, 72.90, 86.34,
87.68 ppm. HRMS (ESI): calcd. for C9H19NO3 [M – H]– 188.1287;
found 188.1280. HPLC (Chiralpak AD-H, 2-propanol/n-hexane =
2:98, flow rate = 0.5 mLmin–1, λ = 210 nm): tR = 30.5 min (anti);
40.4, 43.1 min (syn); syn/anti = 50:50.
1-(4-Chlorophenyl)-2-nitropropan-1-ol (3i):[23] Colorless liquid:
43.5 mg, 81% yield. 1H NMR (400 MHz, CDCl3): δ = 1.32 (d, J =
6.8 Hz, 3 H), 1.48 (d, J = 7.2 Hz, 3 H), 2.87 (br., 1 H), 4.65–4.76
(m, 2 H), 5.01 (d, J = 9.2 Hz, 1 H), 5.38 (d, J = 3.6 Hz, 1 H),
7.27–7.33 (m, 2 H), 7.35–7.4 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 16.38, 75.52, 88.20, 128.34 (127.38), 129.21 (128.94),
135.03, 136.78 ppm. HPLC (Chiralpak AD-H, 2-propanol/n-hex-
ane = 10:90, flow rate = 0.5 mLmin–1, λ = 230 nm): tR = 17.5,
18.5 min (anti); 23.1, 24.8 min (syn); syn/anti = 75:25.
2-Nitroundecan-3-ol (4d):[25] Colorless oil: 40.7 mg, 75% yield. 1H
NMR (400 MHz, CDCl3): δ = 0.85 (t, J = 7.2 Hz, 6 H), 1.25–1.52
(m, 34 H), 2.71 (br., 1 H), 3.83–3.90 (m, 1 H), 4.12–4.17 (m, 1 H),
4.44–4.56 (2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 12.22,
14.05, 16.11, 22.62, 25.09, 25.72, 29.19, 29.32, 29.37, 29.55, 31.80,
32.88, 33.07, 72.16, 72.91, 86.39, 87.83 ppm. HPLC (Chiralpak
AD-H, 2-propanol/n-hexane = 2:98, flow rate = 0.5 mLmin–1, λ =
210 nm): tR = 25.1 min (anti); 34.9, 36.4 min (syn); syn/anti = 46:54.
2-Nitro-1-(4-nitrophenyl)butan-1-ol (3j):[23] White solid: 52.2 mg,
87% yield; m.p. 91–92 °C. H NMR (400 MHz, CDCl3): δ = 0.68–
1
0.89 (m, 6 H), 1.37–1.47 (m, 1 H), 1.72–1.81 (m, 1 H), 1.82–1.91
(m, 1 H), 2.07–2.16 (m, 1 H), 2.84 (d, J = 4.4 Hz, 1 H), 2.99 (d, J
= 2.4 Hz, 1 H), 4.48–4.58 (m, 2 H), 5.11 (dd, J = 4.8, 8 Hz, 1 H),
5.27 (t, J = 3.2 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 2 H), 8.20 (d, J =
8.4 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 10.11 (10.36),
23.88 (21.12), 74.30 (73.20), 94.51, 124.17 (123.97), 127.81 (127.24),
145.55 (148.27) ppm. HPLC (Chiralpak OD-H, 2-propanol/n-hex-
ane = 10:90, flow rate = 0.5 mLmin–1, λ = 215 nm): tR = 24.9,
27.7 min (anti); 33.9 min (syn); syn/anti = 88:12.
2-Nitrotetradecan-3-ol (4e): White solid: 44 mg, 68% yield; m.p. 40–
1
41 °C. H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.4 Hz, 6 H),
1.16–1.58 (m, 46 H), 2.18 (d, J = 7.2 Hz, 1 H), 2.28 (d, J = 4.8 Hz,
1 H), 3.90 (d, J = 5.6 Hz, 1 H), 4.18 (q, J = 3.6 Hz, 1 H), 4.48–
4.56 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 12.36, 14.14,
16.29, 22.70, 25.15, 25.75, 29.34, 29.37, 29.46, 29.48, 29.53, 29.58,
29.61, 31.91, 33.01, 33.03, 72.04, 72.91, 86.34, 87.70 ppm. MS
(ESI): m/z = 259.2 [M]+. C14H29NO3 (259.39): calcd. C 64.83, H
11.27, N 5.40; found C 64.90, H 11.18, N 5.17. HPLC (Chiralpak
AD-H, 2-propanol/n-hexane = 2:98, flow rate = 0.5 mLmin–1, λ =
210 nm): tR = 19.9 min (anti); 27.3, 29.6 min (syn); syn/anti = 59:41.
1-(4-Chlorophenyl)-2-nitrobutan-1-ol (3k):[22,23] Colorless oil:
1
46.9 mg, 82% yield. H NMR (400 MHz, CDCl3): δ = 0.84 (t, J =
7.6 Hz, 3 H), 0.91 (t, J = 7.6 Hz, 3 H), 1.20–1.29 (m, 1 H), 1.32–
1.39 (m, 1 H), 1.75–1.91 (m, 1 H), 2.03–2.13 (m, 1 H), 3.22 (s, 1
H), 4.49–4.57 (m, 2 H), 4.97 (d, J = 9.2 Hz, 1 H), 5.0 (d, J = 5.2 Hz,
1 H), 7.26–7.37 (m, 4 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 10.75 (9.47), 25.19 (23.88), 75.55 (74.07), 95.95 (94.42), 128.14
(127.62), 128.36 (128.13), 129.78 (129.23), 130.07 (130.02), 134.92
(134.51), 137.26 ppm. HPLC (Chiralpak AD-H, 2-propanol/n-hex-
ane = 6:94, flow rate = 0.5 mLmin–1, λ = 200 nm): tR = 18.6,
20.7 min (anti); 27.2, 32.3 min (syn); syn/anti = 94:6.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of the NMR spectra for all compounds and HPLC
data for compounds 3a–l and 4a–4e.
2-Nitro-1-(p-tolyl)butan-1-ol (3l):[22] Colorless oil, 36.6 mg, 70%
1
yield. H NMR (300 MHz, CDCl3): δ = 0.85 (t, J = 7.8 Hz, 3 H),
Acknowledgments
0.93 (t, J = 7.8 Hz, 3 H), 1.28–1.43 (m, 1 H), 1.79–1.96 (m, 2 H),
2.12–2.16 (m, 1 H), 2.34 (s, 3 H), 2.36 (s, 3 H), 2.72 (br., 1 H), 2.85
(br., 1 H), 4.55–4.63 (m, 2 H), 4.97 (d, J = 9.9 Hz, 1 H), 5.09 (d, J
= 4.8 Hz, 1 H), 7.16–7.25 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 10.08 (10.39), 21.16 (21.57), 23.93 (23.39), 75.39
(74.19), 95.33 (94.81), 126.84 (126.19), 129.71 (129.40), 135.75
(135.64), 139.11 (138.60) ppm. HPLC (Chiralpak AD-H, 2-prop-
The authors are grateful to the Department of Science and Tech-
nology (DST), New Delhi (Ref. No. SR/S1/OC-25/2007) for provid-
ing financial support to carry out this work. Analytical support
from Sophisticated Analytical Instrumentation Facility (SAIF),
NEHU, is gratefully acknowledged. Central Instrumentation Facil-
ity, Indian Institute of Technology, Guwahati, is acknowledged for
providing HRMS data. Finally, the authors acknowledge the valu-
able input of the reviewers to revise the manuscript.
anol/n-hexane = 4:96, flow rate = 0.5 mLmin–1, λ = 215 nm): tR
28.4, 30.6 min (anti); 47.0 min (syn); syn/anti = 67:33.
=
2-Nitrohexan-3-ol (4a):[21] Colorless oil: 25.7 mg, 70% yield. 1H
NMR (400 MHz, CDCl3): δ = 0.88–1.05 (m, 6 H), 1.35–1.47 (m, 8
H), 1.51 (d, J = 1.2 Hz, 3 H), 1.53 (d, J = 1.5 Hz, 3 H), 1.99 (br.,
1 H), 2.62 (br., 1 H), 3.90 (br., 1 H), 4.17 (br., 1 H), 4.47–4.57 (m,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.75 (12.26), 13.78
(16.15), 18.37 (18.95), 34.96 (35.07), 72.66 (71.85), 87.86
(86.41) ppm. HPLC (Chiralpak AD-H, 2-propanol/n-hexane =
6:94, flow rate = 0.5 mLmin–1, λ = 210 nm): tR = 17.0, 17.9 min
(anti); 20.0, 23.1 min (syn); syn/anti = 57:43.
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Received: December 13, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21682
/KAP1
Date: 21-03-13 15:20:45
Pages: 9
Henry Reaction in Aqueous Media at Neutral pH
Henry Reaction
P. P. Bora, G. Bez* ........................... 1–9
Henry Reaction in Aqueous Media at Neu-
tral pH
Keywords: Henry reaction / C–C coupling /
β-Nitro alcohols / Asymmetric synthesis /
Diastereoselectivity
Base-free Henry reaction! The synthesis of
a variety of β-nitro alcohols is achieved by
the reaction of aldehydes with nitro alkanes
in aqueous phosphate buffer at pH 7.0.
Good to excellent diastereoselectivities are
achieved in the reactions of aromatic alde-
hydes with higher nitro alkanes.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9