Preparation of β-phenylnitroethanes having electron-donating aryl substitution

Article abstract of DOI:10.1016/j.tetlet.2007.07.098

β-Phenyl-β-hydroxynitroethanes having activating aryl substituents are treated with triethylsilane/trifluoroacetic acid under solventless conditions to give the corresponding phenylnitroethanes. Substrates having no aryl substituents or substituents that

Full text of DOI:10.1016/j.tetlet.2007.07.098

Tetrahedron Letters 48 (2007) 6704–6708
Preparation of b-phenylnitroethanes having electron-donating
aryl substitutionI
Frederick A. Luzzio,* Marek T. Wlodarczyk, Damien Y. Duveau and Juan Chen
Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, KY 40292, USA
Received 1 June 2007; revised 13 July 2007; accepted 18 July 2007
Available online 21 July 2007
Abstract—b-Phenyl-b-hydroxynitroethanes having activating aryl substituents are treated with triethylsilane/trifluoroacetic acid
under solventless conditions to give the corresponding phenylnitroethanes. Substrates having no aryl substituents or substituents
that are only mildly activating or deactivating do not result in appreciable conversion to the title compounds.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
OH
CHO
CHO
+
R
(1)
Alkylnitro compounds are valuable starting materials
and intermediates in all phases of organic synthesis
whether a complex multistep campaign or a simple start-
ing material preparation.2 The saturated C-nitro func-
tionality can serve as a precursor to other functional
groups such as amines,3a ketones,3b aldehydes3c and car-
boxylic acids3d and the nitro group itself is an excellent
carbon activator for making carbon–carbon bonds
through the many variants of the nitroaldol reaction
or the nitronate Michael addition.4,5 Within the broad
class of alkylnitro compounds are the 2-arylnitro-
ethanes, compounds which can serve as precursors to
a diverse array of b-arylethylamines, and with elabora-
tion, structurally complex alkaloids (Scheme 1).6 We
have demonstrated the usefulness of phenyl-substituted
2-phenylnitroethanes 1 when reacted with glutaralde-
hyde in the so-called ‘double Henry’ reaction. On catal-
ysis with N,N,N0,N0-tetramethylguanidine (TMG), the
double nitroaldol thereby provides the meso or the enan-
tiomeric 2-benzyl-2-nitro-1,3-cyclohexanediols depend-
ing on the reaction conditions (Scheme 1). In turn, the
resultant meso cyclohexanediols make excellent sub-
strates for enzymatic desymmetrization.7a,b Typically,
the present routes to 2-arylnitroethanes entail a nitro-
aldol (Henry reaction) of the appropriate substituted
benzaldehyde and nitromethane with promotion by
base. Usually, the intermediate nitroalcohol dehydrates
NO2
NO2
OH
1
alkaloids
(2)
R
NH2
"biogenic amines"
Scheme 1. Synthetic utility of phenylnitroethanes: Eq. 1, ‘double
Henry’ reaction of phenylnitroethanes 1 with glutaraldehyde giving a
meso nitrodiol; Eq. 2, reduction of 1 to biogenic amines-precursors to
several alkaloid families.
under more vigorous Henry conditions and ultimately
provides the nitroolefin as the overall product (Scheme
2). The nitroolefin, in turn, can be partially reduced,
OH
H
NO2
a.
O
R(n)
R(n)
c.
- H2O
NO2
NO2
b.
R(n)
R(n)
q See Ref. 1.
Scheme 2. Preparation of b-arylnitroethane intermediates via the
Henry reaction and dehydration/reduction: (a) base, nitromethane; (b)
NaBH4-mediated reagent systems; (c) direct benzylic deoxygenation.
*
Corresponding author. Tel.: +1 502 852 7323; fax: +1 502 852
8149; e-mail: faluzz01@gwise.louisville.edu
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.098

F. A. Luzzio et al. / Tetrahedron Letters 48 (2007) 6704–6708
6705
under carefully controlled conditions, to the b-arylnitro-
ethyl product,7c or with the use of more robust condi-
tions, directly to the b-arylethylamine.
process involving the reduction of the doubly conju-
gated double bond. Such reductions are problematic
and can lead to complex mixtures of products, including
dimers and carbonyl compounds, as well as the desired
saturated nitro compounds.8 Hence, starting with a b-
aryl-b-hydroxynitroethyl compound, one is only faced
Our goal in preparing b-arylnitroethanes was to bypass
the formation of the nitroolefin thereby excluding any
Table 1. Preparation of b-arylnitroethyl derivatives 1a–i by reaction of b-arylnitroalkanols 2a–i with triethylsilane (TES) and trifluoroacetic acid
(TFA)
Nitroalkanol
Product
Conditionsb (h)
Yielda (%)
Ref.
13
OH
NO2
NO2
OH
3
64
OMe
OMe
2a
1a
NO2
NO2
1
3
90
70
76
85
62
89
47
62c
13
18
14
14
15
18
16
17
MeO
MeO
1b
2b
OH
MeO
NO2
MeO
NO2
OMe
OMe
OH
1c
2c
MeO
MeO
NO2
MeO
NO2
3.5
1.75
16
16
16
5
MeO
1d
2d
OH
NO2
O
O
NO2
O
O
1e
2e
OH
OH
MeO
MeO
NO2
MeO
MeO
NO2
OMe
OMe
1f
2f
NO2
NO2
MeS
MeS
1g
2g
OH
O
NO2
NO2
O
C6H5
C6H5
1h
2h
OMe OH
OMe
MeO
NO2
MeO
NO2
2i
1i
a Isolated yields of chromatographically homogeneous product unless otherwise specified.
b All reactions were run at room temperature.
c Isolated as a chromatographically inseparable 4:1 mixture of desired product/dehydration product.

6706
F. A. Luzzio et al. / Tetrahedron Letters 48 (2007) 6704–6708
with a straightforward deoxygenation of the benzylic
position to a benzylic methine or methylene. A number
of methods are available for the direct deoxygenation of
benzylic alcohols with varied selectivity and include
hydrogenolysis,9a triethylsilane and Lewis9b or Brønsted
acid,9c borane-dimethyl sulfide,9d samarium diiodide/
H2O.9e The direct schemes are exclusive of two step
methods such as radical deoxygenation of preformed
xanthate derivatives or halogenation–reduction.10
yield product, are those bearing one or more electron
releasing groups, for example, the methoxy or the
methylenedioxy group. In cases where the phenyl group
in the nitroalcohol is unsubstituted (2j, Fig. 1) or has
only mildly activating or deactivating groups (2k–n,
Fig. 1), no desired product is recovered and the reaction
mixture only affords unreacted starting material or
dehydration product. The only exception is the ortho-
methyl-substituted substrate 2m (Fig. 1), which gave a
12% yield of the corresponding phenylnitroethane.19
Furthermore, at least one activating substituent (even
in the case of multiple substitution) should be at the
ortho or para positions in the substrates for the reagent
system to be effective. Such substrate selectivity is evi-
denced by 2o (Fig. 1), which has the methoxy group in
the meta position and afforded only unreacted starting
material and no product. Substrates, which bear pro-
tecting groups on the phenolic hydroxyls, give variable
results depending on the reactivity of the protecting
group. Substrates such as 2h give appreciable conversion
to the expected product 1h (Table 1) while a similar ana-
logue having the more sensitive 4-methoxybenzyl (PMB)
group 2r (Fig. 1) affords a 25% yield of deoxygenated
deprotected (phenolic) product. Similar to 2h, substrate
2s was converted to the corresponding product 1s hav-
ing the 4-benzyloxy group intact in 58% yield.20 Treat-
ment of 4-O- and 2-N-acetyl-protected 2p and 2q
(Fig. 1) under normal conditions gave complete cleavage
of the acetyl group, respectively, and afforded none
of the desired O- or N-derivatized product. From a
mechanistic point of view, the substrates bearing
electron-donating substituents yielded the expected
reduced products despite the presence of the electron-
withdrawing b-nitro group. Presumably, the promotion
of the benzylic carbenium ion by the Brønsted acid, with
further facilitation by the electron-donating substitu-
ents, is the overwhelming factor. Ionic reduction of the
carbenium ion through hydride reduction from the
silane then takes place thereby affording the products.12
2. Results and discussion
The protocol for deoxygenation of the aryl-substituted
nitroalcohol substrates to the nitroalkanes is rapid, sim-
ple and straightforward (Eq. 3).
OH
NO2
NO2
TES/TFA
R(n)
R(n)
ð3Þ
R=electron donating groups
After preparation of the Henry products,11 the proce-
dure entails the direct treatment of these intermediates
with triethylsilane and concentrated trifluoroacetic acid
under solventless conditions (Table 1). The crude reac-
tion mixtures are then directly submitted to flash-chro-
matography or distillation after reagent removal with
high vacuum or extractive workup. The reactions are
easily monitored by thin layer chromatography and usu-
ally require 1–16 h of reaction time under nitrogen at
room temperature (20–25 ꢁC). Running the reaction
under solventless conditions is dictated more by neces-
sity than by choice. The employment of chlorinated sol-
vents retard the reaction while the use of solvents such
as toluene or benzene at higher temperatures contribute
to dehydration, which yields the nitroolefin. The results
listed in Table 1 demonstrate that substrates, which
R1 OH
R1 OH
NO2
OH
NO2
NO2
R2
R2
2j
2k, R1=Cl, R2=H
2l, R1=H, R2=Cl
2m, R1=CH3, R2=H (12%)
2n, R1=H, R2=CH3
OH
OH
OH
MeO
NO2
NO2
MeO
NO2
AcO
NHAc
2p
2q
2o
OH
OH
BnO
MeO
NO2
NO2
OPMB
2r (25%)
2s (58%)
PMB=4-methoxybenzyl
Figure 1. Selected substrate nitroalkanols treated with TES/TFA.

F. A. Luzzio et al. / Tetrahedron Letters 48 (2007) 6704–6708
6707
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3. Conclusion
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In summary, we have described a protocol for direct
conversion of ring-activated b-aryl-b-hydroxynitro
compounds to the corresponding b-arylnitroethanes.
Although the direct ionic reduction of activated benzylic
alcohols with TES/TFA is well-precedented, the appli-
cation of this reaction to benzylic b-nitroalkanols repre-
sents a new and useful extension of this transformation
and thus provides intermediates, which can be easily
transformed to the corresponding amines. Though lim-
ited to aryl rings bearing electron donating substituents,
the reaction is a reasonable alternative to both the
nitroaldol/dehydration/reduction sequence and the
Kornblum reaction, which utilizes b-arylhaloethanes
and nitrite ion.
4. Experimental
4.1. Typical procedure for the TES/TFA reduction of
nitroalcohols
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4.1.1. 1,2,3-Trimethoxy-5-(2-nitroethyl)benzene (1f,
Table 1). To a stirred suspension containing 1-(3,4,5-
trimethoxy-phenyl)-2-nitroethanol
(2f,
Table
1)
(32.5 mg, 0.13 mmol) and triethylsilane (200 lL,
1.25 mmol) at 0 ꢁC, was added trifluoroacetic acid
(50 lL, 0.67 mmol) dropwise. As the reaction pro-
ceeded, the suspension turned into a clear solution.
The reaction mixture was stirred from 0 ꢁC to room
temperature for 16 h, after which the reaction mixture
was quenched by the slow addition of saturated aqueous
sodium bicarbonate (2 mL). The product was extracted
with dichloromethane (3 · 2 mL) and the combined or-
ganic layers were washed with brine (2 mL), dried over
sodium sulfate and concentrated. The crude oily residue
was purified by flash column chromatography eluting
first with hexane then followed by hexane/diethyl ether
(1:1) to yield the pure arylalkylnitro compound (1f,
Table 1) as an off-white amorphous solid (19.0 mg,
62%): Rf: 0.18 (petroleum ether/diethyl ether, 1:1); mp:
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Acknowledgements
Support of this work by the Molecular Pharmacology
Research Core and the Clinical Pharmacology Section
of the National Cancer Institute is gratefully
acknowledged.
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Meeting: 515-ORGN Part 2, August 18, 2002; (b) Luzzio,
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