Synthesis of 3-nitropropanol homologues

Article abstract of DOI:10.1055/s-2005-869990

Several high yielding routes to oxygenated nitropropanes have been developed that include a palladium catalyzed nitro allylation of allylic carbonates, nitration of brominated compounds and a nitro aldol condensation/hydrogenation sequence. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-869990

SHORT PAPER
1923
Synthesis of 3-Nitropropanol Homologues
Synthesis
aof 3-Nitrop
m
r
opanol
H
omologue
e
s
s K. Addo,a Paul Teesdale-Spittle,b John O. Hoberg*c
a
b
c
School of Chemical and Physical Sciences, Victoria University of Wellington, Wellington, New Zealand
School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
Department of Chemistry, University of Wyoming, Laramie, WY 82071, USA
Fax +1(307)7662807; E-mail: hoberg@uwyo.edu
Received 20 December 2004
a, b
OH
Abstract: Several high yielding routes to oxygenated nitropro-
panes have been developed that include a palladium catalyzed nitro
allylation of allylic carbonates, nitration of brominated compounds
and a nitro aldol condensation/hydrogenation sequence.
PMBO
c
PMBO
OMe
NO2
2
1
3
d
NO2
MeO
NO2
O
Key words: nitroaldol, 3-nitropropanol, 3-nitropropanal, 3-nitro-
4
propanoic acid, ethyl glyoxylate
Scheme 1 a) ClCO2Et, Py, CH2Cl2, 95%; b) MeNO2, Pd2 (dba)3,
Ph3P, CH2Cl2, 61%; c) O3, CH2Cl2, –78 °C, then Me2S; d) HC(OMe)3,
MeOH, 52% two steps.
Organonitro compounds are valuable compounds in syn-
thetic organic chemistry as they are easily transformed
into a wide variety of functionality, allowing access to tar-
get molecules such as amines, hydroxylamines, imines
and oximes.1–3 Oxygenated nitroalkenes and nitroalkanes
are particularly versatile synthetic intermediates as both
functional groups are capable of being further elaborat-
ed.4,5 We recently required access to 3-nitropropanals and
3-nitropropanols and have investigated routes to these
compounds. Described herein are several routes to homo-
logues of 3-nitropropanols from commercially available
or readily available starting materials. These routes in-
clude a palladium catalyzed nitromethane allylation using
allylic carbonates,6 nitration of bromated compounds7 and
a nitro aldol condensation/hydrogenation sequence.5,8–10
perimental conditions were given.15 Thus, we began with
the optimization of this reaction and found that refluxing
conditions are required for the formation of 3-nitropro-
panol (5a). Encouraged by the simplicity of this reaction,
we treated 3-bromopropanoic acid under identical condi-
tions to give 5b in good yield. This series can be complet-
ed by the formation of nitrobutene 5c followed by
ozonolysis to give 3-nitropropanal (3) in good overall
yield.
a
b
NO2
Br
3
R
R
R = CH2OH
R = CO2H
R = CH=CH2
5a 65% yield
5b 70% yield
5c 80% yield
The traditional method for preparing these compounds is
from acrolein,11 however the toxicity of acrolein detracts
from its use and often limits its availability due to ship-
ping restrictions. We therefore investigated the palladium
catalyzed allylation of nitromethane using allylic carbon-
ates, which has garnered considerable attention recently,6
and was envisioned to give access into our target interme-
diates after subsequent elaboration of the resulting olefin-
ic moiety (Scheme 1). Thus, treatment of 112,13 with ethyl
chloroformate gave the allylic carbonate, which under-
went palladium catalyzed reaction to give nitroalkene 2 in
good overall yield. The 1,5 N-O relationship formed in 2
is a common relationship and thus is useful in itself.14 For
our purpose, subsequent ozonolysis of 2 gave crude 3,
which was converted to the acetal 4, in reasonable overall
yield.
Scheme 2 a) AgNO2, Et2O, reflux; b) O3, CH2Cl2, –78 °C, then
Me2S, 55%.
Finally, we investigated the Henry reaction using ethyl
glyoxylates (Scheme 3). Aldol reaction of nitromethane
with acetaldehyde dimethyl acetal or ethyl glyoxylate
gave the corresponding nitro alcohols, which underwent
elimination via a mesylation/silica gel sequence to give 6a
and 6b, respectively.16,17 Hydrogenation with Pd/C gave
the reduced nitroalkanes 4 and 7b in good overall yields.
Similarly, treatment of ethyl glyoxylate with nitroethane
provided nitroalkene 6c, which also is easily reduced.18
Asymmetric reduction was also attempted using (S,S)-
Me-DUPHOS-Rh as the ligand under transfer hydrogena-
tion conditions with ammonium formate. However, we
obtained only a 25% yield and equally poor enantiomeric
excess. Efforts at optimizing this reaction are underway;
however, Carreira has just recently reported a highly effi-
cient enantioselective reduction of nitroalkenes using
JOSIPHOS and CuF2.19
An alternative to the above strategy involves nitration of
brominated substrates (Scheme 2). Although the addition
of AgNO2 to 3-bromopropanol has been reported, no ex-
SYNTHESIS 2005, No. 12, pp 1923–1925
x
x.
x
x
.
2
0
0
5
In conclusion, several high yielding routes to oxygenated
nitropropanes have been developed that alleviate the need
Advanced online publication: 13.07.2005
DOI: 10.1055/s-2005-869990; Art ID: M09404SS
© Georg Thieme Verlag Stuttgart · New York

1924
J. K. Addo et al.
SHORT PAPER
O
Flash chromatography (15% EtOAc–hexanes) gave 4 as an oil (774
mg, 52% overall yield from 2).
1H NMR: d = 4.48 (m, 3 H), 3.39 (s, 6 H), 2.21 (m, 2 H).
13C NMR: d = 102.1, 71.3, 54.2, 30.6.
c
a, b
NO2
NO2
R
R
R
H
R1
R1
6a 75%, R1 = H
6b 77%, R
4 80% yield
7b 78% yield
7c 75% yield
R = CH(OMe)2
R = CO2Et
R = CO2Et
1 = H
6c 80%, R1 = Me
Reaction of Silver Nitrite with Bromides; General Procedure
Anhydrous Et2O (40 mL) was added to a mixture of AgNO2 (13.68
g, 89.0 mmol) and the bromide (29.6 mmol) in a flask protected
from light. The reaction mixture was refluxed overnight, cooled and
filtered, then purified by distillation or crystallization.
Scheme 3 a) MeNO2 or EtNO2, H2O, alumina; b) MsCl, i-Pr2EtN,
CH2Cl2, silica; c) H2, Pd/C, EtOAc
for toxic acrolein. The ease, simplicity and cost of these
routes provide for straightforward access into this series
of compounds.
3-Nitropropanol (5a)
Yield: 65%.
1H NMR: d = 4.53 (t, J = 7.2 Hz, 2 H), 3.75 (t, J = 5.9 Hz, 2 H), 2.23
(m, 2 H).
1H (300 MHz) and 13C (75 MHz) NMR spectra were recorded on a
Varian spectrometer with chemical shifts reported relative to CDCl3
(d = 7.23 and 77.3 ppm, respectively). All solvents were dried prior
to use, standard syringe techniques were used for handling air-sen-
sitive reagents, and all reactions were carried out under Ar.
13C NMR (CDCl3): d = 72.7, 59.1, 30.0.
3-Nitropropionic Acid (5b)
Yield: 70%.
1H NMR: d = 4.65 (t, J = 6.1 Hz, 2 H), 3.05 (t, J = 6.1, 2 H).
13C NMR (CDCl3): d = 175.6, 69.3, 30.8.
1-p-Methoxybenzyloxy-5-nitro-2-pentene (2)
To a solution of alcohol 1 (3.00 g, 16.8 mmol) in CH2Cl2 (20 mL)
at 0 °C was added pyridine (2.72 mL, 34.0 mmol) followed by drop-
wise addition of ethyl chloroformate (1.61 mL, 16.8 mmol). The re-
action was allowed to warm to r.t. and stirred until TLC indicated
complete reaction. The reaction mixture was quenched by addition
of sat. NH4Cl and extracted with Et2O (3 × 15 mL). The organic
phase was dried with MgSO4, filtered and concentrated in vacuo to
give a residue, which was chromatographed on silica gel (10%
EtOAc–hexanes) to give ethyl 4-p-methoxybenzyloxy-2-butene-1-
carbonate as an oil (4.48 g, 95% yield).
1H NMR: d = 7.26 (d, J = 8.6 Hz, 2 H), 6.86 (d, J = 8.6 Hz, 2 H),
5.89 (m, 2 H), 4.63 (d, J = 4.8 Hz, 2 H), 4.46 (s, 2 H), 4.18 (q, J =
7.2 Hz, 2 H), 4.02 (d, J = 4.5 Hz, 2 H), 3.80 (s, 3 H), 1.30 (t, J = 7.2
Hz, 3 H).
4-Nitro-1-butene (5c)
Yield: 80%.
1H NMR: d = 5.75 (m, 1 H), 5.12 (m, 2 H), 4.42 (t, J = 6.1 Hz, 2 H),
2.76 (m, 2 H).
13C NMR: d = 132.0, 119.0, 74.9, 31.5.
3-Nitropropanal (3)
Nitropropene 5c (1.00 g, 9.98 mmol) was dissolved in CH2Cl2 (15
mL). The solution was cooled to –78 °C with stirring and treated
with ozone for 5 min. The reaction was quenched with dimethyl sul-
fide (1 mL), stirred at –78 °C for 1 h and then evaporated at reduced
pressure to give 3 as an analytically pure oil (560 mg, 55% yield).
As noted in the literature,11b compound 3 is unstable and should be
used immediately upon formation.
13C NMR: d = 159.2, 154.9, 131.7, 130.1, 129.3, 125.8, 113.7, 71.9,
69.3, 67.4, 64.0, 55.2, 14.2.
HRMS: m/z [M + NH4] calcd for C15H24NO5: 298.1654; found:
298.1649.
Formation of 6a–c; General Procedure
Neutral alumina (10 g) was added to a solution of aldehyde (48.0
mmol) dissolved in nitromethane (10 mL, 145.0 mmol) (or nitro-
ethane). The resulting cloudy suspension was stirred at r.t. over-
night then filtered and washed with EtOAc (3 × 15 mL). The
combined filtrate was concentrated in vacuo to give an oil, which
was purified via flash chromatography (10% EtOAc–hexanes) to
give the corresponding nitroalcohol. Spectral data were identical to
that reported previously.16,20 The nitroalcohol was dissolved in
CH2Cl2 (20 mL) and cooled to –78 °C. Then MsCl was added drop-
wise followed by a solution of N,N-diisopropylethylamine (9.69 g,
75.0 mmol) in CH2Cl2 (5 mL). The resulting mixture was stirred at
–78 °C for 2 h and allowed to warm to r.t. After TLC indicated the
reaction was over, the reaction mixture was poured onto ice-cold
water and extracted with CH2Cl2. The organic phase was washed
with H2O, brine, dried with MgSO4 and concentrated in vacuo. The
crude product was chromatographed on silica gel (5% EtOAc–hex-
anes) to give the corresponding nitroalkene.
To a degassed solution of PPh3, (186.2 mg, 10 mol%) and Pd2(dba)3
(162.5 mg, 2.5 mol%, 0.178 mmol) in CH2Cl2 was added ni-
tromethane (5 mL, 92.4 mmol). After stirring for 5 min, the above
carbonate (2.00 g, 7.10 mmol) was added. The resulting mixture
was stirred at r.t. for 2 h and concentrated in vacuo. The crude prod-
uct was directly purified by flash chromatography on silica gel
(10% EtOAc–hexanes) to give 2 as an oil (1.03 g, 61% yield).
1H NMR: d = 7.26 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H),
5.70 (m, 2 H), 4.43 (s, 2 H), 4.42 (t, J = 7.2 Hz, 2 H), 3.95 (d, J =
5.1 Hz, 2 H), 3.80 (s, 3 H), 2.76 (m, 2 H).
13C NMR: d = 159.5, 131.3, 130.4, 129.7, 126.7, 114.1, 75.1, 72.2,
70.0, 55.5, 30.3.
HRMS: m/z [M + NH4] calcd for C13H21N2O4: 269.1501; found:
269.1495.
3-Nitropropanal Dimethyl Acetal (4)
3-Nitro-2-propenal Dimethylacetal (6a)
Compound 2 (2.37 g, 10.00 mmol) was dissolved in CH2Cl2 (15
mL). The solution was cooled to –78 °C with stirring and then treat-
ed with ozone for 5 min. The reaction was quenched with dimethyl
sulfide (1 mL), left to stir at –78 °C for 1 h and then evaporated at
reduced pressure to give crude 3-nitropropanal (3). The oil was dis-
solved in MeOH (15 mL), then trimethyl orthoformate (698 mg,
6.58 mmol) and p-TsOH·H2O (20 mg) were added. The mixture was
stirred at r.t. for 3.5 h and the solvent was removed under vacuum.
1H NMR: d = 7.20 (d, J = 13.5 Hz, 1 H), 7.02 (dd, J = 13.2, 3.2 Hz,
1 H), 5.15 (d, J = 3.4 Hz, 1 H), 3.39 (s, 6 H).
13C NMR: d = 142.7, 136.7, 98.2, 53.2.
Ethyl 3-Nitroacrylate (6b)
1H NMR: d = 7.68 (d, J = 13.6 Hz, 1 H), 7.09 (d, J = 13.6 Hz, 1 H),
4.34 (q, J = 7.1 Hz, 2 H), 1.36 (t, J = 7.1 Hz, 3 H).
Synthesis 2005, No. 12, 1923–1925 © Thieme Stuttgart · New York

SHORT PAPER
Synthesis of 3-Nitropropanol Homologues
1925
13C NMR: d = 162.9, 149.1, 127.9, 62.6, 14.1.
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Ethyl 3-Methyl-3-nitroacrylate (6c)
1H NMR: d = 7.0 (s, 1 H), 4.2 (q, J = 7.2 Hz, 2 H), 2.5 (s, 3 H), 1.2
(t, J = 7.2 Hz, 3 H).
13C NMR: d = 164.2, 160.0, 121.5, 61.8, 14.1, 14.0.
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Hydrogenation of 6a–c; General Procedure
A suspension of nitroalkene (6.89 mmol) and 10% Pd/C (300 mg)
in CH2Cl2 (10 mL) was hydrogenated at r.t. under a balloon of H2
for 2 h. The mixture was filtered, concentrated in vacuo and the res-
idue chromatographed on silica gel with 5% EtOAc–hexanes to
give the corresponding nitroalkane.
Ethyl 3-Nitropropionate (7b)
1H NMR: d = 4.68 (t, J = 6.1 Hz, 2 H), 4.20 (q, J = 7.1 Hz, 2 H), 2.99
(t, J = 6.1 Hz, 2 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR: d = 169.8, 69.9, 61.5, 31.1, 14.1.
HRMS: m/z [M + H] calcd for C5H10NO4: 148.0609; found:
148.0790.
Ethyl 3-Nitrobutanoate (7c)
Alternatively, a mixture of ethyl-3-methyl-3-nitroacrylate (100 mg,
0.628 mmol), (S,S)-Me-DUPHOS-Rh (0.42 mg, 0.000628 mmol,
0.1 mol%), NH4CO2 (119 mg, 1.88 mmol) in CH2Cl2 (15 mL) in a
flask previously evacuated with hydrogen was allowed to stir over-
night. The mixture was filtered through celite and the combined fil-
trate evaporated in vacuo and directly chromatographed on silica
with 5% EtOAc–hexanes as eluent.
1H NMR: d = 4.93 (m, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.17 (dd, J =
8.7, 12.2 Hz, 1 H), 2.72 (dd, J = 5.1, 12.2 Hz, 1 H), 1.62 (d, J = 7.1
Hz, 3 H), 1.26 (t, J = 7.1 Hz, 3 H).
13C NMR: d = 169.4, 78.7, 61.5, 38.7, 19.6, 14.3.
HRMS: m/z [M + H] calcd for C6H12NO4: 162.0766; found:
162.0731.
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Acknowledgment
Financial support was provided by the New Zealand Cancer Socie-
ty, the Public Good Science Fund and the Foundation for Research
Science and Technology, and Victoria University of Wellington.
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Synthesis 2005, No. 12, 1923–1925 © Thieme Stuttgart · New York