Environmentally friendly solvent-free processes: Novel dual catalyst system in Henry reaction

Article abstract of DOI:10.1021/op020222c

Our environmentally benign synthesis of nitroalcohols involves a simple solvent-free condensation of an appropriate aldehyde with a 1-nitroalkane utilizing a novel dual catalytic system consisting of a mineral base and an appropriate surfactant under homo

Full text of DOI:10.1021/op020222c

Organic Process Research & Development 2003, 7, 254−258
Environmentally Friendly Solvent-Free Processes: Novel Dual Catalyst System
in Henry Reaction
Apurba Bhattacharya* and Vikram C. Purohit
Department of Chemistry, Texas A&M UniVersity at KingsVille, KingsVille, Texas 78363 U.S.A.
Frank Rinaldi
Bristol Myers Squibb Corporation, One Squibb DriVe, New Brunswick, New Jersey U.S.A.
Abstract:
the solvent medium, which brings the reactants into closer
proximity.
Our environmentally benign synthesis of nitroalcohols involves
a simple solvent-free condensation of an appropriate aldehyde
with a 1-nitroalkane utilizing a novel dual catalytic system
consisting of a mineral base and an appropriate surfactant
under homogeneous conditions. By proper choice of the catalyst,
base, and/or reaction conditions, the reaction can be performed
to a level of >90% conversion as well as selectivity.
As part of a collaborative research program established
between Texas A&M University, Kingsville and Bristol
Myers Squibb Pharmaceutical Company, we have an interest
in developing environmentally friendly processes for the
pharmaceutical industry.1a The significance of nitroalcohols/
nitroalkenes as valuable pharmaceutical intermediates in
organic synthesis and our continued interest in the develop-
ment of environmentally benign synthetic protocols under
solvent-free conditions1b prompted us to investigate the Henry
reaction involving the condensations of carbonyl compounds
with nitroalkanes.
Herein, we report a novel surfactant induced, dual
catalytic, solvent-free, green technology for the production
of nitroalcohols that can be accomplished in high yield and
efficiency. The solvent-free technology appears to be general
and should be applicable to a broad spectrum of organic
reactions.
Nitroaldol Condensation (Henry Reaction). Nitroalco-
hols are valuable intermediates for the synthesis of pharma-
cologically active â-amino alcohols, the key elements present
in â-blockers and agonists that are highly effective in the
treatment of cardiovascular disease, asthma, and glaucoma.7
Nitroalkenes derived from nitroalcohols possess significant
biological activities such as insecticidal, fungicidal, bacte-
ricidal, rodent-repellant, and antitumor agents and are also
utilized for the preparation of prostaglandins, pyrroles, and
porphyrins.7c-h Traditional syntheses of nitroalcohols involv-
ing the base-catalyzed condensation of aldehydes or silyl
nitronates (Seebach et al.)8c,g with the corresponding nitroal-
kanes are cumbersome, low yielding (50-60%), prohibitively
slow (4-7 days), waste producing (e.g., fluoride salts), or
Introduction
Over the past few years, significant research has been
directed toward the development of new technologies for
environmentally benign processes (green chemistry),1b which
are both economically and technologically feasible.2,3 An
important area of green chemistry deals with solvent
minimization. The United States uses 160 billion gallons of
solvents each year; in a solvent-free process, the cost of
processing, handling, and disposal of the solvent is com-
pletely eliminated, resulting in improved process efficiency.4
Many of the commonly used volatile solvents are listed in
the United States’ Clean Air Act as substances to be avoided.
Other disadvantages include ozone depletion (by chloroflu-
ourocarbons), toxicity of chlorinated solvents, birth defects
from exposure to solvents, and ground level ozone production
(from NOx and volatile solvents) as well as fires and
explosions. Limited success has been achieved with alterna-
tives such as aqueous systems, ionic liquids, immobilized
solvents, dendrimers, amphiphilic star polymers, and super-
critical fluids.5 The major challenge encountered in solvent-
free chemistry is the lack of a common phase provided by
(1) (a) Process Chemistry Collaboration, Education Concentrate. Chem. Eng.
News 2001, 79 (July 23), 41. (b) EnVironmentally Friendly SolVent-Free
Processes: Preparation of Nitro Alcohols, A Class of Valuable Drug
Intermediates by Henry Reaction, American Chemical Society 57th South-
west Regional Meeting, October 2001; pp 17-20.
(2) For related references, see: (a) Cablewski, T.; Faux, F.; Strauss, C. R. J.
Org. Chem. 1994, 59, 3408. (b) Raner, K. D.; Strauss, C. R.; Trainor, R.
W.; Thorn, J. S. J. Org. Chem. 1995, 60, 2456. (c) Strauss, C. R.; Trainor,
R. W. Aust. J. Chem. 1995, 48, 1665.
(3) For related references, see (a) Hall, N. Science 1994, 266, 32. (b) Newman,
A. EnViron. Sci. Technol. 1994, 28 (11), 463A. (c) Sheldon, R. A.
CHEMTECH 1994 (March), 38-47. (d) Amato, I. Science. 1993, 259, 1538.
(e) Ilman, D. L. Chem. Eng. News. 1993, (Sept 6), 26. (f) Ember, L.
CHEMTECH 1993 (June), 3. (g) Crenson, M. Dallas Morning News 1993
(Sept. 13), 1D. Ember. (h) Pollution Prevention Act, U. S. C.13101-13109,
1990, 42. (i) Browner, C. M. EPA Journal 1993, 3 (19), 6-8.
(4) A. R. Gavaskar. Onsite SolVent RecoVery. U.S. EPA/600/R-94/026; Cincin-
nati, Ohio, Sept 1993.
(5) Green Chemistry Theory and Practice; Anastas, P. T., Warner, J. C., Eds.;
Oxford University; pp 1-129.
(6) (a) Henry, L. Compt. Rend. 1895, 120, 1265. (b) Kamlet, J. U.S. Patent
2,151,517, 1939. (c) Fernandez, R. Application to Sugars. Carbohydr. Res.
1993, 247, 239. (d) Kambe, S.; Yasuda, H. Bull. Chem. Soc. Jpn. 1968, 41
(6), 1444.
(7) (a) Sittig, M. Pharmaceutical Manufacturing Encyclopedia, 2nd ed.; Vol.
1 and 2. (b) Pharmazeutische Wirkstoffe, Synthesen. Patente. Anwendungen
Von A. Kleeman und J. Engel. (c) Barrett, A. G. M.; Grabowski G. Chem.
ReV. 1986, 86, 751.(d) Brown, A. W. A.; Robinson, D. B. W.; Hurtig, H.;
Wenner, B. J. Can. J. Res. 1948, 26D, 177. (e) Bousquet, E. W.; Kirby, J.
E.; Searle, N. E. U.S. Patent 2,335,384. (f) Brian, P. W.; Grove, J. F.;
Mcgowan, J. C. Nature 1946, 158, 876. (g) McGowan, J. C.: Brian, P. W.;
Hemming, H. G. Ann. Appl. Biol. 1948, 35, 25. (h) Varma, R. S.; Dahiya,
R.; Kumar. S. Tetrahedron Lett. 1997, 38 (29), 5131 and references cited
therein.
254
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10.1021/op020222c CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/01/2003

Scheme 1. Waste-Free Synthesis of Nitroalcohols
involve use of pyrophoric and environmentally unacceptable
reagents including lithium di-isopropylamide and TMS-
chloride. Proazaphosphotranes in conjunction with excess
magnesium sulfate have been successfully utilized to mediate
nitroaldol reactions, although the catalyst needs to be pre-
pared independently.8h,i An alternate synthesis of nitroalcohol
involving the addition of N2O4 or acylnitrate to an olefin is
impractical and costly and only has academic value.8 An
efficient, solvent-free catalytic method for the production of
nitroalcohols would be highly desirable.
Optimal conditions to effect the nitroaldol condensations
involved treating a mixture of the specified nitroalkane,
saturated aq KOH (1 wt %) and surfactant TritonX-405 (1
wt %) with the specified aldehyde at 60-65 °C, giving rise
to the corresponding nitroaldol products in excellent conver-
sions and selectivity. These conditions were also successfully
applied to prepare a series of nitroalcohols in consistently
high yields (Table 1).
Condensation of nitropropane with propionaldehyde led
to a 1.5:1 ratio (anti:syn) of the two diastereomers. The
identities of the diastereomers were proven by independent
preparation of the syn diastereomer via deprotonation of the
product nitroaldol with LDA (2 mol) followed by stereose-
lective reprotonation of the resulting dianion with acetic acid
(Scheme 2).8g
Complexation of Metal Ions. The Triton-X/base com-
bination plays an important role in the rate of the nitroaldol
reaction. For example, reacting nitropropane with propional-
dehyde, utilizing TritonX-100 as the catalyst, we found KOH
and CsOH to be the most effective bases (>90% after 3 h),
whereas reactions were slower with lithium, sodium, and
tetrabutylammonium hydroxides (approximately 30% comple-
tion after 3 h). No reaction was observed with Ba, Ca, or
Results and Discussions
Initial attempts to condense nitroalkanes with aldehydes
under standard solvent-free conditions in the presence of
catalytic amounts of mineral bases (KOH or NaOH) were
unsuccessful, leading to decomposition of products presum-
ably due to base-catalyzed eliminations of water to form
nitroolefins and their tendency to polymerize readily.8 Further
investigations revealed that the addition of catalytic amounts
of a surfactant, for example, poly(ethylene glycol) (PEG) or
Triton-X, dramatically improved the nitroaldol reaction rate,
leading to faster and cleaner conversions.13 Thus, our solvent-
free nitroaldol protocol involves condensation of an ap-
propriate aldehyde with a 1-nitroalkane utilizing a novel dual
catalytic system consisting of an inexpensive mineral base,
KOH, and an appropriate surfactant (e.g., Triton-X or poly-
(ethylene glycol)).11 The role of surfactant is not totally clear
at this point, and further work is needed. Presumably PEG
type surfactants can act as phase transfer catalysts9 in a
classical sense and compensate for the lack of solvation
(Scheme 1). The PEG (poly(ethylene glycol)) units in
Triton-X are also capable of complexing the metal ion
(analogous to crown ether complexations), thereby solubi-
lizing the base (KOH) in the organic medium.10 Since
Triton-X is a surfactant, fundamentally it could also catalyze
the reaction by increasing the liquid-liquid interfacial area,
thereby improving the reaction kinetics.11
(9) (a) Dehmlow, E. V.; Dehmlow, S. S. In Phase Transfer Catalysis,
Monographs in Modern Chemistry, 11; Ebel, H. F., Ed.; Verlag Chemie:
Weinheim, Germany, 1983. (b) Arkhipovich, G. N.; Ugolkova, E. A.
Koznaski, K. S. Polym. Bull. 1984, 12, 181.
(10) (a) Pittman, C. U.; Evans, G. O. Chem. Technol. 1973, 3, 566. (b) Bailar,
J. C. Catal. ReV. 1974, 10 (1). (c) Hanson, D. L.; Katzer, J. R.; Gates, B.
C.; Schuit, G. C. A. J. Catal. 1974, 32, 204.
(11) Since the reaction occurs in a single liquid phase, the term “dual catalyst”
was introduced to differentiate the role of Triton-X from that of a
conventional phase transfer catalyst (PTC), where the reaction takes place
in the aqueous/organic interface. Triton-X is also differentiated from
traditional crown ethers, since crown ethers do not act as a surfactant. In
this case, although KOH is the active catalyst, the presence of Triton-X is
imperative. Control experiments performed in absence of Triton-X showed
decomposition of both nitroalkanes and aldehyde under otherwise identical
conditions. For references on a similar dual catalytic effect by Triton-X
type surfactants in a chiral PTC system, see: Dolling, U.-H.; Hughes, D.
L.; Bhattacharya, A.; Ryan, K. M.; Karady, S.; Weinstock. L. M.; Grenda,
V. J.; Grabowski, E. J. J. Efficient Asymmetric Alkylations via Chiral Phase-
Transfer Catalysis. In A NoVel Dual Catalysis. Catalysis of Organic
Reactions; Paul N. Rylander, P. N., Greenfield, H., Augustine, R. L., Eds.;
1988; Vol. 33, pp 65-86.
(12) (a) Soladie-Cavalo, A.; Khiar, N. Tetrahedron Lett. 1988, 2189. (b) Susai,
H.; Yamada, Y.; Yoichi, M. A.; Suzuki, T.; Shibasaki, M. Tetraheron Lett.
1994, 50 (43), 12313. (c) Sasai, H.; Kim. W.-S.; Suzuki, T.; Shibasaki, M.;
Mitsuda, M.; Hasegaowa, J.; Ohasi, T. Tetrahedron Lett. 1994, 35 (33),
6123.
(13) (a) Dolling, U.-H.; Hughes, D. L.; Bhattacharya, A.; Ryan, K. M.; Karady,
S.; Weinstock, L. M.; Grabowski, E. J. J. Efficient Asymmetric Alkylations
via Chiral Phase-Transfer Catalysis: Applications and Mechanism; Starks,
C. M., Ed.; In Phase Transfer Catalysis; New Chemistry, Catalysts, and
Applications; ACS Symposium Series 326; American Chemical Society:
Washington, DC, 1987, Chapter 7, pp 67-81. (b) Bhattacharya, A.; Dolling,
U.-H.; Grabowski, E. J. J.; Karady; Ryan, K. M.; Weinstock, L. M. Efficient
Catalytic Asymmetric Alkylations. Angew. Chem. 1986, 98, 442. (c) Dolling,
U.-H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc. 1984, 106, 446.
The reaction is performed neat; the product is directly
obtained and is ready to be utilized for the next step in a
synthetic sequence. No workup is necessary. Overall through-
put of the reaction is 100%.
(8) (a) For base-catalyzed nitroaldol, see: Hoover, F. W.; Hass, H. J. Org.
Chem. 1947, 12, 506. (b) Wollenberg, R. H.; Miller, S. J. Tetrahedron Lett.
1978, 3219. (c) Solladie-Cavalo, A.; Khiar, N. Tetrahedron Lett. 1988, 2189.
(d) Colvin, E. W.; Beck, A. K.; Seebach, D. HelV. Chim. Acta 1981, 64,
2264. (e) Bonetti, G. A.; DeSavigny, C. B.; Michalski, C.; Rosenthal, R. J.
Org. Chem. 1968, 33, 237. (f) Schchter, H.; Gardikes, J.J.; Cantrell, T. S.;
Tiers, G. V. D. J. Am. Chem. Soc. 1967, 89, 3005. (g) Seebach, D.; Beck,
A. K.; Mukhopadhyay, T.; Thomas, E. HelV. Chim. Acta 1982, 65, 1101.
(h) Kisinga, P.; Verkede, G. J. Org. Chem. 1999, 64, 4298. (i) Luzzio, F.
Tetrahedron 2001, 57, 915.
Vol. 7, No. 3, 2003 / Organic Process Research & Development
•
255

Table 1. Preparation of Nitroaldolsa
Table 2. Extent of Dissolution of Metal Hydroxide [M(OH)x]
in Toluene
amount (mL)
of 0.001 N HCl
base
entry [M(OH)x]
needed for
surfactant
titration end point
yield reaction time (h)/
1
2
none
none
TritonX-100 (average
10 PEG units)
TritonX-405 (average
40 PEG units)
TritonX-100
TritonX-405
0a
0
entry
R1s
R2s
(%) temperature (°C)
1
2
3
4
5
6
7
8
9
Mes
Mes
Ets
Ets
Ets
n-Prs
n-Prs
Mes
Ets
Mes
Ets
n-Prs
n-Prs
Ets
91
94
91
93
86
83
88
86
88
70
6/60
4/60
2.5/60
1.5/60
6/60
10/60
6/60
4/35
6/35
15/60
3
4
5
KOH
KOH
KOH
7.0
76.4
31
TritonX-405 red
(the aromatic
ring reduced)
6
7
8
KOH
KOH
KOH
PEG [MW: ∼4600]
29
23
2
PhCH2CH2s
PhCHdCHs(trans) Ets
i-Prs Mes
Ets
uncapped
PEG dimethyl ether
[MW: ∼250]
10
Igepal DM-970
dinonylphenyl ether
(average 150 PEG unit)
Igepal CO-990 nonylphenyl
ether (average 100
PEG unit)
a All products exhibited satisfactory spectral properties (1H and 13C NMR).
9
KOH
3
Scheme 2. Preparation of the Syn Diastereomer
10 NaOH
11 NaOH
12 Ca(OH)2 TritonX-100
13 Ca(OH)2 TritonX-405
14 Mg(OH)2 TritonX-100
15 Mg(OH)2 TritonX-405
TritonX-100
TritonX-405
7.5
6.1
0
0
0
0
Mg hydroxides in conjunction with TritonX-100. TritonX-
405 was also effective with K, Li, and Cs hydroxides. The
topology of the Triton-X/ethylene glycol units might be
responsible for preferential complexation of metal ions
analogous to crown ether complexation of metal ions. In line
with these observations, poly(ethylene glycol) (uncapped)
and poly(ethylene glycol) dimethyl ether (capped) were also
effective when used in conjunction with KOH as base (>90%
after 3 h). Particularly noteworthy and remarkable is the fact
that, in the presence of KOAc as base, nitropropane under-
went smooth condensation with propionaldehyde (>95%
after 20 h at 60-65 °C) utilizing TritonX-100 as catalyst.
TritonX-405, PEG, and PEG dimethyl ether were also
equally effective with KOAc. Such mild conditions, once
expanded to other substrates, will be extremely beneficial
for nitroaldol condensations with more complex substrates.
The complementary nature of the various types of
Triton-X and specific counterions in an organic medium
might originate from crown-ether-like metal ion recognition
by the polyether cavity of Triton-X.15 Control experiments
performed by adding 1 g of KOH (as a representative
hydroxide base) to 100 mL of toluene (as a representative
organic solvent) showed no dissolution of KOH in the
organic layer. Adding Triton-X 405 (1 g) to this mixture
showed significant dissolution of KOH in the toluene layer.
Using different metal hydroxide base/Triton-X combinations
followed by titration of the amount of base transferred to
the toluene layer (with standardized 0.001 N HCl) allowed
16 CsOH
17 CsOH
TritonX-100
TritonX-405
18
780b
a In absence of surfactant, no dissolution of base was detected. b Control
experiments indicated that CsOH is partially soluble in toluene even in absence
of surfactant.
us to quantify the solubilization effect and hence the extent
of M+ ion/surfactant complexation. The titration results are
summarized in Table 2.
The extent of the complexation of K+ ion evidently is a
function of the type of surfactants (number of PEG units)
used (entries 1-9). Clearly, TritonX-405 is a better candidate
for the complexation of K+ ion. Mg(OH)2 and Ca(OH)2 failed
to catalyze the nitroaldol reaction, which is in line with the
values obtained for Mg and Ca (entries 14-17). The
surfactant-specific complexation of metal ions in organic
medium is reminiscent of the cavity selective complexation
that exists between crown ethers and metal ions. Because of
its cost prohibitive nature, crown ethers are unacceptable for
commercial processes, but Triton-X type surfactants could
conceivably be used for such processes because of their ready
availability and low cost.
Summary
We have developed a simple, mild, and efficient green
technology to produce nitroalcohols that are useful synthetic
intermediates for a variety of aminoalcohols utilized as
â-adrenergic blockers, bronchodialators, and vasoconstrictors.
The reactions are performed neat; no workup is necessary.
The fact that the reactions proceed to near quantitative
conversions with 100% overall throughput (vessel efficiency)
also renders the process practical and economically attractive.
Crown ether type selective complexations of metal ions
(14) Lunts, L. H. C.; Main, B. G.; Tucker, H. In Medicinal Chemistry, The Role
of Organic Chemistry in Drug Research; Robert, S. M., Price, B. J., Eds.;
Academic Press: New York, 1985; pp 49-92.
(15) (a) Rebeck, J. Angew. Chem., Int. Ed. Engl. 1990, 29, 245. (b) March, J.
AdVanced Organic Chemistry, 4th ed.; John Wiley; pp 82-93 and references
therein.
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would allow us to adjust the process to make it substrate/
reagent selective. The chiral variant of nitroaldol, if suc-
cessful, would allow us to directly produce physiologically
active enantiomers without a complicated resolution process
and is under active investigation.12-14
rate. The retention times of the reaction mixture species are
as follows: n-propionaldehyde, 6.1 min; 1-nitropropane, 8.20
min; syn-4-nitro-hexan-3-ol, 8.03 min; and anti-4-nitro-
hexan-3-ol, 7.52 min.
The reaction mixture was cooled to 22 °C, and volatile
impurities (e.g., trace of unreacted starting material) were
removed under reduced pressure. The mixture was filtered
through a cotton plug (to remove any suspended impurities),
producing 7.67 g (93% yield) of the two diastereomeric
nitroalcohols (1.5:1 ratio of anti:syn).8g
Experimental Section
Materials and Methods. Reactions were carried out
under an atmosphere of nitrogen and were stirred magneti-
cally unless otherwise noted.16 All the materials (reagent
grade) were purchased from commercial suppliers and were
used without purification. Analytical high performance liquid
chromatography (HPLC) was carried out by using a Waters
501 pump, Waters Millipore gradient controller (automated),
Thermoseparation Products refractomonitor IV, and Hitachi
L 4000 variable wavelength detector. All NMR spectra were
recorded on a Bruker, Avance DPX 300 instrument at the
Pharmaceutical Research Institute, Bristol-Myers Squibb
Company, NJ and a 60 MHz JEOL at Texas A&M Univers-
ity-Kingsville, Texas. All the compounds were dissolved
in deuteriochloroform (CDCl3) for NMR analysis with the
proton chemical shift referenced to residual CHCl3 at 7.27
ppm and carbon chemical shift referenced to CDCl3 at 77.0
ppm.
1
3-Nitrobutan-2-ol (1). H NMR (CDCl3) diastereomer
A 60% δ 4.47 (1H, m), 4.11 (1H, m), 3.00 (OH, bs), 1.50
(3, d, J ) 6.7 Hz), 1.24 (3, d, J ) 6.7 Hz); 1H NMR (CDCl3)
diastereomer B 40% δ 4.47 (1H, m), 4.31 (1H, m), 3.00 (OH,
bs), 1.53 (3H, d, J ) 6.7 Hz), 1.22 (3H, d, J ) 6.7 Hz); 13
C
NMR (CDCl3) δ 87.56, 68.70, 18.58, 14.16; MS 120 (M+
+ 1), 119 (M+).
1
3-Nitropentan-2-ol (2). H NMR (CDCl3) diastereomer
A 60% δ 4.33 (1H, m), 4.12 (1H, m), 2.76 (1H, OH, bs),
1.93 (2H, m), 1.26 (3H, d, J ) 6.2 Hz), 0.96 (3H, t, J ) 7.0
Hz); 1H NMR (CDCl3) diastereomer B 40% δ 4.33 (1H, m),
4.12 (1H, m), 2.76 (1H, OH, bs), 1.93 (2H, m), 1.24 (3H, d,
J ) 6.2 Hz), 0.98 (3H, t, J ) 7.1 Hz); 13C NMR (CDCl3) δ
96.13, 68.35, 24.13, 20.08, 10.46; MS 134 (M+ + 1).
The following scheme was employed to verify the identity
of the products. Two of the compounds, 2-methyl-4-nitro-
hexan-3-ol and 4-nitro-1-phenyl-hex-1-en-3-ol, were fully
characterized using 1- and 2-dimensional NMR spectroscopy
and LC or GC/MS.
1
2-Nitropentan-3-ol (3). H NMR (CDCl3) diastereomer
A 50% δ 4.49 (1H, m), 4.04 (1H, dt, J ) 3.3 Hz, 6.3 Hz),
3.06 (1H, OH, bs), 1.56 (1H, m), 1.39 (1H, m), 1.49 (3H, d,
1
J ) 6.7 Hz), 0.96 (3H, t, J ) 7.4 Hz); H NMR (CDCl3)
diastereomer B 50% δ 4.49 (1H, m), 3.80 (1H, dt, J ) 3.4
Hz, 8.0 Hz), 3.06 (1H, OH, bs), 1.39 (2H, m), 1.49 (3H, d,
J ) 6.7 Hz), 0.96 (3H, t, J ) 7.4 Hz); 13C NMR (CDCl3) δ
86.53, 75.33, 26.56, 13.06, 9.72; MS 134 (M+ + 1).
The fully characterized 1H and 13C NMR spectra of these
two compounds served as a model for the interpretation of
the other analogues. For the identification of the subsequent
analogues, the GC or LC/MS spectra were analyzed for the
1
4-Nitrohexan-3-ol (4). H NMR (CDCl3) diastereomer
1
appropriate mass and the H and 13C NMR spectra were
A 60% δ 4.34 (1H, m), 3.83 (1H, m), 2.73 (OH, bs), 2.15-
1.75 (2H, m), 1.70-1.35 (2H, m), 1.00 (3H, t, J ) 7.4 Hz),
0.95 (3H, t, J ) 7.4 Hz); 1H NMR (CDCl3) diastereomer B
40% δ 4.39 (1H, m), 3.91 (1H, m), 2.73 (OH, bs), 2.15-
1.75 (2H, m), 1.70-1.35 (2H, m), 0.99 (3H, t, J ) 7.4 Hz),
0.96 (3H, t, J ) 7.4 Hz); 13C NMR (CDCl3) δ 94.08, 73.49,
26.75, 21.66, 11.11, 10.32; MS 148 (M+ + 1), 147 (M+).
analyzed for the appropriate chemical shifts and coupling
pattern. The following abbreviations are used to report NMR
data: s ) singlet, d ) doublet, t ) triplet, q ) quartet, b )
broad, and m ) multiplet. The LC/MS data were acquired
at the Bristol-Myers Squibb Pharmaceutical Research Insti-
tute using a Shimadzu SCL-10AD VP HPLC chromatograph
equipped with a Waters Micromass ZQ mass spectrometer.
The GC/MS data was collected using a Hewlett-Packard HP
6890 series GC system with a Hewlett-Packard 5973 mass
selective detector. The melting points were determined using
a Thomas-Hoover capillary melting point apparatus and
were uncorrected.
General Procedure for the Preparation of Nitroalco-
hols. A typical experimental procedure is as follows:
n-Propionaldehyde (3.67 g, 57 mmol) was added via a
syringe to a stirred mixture of 1-nitropropane (5 g, 56 mmol),
aq KOH (60 mg of saturated aqueous solution), and TritonX-
405 (60 mg) kept at 60 °C over a period of 30 min. The
reaction mixture was stirred at 60 °C for 1.5 h, at the end of
which the complete disappearance of starting material and
the formation of the two diastereomeric nitroalchol products
were observed by HPLC analysis. The following isocratic
reverse phase HPLC procedure was used: mobile phase 50/
50 acetonitrile/water (0.1% phosphoric acid), 4.6 mm × 25
cm Altech Hypersil ODS (C18) column, and 0.8 mL/min flow
1
4-Nitroheptan-3-ol (5). H NMR (CDCl3) δ 4.83 (1H,
m), 3.85 (m, 1H), 3.20 (m, 1H), 2.10 (s, 1 H), 1.90 (m, 2H),
1.5 (m, 2H), 0.95 (m, 6H); 13C NMR (CDCl3) δ 88.22, 72.75,
33.7, 27.05, 18.98, 13.25, 7.0; MS 162 (M + 1).
5-Nitrooctan-4-ol (6). 1H NMR (CDCl3) diastereomer A
60% δ 4.39 (1H, m), 3.89 (1H, m), 1.99 (2H, m), 1.74 (1H,
m), 1.41 (5H, m), 0.97 (3H, t, J ) 7.3 Hz), 0.96 (3H, t, J )
7.3 Hz); 1H NMR (CDCl3) diastereomer B 40% δ 4.47 (1H,
m), 4.02 (1H, dt, J ) 4.0 Hz, 8.3 Hz), 1.99 (2H, m), 1.74
(1H, m), 1.41 (5H, m), 0.97 (3H, m), 0.96 (3H, m); 13C NMR
(16) We did not perform any extensive safety studies. In general, nitroalkanes
have low flammability, but they are often chemically unstable. Since the
reactions are conducted in the liquid phase, safety should be less of an issue.
Also, these reactions could potentially be conducted in a continuous or
semicontinuous mode in a flow reactor where only small amount of substrate
comes in contact with the reagent at any given time, instead of a batch
mode, to make the process even safer. The following EPA web page is a
source of excellent information about the safety of reactive groups in-
cluding nitro compounds. [http://www.epa.gov/ceppo/cameo/help/chaptera.
htm#913100].
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(CDCl3) δ 93.15, 72.23, 35.96, 35.59, 19.23, 18.87, 14.10,
13.64; MS 176 (M+ + 1).
4.525 (m, 1H), 3.63 (s, 1H), 1.75 (m, 2H), 0.99 (t, 3H); 13
C
NMR (CDCl3) δ 136.07, 129.52, 129.13, 128.89, 128.72,
95.30, 77.97, 24.30, 10.98; LCMS m/z 222.18 (M+ + 1);
mp 41 °C (dec).
2-Methyl-4-nitrohexan-3-ol (10). 1H NMR diastereomer
A δ 4.5 (1H, m), 3.68 (1H, dd, J ) 5.1 Hz, 6.8 Hz), 2.10
(1H, m), 1.73 (2H, m), 1.02-0.90 (9H, m); 1H NMR (CDCl3)
diastereomer B δ 4.5 (1H, m), 3.75 (1H, t, J ) 5.5 Hz),
1.95 (1H, m), 1.83 (2H, m), 1.02-0.90 (9H, m); 13C NMR
(CDCl3) δ 92.33, 76.70, 30.88, 24.2, 20.01, 16.24, 10.50;
MS 162 (M+ + 1), 161 (M+).
1
3-Nitroheptan-4-ol (7). H NMR (CDCl3) diastereomer
A 60% δ 4.39 (1H, m), 3.95 (1H, m), 2.8 (1H, OH, bs),
2.06 (2H, m), 1.89 (1H, m), 1.46 (3H, m), 0.97 (6H, m); 1H
NMR (CDCl3) diastereomer B 40% δ 4.39 (1H, m), 4.03
(1H, m), 2.8 (OH, bs), 2.06 (2H, m), 1.89 (1H, m), 1.46
(3H, m), 0.97 (6H, m); 13C NMR (CDCl3) δ 94.37, 71.98,
35.86, 21.94, 18.58, 13.99, 10.52; MS 162 (M+ + 1).
1
4-Nitro-1-phenylhexan-3-ol (8). H NMR (CDCl3) di-
astereomer A 60% δ 7.40-7.15 (5H, m), 4.41 (1H, m), 3.90
(1H, m), 2.6-3.0 (2H, m), 2.17 (1H, OH, d, J ) 7.7 Hz),
1
2.09 (2H, m), 1.83 (2H, m), 0.98 (3H, t, J ) 7.4 Hz); H
Acknowledgment
NMR (CDCl3) diastereomer B 40% δ 7.40-7.15 (5H, m),
4.41 (1H, m), 4.05 (1H, m), 2.6-3.0 (2H, m), 2.40 (1H, OH,
d, J ) 4.0 Hz), 2.09 (2H, m), 1.83 (2H, m), 1.00 (3H, t, J )
7.3 Hz); 13C NMR (CDCl3) δ 141.19, 129.00, 128.73,126.65,
94.3,71.7, 35.3, 21.89, 10.75; MS 224 (M+ + 1); mp 41 °C.
4-Nitro-1-phenylhex-1-en-3-ol (9). 1H NMR (CDCl3) δ
7.45 (m, 5H), 6.7 (m, 1H), 6.175 (m, 1H), 4.66 (m, 1H),
Partial financial support provided by the Bristol Myers
Squibb Corporation and Robert A. Welch Foundation is
gratefully acknowledged.
Received for review October 3, 2002.
OP020222C
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