Preparation of novel multifunctional amino alcohols from nitroparaffins and α,β-unsaturated aldehydes

Article abstract of DOI:10.1016/j.tetlet.2012.04.078

A series of novel multifunctional amino alcohols were prepared by tandem Michael-Henry reaction by reacting nitroalkanes such as 2-nitropropane with readily available α,β-unsaturated aldehydes. The dinitro compounds were further reduced by catalytic hydro

Full text of DOI:10.1016/j.tetlet.2012.04.078

Tetrahedron Letters 53 (2012) 3322–3324
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Tetrahedron Letters
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Preparation of novel multifunctional amino alcohols from nitroparaffins
and a,b-unsaturated aldehydes
Asghar A. Peera a, , Ian A. Tomlinson b
⇑
a The Dow Chemical Company, 1500 E. Lake Cook Road, Buffalo Grove, IL, USA
b The Dow Chemical Company, 1691 N. Swede Road, Midland, MI, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel multifunctional amino alcohols were prepared by tandem Michael–Henry reaction by
Received 29 March 2012
Revised 12 April 2012
Accepted 17 April 2012
Available online 24 April 2012
reacting nitroalkanes such as 2-nitropropane with readily available a,b-unsaturated aldehydes. The dini-
tro compounds were further reduced by catalytic hydrogenation to obtain respective diamines. This syn-
thetic route provides a very convenient method of preparing multifunctional amino alcohols.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Michael addition
Henry reaction
Amino alcohol
Hydrogenation
Nitroalkane
The conjugate addition of carbanions to electron poor alkenes is
one of the most fundamental carbon–carbon bond forming reac-
tion in organic synthesis. This process is referred to as Michael
addition.1 Conjugate addition using highly stabilized carbanions
are of great interest since a growing number of reactions can be
carried out in environmentally benign solvents such as water and
using only catalytic amount of basic promoter.2 Nitroalkanes are
important source of stabilized carbanions since the high electron
withdrawing power of the nitro group provides an outstanding
advantage of the both reactive sites to introduce tandem Mi-
chael–Henry reaction to prepare dinitro alcohols (Scheme 1).
The R1 and R2 groups comes from the nitroparaffin while the R
group is dependent on the a,b-unsaturated aldehyde. This route al-
lows the efficient synthesis of highly functionalized molecules in
fewer steps and also permits the addition of a variety of moieties
ranging from long chain hydrocarbons, cyclic alkanes and aromatic
systems. The manipulation of the R1 and R2 group in the nitroal-
kane and the R group on the
a,b-unsaturated aldehydes creates
enhancement of the hydrogen acidity at the
a
-position.3–5 Nitro-
the ability to build a library of useful materials. The other advan-
tage this route provides is to obtain materials with only primary
amines which have markedly different reactivities and are antici-
pated to be very useful in combinatorial synthesis. These materials
are also anticipated to be better and more efficient neutralizers and
can be used in smaller quantities making them more cost efficient
when used in coatings or metal working formulations.
alkanes when treated with a wide variety of both organic and inor-
ganic bases can easily generate nitronate anions which act as
carbon nucleophiles and can further be reacted with common elec-
trophiles such as haloalkanes,6 aldehydes (Henry reaction),4,7 Mi-
chael acceptors leading to carbon–carbon bond formation.1 The
nitro groups can further be reduced to their respective amines by
catalytic hydrogenation.
In this study, 2-nitropropane (2-NP) was choosen as the nitro-
alkane while crotonaldehyde and cinnamaldehyde were selected
There are several reports in the open literature that talk about
Michael reactions of nitroalkanes. However, most of them are lim-
as the
a,b-unsaturated aldehydes due to their cost and availability.
ited to
a,b-unsaturated ketones, esters or amides. Achieving a
These two materials also allow an initial evaluation of the
clean Michael reaction of
a
,b-unsaturated aldehydes is thought
R
OH
to be difficult because of the competitive Henry reaction occuring
readily due to the highly reactive aldehyde. Specialized organocat-
alysts are needed to obtain the reactivity only at the alkene posi-
tion and leaving the aldehyde unreacted.8 In this report we take
NO2
R
H
Base
R1
R2
NO2
R2
+
R1
R2
O
NO2
R1
R = H, Me, Ph; R1 = H, Me, Alkyl; R2 = H.Me, Alkyl
Scheme 1. Generalized tandem Michael–Henry reaction scheme.
⇑
Corresponding author. Tel.: +1 847 808 3792; fax: +1 847 808 3708.
E-mail address: APeera@dow.com (A.A. Peera).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.078

A. A. Peera, I. A. Tomlinson / Tetrahedron Letters 53 (2012) 3322–3324
3323
structure–property relationship in a particular application due to
the difference in the moiety at the R position. The first reaction per-
formed was reacting excess 2-NP with crotonaldehyde in the pres-
ence of catalytic amount of base. Reaction depicted in Scheme 2,
gave 2,5,6-trimethyl-2,6-dinitroheptan-3-ol (1) as a white solid
in high yield.9
Several bases were evaluated including 1,1,3,3-tetramethyl-
guanidine (TMG), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and
triethylamine. When DBU was used as a base, the reaction pro-
ceeded more rapidly and the product was obtained in higher pur-
ity. The reaction was also conducted with varying the molar ratio
of crotonaldehyde to 2-NP. The amount of 2-NP used in excess
was from 2.1 to 6 equiv. At 6 equiv the reaction rapidly went to
completion, however, almost 4 equiv of 2-NP are wasted because
recovery of the nitroalkanes is typically avoided due to the poten-
tial hazards. Optimization of the reaction conditions with 2-NP
used at 2.8 M equiv with respect to crotonaldehyde gave the de-
sired product in acceptable reaction time and yield.
The reaction conditions were also studied to obtain insight into
the relative reaction kinetics of the Michael addition and the Henry
reaction. The Michael addition of the nitroalkane to the olefin of
crotonaldehyde occurs efficiently when the nitroalkanes/base solu-
tion was maintained between 0 and 10 °C, the reaction required
room temperature or higher to obtain an efficient nitroaldol reac-
tion between the aldehyde and the nitroalkane. This difference in
relative reaction conditions is maintained at ambient temperatures
and it was determined that dropwise addition of the crotonalde-
hyde to the nitroalkane at room temperature was suitable to get
both the Michael and Henry reaction to go sequentially. This reac-
tion of 2-NP with crotonaldehyde is highly exothermic and careful
monitoring of the reaction is necessary to prevent a potential run-
away reaction in scale-up. Lower temperatures are only useful if
the intention is to add only 1 equiv of nitroalkane at the alkene po-
sition and avoid getting the nitroaldol reaction. For these studies it
was desirable to drive the reactions to completion at both active
sites of the molecule.
in the presence of Raney Nickel as catalyst to give the correspond-
ing amino compounds (Scheme 4).
The reaction was run using THF as the solvent due to the dinitro
material having higher solubility (>50%) compared to methanol
where the solubility was less than 30%. The reduction reactions
were straightforward and went to completion in 2 h or less.
In the case of compound (1), the reaction was carried out at
55 °C under 600 psi of hydrogen pressure and using 10–20% by
weight of nickel catalyst. The reaction progressed well, giving the
desired compound, 2,6-diamino-2,5,6-trimethylheptan-3-ol (3) as
the major product with 2,2,3-trimethylpyrrolidine (m/z = 113,
[M+H] = 114) as a minor impurity as determined by GC/MS. It is
believed that the 2,2,3-trimethylpyrrolidine is formed as a result
of reversal of the Henry reaction in compound (1) in the autoclave.
The presence of an amine and carbonyl in the same molecule re-
sults in imine formation followed by reduction to the 2,2,3-trim-
ethylpyrrolidine. The boiling point of the impurity is sufficiently
different than the desired product and can be readily removed by
prolonged evaporation on a rotary evaporator at 55–60 °C. Com-
pound (2) was also reduced by catalytic hydrogenation under the
same conditions as adopted for the compound (1). In this case also,
the major product was the desired compound, 2,6-diamino-2,6-di-
methyl-5-phenylheptan-3-ol (4) (Scheme 3). However, some
reversal of Henry reaction was also observed, resulting in 2,2-di-
methyl-3-phenylpyrrolidine (m/z = 175, [M+H] = 176) as an impu-
rity as established by GC/MS. This material also could be
separated easily but only by Kugelrohr distillation.
The reaction sequence has been extended with other nitro
compounds. For example, nitrocyclohexane has been used with
crotonaldehyde to prepare 1,3-bis(1-nitrocyclohexyl)butan-1-ol
(5). This dinitro compound was further reduced under the same
hydrogenation conditions describe earlier to form the desired
NH2
NH2
NO2
NO2
Ni (cat), H2
THF
OH
(3)
OH
(1)
The subsequent reaction used cinnamaldehyde as the
a,b-
unsaturated aldehyde target. This allows the introduction of a phe-
nyl moiety into the product which could be of significant interest
in some applications especially when low volatile organic com-
pounds (VOC) and thermal stability is desired. The reaction condi-
tions were similar to those used for efficient conversion of
crotonaldehyde. Once again the best results to get 2,6-dimethyl-
2,6-dinitro-5-phenylheptan-3-ol (2)10 was with dropwise addition
of the cinnamaldehyde at room temperature in the presence of
DBU (Scheme 3).
NO2
NO2
NH2
NH2
Ni (cat), H2
THF
OH
(2)
OH
(4)
Compounds (1) and (2) obtained from the tandem Michael–
Henry reaction were further hydrogenated under high pressure
Scheme 4. Reduction reaction of compounds (1) and (2) to get the desired diamino
materials.
NO2
NO2
NO2
H3C
H
NO2
O
DBU (cat)
OH
OH
O2N
NO2
H3C
O
(1)
H
DBU (cat)
Scheme 2. Reaction of crotonaldehyde with 2-NP.
(5)
OH
OH
NO2
NO2
NO2
H2N
NH2
O2N
NO2
Ni (cat), H2
THF
O
OH
(2)
H
DBU (cat)
(5)
(6)
Scheme 5. Reaction scheme to prepare 1,3-bis(1-nitrocyclohexyl)butan-1-ol (5)
and 1,3-bis(1-aminocyclohexyl)butan-1-ol (6).
Scheme 3. Reaction of cinnamaldehyde with 2-NP.

3324
A. A. Peera, I. A. Tomlinson / Tetrahedron Letters 53 (2012) 3322–3324
amino alcohol that is 1,3-bis(1-aminocyclohexyl)butan-1-ol (6)
(m/z = 268.3, [M+H] = 269.3) (Scheme 5)
GC–MS of all new compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.04.078.
In summary, we have developed an efficient two steps route to
preparing multifunctional amino alcohols. The first step allows us
to obtain dinitro compounds by tandem Michael–Henry reaction
followed by catalytic hydrogenation as the second step of the se-
quence. These novel multifunctional materials can be used in a
variety of applications such as neutralizer in coatings and personal
care, curing agents and crosslinkers for epoxy and polyurethane
applications, gas scavengers and corrosion inhibitors.11
References and notes
1. Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon
Press: Oxford, 1992.
2. Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem. Rev. 2005, 105,
933.
3. Rosini, G.; Ballini, R. Synthesis 1988, 833.
4. Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, 2001.
5. Patai, S. The Chemistry of Amino, Nitroso, Nitro and Related Groups; Wiley:
Chichester, 1996.
Acknowledgment
6. Seebach, D.; Lehr, F. Angew. Chem., Int. Ed. Engl. 1976, 15, 505.
7. Luzzio, F. Tetrahedron 2001, 57, 915.
8. (a) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307; (b) Manzano, R.;
Andrés, J.; Álvarez, R.; Muruzábal, M.; de Lera, A.; Pedrosa, R. Chem. Eur. J. 2011,
17, 5931.
The authors would like to thank Dr. Li Wang for providing ana-
lytical support in characterizing all the new materials reported in
the manuscript
9. Smith, C. W. U.S. Patent 1949, US 2475996 19490712.
10. Black, D.; Boscacci, A. Aust. J. Chem. 1976, 29, 2511.
11. Peera, A.; Tomlinson, I. U.S. Patent 2011 US 20110152574; Peera, A.;
Tomlinson, I. U.S. Patent 2011 US 20110152401; Peera, A.; Tomlinson, I. U.S.
Patent 2011 US 20110147649; Peera, A.; Tomlinson, I. U.S. Patent 2011 US
20110152407.
Supplementary data
Supplementary data (detailed experimental procedures, full
characterization, copies of 1H, 13C and 13C DEPT-135 NMR and