Cyclen-catalyzed Henry reaction under neutral conditions

Article abstract of DOI:10.1016/j.tetlet.2010.06.106

A convenient cyclen-catalyzed Henry reaction of aldehydes with nitroalkanes under mild and neutral conditions is reported. This procedure constitutes the first cyclen-catalyzed synthesis of nitroalcohols and is adapted to the condensation of both aromatic and aliphatic aldehydes with nitromethane in THF at room temperature without addition of stoichiometric amount of the base. A wide range of substrates, β-nitroalcohols, were obtained in moderate to good yields (up to 98%) using this methodology.

Full text of DOI:10.1016/j.tetlet.2010.06.106

Tetrahedron Letters 51 (2010) 4555–4557
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Tetrahedron Letters
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Cyclen-catalyzed Henry reaction under neutral conditions
*
Chloé Vovard-Le Bray, Fan Jiang, Xiao-Feng Wu, Jean-Baptiste Sortais, Christophe Darcel
UMR 6226 CNRS-Université de Rennes 1 ‘Sciences Chimiques de Rennes’, Equipe ‘Catalyse et Organométalliques’, Campus de Beaulieu, Bat 10C, Avenue du Général
Leclerc, 35042 Rennes Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient cyclen-catalyzed Henry reaction of aldehydes with nitroalkanes under mild and neutral
conditions is reported. This procedure constitutes the first cyclen-catalyzed synthesis of nitroalcohols
and is adapted to the condensation of both aromatic and aliphatic aldehydes with nitromethane in
THF at room temperature without addition of stoichiometric amount of the base. A wide range of sub-
strates, b-nitroalcohols, were obtained in moderate to good yields (up to 98%) using this methodology.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 30 April 2010
Revised 20 June 2010
Accepted 22 June 2010
Available online 25 June 2010
Keywords:
Organocatalysis
Henry reaction
b-Nitroalcohols
Cyclen
Aldehydes
The Henry reaction (or nitroaldol reaction) discovered in 18951
is an efficient method for C–C bond construction, the result of the
reaction of a nitroalkane with an electrophilic carbonyl derivative
(aldehyde or ketone). This reaction became very popular because
the resulting b-nitroalcohols are highly valuable synthons for the
preparation of useful intermediates in synthetic organic chemis-
try.2 Their preparation in high yield and selectivity following a safe
and economic procedure is still challenging. The scope of this reac-
tion depends largely on the nature of the catalyst used as well as
on the reaction conditions and has already been described in sev-
eral reviews.3 Among the large variety of catalysts which are
known in this reaction, alkali metal bases and alkaline alkoxides
in alcoholic solution,4 simple amines,5 ammonium salts,6 guani-
dine derivatives,7 organo-phosphorus derivatives,8 and lithium-
aluminum hydride9 were used successfully. Furthermore, asym-
metric versions of this reaction were reported since the pioneering
report of Shibasaki.10
83% yield. While this result appeared promising, control experi-
ments proved to be even more enlightening. In the presence of
5 mol % of Fe2(SO4)3ÁxH2O without the cyclen ligand no nitroaldol
product 3a was detected while cyclen alone gave a very good con-
Cyclen
HN
HN
NH
NH
O
(5 mol%)
OH
+ CH3NO2
Cyclen =
NO2
R
H
r.t.
R
Scheme 1. Cyclen-catalyzed Henry reaction of aldehydes with nitromethane.
Table 1
Optimization of the reaction conditionsa
O
Cyclen (5 mol%)
THF, rt, 24 h
OH
We described herein our preliminary results concerning the cy-
clen-catalyzed addition of nitoalkanes to aldehydes using an effi-
cient and mild procedure (Scheme 1).
+ CH3NO2
NO2
Ph
H
Ph
1a
2
3a
In the course of our research program on iron-catalyzed reac-
tions,11 and in the light of the use of a cyclen/iron system to pro-
mote direct C-arylation,12 we decided, in an initial attempt to
synthesize nitroalcohol from benzaldehyde (1 mmol) and nitro-
methane (2 mmol) in THF, to use a combination of Fe2(SO4)3ÁxH2O
and cyclen as a catalyst (5 mol %) for the Henry reaction. Starting
with benzaldehyde provided the desired nitroaldol product 3a in
Entry
Cyclen (mol %)
CH3NO2 (equiv)
Yieldb (%)
1
2
3
4
5
/
2
0
25
86
85
80
5
5
5
5
Solventc
2
5
10
a
Experimental conditions: benzaldehyde (1 mmol), nitromethane, cyclen (2–
10 mol %) in 1 mL of THF for 24 h.
b
Determined by NMR.
Nitromethane was used as the solvent instead of THF.
* Corresponding author. Tel.: +33 2 23 23 62 71; fax: +33 2 23 23 69 39.
E-mail address: christophe.darcel@univ-rennes1.fr (C. Darcel).
c
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.106

4556
C. Vovard-Le Bray et al. / Tetrahedron Letters 51 (2010) 4555–4557
version, implicating cyclen as the active catalyst (Table 1, entry 3).
Control experiments in the absence of cyclen (Table 1, entry 1)
show no reaction and confirmed the crucial role of the tetraaza-
macrocycle catalyst played in the described transformation.
A systematic study was then undertaken to define the best reac-
tion conditions, and Table 1 lists the representative data obtained
for the synthesis of 2-nitro-1-phenylethanol 3a under various
experimental conditions.
In general, 5 mol % of cyclen was applied as the catalyst in THF
and the reaction mixture was stirred at room temperature for 24 h.
First of all, when cyclen was employed as the catalyst (5 mol %),
in nitromethane as the solvent, low conversion was observed (25%,
Table 1, entry 2). Among the different amounts of nitromethane
used in THF as the solvent, the best result was achieved when
the reaction was performed with 2 equiv, furnishing the 2-nitro-
1-phenylethanol 3a in 86% conversion (Table 1, entry 3). Hence,
the optimized conditions found for the synthesis of 2-nitroalcohols
starting from aldehyde and nitromethane are the use of 1 equiv of
aldehyde, 2 equiv of nitromethane in the presence of 5 mol % of cy-
clen in THF at room temperature for 24 h under air.
hydes bearing electron-donating groups such as p-anisaldehyde
also reacted under our general conditions, but the reaction did
not go to completion, resulting in 30–75% of the corresponding
nitroalcohol (Table 2, entries 9–11). In these cases, the reactions
were clean and no dehydration of 2-nitroalcohols to the corre-
sponding nitroalkenes was observed in the crude reaction mixture
in 1H NMR and the conversion determined by 1H NMR was in the
same range as the isolated yields. Furthermore, the reaction did
not proceed when a free phenolic hydroxyl or a dimethylamino
moiety was present on the aromatic ring.
Principles of this cyclen-catalyzed Henry reaction can also be
extended to heterocyclic aldehydes. Thus, 2-pyridylaldehyde could
be smoothly converted into 1-pyridyl-2-nitroethanol 3l in 62% iso-
lated yield (Table 2, entry 12). When 2-furaldehyde, 3-furaldehyde,
and 2-thiophenealdehyde were used, the corresponding 2-nitroal-
cohols 3m–o were isolated in 55%, 62%, and 55% yield, respectively
(Table 2, entries 13–15). It must be pointed out that to obtain
cleanly these heteroarylnitroalcohols, the reaction must be con-
ducted under argon at 5 °C. Furthermore, at the end of the reaction
the reaction mixture had to be washed with a 1-M HCl solution to
remove the cyclen catalyst and avoid any degradation of the nitro-
alcohol derivatives.
In order to prove the generality of the method, various aliphatic
aldehydes were condensed with nitromethane and the results ob-
tained are summarized in Table 2 (entries 18 and 19).
We successfully extended the procedure to include other nitro-
alkanes such as nitroethane (entry 16) and nitropropane (entry
17). In these cases, the reactions proceeded at room temperature
for 24 h and led to the corresponding nitroalcohols in moderate
isolated yields (50–51%).
In conclusion, we have developed a cyclen-catalyzed Henry
reaction which involves an efficient and simple method providing
in most cases the desired b-nitroalcohol in moderate to good
yields. Cyclen catalyst is shown to be highly efficient especially
in terms of milder reaction conditions (room temperature, with
5 mol % of cyclen and 2 equiv of nitroalkane). It should be under-
lined that the mild reaction conditions and the easy work up pre-
vents typical side reactions usually observed while using amines as
catalysts such as the retro-aldol reaction, the dehydration of the 2-
nitro alcohol into nitroalkene even if aromatic aldehydes are used,
or the formation of 1,3-dinitroalkene derivatives.
The substrate scope was then investigated. A variety of alde-
hydes and nitroalkanes were tested under the optimized condi-
tions using cyclen as the catalyst (Table 2). As shown in Table 2,
b-nitroalcohols 3 are obtained in good to excellent yields; it should
be underlined that the by-products resulting from typical side
reactions such as the retro-aldol reaction1 or the dehydration of
the 2-nitroalcohol into nitroalkene13 were not observed due to
the mild reaction conditions.
It turned out that this cyclen-catalyzed Henry reaction could
adapt to various aldehydes. For arylaldehydes bearing electron-
withdrawing groups, the reaction proceeded smoothly and gave
rise to the corresponding b-nitroalcohols 3b–f in moderate to good
isolated yields ranging from 75% to 98% (Table 2, entries 2–6)14
.
Interestingly, when the reaction was performed with m- and o-bro-
mobenzaldehyde, the corresponding 2-nitroalcohols 3g–h were
obtained in 97% and 70% isolated yields, which shows that the
meta- or ortho-substituents did not hamper the reaction. Arylalde-
Table 2
Scope of the reactiona
O
Cyclen (5 mol%)
THF, rt
OH
+ R2-NO2
Acknowledgments
R1
H
NO2
R1
1
2
3
We are grateful to the CNRS, the University of Rennes 1, Rennes
Métropole council, and the Ministère de l’Enseignement Supérieur
et de la Recherche for providing the financial support. We also thank
ProfessorF. Denat(UniversitédeBourgogne, France)and Dr. Frédéric
Boschetti (Chematech, Dijon, France) for the gift of cyclen.
Entry
R1
R2
Time
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
24 h
22 h
24 h
24 h
19 h
24 h
22 h
22 h
21 h
23 h
24 h
23 h
24hb
24 hb
24 hb
24 h
24 h
24 h
24 h
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
80
78
88
98
90
75
97
70
30
62
75
62
55
62
55
50
51
70
71
4-NO2–C6H4
4-NC–C6H4
4-F3C–C6H4
4-Ph–C6H4
4-Br–C6H4
3-Br–C6H4
2-Br–C6H4
4-MeO–C6H4
3,4,5-(MeO)3–C6H2
3,5-(MeO)2–C6H3
Pyrid-2-yl
Furan-2-yl
Furan-3-yl
Thiophen-2-yl
Ph
Supplementary data
Supplementary data (typical experimental procedures and cop-
ies of 1H and 13C NMR spectra of all the products) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.06.106.
References and notes
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Yoshimura, J. J. Org. Chem. 2008, 73, 1234–1242; (c) Li, Y.; Feng, J. P.; Wang, W.
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Ph
Pr
Me
Me
Cyclohexyl
Propyl
a
Experimental conditions: aldehyde (1 mmol), nitroalkane (2 mmol), cyclen
(0.05 mmol, 5 mol %) in 1 mL of THF.
b
The reaction was performed at 5 °C under argon.

C. Vovard-Le Bray et al. / Tetrahedron Letters 51 (2010) 4555–4557
4557
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14. Representative experimental procedure: In
a 10-mL vial equipped with a
magnetic stirring bar, 2 mmol (105 L) of nitromethane was added to the
l
solution of 3-bromobenzaldehyde (185 mg, 1 mmol) in tetrahydrofuran
(1 mL). Cyclen (8.6 mg, 0.05 mmol, 5 mol %) was then added. The solution
was stirred at room temperature for 16 h. Volatile components were then
removed under reduced pressure and the product was isolated by column
chromatography over silica gel with mixed solvent (pentane/diethyl ether) to
give a clear yellow oil (97% isolated yield). 1H NMR (300 MHz, CDCl3): d 2.95 (s,
1H), 4.47–4.62 (m, 2H), 5.43 (dd, 1H, J = 3.3, 9.0), 7.25–7.34 (m, 2H), 7.49 (m,
1H), 7.58 (m, 1H). 13C{1H} NMR (75 MHz, CDCl3): d 140.2, 132.0, 130.6, 129.1,
124.5, 123.1, 80.9, 70.2.