Facile and highly stereoselective one-pot synthesis of either (E)- or (Z)-nitro alkenes

Article abstract of DOI:10.1021/ol800224k

(Chemical Equation Presented) Aliphatic aldehydes were reacted with nitro alkanes in the presence of catalytic amounts of piperidine over 4 A molecular sieves. Simply by changing reaction conditions (solvent and temperature) it is possible to control the stereochemical outcome of the reactions, obtaining pure (E)- and (Z)-nitro alkenes in high to excellent yields. The role of molecular sieves on the stereochemical control seems crucial in addition to that of piperidine, especially for the synthesis of the Z isomer.

Full text of DOI:10.1021/ol800224k

ORGANIC
LETTERS
2
008
Vol. 10, No. 7
449-1451
Facile and Highly Stereoselective
One-Pot Synthesis of Either (E)- or
1
(Z)-Nitro Alkenes
Stefania Fioravanti,* Lucio Pellacani,* Paolo A. Tardella,* and
Maria Cecilia Vergari
Dipartimento di Chimica, UniVersit a` degli Studi “La Sapienza”, P.le Aldo Moro 2,
I-00185 Roma, Italy
lucio.pellacani@uniroma1.it
Received January 31, 2008
ABSTRACT
Aliphatic aldehydes were reacted with nitro alkanes in the presence of catalytic amounts of piperidine over 4 Å molecular sieves. Simply by
changing reaction conditions (solvent and temperature) it is possible to control the stereochemical outcome of the reactions, obtaining pure
(E)- and (Z)-nitro alkenes in high to excellent yields. The role of molecular sieves on the stereochemical control seems crucial in addition to
that of piperidine, especially for the synthesis of the Z isomer.
5
Conjugated nitro alkenes have proved to be versatile
compounds that have widespread use in organic chemistry.
They are powerful electrophiles that readily undergo Diels-
Alder reaction or Michael addition with many different
nitro alkane, followed by the dehydration of the resulting
â-nitro alcohol (Scheme 1). The Henry reaction is one of
1
nucleophiles. This peculiar reactivity is due to the electron-
Scheme 1. Classical Synthesis of (E/Z)-Nitro Alkene Mixtures
withdrawing nature of the nitro group, which represents a
very important functionality in organic synthesis due to its
2
easy conversion into a variety of functionalities. Moreover,
conjugated nitro alkenes are important because of their
biological use as insecticides, fungicides, and pharmacologi-
cally active substances.3
The most common two-step preparation of nitro alkenes
4
is the Henry reaction between a carbonyl compound and a
the typical C-C bond-formation processes and is commonly
performed under mild conditions. On the contrary, the
dehydration step can require harsh conditions, which strongly
influence the overall yield. The E isomer is obtained as the
(
1) (a) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701-1716. (b) Ballini,
R.; Palmieri, A.; Fiorini, D. ARKIVOC 2007, 172-194. (c) Almasi, D.;
Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299-365.
(
d) Bianchi, L.; Maccagno, M.; Petrillo, G.; Sancassan, F.; Spinelli, D.;
Tavani, C. In Targets in Heterocyclic Systems: Chemistry and Properties;
Attanasi, O. A., Spinelli, D., Eds.; Societ a` Chimica Italiana: Rome, 2006;
Vol. 10, pp 1-23. (e) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.;
Petrini, M. Chem. ReV. 2005, 105, 933-971. (f) Berner, O. M.; Tedeschi,
L.; Enders, D. Eur. J. Org. Chem. 2002, 1877-1894. (g) Barrett, A. G.
M.; Graboski, G. G. Chem. ReV. 1986, 66, 751-762.
(3) (a) Bhaduri, A. P. Synlett 1990, 557-564. (b) Talalay, P.; De Long,
M. J.; Prochaska, H. J. Proc. Natl. Acad. Sci. U.S.A. 1988, 85, 8261-
8265. (c) Alston, T. A.; Porter, D. J. T.; Bright, H. J. Bioorg. Chem. 1985,
13, 375-403. (d) Averbeck, D.; Averbeck, S.; Rene, L.; Buisson, J. P.;
Royer, R. Eur. J. Med. Chem. 1980, 15, 539-544.
(4) Henry, L. C. R. Hebd. Seances Acad. Sci. 1895, 120, 1265-1270.
(5) Rewiews: (a) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem.
2007, 2561-2574. (b) Boruwa, J.; Gogoi, N.; Saikia, P. P.; Barua, N. C.
Tetrahedron: Asymmetry 2006, 17, 3315-3326. (c) Luzzio, F. A. Tetra-
hedron 2001, 57, 915-945.
(
2) (a) Ballini, R.; Fiorini, D.; Maggi, R.; Oro, C.; Palmieri, A.; Sartori,
G. Synlett 2006, 1849-1850. (b) Lee, J. Y.; Hong, Y.-T.; Kim, S. Angew.
Chem., Int. Ed. 2006, 45, 6182-6186. (c) Ballini, R.; Barboni, L.; Fiorini,
D.; Palmieri, A.; Petrini, M. ARKIVOC 2006, 127-152. (d) Mendler, B.;
Kazmaier, U. Org. Lett. 2005, 7, 1715-1718.
1
0.1021/ol800224k CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/27/2008

1
only or the major product, the Z isomer being always the
minor product.
was obtained, as confirmed by H NMR analysis performed
6
on the crude mixtures. A simple filtration under argon
To the best of our knowledge, only one stereoselective
multistep sequence was reported to obtain (Z)-nitro alkenes,
involving the stereospecific nitroselenylation procedure start-
2 2
through plugs of celite using CH Cl as eluent gives the pure
isomer in very good yields. The method seems to suffer from
steric hindrance (entries 7 and 8) when the reactions were
7
11
ing from unfunctionalized symmetric alkenes, and there is
performed at room temperature; on the contrary the pure
1
2
no direct access to Z compounds available. Few examples
of stereoselective isomerization of (E)-nitro alkenes have
E isomers 9 and 10 were obtained when working at reflux
of toluene.
8
been reported to obtain the corresponding Z isomers.
To obtain information on the different stereochemical
outcome observed by varying the reaction temperature and
on the role played by molecular sieves, the condensation
reaction between 1c and 2a was performed at different temp-
eratures without the presence of molecular sieves (Table 2).
Being interested into the synthesis and reactivity of EWG-
9
substituted alkenes, here we report the first results of a
simple and efficient one-pot method to obtain the stereose-
lective synthesis of (E)- or (Z)-nitro alkenes, by changing
only the solvent and the reaction temperature.
Aliphatic aldehydes 1a-e were reacted with nitro alkanes
a,b in the presence of catalytic amounts of piperidine over
10
2
Table 2. Condensation Reactions Performed without Molecular
Sieves
4
Å molecular sieves (MS), using toluene at reflux or
methylene chloride at room temperature under anhydrous
conditions and inert atmosphere (Ar). In these conditions only
(E)-nitro alkenes 4-10 or (Z)-nitro alkenes 3-8 were
obtained in high to excellent yields. The results are reported
in Table 1.
solvent
temp
rt
rt
115 °C
time, h
E/Za
conversion, %b
Table 1. Stereoselective One-Pot Synthesis of (Z)- or (E)-Nitro
Alkenes
PhCH3
CH Cl
1
1
4
1/1
1.1/1
1.3/1
67
70
73
2
2
PhCH3
a
By H NMR. b Calculated from the crude mixture by H NMR with
1
1
respect to aldehydic proton.
As shown in Table 2, the synthesis of nitro alkenes occurs
unexpectedly in all conditions, but leading to an E/Z
1
3
mixture.
Consequently, molecular sieves seem to affect mainly the
stereoselectivity of the reaction. To gain further data, the
â-nitro alcohol 11 was synthesized through a typical Henry
reaction and allowed to react under the same conditions used
for the one-pot synthesis of E- and Z-nitro alkene 7 (Scheme
nitro
alkene
yield, % Z
(method A)
yield, % E
(method B)
a
a
entry
R
R′
6d
1
2
3
4
5
6
7
8
3
4
5
6
7
8
9
10
Et
Et
Bu
Me
Et
Me
Et
Me
Et
Me
Me
93
86
90
89
95
90
c
b
86
92
83
81
87
96
79
2
).
While the dehydration reaction takes place at reflux in
toluene in the presence of either piperidine or triethylamine,
Bu
pentyl
pentyl
i-Bu
t-Bu
1
4
giving as expected only the E isomer 7, no reaction was
promoted in CH Cl and 11 was recovered as the only
product even after 24 h.
c
2
2
a
After filtration of the crude mixture on celite. b Bp of 2a is too low.
c
No nitro alkenes were detected.
(9) (a) Fioravanti, S.; Marchetti, F.; Pellacani, L.; Ranieri, L.; Tardella,
P. A. Tetrahedron: Asymmetry 2008, 19, 231-236. (b) Fioravanti, S.;
Pellacani, L.; Tardella, P. A.; Morreale, A.; Del Signore, G. J. Comb. Chem.
As reported in Table 1, the synthesis of nitro alkenes is
highly stereoselective, and in all cases only the E or Z isomer
2
006, 8, 808-811. (c) Fioravanti, S.; Morreale, A.; Pellacani, L.; Tardella,
P. A. Synlett 2004, 1083-1085.
10) Using a stoichiometric amount of piperidine, a complex mixture
(
was obtained, in which it was not possible to detect either nitro alkenes or
their precursors.
(
6) (a) Hubner, J.; Liebscher, J.; P a¨ tzel, M. Tetrahedron 2002, 58,
0485-10500. (b) Kawai, Y.; Inaba, Y.; Tokitoh, N Tetrahedron: Asym-
metry 2001, 12, 309-318. (c) Lee, K.; Oh, D. Y. Synth. Commun. 1989,
9, 3055-3060. (d) Knochel, P.; Seebach, D. Synthesis 1982, 1017-1018.
7) Hayama, T.; Tomoda, S.; Takeuchi, Y.; Nomura, Y. Tetrahedron
Lett. 1982, 23, 4733-4734.
8) (a) Ono, N.; Kamimura, A.; Sasatani, H.; Kaji, A. J. Org. Chem.
987, 52, 4133-4135. (b) Ono, N.; Kamimura, A.; Kawai, T.; Kaji, A.
Chem. Commun. 1987, 1550-1551.
1
(11) Attempts to obtain nitro alkenes by using a 2-fold excess of 1d and
1e, a longer reaction time, and/or CH2Cl2 at reflux failed.
(12) Kawai, Y.; Inaba, Y.; Tokitoh, N. Tetrahedron: Asymmetry 2001,
12, 309-318.
1
(
(13) For a different synthesis of (E)- and (Z)-7 see: Dumez, E.; Faure,
R.; Dulc e` re, J.-P. Eur. J. Org. Chem. 2001, 2577-2588.
(14) By using Et3N as the base traces of Z isomer were also observed in
(
1
1
H NMR spectrum of the crude mixture.
1450
Org. Lett., Vol. 10, No. 7, 2008

triethylamine instead of piperidine failed, and 1c and 2a were
recovered after 24 h.
Scheme 2. Synthesis and Dehydration of 11
In conclusion, first results of a highly stereoselective one-
pot synthesis of either (E)- or (Z)-nitro alkenes were reported.
The methodology allows an easy control of the product
configuration, and it seems especially appealing to obtain
the Z isomer in high yields, avoiding multistep and expensive
purification procedures. Further studies are in progress to
broaden the potentiality of the procedure and to better clarify
the reaction pathway.
Acknowledgment. This research was carried out within
the framework of the National Project “Stereoselezione in
Sintesi Organica. Metodologie ed Applicazioni”, supported
by the Italian Ministero dell’Istruzione dell’Universit a` e della
Ricerca (MIUR) and by the Universit a` degli Studi di Roma
“La Sapienza”. We thank Dr. Luca Ranieri for experimental
assistance.
These results support the role of molecular sieves in the
stereochemical control of the one-pot synthesis of nitro
alkenes and moreover suggest a different reaction pathway
for the synthesis of the Z isomer. The formation of this
isomer could be explained by a nucleophilic catalysis that
leads to the formation of a protonated imine as the
intermediate; this latter then can undergo the nucleophilic
attack by the nitronate, the same piperidine acting both as a
nucleophile toward the aldehyde and as a base toward the
nitro alkane. Finally an elimination gives only the Z-nitro
alkene.
Supporting Information Available: Experimental pro-
cedures, analytical and spectroscopic data for (Z)-3, (E)- and
1
13
(
Z)-4-6, 8 and H and C NMR spectra of (Z)-4 and (E)-9.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In support of our hypothesis on the role of a secondary
amine, attempts to synthesize (Z)-7 at room temperature using
OL800224K
Org. Lett., Vol. 10, No. 7, 2008
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