An efficient synthesis of nitroalkenes by alkene cross metathesis: Facile access to small ring systems

Article abstract of DOI:10.1021/ol070557k

Equation Presented A synthesis of highly functionalized nitroalkenes is reported that utilizes a cross metathesis (CM) reaction between simple aliphatic nitro compounds and a range of substituted alkenes. This chemistry offers a simple and attractive route to nitroalkenes that would otherwise be difficult to prepare, and that have a very useful application as precursors to a variety of heterocyclic entities.

Full text of DOI:10.1021/ol070557k

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2613-2616
An Efficient Synthesis of Nitroalkenes
by Alkene Cross Metathesis: Facile
Access to Small Ring Systems
Graham P. Marsh,† Philip J. Parsons,*,† Clive McCarthy,‡ and
Xavier G. Corniquet†
Department of Chemistry, School of Life Sciences, UniVersity of Sussex, Falmer,
Brighton, BN1 9QJ, United Kingdom, and NoVartis Institutes for Biomedical Research,
Lichtstrasse 35, CH-4056 Basel, CH, Switzerland
p.j.parsons@sussex.ac.uk
Received March 6, 2007
ABSTRACT
A synthesis of highly functionalized nitroalkenes is reported that utilizes a cross metathesis (CM) reaction between simple aliphatic nitro
compounds and a range of substituted alkenes. This chemistry offers a simple and attractive route to nitroalkenes that would otherwise be
difficult to prepare, and that have a very useful application as precursors to a variety of heterocyclic entities.
The chemistry of the nitro group is very wide-ranging in
organic synthesis.1 Carreira has recently demonstrated that
optically pure nitroalkanes can be converted, while retaining
optical integrity, into aldoximes, which are convenient
precursors of nitriles2 and nitrile oxides.3 Aside from the
nitroaldol (Henry) reaction, the introduction of a nitro group
is commonly effected by the displacement of a halide with
a nitrite anion,4 but this reaction can often be unreliable with
sensitive or highly functionalized haloalkanes. Addressing
this challenge, Ballini and co-workers have recently shown
that the use of silver nitrite in aqueous media5 is a more
robust and effective protocol, in certain cases, than the use
of sodium or silver nitrite in solvents such as dimethyl-
formamide or dimethyl sulfoxide.
Alkene metathesis6 has become a fundamental carbon-
carbon bond-forming tool for organic chemists, seeing wide
application in many areas, including total syntheses of
complex natural products and polymer chemistry.
In particular, the well-known cross metathesis (CM)
reaction7 has been extensively employed to form a range of
substituted alkenes. The development of potent catalysts8 to
execute this type of transformation, coupled with an ever
† University of Sussex.
‡ Novartis.
(1) Barrett, A. G. M.; Graboski, G. G. Chem. ReV. 1986, 86, 751.
(2) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2005, 44, 612.
(3) (a) Torsell, K. B. G. Nitrile Oxides, Nitrones and Nitronates in
Organic Synthesis; VCH: Weinhelm, Germany, 1988; (b) Larsen, K. E.;
Torsell, K. B. G. Tetrahedron 1984, 40, 2985.
(4) Kornblum, N.; Larson, H. O.; Blackwood, R. K.; Mooberry, D. D.;
Oliveto, E. P.; Graham, G. E. J. Am. Chem. Soc. 1956, 78, 1497.
(5) Ballini, R.; Barboni, L.; Giarlo, G. J. Org. Chem. 2004, 69, 6907.
(6) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4490. (b) Grubbs, R. H. Tetrahedron 2004, 60, 7117. (c)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
10.1021/ol070557k CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/06/2007

Table 1. Functionalized Aliphatic Nitro Compounds by CM
a (E) exclusively (1H NMR).
improving model to understand and predict selectivity,9
makes this reaction a powerful tool for the introduction of a
plethora of functionality. To illustrate, CM has lately been
reported with amide- and urea-functionalized olefins10 and
also with vinyl boronates.11 In addition to instances of the
application of CM to the construction of natural products, a
number of accounts have amassed in the recent literature of
CM being used in sequential catalysis and tandem pro-
cesses.12
required an efficient method for the production of highly
substituted nitro compounds.
Hitherto, to our knowledge no example of a cross
metathesis reaction to form substituted aliphatic nitro olefins
has been reported.
When 6-nitrohex-1-ene 1 was treated with tert-butyl
acrylate and Grubbs second generation catalyst16 in boiling
(12) Recent examples: (a) Beligny, S.; Eibauer, S.; Maechling, S.;
Blechert, S. Angew. Chem., Int. Ed. 2006, 45, 1900. (b) Gebauer, J.; Blechert,
S. J. Org. Chem. 2006, 71, 2021. (c) Finnegan, D.; Seigal, B. A.; Snapper,
M. L. Org. Lett. 2006, 8, 2603. (d) Hodgson, D. M.; Angrish, D.; Labande,
A. H. Chem. Commun. 2006, 6, 627. (e) Lee, C.-H. A.; Loh, T.-P.
Tetrahedron Lett. 2006, 47, 809. (f) Gebauer, J.; Dewi, P.; Blechert, S.
Tetrahedron Lett. 2005, 46, 43.
In our laboratory we have for some time been interested
in isoxazolines,13,14 and also more broadly in the general area
of nitrile oxide cycloaddition chemistry.14,15 As such, we have
(7) (a) Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900.
(b) Blackwell, H. E.; O’Leary, D. J.; Chatterjee, A. K.; Washenfelder, R.
A.; Bussmann, D. A.; Grubbs, R. H. J. Am. Chem. Soc. 2000, 122, 58.
(8) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(9) Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(10) Forment´ın, P.; Gimeno, N.; Steinke, J. H. G.; Vilar, R. J. Org. Chem.
2005, 70, 8235.
(11) Morrill, C.; Grubbs, R. H. J. Org. Chem. 2003, 68, 6031.
(13) Pennicott, L.; Lindell, S. Synlett 2006, 3, 463.
(14) Parsons, P. J.; Charles, M. D.; Harvey, D. M.; Sumoreeah, L. R.;
Shell, A.; Spoors, G.; Gill, A. L.; Smith, S. Tetrahedron Lett. 2001, 42,
2209.
(15) (a) Fe´dou, N. M.; Parsons, P. J.; Viseux, E. M. E.; Whittle, A. J.
Org. Lett. 2005, 7, 3179. (b) Parsons, P. J.; Penkett, C. S.; Shell, A. J.
Chem. ReV. 1996, 96, 195. (c) Knight, J.; Parsons, P. J. J. Chem. Soc.,
Perkin Trans. 1 1989, 979.
2614
Org. Lett., Vol. 9, No. 14, 2007

dichloromethane, the R,â-unsaturated ester 2 was formed in
85% isolated yield (Scheme 1).
Table 2. Preparation of Substituted Cyclopentanesa
Scheme 1. CM Involving an Aliphatic Nitro Compound
By application of the same methodology we were able to
prepare a range of substituted nitroalkenes (Table 1), finding
that the aliphatic nitro group neither interfered with the CM
process nor deactivated the catalyst.
a Cis/trans ) 1:7. b Trans isomer observed exclusively.
The helpful report on selectivity in CM recently published
by Grubbs and co-workers9 classifies terminal alkenes
bearing a variety of functionality according to their readiness
to participate in a CM reaction, and provides an illustration
of the vast functional group tolerance of this process. This
highly developed model allows the synthetic chemist, by
consideration of relative rates of homodimerization under
the metathesis conditions, to prepare the desired CM product
in high yield. Due to a rapid rate (10-15 min) of ho-
modimerization, we suggest that 6-nitrohex-1-ene 1 should
be classified as a type I alkene according to Grubbs’ model
(Scheme 2). Indeed, such a designation is also corroborated
sulfurated sodium borohydride reagent18 afforded the cor-
responding amine, which subsequently cyclized to give 23.
Scheme 3. Synthesis of Piperidine 23
Intramolecular [3+2] nitrile oxide cycloaddition reactions
were also carried out by treating the CM products 2, 6, and
10 with phenyl isocyanate and a catalytic amount of
triethylamine in benzene according to the published proce-
dure.19 This afforded the highly desirable functionalized
isoxazolines 24-26 (Table 3).
Scheme 2. Homodimerization of 6-Nitro-1-hexene
In conclusion, we report an efficient CM protocol to
prepare functionalized aliphatic nitro compounds which are
by the observed activity of 1 under CM conditions with the
substituted olefins reported in Table 1.
This CM methodology offered us an expedient route to
the substituted aliphatic nitro compounds we desired. In
addition, we have also observed that the aforementioned CM
products can provide facile access to a number of extremely
useful cyclic entities.
Table 3. Preparation of Substitued Isoxazolines
To illustrate, fluoride ion-mediated intramolecular conju-
gate additions could be realized from the Michael accepting
precursors,17 and so when the CM products 2 and 5 were
treated with stoichiometric amounts of tetrabutylammonium
fluoride in tetrahydrofuran at 0 °C, rapid conversions to the
substituted cyclopentanes 21 and 22 occurred (Table 2).
Furthermore, as illustrated in Scheme 3, we also observed
that the facile reduction of nitroalkene 2 with the mild
(16) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(17) Soengas, R. G.; Este´vez, J. C.; Este´vez, R. J.; Maestro, M. A.
Tetrahedron: Asymmetry 2003, 14, 1653.
Org. Lett., Vol. 9, No. 14, 2007
2615

not commercially available, and would otherwise be difficult
to access. These CM products have wide application as
precursors for many transformations.
of Drs. Gurdip Bhalay and Alice Brewer in this work. We
also thank Dr. Ali Abdul-Sada at the University of Sussex
for mass spectrometry measurements and Drs. Justin Cowell
and Nicolas Fe´dou for useful discussion.
Acknowledgment. We gratefully acknowledge generous
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1-3 and
5-26. This material is available free of charge via the
Internet at http://pubs.acs.org.
financial support from Novartis, and appreciate the interest
(18) (a) Lalancette, J. M., Jr.; Freche, A.; Birndle, J. R.; Laliberte, M.
Synthesis 1972, 527. (b) Lalancette, J. M., Jr.; Freche, A.; Montreux, R.
Can. J. Chem. 1968, 46, 2754.
(19) (a) Yuan, C.; Li, C. Tetrahedron Lett. 1993, 34, 5959. (b) Curran,
D. P. J. Am. Chem. Soc. 1983, 105, 5826.
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