Rapid decarboxylative allylation of nitroalkanes

Article abstract of DOI:10.1021/ol902828p

Allyl nitroacetates undergo decarboxylative allylation to provide tertiary nitroalkanes In high yield. Moreover, the transformations are complete within several minutes under ambient conditions. High yields result because O-allylation of the intermediate

Full text of DOI:10.1021/ol902828p

ORGANIC
LETTERS
2010
Vol. 12, No. 4
740-742
Rapid Decarboxylative Allylation of
Nitroalkanes
Alexander J. Grenning and Jon A. Tunge*
Department of Chemistry, The UniVersity of Kansas, Lawrence, Kansas 66045
tunge@ku.edu
Received December 8, 2009
ABSTRACT
Allyl nitroacetates undergo decarboxylative allylation to provide tertiary nitroalkanes in high yield. Moreover, the transformations are complete within
several minutes under ambient conditions. High yields result because O-allylation of the intermediate nitronates, which is typically problematic, is
reversible under conditions of the decarboxylative allylation process. Lastly, the preparation of substrate allyl nitroacetates by tandem Knoevenagel/
Diels-Alder sequences allows the facile synthesis of relatively complex substrates that undergo diastereoselective decarboxylative allylation.
The development of new reactions that allow the incorporation
of nitrogen into useful building blocks is a necessity for more
efficient synthesis of alkaloids and other biologically active
nitrogenous compounds. With this in mind, the synthesis of
homoallylic amines1 has been given great attention due to their
synthetic flexibility. Previously, we developed a decarboxylative
coupling of R-amino acid derivatives that gave rise to protected
homoallylic amines2 and Chruma has developed a similar
coupling that provides simple access to a variety of non-natural
amino acid substrates.3,4 That said, the decarboxylative
coupling of amino acid esters exhibits poor regioselectivity
and thus does not allow the efficient formation of tertiary
amines (eq 1). Herein we report an efficient palladium-
catalyzed decarboxylative coupling of allyl R-nitro acetates
that provides access to R-tertiary homoallylic amines.
While there are numerous publications on the use of highly
stabilized nitroenolates (pKa ≈ 8 in DMSO) in Tsuji-Trost type
allylations,5 there are currently few effective methods for
allylating nonstabilized nitronates (pKa ≈ 17 in DMSO).6,7 An
extensive early study showed that even moderately sterically
demanding nitronates suffer from competing O-allylation and
thus low yields of C-allylation products.6 More recently,
Shibasaki developed an improved procedure to facilitate
C-allylation; however, that reaction requires base additives
and long (48 h) reaction times at 50 °C for most substrates.7
In 1987, Tsuji reported a single example of the decarboxy-
lative coupling of a nitroacetic ester that indicated that decar-
boxylative coupling would allow the rapid synthesis of tertiary
homoallylic amine precursors under mild conditions without
added base (eq 2).8 Unfortunately, the reaction was plagued
by competing O-allylation. The amount of O-allylation could
be somewhat reduced at -50 °C, but C-allylation was still
(1) For reviews of allylation of aldimines, see: Ding, H.; Friestad, G. K.
Synthesis 2005, 2815–282. (b) Shibasaki, M.; Kanai, M. Chem. ReV. 108,
2853, 287.
(2) Burger, E., C.; Tunge, J. A. J. Am. Chem. Soc. 2006, 128, 10002–
10003.
(5) Ono, N. The Nitro Group in Organic Synthesis; Feuer, H., Ed.;
Wiley-VCH: New York, 2001; pp 140-147.
(3) Yeagley, A. A.; Chruma, J. J. Org. Lett. 2007, 9, 2979–2882
.
(4) (a) Shimizu, I.; Yamada, T.; Tsuji, J. Tetrahedron Lett. 1980, 3199.
(b) Tsuda, T.; Chujo, Y.; Nishi, S.-i.; Tawara, K.; Saegusa, T. J. Am. Chem.
Soc. 1980, 102, 6381. (c) Waetzig, S. R.; Tunge, J. A. J. Am. Chem. Soc.
2007, 129, 14860–14861. (d) Weaver, J. D.; Tunge, J. A. Org. Lett. 2008,
(6) (a) Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Tetrahedron 1982,
38, 1321–1327. (b) Wade, P. A.; Morrow, S. D.; Hardinger, S. A. J. Org.
Chem. 1982, 47, 365–367.
(7) Maki, K.; Kanai, M.; Shibasaki, M. Tetrahedron 2007, 63, 4250–
4257. Isolated yields were not reported.
10, 4657–4660
.
10.1021/ol902828p  2010 American Chemical Society
Published on Web 01/20/2010

favored only by a 2:1 ratio. Thus, to begin developing a
synthetically useful method, it was necessary to explore reaction
conditions that would provide high yields of C-allylation product
and minimize the amount of O-allylation.
products. In every case, the reactions were complete within 10
min at 25 °C. Due to these mild conditions, the reaction is
tolerant of functionality including R-fluorination (entry 3) as
well as pendant esters (entries 5-6) or ketones (entry 4). Lastly,
when unsymmetrical allyls are utilized, the decarboxylative
coupling is highly regioselective in favor of the linear regioi-
somer (entries 7-8). Importantly, the aliphatic allylic alcohol
derivative shown in entry 8 undergoes reaction without observ-
able elimination.
The cinnamyl derivative 1h performed better under conditions
at higher catalyst loadings (10 mol %); at 5 mol % a significant
amount of cinnamaldehyde was formed instead of desired
allylated nitroalkane (1.5:1 2h:RCHO).6 The cinnamaldehyde
is most likely derived from the O-allyl nitronate via elimination
(Scheme 2).6 Thus, in the case of 1h, we observe less
Toward that end, a simple allyl R,R-dialkyl nitroacetate
was synthesized and evaluated in decarboxylative coupling.
To our delight, the decarboxylative coupling of 1a in CH2Cl2
solvent proceeded quickly and cleanly in the presence of 5
mol % Pd(PPh3)4 to form the desired C-allylated nitroalkane
in high yield (Scheme 1).9 Moreover, the reaction was very
Scheme 1
Scheme 2
rapid, forming product in just 5 min at room temperature;
to generate a comparable yield of such a product using known
methodology would require 78 h at 15 °C6 or 48 h at 25
°C7 depending on the method of choice.10
Next, we chose to explore more sterically demanding
nitronates that can prove to be problematic due to competing
O-allylation. As can be seen in Table 1, simple R,R-dialkyl
nitroacetates react to provide good yields of the nitroalkane
O-allylation at higher catalyst loading. This suggests that
palladium plays a direct role in conversion of the O-allylated
intermediate (B) to the C-allylated product (2h). Such behavior
can be rationalized if one proposes that O-allylation is reversible.
In such a case palladium can engage the O-allyl nitronate (B)
to reform intermediate π-allyl complex (A) which then produces
C-allyl product (Scheme 2). Thus, the Pd concentration needs
to be high enough that the bimolecular π-allyl palladium
formation from the O-allyl nitronate is faster than unimolecular
elimination to form cinnamaldehyde. This hypothesis suggests
that reactions that are run at higher concentration should produce
more C-allylation product (2h) and reduce the amount of
cinnamaldehyde. Indeed, when the decarboxylative allylation
is run with 5 mol % Pd(PPh3)4, the ratio of 2h:RCHO improves
from 1.2:1 to 2.2:1 on increasing the concentration of 1h from
0.05 to 0.1 M. A further improvement to 4.5:1 2h:RCHO is
achieved at 0.3 M substrate. These results suggest that high
yields of C-allylation products can result from favoring rapid
reversible O-allylation rather than by avoiding O-allylation.
Aside from the rapid, base-free reactions, a significant
advantage of decarboxylative allylation is the ability to
construct the desired nucleophile prior to coupling (Scheme
3). This process is facilitated by the acidity of the R-
hydrogens, which allows one to use acetoacetic ester-type
synthesis to rapidly provide derivatives. In addition, one can
rapidly access more complex substrates via tandem Knoev-
enagel condensation/Diels-Alder cycloaddition chemistry
(Scheme 3).11
Table 1. Decarboxylative Coupling of Nitroalkanes
a Isolated yield, 0.2 M substrate in CH2Cl2, 5 mol % Pd(PPh3)4, rt, 10
min b Pd(PPh3)4 (10 mol %). c l:b ) >20:1.
Decarboxylative allylation of the substrates generated by
Knoevenagel/Diels-Alder chemistry provides high yields of
Org. Lett., Vol. 12, No. 4, 2010
741

Scheme 3
Scheme 4
amines, while reductions of appropriately substituted deriva-
tives proceed directly to heterocyclic analogs (Scheme 5).
the allylated nitro alkanes (Table 2). Once again, both aryl
(2p,2q) and alkyl-substituted (2r,2s) allyl groups are excel-
Scheme 5
Table 2. Diels-Alder/Decarboxylative Coupling
In conclusion, we have developed a practical decarboxy-
lative allylation of nitroalkanes that provides rapid access
to a variety of homoallylic amine derivatives. High yields
are obtained by using a catalyst/solvent combination wherein
O-allylation is rapid and reversible, thus favoring the
irreversible C-allylation process. Lastly, the diastereoselec-
tivity of the allylation suggests that the allylation process
occurs with simple steric control.
a 10 mol % Pd(PPh3)4 l:b ) >20:1. b l:b ) 3.3:1. c l:b ) 5:1.
Acknowledgment. We thank the National Institute of
General Medical Science (1R01GM079644) for support of
this work.
lent reaction partners in this chemistry. In addition, these
substrates also allow us to explore the diastereoselectivity
of allylation; the 1,2-diastereoselectivity of decarboxylative
allylations has not been systematically investigated. As can
be seen from examples 2k, 2l and 2m, 1,2-stereocontrol
favors the anti- or exo-allylation, suggesting a sterically
controlled allylation. Lastly, the decarboxylative allylation
is stereoconvergent, so both diastereomers of the reactant
form the product with the same relative stereochemistry
(Scheme 4). Thus, even poorly selective Diels-Alder reac-
tions can give rise to diastereoenriched products.12
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL902828P
(8) Tsuji, J.; Yamada, T.; Minami, I.; Yuhara, M.; Nisar, M.; Shimizu,
I. J. Org. Chem. 1987, 52, 2989–2995.
(9) Pd2(dba)3 with the chelating ligand (rac)-BINAP failed to give any
conversion under these conditions.
(10) Allylation of R-bromo nitroalkanes with allylstannanes: Ono, N.;
Zinmeister, K.; Kaji, A. Bull. Chem. Soc. Jpn. 1985, 38, 1069–1070.
(11) Wade, P. A.; Murray, J. K., Jr.; Shah-Patel, S.; Carroll, P. J.
Tetrahedron Lett. 2002, 43, 2585–2588.
As expected, the resulting allylated nitroalkanes are
excellent precursors to homoallylic amine derivatives. Simple
reduction using zinc dust and HCl gives rise to homoallylic
(12) See Supporting Information for a table of substrate and product
dr’s.
742
Org. Lett., Vol. 12, No. 4, 2010