Unusual regioselectivity in Pd(0)-catalyzed coupling of allylic monoacetates and nitroalkanes: one-pot isomerization-alkylation

Article abstract of DOI:10.1016/j.tetlet.2010.01.025

A hitherto unknown palladium-catalyzed reaction of nitroalkanes with hydroxy allylic acetates is reported. The reaction led to the formation of γ-nitrocarbonyl compounds instead of the usual unsaturated nitroalcohol expected upon displacement of the allylic acetate group.

Full text of DOI:10.1016/j.tetlet.2010.01.025

Tetrahedron Letters 51 (2010) 1407–1410
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Tetrahedron Letters
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Unusual regioselectivity in Pd(0)-catalyzed coupling of allylic monoacetates and
nitroalkanes: one-pot isomerization–alkylation
*
Pasha M. Khan, Kirpal S. Bisht
Department of Chemistry, University of South Florida, 4202 East Fowler Avenue, Tampa, FL 33620, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A hitherto unknown palladium-catalyzed reaction of nitroalkanes with hydroxy allylic acetates is
Received 5 November 2009
Revised 6 January 2010
Accepted 7 January 2010
Available online 13 January 2010
reported. The reaction led to the formation of
rated nitroalcohol expected upon displacement of the allylic acetate group.
c-nitrocarbonyl compounds instead of the usual unsatu-
Ó 2010 Elsevier Ltd. All rights reserved.
Palladium-catalyzed allylic alkylation, also known as Tsuji–
Trost reaction, has been extensively used in organic syntheses.1
Previous report:
R3
A
R3
R4
NO2
Pd(0)
R1
R1
R2
5
NO2
broad range of nucleophiles, which include, active methylene and
methine compounds, and various heteroatom (N, O, S) nucleo-
philes have been employed in this type of reaction. The survey of
the literature1,2 reveals that in Pd-catalyzed alkylation the new
carbon–carbon bond is formed at the allylic carbon of the electro-
phile, that is, unsaturated compounds are formed and the new car-
bon–carbon bond is formed at the C-2 or C-4 (Scheme 1). Recently,
we reported chemoenzymatic synthesis of furan and isoxazoline
derivatives via Pd-catalyzed allylic alkylation and cyclizations
starting from a meso-diol.3
R4
1
4
2
3
R1, R2 = OAc, OCO2R
Current report:
O
Pd(PPh3)4 (5 mol%)
PPh3, K2CO3
n
4
1
OAc
R3
R4
HO
n
NO2
2
3
NO2
R3
THF
n=0,1,2
R4
4 - 6
1 - 3
Scheme 1. Pd-catalyzed alkylations of nitroalkanes.
In our quest for enzyme-coupled Pd(0)-catalyzed reactions, we
have investigated coupling reaction of allylic monoacetate and
nitroalkanes. Surprisingly, nitroalkanes have received little atten-
tion in Pd-catalyzed allylic alkylations as a nucleophile source even
though nitro group can be easily converted to other functional
groups.4 The scarce utilization of nitroalkanes in Pd(0)-catalyzed
allylic alkylations can presumably be attributed to their ambident
nature (C- vs O-alkylation), low reactivity of bulky nitroalkanes,
and formation of side products.5 In this Letter, we report a hitherto
unknown Pd-catalyzed reaction of nitroalkanes with hydroxy
allylic acetates 1–3 (Scheme 1).
of this reaction and establish a plausible mechanistic explanation
for the ‘isomerization–alkylation’ are described in this Letter.
To understand the mode of the reaction, various solvents, bases,
catalyst, and ligands were evaluated (Table 1). The reaction was
highly dependent on the nature of the solvent. No reaction was ob-
served in protic solvents (t-BuOH, t-BuOH + THF) or in nonpolar
solvents (toluene, CHCl3) with full recovery of the starting mate-
rial. In polar aprotic solvents (DMF, DMSO, THF), however, the
reaction resulted in the
c-nitro carbonyl compound 4c in 10–
12 h. Owing to its relative ease of handling, THF was selected as
the solvent of choice for subsequent investigations. The rate and
outcome of the reaction also depended on the base used. While
KOtBu and DABCO led to the product formation, K2CO3 proved to
be the most effective base for this reaction. We also found that
Pd(OAc)2 and PdCl2 did not catalyze the reaction suggesting that
the reaction was only catalyzed by Pd(0) complexes. In order to
study the substrate scope of the reaction, cyclic and acyclic allylic
acetates as well as primary and secondary nitroalkanes were sub-
jected to the alkylation (Table 2). Allylic cyclic acetates 1 and 2 re-
The reactions with 1° and 2° nitroalkanes led to the formation of
c-nitro carbonyl compounds instead of the usual unsaturated
nitroalkanes expected upon displacement of the allylic acetate
group. This represents the first example of Pd-catalyzed one-pot
synthesis of c-nitro carbonyl compounds. Another interesting fea-
ture of this reaction was the unusual regioselectivity of the new C–
C bond formation from the expected C-4 to C-3 (Scheme 1) sug-
gesting an isomerization to be involved in the reaction pathway.
This reaction adds a new tool to the arsenal of Pd-mediated C–C
bond-forming methodologies. Our efforts to evaluate the utility
sulted in the formation of the corresponding
5, respectively. The acyclic acetate 3 led to
c
-nitro ketones 4 and
c
-nitro aldehydes 6. 1°
and 2° nitroalkanes reacted with equal ease under these reaction
conditions; even bulky nitroalkanes, such as nitrocyclohexane,
* Corresponding author. Tel.: +1 813 974 0350; fax: +1 813 974 3203.
E-mail address: kbisht@cas.usf.edu (K.S. Bisht).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.01.025

1408
P. M. Khan, K. S. Bisht / Tetrahedron Letters 51 (2010) 1407–1410
Table 1
Solvent and base effect
reacted successfully with both acyclic and cyclic hydroxyl allylic
substrates. The reaction required 5–8 mol % catalyst loading and
was completed in 10–12 h. The structures of the -nitro carbonyl
compounds were established unambiguously from the analysis of
the 1H and 13C NMR spectral data and its comparison with the lit-
erature data when available.6 The reaction conversions were deter-
mined using gas chromatography and the products were isolated
by column chromatography over silica gel.
Pd(PPh3)4 (5 mol%)
PPh3, Base
c
HO
OAc
NO2
O
Solvent
Ac
NO2
4c
1
Entry
Base
Solvent
Yielda
drd
1
2
3
4
5
6
7
8
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KOtBu
DIPA
THF
60
54
53
1:1
1:1.1
1:1
—
—
—
—
—
1.7:1
—
The stereochemical analyses of the products identified these to
be a mixture of diastereomers and enantiomers, for example, start-
ing from the optically pure (1S, 4R)-4-acetoxylcylcopent-2-en-1-ol
(1)7 a racemic mixture of the respective products 4a–e was ob-
tained. Products 4b and 4c were separated into its corresponding
diastereomers by column chromatography and were identified to
be racemic mixture of enantiomers. The loss of optical purity
was somewhat intriguing as the Pd(0)-catalyzed reactions are
known to proceed with stereochemical retention via a double
inversion.1b,1c,3,7 Importantly, the reactions performed in the pres-
ence of chiral ligands such as (R)-BINAP and (S)-TolBINAP did not
lead to optically pure products; only marginal influence on diaste-
reomeric ratio was observed. It was evident that the mechanistic
pathway of the reaction involved loss of stereochemistry possibly
through racemization of the reaction intermediates.
DMF
DMSO
CHCl3
Toluene
t-BuOH
t-BuOH + THF(1:1)
THF
b
—
—
—
—
b
b
b
c
—
THF
THF
THF
40c
b
10
11
—
DABCO
52
1.1:1
a
b
c
Isolated yields.
Starting material was recovered.
meso-Cyclopent-2-en-1,4-diol was also formed (20%).
Diastereomeric ratio (dr) based on GC analyses.
d
Hegedus et al8 reported the first example of cyclopropanation of
ester enolates and has proposed a mechanism involving a pallada-
cyclobutane for direct nucleophilic attack on the central carbon of
Table 2
Pd-catalyzed isomerization–alkylation of allylic acetates
Entry Acetate
Nitroalkane
Product
Conv.a
isolatedb
the p-allyl system. We carefully considered the possibility of a di-
rect nucleophilic attack on the C-3 carbon leading to a palladacyc-
lobutane intermediate, followed by b-H elimination to produce the
O
NO2
1
CH3NO2
88 (65)
enol which tautomerizes to give
final product (Supplementary data, Scheme S1). However, it has
been reported that only -donor ligands (e.g., TMEDA, bipy) favor
attack on the central carbon, while phosphorus ligands with dis-
tinct -acceptor character (PPh3, dppf) favor attack on the terminal
carbon.9 In case of
-acceptor ligands, the Pd-complex has more
c-nitro carbonyl compound as the
4a
r
O
O
NO2
OH
2
C2H5NO2
85 (59)
4b
4c
p
p
cationic character and the positive charge is located on the termi-
nal carbons of the allyl system.9 Also, in the cyclopentane and
cyclohexane monoacetate substrates, low kinetic stability of such
OAc
3
4
5
C3H7NO2
83 (60)
88 (58)
90 (62)
(> 99% ee)
NO2
(1)
a palladacyclobutane bearing a
c-OH substituent is certainly a
O
O
NO2
cause for concern.10 Furthermore, this mechanism involving a pal-
ladacyclobutane intermediate does not explain the loss of stereo-
chemistry in the final product.
NO2
NO2
4d
NO2
Another possibility involving an initial isomerization of the
allylic acetate to
addition using nitroalkane as a nucleophile was also considered.
Though formation of ,b-unsaturated carbonyls has been reported
a,b-unsaturated ketone followed by a Michael
4e
5a
OH
NO2
O
O
a
6
7
75b
85b
but only in aqueous or AcOH containing solvents and not in anhy-
drous solvents.11 In the absence of the nitroalkane, 3-cyclopente-
none was the only product isolated upon treatment of the
monoacetate 1 with PPh3, Pd(PPh3)4, and K2CO3 at 50 °C, which
was in agreement with the previous reports.12 The reaction was
monitored using NMR (see Supplementary data, Fig. S1) for up to
72 h. New resonances were observed within half an hour at 2.89
and 6.1 ppm which corresponded to H-6 and H-7, respectively, of
the 3-cyclopentenone. Within 16 h all starting monoacetate was
consumed and no significant isomerization was observed even
after 72 h of heating, which is important as the 2-cyclopentenone
is the more thermodynamically stable enone product. The forma-
tion of 3-cyclopentenone, however, can be easily explained from
NO2
OAc
NO2
NO2
( ) (2)
5b
H
NO2
8
9
C3H7NO2
82 (58)
77 (53)
O
O
OH
6a
H
NO2
NO2
NO2
OAc
(3)
6b
both
tautomerization (see Supplementary data, Scheme S2).13 Since
the formation of the ,b-unsaturated ketone was not observed
p-allyl complexes II and III via a b-hydride elimination and
H
NO2
a
O
10
76 (60)
and no C-3 alkylation took place with other nucleophiles (active
methylene compounds),1b,1c,3,7 a different mechanism is suggested.
Attempts in isolating the intermediate Pd complex were
unsuccessful.
6c
a
Based on GC analyses of the reaction mixture.
Isolated yield after column chromatography.
b

P. M. Khan, K. S. Bisht / Tetrahedron Letters 51 (2010) 1407–1410
1409
Based on the above-mentioned facts and the following observa-
tions; (i) carbonyl group instead of an allylic alcohol is formed, (ii)
the new C–C bond formation at C-3 instead of C-4 of the allylic sys-
tem, and (iii) the loss of stereochemistry, we herein propose a cat-
alytic cycle for the isomerization–alkylation reaction (Scheme 2).
The catalytic cycle involves oxidative addition of Pd(0) to the allylic
acetate resulting in the formation of the Pd-allyl complex (I) which
upon ligand exchange generates the complex II. Complex II is a key
intermediate as it can isomerize to a more stabilized complex III.
Isomerization of p-allyl palladium complexes has been put forward
to explain the loss of stereospecificity in some Pd-catalyzed allylic
alkylations.14
Complex III is attacked by the nitroalkane carbanion at the ste-
rically favorable C-3 position followed by reductive elimination to
yield IV which produced the enol V and regenerated Pd(0). Enol V
Scheme 4. The competing alkylations: C-3 versus C-4.
tautomerizes to give the c-nitro carbonyl compound. The isomeri-
zation of II to III is manifested in the formation of the new C–C
bond at the C-3 and not at the carbon bearing the leaving acetoxy
group (C-4). The involvement of III is also supported by stereo-
chemical scrambling observed in 1, an optically pure substrate,
anes along with inductive effects of the alkyl groups makes the
whole process extremely slow.15 This unusual property of the nit-
roalkane combined with the availability of the allylic hydroxyl
group results in this unusual isomerization–alkylation reaction to
resulting in optically inactive c-nitro carbonyl compounds. Impor-
tantly, the hydroxyl-bearing carbon in III is sp2-hybridized which
makes the complex racemic and explains the loss of optical purity
in the products. The isomerization of complex II can be explained
c-nitro carbonyl compounds.
A schematic of the competing processes in an allylic alkylation
of the nucleophiles generated from a diester and nitroalkane is de-
picted in Scheme 4.1b,1c,3,7 The coupling with diethyl malonate (fast
deprotonation) results in the formation of the allylic alcohols with
the new C–C bond formed at the C-4, while in nitroalkanes (slow
deprotonation), the new C–C bond is formed at the C-3 resulting
as shown in Scheme 3. Initially formed
dergo interconversion to A which upon syn b-H elimination
will yield dienol complex B. Complex B can be represented as g4
p-allyl complex II can un-
p–r
complex C which upon regioselective re-addition (E) and
r–p
in
c-nitro carbonyl compounds.
interconversion can yield complex III.
In conclusion, a hitherto unknown C-3 regioselective Pd-cata-
lyzed coupling of allylic monoacetates and nitroalkanes has been
discovered which provides an easy route to synthetically impor-
The formation of III via an isomerization of II is dependent on
two very important factors; (1) The availability of the free hydroxyl
group to stabilize the resulting carbocation through nonbonding
electron pair donation; (2) The slow generation of the carbanion
from the nitroalkane. The large degree of charge buildup on the
tant
c-nitro-ketones and aldehydes. The reaction requires easily
obtainable allylic monoacetates and works with a variety of 1°,
2° nitroalkanes. This new Pd(0)-catalyzed alkylation of nitroalk-
anes can be carried out under mild conditions and the outcome
of the reaction is highly dependent on the nature of the solvent.16
Careful optimization of the reaction conditions proved potassium
carbonate and THF to be the best base and solvent, respectively.
carbon atom during deprotonation of the
a-hydrogen in nitroalk-
The resultant c-nitro carbonyl compounds that can easily be con-
verted to other synthetically important analogs should be valuable
as synthons in natural product synthesis.
Acknowledgments
Financial support for this work from the American Cancer Soci-
ety, the Herman Frasch Foundation, and the American Lung Asso-
ciation is greatly appreciated. We thank Professors Peter Zhang
and Wayne Guida for helpful insight and discussion of the pro-
posed mechanism. We also extend our thanks to Professor Bill Ba-
ker for providing access to the optical polarimeter.
Supplementary data
Scheme 2. The proposed catalytic cycle.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.01.025.
References and notes
1. (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442;
(b) Trost, B. M. Chem. Pharm. Bull. 2002, 50; (c) Tsuji, J. In Palladium Reagents and
Catalysts; John Wiley and Sons: New York, 2004; (d)Metal-Catalyzed Cross-
Coupling Reactions; deMeijere, A., Diederich, F., Eds., second ed.; Wiley-VCH:
Weinheim, 2004; (e) Hegedus, L. S. In Transition Metals in the Synthesis of
Complex Organic Molecules, 2nd ed. University Science Books: Sausalito, 1999;
(f)Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.;
Wiley Interscience: New York, 2002; (g)Cross-Coupling Reactions: A Practical
Guide; Miyaura, N., Ed.; Springer: Berlin, 2002; (h)Organometallics in Synthesis;
Scheme 3. The 2,4- to 1,3-g3 allylic isomerization.

1410
P. M. Khan, K. S. Bisht / Tetrahedron Letters 51 (2010) 1407–1410
Schlosser, M., Ed.; John Wiley and Sons: New York, 1994; pp 383–461. Chapter
5; (i) Kobayashi, Y. Curr. Org. Chem. 2003, 7, 133.
8. (a) Hegedus, L. S.; Darlington, W. H.; Russell, C. E. J. Org. Chem. 1980, 45, 5193;
(b) Hoffmann, H. M. R.; Otte, A. R.; Wilde, A.; Menzer, S.; Williams, D. J. Angew.
Chem., Int. Ed. Engl. 1995, 34, 100.
9. (a) Castanõ, A. M.; Aranyos, A.; Szabó, K. J.; Bäckvall, J. E. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2551; (b) Aranyos, A.; Szabó, K. J.; Castanõ, A. M.; Bäckvall, J. E.
Organometallics 1997, 16, 1058.
2. (a) Wade, P. A.; Morrow, S. D.; Hardinger, S. A. J. Org. Chem. 1982, 47, 365; (b)
Trost, B. M.; Surivet, J.-P. J. Am. Chem. Soc. 2000, 122, 6291; (c) Tsuji, J.;
Yamakawa, T.; Mandai, T. Tetrahedron Lett. 1978, 19, 565; (d) Tsuji, J.; Shimizu,
I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K. J. Org. Chem. 1985, 50, 1523;
(e) Deardorff, D. R.; Savin, K. A.; Justman, C. J.; Karanjawala, Z. E.; Sheppeck, J.
E.; Harger, D. C.; Aydin, N. J. Org. Chem. 1996, 61, 3616; (f) Maki, K.; Kanai, M.;
Shibasaki, M. Tetrahedron 2007, 63, 4250.
10. Szabó, K. J. THEOCHEM 1998, 455, 205.
11. Minami, T.; Hanaoka, M. Tetrahedron Lett. 1994, 35, 9425.
12. Suzuki, M.; Oda, Y.; Noyori, R. J. Am. Chem. Soc. 1979, 101, 1623.
13. (a) Buckley, S. L. J.; Harwood, L. M.; Macias-Sanchez, A. J. ARKIVOC 2002, 8, 46;
(b) Tsuda, T.; Tokai, M.; Ishida, T.; Saegusa, T. J. Org. Chem. 1986, 51, 5216.
14. (a) Trost, B. M.; Verhoeven, T. R. J. Am. Chem. Soc. 1980, 102, 4730; (b) Granberg,
K. L.; Bäckvall, J. E. J. Am. Chem. Soc. 1992, 114, 6858; (c) Brunel, J. M.; Maffei,
M.; Muchow, G.; Buono, G. Eur. J. Org. Chem. 2000, 1799; (d) Brunel, J. M.;
Maffei, M.; Muchow, G.; Buono, G. Eur. J. Org. Chem. 2001, 1009.
3. Khan, P. M.; Wu, R.; Bisht, K. S. Tetrahedron 2007, 63, 1116.
4. (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York, 2001;
(b) Luzzio, F. A. Tetrahedron 2001, 57, 915; (c) Ballini, R.; Petrini, M. Tetrahedron
2004, 60, 1017; (d) Barrett, A. G. M.; Grabowski, G. G. Chem. Rev. 1986, 86, 751;
(e) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877; (f)
Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Helv. Chim. Acta 1985, 68, 1592;
(g) Brown, B. R. The Organic Chemistry of Aliphatic Nitrogen Compounds; Oxford
University: Oxford, 1994; (h) Patai, S., Ed.The Chemistry of Amino, Nitro and
Related Groups; John Wiley & Sons: Chichester, 1996.
5. (a) Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Tetrahedron 1982, 38, 1321; (b)
Aleksandrowicz, P.; Piotrowska, H.; Sas, W. Monatsh. Chem. 1982, 113, 1221; (c)
Genet, J. P.; Grisoni, S. Tetrahedron Lett. 1988, 29, 4543; (d) Rieck, H.; Helmchen,
G. Angew. Chem., Int. Ed. Engl. 1995, 34, 2687.
6. (a) Hanessian, S.; Pham, V. Org. Lett. 2000, 2, 2975; (b) Hanessian, S.; Shao, Z.;
Warrier, J. S. Org. Lett. 2006, 8, 4787.
7. (a) Deardorff, D. R.; Matthews, A. J.; McMeekin, D. S.; Craney, C. L. Tetrahedron
Lett. 1986, 27, 1255; (b) Siddiqi, S. M.; Chen, X.; Schneller, S. W. Nucleosides and
Nucleotides 1993, 12, 267.
15. Green, D.; Johnson, T. Innovations Pharm. Technol. 2000, 79.
16. General procedure for Pd-catalyzed alkylation of nitroalkane: To a solution of
allylic acetate 1 (100 mg, 0.704 mmol) in dry THF (10 mL) at room temperature
were added Pd(PPh3)4 (40 mg, 0.035 mmol) and PPh3 (184 mg, 0.704 mmol)
under a nitrogen atmosphere. The reaction mixture was allowed to stir for
5 minutes and then nitropropane (63 mg, 0.704 mmol) and K2CO3 (97 mg,
0.704 mmol) were added. The reaction mixture was refluxed for 12 h and then
vacuum filtered through celite with subsequent concentration of the filtrate.
The product was purified by column chromatography using ethyl acetate/
hexane (1:2) to afford 4c (72 mg, yield = 60%) as a viscous liquid.