Novel synthetic approach toward (±)-β-cuparenone via palladium-catalyzed tandem Heck cyclization of 1-bromo-5-methyl-1-aryl-hexa-1,5- dien-3-ol derivatives

Article abstract of DOI:10.1021/ol062418t

(Chemical Equation Presented) A novel and convenient synthetic route toward (±)-β-cuparenone and many other sesquiterpene natural product precursors has been developed via palladium-catalyzed tandem Heck cyclization of 1-bromo-5-methyl-1-aryl-hexa-1,5-die

Full text of DOI:10.1021/ol062418t

ORGANIC
LETTERS
2007
Vol. 9, No. 2
191-194
Novel Synthetic Approach Toward
)- -Cuparenone via
Palladium-Catalyzed Tandem Heck
Cyclization of
(± â
1-Bromo-5-methyl-1-aryl-hexa-1,5-dien-3-ol
Derivatives
Devalina Ray and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
jkray@chem.iitkgp.ernet.in
Received October 2, 2006
ABSTRACT
A novel and convenient synthetic route toward (±)-â-cuparenone and many other sesquiterpene natural product precursors has been developed
via palladium-catalyzed tandem Heck cyclization of 1-bromo-5-methyl-1-aryl-hexa-1,5-dien-3-ols.
As part of our ongoing interest in palladium-catalyzed Heck
reactions,1 we were interested in developing a new method-
ology and extending it to the synthesis of some of the sesqui-
terpene natural product precursors. A large number of multi-
step methods have been developed for the synthesis of (()-
R- and (()-â-cuparenone, (()-herbertene, etc., where the
synthetic approaches are lengthy, hazardous, or low yielding.2-6
A single-step synthesis of (()-R-cuparenone has also been
reported with an overall yield of 18% of the desired product.7
In contemplating ways to reduce the steps as well as to keep
the yield moderate, we found that one of the potential
solutions would be to explore the option of synthesizing the
precursors through palladium-catalyzed intramolecular Heck
reactions which could be converted to the desired natural
product, i.e., (()-â-cuparenone, in one step.8 Other natural
products such as (()-cuparene, (()-herbertene, (()-R-
herbertenol, and (()-â-herbertenol can be synthesized in two
or three steps from our precursors. In contrast to other
methodologies aiming at a similar goal,9 our approximation
leads to a simple, efficient, and good yielding route. Our
urge to develop a practical and good yielding technique with
less steps rendered the objective of investigating an unusual
palladium-catalyzed tandem Heck cyclization.
(1) (a) Mal, S. K.; Ray, D.; Ray, J. K. Tetrahedron Lett. 2004, 45, 277.
(b) Ray, D.; Mal, S. K.; Ray, J. K. Synlett 2005, 14, 2135.
(2) Castro, J.; Moyano, A.; Pericas, M. A.; Riera, A.; Greene, A. E.;
Larena, A. A.; Piniella, J. F. J. Org. Chem. 1996, 61, 9016.
(3) (a) Srikrishna, A.; Sundarababu, G. Tetrahedron 1991, 47, 481. (b)
Jung, M. E.; Radcliffe, C. D. Tetrahedron Lett. 1980, 21, 4397.
(4) (a) Srikrishna, A.; Krishna, K.; Venkateswarlu, S.; Kumar, P. J. Chem.
Soc., Perkin Trans. 1 1995, 2033. (b) Sato, T.; Hayashi, M.; Hayata, T.
Tetrahedron 1992, 48, 4099. (c) Nakashima, H.; Sato, M.; Taniguchi, T.;
Ogasawara, K. Tetrahedron Lett. 2000, 41, 2639.
In this context, we wish to highlight the formation of the
gem dimethyl cyclopentenone moiety from 1-bromo-5-
(7) Hayakawa, Y.; Shimizu, F.; Noyori, R. Tetrahedron Lett. 1978, 11,
993.
(5) Chavan, S. P.; Ravindranathan, T.; Patil, S. S.; Dhondge, V. D.;
Dantale, S. W. Tetrahedron Lett. 1996, 37, 2629.
(6) Leriverend, M. L.; Vazeux, M. J. Chem. Soc., Chem. Commun. 1982,
866.
(8) (a) Greene, A. E.; Lansard, J.-P.; Luche, J.-L.; Petrier, C. J. Org.
Chem. 1984, 49, 931. (b) Takano, S.; Moriya, M.; Ogasawara, K.
Tetrahedron Lett. 1992, 33, 329.
(9) Jung, M. E.; Radcliffe, C. D. Tetrahedron Lett. 1980, 21, 4397.
10.1021/ol062418t CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/29/2006

methyl-1-aryl-hexa-1,5-dien-3-ol using palladium-catalyzed
Heck reaction conditions.
Table 1. Optimization Studiesa
Scheme 1
time 3a 6a 7a
entry
catalyst
base
solvent
(h) (%) (%) (%)
1
2
Pd(OAc)2/A K2CO3
Pd(OAc)2/A K2CO3
CH3CN
DMF
8
8
28 20 40
35 15 30
3
4
5
6
7
8b,c
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
HCOONa DMF
3
6
9
8
12
8
5
0
50
40 12
45
12
55 10
K2CO3
DMF
9
8
3
Well aware of the possibilities offered by this reaction, we
utilized the method to obtain two different products from a
common starting material by varying the reaction conditions
(Schemes 1 and 2). Here lies the beauty of our methodology.
Cs2CO3
K2CO3
Na2CO3
Na2CO3
Na2CO3
DMF
dioxane
toluene
DMF
3
0
20
35
0
50 10
70
DMF
6
0
a
All the reaction mixtures were heated to 80 °C. A: 1 equiv of sodium
b
formate was added after the reaction mixture was heated for 2 h. 0.5
Scheme 2. Retrosynthetic Approach of 1a-d
equiv of PPh3 was added to the reaction mixture in all the cases except
entry 8. 1 equiv of Bu4NCl was added.
c
substrate 5a, Pd(OAc)2, base, and DMF was first heated for
2 h and then sodium formate was added to it as a terminator.
However, we obtained the gem dimethyl substituted cyclo-
pentenone derivative along with a significant amount of
uncyclized, dehalogenated products. We then tried other
options by eliminating the base and carrying out the reaction
with sodium formate only. This time we obtained no keto
compound, but the gem dimethyl substituted alcohol deriva-
tive along with a small amount of uncyclized dehalogenated
substrates were the isolable products. This initial screening
indicated that the keto derivative could not be obtained
significantly in the presence of sodium formate. During our
effort to find the appropriate conditions, we finally succeeded
in getting our desired keto compound by eliminating sodium
formate and carrying out the reaction in the presence of
sodium carbonate. The terminating species must have come
from the substrate itself, otherwise the gem dimethyl group
could not have been generated.
The convergent approach involved preparation of the
cyclization precursors 5a-g, which could be efficiently
assembled from indium-mediated methallylation of 1-bromo-
2-methyl-2-propene with corresponding bromoaldehydes
2a-g in 80-90% yield1 (Scheme 3).
Next, we investigated several additional solvents and bases
to improve the yield of our desired product. The reaction
also worked under ligandless conditions, but the yield was
somewhat low. Finally, we concluded that, when the reaction
was carried out with 2 mol % of Pd(OAc)2, 0.5 equiv of
PPh3, and 1.5 equiv of Na2CO3 in DMF at 80 °C for 5 h,
the yield of 3a increased to 70% (Table 2).
Scheme 3
Compound 3a led to (()-â-cuparenone (8a) in a single
step (Scheme 4).8
In previous communications,1 we were able to obtain the
methyl-substituted oxidized product through the isomeriza-
tion of an exocyclic double bond formed by intramolecular
cyclization of the allylated and propargylated derivatives of
vinyl bromoaldehyde. The possibility of formation of an
exocyclic double bond could be discarded because of the
unavailability of â-hydrogen for elimination after cyclization
through a 5-exo-trig pathway. Still, we had isolated the gem
When the precursors were subjected to Heck reaction con-
ditions in the presence of bases other than sodium formate,
gem dimethyl cyclopentenone derivatives were obtained. The
reaction was then attempted by changing the base, solvent,
and catalyst to optimize the reaction conditions (Table 1).
Because a terminating species is required for the generation
of the gem dimethyl group, the reaction mixture containing
192
Org. Lett., Vol. 9, No. 2, 2007

Scheme 5. Mechanistic Pathway
Table 2. Synthesis of Gem Dimethyl Cyclopentenone
Derivatives through Palladium-Catalyzed Tandem Heck
Cyclization of 5a-ga
trig cyclization occurred probably because of the presence
of the -CHOH group which donated a hydride for termina-
tion, itself being converted to -CdO. By changing the
reaction condition, i.e., using sodium formate as a hydride
donor in the absence of base, we were able to isolate the
cyclized unoxidized derivative as our isolable product. This
might be because in the absence of base no hydride transfer
occurred and hence no proton abstraction resulted to form
the palladium hydride intermediate. The palladium bromide
intermediate directly cyclized which in turn terminated
through hydride capture from sodium formate to generate an
unoxidized gem dimethyl cyclopentenol derivative (Table 3).
Table 3. Synthesis of Gem Dimethyl Cyclopentenol
Derivativesa
entry
substrates
products
yield (%)b
a All the reactions were carried out with 2 mol % of Pd(OAc)2, 0.5 equiv
of PPh3, and 1.5 equiv of Na2CO3 in DMF at 80 °C for 5 h. Isolated
yields after purification.
b
1
2
3
4
5a
5b
5f
6a
6b
6f
50
56
60
58
5g
6g
dimethyl cyclopentenone derivative surprisingly as the major
product. The mechanism hence seems to follow a different
pathway (Scheme 5).
a
All the reactions were carried out with 2 mol % of Pd(OAc)2, 0.5
b
equiv of PPh3, and 1.2 equiv of HCOONa in DMF at 80 °C for 3 h.
Isolated yields.
In a recent communication,10 it has been established that
in the absence of a terminating agent this type of substrate
undergoes a 6-endo mode olefin insertion. In our case, 5-exo-
So, we are able to establish two different reaction
conditions to obtain two mechanistically different products,
one of which directly leads to sesquiterpene precursors.
In conclusion, palladium-catalyzed intramolecular Heck
cyclization has proven to be a practical, shorter, and good
yielding means for the preparation of sesquiterpene precur-
sors. We are gratified to prove that this methodology has
the potential to be of great benefit in the convergent synthesis
of a number of natural product moieties.
Scheme 4
(10) Kong, A.; Han, X.; Lu, X. Org. Lett. 2006, 8, 1339.
Org. Lett., Vol. 9, No. 2, 2007
193

compounds synthesized. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from CSIR (New
Delhi) is gratefully acknowledged.
Supporting Information Available: Complete experi-
mental details along with spectroscopic data for new
OL062418T
194
Org. Lett., Vol. 9, No. 2, 2007