Rhodium-catalyzed tandem heterocyclization and carbonylative [(3+2)+1] cyclization of diyne-enones

Article abstract of DOI:10.1021/ol102920f

A simple and highly efficient rhodium-catalyzed tandem heterocyclization and carbonylative [(3+2)+1] cyclization reaction of readily available diyne-enone and carbon monoxide was developed, leading to a novel polycyclic furan scaffold. Synthetically usefu

Full text of DOI:10.1021/ol102920f

ORGANIC
LETTERS
2011
Vol. 13, No. 4
688–691
Rhodium-Catalyzed Tandem
Heterocyclization and Carbonylative
[(3þ2)þ1] Cyclization of Diyne-enones
Wanxiang Zhao and Junliang Zhang*
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of
Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai
200062, P. R. China, and State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. China
jlzhang@chem.ecnu.edu.cn
Received December 2, 2010
ABSTRACT
A simple and highly efficient rhodium-catalyzed tandem heterocyclization and carbonylative [(3þ2)þ1] cyclization reaction of readily available
diyne-enone and carbon monoxide was developed, leading to a novel polycyclic furan scaffold. Synthetically useful highly substituted phenols
can also be easily prepared via a straightforward one-pot synthetic strategy.
Transition-metal-catalyzed cyclization reactions have
proven to be one of the most efficient and straightforward
methods to construct complex polycyclic systems.1 Among
them, the construction of polycyclic compounds contain-
ing six-membered rings is actively pursued because of their
significant roleinmanynatural products and versatile app-
lications as useful building blocks.2 Thus, developing new
strategies, such as three-component [m þ n þ o] cycliza-
tions, has become increasingly important.3 In the past
decade, rhodium-catalyzed[2þ2þ2] and[4þ2] cyclizations
have been elegantly demonstrated to assemble various six-
membered carbocycles.1b,4,5 However, only limited examples
of [3þ2þ1] cyclizations catalyzed by rhodium are reported
where CO acts as a one-carbon synthon.6 Recently, we
have reported a rhodium-catalyzed domino heterocycliza-
tion and [(3þ2)þ2] carbocyclization of diyne-enone 1 and
alkyne to afford fused tricycloheptadienes via a proposed
metallacycle intermediate4,7 where diyne-enone 1 could be
easily prepared by the palladium-catalyzed Sonogashira
(2) (a) Klunder, A. J. H.; Zhu, J.; Zwanenburg, B. Chem. Rev. 1999,
99, 1163. (b) Ho, T.-L. Enantioselective Synthesis: Natural Products
Synthesis from Chiral Terpenes; Wiley: New York, 1992. (c) Corey, E. J.
Angew. Chem., Int. Ed. 2002, 41, 1650. (d) Nicolaou, K. C.; Snyder, S. A.;
Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002, 41,
1668. (e) Mohr, P. J.; Halcomb, R. L. J. Am. Chem. Soc. 2003, 125, 1712. (f)
Furuya, S.; Terashima, S. Tetrahedron Lett. 2003, 44, 6875. (g) Taber, D. F.;
Storck, P. H. J. Org. Chem. 2003, 68, 7768. (h) Booker-Milbum, K. I.;
Jenkins, H.; Charmant, J. P. H.; Mohr, P. Org. Lett. 2003, 5, 3309. (i) Goeke,
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Takao, K.; Munakata, R.; Tadano, K. Chem. Rev. 2005, 105, 4779. (l)
Wilson, E. M.; Trauner, D. Org. Lett. 2007, 9, 1327. (m) Wessig, P.; M€uller,
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2008, 108, 5359. (o) Pellissier, H. Tetrahedron 2009, 65, 2839. (p) Juhl, M.;
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Rev. 1996, 96, 635. (b) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901.
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Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (e) Rubin, M.;
Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (f) Wender, P. A.;
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r
10.1021/ol102920f
Published on Web 01/06/2011
2011 American Chemical Society

cross-coupling reaction of R-bromo(iodo)-enones with
1,6-diynes. We envisaged that metallacycle intermediate
4 may be trapped by CO leading to a tricyclic scaffold 2.
Herein we describe a rhodium-catalyzed tandem hetero-
cyclization and [(3þ2)þ1] cyclization of diyne-enones 1
and CO to afford polycyclic furan scaffold 2, which could
be easily converted to highly substituted bicyclic phenols 3
in the presence of an oxidant (Scheme 1).8
Scheme 1. Rhodium-Catalyzed Carbonylative [(3þ2)þ1]
Cyclization
On the other hand, polycyclic furan structural units are
unique architectures usually found in biologically active
compounds.9 The viridin family (Figure 1, viridin, virone,
and wortmannolone) containing a fused tricyclic furan
scaffold has been attracted attention because of the potent
antiinflammatory and antibiotic properties and ability to
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reactions, see: (a) Murakami, M.; Itami, K.; Ubukata, M.; Tsuji, I.;
Ito, Y. J. Org. Chem. 1998, 63, 4. (b) Kamitani, A.; Chatani, N.; Morimoto,
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M. Chem. Commun. 2010, 5470.
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Soc. 2004, 126, 2714. (b) Jiao, L.; Lin, M.; Zhuo, L.-G.; Yu, Z.-X. Org. Lett.
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Zhang, S.; Wender, P. A.; Yu, Z.-X. J. Am. Chem. Soc. 2007, 129, 10060. (f) For
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Yamaura, R.; Ryu, I. Org. Lett. 2007, 9, 587.
Figure 1. Some natural products containing polycyclic furan or
phenol.
selectively block certain intracellular signaling pathways
associated with cell growth and development.9 Moreover,
phenols are commonly observed structural units in many
natural products, polymers, and pharmaceuticals.10 For
example, ligudentatol and ligujapone (Figure 1) are iso-
lated from Ligularia dentata roots that have been long
used as a medicinal herb for easing breathing, stimulating
blood flow, reducing inflammation, alleviating pain, stop-
ping coughs, and getting rid of phlegm.11 Furthermore,
bicyclic phenol compound 5 potentiated TXA2/PGH2
receptor antagonistic activities.12
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Lepage, L.; Lepage, Y. Synthesis 1983, 1018. (b) O'brien, B. A.; Lam,
W. Y.; DesMarteau, D. D. J. Org. Chem. 1986, 51, 4466. (c) Manfredi, K. P.;
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Org. Lett., Vol. 13, No. 4, 2011
689

Table 1. Optimization of Reaction Conditions
Scheme 2. Rhodium-Catalyzed [(3þ2)þ1] Cycloaddition
Reaction
entry
conditionsa
yield (%)b
1
[RhCl(cod)]2, toluene, 1 h
[RhCl(cod)]2, THF, 9 h
21
2
trace
41
3
[RhCl(cod)]2, Dioxane, 5 h
[RhCl(cod)]2, DCE, 2 h
4c
5
93
[RhCl(CO)2]2, DCE, 8 h
82
6d
7
[RhCl(CO)(PPh3)2], DCE, 30 h
[RhCl(cod)]2/AgSbF6 (10 mol %), DCE, 1.5 h
[RhCl(cod)]2, DCE, 4 h
-
trace
8e
90
a Conditions (unless otherwise noted): Rhodium (5.0 mol %), 1a
(0.01 M), CO (1.0 atm), 60 °C. b Yield determined by 1H NMR spectro-
scopy using dibromomethane as internal standard. c Yield of isolated
product. d The compound 3a was obtained in 48% isolated yield.
e Reaction carried out under 0.2 atm of CO (1 atm of mixture gas CO/
N2 = 1:4).
To optimize the reaction conditions for this rhodium-
catalyzed tandem heterocyclization and carbonylative
[(3þ2)þ1] cyclization, the influences of solvent, catalysts,
and the pressureofCOwere investigated forthereactionof
diyne-enone 1a with CO (Table 1). We began this exam-
ination by treating 1a with [RhCl(cod)]2 (5.0 mol %) in
toluene at 60 °C under carbon monoxide at atmospheric
pressure. To our delight, the [(3þ2)þ1) cyclization indeed
occurred, and the racemic tricyclic furan 2a was formed in
21% yield after 1 h (Table 1, entry 1). To further identify
optimal reaction conditions, THF, 1,4-dioxane, and 1,2-
dichloroethane (DCE) were screened, and it proved that
DCE is the best solvent for this transformation, affording
2a in 93% isolated yield after 2 h (Table 1, entries 2-4). We
then turned our attention to other rhodium complexes.
[RhCl(CO)2]2 can also catalyze this reaction but is less
efficient (Table 1, entry 5). Interestingly, when 1a is treated
with [RhCl(CO)(PPh3)2], a bicyclic phenol 3a can be
isolated in 48% yield, which may be converted from 2a
in the presence of oxygen that acts as the oxidant and
occasionally come into the reaction system from the air
(Table 1, entry 6).8g-j Furthermore, Rh(I)þ species
(genernated from 1:1 ratio [RhCl(cod)]2 þ AgSbF6 in situ)
failed to catalyze this transformation (Table 1, entry 7).
The reaction proceeds well under the lower pressure of CO
albeit it requires reaction time (Table 1, entry 8).
a Yield determined by 1H NMR spectroscopy using dibromomethane
as internal standard.
of 2h was further confirmed by the X-ray crystallographic
analysis.14 This study also demonstrated that carbon
and nitrogen tethers can be well tolerated (compounds
2a-k);13 however the oxygen-tethered substrate was de-
composed under the reaction conditions. Gratifyingly,
it is noteworthy that the diyne-enone 1l with a cyclohex-
enone moiety can also undergo the [(3þ2)þ1) cyclization
to afford the corresponding tetracyclic furan compound
2l in 88% yield under the standard reaction conditions
[eq 1] .
The scope of this rhodium-catalyzed [(3þ2)þ1] cycliza-
tion reation was next investigated using various diyne-
enone substrates (Scheme 2). The results indicate that this
cyclization is tolerant of different substitutions (R1-R3)
on the alkene, alkyne, and carbonyl moieties. The alkyne
terminus R3 can be the H, aryl, alkyl and trimethylsilyl
group, which has a great impact on the reaction rate but
has little effect on the yield (compounds 2a-j). The structure
(13) Attempted isolation of the compounds 2b and 2k resulted in
either decomposition or further oxidation.
(14) CCDC 795202 (2h) and 795203 (3a) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/datarequest/cif.
690
Org. Lett., Vol. 13, No. 4, 2011

To show the synthetic application of polycyclic furan
compounds, weinvestigatedaone-potsyntheticstrategyto
construct highly substituted polycyclic phenols 3 which
can be found in a wide range of compounds possessing
diverse biological activities. Fortunately, after several at-
tempts, we discovered that the polycyclic phenol structure
3a could be synthesized in 61% yields (two steps) by a
simple sequential one-pot operation, that is, Rh-catalyzed
carbonylative [(3þ2)þ1] cycloaddition of diyne-enone in
1,2-dichloroethane (DCE) at 60 °C, followed by treatment
with1.5 equivof3-chlorobenzoperoxoicacid(m-CPBA) at
room temperature (Scheme 3). The structure of 3a was
further confirmed by the X-ray crystallographic analysis.14
Scheme 3. One-Pot Synthesis of Polycyclic Phenols
Studies on the scope of this one-pot sequential reaction
indicate that it can be used to synthesize various multi-
functional highly substituted phenol derivatives 3 in mod-
erate to good yields, which are useful building blocks for
further functional transformation (Scheme 3). Different
R1-substituted carbonyls and R2-substituted alkenyls, in-
cluding alkyls and aryls, were proven to be efficient to
afford the desired products (compounds 3a-c). It is
noteworthy that the substrate containing both an alkyl
substituted carbonyl and alkene moiety can give the
corresponding bicyclic phenol 3c in 79% yield. In addition,
this one-pot operation strategy can be applied to various
substrates with different substituents on the alkyne moiety
(R3) to furnish the corresponding products (compounds
3d-i) in reasonable yields. The 1,2,3,4-tetrahydroisoqui-
nolin-7-ol derivative 3k can be afforded in 76% yield from
the corresponding TsN-tethered substrate. The use of 1l
bearing a cyclohexenone moeity again led to tricyclic
phenol compound 3l. A halogen on the substitutent is aslo
compatible (compounds 3m-n).
In conclusion, we have developed a simple and highly
efficient rhodium-catalyzed tandem heterocyclization and
carbonylative [(3þ2)þ1] cyclization reaction of readily
available diyne-enones and carbon monoxide for the
synthesis of a novel polycyclic furan scaffold with product
yields up to 96%, and a one-pot synthetic strategy to
construct synthetically useful polycyclic phenols. Current
efforts directed toward exploration of the full synthetic
potential of this methodology, including catalytic asymmetric
catalysis and its application in the synthesis of the natural
products, are ongoing in our laboratory.
Acknowledgment. We are grateful to the National Nat-
ural Science Foundation of China (20972054), Ministry of
Education of China (20090076110007, NCET), and 973
Program (2009CB825300) for financialsupport. This work
is also sponsored by the Fundamental Research Funds for
the Central Universities.
Supporting Information Available. Experimental pro-
cedures, spectroscopic data for the substrates and prod-
ucts (PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 4, 2011
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