Palladium-promoted [2 + 2 + 2] cocyclization of arynes and unsymmetrical conjugated dienes: Synthesis of justicidin B and retrojusticidin B

Article abstract of DOI:10.1021/ol3028658

A facile synthesis of natural and unnatural arylnaphthalenes has been demonstrated via the unprecedented palladium-promoted [2 + 2 + 2] cocyclization of arynes and unsymmetrical conjugated dienes using the N-heterocyclic carbene as a ligand. The unsymmetr

Full text of DOI:10.1021/ol3028658

ORGANIC
LETTERS
2013
Vol. 15, No. 1
14–17
Palladium-Promoted [2 þ 2 þ 2]
Cocyclization of Arynes and Unsymmetrical
Conjugated Dienes: Synthesis of Justicidin
B and Retrojusticidin B
Ramesh M. Patel and Narshinha P. Argade*
Division of Organic Chemistry, National Chemical Laboratory (CSIR), Pune 411 008,
India
np.argade@ncl.res.in
Received October 18, 2012
ABSTRACT
A facile synthesis of natural and unnatural arylnaphthalenes has been demonstrated via the unprecedented palladium-promoted [2 þ 2 þ 2]
cocyclization of arynes and unsymmetrical conjugated dienes using the N-heterocyclic carbene as a ligand. The unsymmetrical dienes used herein
are actually R-coupled acrylateꢀcinnamate combinations bearing two β-positive carbons and follow the key [2 þ 2 þ 2] cocyclization pathway.
A transition-metal-catalyzed [2 þ 2 þ 2] cocyclization of
multiple bonds has been an atom economical and useful
methodology for the synthesis of an array of polycyclic
compounds.1 The recent development of new methods
for generation of arynes under mild conditions has led to
the promising exploration of metal-mediated cocyclization
reactions of arynes.2 A large number of nickel-/palladium-
catalyzed [2 þ 2 þ 2] cocyclizations of arynes with several
electron-rich substrates such as alkynes, diynes, allyl deriv-
atives, allenes, ortho-halobiphenyls, halo-styrenes, and
carbon monoxide have been reported in the literature.3
However, the metal-catalyzed [2 þ 2 þ 2] cocyclization of
arynes with different types of alkenes result in the cotrimer-
ization adducts utilizing the two units of corresponding
arynes and/or ortho-olefinated biaryls.4 There have been no
reports on metal-catalyzed [2 þ 2 þ 2] cocyclizations of
arynes by using two kinds of alkenes or dienes as an
arynophile. Recently, our research group has reported the
first SN20 coupling reaction of Wittig reagents with dimethyl
(1) (a) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539.
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A.; Sato, Y. Chem. Commun. 2009, 4284.
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1211. (b) Kitamura, T.; Yamane, M.; Inoue, K.; Todaka, M.; Fukatsu,
N.; Meng, Z.; Fujiwara, Y. J. Am. Chem. Soc. 1999, 121, 11674. (c) Pena,
D.; Escudero, S.; Perez, D.; Guitian, E.; Castedo, L. Angew. Chem., Int.
Ed. 1998, 37, 2659. (d) Yoshioka, E.; Kohtani, S.; Miyabe, H. Angew.
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D. G.; Finlayson, J.; Greaney, M. F. Org. Lett. 2011, 13, 3667. (f)
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2022 and references cited therein.
r
10.1021/ol3028658
Published on Web 12/13/2012
2012 American Chemical Society

Table 1. Optimization of Reaction Conditions for Palladium-
Promoted [2 þ 2 þ 2] Cocyclization of Diene 4a with an Arynea
entry
reaction conditionsb
5/6a (% yield)
1
2
3
4
5
6
7
8
9
CsF, CH3CN, rt, 24 h
5 (32)
5 (11)
NRc
CsF, CH3CN, reflux, 24 h
Ni(cod)2, PPh3, CsF, CH3CN, rt, 24 h
Ni(cod)2, PPh3, CsF, CH3CN, reflux, 24 h
Pd2(dba)3, CsF, CH3CN, rt, 24 h
NRc
NRc
Pd2(dba)3, CsF, CH3CN, reflux, 24 h
Pd2(dba)3, PPh3, CsF, CH3CN, reflux, 24 h
Pd2(dba)3, P(o-tol)3, CsF, CH3CN, reflux, 24 h
Pd(PPh3)4, CsF, CH3CN, reflux, 24 h
6a (42)
6a (23)
6a (20)
6a (08)
NRc
10 PdCl2(PPh3)2, CsF, CH3CN, reflux, 24 h
Figure 1. Naturally occurring bioactive arylnaphthalenes.
11 Pd2(dba)3, IMes.HCl, CsF, CH3CN, reflux, 24 h
6a (62)
a In all the above mentioned reactions in Table 1, formation of a
small amount of benzyne trimer, dimer of diene, and polymeric gums
were noticed on prolonged stirring at rt or under the reflux conditions.
b 15 mol % of catalyst, 30 mol % of ligand, 1.50 equiv of diene 4a, and
3.00 equiv of CsF were used. c NR: No reaction.
bromomethylfumarate to synthesize various enes/dienes
and utilize them to construct a lignan class of natural
products.5,6 We reasoned that these unsymmetrical conju-
gated dienes are indeed R-coupled to two different dieno-
philes and their cocyclization reactions with arynes would
provide a new approach to regioselectively construct a
broad range of an arylnaphthalene class of natural products
(Figure 1). In this context, we herein report our results on
the synthesis of a variety of natural and unnatural aryl-
naphthalene architectures (Schemes 1ꢀ4 and Table 1).
the corresponding air oxidized [4 þ 2] cycloaddition
product 3 in 92% yield (Scheme 1). The possible driving
force for the present [4 þ 2] cycloaddition could be the
zero dipole moment at the carbonꢀcarbon single bond in
compound 2. However, the reaction of aryne and β-sub-
stitued unsymmetrical conjugated diene 4a at room tem-
perature under a similar set ofreaction conditionsfollowed
a different course and formed cyclobutane derivative 5
in 32% yield with the recovery of ∼30% starting diene
(Table 1, entry 1). The same reaction in refluxing CH3CN
formed a complex reaction mixture and provided an even
lesser amount of dipolar [2 þ 2] cycloaddition product 5
(11%), devoid of the formation of even traces of a [4 þ 2]
cycloaddition product (Table 1, entry 2). The above spec-
ified reactions followed an alternate dipolar [2 þ 2]
cycloaddition route selectively utilizing the less substituted
more reactive carbonꢀcarbon double bond from the
acrylate part in the unsymmetrical conjugated diene 4a.
The clockwise/anticlockwise electron cascade for the [4 þ 2]
cycloaddition reaction with unsymmetrical conjugated
diene 4a would be against the thermodynamics due
the presence of two different R,β-unsaturated systems
(two β-positive carbons). Therefore a systematic study
of transition-metal-catalyzed [2 þ 2 þ 2] cycloaddition
reactions of arynes and unsymmetrical conjugated dienes
was undertaken to achieve the formation of six-membered
cycloadducts to provide a new general approach to an
arylnaphthalene structural design.
Scheme 1. [4 þ 2] Cycloaddition Reaction of Symmetrical
Conjugated Diene 2 with an Aryne
A pilot reaction of aryne and symmetrical conjugated
diene 2 in CH3CN at room temperature directly furnished
(5) Patel, R. M.; Argade, N. P. J. Org. Chem. 2007, 72, 4900.
(6) (a) El-Assal, L. S.; Shehab, A. H. J. Chem. Soc. 1963, 2983. (b)
Rao, B. W. G.; Row, L. R.; Satyanarayan, P. Indian J. Chem. 1978, 16B,
68. (c) Ogiku, T.; Yoshida, S.; Ohmizu, H.; Iwasaki, T. J. Org. Chem.
1995, 60, 4585. (d) Kobayashi, K.; Uneda, T.; Takeda, K.; Tanaka, H.;
Kitamura, T.; Morikawa, O.; Konishi, H. J. Org. Chem. 1997, 62, 664.
(e) Charlton, J. L.; Oleschuk, C. J.; Chee, G.-L. J. Org. Chem. 1996, 61,
3452. (f) Sugahara, M.; Moritani, Y.; Terakawa, Y.; Ogiku, T.; Ukita,
T.; Iwasaki, T. Tetrahedron Lett. 1998, 39, 1377. (g) Ukita, T.;
Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Takahashi, M.; Kotera, J.;
Ikeo, T. J. Med. Chem. 1999, 42, 1293. (h) Iwasawa, N.; Shido, M.;
Maeyama, H. J. Am. Chem. Soc. 2000, 122, 10226. (i) Mizuhune, H.;
Nakamura, M.; Mitsudera, H. Tetrahedron Lett. 2001, 42, 437. (j) Pelter,
A.; Ward, R. S.; Venkateswarlu, R.; Kamakashi, C.; Moinuddin,
S. G. A.; Subhash, P. V.; Hursthouse, M. B.; Coles, S. J.; Light, M. E.
Tetrahedron 2001, 57, 7755. (k) Huang, Q.; Larock, R. C. J. Org. Chem.
2003, 68, 7342. (l) Nishii, Y.; Yoshida, T.; Asano, H.; Wakasugi, K.;
Morita, J.-I.; Aso, Y.; Yoshida, E.; Motoyoshiya, J.; Aoyama, H.;
Tanabe, Y. J. Org. Chem. 2005, 70, 2667. (m) Foley, P.; Eghbali, N.;
Anastas, P. T. J. Nat. Prod. 2010, 73, 811 and references cited therein.
The reaction of aryne and diene 4a in CH3CN using
the Ni(cod)2 catalyst and PPh3 ligand at room temperature
or under reflux conditions was futile with the reasonable
recovery of starting diene (Table 1, entries 3 and 4). The
palladium-promoted [2 þ 2 þ 2] cocyclization reaction of
Org. Lett., Vol. 15, No. 1, 2013
15

complex mixture. These observations preclude the possi-
bility of 5 being the intermediate in the formation of prod-
uct 6a. Finally, the unprecedented palladium-catalyzed
[2 þ 2 þ 2] cocyclization of unsymmetrical conjugated
dienes was generalized by using aryne precursors 1a/b and
dienes4aꢀc todirectly obtain the desiredarylnaphthalenes
6aꢀf in 58ꢀ66% yields (Scheme 2).
Scheme 2. Generalization of Palladium-Promoted [2 þ 2 þ 2]
Cocyclization of Unsymmetrical Dienes 4aꢀc with Arynes
In the above-mentioned reactions, the net [4 þ 2] addi-
tion products are formed via a [2 þ 2 þ 2] cocyclization
mechanism utilizing the directionally opposite Michael
type addition reactions of two different R-coupled dieno-
philes. Aplausiblemechanism forthepalladium-promoted
[2 þ 2 þ 2] cocyclization of aryne and diene 4a has been
depicted in Scheme 3. The catalytic cycle initiates with
the oxidative insertion of Pd0 to aryne and the less sub-
stituted double bond of diene to form a five-membered
palladacycle A. The formed palladacycle is stabilized by an
intramolecular coordination of the carbonyl oxygen atom
from an R,β-unsaturated ester moiety with the formation
of a five-membered transition state.8 Subsequent insertion
of the more substituted double bond into the PdꢀC (alkyl)
bond via rearrangement of a five-membered palladacycle
A to a seven-membered palladacycle forms the intermedi-
ate B. The reductive removal of zerovalent Pd from inter-
mediate B leads to intermediate C with the regeneration of
the catalyst. The intermediate C bears an activated allylic-
doubly benzylic reactive carbon atom. Thus the highly
oxidation prone intermediate C instantaneously oxidizes
to arylnaphthalene 6a during the workup operations of the
reaction mixture. The alternate possibility of diene 4a
forming the five-membered palladacycle followed by the
reaction with aryne to form the intermediate B would also
be a stepwise [2 þ 2 þ 2] cocyclization process due to the
presence of two β-positive carbons in the unsymmetrical
conjugated diene 4a.
aryne and diene 4a in CH3CN using the Pd2(dba)3 catalyst
was also unsuccessful at room temperature (Table 1, entry 5).
The same reaction under reflux conditions delivered the
desired arylnaphthalene product 6a in 24% yield follow-
ing the [2 þ 2 þ 2] cocyclization and postreaction facile air
oxidation pathways. All our attempts to isolate the corre-
sponding formed dihydronaphthalene intermediates failed
due to the very high air oxidation propensity of these
superactivated systems to gain complete aromaticity. On
optimization of reaction conditions, the yield of arylnaphtha-
lene 6a improved only up to 42% (Table 1, entry 6).
Attempts to further improve the yield using different
ligands such as PPh3, P(o-tol)3, and dppf; various solvents
such as toluene or a toluene/CH3CN mixture; varying
molar ratios of reactant/reagents; and different palladium
catalysts such as Pd(PPh3)4, PdCl2(PPh3)2, and Pd(OAc)2
were also ineffective (Table 1). Finally, the promising
N-heterocyclic carbene ligand was used for the further
improvement of yield.7 The use of aryne precursor 1a
(1.00 equiv), diene 4a (1.50 equiv), the Pd2(dba)3 catalyst
(15 mol %), the 1,3-bis(2,4,6-trimethyl)phenyl imidazo-
Scheme 3. Plausible Mechanism for Palladium-Promoted
[2 þ 2 þ 2] Cocyclization of an Unsymmetrical Conjugated
Diene with an Aryne
lium chloride ligand (IMes HCl) (30 mol %), and CsF
3
(3.00 equiv) in CH3CN under reflux conditions furnished
the desired product 6a in 62% yield (Table 1, entry 11).
Herein the use of 15 mol % palladium catalyst was
essential as the use of catalytic amounts majorly resulted
in a mixture of undesired coupling products. In the above-
mentioned palladium promoted formation of compound
6a, we never noticed the generation of compound 5 as the
possible intermediate at room temperature/reflux condi-
tions before or after the workup (Table 1, entries 5 and 6).
In our hands 5 on exposure to a similar set of palladium-
catalyzed cocyclization reaction conditions resulted in the
(7) (a) Nolan, S. P. U.S. Pat. Appl. Publ. 20067109348 B1, 2006. (b)
Hintermann, L. Beilstein J. Org. Chem. 2007, 3, No. 22. (c) Herrmann,
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The utility of synthesized imperative advanced inter-
mediates 6b, 6c, and6e has been previously well demonstrated
(8) Qiu, Z.; Xie, Z. J. Am. Chem. Soc. 2009, 131, 2084.
Org. Lett., Vol. 15, No. 1, 2013
16

product justicidin B (8) in 28% yield.9 Starting from diene
4b, the total synthesis of justicidin B (8) and retrojusticidin
B (9) was completed in three steps with 44% and 39%
overall yields respectively. The analytical and spectral data
obtained for both natural products were in complete
agreement with reported data.9ꢀ11
Scheme 4. Concise Synthesis ofJusticidin B andRetrojusticidin B
In summary, a novel palladium-promoted [2 þ 2 þ 2]
cocyclization of arynes and apparently conjugated unsym-
metrical dienes to arylnaphthalene frameworks with the
stepwise formation of two new carbonꢀcarbon bonds has
been described. The versatility of this method is demon-
strated through the concise synthesis of justicidin B and
retrojusticidin B and formal synthesis of several analogous
bioactive natural products. The described convergent ap-
proach is general in nature and would provide a facile
pathway for the synthesis of various symmetrical/unsym-
metrical arylnaphthalene lignans. The present strategy for
the generation of biaryl systems without the arylꢀaryl
coupling is noteworthy.12
in the synthesis of several bioactive natural products.9,10
The synthesis of anti-HIV natural products justicidin B
and retrojusticidin B was planned from product 6e.11 The
sterically unhindered ester in compound 6e was regioselec-
tively hydrolyzed by using potassium trimethylsilonate in
THF at room temperature to form compound 7 in 87%
yield (Scheme 4). The chemoselective reduction of an acid
functionality in 7 with a borane dimethyl sulfide complex
followed by an acidic workup gave the justicidin B (8)
in 76% yield.9 Alternatively, chemoselective ester reduc-
tion of the sodium salt of compound 7 with the lithium
borohydride followed by an acidification gave a column
chromatographically separable mixture of expected major
product retrojusticidin B (9) in 67% yield and minor
Acknowledgment. R.M.P. thanks CSIR, New Delhi,
for the award of a research fellowship. N.P.A. thanks the
Department of Science and Technology, New Delhi for
financial support.
Supporting Information Available. Experimental pro-
1
cedures; tabulated analytical and spectral data; and H
NMR, 13C NMR, and DEPT spectra of compounds 3, 5,
6aꢀf, and 7ꢀ9. This material is available free of charge
via the Internet at http://pubs.acs.org.
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The authors declare no competing financial interest.
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