Synthesis of benzodiquinanes via tandem palladium-catalyzed semipinacol rearrangement and direct arylation

Article abstract of DOI:10.1021/ol1026415

A palladium-catalyzed tandem semipinacol rearrangement/direct arylation reaction using α-aryl isopropenyl-tert-cyclobutanols has been developed. This reaction gives access to benzodiquinanes in moderate to good yields and tolerates alkyl-, alkoxy-, and ha

Full text of DOI:10.1021/ol1026415

ORGANIC
LETTERS
2011
Vol. 13, No. 2
232-235
Synthesis of Benzodiquinanes via
Tandem Palladium-Catalyzed
Semipinacol Rearrangement and Direct
Arylation
Angelika Schweinitz, Andrei Chtchemelinine, and Arturo Orellana*
Department of Chemistry, York UniVersity, 440 Chemistry Building,
4700 Keele Street, Toronto, ON, Canada M3J 1P3
aorellan@yorku.ca
Received October 31, 2010
ABSTRACT
A palladium-catalyzed tandem semipinacol rearrangement/direct arylation reaction using r-aryl isopropenyl-tert-cyclobutanols has been developed.
This reaction gives access to benzodiquinanes in moderate to good yields and tolerates alkyl-, alkoxy-, and halogen-substituted aryl groups.
Palladium-catalyzed reactions have had a great impact on
our ability to construct complex molecules. Traditionally,
palladium-catalyzed carbon-carbon bond forming cross-
coupling reactions have required the use of an oxidative
addition partner and an organometallic reagent.1 More
recently there has been significant focus on carbon-carbon
bond-forming reactions that do not require the use of an
oxidative addition partner, an organometallic partner, or
either. Research into direct arylation reactions involving aryl-
and benzylpalladium(II) intermediates has been particularly
intense.2 In contrast, reports of direct arylation reactions
proceeding through alkylpalladium(II) intermediates are
relatively rare,3 reflecting the difficulties resulting from
competitive ꢀ-hydride elimination processes.4 Not surpris-
ingly, alkylpalladium(II) intermediates incapable of ꢀ-hydride
elimination have been strategically utilized in direct aryla-
tions. Methods to generate these intermediates include
migratory insertion across a 1,1-disubstituted alkene and
palladium-catalyzed fragmentation of 2,2-disubstituted tert-
cyclobutanols.5
The indane and diquinane scaffolds are commonly occur-
ring features in pharmaceutical agents and natural products.
(1) For reviews on traditional cross-coupling reactions, see: (a) Diederich,
F.; Stang, P. J. Eds. Metal-Catalyzed Cross-Coupling Reactions; Wiley-
VCH: New York, 1998. (b) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. ReV. 2002, 102, 1359.
(3) For a discussion, see: (a) Rene´, O.; Lapointe, D.; Fagnou, K. Org.
Lett. 2009, 11, 4560. For examples of direct arylation with alkyl palla-
dium(II) intermediates capable of ꢀ-hydride elimination see: (b) Song, Z. Z.;
Wong, H. N. C. J. Org. Chem. 1994, 59, 33. (c) Hu, Y.; Yu, C.; Ren, D.;
Hu, Q.; Zhang, L.; Cheng, D. Angew. Chem., Int. Ed. 2009, 48, 5448.
(4) (a) Ozawa, F.; Ito, T.; Yamamoto, A. J. Am. Chem. Soc. 1980, 102,
6457. (b) Hartwig, J. Organotransition Metal Chemistry: From Bonding to
Catalysis; University Science Books: Sausalito, CA, 2009; Chapter 10, pp
398-402.
(5) For examples of direct arylation using alkylpalladium intermediates
generated from cyclobutanol fragmentation, see: (a) Nishimura, T.; Ohe,
K.; Uemura, S. J. Am. Chem. Soc. 1999, 121, 2645. (b) Nishimura, T.;
Ohe, K.; Uemura, S. J. Org. Chem. 2001, 66, 1455. For the analogous
reaction using cyclobutanone oximes, see: (c) Nishimura, T.; Uemura, S.
J. Am. Chem. Soc. 2000, 122, 12049.
(2) For selected recent reviews on direct arylation, see: (a) Bellina, F.;
Rossi, R. Chem. ReV. 2010, 110, 1082. (b) Bellina, F.; Rossi, R. Tetrahedron
2009, 65, 10269. (c) McGlacken, G. P.; Bateman, L. M. Chem. Soc. ReV.
2009, 38, 2447. (d) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu,
J.-Q. Chem. Soc. ReV. 2009, 38, 3242. (e) Ackermann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (f) Catellani, M.;
Motti, E.; Della Ca, N. Acc. Chem. Res. 2008, 41, 1512. (g) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174. (h) Campeau, L.-C.;
Stuart, D. R.; Fagnou, K. Aldrichimica Acta 2007, 40, 35. (i) Satoh, T.;
Miura, M. Chem. Lett. 2007, 36, 200. (j) Campeau, L.-C.; Fagnou, K. Chem.
Commun. 2006, 1253.
10.1021/ol1026415  2011 American Chemical Society
Published on Web 12/16/2010

In contrast, the benzodiquinane6 framework is relatively rare;
nevertheless, its synthesis has attracted some attention.
Sporadic reports of benzodiquinane synthesis initiated by
oxidative addition of Pd(0) across an Ar-X bond have
appeared.7 In addition, two methods for the synthesis of
benzodiquinanes via direct arylation have been developed.
In 2002 Toyota and Ihara8 reported a few examples of
the direct coupling of palladium enolates with tethered
aryl groups to generate benzodiquinanes (eq 1). One
drawback of this method is the need for stoichiometric
palladium. More recently, Willis9 reported an efficient
intramolecular direct arylation route to this class of
compounds (eq 2).
Scheme 1. Proposed Synthesis of Benzodiquinanes
Substrates for this study could be readily prepared from
the corresponding benzaldehydes using a three-step sequence
involving methylenecyclopropane synthesis, oxidative rear-
rangement to an R-arylcyclobutanone, and diastereoselective
1,2-addition of an isopropenyl Grignard (eq 3).13 Importantly,
the synthesis of R-arylcyclobutanones is subject to enanti-
oselective synthesis.14
Our interest in expanding the chemistry of palladium
homoenolates10 and palladium-catalyzed strain-releasing
reactions, coupled with the relatively few methods available
for the synthesis of benzodiquinanes, prompted us to explore
a new strategy for their preparation. We envisioned that the
alkene function of an R-aryl substituted alkenyl tert-
cyclobutanol I would coordinate with an electrophilic pal-
ladium intermediate and promote a 1,2-alkyl shift11 to
generate a palladium homoenolate IV (Scheme 1). We
surmised that a certain degree of selectivity could be achieved
if the palladium electrophile could coordinate the alkene and
the hydroxy group simultaneously as in III.12 The resulting
palladium homoenolate could in principle participate in a
direct arylation reaction to generate the target compound V.
Initial experiments conducted on tert-cyclobutanol 1 and
using stoichiometric amounts of PdCl2 resulted in the
formation of the desired benzodiquinane product 2 in 10%
yield (Table 1, entry 1). A suite of NMR experiments was
used to establish the structure of the product, and NOE
difference experiments confirmed the cis-fusion of the
diquinane (inset). The use of 20 mol % Pd(OAc)2 and
molecular oxygen did not result in a significant improvement
(entry 2). A further increase in yield was observed when
Ag2CO3 was used as the base and oxidant in solvent mixtures
containing DMSO (entries 4 to 7). The use of DMSO in
toluene in an overnight reaction provided ketone 2 in 48%
yield accompanied with a 16% yield of the R,ꢀ-unsaturated
ketone 3 (entry 5). Under the same conditions, a 58% yield
of 2 was obtained after 1 h (entry 6). A comparable yield
was obtained when the reaction was conducted in DMSO
after 5 h (entry 7). When CH3CN was used as the sole solvent
ketone 2 was obtained in 56% yield; however the reaction
time was not practical (entry 8). Using a mixture of DMSO
(6) Buchanan, G. O.; Williams, P. G.; Feling, R. H.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Org. Lett. 2005, 7, 2731.
(7) Cascade Heck reaction: (a) Abelman, M. M.; Overman, L. E. J. Am.
Chem. Soc. 1988, 110, 2328. Carbonylative polyene cyclization: (b) Cope´ret,
C.; Ma, S.; Negishi, E. Angew. Chem., Int. Ed. Engl. 1996, 35, 2125.
Reductive Heck reaction: (c) Corkey, B. K.; Toste, F. D. J. Am. Chem.
Soc. 2007, 129, 2764. Fragmentation of tert-cyclobutanols: (d) Ethirajan,
M.; Oh, H.-S.; Cha, J. K. Org. Lett. 2007, 9, 2693. C(sp3)-H activation:
(e) Hitce, J.; Retailleau, P.; Baudoin, O. Chem.sEur. J. 2007, 13, 792. (f)
Rousseaux, S.; Davi, M.; Sofack-Kreutzer, J.; Pierre, C.; Kefalidis, C. E.;
Clot, E.; Fagnou, K.; Baudoin, O. J. Am. Chem. Soc. 2010, 132, 10706.
(8) Toyota, M.; Ilangovan, A.; Okamoto, R.; Masaki, T.; Arakawa, M.;
Ihara, M. Org. Lett. 2002, 4, 4293.
(9) Cruz, A. C. F.; Miller, N. D.; Willis, M. C. Org. Lett. 2007, 9, 4391.
(10) For a good entry into the metal homoenolate literature, see: (a)
Molander, G. A.; Jean-Ge´rard, L. J. Org. Chem. 2009, 74, 1297. For
examples of palladium homoenolate formation Via directed C(sp3)-H
activation and subsequent cross-coupling, see: (b) Giri, R.; Maugel, N.; Li,
J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am.
Chem. Soc. 2007, 129, 3510. (c) Wang, D.-H.; Wasa, M.; Giri, R.; Yu,
J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. (d) Wasa, M.; Engle, K. M.; Yu,
J.-Q. J. Am. Chem. Soc. 2009, 131, 9886. For a recent example of formal
homoenolate arylation, see: (e) Renaudat, A.; Ludivine, J.-G.; Jazzar, R.;
Kefalidis, C. E.; Clot, E.; Baudoin, O. Angew. Chem., Int. Ed. 2010, 49,
7261.
(12) This type of coordination of alkenylcyclobutanols has been invoked
before; see: (a) Nemoto, H.; Miyata, J.; Yoshida, M.; Raku, N.; Fukumoto,
K. J. Org. Chem. 1997, 62, 7850. (b) Nemoto, H.; Yoshida, M.; Fukumoto,
K.; Ihara, M. Tetrahedron Lett. 1999, 40, 907. (c) Yoshida, M.; Ismail,
M. A.-H.; Nemoto, H.; Ihara, M. J. Chem. Soc., Perkin Trans. 1 2000,
2629.
(13) See Supporting Information for details.
(14) Wang, B.; Shen, Y.-M.; Shi, Y. J. Org. Chem. 2006, 71, 9519.
(11) Trost, B. M.; Xie, J. J. Am. Chem. Soc. 2008, 130, 6231.
Org. Lett., Vol. 13, No. 2, 2011
233

Table 1. Reaction Developmenta
Table 2. Scope of the Benzodiquinane Synthesisa b
,
PdX2
base and
time (h),
entry (equiv) oxidant (equiv) solvent temp (°C) yieldc d(%)
,
1
2
PdCl2 (1.0) Cs2CO3 (1.1)
Pd(OAc)2 K2CO3 (1.0)
DMA
48, 80
5, 100
4, 100
68, 75
10
(0.2)
O2 (ballon)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
DMA
DMF/
23
3
4
5
6
7
8
9
Pd(OAc)2
(0.2)
DMSOb
37
Pd(OAc)2
(0.2)
Pd(OAc)2
(0.1)
Pd(OAc)2
(0.1)
Pd(OAc)2
(0.1)
Pd(OAc)2
(0.1)
Pd(OAc)2
(0.1)
CH3CN/
DMSOb
48
toluene/
DMSOb 14, 100
48 (16)d
58
toluene/
DMSOb
1, 100
5, 100
69, 75
72, 85
DMSO
50
CH3CN
56
toluene/
DMSOb
48 (29)d
a All reactions were conducted on 30 mg of substrate at 0.14 M
concentration. b A 5% solution of DMSO in the corresponding solvent was
used. c Isolated yields of benzodiquinane 2. d Yield of unsaturated ben-
zodiquinane 3 in parentheses.
in toluene and reducing the reaction temperature to 85 °C
increased the overall yield (2 + 3) of the reaction to 77%
albeit over an extended reaction time (entry 9).
The scope of the reaction was explored using a toluene/
DMSO solvent mixture at 100 °C to maintain short
reaction times and avoid the formation of overoxidized
product (Table 1, entry 6). A variety of substrates bearing
methyl, alkoxy, and halogen substituents were readily
prepared. The preparation of substrates bearing electro-
philic substituents, (i.e., ketones or esters) on the aryl
groups is hampered by the low nucleophilicity of the
methylenecyclopropanes used for the synthesis of R-aryl
cyclobutanones. Furthermore, ketones and esters would
be subject to nucleophilic attack by the Grignard reagents
and were therefore not explored.
Substrates bearing a phenyl or p-tolyl ring provided the
benzodiquinane products in 48% and 66% yields, respec-
tively (Table 2, entries 1 and 2). Substrates bearing
p-fluorophenyl, p-chlorophenyl, and o,p-dichlorophenyl
groups provided the benzodiquinane products in 45%,
48%, and 56% yields, respectively (entries 3, 4, and 6).
A significantly lower yield was obtained with a substrate
bearing a p-bromophenyl substituent, presumably due to
an undesired oxidative addition to the aryl bromide (entry
5). Substrates bearing o-anisyl and 3,4,5-trimethoxyphenyl
groups provided the benzodiquinane products in 53% yield
(entries 7 and 8).
a All reactions were conducted on 30 mg of substrate and 20 mol % of
Pd(OAc)2 using the reactions conditions in Table 1, entry 6. b Isolated yields
of the benzodiquinane products.
We explored the possibility of the halogen or alkoxy
substituents exerting a directing effect during the direct
arylation step (Table 3). Subjection of tert-cyclobutanol 20,
bearing a m-bromophenyl group capable of direct arylation
at two distinct sites, provided benzodiquinanes 22 and 23 in
a nearly 1:1 ratio and low yield. In contrast, the use of
substrate 21, bearing a 3-methoxy-4-ethoxyphenyl group,
provided benzodiquinanes 24 and 25 in a 1:3.4 ratio and 48%
overall yield.
The generally moderate yields observed in this reaction
suggest that at least one alternative reaction pathway leading
to undesired products is available. For instance, we have
observed the formation of products arising from a palladium-
234
Org. Lett., Vol. 13, No. 2, 2011

Table 3. Regioselectivity of Benzodiquinane Synthesisa b
,
In conclusion, we have developed a new palladium-
catalyzed route to the benzodiquinane scaffold using
R-aryl isopropenyl-tert-cyclobutanols, proceeding through
a semipinacol rearrangement and direct arylation. A
variety of tert-cyclobutanols bearing alkyl-, halo-, and
alkoxy-substituted aryl groups participate in this reaction
and provide the desired products in moderate to good
yields.
Acknowledgment. We gratefully acknowledge the support
of this work from York University and the Natural Sciences
and Engineering Research Council of Canada (Discovery and
RTI programs).
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://
pubs.acs.org.
a All reactions were conducted using 20 mol % Pd(OAc)2 using the
reaction conditions in Table 1, entry 6. b Isolated yields of the ben-
zodiquinane products.
OL1026415
(15) For an early example of palladium-catalyzed ꢀ-carboelimination
of alkenyl-tert-cyclobutanols under oxidative conditions, see ref 5b. For a
related rhodium-catalyzed C-C activation of allenyl-tert-cyclobutanols, see:
(b) Seiser, T.; Cramer, N. Angew. Chem., Int. Ed. 2008, 47, 9294.
(16) Zhang, H.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem., Int. Ed.
2004, 43, 6144.
catalyzed ꢀ-carboelimination15 and ꢀ-hydride elimination
process using the reaction conditions developed by Stoltz16
for oxidative Heck reactions using electron-rich arenes (eq
3).
Org. Lett., Vol. 13, No. 2, 2011
235