Palladium-catalyzed cyclization of 1,ω-dienols: Multiple ways to intramolecularly trap a carbocation

Article abstract of DOI:10.1021/jo0705871

(Chemical Equation Presented) The tandem catalytic cyclization- rearrangement of 1,ω-dien-3-ols by palladium(II) produces different types of products, depending on the structure of starting material. The pinacol rearrangement, benzannulation, and oxy-Cope rearrangement are major pathways of transforming the putative σ-alkylpalladium carbocation. Turnover of the cyclization is achieved by β-hydride elimination and reoxidation of palladium with benzoquinone. The overall course of the reaction is very sensitive to small changes in the substrate structure.

Full text of DOI:10.1021/jo0705871

Palladium-Catalyzed Cyclization of 1,ω-Dienols: Multiple Ways to
Intramolecularly Trap a Carbocation
Vasily N. Korotchenko and Michel R. Gagne´*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599-3290
mgagne@unc.edu
ReceiVed March 26, 2007
The tandem catalytic cyclization-rearrangement of 1,ω-dien-3-ols by palladium(II) produces different
types of products, depending on the structure of starting material. The pinacol rearrangement,
benzannulation, and oxy-Cope rearrangement are major pathways of transforming the putative σ-alkyl-
palladium carbocation. Turnover of the cyclization is achieved by â-hydride elimination and reoxidation
of palladium with benzoquinone. The overall course of the reaction is very sensitive to small changes in
the substrate structure.
SCHEME 1
The electrophilic activation of unactivated double bonds by
palladium(II) toward O-, N-, and C-nucleophiles constitutes an
important class of complexity generating reactions.1,2 Nucleo-
philic attack on the palladium-olefin complex results in a new
nucleophile-carbon bond and a σ-alkylpalladium complex,
which may then participate in additional reactions.3 In Pd(II)-
catalyzed Cope reactions of 1,5-dienes, the nucleophile is
another alkene and these processes transiently create carbenium
ion character at C5 of a cyclic intermediate (Scheme 1),4 which
subsequently fragments to product and regenerated catalyst.5
Mechanistic studies additionally implicated antarafacial attack
at the Pd-alkene and a chairlike transition structure.6,7
Recent efforts in our laboratory have sought to trap this
putative cation prior to the fragmentation; an example of
intramolecular trapping by a pendant phenol is shown in Scheme
2.8,9 Catalyst turnover in this instance was achieved by
(1) Palladium reagents and catalysts: new perspectiVes for the 21st
century; Tsuji, J., Ed.; Wiley: Hoboken, NJ, 2004.
(2) Transition Metals in the Synthesis of Complex Organic Molecules;
Hegedus, L. S., Ed.; University Science Books: Sausalito, CA, 1999.
(3) For several recent forum articles on this topic see: (a) Cornell, C.
N.; Sigman, M. S. Inorg. Chem. 2007, 46, 1903-1909. (b) Kotov, V.;
Scarborough, C. C.; Stahl, S. S. Inorg. Chem. 2007, 46, 1910-1923.
(4) (a) Overman, L. E.; Knoll, F. M. J. Am. Chem. Soc. 1980, 102, 865-
867. (b) Overman, L. E.; Jacobsen, E. J. J. Am. Chem. Soc. 1982, 104,
7225-7231. (c) Overman, L. E. Angew. Chem., Int. Ed. 1984, 23, 579-
586. (d) Overman, L. E.; Renaldo, A. F. J. Am. Chem. Soc. 1990, 112,
3945-3949.
(5) For early cases with stoichiometric quantities of Pd(II), see: (a)
Trebellas, J. C.; Olechovski, J. R.; Jonassen, H. B. J. Organomet. Chem.
1966, 6, 412-420. (b) Heimbach, P.; Molin, M. J. Organomet. Chem. 1973,
49, 477-482. (c) Heimbach, P.; Molin, M. J. Organomet. Chem. 1973, 49,
483-494. (d) Brown, E. D.; Sam, T. W.; Sutherland, J.; K.; Torre, A. J.
Chem. Soc., Perkin Trans. 1 1975, 2326-2332. (e) Hegedus, L. S.; Williams,
R. E.; McGuire, M. A.; Hayashi, T. J. Am. Chem. Soc. 1980, 102, 4973-
4979.
(6) Electron withdrawing groups can cause nonfragmenting pathways
to dominate, see: Overman, L. E.; Renaldo, A. F. Tetrahedron Lett. 1983,
24, 2235-2238.
(7) For several examples where a nucleophilic alkene (enol, indole, etc.)
leads to a cyclic product, see: (a) Widenhoefer, R. A. Pure Appl. Chem.
2004, 76, 671-678. (b) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc.
2004, 126, 10250-10251. (c) Toyota, M.; Ihara, M. Synlett 2002, 8, 1211-
1222. (d) Yang, D.; Li, J.-H.; Gao, Q.; Yan, Y.-L. Org. Lett. 2003, 5, 2869-
2871. (e) Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578-
9579.
(8) Koh, J. H.; Mascarenhas, C.; Gagne´, M. R. Tetrahedron 2004, 60,
7405-7410.
(9) Despite how the reaction is shown to proceed in Scheme 2, we suspect
that a free carbocation is not likely to form and that the phenol serves to
stabilize developing charge. This notion is supported by DFT studies with
pincer ligated Pt-dicationic catalysts. See: Nowroozi-Isfahani, T.; Musaev,
D. G.; Morokuma, K.; Gagne´, M. R. Organometallics 2007, 26, 2540-
2549.
10.1021/jo0705871 CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/27/2007
J. Org. Chem. 2007, 72, 4877-4881
4877

Korotchenko and Gagne´
TABLE 1. Optimization of Reaction Conditionsa
SCHEME 2
time
(h)
yield
(%)
entry catalyst (10 mol %) solvent
cooxidant
1
2
3
4
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
(2 mol %)
MeCN BQ 1.5 equiv
CHCl3 BQ 1.5 equiv
8
5
18
80
54b,c
26b
11
THF
BQ 1.5 equiv
MeCN BQ 1.5 equiv 120
5
6
7
8
9
10
11
12
13
14
Pd/C (5 wt %)
PdCl2
Pd(acac)2
Pd(dba)2
Pd(OAc)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
PdCl2(PhCN)2
MeCN BQ 1.5 equiv
MeCN BQ 1.5 equiv
MeCN BQ 1.5 equiv
MeCN BQ 1.5 equiv
MeCN BQ 1.5 equiv
MeCN BQ 4 equiv
MeCN BQ 1.2 equiv
MeCN BQ 1.1 equiv
MeCN BQ 1 equiv
MeCN 1,3-dinitro-
benzene
18
18
18
44
21
6
8
8
44
27
NR
NR
NR
NR
NR
45
SCHEME 3
96
57
65b
29b
15
16
PdCl2(PhCN)2
PdCl2(PhCN)2
MeCN Cu(OAc)2
MeCN Cu(OAc)2
(20%)/O2
44
65
10b
very slow
reactionb
a Conditions: 0.05 M in 1, refluxing in solvent. b Determined by GCMS.
c Multiple byproducts formed.
SCHEME 4
â-hydrogen elimination and palladium reoxidation with 1,4-
benzoquinone (BQ). Key to controlling the point of initiation
in these reactions is the strong propensity of Pd(II) and Pt(II)
electrophiles to coordinate, and thus activate, the least substituted
double bond.2,8,10 This preference contrasts the behavior of
traditional electrophiles (H+, Br+, RSe+, etc).
1,5-Dien-3-ol 1-cis was also examined in the palladium-
catalyzed cyclization.8 The guiding notion in this case was to
trap the putative carbocation with a ring-expanding/contracting
pinacol rearrangement, in analogy to the Lewis acid initiated
processes successfully employed by Overman in natural product
synthesis.11 In the event, the cyclization went as expected and
catalyst turnover by â-hydride elimination provided bicyclic
ketone 2 as a mixture of regioisomers (Scheme 3). Under
oxidizing conditions the resulting “Pd-H” was recycled to the
reactive Pd(II) state (BQ proved optimum). The cis-fused bicycle
ketone was the major product of this reaction, a ring junction
that had previously been rationalized by invoking a chairlike
topology in the bond migration transition state.11
paying particular attention to the reoxidation conditions, but also
examining palladium source and solvent. The previous condi-
tions utilizing bis(benzonitrile)palladium dichloride (PdCl2-
(PhCN)2) in refluxing acetonitrile smoothly converted 1-cis to
ketone 2 in 80% yield (Table 1, entry 1). Additional optimization
studies revealed that benzoquinone loadings could be reduced
to 1.2 equiv, which improved the purification procedure and
the yield of 2 (96%, entry 11). As before, 2 was obtained as a
mixture of four alkene isomers, which converted to an 80:20
mixture of cis and trans 3a-methylperhydroazulenones 2-H upon
hydrogenation (H2, Pd/C).
Cyclization of the trans-isomer of dienol 1 (1-trans) gave
the same bicyclic ketone 2-H as an 86:14 mixture of isomers
(Scheme 4) after hydrogenation. We speculate that our stereo-
chemical leakage comes from the rapid Pd-catalyzed alkene
migration, which compromises the C-8a stereo center and is
also responsible for the multiple alkene isomers of product.12
Results and Discussion
Reaction Scope
We report herein additional details of scope and efficiency
of the palladium-catalyzed cyclization-rearrangement of 1,ω-
diene-3-ols. This study was initiated by revisiting the reaction
conditions originally reported for the cascade cyclization,8
The optimized protocol (Table 1, entry 11) was then applied
to a variety of dienols capable of trapping the putative cation
via a pinacol rearrangement. In addition to the pinacol reactivity,
a priori consideration of alternative reaction pathways predicted
multiple routes for transforming the 1,ω-dienols (Schemes 5
(10) Koh, J. H.; Gagne´, M. R. Angew. Chem., Int. Ed. 2004, 43, 3459-
3461.
(11) (a) Herrington, P. M.; Hopkins, M. H.; Mishra, P.; Brown, M. J.;
Overman, L. E. J. Org. Chem. 1987, 52, 3711-3712. (b) Hirst, G. C.;
Howard, P. N.; Overman, L. E. J. Am. Chem. Soc. 1989, 111, 1514-1515.
(c) Overman, L. E. Acc. Chem. Res. 1992, 25, 352-359. (d) Ando, S.;
Minor, K. P.; Overman, L. E. J. Org. Chem., 1997, 62, 6379-6387. (e)
Overman, L. E.; Wolfe, J. P. J. Org. Chem. 2002, 67, 6421-6429. (f)
Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143-7157.
(12) We and others have also sought methods that activate alkenes toward
nucleophilic attack, but otherwise inhibit â-H elimination as a default method
of catalytic turnover. (a) Hahn, C.; Cucciolito, M. E.; Vitagliano, A. J. Am.
Chem. Soc. 2002, 124, 9038-9039. (b) Kerber, W. D.; Koh, J. H.; Gagne´,
M. R. Org. Lett. 2004, 6, 3013-3015. (c) Kerber, W. D.; Gagne´, M. R.
Org. Lett. 2005, 7, 3379-3381.
4878 J. Org. Chem., Vol. 72, No. 13, 2007

Palladium-Catalyzed Cyclization of 1,ω-Dienols
SCHEME 5
SCHEME 7
SCHEME 6
1-cis (59 vs 96% yield). Compound 10 was prepared as a
mixture of cis- and trans-isomers and was used as is since it
was prone to decomposition and isomerization on silica.
Treatment of dienol 3 with catalytic quantities of PdCl2-
(PhCN)2 with or without benzoquinone resulted in the formation
of trans-cycloundecenone 13, which was characterized by the
alkene’s large trans coupling constant (3JHH ) 15.2 Hz) (eq 1).
and 6). The desired cyclization manifold is termed Type I,
cyclization accompanied by dehydration and aromatization is
termed Type II, while the oxy-Cope type pathway is termed
Type III. Literature precedence suggested that Type III trans-
formations were entirely reasonable while the Lewis acid
reaction conditions suggested the reasonableness of aromatiza-
tion processes.13
For 1,ω-dienols with a longer chain between the double
bonds, additional Pd-mediated migration of the double bond to
an internal position (Type IV) and Wacker-like nucleophilic
attack of the hydroxyl group on the electrophilic palladium-
alkene complex (Type V) were also considered (Scheme 6).
A series of substrates were designed to investigate the impact
of ring size, distance between the two double bonds, and the
effect of steric and electronic perturbations on the mode of
cyclization. All the substrates contained the structural features
of having a mono- (or 1,2-disubstituted) double bond as the
initiation point for complexation by Pd(II), a second nucleophilic
alkene for generating a stabilized carbocation,14 and a tertiary
allylic alcohol for initiating the pinacol rearrangement
(Scheme 7).
The analogous transformation was previously described by
Malacria and co-workers, who studied the oxy-Cope rearrange-
ment of cyclic and acyclic hexa-1,5-dien-3-ols, initiated
either catalytically (Pd(II))18 or by stoichiometric quantities of
Hg(CF3COO)2.19 Thermal17,20 or anionic21 cyclizations of
structurally related 1,2-divinylcyclohexanols similarly gen-
erated cyclodecenones. We presume that the course of
this reaction is driven by the ring strain in the putative
[6.3.0]bicycloundecanone.
In contrast to the parent 1,5-dien-3-ol 1-cis, the homologous
1,6-dien-3-ol 4 was considerably more capricious. Under
identical reaction conditions total consumption of 4 required
only 0.5 h. However, the desired ketone 14, accompanied by
Substrates 3-9 were prepared by the cis-selective addition
of the appropriate organometallic reagent to the 2-substituted
cycloalkanones.15-17 The cis-isomers of the 1,2-dialkenylcy-
cloalkanols were a priori considered most favorable since both
alkenyl substituents orient equatorially in the cyclization transi-
tion state (Schemes 1 and 3). Partially supporting this notion is
the lowered yield on cyclizing 1-trans (Scheme 4) instead of
(18) Bluthe, N.; Malacria, M.; Gore. J. Tetrahedron Lett. 1983, 24, 1157-
1160.
(19) (a) Bluthe, N.; Malacria, M.; Gore. J. Tetrahedron Lett. 1982, 23,
4263-4266. (b) Bluthe, N.; Malacria, M.; Gore. J. Tetrahedron 1984, 40,
3277-3284.
(20) (a) Sworin, M.; Lin, K.-C. J. Am. Chem. Soc. 1989, 111, 1815-
1825. (b) Warrington, J. M.; Yap, G. P. A.; Barriault, L. Org. Lett. 2000,
2, 663-665. (c) Barriault, L.; Denissova, I. Org. Lett. 2002, 4, 1371-
1374. (d) Farand, J. A.; Denissova, I.; Barriault, L. Heterocycles 2004, 62,
735-748.
(21) (a) Paquette, L. A.; Shi, Y.-J. J. Am. Chem. Soc. 1990, 112, 8478-
8489. (b) Jisheng, L.; Gallardo, T.; White, J. B. J. Org. Chem. 1990, 55,
5426-5428. (c) Chu, Y.; Colclough, D.; Hotchkin, D.; Tuazon, M.; White,
J. B. Tetrahedron 1997, 53, 14235-14246. (d) Chu, Y.; White, J. B.; Duclos,
B. A. Tetrahedron Lett. 2001, 42, 3815-3817. (e) White, B. H.; Snapper,
M. L. J. Am. Chem. Soc. 2003, 125, 14901-14904.
(13) Grise, C. M.; Barriault, L. Org. Lett. 2006, 8, 5905-5908.
(14) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66-
77.
(15) Ashby, E. C.; Laemmle, J. T. Chem. ReV. 1975, 75, 521-546.
(16) Holt, D. A. Tetrahedron Lett. 1981, 22, 2243-2246.
(17) DiMartino, G.; Hursthouse, M. B.; Light, M. E.; Percy, J. M.;
Spencer, N. S.; Tolley, M. Org. Biomol. Chem. 2003, 1, 4423-4434.
J. Org. Chem, Vol. 72, No. 13, 2007 4879

Korotchenko and Gagne´
extensive double bond migration, proved to be a minor product
(eq 2). Dominant were dehydration/aromatization pathways that
presumably proceeded through a similar putative bicyclo[4.4.0]-
carbocation A (Scheme 3). Dimethyltetraline 15 (39% yield,
or 88% of the aromatized products) along with several minor
naphthalene-type products (inferred from GC-MS analysis) were
obtained (eq 2).
6-exo Wacker-type cyclization,22 followed by alkene migration
to the more highly substituted position.
Complete consumption of 1,8-dien-3-ol 7 under standard
conditions was similarly slow (47 h), and resulted in an
inseparable mixture of two isomers of starting material and four
isomers of cycloadduct 18. Hydrogenation of the mixture
provided bicyclic ketone 18-H as a single diastereomer and
dialkylcyclohexanol 19 (Scheme 10). Longer reflux times (168
h) decreased the amount of starting material isomers, but did
not increase the yield of 18 (17%). Formation of 18 is only
possible if migration of the terminal double bond precedes the
cyclization.
Aromatization could almost be suppressed in stoichiometric
reactions of 4 with PdCl2(PhCN)2 at room temperature (Scheme
8). However, under these conditions along with desired adduct
14, multiple isomers of starting material were obtained, hydro-
genation of which provided a single isomer of 1-isopropyl-2-
propylcyclohexanol 16. Separate hydrogenation of the expected
unsaturated ketone 14 (obtained as a mixture of three isomers
in the ratio 49:22:18) provided perhydrogenated azulenone 14-H
as single diastereomer. Efforts to modify the reaction conditions
and improve the reaction selectivity were unsuccessful.
SCHEME 10
SCHEME 8
Our attempts to promote the cyclization of dienol 8 were
unsuccessful; dehydration and decomposition of starting material
were the primarily reaction products observed by GC-MS, with
only minor amounts of desired adduct detectable. The tetra-
substituted double bond in 8 is apparently too hindered for
efficient addition to the electrophilic palladium-alkene complex.
The 1,5-dien-3-ols 9 and 10 contained more nucleophilic
trisubstituted double bonds and demonstrated another behavior
in the palladium-catalyzed cyclization. These reactions were
characterized by rapid rates of starting material consumption
and the formation of the aromatic products 20 and 21 (eqs 4
and 5). Attempts to minimize this reaction pathway were
unsuccessful. Gold-catalyzed benzannulation of structurally
related 3-hydroxy-1,5-enynes was reported recently.13
Cyclization of isomeric dienol 5 required more time, but
provided the same stereoisomer of ketone 14-H after hydroge-
nation (Scheme 9). The strong coordination preference of
Pd(II) for monosubstituted alkenes explains the observed 50-
fold difference in activity between 4 and 5.
SCHEME 9
Although the cyclization of dienol 11 resulted in inseparable
dimers and oligomers of starting material, dienol 12 underwent
Much longer reaction times (36 h) were required for full
conversion of 1,7-dien-3-ol 6, and instead of the expected
bicyclic ketone only hexahydrochromene derivative 17 was
isolated (eq 3). This product presumably forms as a result of
(22) For a recent review of oxy-palladation of alkenes, see: Muzart, J.
Tetrahedron 2005, 61, 5955-6008.
4880 J. Org. Chem., Vol. 72, No. 13, 2007

Palladium-Catalyzed Cyclization of 1,ω-Dienols
SCHEME 11
are possible. Formation of the products of pinacol rearrangement
(Type I), benzannulation (Type II), and oxy-Cope rearrangement
(Type III) are together supportive of the formation of intermedi-
ate carbocation A (Scheme 1). Other possible Pd-catalyzed
transformations included Wacker-type cyclization (Type V) and
precyclization migration of the double bond (Type IV). Turnover
of the cyclizations is achieved by â-hydride elimination and
reoxidation of palladium with benzoquinone.
Experimental Section
General Procedure for Catalytic Cyclization and Hydrogena-
tion of Products. Palladium-catalyzed cyclization reactions were
performed under an argon atmosphere with use of standard Schlenk
techniques. To a solution of dienol 1 (166 mg, 1 mmol) and
p-benzoquinone (129.6 mg, 1.2 mmol) in dry acetonitrile (20 mL)
was added PdCl2(PhCN)2 (38.3 mg, 0.1 mmol). The resulting
solution was stirred at 80 °C for 8 h and monitored by GCMS.
After complete consumption of starting material the reaction mixture
was cooled to room temperature, concentrated under vacuum, and
chromatographed (hexanes-EtOAc 9:1) to give a mixture of
bicyclic products 2 (157 mg, 96%) as a colorless oil. The oil was
taken up in MeOH (10 mL), and Pd/C (5 mol %) was added. The
resulting suspension was stirred under hydrogen atmosphere (1 atm)
at room temperature for 4 h. The reaction mixture was filtered
through a plug of Celite and washed with ether. The filtrate was
concentrated under vacuum to give a colorless oil of bicyclic ketone
2-H (151 mg, 95%) as an 80:20 mixture of adducts.
a comparatively smoother reaction. After 24 h the starting
material was consumed, and an inseparable mixture of six
products (GC-MS) was obtained in 42% yield. Four of these
compounds had molecular weights equal to the starting dienol
and two had molecular weights indicating net dehydrogenation.
Catalytic hydrogenation of this mixture provided 22-H in the
3.5:1 mixture with alcohol 23-H (obtained as a mixture of two
diastereomers by NMR). Formation of cyclic adduct 22-H
confirmed that ring contractive alkyl migration in a putative
monocyclic cation can indeed occur (Scheme 11), while
formation of 23 indicates that oxy-Cope-type rearrangements
can be competitive.23 Unfortunately, the complex nature of the
reaction mixture makes additional comments on competing arene
transfer suspect.
Acknowledgment. The National Institute of General Medi-
cine (GM-60578) is gratefully acknowledged for support. We
also thank Dr. Marc ter Horst (University of North Carolina at
Chapel Hill) for assistance with NMR experiments.
We report herein our investigation of the palladium-catalyzed
cyclization of compounds containing the 1,ω-diene-3-ol struc-
tural motif. Depending on the structural features of the
substrates, numerous cyclization and/or rearrangement pathways
Supporting Information Available: Detailed experimental
procedures, synthesis of the substrates, streochemistry proof, NMR
spectra, and characterization data for all new products. This material
is available free of charge via the Internet at http://pubs.acs.org.
(23) Hydrogenation of unsaturated ketones 22 and 23 proceeds with
carbonyl reduction, see: (a) Sajiki, H.; Hattori, K.; Hirota, K. J. Chem.
Soc., Perkin Trans. 1 1998, 4043-4044. (b) Mori, A.; Mizusaki, T.;
Miyakawa, Y.; Ohashi, E.; Haga, T.; Maegawa, T.; Monguchi, Y.; Sajiki,
H. Tetrahedron 2006, 62, 11925-11932 and references cited therein.
JO0705871
J. Org. Chem, Vol. 72, No. 13, 2007 4881