A cascade palladium-mediated cross-coupling/electrocyclization approach to the construction of fused Bi- and tricyclic rings

Article abstract of DOI:10.1021/ol8007952

(Chemical Equation Presented) A versatile palladium-catalyzed cyclization/cross-coupling/electrocyclization strategy for the synthesis of fused bi- and tricyclic ring systems is described. Excellent yields of the polycyclic products are obtained with a range of tethering ring sizes and functionality, including an unprecedented 5,6,4,5-fused tetracycle. The reaction mechanism features two unusual palladium-mediated isomerizations prior to electrocyclization.

Full text of DOI:10.1021/ol8007952

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2323-2326
A Cascade Palladium-Mediated
Cross-Coupling/Electrocyclization
Approach to the Construction of Fused
Bi- and Tricyclic Rings
S. B. Jennifer Kan† and Edward A. Anderson*
Chemistry Research Laboratory, UniVersity of Oxford, 12 Mansfield Road,
Oxford OX1 3TA, U.K.
edward.anderson@chem.ox.ac.uk
Received April 7, 2008
ABSTRACT
A versatile palladium-catalyzed cyclization/cross-coupling/electrocyclization strategy for the synthesis of fused bi- and tricyclic ring systems
is described. Excellent yields of the polycyclic products are obtained with a range of tethering ring sizes and functionality, including an
unprecedented 5,6,4,5-fused tetracycle. The reaction mechanism features two unusual palladium-mediated isomerizations prior to
electrocyclization.
The use of cascade reactions to construct complex molecular
skeletons with high efficiency is an appealing strategy in
Scheme 1
.
Conceptual Cascade Approach to Bi- and Tricyclic
Rings
organic synthesis.1 Transition metal-catalyzed reactions in
particular offer exciting opportunities due to their high
functional group tolerance and ability to construct multiple
carbon-carbon bonds in a single step. We report a versatile
palladium-catalyzed cascade cyclization which accesses a
wide range of fused ring systems from acyclic precursors
and which features two unusual palladium-mediated isomer-
izations.
We envisaged that treatment of a suitable bromoenyne (1,
Scheme 1) with a palladium(0) catalyst would initiate a
cascade polycyclization: initial syn-carbopalladation followed
by cross-coupling with alkenylstannane 2 would give triene
† Previous address: Department of Chemistry, University of Cambridge,
Lensfield Road, Cambridge CB2 1EW, U.K.
(1) (a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Nicolaou, K. C.;
Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (c)
Tietze, L. F. Chem. ReV. 1996, 96, 115.
3, which could undergo 6π-electrocyclization to polycycle
4. An alternative coupling with a dienylstannane (5) would
terminate with an 8π-electrocyclization of tetraene 6 to afford
polycycle 7. Overall, these processes achieve the formation
10.1021/ol8007952 CCC: $40.75
Published on Web 05/08/2008
2008 American Chemical Society

of three carbon-carbon bonds and two rings in a single step
and, significantly, represent a general and diversifiable
approach to fused rings with polyene cores primed for further
chemistry.
Table 1. Initial Cascade Reaction Optimizationa
Although palladium-mediated carbopalladations2 of ha-
loenynes and their subsequent cross-couplings3,4 have been
well studied, the incorporation of an in situ electrocyclization
has less precedent, with the exception of the elegant work
of de Meijere5 and Suffert.6 The potential to generalize such
a reaction to access a wide array of valuable polycyclic
skeletons remains an important aim.
We began our investigations into the feasibility of this
cascade process using the malonate-derived bromoenyne 8a7
(Table 1), treatment of which with vinyltributyltin and 10
mol % of Pd(PPh3)4 in refluxing benzene led to a single
product (73%, entry 1). 1H NMR spectroscopy NOE studies
revealed that this product was not the anticipated electro-
cyclized 5,6-bicyclic diene 10a, but rather the anti-triene
11a,7 which had presumably arisen from an unexpected
entry sm
catalyst
solvent time (h) yieldb (%) 10/11c
1
2
3
8a Pd(PPh3)4
8b Pd(PPh3)4
8c Pd(PPh3)4
PhH
PhH
PhH
10
4
10
24
1
24
4
24
7
73
70
sd
74
sd
86
sd
86
94
0:1
1:0
2:1
1:0
5:1
1:0
8:1
1:0
1:0
4
5
6
7
8
Pd(PPh3)4
PhMe
PdCl2(PPh3)2 PhMe
PdCl2(PPh3)2 PhMe
Pd(PPh3)4
(1 mol %)
Pd(PPh3)4
(0.1 mol %)
PhMe
PhMe
PhMe
20
77
1:0
(2) For an excellent review, see:(a) Negishi, E.-I.; Cope´ret, C.; Ma, S.;
Liou, S.-Y.; Liu, F. Chem. ReV. 1996, 96, 365. (b) Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John
Wiley and Sons, Inc.: New York, 2002; Vol. 1, Section IV. (c) Poli, G;
Giambastiani, G; Heumann, A. Tetrahedron 2000, 56, 5959. (d) Grigg, R.;
Sridharan, V. J. Organomet. Chem. 1999, 576, 65.
8d Pd(PPh3)4
20
83
1:0
a Conditions: reflux, 1.3 equiv of 9a, 10 mol % of catalyst, unless
indicated. b Isolated yields. c Ratios determined by 1H NMR spectroscopy.
d Ratio determined by 1H NMR during the reaction; products not isolated.
(3) Selected examples of carbopalladation/Stille coupling:(a) Burns, B.;
Grigg, R.; Ratananukul, P.; Sridharan, V.; Stevenson, P.; Sukirthalingam,
S.; Worakun, T. Tetrahedron Lett. 1988, 29, 5565. (b) Negishi, E.-I.; Noda,
Y.; Lamaty, F.; Vawter, E. J. Tetrahedron Lett. 1990, 31, 4393. (c) Luo,
F.-T.; Wang, R.-T. Tetrahedron Lett. 1991, 52, 7703. (d) Nuss, J. M.;
Murphy, M. M.; Rennels, R. A.; Heravi, M. H.; Mohr, B. J. Tetrahedron
Lett. 1993, 34, 3079. (e) Fretwell, P.; Grigg, R.; Sansano, J. M.; Sridharan,
V.; Sukirthalingam, S; Wilson, D; Redpath, J. Tetrahedron 2000, 56, 7525.
complete isomerization of the alkenylpalladium intermediate
prior to intermolecular cross-coupling (a formal anti-carbo-
palladation). Although such processes are precedented,8 their
generality and origin has not been explored, and this degree
of isomerization is highly unusual.
See also refs 8 and 9
.
(4) Selected carbopalladations terminating with other cross-coupling
manifolds; see ref 2a and: (a) Zhang, Y.; Negishi, E.-I. J. Am. Chem. Soc.
1989, 111, 3454. (b) Negishi, E.-I.; Ay, M.; Sugihara, T. Tetrahedron 1993,
49, 5471. (c) Ishikura, M. J. Chem. Soc., Chem. Commun. 1995, 409. (d)
Grigg, R.; Sansano, J. M.; Santhakumar, V.; Sridharan, V.; Thangavelan-
thum, R.; Thornton-Pett, M.; Wilson, D. Tetrahedron 1997, 53, 11803. (e)
Oh, C. H.; Lim, Y. M. Tetrahedron Lett. 2003, 44, 267. (f) Couty, S.;
Lie´gault, B.; Meyer, C.; Cossy, J. Org. Lett. 2004, 6, 2511. (g) Torii, S.;
Okumoto, H.; Nishimura, A. Tetrahedron Lett. 1991, 32, 4167. (h) Teply,
F.; Stara´, I. G.; Stary, I.; Kollarovic, A.; Saman, D.; Fiedler, P. Tetrahedron
2002, 58, 9007. (i) Burns, B.; Grigg, R.; Sridharan, V.; Stevenson, P.;
Sukirthalingam, S.; Worakun, T. Tetrahedron Lett. 1989, 30, 1135. (j) Wang,
Hypothesizing that the steric bulk of palladium relative
to hydrogen might drive this syn-anti isomerization, we
subjected TBS-substituted bromoenyne 8b to the same
reaction conditions. To our delight, this led exclusiVely to
the formation of the 5,6-bicycle 10b (70%, entry 2).
Interestingly, the sterically less demanding TMS substituent
of 8c gave a 2:1 mixture of products (10 h, entry 3), albeit
in favor of the desired 5,6-bicycle 10c. Even more gratifying
but rather surprising was the observation that under prolonged
heating (24 h), the undesired anti-triene 11c was converted
to the targeted bicycle 10c (74% overall), presumably through
a second isomerization9 of 11c back to the syn-triene,
followed by electrocyclization. Further optimization (entries
4-7) showed that the use of toluene as solvent led to shorter
reaction times, that PdCl2(PPh3)2 was also a suitable catalyst,
and that the catalyst loading could be reduced with no loss
of reaction efficiency. Alkyl-substituted alkyne 11d also
underwent efficient cyclization under the optimized condi-
tions (83%, entry 8).
R.-T.; Chou, F.-L.; Luo, F.-T. J. Org. Chem. 1990, 55, 4846
.
(5) de Meijere has focused mainly on fully intramolecular variants:(a)
Meyer, F. E.; Henniges, H.; de Meijere, A. Tetrahedron Lett. 1992, 33,
8039. (b) Meyer, F. E.; Brandenberg, J.; Parsons, P. J.; de Meijere, A.
J. Chem. Soc., Chem. Commun. 1992, 390. (c) Henniges, H.; Meyer, F. E.;
Schick, U.; Funke, F.; Parsons, P. J.; de Meijere, A. Tetrahedron 1996, 52,
11545. For a review, see: (d) de Meijere, A.; Bra¨se, S. J. Organomet. Chem.
1999, 576, 88. For a stepwise construction of the electrocyclization substrate,
see: (e) von Zezschwitz, P.; Petry, F.; de Meijere, A. Chem. Eur. J. 2001,
7, 4035.
(6) Suffert has mainly studied specific 4- and 5-exo-dig cyclizations;
for leading references, see: (a) Suffert, J.; Salem, B.; Klotz, P. J. Am. Chem.
Soc. 2001, 123, 12107. (d) Salem, B.; Klotz, P.; Suffert, J. Org. Lett. 2003,
5, 845. (c) Salem, B; Klotz, P; Suffert, J. Synthesis, 2004, 298. (d) Salem,
B.; Suffert, J. Angew. Chem., Int. Ed. 2004, 43, 2826. (e) Bour, C.; Blond,
G.; Salem, B.; Suffert, J. Tetrahedron 2006, 62, 10567, and references
therein. (f) Bour, C.; Suffert, J. Eur. J. Org. Chem. 2006, 1390. For an
outstanding recent application to fenestrane synthesis, see: (g) Hulot, C.;
Blond, G.; Suffert, J. J. Am. Chem. Soc. 2008, 130, 5046. For other related
6π-processes, see: (h) Grigg, R.; Savic, V.; Sridharan, V.; Terrier, C.
Tetrahedron 2002, 58, 8613. (i) Wang, F.; Tong, X.; Cheng, J.; Zhang, Z.
Chem. Eur. J. 2004, 10, 5338. (j) Tambar, U. K.; Kano, T.; Zepernick,
J. F.; Stoltz, B. M J. Org. Chem. 2006, 71, 8357. For a review of cross-
coupling/electrocylization in synthesis, see: (k) Beaudry, C. M.; Malerich,
J. P.; Trauner, D. Chem. ReV. 2005, 105, 4757.
With suitable reaction conditions established, efforts were
now concentrated on exploring the reaction scope. Variation
(8) See refs 3e, 6, and: (a) Chung, W. S.; Patch, R. J.; Player, M. R. J.
Org. Chem. 2005, 70, 3741. For an informative mechanistic discussion,
see: (b) Amatore, C.; Bensalem, S.; Ghalem, S.; Jutand, A. J. Organomet.
Chem. 2004, 689, 4642.
(7) See the Supporting Information for details of substrate preparation
and proof of stereochemistry.
(9) (a) Sen, A.; Lai, T. W. Inorg. Chem. 1984, 23, 3257. (b) Yu, J.;
Gaunt, M. J.; Spencer, J. B. J. Org. Chem. 2002, 67, 4627.
2324
Org. Lett., Vol. 10, No. 11, 2008

of the substrate tether length showed that the methodology
was able to accommodate a variety of ring sizes (Table 2,
yields and short reaction times. Both the nitrogen- and
oxygen-tethered bromoenynes 8k and 8l also underwent
smooth cyclization with 9b, leading to the formation of
heterocycles 10k (95%) and 10l (77%) (entries 7, 8). In
several cases, the yields, product ratios, and reaction times
could be improved by using PdCl2(PPh3)2 as catalyst.
Satisfied with the synthesis of n,6-bicycles, we now
investigated the formation of fused n,8-rings, using dienyl-
stannane 9d10 (Table 3). Pleasingly, the 5,8-bicyclic products
Table 2. Cascade Cross-Coupling/6π-Electrocyclization:
Synthesis of n,6-Bicycles
Table 3. Cascade Cross-Coupling/8π-Electrocyclization:
Synthesis of n,8-Bicyclesa
a Reactions conducted with 10 mol % of catalyst and 1.3 equiv of
stannane. b Isolated yields. c Ratios determined by 1H NMR spectroscopy.
a Reactions conducted with 10 mol % of catalyst, 1.3 equiv of stannane.
b Isolated yields. c Ratios determined by 1H NMR spectroscopy. d Time
required for complete conversion of 11 to 10. e Ratio of 10h/11h-syn.
12c (80%), 12k (83%), and 12l (60%) were formed from
the reactions of bromoenyne 8c, tosylamide 8k, and ether
8l respectively, demonstrating the success of the 8π-cascade
(entries 1-3). As is precedented in fused ring systems,11 no
subsequent 6π-electrocyclization was observed, likely due
to the increase in ring strain that would result at the n,6,4-
ring junction carbon.
entries 1-5), and formation of the 6,6-bicycle 10e (88%)
and the more demanding 7,6-bicycles 10f (90%) and 10g
(71%) posed no difficulties.
Interestingly, enoate 8h gave a 1.4:1 mixture of the 8,6-
diene 10h and the “correct” syn-triene, suggesting a reduced
tendency of this alkenylpalladium intermediate to isomerize
relative to those of other tethering ring sizes. ꢀ-Substituted
stannanes7 9b and 9c proved excellent substrates, affording
the cyclized products (10i and 10j, entries 5, 6) in excellent
(10) Bialy, L.; Waldmann, H. Chem. Eur. J. 2004, 10, 2759.
(11) For an example of fused-ring cyclooctatrienes that do not undergo
6π-electrocyclization, see: (a) Paquette, L. A.; Photis, J. M.; Micheli, R. P.
J. Am. Chem. Soc. 1977, 99, 7899. (b) Hayashi, R.; Ferna´ndez, S.; Okamura,
W. H. Org. Lett. 2002, 4, 851. (c) Varela, J. A.; Castedo, L.; Saa´, C. Org.
Lett. 2003, 5, 2841. See also ref 10.
Org. Lett., Vol. 10, No. 11, 2008
2325

Interestingly, reaction of substrate 11e (entry 4) led to an
inseparable 1:1 mixture of two products: the expected 6,8-
fused bicycle 12e, and tetraene 13e (72%). The latter had
arisen from a 1,7-hydride shift of the anti-tetraene (from
formal anti-carbopalladation), which prevents reisomeriza-
tion/electrocyclization. Of particular note is the highly
efficient preparation of 7,8-fused medium-ring systems 12f
(72%) and 12g (83%) (entries 5, 6), for which the use of
PdCl2(PPh3)2 reduced the levels of 1,7-hydride shift products.
Attention was next turned to the challenging preparation
of n,8,m-tricycles (Scheme 2). Cyclic dienyl stannane 9e12
the third ring was tested using vinylfuranylstannane 9f.
Reaction with 8c led to a single product (87%), which was
identified as the remarkable 5,6,4,5-fused tetracycle 15. The
formation of this skeleton is likely driven by 6π-electrocylic
rearomatization13 of the intermediate tetraene furan obtained
upon 8π-electrocyclization. Finally, we briefly examined a
product application which increases the reaction scope; a
direct oxidative workup of the reaction of 8c with 9c (DDQ)
led to a 65% yield of the highly functionalized biaryl 16.
In conclusion, we have developed a cascade reaction which
sequences carbopalladation/cross-coupling with a 6π- or 8π-
electrocylization to provide a variety of polycyclic fused ring
systems, including one-pot construction of 8-membered
bicycles and an unprecedented 5,6,4,5-tetracycle. Ongoing
work toward the elucidation of the isomerization mecha-
nisms, further exploitation of the cyclization products, and
applications in synthesis, will be reported in due course.
Scheme 2. Extension to Polycycles and a Biaryl Ring System
Acknowledgment. This work was supported by the EPSRC
(Advanced Research Fellowship to EAA). We thank Prof. Ian
Paterson (University of Cambridge) for helpful discussions and
for extremely generous provision of laboratory space and
chemicals (EPSRC Grant No. GR/C541677/1).
Supporting Information Available: Spectroscopic data
for cyclization substrates and products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL8007952
was first employed as the coupling partner, and, to our
delight, underwent cross-coupling/8π-cyclization with 8c to
give 5,8,5-tricycle 14 (77%). Variation of the position of
(13) For a single previous instance of a presumed 8π/aromatization-
driven 6π-cyclization, see: Pelly, S. C.; Parkinson, C. J.; van Otterlo,
W. A. L.; de Koning, C. B. J. Org. Chem. 2005, 70, 10474. While this
work was in progress, an elegant synthesis of fenestranes via 8π/6π-
cyclization was reported by Suffert; see ref 6f.
(12) Lautens, M.; Smith, N. D.; Ostrovsky, D. J. Org. Chem. 1997, 62,
8970.
2326
Org. Lett., Vol. 10, No. 11, 2008