Fluorenes and styrenes by Au(I)-catalyzed annulation of enynes and alkynes

Article abstract of DOI:10.1021/ja710990d

Intermolecular annulation of enynes and propargyl esters to selectively produce styrenes or fluorenes is reported. The divergent arene syntheses involve a Au-catalyzed, two-pot, multistep process proceeding by cis-diastereoselective cyclopropanation, cycloisomerization, and, finally, annulation or elimination. Copyright

Full text of DOI:10.1021/ja710990d

Published on Web 03/06/2008
Fluorenes and Styrenes by Au(I)-Catalyzed Annulation of Enynes and Alkynes
David J. Gorin, Iain D. G. Watson, and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California, 94720
Received December 10, 2007; E-mail: fdtoste@berkeley.edu
Metal-catalyzed cycloaddition reactions provide attractive and
efficient methods for the synthesis of arenes, although regioselec-
tivity presents a major challenge for intermolecular reactions.1 The
synthesis of polysubstituted benzenes by the [2 + 2 + 2]
cyclotrimerization of alkynes2 has been extensively studied, as has
the Pd-catalyzed [4 + 2] cycloaddition of enynes and activated
alkynes.3 We report herein a mechanistically distinct intermolecular
annulation of enynes and alkynes to produce multiply substituted
arenes (eq 1); styrene or fluorene products can be selectively
accessed by judicious choice of reaction conditions.
Table 1. Au(I)-Catalyzed Arene Synthesis: Enyne Scope
Given the synthetic utility of vinyl cyclopropanes,4 we anticipated
that alkynyl cyclopropanes derived from the cyclopropanation of
1,3-enynes would provide similar opportunities for organic syn-
thesis.5 In light of our previous work employing propargyl esters
as carbene precursors in Au(I)-catalyzed cyclopropanation reactions
of olefins,6,7 the reaction of 1 with enyne 2 was investigated.8
Initially, treatment of 1 and 2 with a cationic phosphinegold(I)
complex resulted in a mixture of products, including styrene 3,
fluorene 4, and cyclopropane trans-5 (eq 2). The unexpected
products 3 and 4 were intriguing; 3 formally results from a
completely regioselective [4 + 2] cross-dimerization of two different
enynes, while compounds such as 4 are of interest due to the blue-
light emitting properties of polyfluorenes.9,10
a
Isolated yields of cis-cyclopropane. Reactions run with 3:1 ratio of
1/enyne. b A: 5% AgOTf, 5% (ArO)3PAuCl, CH2Cl2. B: 5% AgSbF6, 5%
(ArO)3PAuCl, CH2Cl2. c Isolated yields. d Ratio of regioisomers. e Conditions
B were not investigated with 58, 61, and 64.
The substrate scope of the two-step, divergent syntheses of
fluorenes and styrenes was investigated with other enynes (Table
1).14 Aryl enynes with a variety of substitution patterns and
functional groups were tolerated, demonstrating the power of this
method to prepare multiply substituted arenes from simple starting
materials (entries 1-13). Moreover, both electron-rich and electron-
poor enynes 14 and 18 undergo the cyclopropanation and arene
syntheses; however, commensurate with the expected nucleophi-
licities of the aryl group, they demonstrated diametric preferences
for styrenes versus fluorene formation (entries 3,4). Alkyl-
substituted enynes are also tolerated in both the cyclopropanation
and annulation steps (entries 14-16).
Since cyclopropane 5 was obtained exclusively as the trans-
diastereomer, we hypothesized that 3 and 4 arose from the cis-
diastereomer. Therefore, we were pleased to find that the less
reactive AuCl cleanly catalyzed the synthesis of cyclopropane 5
with high cis-diastereoselectivity and complete regioselectivity.
With ready access to cis-5, we next investigated its transformation
to 3 and 4.
The carbene precursor was also varied (Table 2). The pivaloate
ester provided the best selectivity in differentiating between the
styrene and fluorene pathways (entries 1-3). [9,9]-Dibutyl-
substituted fluorene 82 was prepared (entry 6); such hydrophobic
solubilizing groups are often found in fluorenes designed for
subsequent polymerization. Additionally, the use of unsymmetrical
pivaloate 83 readily provided 85 or 86 (entries 7).
Gratifyingly, either compound could be selectively prepared
simply by changing the silver salt cocatalyst in conjunction with
triarylphosphitegold(I) chloride (Ar ) 2,4-di-tert-butylphenyl).11,12
Thus, reaction of cis-5 with the Au complex and AgOTf provided
3 in 89% yield, while the reaction with AgSbF6 under otherwise
identical conditions provided 4 in 76% yield (eq 3).13
A mechanism accounting for the observed products begins with
the formation of 5 by intermolecular cyclopropanation of enyne 2
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10.1021/ja710990d CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Au(I)-Catalyzed Arene Synthesis: Propargyl Ester Scope
Acknowledgment. We gratefully acknowledge NIHGMS (RO1
GM073932), Merck Research Laboratories, Bristol-Myers Squibb,
Amgen Inc., and Novartis for funding. D.J.G. thanks the ACS
Organic Division (Merck) and Bristol Myers-Squibb for predoctoral
fellowships. I.D.G.W. thanks NSERC for a postdoctoral fellowship.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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2901. Intramolecular annulation of enynes and alkynes: (b) Dunetz, J.
R.; Danheiser, R. L. J. Am. Chem. Soc. 2005, 127, 5776. (c) Danheiser,
R. L.; Gould, A. E.; de la Pradilla, R. F.; Helgason, A. L. J. Org. Chem.
1994, 59, 5514. Intramolecular annulation of arene-ynes and alkynes: (d)
Lian, J.-J.; Chen, P.-C.; Lin, Y.-P.; Ting, H.-C.; Liu, R.-S. J. Am. Chem.
Soc. 2006, 128, 11372. (e) Rodriguez, D.; Martinez-Esperon, M. F.;
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(2) (a) Agenet, N.; Gandon, V.; Vollhardt, K. P. C.; Malacria, M.; Aubert,
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P. R.; Louie, J. AdV. Synth. Catal. 2006, 348, 2307.
a
Isolated yields of cis-cyclopropane. Reactions run with 3:1 ratio of
b
propargyl ester/2. A: 5% AgOTf, 5% (ArO)3PAuCl, CH2Cl2. B: 5%
AgSbF6, 5% (ArO)3PAuCl, CH2Cl2. Isolated yields. E/Z ratio.
c
d
(3) (a) Rubina, M.; Conley, M.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128,
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(5) Cyclopropanations of enynes are surprisingly undeveloped. (a) Gmyzina,
R. N.; D’yakonov, I. A.; Danilkina, L. P. Zhur. Obshch. Khimii 1970, 6,
2168. (b) Shapiro, E. A.; Romanova, T. N.; Dolgii, I. E.; Nefedov, O. M.
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Du, H.; Long, J.; Shi, Y. Org. Lett. 2006, 8, 2827.
Scheme 1. Proposed Mechanism for the Formation of 3 and 4
(6) (a) Gorin, D. J.; Dube, P.; Toste, F. D. J. Am. Chem. Soc. 2006, 128,
14480. (b) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D. J.
Am. Chem. Soc. 2005, 127, 18002. (c) Shi, X.; Gorin, D. J.; Toste, F. D.
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(10) The synthesis of substituted fluorenes is generally accomplished by [9,9]-
dialkylation of fluorene followed by [2,7]-dibromination and subsequent
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G. A.; Soloducho, J.; Katritzky, A. R.; Reynolds, J. R. J. Mater. Chem.
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M.; Bats, J. W. J. Am. Chem. Soc. 2000, 122, 11553. (b) Dankwardt, J.
W. Tetrahedron Lett. 2001, 42, 5809. (c) Asao, N.; Takahashi, K.; Lee,
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J. Am. Chem. Soc. 2006, 128, 7436. Also see refs 1d , 6a.
(13) Other phosphine catalysts provided lower selectivity. For example,
treatment of cis-5 with PPh3AuCl/AgSbF6 resulted in 63% 4 and 34% 3.
(14) Optimization of the one-pot synthesis produced 4 in lower yield from 1
and 2. See Supporting Information.
(15) 89 was isolated and resubjected to the reaction conditions with and without
the addition of triarylphosphite gold(I) chloride to afford the expected
products, suggesting the possibility for silver or acid catalysis in the final
step. Control experiments indicate that neither AgOTf nor HOTf catalyze
the cycloisomerization of 5. See Supporting Information.
Via the gold carbenoid produced from rearrangement of propargyl
ester 1. Following coordination of the cationic gold catalyst to the
resulting alkyne, the pendant olefin can participate in either a
5-endo-dig or 6-endo-dig cyclization (Scheme 1). When tertiary
propargyl esters are employed in the gold-catalyzed annulation, the
5-endo-dig cyclization to generate tertiary carbocation 87 dominates.
Subsequent migration of the pivaloyloxy group gives allylic cation
88 that may be further stabilized by delocalization of the charge
onto gold. Cyclopropyl ring opening leads to 89 Via a pentadientyl
cation, which is most likely converted to 3 and 4 by E1 and SN1
mechanisms, respectively.15,16
Use of secondary propargyl pivaloate 90 diverted the reaction
pathway toward the 6-endo-dig cyclization and formation of
cycloheptatriene 92 (eq 4). Selectivity for the 5-endo-dig path-
way could be partially restored using 94, which predominantly
provided the fluorene 97, suggesting that, for trisubstituted olefins,
electronic factors govern the regioselectivity of the cycloisomer-
ization.
(16) Further experiments (see Supporting Information) indicate that 3 readily
isomerizes to 4 under strongly acidic conditions. A deuterium-labeling
experiment suggested that this is not a major pathway for the formation
of 4 under our reaction conditions:
In conclusion, readily available enynes and propargyl esters may
be selectively transformed into styrenes or fluorenes under catalyst
control Via two new Au(I)-catalyzed processes. Synthesized by a
rarely investigated, highly selective cyclopropanation of 1,3 enynes,
cis-vinyl-alkynyl-cyclopropanes undergo a novel cycloisomerization
reaction, the outcome of which may be controlled simply through
the choice of catalyst counterion.
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