Ruthenium-catalyzed carboxylative cyclization of 1,6-diynes

Article abstract of DOI:10.1021/ja067336e

A ruthenium-catalyzed carboxylative cyclization of 1,6-diynes has been developed. In the presence of catalytic amounts of [Ru(p-cymeme)Cl₂]₂ (2.5 mol %), P(4-F-C₆H₄)₃ (7.5 mol %) and 4-dimethylaminopy

Full text of DOI:10.1021/ja067336e

Published on Web 01/13/2007
Ruthenium-Catalyzed Carboxylative Cyclization of 1,6-Diynes
Hahn Kim, Stephen D. Goble, and Chulbom Lee*
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey 08544
Received October 12, 2006; E-mail: cblee@princeton.edu
Table 1. Ru-Catalyzed Addition-Cyclization of 1 with Benzoic
Over the last two decades, metal vinylidene-mediated catalysis
Acida
has emerged as a useful means of alkyne functionalization.1 At the
core of these developments resides the multifaceted reactivity of
metal vinylidenes, from which a wide variety of transformations
may be derived. For example, metal vinylidenes (MdCRdCâ) can
react with a nucleophile through the electrophilic R-carbon2 or
engage in bond formation through their two π-systems.3 However,
rarely have these reactivities been probed in mechanistically
interwoven contexts, whereas simultaneous exploitation of distinc-
tive processes has been a successful approach in other metal-
mediated catalyzes of alkynes.4 In ongoing efforts aimed at the
development of metal vinylidene-catalyzed C-C bond-forming
reactions,5 we recently questioned whether the addition reactions
involving a nucleophile (eq 1) and a π-unsaturation (eq 2), the two
most well-studied subjects in metal vinylidene catalysis, could be
formulated into a tandem process. Conceivably, this reaction would
allow for coupling of two or more components through construction
of C-O and C-C bonds with potential control of selectivity (eq
3). In this paper, we report the discovery of a ruthenium-catalyzed
addition-cyclization of 1,6-terminal alkynes with carboxylic acids.6
entry
ligand
solvent
yieldb
ratioc 2a/2b/2c
1
2
3
4
5
6
7
8
9
P(4-Cl-C6H4)3
P(4-Cl-C6H4)3
P(4-Cl-C6H4)3
P(4-Cl-C6H4)3
P(4-Cl-C6H4)3
P(4-Cl-C6H4)3
P(OPh)3
PCy3
P(3-Cl-C6H4)3
P(4-F-C6H4)3
toluene
DCE
acetone
CH3CN
THF
dioxane
dioxane
dioxane
dioxane
dioxane
42%
30%
35%
10%
45%
68%
<5%
10%
62%
74%
64:9:27
50:17:33
70:12:18
75:8:17
100:0:0
29:57:14
100:0:0
100:0:0
10
a All reactions were run with a 1:1 mixture of benzoic acid and diyne 1.
b Isolated yields of 2a. c Determined by H NMR.
1
Table 2. Scope of the Carboxylative Cyclization of 1,6-Diynesa
To commence the studies, a 1:1 mixture of diyne 1 and benzoic
acid was exposed to a series of ruthenium catalysts known to form
a metal vinylidene species (Table 1). However, this initial set of
experiments was not fruitful, as the majority of Ru(II) complexes
induced no reaction or a simple addition of benzoic acid to 1 to give
enol benzoates 2b and 2c as (E)- and (Z)-mixtures in low yields. A
more encouraging result came from the reaction with [Ru(p-cy-
mene)Cl2]2/P(4-Cl-C6H4)3/DMAP, a catalyst system used to promote
a Z-selective anti-Markovnikov addition of carboxylic acids to al-
kynes,7 which produced cyclohexenylidene enol ester 2a, and un-
cyclized mono- and bisbenzoates 2b and 2c in 42%, 6%, and 20%
yields, respectively (entry 1).8 Further screening efforts led to the
following findings: (1) The best results were obtained using 1,4-
dioxane as the solvent. Nonpolar media gave good conversion but
decreased the selectivity while coordinating solvents resulted in
poor conversion (entries 1-6). (2) Moderately electron-withdrawing
phosphine ligands proved most efficient, among which P(4-F-C6H4)3
gave the best outcome (entry 10). (3) Replacement of DMAP with
other amine additives was found to be detrimental to the reaction,
significantly diminishing both the yield and selectivity.9
a All reactions were carried out using 2.5 mol % [Ru(p-cymene)Cl2]2,
7.5 mol % P(4-F-C6H4)3 and 10 mol % DMAP in 1,4-dioxane (0.25 M) for
24 h at 65 °C. All yields are isolated yields.
enol esters as single geometric isomers. In all cases, formation of
the simple addition products such as 2b and 2c was not observed
or amounted only to less than 5%. As expected from the isolation
of both acid- and base-sensitive enol carboxylates as the products,
the reaction tolerated various functional groups such as ester, ketone,
silyl ether, ketal, and tosyl amine. While the nature of the carboxylic
acids had only a small influence on the reaction (cf. 3-6), variations
in the tether led to a wide fluctuation in the yield.10
With the optimized reaction conditions in hand, we then tested
an assortment of 1,6-diynes and carboxylic acids to evaluate the
scope of the addition-cyclization process (Table 2). The survey
revealed a range of aliphatic and aromatic carboxylic acids to be
good participants of the reaction, giving rise to the corresponding
9
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J. AM. CHEM. SOC. 2007, 129, 1030-1031
10.1021/ja067336e CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Proposed Mechanism for Carboxylative Diyne
Cyclization
Acknowledgment. We thank the NSF (Grant CHE 518559) and
Amgen for financial support of this research, Princeton University
for a Harold W. Dodds Fellowship (H.K.), and Merck for graduate
support (S.D.G.). We also thank Jimin Kim and Dr. Doug Ho for
the X-ray analysis of 2a.
Supporting Information Available: Experimental details (pdf and
cif). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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1999, 5, 3103.
Several observations made in a set of further experiments are
noteworthy (eq 4-6). When monobenzoate 2b was resubjected to
the standard conditions, only bisbenzoate 2c was generated over a
prolonged reaction time (ca. 10%, 48 h) (eq 4). This result renders
the possibility of 2b as an intermediate of the reaction highly
unlikely, thereby excluding the mechanism involving an enyne
cycloisomerization of 2b to 2a.11 The present addition-cyclization
proved infeasible with the methyl-substituted diyne 1a. Interestingly,
the reaction of a 1:1:2 mixture of 1, 1a, and benzoic acid gave
only a 20% yield of 2a with nearly quantitative recovery of
unreacted 1a, indicating possible deactivation of the catalyst by 1a
(eq 5). Finally, the formation of (E)-isomers as the products appears
to be kinetic in origin, since no isomerization occurs under the
reaction conditions (eq 6).
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(a) Doucet, H.; Ho¨fer, J.; Bruneau, C.; Dixneuf, P. H. J. Chem. Soc.,
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Organometallics 1996, 15, 5275. Alkyne-alkene coupling: (f) Murakami,
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J. Chem. ReV. 1996, 96, 635. For examples of addition/cyclization of 1,6-
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D. J. Org. Chem. 1997, 62, 8970. Stannylsilanes: (c) Greau, S.; Radetich,
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M. Organometallics 1997, 16, 5389. Hydrogen: (f) Jang, H. Y.; Krische,
M. J. J. Am. Chem. Soc. 2004, 126, 7875. Hydrogen equivalent: (g) Trost,
B. M.; Lee, D. C. J. Am. Chem. Soc. 1988, 110, 7255. Hydrosilylation:
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(5) (a) Kim, H.; Lee, C. J. Am. Chem. Soc. 2005, 127, 10180. (b) Chen, Y.;
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(8) The structure of 2a has been determined by an X-ray crystallographic
analysis. See Supporting Information for details.
While further studies are currently in progress, a mechanistic
proposal may be advanced on the basis of the observations made
thus far (Scheme 1). Upon formation of ruthenium vinylidene A,
the pendent alkyne is coordinated to the metal center. While it may
not or may only reversibly undergo a [2+2] cycloaddition to B,
addition of the benzoate anion induces cyclization of A to C or D.
Given the exclusive generation of 2a in (E)-configuration, the outer-
(path a) rather than innersphere (path b) nucleophlic attack appears
to be favored, a type of process reminiscent of the nucleophile-
promoted electrophilic cyclization of alkynes.12 The final protio-
demetalation then furnishes the product and turns the catalyst over.
Alternatively, C may be formed via R-migration of F which could
arise from vinyl ruthenium E.13
In summary, we have developed a ruthenium-catalyzed tandem
addition-cyclization of 1,6-terminal diynes and carboxylic acids.
In contrast to typical metal-mediated processes of diynes that give
five-membered-ring products, the reaction provides six-membered-
carbo- and heterocyclic systems decorated with useful functional
groups.14 Also proposed here is an unprecedented anti attack of a
nucleophile on a π-alkyne runthenium vinylidene complex. This
new reactivity is anticipated to open up new opportunities for further
development of catalytic alkyne functionalization.
(9) For comprehensive screening results, see Supporting Information.
(10) The reaction of substrates with an ether tether gave a complex mixture of
intractable products presumably due to the formation of allenylidene and/
or alkenyl alkylidene complexes. For examples, see ref 1a and (b)
Castarlenas, R.; Eckert, M.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2005,
44, 2576. The reactions of 1,5- and 1,7-diynes did not give the cyclized
product, but led to alkyne dimerization after 48 h (see ref 3).
(11) See ref 5a and: Grigg, R.; Stevenson, P.; Worakun, T. Tetrahedron 1988,
44, 4967.
(12) Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc. 1988, 110, 612.
(13) This pathway involving the transient formation of F was suggested by a
reviewer. The possible intermediacy of G and H cannot be excluded at
the present time. The deuterium labeling experiments were inconclusive
because of significant scrambling. For details, see Supporting Information.
(14) For examples showing the product utility, see Supporting Information.
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