Tandem cyclization of alkynes via rhodium alkynyl and alkenylidene catalysis

Article abstract of DOI:10.1021/ja066374v

A rhodium(I)-catalyzed tandem cyclization of alkynes has been developed. The reaction allows for multiple bond formations to occur at both the α- and β-positions of alkynes under mild conditions to yield a variety of fused ring systems as the products. In

Full text of DOI:10.1021/ja066374v

Published on Web 10/31/2006
Tandem Cyclization of Alkynes via Rhodium Alkynyl and Alkenylidene
Catalysis
Jung Min Joo, Yu Yuan, and Chulbom Lee*
Department of Chemistry, Princeton UniVersity, Princeton, New Jersey, 08544
Received September 2, 2006; E-mail: cblee@princeton.edu
Table 2. Rhodium-Catalyzed Alkylative Cyclization of Iodoenynesa
Transition metal alkynyl σ-complexes are among the mainstay
organometallics that are of broad utility in organic synthesis.1 The
sp-hybridized carbon-metal bond of such complexes reacts with
electrophiles typically through the R-carbon to effect alkynylation
under metal catalysis.2,3 An alternative pathway of metal alkynyls
involves a reaction of the â-carbon that leads to the formation of a
metal alkenylidene (vinylidene) species (Scheme 1). Unlike the alkyn-
ylation process, however, this type of reactivity has been established
only in stoichiometric settings, requiring a preformed metal alkynyl
and a separate step for demetalation of the resulting alkenylidene
complex.4,5 Despite its conceivable synthetic value, a catalytic
protocol accomplishing bond formation based on this modality
remains to be developed.6 Noting the feasibility of the generation
and turnover of metal alkynyls and alkenylidenes via catalytic
mechanisms,7 we envisioned a tandem process that could couple
these events with a â-alkylation as mediated by a single catalyst.
This process would enable multiple C-C bond formations to occur
at both the R- and â-positions of alkynes in one synthetic operation.
In this communication, we report a tandem cyclization of terminal
alkynes that provides expedient access to fused ring systems via
combined rhodium alkynyl/alkenylidene-mediated catalysis.
In light of our previous experience in the Rh(I)-catalyzed enyne
cycloisomerization,8 the present study was initiated by examining
Scheme 1. Strategy for Catalytic Terminal Alkyne
Functionalization
Table 1. Rhodium-Catalyzed Alkylative Cyclization of Enyne 1a
a
All reactions were performed with 0.20 mmol of substrate, 0.40 mmol
entry
X
ligand
base
yield (%)b
of TEA, 3 mol % of [Rh(COD)Cl]2, and 12 mol % of P(4-F-C6H4)3 at 85
b
°C in DMF (0.1 M), unless otherwise noted. Isolated yield. For entries
1
2
3
4
5
6
7
8
9
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
I (1a)
Br (1b)
OTs (1c)
P(4-F-C6H4)3
P(4-F-C6H4)3
P(4-F-C6H4)3
P(4-F-C6H4)3
P(4-F-C6H4)3
P(4-F-C6H4)3
PPh3
P(4-MeO-C6H4)3
P(3-Cl-C6H4)3
P(3,5-CF3-C6H3)3
P(4-F-C6H4)3
P(4-F-C6H4)3
-
-
-
c
2, 3, 4, 7, and 8, the yields were averaged over two runs. DI (Deuterium
DABCO
DBU
NMMc
DIPEA
TEA
TEA
TEA
TEA
TEA
d
e
incorporation) ) 86%. DI ) 83%. Diastereomeric mixtures were
25
62
80
85
80
73
69
50
62
46
f
employed and obtained (dr ) 1.2:1). [Rh(C2H4)2Cl]2 was used as the
catalyst at 25 °C. The reaction was performed in THF for 48 h.
g
the possibility of these catalyst systems to promote a â-alkylation
in the context of 3-haloalkyl-1,6-enyne system 1 (Table 1). While
subjecting 1a to our previously developed conditions gave none of
2 (entries 1 and 2),9 the otherwise same reaction in the presence of
DBU resulted in a yield of 25% (entry 3). Further screening revealed
TEA to be an optimal base increasing the yield to 85% (entry 6).
The electronic character of the arylphosphines exerted only marginal
effects on the present reaction with P(4-F-C6H4)3 being most
effective (entries 6-10). The double cyclization could also be
10
11
12
TEA
TEA
a
All reactions were performed with 0.20 mmol of 1 and 0.40 mmol of
b
c
base at 85 °C in DMF (0.1 M) for 14 h. Isolated yield of 2. NMM )
N-methylmorpholine.
9
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J. AM. CHEM. SOC. 2006, 128, 14818-14819
10.1021/ja066374v CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Proposed Mechanism for the Rh-Catalyzed
Alkylation-Cycloaddition of 3-Haloalkyl-1,6-enynes
In summary, we have developed a rhodium-catalyzed tandem
cyclization of alkynes. The reaction allows for the rapid assembly
of various fused ring systems from terminal alkyne derivatives in
a single step under mild conditions through a novel mechanism
that merges transition metal alkynyl and alkenylidene chemistry.
The findings described in this paper suggest that the uniquely unified
catalytic cycle may be permuted in many ways for further
development of new methods of alkyne functionalization.
Acknowledgment. We thank the NSF (CHE 0518559) and the
NIH-NIGMS (GM 073065) for support of this research, Princeton
University for a Hugh Stott Taylor fellowship (J.M.J.), and FMC
Corporation for a graduate fellowship (Y.Y.).
carried out with substrates bearing bromide (1b) and tosylate (1c)
leaving groups, albeit with diminished yields (entries 11 and 12).
Reaction scope was probed with a range of substrates (Table 2).
Similar to the model study, hydrindene ring systems possessing
substituents of differential positions and stereochemistry (entries
1-3) as well as a spirotricyclic derivative (entry 4) were accessed
from the corresponding enynes. In addition to these carbocycles,
the Rh(I)-catalyzed tandem cyclization proved feasible for the
preparation of various aza- (entry 5) and oxacycles (entries 6-9),
including the tricyclic hydrofurodecaline 18. For the reaction of
19, the use of [Rh(C2H4)2Cl]2 was found to be effective inducing
the cyclization at 25 °C (entry 9). Interestingly, the simple enyne
cycloisomerization without alkylation of the iodide took place when
the reaction was performed in THF instead of DMF (entry 10).
This dichotomy of reaction pathways suggests the presence of a
subtle kinetic balance in the catalytic cycle (vide infra).
The mechanism of the present tandem cyclization is proposed
to involve a reversible formation of rhodium alkynyl complex B
(Scheme 2). Subsequent to an irreversible alkylation with the
pendent alkyl halide, the resultant â,â-substituted alkenylidene C
undergoes a [2 + 2] cycloaddition to accomplish an additional ring
closure via D and E.10 When the alkylation step is slow or infeasible,
intermediate A, existing in equilibrium with B,11 may directly enter
on the cycloisomerization course to give rise to a monocyclization
product such as 21.
On the basis of the intermediacy of an alkenylidene complex of
type C, we hypothesized that the alkylative approach might be
extended to construct other ring structures by replacing the alkene
with other reactive components such as hydroxyl (22) and phenyl
(26) groups. Under the same reaction conditions employed for the
alkylation-cycloaddition, alcohol 22 was converted to enol ether
24 in 52% yield, presumably through â-alkylation followed by
addition of the hydroxyl group to the rhodium alkenylidene 23,
and the simple cycloisomerization product 25 in 15% yield (eq
1).7c,12 A tandem cyclization took place in the reaction of 26, which
afforded the tetracyclic naphthalene 28 in 83% yield (eq 2). In this
case, the incipient alkenylidene 27 is believed to follow a
6π-electrocyclization process,13 leading to aromatization.14
Supporting Information Available: Experimental details and NMR
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) Long, N. J.; Williams, C. K. Angew. Chem., Int. Ed. 2003, 42, 2586.
(2) For reviews on the alkynylation via cross-coupling reactions, see: (a)
Sonogashira, K. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-i. Ed., Wiley-Interscience: New York, 2002; pp
493-529. (b) Negishi, E.-i.; Anastasia, L. Chem. ReV. 2003, 103, 1979.
(c) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566.
(3) For reviews on the alkyne additions, see: (a) Pu, L. Tetrahedron 2003,
59, 9873. (b) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org.
Chem. 2004, 4095. (c) Wei, C.; Li, Z.; Li, C.-J. Synlett 2004, 1472.
(4) (a) Davison, A.; Selegue, J. P. J. Am. Chem. Soc. 1978, 100, 7763. (b)
Bruce, M. I.; Swincer, A. G.; Wallis, R. C. J. Organomet. Chem. 1979,
171, C5. (c) Abbott, S.; Davies, S. G.; Warner, P. J. Organomet. Chem.
1983, 246, C65. (d) Gamasa, M. P.; Gimeno, J.; Lastra, E.; Martin, B.
M.; Anillo, A.; Tiripicchio, A. Organometallics 1992, 11, 1373. (e) Bruce,
M. I.; Koutsantonis, G. A.; Liddell, M. J. J. Organomet. Chem. 1987,
321, 217. (f) Bruce, M. I.; Humphrey, M. G.; Liddell, M. J. J. Organomet.
Chem. 1987, 321, 91. (g) Ting, P.-C.; Lin, Y.-C.; Cheng, M.-C.; Wang,
Y. Organometallics 1994, 13, 2150. (h) Ting, P.-C.; Lin, Y.-C.; Lee, G.-
H.; Cheng, M.-C.; Wang, Y. J. Am. Chem. Soc. 1996, 118, 6433. (i) Liang,
K.-W.; Li, W.-T.; Peng, S.-M.; Wang, S.-L.; Liu, R.-S. J. Am. Chem.
Soc. 1997, 119, 4404. (j) Liang, K.-W.; Chandrasekharam, M.; Li, C.-L.;
Liu, R.-S. J. Org. Chem. 1998, 63, 7289. (k) Yang, J.-Y.; Huang, S.-L.;
Lin, Y.-C.; Wang, Y. Organometallics 2000, 19, 269. (l) Huang, H.-L.;
Sung, W.-H.; Liu, R.-S. J. Org. Chem. 2001, 66, 6193. (m) Madhushaw,
R. J.; Hu, C.-C.; Liu, R.-S. Org. Lett. 2002, 4, 4151. (n) Madhushaw, R.
J.; Li, C.-L.; Su, H.-L.; Hu, C.-C.; Lush, S.-F.; Liu, R.-S. J. Org. Chem.
2003, 68, 1872.
(5) For related examples, see: (a) Merrill, R. E.; Allen, J. L.; Abramovitch,
A.; Negishi, E.-i. Tetrahedron Lett. 1977, 1019. (b) Corey, E. J.; Seibel,
W. L. Tetrahedron Lett. 1986, 27, 905 and 909. (c) Harada, T.; Wada, H.;
Oku, A. J. Org. Chem. 1995, 60, 5370. (d) Harada, T.; Iwazaki, K.; Otani,
T.; Oku, A. J. Org. Chem. 1998, 63, 9007. (e) Harada, T.; Fujiwara, T.;
Iwazaki, K.; Oku, A. Org. Lett. 2000, 2, 1855. (f) Harada, T.; Oku, A. J.
Synth. Org. Chem. Jpn. 2001, 59, 101.
(6) For related catalytic atom-transfer processes under anionic conditions,
see: (a) Harada, T.; Muramatsu, K.; Fujiwara, T.; Kataoka, H.; Oku, A.
Org. Lett. 2005, 7, 779. (b) Harada, T.; Mizunashi, K.; Muramatsu, K.
Chem. Commun. 2006, 638.
(7) (a) Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int. Ed. 2006, 45, 2176.
(b) Trost, B. M. Acc. Chem. Res. 2002, 35, 695. (c) McDonald, F. E.
Chem.-Eur. J. 1999, 5, 3103. (d) Puerta, M. C.; Valerga, P. Coord. Chem.
ReV. 1999, 193-195, 977.
(8) (a) Kim, H.; Lee, C. J. Am. Chem. Soc. 2005, 127, 10180. (b) Kim, H.;
Lee, C. J. Am. Chem. Soc. 2006, 128, 6336.
(9) While the base-free conditions (ref 8a) returned unreacted 1a (64%) along
with 19% of its formate (X ) OCHO) derived from a DMF adduct of 1a
after 6 h, the reaction in the presence of DABCO (ref 8b) led to rapid
decomposition of 1a, presumably via N-alkylation.
(10) The formation of 4b from 3b (entry 1, Table 2) together with the results
of the labeling studies reported in ref 8a supports this mechanism.
(11) (a) Werner, H.; Wolf, J.; Alonso, F. J. G.; Ziegler, M. L.; Serhadli, O.
J. Organomet. Chem. 1987, 336, 397. (b) Bianchini, C.; Meli, A.;
Peruzzini, M.; Zanobini, F.; Zanello, P. Organometallics 1990, 9, 241.
(c) Perez-Carreno, E.; Paoli, P.; Ienco, A.; Mealli, C. Eur. J. Inorg. Chem.
1999, 1315. (d) Wakatsuki, Y.; Koga, N.; Werner, H.; Morokuma, K. J.
Am. Chem. Soc. 1997, 119, 360. (e) Grotjahn, D. B.; Zeng, X.; Cooksy,
A. L. J. Am. Chem. Soc. 2006, 128, 2798.
(12) Trost, B. M.; Rhee, Y. H. J. Am. Chem. Soc. 2003, 125, 7482.
(13) Merlic, C. A.; Pauly, M. E. J. Am. Chem. Soc. 1996, 118, 11319.
(14) Dankwardt, J. W. Tetrahedron Lett. 2001, 42, 5809.
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