Rhodium(I)-catalyzed [4+2+2] cycloadditions of 1,3-dienes, alkenes, and alkynes for the synthesis of cyclooctadienes

Article abstract of DOI:10.1021/ja060878b

The first [4+2+2] cycloadditions involving terminal alkynes and diene-enes, including a fully intramolecular example, are reported resulting in the formation of cyclooctadienes using [RhCl(CO)₂]₂ (5 mol %) treated with AgSbF₆

Full text of DOI:10.1021/ja060878b

Published on Web 04/01/2006
Rhodium(I)-Catalyzed [4+2+2] Cycloadditions of 1,3-Dienes, Alkenes, and
Alkynes for the Synthesis of Cyclooctadienes
Paul A. Wender* and Justin P. Christy
Departments of Chemistry and of Molecular Pharmacology, Stanford UniVersity, Stanford, California 94305-5080
Received February 8, 2006; E-mail: wenderp@stanford.edu
Scheme 1. Trapping of Metallacycles with π-Components
In 1989, we reported the first transition metal-catalyzed, intra-
molecular [4+2] cycloadditions of dienes and alkynes, representing
a mechanistically novel and synthetically useful route to cyclo-
hexadienes (a to f, Scheme 1) that works effectively often at room
temperature, even when the corresponding Diels-Alder reaction
requires forcing conditions or is ineffective.1 This reaction was
subsequently shown to work with dienes and alkenes2 or allenes.3
We anticipated that the metallacyclic intermediates (b and d)
presumably involved in these reactions could be intercepted with
various 1- to n-carbon trapping agents to produce higher order
[2+2+n] and [4+2+n] cycloadducts. Subsequent studies showed
that the [4+2] cycloaddition of dienes and alkynes could indeed
be diverted with CO to produce a three-component [4+2+1]
product (cycloheptadienone e) as well as [2+2+1] product (cyclo-
pentenone c).4 In 2002, the Gilbertson group creatively showed that
the metallacycles involved in these processes could also be captured
by alkynes to give a [4+2+2] cyclooctatriene product g.5 An
equally impressive, alternative [4+2+2] process for eight-
membered ring synthesis based on enynes and dienes was also
reported by the P. A. Evans group.6
Table 1. Initial Catalyst Screen with Diene-ene 1 and Methyl
Propargyl Ether
In our studies on the [2+2+1] reactions of dienes, alkynes, and
CO (a to c), we observed that dienes accelerate the reaction relative
to alkenes, providing a new route to alkenyl-substituted cyclopen-
tenones c, a dienyl Pauson-Khand reaction. This observation
suggested that dienes, unlike alkenes, might react with a tethered
alkene in the presence of CO to produce cyclopentanones c, a
previously unknown process. This led to the first examples of a
catalytic [2+2+1] route to cyclopentanones.4 Given the enhanced
reactivity of dienes observed in these studies, we have now
examined the reaction of dienes as 4-carbon components tethered
to alkenes in the presence of alkynes as trapping agents. We report
herein the first examples of this combination in a metal-catalyzed
[4+2+2] cycloaddition, producing cyclooctadienes often in high
yields and with regiocontrol.7 In preliminary studies, we have also
established the first fully intermolecular example of this three-
component process.
The results of a preliminary screen of several rhodium(I) catalysts
are shown in Table 1. It is noteworthy that these catalysts favor
the [4+2+2] reaction over the otherwise facile intramolecular [4+2]
process, even when only 1.1 equiv of an alkyne trapping agent is
used. [RhCl(CO)2]2 modified with AgSbF6 results in the highest
combined yield of [4+2+2] cycloadducts under the conditions
described in Table 1 (85%, entry 2). Lower temperatures (60 to 40
°C) were also found to favor the three-component process. Further
optimization studies showed that increasing the reaction concentra-
tion from 0.01 to 0.10 M also leads to overall higher yields of the
desired products. It should be noted that only trace amounts (<5%)
of the intramolecular [4+2] product are ever observed under the
optimized conditions.
a Conditions (unless otherwise noted): DCE (0.01 M), 65 °C, 1.1 equiv
of methyl propargyl ether. b 5 mol %. c 5 mol %. d GC yield. e DCE (0.10
M), 40 °C, 1.2 equiv of methyl propargyl ether. f Determined by 1H NMR.
Internal alkynes such as 1,4-dimethoxybut-2-yne and hex-3-yn-2-
one react inefficiently under the reaction conditions. The regio-
selectivity of the alkyne insertion is influenced by both steric and
electronic features of the alkyne. Both methyl and tert-butyl-
dimethylsilyl (TBS) propargyl ethers give comparable yields and
regioselectivities (entries 1 and 2). Replacing the methylene-
methoxy group with a bulkier cyclopropyl group increases the
regioselectivity from 4.2:1 to 11.7:1 (entry 1 versus 3). When ethyl
propiolate is used, cycloadducts 5a and 5b are formed in 72% yield
(ratio 6.4:1, entry 4). Additionally, when the reaction is run with
3-butyn-2-one the regioselectivity is reversed, favoring the 6b
isomer (ratio 1:1.9, combined yield 81%, entry 5). Significantly,
the [4+2+2] reaction can also be carried out under one atm of
acetylene, yielding cycloadduct 7 in 75% yield (entry 6). The scope
of the reaction with respect to diene-ene substitution and tether
type is shown in Table 3. Substitution in the 2-position of the diene
results in higher yields and accelerated reaction rates relative to
those obtained with the unsubstituted diene (entries 1-3). This is
similar to the substituent effects observed in dienyl [2+2+1] cyclo-
The [4+2+2] reaction has been found to proceed efficiently with
a variety of terminal alkynes having ether, alkyl, ester, or ketone
substituents (Table 2). Reaction times ranged from minutes to 5 h.
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10.1021/ja060878b CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Diene-ene Scope of the [4+2+2] Reactiona
Table 2. Alkyne Scope of the [4+2+2] Reactiona
a Conditions (unless otherwise noted): 5 mol % [RhCl(CO)2]2, 10 mol
% AgSbF6, DCE (0.10 M), 40 °C, 1.2 equiv of alkyne. b 2.0 equiv of alkyne.
c 80 °C. d Determined by H NMR.
1
a Conditions same as in Table 2 (unless otherwise noted), methyl
propargyl ether (1.2 equiv). b 2.0 equiv of alkyne. c 3.0 equiv of alkyne.
d 60 °C. e 5.0 equiv of diene, 6.0 equiv of norbornene. f Determined by 1H
NMR.
additions.4 With R ) i-Pr the reaction was complete in 3 h, pro-
viding cycloadducts 2a and 2b in 85% combined yield (entry 1).
Substrates containing heteroatoms were also tolerated and
allowed for the efficient formation of the corresponding heterocycles
(entries 4 and 5). Significantly, substitution at the 2-position of the
alkene moiety results in the formation of cycloadducts 18a and
18b (68% combined yield), a noteworthy result due to its stereo-
selectivity (cis-fusion) and its creation of an angular quaternary
center (entry 6). Methyl substitution at the terminal position of the
diene (entry 7) results in regio- and stereoselective formation of
19a (37% yield). Replacing the allyl group with a crotyl group or
a homoallyl group to produce bicyclo[6.4.0] systems results thus
far in only trace conversions, even when the reaction is heated (60
°C) for 24 h (not shown).
Remarkably, the [4+2+2] cycloaddition can be carried out
intermolecularly, as demonstrated by the chemo-, diastereo-, and
regioselective conjunction of three different π-systems (norbornene,
2,3-dimethyl-1,3-butadiene, and methyl propargyl ether) to produce
cycloadduct 20 (entry 8). This is the first example of a nontethered,
three-component [4+2+2] cycloaddition.
Supporting Information Available: Full experimental details and
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) Wender, P. A.; Jenkins, T. E. J. Am. Chem. Soc. 1989, 111, 6432-6434.
(2) (a) Jolly, R. S.; Luedtke, G.; Sheehan, D.; Livinghouse, T. J. Am. Chem.
Soc. 1990, 112, 4965-4966. (b) McKinstry, L.; Livinghouse, T. Tetra-
hedron 1994, 50, 6145-6154.
(3) Wender, P. A.; Jenkins, T. E.; Suzuki, S. J. Am. Chem. Soc. 1995, 117,
1843-1844.
(4) For examples of [4+2+1] and [2+2+1] reactions with diene-ynes, see:
(a) Wender, P. A.; Deschamps, N. M.; Gamber, G. G. Angew. Chem.,
Int. Ed. 2003, 42, 1853-1857. For examples of [2+2+1] reactions with
diene-enes, see: (b) Wender, P. A.; Croatt, M. P.; Deschamps, N. M. J.
Am. Chem. Soc. 2004, 126, 5948-5949. For an impressive alternative
[4+2+1] cycloaddition, see: (c) Ni, Y.; Montgomery, J. J. Am. Chem.
Soc. 2006, 128, 2609-2614 and references therein.
(5) Gilbertson, S.; DeBoef, B. J. Am. Chem. Soc. 2002, 124, 8784-8785.
(6) (a) Evans, P. A.; Robinson, J. E.; Baum, E. W.; Fazal, A. N. J. Am. Chem.
Soc. 2003, 125, 14648; J. Am. Chem. Soc. 2002, 124, 8782-8783. (b)
Evans, P. A.; Baum, E. W. J. Am. Chem. Soc. 2004, 126, 11150-11151.
(c) Evans, P. A.; Baum, E. W.; Fazal, E. W.; Aleem, N.; Pink, M. Chem.
Commun. 2005, 1, 63-65. (d) Baik, M.; Baum, E. W.; Burland, M. C.;
Evans, P. A. J. Am. Chem. Soc. 2005, 127, 1602-1603.
In summary, initial examples of rhodium(I)-catalyzed [4+2+2]
cycloadditions between diene-enes and terminal alkynes are de-
scribed along with studies on substituent effects and the regio- and
the diastereoselectivity of the reaction. Additionally, the first
example of a three-component [4+2+2] cycloaddition is reported.
These processes allow for the rapid and efficient construction of a
wide variety of eight-membered ring systems.
(7) For other examples of related metal-catalyzed [4+2+2] cycloadditions,
see: (a) Chen, Y.; Kiattansakul, R.; Ma, B.; Synder, J. K. J. Org. Chem.
2001, 66, 6932-6942. (b) Ma, B.; Snyder, J. K. Organometallics 2002,
21, 4688-4695. (c) Varela, J.; Castedo, L.; Saa, C. Org. Lett. 2003, 5,
2841-2844. (d) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem.
Soc. 2006, 128, 2166-2167. For a review of related rhodium-catalyzed
cycloadditions, see: Modern Rhodium-Catalyzed Organic Reactions;
Evans, P. A., Ed.; Wiley-VHC Verlag GmbH & Co.: Weinheim,
Germany, 2005.
Acknowledgment. This research was supported by a grant
(CHE-0131944) from the National Science Foundation. HRMS was
provided by the University of California, San Francisco.
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