Dimerization of cyclopropyl ketones and crossed reactions of cyclopropyl ketones with enones as an entry to five-membered rings

Article abstract of DOI:10.1021/ja0602187

An unexpected dimerization of cyclopropyl ketones was observed, and analysis of the reaction pathway led to development of a synthetically useful crossed reaction between cyclopropyl ketones and enones to afford densely functionalized cyclopentane product

Full text of DOI:10.1021/ja0602187

Published on Web 03/30/2006
Dimerization of Cyclopropyl Ketones and Crossed Reactions of Cyclopropyl
Ketones with Enones as an Entry to Five-Membered Rings
Lei Liu and John Montgomery*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055, and Department of Chemistry,
Wayne State UniVersity, Detroit, Michigan 48202
Received January 11, 2006; E-mail: jmontg@umich.edu
[3 + 2] Cycloadditions are among the most powerful strategies
Table 1. Cyclopropyl Ketone Dimerizations
for the synthesis of five-membered carbocyclic and heterocyclic
ring systems.1 Among the reactions useful in the synthesis of
2
cyclopentanes, trimethylene methane precursors, activated cyclo-
3
4
propanes, and allyl and propargylsilanes are arguably the most
useful three-carbon units in [3 + 2] cycloadditions. Methylene
cyclopropanes are known to be versatile precursors in metal-
catalyzed [3 + 2] cycloadditions involving either trimethylene
methane intermediates or four-membered metallacycles, depending
on whether the σ-bond proximal or distal to the exocyclic methylene
undergoes oxidative addition with the low-valent transition metal.3
Vinylcyclopropanes are also excellent substrates in metal-catalyzed
entry (substrate)
R1
R2
product (% yield, dr)
1
(1a)
Ph
4-MeO(C H )
4-F(C6H4)
thiophen-2-yl
furan-2-yl
Ph
H
H
H
H
H
Me
3a (85, 98:2)
3b (90, 99:1)
3c (85, 98:2)
3d (88, 99:1)
3e (83, 90:10)
5
cycloadditions and rearrangements in several contexts. However,
2 (1b)
3 (1c)
6
4
cyclopropanes that lack exomethylene or vinyl substituents have
received relatively little attention as useful precursors in metal-
catalyzed cycloaddition processes. Donor-acceptor cyclopropanes
are highly versatile substrates in five-membered ring synthesis via
4
5
6
(1d)
(1e)
(1f)
a
3f (24)
6
a
Lewis acid catalysis. However, Lewis acid-promoted [3 + 2]
3-Methyl-1-phenylbut-2-en-1-one was obtained in 66% yield.
cycloadditions of simple cyclopropyl ketones are typically not
efficient. Given the lack of utility of simple cyclopropyl ketones
in both Lewis acid-catalyzed and transition metal-catalyzed cy-
cloadditions, we have initiated an exploratory investigation of this
potentially useful substrate class in nickel-catalyzed reactions.
In gauging the reactivity of cyclopropyl ketone 1a with a catalyst
Scheme 1. Proposed Mechanism
2
derived from Ni(COD) , imidazolium chloride 2, and potassium
7
tert-butoxide, we made the surprising observation that 1a undergoes
an efficient and highly diastereoselective dimerization to trisubsti-
tuted cyclopentane 3a in 85% yield. A variety of aromatic ketones
undergo the process efficiently (Table 1, entries 1-5), and aliphatic
ketones were significantly less reactive in the process. Variation
of the cyclopropyl unit was difficult since even a simple methyl
substituent led to low yields of expected adduct 3f along with 66%
yield of 3-methyl-1-phenylbut-2-en-1-one (Table 1, entry 6). We
reasoned that this remarkable transformation likely involves the
oxidative addition of Ni(0) to 1 to afford metallacycle 4a or 4b,8
which undergoes a sequence involving â-hydride elimination to
afford enone 5a or 5b along with regeneration of Ni(0) (Scheme
9
1
). Enone 5a then undergoes addition to another equivalent of 4b
2
to afford [3 + 2] cycloaddition product 3 (when R ) H, note that
a ) 4b and 5a ) 5b, with alkene stereochemistry arbitrarily
4
shown). The formation of an enone as the major product in reactions
of substrate 1f provided direct evidence for the 1 to 5b conversion.
Analysis of the overall mass balance of entry 6 (Table 1) illustrates
that metallacycle 4b is favored via oxidative addition to the least
hindered carbon-carbon bond of 1, although both 4b and 5a are
required for the formation of 3f.
The crossed reaction of differentially substituted cyclopropyl
ketones and enones was attempted in order to advance the synthetic
utility of the process and to provide further evidence for the
proposed reaction pathway. However, initial attempts failed since
stoichiometric addition of the enone effectively inhibits the [3 + 2]
process, presumably due to its π-acidity. However, keeping the
enone concentration low by syringe drive addition over 2 h
duplicates the slow release of enone suggested in the proposed
mechanism, and crossed reactions now become possible (Table 2).
Yields were typically modest to good, and the cyclopropyl ketone
dimer 3 is nearly always observed as a component of the reaction
mixture. While not strictly required, Ti(O-iPr) or Ti(O-tBu) as
4 4
an additive improves yields and increases reaction rates. The crossed
reactions of differentially substituted cyclopropyl ketones and
5348
9
J. AM. CHEM. SOC. 2006, 128, 5348-5349
10.1021/ja0602187 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Crossed Reactions of Cyclopropyl Ketones and Enones
suspect that prior coordination of the imine nitrogen to nickel may
facilitate oxidative addition into the cyclopropane carbon-carbon
bond.10 Future studies will focus on further development of
cyclopropyl imine cycloadditions and elucidation of the mechanistic
basis for reaction acceleration with imine derivatives.
entry
R1
R2
R3
R4
producta (% yield, dr)
1
2
3
4
5
6
7
8
9
4-F(C6H4)
thiophen-2-yl
Ph
furan-2-yl
4-F(C6H4)
4-F(C6H4)
Ph
Me
Ph
Ph
H
H
H
H
H
H
H
H
Ph
Ph
furan-2-yl
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
C6H13
Ph
SiMe3
Me
Me
Me
9a (77, 94:6)
9b (59, 97:3)
9c (58, 96:4)
9d (42, 90:10)
9e (66, 93:7)
9f (59, 39:61)b
9g (41, >97:3)
9h (47, 93:7)
9i (52, 75:25)
9j (41, 88:12)
In summary, a new nickel-catalyzed cycloaddition process
involving simple cyclopropyl ketones has been developed. An
unexpected dimerization of cyclopropyl ketones was observed, and
analysis of the reaction pathway led to development of a syntheti-
cally useful crossed reaction between cyclopropyl ketones and
enones to afford densely functionalized cyclopentane products.
Me
Me
10
furan-2-yl
a
Typically, equimolar amounts of 1 and 7 were used. Most of the
remaining mass balance was the dimer of 1. See Supporting Information
for details. The major product is the trans/trans isomer of 9.
b
Acknowledgment. The authors wish to acknowledge receipt
of NSF Grant CHE-0553895. We thank Dr. Beth Knapp-Reed for
helpful discussions, and the Roush group for assistance with and
use of their preparative HPLC.
enones that both possess aromatic substitution at the carbonyl
proceed efficiently by this procedure (entries 1-4). Notably, a
comparison of entries 3 and 4 illustrates that diastereoselectivities
are kinetically controlled, and that either cis-trans diastereomer
may be obtained by simply swapping the ketone substituents on
the two reaction partners. Additionally, use of an enone reactant
Supporting Information Available: Full experimental details and
copies of NMR spectral data (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
4
now allows additional flexibility in the R functionality, as illustrated
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