[3+2] cycloadditions of aryl cyclopropyl ketones by visible light photocatalysis

Article abstract of DOI:10.1021/ja107849y

We report a new method for the formal [3+2] reaction of aryl cyclopropyl ketones with olefins to generate highly substituted cyclopentane ring systems. The key initiation step in this process is the one-electron reduction of the ketone to the correspondin

Full text of DOI:10.1021/ja107849y

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[3þ2] Cycloadditions of Aryl Cyclopropyl Ketones by Visible Light
Photocatalysis
Zhan Lu, Meihua Shen, and Tehshik P. Yoon*
Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S Supporting Information
b
Scheme 1
ABSTRACT: We report a new method for the formal [3þ2]
reaction of aryl cyclopropyl ketones with olefins to generate
highly substituted cyclopentane ring systems. The key initia-
tion step in this process is the one-electron reduction of the
ketone to the corresponding radical anion, which is accom-
2þ
plished using a photocatalytic system comprising Ru(bpy)3
La(OTf)3, and TMEDA.
,
yclopentanes are important structural elements of a wide
variety of organic compounds. One particularly attractive
C
strategy for their synthesis is the [3þ2] cycloaddition reaction of
activated cyclopropanes with olefins.1 Several straightforward and
robust methods for the synthesis of cyclopropyl ketones are
available,2 and the strain associated with the three-membered ring
provides a substantial driving force for the synthesis of larger
carbocycles. However, most [3þ2] cycloadditions of cyclopro-
panes reported to date have utilized “donor-acceptor” cyclo-
propanes,3 methylene cyclopropanes,4 or similar highly activated
cyclopropanes that bear substituents that predispose them toward
ring-opening.5 Recently, Montgomery and Ogoshi independently
reported cycloadditions of simple cyclopropyl ketones with olefins
that are catalyzed by Ni0 complexes.6 Herein, we report a mechan-
istically distinct method for the activation and [3þ2] cycloaddition
of simple aryl cyclpropyl ketones based upon our strategy for
formation of anion radicals by visible light photocatalysis.7-9
The chemistry of cyclopropyl ketyl radicals has been studied in
a variety of contexts.10 Synthetically, they have most commonly
been exploited for their propensity to undergo reductive frag-
mentations.11,12 To the best of our knowledge, however, they have
not been examined as intermediates in [3þ2] cycloaddition
reactions. Werecentlyshowedthata Ru(bpy)32þ photocatalyst can
readily promote the one-electron reduction of a variety of aryl
enones upon irradiation with visible light, and we have reported
[2þ2] cycloadditions involving radical anions generated in this
manner.7 We wondered if similar photocatalytic conditions might
be used to effect the one-electron reduction of aryl cyclopropyl
ketone 1 (Scheme 1). We expected the resulting radical anion 2 to
be capable of ring-opening to distonic radical anion 3. Sequential
radical cyclizations might then give rise to cyclized ketyl radical 5,
which, upon loss of an electron, would produce 6 as the product of
formal intramolecular [3þ2] cycloaddition of 1.
Table 1. Optimization and Control Studiesa
entry mol % Ru Lewis acid amine (equivs)
yieldb
drc
1
5
LiBF4
i-Pr2NEt (10)
0%
-
2
5
Zn(OTf)2
i-Pr2NEt (10) <5%
-
3
5
Gd(OTf)3 i-Pr2NEt (10)
7%
32%
7%
7:1
4
5
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
none
i-Pr2NEt (10)
Et3N (10)
6:1
6:1
9:1
6:1
5
5
6
5
TMEDA (5)
TMEDA (5)
TMEDA (5)
TMEDA (5)
none
73%
87% (83%)d
0%
7
2.5
0
8
-
9
2.5
2.5
2.5
2.5
0%
-
-
-
10
11e
12f
La(OTf)3
La(OTf)3
La(OTf)3
0%
TMEDA (5)
0%
TMEDA (5)
82%
7:1
aSubjected to irradiation with a 23 W compact fluorescent bulb unless
otherwise noted. b Determined by H NMR unless otherwise noted.
1
c Ratio of major isomer to all other isomers, as determined by GC.
d Isolated yield in parentheses. e No light. f No MgSO4.
our original studies, we had discovered that the Lewis acidity of the
lithium cation was critical to the success of the reaction and
speculated that it served to activate the carbonyl compound toward
one-electron reduction. We reasoned, therefore, that stronger
Lewis acid additives might better activate the cyclopropyl ketone
However, under the conditions we had utilized for [2þ2]
cycloadditions of enones (Ru(bpy)3Cl2, LiBF4, i-Pr2NEt), we
observed no evidence of ring-opening of 1 (Table 1, entry 1). In
Received: September 1, 2010
Published: January 7, 2011
r
2011 American Chemical Society
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|

Journal of the American Chemical Society
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Table 2. Scope Studies of Intramolecular [3þ2]
the key radical.13 On the other hand, the use of MgSO4 or other
drying agents was not necessary, but its omission resulted in
somewhat lower yields and poorer reproducibility (entry 12).
Having developed conditions for this novel [3þ2] cycloaddition,
we conducted an initial investigation of the scope of this reaction
(Table 2). Variation of the enone moiety revealed that a variety of
esters, ketones, and thioesters participated in this cycloaddition but
that the presence of an R-substituent increased the efficiency and
stereoselectivity of the process; reactions of R-substituted thioesters
were particularly diastereoselective (entries 1-7). We found that
aliphatic cyclopropyl ketones were not successful substrates for this
reaction, presumably due to the greater difficulty of generating their
radical anions. On the other hand, a variety of substituted aryl
ketones were easily tolerated (entries 8 and 9), although electron-
donating substituents resulted in sluggish reactions. Cycloadditions
with various tethers, including three-carbon, four-carbon, and
heteroatom linkers, were successful (entries 10-14).14 Finally, in
contrast to the [2þ2] process of the parent bis(enones), we found
that coupling with an enone acceptor was not a requirement;
styrenes also resulted in successful [3þ2] cycloadditions (entries
12 and 13). Cyclic aliphatic olefins also participated in this reaction,
enabling the synthesis of tricyclic structures (entry 14). Finally, both
aryl and aliphatic alkynes were excellent reaction partners (entries
15 and 16), although in the latter case we observed migration of the
alkene into conjugation with the ketone.
Cycloadditionsa
We also performed the [3þ2] cycloaddition of cyclopropane 7
(eq 1). This substrate was prepared as a 1:1 mixture of dia-
stereomers.15 Nevertheless, cycloaddition under our optimized
conditions affords the tricyclic cycloadduct 8 as a single diasteromer,
which is consistent with the intermediacy of a non-stereogenic ring-
opened distonic radical anion in which the stereochemical integrity
of the cyclopropane is lost. Thus, the results of this experiment are in
good agreement with the design plan outlined in Scheme 1.
a Conditions: 2.5 mol % Ru(bpy)3Cl2, 1 equiv of La(OTf)3, 5 equiv of
TMEDA, 200 wt % MgSO4, MeCN, 23 °C. Reactions were irradiated
with a standard consumer 23 W compact fluorescent light bulb.
b Averaged isolated yields from two reproducible experiments. c Ratio
of major diastereomer to all other diastereomers as determined by GC.
Finally, we are also interested in developing an intermolecular
version of this [3þ2] cycloaddition. As an initial exploration of
this possibility, we irradiated cyclopropyl phenyl ketone (9) with
methacrylonitrile (10) under conditions similar to those we had
optimized for the intramolecular cycloaddition and observed
successful formation of [3þ2] cycloadduct 11 (eq 2). However,
the yield and diastereoselectivity of this process are low, and
efforts to optimize this promising initial result are continuing in
our laboratories.
toward one-electron reduction, better stabilize the ketyl radical
intermediate, and thus increase the likelihood of productive
cycloaddition. Indeed, modest conversion to 6 was observed using
a variety of Lewis acidic additives including Zn(OTf)2, Gd(OTf)3,
and La(OTf)3 (entries 2-4). A brief screen of amine additives
revealed that TMEDA afforded significantly higher yields of the
cycloadduct (entries 5 and 6). Finally, reducing the loading of the
photocatalyst to 2.5 mol % produced an additional increase in the
yield of the reaction, and under these conditions we were able to
isolate 83% of cyclopentane 6 (entry7). We also conducted control
experiments to verify the necessity of each component of the
reaction mixture and found that the starting cyclopropane re-
mained unchanged when the Ru(bpy)3Cl2, La(OTf)3, or TMEDA
was omitted from the reaction (entries 8-10). These experiments
indicate the critical role of the photocatalyst, Lewis acid, and
reductive quencher, respectively, for the successful generation of
In conclusion, we have developed a new, mechanistically novel
[3þ2] cycloaddition of simple aryl cyclopropyl ketones that exploits
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Journal of the American Chemical Society
COMMUNICATION
our recently reported strategy for visible light photocatalysis.
A variety of reaction partners are suitable, but R-substituted enoates
work particularly well, enabling the rapid diastereoselective con-
struction of quaternary carbon stereocenters within a cyclopentane-
containing framework. The further development of this and other
synthetically valuable photocatalytic processes is a continuing effort
in our laboratories.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
Corresponding Author
tyoon@chem.wisc.edu
’ ACKNOWLEDGMENT
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Financial support from the ACS PRF (49817-ND1), NIH
(GM095666), Sloan Foundation, Beckman Foundation, and
Research Corporation is gratefully acknowledged. The NMR
facilities at UW-Madison are funded by the NSF (CHE-9208463,
CHE-9629688) and NIH (RR08389-01).
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