Crossed intermolecular [2+2] cycloadditions of acyclic enones via visible light photocatalysis

Article abstract of DOI:10.1021/ja903732v

(Figure Presented) Efficient [2+2] heterodimerizations of dissimilar acyclic enones can be accomplished upon visible light irradiation in the presence of a ruthenium(II) photocatalyst. Similar cycloadditions under standard UV photolysis conditions are ine

Full text of DOI:10.1021/ja903732v

Published on Web 05/27/2009
Crossed Intermolecular [2+2] Cycloadditions of Acyclic Enones via Visible
Light Photocatalysis
Juana Du and Tehshik P. Yoon*
Department of Chemistry, UniVersity of Wisconsin-Madison, 1101 UniVersity AVenue, Madison, Wisconsin 53705
Received May 7, 2009; E-mail: tyoon@chem.wisc.edu
The first example of a photoinitiated [2+2] enone cycloaddition
was reported by Ciamician in 1908 and involved the intramolecular
cyclobutanation of carvone upon prolonged exposure to intense
sunlight.1 In the century since this initial discovery, [2+2] enone
cycloaddition reactions promoted by UV irradiation have become
recognized as an efficient method for the construction of cyclobu-
tane-containing structures.2 Nevertheless, the synthetic utility of
this reaction has been largely limited to cycloadditions of cyclic
enones. Photoexcited acyclic enones undergo rapid relaxation to
the ground state by cis-trans isomerization,3 an energy-wasting
process that dramatically diminishes the efficiency of productive
cycloaddition. Thus, efficient intermolecular photochemical [2+2]
cycloadditions of acyclic enones are a long-standing unsolved
problem in synthetic chemistry.
Recently, our laboratory has become interested in designing new
reactions initiated by visible light photoexcitation of organometallic
complexes.4 We have reported that Ru(bipy)32+ serves as an excellent
photocatalyst for intramolecular anion radical-mediated [2+2] enone
cycloadditions,5 which were first described by Krische and Bauld.6 In
accord with this precedent, we found that only aryl enones could be
used to initiate the cycloaddition, presumably due to the greater ease
of generating the requisite radical anion intermediate, but that the
reacting partner could be any suitable Michael acceptor (Scheme 1).
In contrast to the Krische and Bauld precedent, however, efficient
intermolecular dimerizations of enones could be performed under the
photocatalytic conditions we had developed. We wondered, therefore,
if crossed intermolecular [2+2] heterodimerizations would be possible
using two dissimilar enone substrates.
highly chemoselective formation of the crossed [2+2] cycloadduct
3 in 84% isolated yield (eq 1). Only trace amounts of products
arising from the homocoupling of 1 and none of the product from
dimerization of 2 could be observed upon NMR analysis of the
reaction mixture. In addition, the cycloaddition proceeded with
excellent diastereoselectivity (>10:1 dr).7
Next, we examined the scope of the aryl enone in the crossed
cycloaddition, using 2 as the Michael acceptor (Table 1). Both electron-
poor and electron-rich substrates are amenable to cycloaddition (entries
1-3), as are heteroaryl enones (entry 4). On the other hand, aliphatic
enones are completely unreactive (entry 5), which is consistent with
our design plan and our understanding of the mechanism of this
process. Variation of the ꢀ-substituent is also possible; however, the
reaction is sensitive to steric bulk. While reactions of enones bearing
primary aliphatic substituents proceed smoothly (entry 6), secondary
substituents at this position retard the reaction rate (entry 7), and
Table 1. Effect of Aryl Enone Structure in Photocatalytic Crossed
Cycloadditions with Methyl Vinyl Ketone 2a
Scheme 1
We first set out to probe the feasibility of the intermolecular
heterocoupling process by studying the reaction shown in eq 1.
The design of this experiment was based upon two main consid-
erations. First, given the requirement that a reducible aryl enone
serve as an electrophore in this process, we selected enone 1 to
serve as the precursor to the key radical anion intermediate. Second,
we recognized that the reaction partner must be a more reactive
Michael acceptor than 1 to minimize the undesired homodimer-
ization, but be less susceptible to one-electron reduction by the
photocatalyst. Ultimately, we selected methyl vinyl ketone 2, which
we expected should be less easily reduced than 1, but, due to the
lack of a ꢀ-substituent, should serve as a better electrophilic reaction
partner for the radical anion intermediate. In the event, we observed
a Unless otherwise noted, reactions conducted using 2.5 equiv of 2
and 5 mol % Ru(bipy)3Cl2 in the presence of LiBF4 and i-Pr2NEt in
MeCN. Irradiation time using a 23 W compact fluorescent bulb at 30
cm was 4 h. b Isolated yields and diastereomer ratios are the averaged
results of two reproducible experiments. c 12 h irradiation. d 24 h
irradiation.
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10.1021/ja903732v CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
reactions of enones bearing tertiary alkyl substituents fail to proceed
at synthetically useful rates (entry 8). On the other hand, heteroatom-
bearing substituents are easily tolerated (entry 9).
visible light source. To demonstrate this principle, we conducted a
gram-scale cycloaddition experiment on the roof of our laboratory
building (eq 3). The [2+2] cycloaddition between 1 and 2 was
equally efficient in ambient sunlight as it was in our laboratory
experiments and produced a single diastereomer of the crossed
cycloadduct 3 in 84% yield.
Experiments exploring the generality of the crossed reaction with
respect to the Michael acceptor are summarized in Table 2. A
variety of aliphatic enones are good reaction partners for the crossed
[2+2] cycloaddition (e.g., entries 1-2). Acrylate esters also
participate, but given their reduced electrophilicity, several ad-
ditional equivalents are required to out-compete homodimerization
of 1 (entry 3). Thioesters, on the other hand, are excellent acceptor
enones and provide high yields of the heterocoupling product (entry
4). Substrates bearing alkyl substituents at the R-position also
participate and provide access to cyclobutane structures bearing
all-carbon quaternary stereocenters with high selectivity (entry 5).
On the other hand, as expected, ꢀ-substituents that sterically
deactivate the Michael acceptor ability of the enone cause ho-
modimerization of 1 to predominate. Nevertheless, the heterocou-
pling product can be isolated when a larger excess of the acceptor
enone is used (entries 6 and 7).
In summary, we have developed an efficient method for crossed
[2+2] cycloadditions of acyclic enones promoted by visible light.
The excellent chemo- and stereoselectivity observed in this reaction
represents a considerable advance in the construction of strained
four-membered rings and should have a significant impact on the
approach toward synthesis of cyclobutane-containing structures.
Furthermore, the success of this method provides corroborative
evidence for our mechanistic hypothesis and establishes a solid
framework for the further development of our research program in
visible light photocatalysis.
Table 2. Effect of Michael Acceptor Structure in Photocatalytic
Crossed Cycloadditions with Phenyl Enone 1a
Acknowledgment. We thank the Beckman Foundation and the
Research Corporation for financial support. The NMR facilities at
UW-Madison are funded by the NSF (CHE-9208463, CHE-
9629688) and NIH (RR08389-01).
Supporting Information Available: Experimental procedures and
spectral data for all new compounds are provided. This information is
available free of charge via the Internet at http://pubs.acs.org.
References
(1) Ciamician, G.; Silber, P. Chem. Ber. 1908, 41, 1928–1935.
(2) (a) For recent reviews of [2+2] enone photocycloadditions, see: Baldwin,
S. W. In Organic Photochemistry; Padwa, A., Ed; Marcel Dekker: New
York, 1981; Vol. 5, pp 123-225. (b) Crimmins, M. T. Chem. ReV. 1988,
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a Unless otherwise noted, reactions conducted using 1 equiv of 1, 2.5
equiv of Michael acceptor, and 5 mol % Ru(bipy)3Cl2 in the presence of
LiBF4 and i-Pr2NEt in MeCN. Irradiation time using a 23 W compact
fluorescent bulb at 30 cm was 4 h. b Isolated yields and diastereomer
ratios are the averaged results of two reproducible experiments. c 6
(3) Morrison, H.; Rodriguez, O. J. Photochem. 1974, 3, 471–474.
(4) For reviews of transition metal mediated photocatalysis in organic synthesis,
see: (a) Salomon, R. G. Tetrahedron 1983, 39, 485–575. (b) Hennig, H.
Coord. Chem. ReV. 1999, 182, 101–123.
equiv of Michael acceptor and 12
homodimerization product of 1 was isolated in 65% yield.
h
irradiation time. d The
(5) Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am. Chem. Soc.
2008, 130, 12886–12887.
An important feature of this process is that the reaction is initiated
by photoexcitation of the ruthenium catalyst and does not access
electronically excited states of the enone. Thus, this method avoids
some of the synthetic limitations of cycloadditions conducted under
standard UV photolysis conditions. A solution of enones 1 and 2
irradiated in a Rayonet reactor (300 nm) fails to produce any
observable cycloaddition products; the only new products observed
in the reaction mixture arise from E/Z isomerization of enone 1
(6) (a) Baik, T.-G.; Luis, A. L.; Wang, L.-C.; Krische, M. J. J. Am. Chem. Soc.
2001, 123, 6716–6717. (b) Wang, L.-C.; Jang, H.-Y.; Roh, Y.; Lynch, V.;
Schultz, A. J.; Wang, X.; Krische, M. J. J. Am. Chem. Soc. 2002, 124, 9448–
9453. (c) Roh, Y.; Jang, H.-Y.; Lynch, V.; Bauld, N. L.; Krische, M. J.
Org. Lett. 2002, 4, 611–613. (d) Yang, J.; Cauble, D. F.; Berro, A. J.; Bauld,
N. L.; Krische, M. J. J. Org. Chem. 2004, 69, 7979–7984. (e) Yang, J.;
Felton, G. A. N.; Bauld, N. L.; Krische, M. J. J. Am. Chem. Soc. 2004, 126,
1634–1635.
(7) Although LiBF4 and iPr2NEt are not consumed in the reaction, highly
diastereoselective cycloaddition is only observed when these additives are
present in excess. The reason for this dependence is not clear at this time
and is the subject of ongoing investigation in our lab.
2+
(eq 2). On the other hand, in the presence of the Ru(bipy)3
photocatalyst, this reaction proceeds upon irradiation with any
JA903732V
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