Photocatalytic [2+2] cycloadditions of enones with cleavable redox auxiliaries

Article abstract of DOI:10.1021/ol3000298

α,β-Unsaturated 2-imidazolyl ketones undergo [2 + 2] cycloaddition with a variety of Michael acceptors upon irradiation with visible light in the presence of Ru(bpy)₃²⁺. Cleavage of the imidazolyl auxiliary from the cycloadducts affords cyclobutane carboxamides, esters, thioesters, and acids that would not be accessible from direct cycloaddition of the corresponding unsaturated carbonyl compounds.

Full text of DOI:10.1021/ol3000298

ORGANIC
LETTERS
2012
Vol. 14, No. 4
1110–1113
Photocatalytic [2 þ 2] Cycloadditions of
Enones with Cleavable Redox Auxiliaries
Elizabeth L. Tyson, Elliot P. Farney, and Tehshik P. Yoon*
Department of Chemsitry, University of WisconsinꢀMadison, 1101 University Avenue,
Madison, Wisconsin 53706, United States
tyoon@chem.wisc.edu
Received January 6, 2012
ABSTRACT
R,β-Unsaturated 2-imidazolyl ketones undergo [2 þ 2] cycloaddition with a variety of Michael acceptors upon irradiation with visible light in the
presence of Ru(bpy)32þ. Cleavage of the imidazolyl auxiliary from the cycloadducts affords cyclobutane carboxamides, esters, thioesters, and
acids that would not be accessible from direct cycloaddition of the corresponding unsaturated carbonyl compounds.
2þ
Cyclobutanes are synthetically interesting both because
of the diverse structures of cyclobutane-containing natural
products1 and because of the utility of strain-releasing
ring fragmentations in the preparation of more complex
medium-sized ring systems.2 Conventional photochemical
methods3 for the synthesis of cyclobutanes are generally
efficient only when cyclic enones are utilized; the triplet
excited state of acyclic enones undergoes a rapid, energy-
wasting olefin isomerization that outcompetes productive
intermolecular cyclizations.4 We recently reported that
Ru(bpy)3 complexes are useful photocatalysts for the
[2 þ 2] cycloadditions of aryl enones upon irradiation with
visible light.5,6 This method avoids the formation of the
problematic triplet excited state of the enone and thus
works well with acyclic enones. However, we found the
scope of this method to be limited; the involvement of an
aryl enone in the reaction was found to be a strict require-
ment for successful cycloaddition.
We proposed a mechanism for the cycloaddition that
rationalizes this constraint (Scheme 1). The key reactive
intermediate in this process is an enone radical anion
generatedbysingleelectrontransferfrom aphotogenerated
(1) Hansen, T. V.; Stenstrøm, Y. Naturally Occurring Cyclobutanes.
In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.; Elsevier:
Oxford, U.K., 2001; Vol. 5, pp 1ꢀ38. (b) Dembitsky, V. M. J. Nat. Med.
2008, 62, 1–33.
(2) Oppolzer, W. Acc. Chem. Res. 1982, 15, 135–141. (b) Winkler,
J. D.; Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95, 2003–2020. (c) Lee-
Ruff, E.; Mladenova, G. Chem. Rev. 2003, 103, 1449–1483. (d) Namyslo,
J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485–1537.
(3) For reviews of [2 þ 2] enone photocycloadditions, see: (a) de
Mayo, P. Acc. Chem. Res. 1971, 4, 41–47. (b) Baldwin, S. W. Org.
Photochem. 1981, 5, 123–225. (c) Crimmins, M. T. Chem. Rev. 1988, 88,
1453–1473. (d) Demuth, M.; Mikhail, G. Synthesis 1989, 145–162.
(e) Schuster, D. I.; Lem, G.; Kaprinidis, N. A. Chem. Rev. 1993, 93, 3–22.
(f) Iriondo-Alberdi, J.; Greaney, M. F. Eur. J. Org. Chem. 2007, 4801–4815.
(g) Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed. 2011, 50, 1000–1045.
(4) Morrison, H.; Rodriguez, O. J. Photochem. 1974, 3, 471–474.
(5) Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am. Chem.
Soc. 2008, 130, 12886–12887. (b) Du, J.; Yoon, T. P. J. Am. Chem. Soc.
2009, 131, 14604–14605.
(6) For reviews on recent developments in transition metal photo-
redox catalysis in organic synthesis, see: (a) Zeitler, K. Angew. Chem.,
Int. Ed. 2009, 48, 9785–9789. (b) Yoon, T. P.; Ischay, M. A.; Du, J. Nat.
Chem. 2010, 2, 527–532. (c) Narayanam, J. M. R.; Stephenson, C. R. J.
Chem. Soc. Rev. 2011, 40, 102–113. (d) Teply, F. Collect. Czech. Chem.
Commun. 2011, 76, 859–917.
(7) The reduction potential of Ru(bpy)3þ, which we presume to be
the catalytically relevant photoreductant in this process, is ꢀ1.2 V vs
SCE. For a review of the photoelectrochemistry of Ru(bpy)32þ, see:
Kalyanasundaram, K. Coord. Chem. Rev. 1982, 46, 159–244.
r
10.1021/ol3000298
Published on Web 02/09/2012
2012 American Chemical Society

Ru(bpy)3þ complex7 to a Lewis acid activated enone. The
one-electron reduction of aryl enones is significantly more
facile than the corresponding reduction of less-conjugated
enone substrates. Enoate esters, for example, possess
reduction potentials ca. 700 mV more negative than
aryl enones,8 which precludes formation of the corre-
sponding enoate radical anions under these photocatalytic
conditions.
Table 1. Dimerizations of Candidate Enonesa
Scheme 1. Mechanism of Radical Anion [2 þ 2] Cycloaddition
a Reactions performed with 5% Ru(bpy)3Cl2, 2.0 equiv of LiBF4,
and 2.0 equiv of i-Pr2NEt in 0.1 M MeCN. Molar ratios for intermo-
lecular dimerizations calculated with respect to theoretical yield of
product (e.g., 2.5 mol % catalyst with respect to enone).
Upon exposure to the conditions we had optimized for
intermolecular [2 þ 2] cycloaddition of aryl enones, un-
saturated acyl phosphonates11 underwent rapid decompo-
sition (entry 1). N-Acyl pyrroles12 and pyrazoles13 reacted
sluggishly and gave unsatisfactory yields of the correspond-
ing dimerized cyclobutanes (entries 2 and 3). On the
other hand, R,β-unsaturated 2-acylimidazoles14 reacted
smoothly and furnished the desired [2 þ 2] cyclodimer in
82% yield.15 We therefore elected to continue our studies
using enones bearing an N-methylimidazol-2-yl auxiliary
group.
Next, we studied the crossed intermolecular [2 þ 2]
cyclization of acyl imidazole 1 with methyl acrylate
(Table 2). The conditions we had previously reported for
[2 þ 2] cycloaddition of phenyl enones withmethyl acrylate
afforded only 43% of the desired crossed cycloadduct in
5:1 dr (entry 1); the undesired homodimerization of 1 was a
significant competitive process. Higher concentrations of
We wondered if we might circumvent this limitation
in scope by installing a cleavable auxiliary group onto
the enone substrate that (1) would facilitate one-electron
reduction and subsequent cycloaddition of the enone sub-
strate and (2) could be transformed into a carboxylic acid,
ester, amide, or similar carbonyl-containing functional
group after the cycloaddition. This cleavable group might
be considered a “redox auxiliary”9,10 that temporarily
modulates the reduction potential of an otherwise redox-
inactive enoate substrate, just as a chiral auxiliary tempo-
rarily differentiates the prochiral faces of an otherwise
achiral substrate.
Table 1 summarizes our studies to identify a suitable
redox auxiliary for the [2 þ 2] cycloaddition. We examined
the homodimerization of a number of R,β-unsaturated
carbonyl compounds that have been validated as surro-
gates of carboxylate esters in other synthetic methods.
(12) Lee, S. D.; Brook, M. A.; Chan, T. H. Tetrahedron Lett. 1983, 24,
1569–1572. (b) Kinoshita, T.; Okada, S.; Park, S. R.; Matsunaga, S.;
Shibasaki, M. Angew. Chem., Int. Ed. 2003, 42, 4680–4684. (c) Shaghafi,
M. B.; Kohn, B. L.; Jarvo, E. R. Org. Lett. 2008, 10, 4743–4746.
(13) Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc.
1998, 120, 6615–6616. (b) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc.
2002, 124, 13394–13395. (c) Ishihara, K.; Fushimi, M. Org. Lett. 2006, 8,
1921–1924. (d) Sibi, M. P.; Itoh, K. J. Am. Chem. Soc. 2007, 129, 8064–
8065.
(14) (a) Davies, D. H.; Haire, N. A.; Hall, J.; Smith, E. H. Tetra-
hedron 1992, 48, 7839–7856. (b) Evans, D. A.; Song, H.-J.; Fandrick,
K. R. Org. Lett. 2006, 8, 3351–3354. (c) Andrus, M. B.; Christiansen,
M. A.; Hicken, E. J.; Gainer, M. J.; Bedke, D. K.; Harper, S. R.;
Dodson, D. S.; Harris, D. T. Org. Lett. 2007, 9, 4865–4868. (d) Evans,
D. A.; Fandrick, K. R.; Song, H. J.; Scheidt, K. A.; Xu, R. J. Am. Chem.
Soc. 2007, 129, 10029–10041. (e) Trost, B. M.; Lehr, K.; Michaelis, D. J.;
Xu, J.; Buckl, A. K. J. Am. Chem. Soc. 2010, 132, 8915–8917.
(15) Consistent with this observation, cyclic voltammetry revealed
that the R,β-unsaturated 2-acylimidazole reduces at a significantly less
negative peak potential than the other test substrates depicted in Table 1.
See the Supporting Information for details of these electrochemical
measurements.
(8) House, H. O.; Huber, L. E.; Umen, M. J. J. Am. Chem. Soc. 1972,
94, 8471–8475.
(9) Facilitation of electrochemical reactions using a noncleavable
redox-active group has been termed a 00redox tag00 strategy by Chiba. See:
(a) Okada, Y.; Akaba, R.; Chiba, K. Org. Lett. 2009, 11, 1033–1035.
(b) Okada, Y.; Nishimoto, A.; Akaba, R.; Chiba, K. J. Org. Chem. 2011,
76, 3470–3476.
(10) Similarly, facilitation of electrochemical reactions using a silyl
or stannyl electrofugal group has been termed an 00electroauxiliary00
approach by Yoshida. See: (a) Yoshida, J.; Takada, K.; Ishichi, Y.; Isoe,
S. J. Chem. Soc., Chem. Commun. 1994, 2361–2362. (b) Yoshida, J.;
Nishiwaki, K. J. Chem. Soc., Dalton Trans. 1998, 2589–2596.
(11) Evans, D. A.; Johnson, J. S. J. Am. Chem. Soc. 1998, 120, 4895–
4896. (b) Evans, D. A.; Scheidt, K. A.; Fandrick, K. R.; Lam, H. W.;
Wu., J. J. Am. Chem. Soc. 2003, 125, 10780–10781. (c) Takenaka, N.;
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~
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Org. Lett., Vol. 14, No. 4, 2012
1111

the Lewis acidic additive (LiBF4) increased the dr without
increasing the yield of 3, while lower Lewis acid loadings
favored homodimerization (entries 2 and 3). We observed
a modest increase in selectivity for the heterodimer when
the catalyst loading was lowered to 2.5 mol % (entry 4).
The best yield and highest dr were obtained when 1 was
added slowly via syringe pump to the reaction mixture,
which presumably minimizes the homodimerization by
minimizing the concentration of 1 with respect to methyl
acrylate while keeping the ratio of Lewis acid to substrate
high. By using this slow addition protocol, the desired
heterodimer 3 could be isolated in 67% yield and with
excellent diastereoselectivity (entry 6).
Table 2. Optimization Studiesa
Figure 1. Scope of the intermolecular coupling reaction. Un-
less otherwise noted, reactions were performed with 5.0 equiv
of Michael acceptor with respect to 1.0 equiv of aryl enone,
2.5 mol % Ru(bpy)3Cl2, 2.0 equiv of LiBF4, and 2.0 equiv of
i-Pr2NEt in 0.1 M MeCN; aryl enone was added dropwise over a
45 min period. Isolated yields and diastereomer ratios are the
averaged results of two reproducible experiments. For 5 and 6,
0.5 equiv of LiBF4 was used. For 8, 4.0 equiv of LiBF4 was used;
aryl enone was added in one portion.
mol %
Ru
equiv
% yield of
% yield
entry
LiBF4
2b
3 (dr)b
1
5.0
5.0
5.0
2.5
2.5
2
24
13
50
19
<5
43 (5:1)
2
4
42 (10:1)
21 (2:1)
3c
4d
5e
0.5
2
51 (5:1)
2
67 (>10:1)
a Reactions performed with 2.0 equiv of i-Pr2NEt in 0.1 M MeCN,
and indicated amounts of photocatalyst and LiBF4 with respect to the
theoretical yield of product 3 and an irradiation time of 90 min. b Isolated
yields with respect to theoretical yield of 2 or 3, respectively. c Irradiated
for 120 min. d Irradiated for 150 min. e Aryl enone added dropwise over a
45 min period.
The use of an R-substituted Michael acceptor required
prolonged reaction times, but the expected cycloadduct
bearing a quaternary stereocenter (16) was produced with
excellent diastereoselectivity.
Finally, we investigated conditions for transformation
of the 2-acylimidazole moiety into carboxylic acid deri-
vatives14 (Table 3). The auxiliary group of cycloadduct 12
can easily be N-alkylated with MeOTf to afford the
corresponding imidazolium salt. Upon recrystallization,
thiswhitecrystalline materialisstabletoprolonged storage
on the bench for at least six months.16 Displacement of the
imidazolyl group proceeds smoothly with a variety of
oxygen nucleophiles without loss of stereochemical integ-
rity (entries 1ꢀ3). While bulky tertiary alcohols did not
react with the imidazolium salt (entry 4), the more nucleo-
philictert-butyl thiol producedthe corresponding thioester
in quantitative yield (entry 5). Finally, the 2-acylimidazolium
moiety could be transformed into an amide functional
group upon treatment with either primary or secondary
Figure 1 summarizes experiments probing the scope of
the crossed intermolecular [2 þ 2] cycloaddition using
2-acylimidazoles. AvarietyofMichaelacceptors, including
R,β-unsaturated esters, thioesters, and ketones, provided
good yields and high diastereoselectivities in cycloadditions
with 1 (Figure 1, 3ꢀ5). As we had observed in our previous
studies, high selectivity for the crossed cycloadduct requires
the use of a β-unsubstituted Michael acceptor as the re-
action partner. However, β-substitution on the acyl imida-
zole is easily accommodated. Substrates of increased steric
demand worked well in this reaction (6ꢀ8), and protected
heteroatomic functional groups were tolerated under opti-
mized reaction conditions (9ꢀ11).
We also explored intramolecular [2 þ 2] cycloadditions
of 2-acylimidazoles. In these experiments, we observed
somewhat higher yields when the loading of LiBF4 was
reduced to 0.5 equiv. These conditions enabled intramolec-
ular cycloadditions with a variety of acceptor moieties,
including esters, ketones, and amides (Figure 2, 12ꢀ15).
(16) The subsequent cleavage of the imidazolyl group could also be
achieved without isolation of the acylimidazolium salt; however, we
found that the yields of the cleavage products were somewhat lower
when this one-pot protocol was utilized.
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Org. Lett., Vol. 14, No. 4, 2012

Table 3. Cleavage of the Redox Auxiliarya
entry
NucH
H2O
yieldb
dr
1c
2c
3
52%c
86%c
88%
0%
>10:1
>10:1
>10:1
n.d.
MeOH
i-PrOH
t-BuOH
t-BuSH
BnNH2
pyrrolidine
4
5
99%
98%
75%
>10:1
>10:1
>10:1
6d
7d
a Unless otherwise noted, cleavage of the imidazolium group was
conducted using an excess of the nucleophile and 3.5 equiv of DBU in
CH2Cl2. b Isolated yields. c Cleavage conducted in Et2O. d No DBU added.
susceptible to cleavage with a variety of nucleophiles under
mild conditions. This redox auxiliary approach could be
applied to other reactions that involve the reduction of
carbonyl compounds to the corresponding radical anions.
Continued studies in our laboratory will apply these con-
cepts to other reactions of photogenerated radical ions.
Figure 2. Scope of intramolecular [2 þ 2] reaction. Unless
otherwise noted, reactions were performed using 2.5 mol %
Ru(bpy)3Cl2, 0.5 of equiv LiBF4, and 2.0 equiv of i-Pr2NEt in
0.1 M MeCN. Isolated yields and diastereomer ratios are the
averaged results of two reproducible experiments. For 14, the
reaction was conducted using 0.5 equiv of i-Pr2NEt.
Acknowledgment. Financial support from the NIH
(GM095666) and Sloan Foundation is gratefully acknowl-
edged. The NMR facilities at UW-Madison are funded
by the NSF (CHE-9208463, CHE-9629688) and NIH
(RR08389-01).
amines (entries 6 and 7). Thus, the use of this redox auxi-
liary strategy enables the synthesis of a variety of cyclobu-
tane carboxylic acid derivatives that would not otherwise
be accessible using our previously reported photocatalytic
[2 þ 2] cycloaddition methodology.
In conclusion, we have circumvented a limitation in the
scope of the photocatalytic [2 þ 2] cycloaddition developed
in our laboratory by using unsaturated 2-acylimidazole
groups as redox auxiliaries. These heteroaryl groups facil-
itate the reduction of the enone substrate to the key radical
anion intermediate required for cycloaddition and are then
Supporting Information Available. Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 4, 2012
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