In situ reduction in photocycloadditions: A method to prevent Secondary photoreactions

Article abstract of DOI:10.1021/ol8026494

Secondary photoreactions are a common cause for the low yields often observed in photochemical reactions, preventing their widespread deployment in synthesis. In situ reductions which remove the chromophore from the product as it is formed provide a conve

Full text of DOI:10.1021/ol8026494

ORGANIC
LETTERS
2009
Vol. 11, No. 4
811-814
In situ Reduction in
Photocycloadditions: A Method to
Prevent Secondary Photoreactions
Lauren M. Tedaldi and James R. Baker*
Department of Chemistry, UniVersity College London, 20 Gordon St, London,
WC1H 0AJ United Kingdom
j.r.baker@ucl.ac.uk
Received November 17, 2008
ABSTRACT
Secondary photoreactions are a common cause for the low yields often observed in photochemical reactions, preventing their widespread
deployment in synthesis. In situ reductions which remove the chromophore from the product as it is formed provide a convenient method to
prevent these secondary photoreactions.
Photochemical reactions are extremely powerful methods for
application in organic synthesis. By accessing electronically
excited states, modes of reactivity can be exploited that are
not available to molecules in the ground state. An example
is the [2+2] photocycloaddition, which provides convenient
access to 4-membered rings that would otherwise be
extremely challenging to synthesize by thermal means.
However, despite the unique abilities of photochemical
reactions these methods are still much underused in synthesis.
One of the main reasons for this is the unpredictable yields
associated with such reactions. In a number of cases this
can be attributed to problems of secondary photoactivity,
which can occur when the initial photoproducts retain a
chromophore and undergo excitation leading to further
reactions.1
In a few cases narrow-band light sources or filters have
been reported to prevent secondary photoreactions by
controlling the wavelengths of light that are incident on the
solution such that only the starting material can absorb and
not the product.2,1f However, the success of this method relies
on the starting material and products absorbing in different
regions of the spectrum, which is often not the case.
Furthermore, such lamps and filters are only available for a
few specific wavelength selections. It is clear that new
methods to prevent secondary photoreactions would broaden
the scope of viable photochemical reactions, leading to their
greater deployment in synthesis.
We are proposing that the use of trapping agents that react
with the desired photoproduct as it is formed, removing the
chromophore, will serve to prevent secondary photoreactions
and prove a valuable method. We are initially investigating
this approach by considering the use of reducing agents in
the [2+2] photocycloaddition of enones with alkenes. This
photocycloaddition is an extremely useful method for the
formation of cyclobutanes2c,3 but suffers from the continued
(1) (a) Mancini, I.; Cavazza, M.; Guella, G.; Pietra, F. J. Chem. Soc.,
Perkin Trans. 1 1994, 2181. (b) Matlin, A. R.; Turk, B. E.; McGarvey,
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Lin, C.; Chodosh, D. F. J. Org. Chem. 1985, 50, 5815. (d) Cantrell, T. S.;
Solomon, J. S. J. Am. Chem. Soc. 1970, 92, 4656. (e) Cavazza, M.; Pietra,
F. J. Chem. Soc., Chem. Commun. 1986, 1480. (f) Demuth, M.; Pandey,
B.; Wietfeld, B.; Said, H.; Viader, J. HelV. Chim. Acta 1988, 71, 1392. (g)
Mazzocchi, P. H.; Khachik, F.; Wilson, P.; Highet, R. J. Am. Chem. Soc.
1981, 103, 6498. (h) Booker-Milburn, K. I.; Anson, C. E.; Clissold, C.;
Costin, N. J.; Dainty, R. F.; Murray, M.; Patel, D.; Sharpe, A. Eur. J. Org.
Chem. 2001, 1473.
(2) (a) Swenton, J. S.; Fritzen, E. L. Tetrahedron Lett. 1979, 1951. (b)
Koft, E. R.; Smith, A. B. J. Am. Chem. Soc. 1982, 104, 5568. (c) Crimmins,
M. T. Chem. ReV. 1988, 88, 1453
(3) (a) Demuth, M.; Mikhail, G. Synthesis 1989, 145. (b) Corey, E. J.;
Lemahieu, R.; Mitra, R. B.; Bass, J. D. J. Am. Chem. Soc. 1964, 86, 5570
.
.
10.1021/ol8026494 CCC: $40.75
Published on Web 01/22/2009
2009 American Chemical Society

photoactivity of the carbonyl in the product. Secondary
photoreactions observed in such systems include Norrish type
I1b-d,4 and type II processes5 and acyl shifts.1a,e We report
herein on our initial results with the intramolecular [2+2]
photocycloaddition of vinylogous ester 1 serving as the
model system.
the necessary chemoselectivity. To confirm that reduction
of the starting material 1 would be insignificant on the
reaction time scale we treated it with either NaBH4 or LiBH4
in acetonitrile and observed negligible reduction (<5%) after
2 h. The trapping experiments were thus carried out by
inclusion of reducing agents in the photochemical reaction
(Table 1).
The photocycloaddition of vinylogous ester 1 is an
apparently simple reaction that is conspicuous in its absence
from the literature. We postulated that secondary photoac-
tivity was likely to be the problem as other similar cycload-
ditions have been reported.6 Indeed when we irradiated 1
for 1.5 h we observed complete consumption of starting
material to afford a complex mixture from which the initial
photocycloaddition product 2 could be isolated in just 13%
yield (Figure 1a). This was found to be the maximum yield
obtainable with variations in solvent (benzene, acetone,
i-PrOH, MeOH) and concentration proving deleterious. To
confirm that photochemical degradation was responsible for
the low yield obtained we resubmitted the isolated ketone 2
to irradiation and observed complete degradation in 1.5 h to
afford a complex mixture of unidentifiable products. We also
confirmed that thermal decomposition of ketone 2 was not
occurring by stirring it in acetonitrile in the dark and
observing no change after 24 h.
Table 1. Various Reducing Agents Included in the
Photochemical Reaction to Trap Out the Ketone 2 As Alcohol 3
entry
reducing agent
equiv
yield of 3 (%)
1
2
3
4
5
6
7
8
9
NaBH4
NaBH4
LiBH4
LiBH4
1
2
1
2
3
2
2
2
2
36
42
57
71
60
40
0
LiBH4
NaBH(OAc)3
NaBH3(OAc)
ZnBH4
19
13
a
LiBH4
a LiBH4 added after irradiation.
With NaBH4 the photocycloaddition-reduction sequence
was complete in 1 h and 45 min and successfully afforded
alcohol 3 in 36%, proving that removing the chromophore
in the product could affect an increase in yield of product
isolable. We postulated that this reagent was still not reducing
ketone 2 fast enough and thus sought more reactive condi-
tions. Two equivalents of NaBH4 led to a small increase in
the yield, but it was the use of 2 equiv of LiBH4 that led to
a significant improvement (Table 1, entry 4). Other reducing
agents such as acetoxy borohydrides and zinc borohydride
failed to improve on this. We also confirmed that the
reducing agent needed to be present during the irradiation
to prevent secondary photoreactions, by carrying out a
reaction in which the LiBH4 was only added at the end (entry
9). The 13% yield of alcohol 3 in this case matched the yield
of ketone 2 that was obtained in the absence of reducing
agent.
Interestingly, in this system only one diastereomer of the
product is obtained, with the stereochemistry confirmed by
NOESY analysis. The photocycloaddition forms three of the
centers fixed as the cyclobutane must be cis-fused to both
five-membered rings. The reduction is then remarkably
selective with attack only taking place on the opposite face
to the cyclobutane. Indeed a model of 2 shows the hydrogens
protruding from the cyclobutane provide significant steric
hindrance to this face and that the system lacks any
conformational flexibility of note.
Figure 1. (a) Vinylogous ester 1 undergoes photocycloaddition
followed by degradation of ketone 2 by secondary photoreactions.
(b) UV spectra of the starting material 1 (solid line) overlaid with
the product 2 (broken line).
UV spectra of the starting material 1 and the product 2
(Figure 1b) reveal the fundamental limitation with relying
on filters to prevent secondary photoreactions. The n-π*
absorbances involved have λmax of 282 and 274 nm,
respectively, and are clearly overlapping preventing selective
excitation of just the starting material.
Having confirmed that secondary photoreactions were a
major problem in this system we selected a range of reducing
agents for trial as trapping agents. The conjugation in
vinylogous ester 1 ensured that the starting material would
be less reactive to reducing agents than the product, providing
(4) Wagner, P. J.; Spoerke, R. W. J. Am. Chem. Soc. 1969, 91, 4437
(5) Mal, J.; Venkateswaran, R. V. J. Org. Chem. 1998, 63, 3855.
.
(6) (a) Carreira, E. M.; Hastings, C. A.; Shepard, M. S.; Yerkey, L. A.;
Millward, D. B. J. Am. Chem. Soc. 1994, 116, 6622. (b) Pirrung, M. C.;
Webster, N. J. G. J. Org. Chem. 1987, 52, 3603.
We also carried out a solvent and concentration screen to
optimize the photocycloaddition-reduction sequence (Table
812
Org. Lett., Vol. 11, No. 4, 2009

Table 2. Solvent and Concentration Study to Optimize the
Reaction Conditions
Scheme 1
.
Postulated Norrish Type I pathway for the Formation
of Alcohol 4
entrya
solvent
MeCN
dry MeCN
3:1 MeCN:H2O
benzene
isopropanol
hexane
DCM
MeCN
MeCN
MeCN
concn (M)
yield of 3 (%)
1
2
3
4
5
6
7
8
9
0.04
0.04
0.04
0.04
0.04
0.04
0.04
0.01
0.02
0.08
0.02
71
63
72
52
39
28
20
78
79
12
83
Scheme 2
.
Reoxidation of Alcohol 3 Providing the First Viable
Route to Ketone 2
10
11a
MeCN
a Column eluent includes NEt3 (1%).
2). It was difficult to predict the conditions that would be
favored as such photocycloadditions can variously be favored
in polar or nonpolar solvents.2c Furthermore, while the LiBH4
reduction would be faster in polar protic solvents,7 competing
reaction of the reducing agent with the solvent would occur.
We found that acetonitrile or an acetonitrile-water mix
yielded the best results with no improvement shown by other
solvents. The water likely serves to solubilize and increase
the reactivity of the LiBH4. The ideal concentration was
found to be 0.02 M. Notably by 0.08 M the yield drops off
substantially, which is likely due to competing intermolecular
reactions.
A), and then in the presence of LiBH4 (method B) to give
the alcohol. We found that in all cases the ketones were being
consumed by secondary photoreactions, leading to poor
yields of the ketone isolable, if any at all. The inclusion of
LiBH4 (method B) then led to the prevention of secondary
Table 3. Photocycloaddition-Reduction Sequence in More
Complex Examples
We observed that column purification was leading to some
degradation of the product by an unknown mechanism, likely
to involve cleavage of the strained cyclobutane. We were
able to limit this by using NEt3 (1%) in the column eluent
resulting in an improved 83% yield (entry 11, Table 2).
It is notable that in these reactions a small amount (∼1%)
of an impure compound was commonly isolated, which we
have tentatively assigned as alcohol 4 by 1H NMR analysis
(Scheme 1). This compound is formed by a well-precedented
Norrish type 1 cleavage-disproportionation sequence fol-
lowed by reduction of the resulting aldehyde 5 by the
reducing agent. This was the first clear indication of the
nature of the secondary photoreactions that were occurring
in this system.
To show that ketone 2 could be accessed in good overall
yield for the first time using this methodology, we reoxidized
alcohol 3 (Scheme 2) to afford the ketone in good yield.
To illustrate the scope of this in situ reduction methodol-
ogy we tried it on a number of related substrates (Table 3).
Each substrate was irradiated initially in the absence of
reducing agent, to attempt to isolate the ketones (method
a 13% of a de-Mayo fragmentation product also isolated. b 1:1 ratio of
diastereomers obtained.
(7) Brown, H. C.; Mead, E. J.; Rao, B. C. S. J. Am. Chem. Soc. 1955,
77, 6209.
Org. Lett., Vol. 11, No. 4, 2009
813

photoreactions with the alcohol being obtained in good
yields. Single diastereomers were obtained in all cases with
the exception of entry 4 in which the triplet nature of these
photocycloadditions is revealed by the loss of stereochemical
control at one center. This example still shows the power of
photochemistry to form complex strained structures in a
single step from a simple starting material.
In conclusion we have illustrated that in situ reduction can
be effectively employed in photochemical reactions to
prevent undesired secondary photoreactions. A protocol with
LiBH4 in the intramolecular [2+2] photocycloaddition of
vinylogous esters has been developed. We are currently
investigating the application of a variety of trapping agents,
and envisage that this methodology will be widely employed
to broaden the scope of viable photochemical reactions.
Acknowledgment. This research was supported by a
Royal Society research grant.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8026494
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Org. Lett., Vol. 11, No. 4, 2009