Photochemistry of allenyl salicylaldehydes

Article abstract of DOI:10.1021/ol800806a

(Chemical Equation Presented) The intramolecular photocycloaddition of aryl aldehydes containing allene side chains is a versatile reaction as it provides a rapid and efficient access to original complex structures such as 1,3,4-tetrahydro-1,4-epoxy-5-alk

Full text of DOI:10.1021/ol800806a

ORGANIC
LETTERS
2008
Vol. 10, No. 15
3175-3178
Photochemistry of Allenyl
Salicylaldehydes
Fre´de´ric Birbaum,† Antonia Neels,‡ and Christian G. Bochet*,†
Department of Chemistry, UniVersity of Fribourg, Chemin du Muse´e 9, CH-1700
Fribourg, Switzerland, and Institut de Microtechnique, UniVersity of Neuchaˆtel,
Jacquet-Droz 1, CH-2002 Neuchaˆtel, Switzerland
christian.bochet@unifr.ch
Received April 9, 2008
ABSTRACT
The intramolecular photocycloaddition of aryl aldehydes containing allene side chains is a versatile reaction as it provides a rapid and efficient
access to original complex structures such as 1,3,4-tetrahydro-1,4-epoxy-5-alkylidene-2-benzoxepines 2 and substituted 2-oxa-tricyclo[5.2.2.0]1,5undeca-
4,8,10-triene-9-carbaldehydes 3. Novel polycyclic structures are characterized, and optimized strategies for the synthesis of the substrates 1
are described.
Creating complexity by the formation of new cores, stereo-
centers, and strained rings in one step from simple precursors
is one of the many challenges of organic chemistry.
Photochemistry is particularly attractive from this perspective
because it may provide access to polycyclic structures
without the need of aggressive reagents such as oxidants,
reductants, acids, and bases. Tandem photocycloaddition/
fragmentation reactions and their applications in synthesis
have been widely reviewed, but there is still a considerable
potential for discovery.1 In the past few years, we have been
interested in the formation of unusual ring systems. The 1,4-
cycloaddition of alkenes with arenes (para cycloaddition)
has been well documented, but the similar process with
allenes is much less understood. Our interest has focused
on the photochemical reactivity of aryl aldehydes containing
an allene side chain. In particular, when the substrate contains
an aldehyde, the competition with a Paterno`-Bu¨chi-type
reaction has to be considered. We report here the photo-
chemical reactivity of ortho-allenyl benzaldehydes.
For this purpose, we prepared the o-allenyl-benzaldehyde
6a-f substrates (Scheme 1) following a strategy described
(1) For reviews on photocycloaddition reactions, see: (a) Hoffmann, N.
In Synthetic Organic Photochemistry; Griesbeck, A. G., ; Mattay, J., Eds.;
Marcel Dekker, 2005; Vol. 12, pp 529-552. (b) Sieburth, S. McN. In
Synthetic Organic Photochemistry; Griesbeck, A. G., ; Mattay, J., Eds.;
Marcel Dekker, 2005; Vol. 12, pp 239-237. (c) Margaretha, P. In Synthetic
Organic Photochemistry; Griesbeck, A. G., ; Mattay, J., Eds.; Marcel
Dekker, 2005; Vol. 12, pp 211-237. (d) Fleming, S. A. In Synthetic Organic
Photochemistry; Griesbeck, A. G., ; Mattay, J., Eds.; Marcel Dekker, 2005;
Vol. 12, pp 141-160. (e) Griesbeck, A. G. In Synthetic Organic Photo-
chemistry; Griesbeck, A. G., ; Mattay, J., Eds.; Marcel Dekker, 2005; Vol.
12, pp 89-139. (f) Horspool, W. M. Photochemistry 1999, 30, 119–148.
(g) Bach, T. Synthesis 1998, 5, 683–703. (h) Winkler, J. D.; Bowen, C. M.;
Liotta, F. Chem. ReV. 1995, 95, 2003–2020. (i) Wender, P. A.; Siggel, L.;
Nuss, J. M. Org. Photochem. 1989, 10, 357–473. (k) Oppolzer, W. Acc.
Chem. Res. 1982, 15, 135–141.
† University of Fribourg.
‡ University of Neuchaˆtel.
10.1021/ol800806a CCC: $40.75
Published on Web 07/03/2008
2008 American Chemical Society

mechanism involves the addition of carbonyl triplets to the
allenes.5 A limited range of allenes were used, and further
reaction to give dioxaspiroheptanes is common.6 An impor-
tant issue with alkylideneoxetanes is their sensitivity with
respect to the purification conditions. They are unstable
toward distillation, silica gel, Florisil, and even neutral
alumina. Hydrolysis in aqueous acid gives back the original
aldehyde and the ketone that is formally derived by the
addition of water to the allene. On this basis, we expected
to obtain 2-alkylideneoxetanes by intramolecular photo-
cycloadditions between allenes and aromatic aldehydes or
their decomposition products.
Scheme 1. Synthesis of the Precursors 6a-f
We first attempted the intramolecular photocycloaddition
with 2-buta-2,3-dienyloxy-benzaldehyde 6a (Scheme 3).
by Molander et al.2 Thus, simple nucleophilic substitution
of allenyl bromide with a series of substituted salicylalde-
hydes gave 6a-f in moderate to excellent yields (60-100%).
A variety of electron-withdrawing and electron-releasing
groups were chosen to study the electronic requirements of
the photocycloaddition.
Scheme 3
.
Effect of Substituents on the Regioselectivity of the
Photocycloaddition
The substituted allene 11 was also synthesized to examine
the influence of a terminal substituent. For this substrate,
the convergence point is much earlier, the methylallenyl unit
being introduced by a two-step sequence. Thus, alkylation
of the acetylide with acetaldehyde was followed by a Myers-
type allenylation (Scheme 2).3
Scheme 2
.
Synthesis of a Terminally Substituted
Allenyloxybenzaldehyde
Surprisingly, irradiation of 6a at room temperature in
dichloromethane did not lead to the expected 2-methylene-
oxetane, but rather to a mixture of 1,3,4-tetrahydro-1,4-
epoxy-5-alkylidene-2-benzoxepine 12a (28%) and 2-oxa-
tricyclo[5.2.2.0]1,5undeca-4,8,10-triene-9-carbaldehyde 13a
(48%). Obviously, more complex reaction pathways have
to be considered.
Typical conditions for the reaction are the irradiation of a
10-2 M solution in dichloromethane at room temperature
(350 nm, Rayonet Photochemical Reactor). When the reac-
tion is carried out at -70 °C for 90 min, the yield of 12a
decreases (10%) but has little influence on the formation of
the bicyclo[2.2.2]octane derivative 13a (42%).
Compared to the unsubstituted arene 6a, electron-releasing
groups slightly favor the 1,4-adduct 13 at the C-3 position
(Table 1, entries 3 and 4), more at the C-5 position (entry
5), and even make the reaction fully regioselective with two
groups (entry 2). An electron-withdrawing group at the C-5
position slightly reverses the ratio.
(4) (a) Arnold, D.; Glick, A. J. Chem. Soc., Chem. Commun. 1966, 81,
3–814. (b) Gotthardt, H.; Steinmetz, R.; Hammond, G. S J. Org. Chem.
1968, 33, 2774–2780. (c) Gotthardt, H.; Hammond, G. S Chem. Ber. 1974,
107, 3922–3927. (d) Hudrlik, P. F.; Hudrlik, A. M.; Wan, C.-N. J. Org.
Chem. 1975, 40, 1116–1120. (e) Gandhi, R. P.; Ishar, M. P. S. Tetrahedron.
1991, 47, 2211–2220.
Previous studies of intermolecular photochemical cyclo-
additions of carbonyl compounds with allenes giving strained
2-alkylideneoxetanes have been published.4 The proposed
(5) Gotthardt, H.; Steinmetz, R.; Hammond, G. S. J. Org. Chem. 1968,
33, 2774–2779.
(2) Molander, G. A.; Cormier, E. P. J. Org. Chem. 2005, 70, 2622–
2626.
(6) Dollinger, L. M.; Howell, A. R. J. Org. Chem. 1996, 61, 7248–
7249.
(3) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492–4493.
3176
Org. Lett., Vol. 10, No. 15, 2008

The Z and E products are not formed at the same rate.
However, after 2 h of irradiation of 11, isomerization and/
or selective degradation of the products gives an apparent
stationary ratio of Z and E isomers of 1:1.8
To verify the photochemical nature of the processes, the
o-allenyl-benzaldehydes were refluxed in dichloromethane
over a period of 24 h. NMR analysis only showed the starting
compounds. Likewise, the starting allene 6a is stable upon
heating up to 170 °C under microwave irradiation. Above
200 °C, decomposition is observed but without traces of any
of the cycloadducts.
Table 1. Effect of Substituents on the Regioselectivity of the
Photocycloaddition
time
[min]
entry
substrate
6a, R ) H
6b, R ) 3,5-ditBu
6c, R ) 3-OCH3
6d, R ) 3-CH3
6e, R ) 5-CH3
6f, R ) 5-Cl
[%]a [4 + 2] [%]
1
2
3
4
5
6
90
5
30
160
165
120
12a
12b
12c
12d
12e
12f
28
-
23
36
22
44
13a
13b
13c
13d
13e
13f
48
94
57
46
65
31
A reasonable mechanistic explanation for the formation of
the benzoxepines 12 and 14 would be a sequence of intramo-
lecular formal hetero Diels-Alder followed by an oxygen-to-
carbon formal 1,3-sigmatropic migration. The thermal 1,3-
oxygen-to-carbon rearrangement (requiring temperatures as high
as 130-160 °C) and the photochemical rearrangement involving
a singlet excited-state have been both described earlier.9 This
rearrangement is facilitated by the formation of aromatic
products such as benzoxepines 12 and 14.
a Yields determined by GC.
The structures have been established by NMR techniques
(1H, 13C, DEPT, COSY, and HETCOR sequences)7 and
confirmed by X-ray analysis on benzoxepine 12d and
bicyclo[2.2.2]octane derivative 13b (Figure 1).
The formation of the bicyclo[2.2.2]octanes 13 might occur
through a formal [4 + 2] photocycloaddition or para
photocycloaddition mechanism for which the aldehyde plays
a crucial role even if it is not the reacting species (Scheme
5).1a,10 The reaction does not seem to be reversible: 13b is
Scheme 5
.
Plausible Mechanism for the Formation of
Benzoxepine 12 and 13
Figure 1. X-ray structure of 12d and 13b.
The presence of a methyl group on the terminal part of
the allene increases the yield of the formation of the
benzoxepine, but the corresponding bicyclo[2.2.2]octane
derivative is not observed. Thus, irradiation of 2-penta-2,3-
dienyloxy-benzaldehyde 11 (rt, CH2Cl2, 350 nm, Scheme 4)
Scheme 4. Irradiation of 2-Penta-2,3-dienyloxy-benzaldehyde
stable toward irradiation at 350 nm for 20 min. At 300 nm,
ca. 50% degradation to an unidentified distribution of
(8) The reaction rate is followed by GC and shows the formation of
both Z and E products. NMR analysis of the isolated compound shows a
1:1 mixture of Z/E diastereomers.
(9) (a) Wang, S.; Callian, A.; Swenton, S. J J. Org. Chem. 1989, 54,
5364–5371. (b) Wang, S.; Callian, A.; Swenton, S. J. J. Org. Chem. 1990,
55, 2272–2274.
affords the benzoxepine 14 in 68% yield (GC). On the other
hand, when the aldehyde 6b is reduced into the corresponding
alcohol, no photocycloaddition is observed.
(10) (a) Hoffmann, N. In Synthetic Organic Photochemistry; Griesbeck,
A. G., ; Mattay, J., Eds.; Marcel Dekker, 2005; Chap. 17, Vol. 12. For a
review on photochemical cycloaddition between benzene derivates and
alkenes, see: (b) Hoffman, N. Synthesis 2004, 4, 481–495. (c) Kishikawa,
K.; Akimoto, S.; Kohmoto, S.; Yamamoto, M.; Yamada, K. J. Chem. Soc.,
Perkin Trans. 1 1997, 77. (d) Gilbert, A.; Taylor, G. N. J. Chem. Soc.,
Perkin Trans. 1 1980, 1761. (e) Gilbert, A.; Foulger, B. E.; Bryce-Smith,
(7) The 1H NMR spectrum of an epoxy benzoxepine is described in:
Arcoleo, A.; Fontana, G.; Giammona, S.; Curcio, S. L.; Marino, M. L. Chem.
Ind. 1977, 455.
D. J. Chem. Soc., Chem. Commun. 1972, 664–665
.
Org. Lett., Vol. 10, No. 15, 2008
3177

2-benzoxepines and 2-oxa-tricyclo[5.2.2.0]1,5undeca-4,8,10-
triene-9-carbaldehydes. On the other hand, [2 + 2] photo-
cycloaddition giving 2-alkylidene oxetane in the intermolecular
version is not observed. It seems that the electronic density
and the bulkiness of both aldehyde and allene could influence
the regioselectivity of the photocycloaddition. Indeed, when
the arene contains electron donor groups such as tert-butyl,
only the para-photocycloaddition is observed, whereas a
methyl group on the terminal part of the allene only gives
the benzoxepine product. Further studies of this novel
intramolecular photocycloaddition of ortho-allenylbenzal-
dehyde are ongoing.
Figure 2. Related cores en route toward natural products.
products was observed after 20 min. Absorbance of 13b starts
at 320 nm.
Bicyclo[2.2.2]octane derivatives are versatile synthetic
intermediates in total synthesis of natural products with a
variety of types of carbon skeletons (Figure 2). For example,
Yamada et al. described the formation of hemiacetal 15 in
an 11-step sequence in the total synthesis of (-)- and (+)-
sanadaol.11,12 Likewise, to overcome the lack of effective
and practical preparative methods for the synthesis of
bicyclo[2.2.2]octane, Danishefsky et al. described an oxida-
tive dearomatization-Diels-Alder cascade strategy to allow
the assembly of the core structure of 11-O-debenzoyltashi-
ronin 16.13 The latter compound has been shown to promote
neurite outgrowth.
Acknowledgment. Financial support of the Swiss National
Science Foundation (grant 200020-109316) is gratefully
acknowledged.
Supporting Information Available: Selected experimen-
tal procedures and spectral data (X-Ray, NMR, IR, MS). This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800806A
(11) Nagaoka, H.; Kobayashi, K.; Okamura, T.; Yamada, Y. Tetrahedron
Lett. 1987, 6641–6644.
It follows from this work that intramolecular photocy-
cloadditions of o-allenyl-benzaldehyde efficiently build
complex polycyclic 1,3,4-tetrahydro-1,4-epoxy-5-alkylidene-
(12) Nagaoka, H.; Kobayashi, K.; Yamada, Y. Tetrahedron Lett. 1988,
46, 5945–5946.
(13) Cook, S. P.; Danishefsky, S. J. Org. Lett. 2006, 8, 5693–5695.
3178
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