Photochemical Myers-Saito and C2-C6 cyclizations of enyne-allenes: Direct detection of intermediates in solution

Article abstract of DOI:10.1021/ja044890k

Several examples of the photochemical Myers-Saito and C²-C⁶ cyclization of enyne-allenes are described. The presence of a triplet sensitizing unit at the allene terminus and laser flash photolysis results suggest that the cyclization

Full text of DOI:10.1021/ja044890k

Published on Web 03/22/2005
Photochemical Myers-Saito and C2-C6 Cyclizations of Enyne-Allenes:
Direct Detection of Intermediates in Solution
Michael Schmittel,*,‡ Atul A. Mahajan,‡ and Go¨tz Bucher†
Organische Chemie I, FB 8 (Chemie-Biologie), UniVersita¨t Siegen, Adolf-Reichwein-Str.,
D-57068 Siegen, Germany, and Lehrstuhl fu¨r Organische Chemie II, Ruhr-UniVersita¨t Bochum,
UniVersita¨tsstr. 150, D-44801 Bochum, Germany
Received August 24, 2004; E-mail: schmittel@chemie.uni-siegen.de
Natural enediyne antitumor antibiotics utilize two thermally
triggered biradical cyclizations to ultimately damage DNA by
hydrogen abstraction: the Bergman1 and Myers-Saito2 reaction.
In recent years, photochemical analogues3 of the Bergman cycliza-
tion4 and alternative photochemically triggered enediyne5 processes
have attracted numerous research activities due to their potential
applicability for photodynamic therapy (PDT).6 In contrast, pho-
tochemical analogues of the Myers-Saito or the C2-C6 cyclization
of enyne-allenes have remained a terra incognita.
To design photochemically ignitable enyne-allenes, we resorted
to the recently described photochemical reactions of enyne-hetero-
allenes,7 that is, enyne-carbodiimides and enyne-ketenimines, for
some meaningful clues. These cyclizations occur very effectively
along the C2-C6, but interestingly not along the C2-C7 (Myers-
Saito) path. Theoretical studies by Engels8 explained the preference
for the C2-C6 route and suggested, as did our experimental results,7
that the process is initiated by triplet sensitization. Moreover, for a
photochemical enyne-allene cyclization to be successful, the study
recommended to avoid benzannulated derivatives due to their high
excitation energy.8 Herein, we wish to illustrate that photochemical
C2-C7 and C2-C6 cyclizations of enyne-allenes can be ignited
when specially designed systems are used.
triphenylamine, and carbonyl groups), and (iv) use a TIPS group
at the alkyne to raise the cyclization barrier and thus to avoid
thermal reactions during photolysis.9a
As programmed, enyne-allenes 1 underwent thermal cyclization
only at elevated temperatures (DSC9b results: 1a, Tonset ) 152 °C;
1b, Tonset ) 135 °C; 1c, Tonset ) 143 °C; 1d, Tonset ) 151 °C; 1e,
Tonset ≈ 190 °C [affected by polymerization]). In line with other
enyne-allenes10a-c carrying bulky groups10d at the alkyne terminus,
the thermal cyclization of 1a-e furnished only C2-C6 products
(i.e., 2a-e) by a stepwise ene process. Formal Diels-Alder
products10c were not formed except for trace amounts of 3 from
1b. Loss of the TIPS group in 3 may be due to desilylation of the
highly strained 3′ in the chromatographic process.11
Scheme 1. Thermal and Photochemical Myers-Saito (C2-C7)
and C2-C6 Cyclizations of Enyne-Allenes
All efforts to photocyclize 1a in hexane or toluene were met
with failure, most likely due to the low triplet energy (ET) of
bromonaphthalene (ET ) 59 kcal mol-1),12 suggesting to go to
stronger internal triplet sensitizers. Indeed, irradiation of 1b (R′ )
biphenyl; ET ) 65.0 kcal mol-1 12
in toluene at 300 nm in the
)
Scheme 2. Model Compounds 1a-e
presence of 1,4-cyclohexadiene led to photocyclization (Table 1)
revealing both the C2-C6 product 3 (12%) and the Myers-Saito
product 4 (24%). Their structures were confirmed using NMR
techniques and also by spectral comparison of 4 with independently
synthesized 6. 4 and 6 showed a characteristic triplet for the
benzhydrylic hydrogen at ∼3.8 ppm (3J ∼ 7.5 Hz). Notably,
calculations8 predicted parallel formation of both Myers-Saito and
C2-C6 products via triplet excitation of simple enyne-allenes,
although with a preference for C2-C6 products.
Enyne-allenes 1a-e (Scheme 2) were composed along the input
requirements: (i) avoid benzannulation, (ii) use cycloalkenes to
prevent cis-trans isomerization, (iii) attach internal triplet sensitizer
units as in enyne-heteroallenes7 at position R′ (e.g., naphthalene,
‡ Universita¨t Siegen.
† Ruhr-Universita¨t Bochum.
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J. AM. CHEM. SOC. 2005, 127, 5324-5325
10.1021/ja044890k CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Yields of Photochemical Myers-Saito (C2-C7)and C2-C6
Cyclization Products (1,4-CHD: 1,4-cyclohexadiene) at 17 ( 2 °C
compound
(conc)
solvent
(irradiation time)
λ
max/nm
(in hexane)
C2
−
C6 products
(yield)
C2 C7
−
products (yield)
1a
(1.78 mM) (6 h)
toluene + 1,4-CHDa 283, 300
1b
toluene + 1,4-CHDa 290, 300 (sh)
3
4
(1.96 mM) (7 h)
(12%)b
(24%)b
1c
toluene + 1,4-CHDa 320
2c (15%) +
(1.36 mM) (6 h)
7 (15%)c
1d
2:1 hexane/1,4-CHD 277, 290 (sh) 2d
(5.28 mM) (14 h)
(32%)d
1d
2:1 hexane/1,4-CHD 277, 290 (sh) 2d
(5.28 mM) (4 h)
(61%)e
2e
1e
toluene + 290 equiv 282, 296
(7.29 mM) of 1, 4-CHD (22 h)
(7%)c
triplet sensitizing unit at the allene terminus and the LFP results
suggest that the cyclization proceeds along the triplet manifold as
predicted by DFT calculations.8 An intermediate with τ ) 33 ( 5
µs was tentatively assigned to a singlet biradical. Further studies
to elucidate the details of the photochemical initiation for enyne-
allenes and other Cope-type16 cyclizations are underway.
a 100-fold amount of 1,4-CHD compared to 1. b Isolated yield based on
1b. c Isolated yield. d Isolated yield based on 1d: 75:25 mixture of 2d and
a geometrical isomer. e Yield based on 1d after 4 h (18% conversion).
In contrast to that of 1b, the photochemical reaction of 1c-d
provided only C2-C6 products. Irradiation of 1c at 300 nm furnished
a 1:1 mixture of 2c and 7. The latter is again a formal Diels-
Alder product that lost a TIPS group.11 Irradiation of 1d under
analogous conditions afforded 2d in 32% yield after isolation as a
mixture of cis-trans isomers. Due to the photolability of 2d, the
reaction was studied at low conversion (18%). Now, 2d was the
sole isolable product in 61% yield. Due to ring strain effects,13 we
had originally expected that photolysis of cyclopentenyne-allene
1e could be directed toward the Myers-Saito pathway, but again
a C2-C6 product (i.e., 2e) was furnished (Table 1).
Acknowledgment. We are very much indebted to the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Industrie
for continued support of our research. Also, we thank Prof. Dr. B.
Engels (Wu¨rzburg) for his helpful assistance.
Supporting Information Available: Experimental procedures, 1H,
13C spectra for all compounds, and LFP results. This material is
available free of charge via the Internet at http://pubs.acs.org.
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A laser flash photolysis (LFP) study of 1c (excitation at 355
nm) revealed the existence of two transients. The first one (λmax
)
440 and 505 nm) with a decay rate constant k ) (3 ( 1) × 107 s-1
(τ ∼ 30 ns) was quenched by 3O2 at a diffusion-controlled rate. Its
absorption maximum at 505 nm is actually typical for a triplet state
of triphenylamine derivatives.14 Hence, we assigned this transient
to 31c*. The second transient (λmax ) 470 nm) exhibited a lifetime
τ ) 33 ( 5 µs with k ) (3.0 ( 0.4) × 104 s-1. Stern-Volmer
3
3
quenching of the long-lived transient by O2 indicated that 1c* is
a precursor. Since the long-lived transient itself did not react with
3O2, nBu3SnH, and by 1,4-cyclohexadiene, we assigned it to the
singlet biradical. Due to a high barrier (ca. 16 kcal mol-1),15 it
should exist as two noninterconverting rotamers (8 and 9), whose
ratio is reflected in the product ratio 7/2c. After the decay of the
long-lived transient, a residual broad absorption band remained that
coincided largely with that of 2c.
It is interesting to see that the products of the photocyclization
of cyclohexenyne-allenes 1a-d are related to the triplet energies
of the substituents R′. Hence, with a triplet energy of about 59
kcal mol-1, as in 1a, no photocyclization occurred, whereas
cyclization was seen with 1b containing a biphenyl (ET ) 65.0
kcal mol-1),12 remarkably, mostly toward the Myers-Saito pathway.
With even higher triplet energies (ET: triphenylamine, 70 kcal
mol-1; ketone, 80 kcal mol-1 12
) of groups R′, the photocyclization
exclusively furnished C2-C6 products.
To summarize, we have realized the first photochemical Myers-
Saito and C2-C6 cyclizations of enyne-allenes. The presence of a
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