Intramolecular photocycloaddition of olefin-tethered benzo[a]spiro[2,5]octa-1,4-dien-3-one derivatives

Article abstract of DOI:10.1016/S0040-4039(02)00518-X

Photolysis of benzo[a]spiro[2,5]octa-1,4-dien-3-one derivative 8a afforded spiro-fused tetracycles 10 as a pair of diastereomers in 1.7:1 ratio. The photochemical process occurred by cycloaddition of the intermediate-sulfone stabilized biradical 9 to the

Full text of DOI:10.1016/S0040-4039(02)00518-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3239–3242
Intramolecular photocycloaddition of olefin-tethered
benzo[a]spiro[2,5]octa-1,4-dien-3-one derivatives
Xuqing Zhang* and Arthur G. Schultz†
Rensselaer Polytechnic Institute, Chemistry Department, 110 8th St., Troy, NY 12180, USA
Received 19 November 2001; revised 23 January 2002; accepted 1 March 2002
Abstract—Photolysis of benzo[a]spiro[2,5]octa-1,4-dien-3-one derivative 8a afforded spiro-fused tetracycles 10 as a pair of
diastereomers in 1.7:1 ratio. The photochemical process occurred by cycloaddition of the intermediate-sulfone stabilized biradical
9 to the tethered olefin. Photolysis of dienone 8b gave only spiro-fused tetracycle 11 without bridged adduct 12. © 2002 Elsevier
Science Ltd. All rights reserved.
1,3-Biradical chemistry has emerged as one of the most
attractive methodologies for creation of polycyclic car-
bocycles and heterocycles with one- or more five-mem-
bered rings.1 The 1,3-biradical, commonly generated
from homolytic cleavage of a cyclopropane ring or
extrusion of N2 on a diazene precursor, can undergo
various transformations depending on reaction condi-
tions and also substrates.2 The Schuster research group
has conducted detailed mechanistic studies on the pho-
model system for 1,3-diradical chemistry.3 We are par-
ticularly interested in 1,3-biradical chemistry of this
unique substrate when it incorporates an electron-with-
drawing group on the cyclopropane ring. Recently, our
research group demonstrated that the photolysis of
spiro[2,5]octa-1,4-diene-3-one 1 as an 8:1 mixture of
diastereomers 1a (A) and 1b (B) resulted in photo-iso-
merization to a photostationary state mixture A and B
in a ratio of ꢀ1.6:1.4 It is assumed that the mechanism
of isomerization involves homolytic cleavage of the
tolysis of benzo[a]spiro[2,5]octa-1,4-dien-3-one,
a
O
O
O
hυ
hυ
R
MeO
R
MeO
R
MeO
CN
H
H2C CH CN
H
CN
R = H or OMe, 1a (A)
R = H or OMe, 1b (B)
Me
Me
Me
Me
O
MeO
NC
R
Me
Me
Me
Me
R = OMe, 2
Keywords: 1,3-biradical; photocycloaddition; isomeric interconversion.
* Corresponding author. Present address: R.W. Johnson Pharmaceutical Research Institute, Medicinal Chemistry, 1000 Rt. 202, Box 300, Raritan,
NJ 08869, USA. Tel.: (908) 704-5319; fax: (908) 526-6469.; e-mail: xzhang5@prius.jnj.com
† Deceased on Jan. 20, 2000.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00518-X

3240
X. Zhang, A. G. Schultz / Tetrahedron Letters 43 (2002) 3239–3242
R
1) s-BuLi,
K, LiBr, NH3, t-BuOH
X
R
R
Me
ClCH2SPh, NH4Cl
2) K2CO3, Me2SO4
CO2Me
CO2Me
CO2H
SPh
X = Br, R = H, 65%, 4a
X = Cl, R = Me, 43%, 4b
3
R = H, 74%, 5a
R = Me, 73%, 5b
1) LAH
2) MsCl, Et3N
O
O
1) OXONE,
MeOH: H2O = 1:1
t-BuOK, 0 oC
R
R
R
in t-BuOH
2) PDC, t-BuOOH
O S
O
OMs
SPh OMs
Ph
SO2Ph
R = H, 65%, 8a (7:1 diastereomers)
R = Me, 60%, 8b (8:1 diastereomers)
R = H, 59%, 7a
R = Me, 56%, 7b
R = H, 85%, 6a
R = Me, 72%, 6b
Scheme 1.
cyclopropane ring to give the intermediate nitrile-stabi-
lized biradical. Photolysis of 1 (R=OMe) in the pres-
ence of tetramethylethylene gave spiro[4,5]deca-1,4-
diene-3-one 2 by cycloaddition of the intermediate
biradical. In an ongoing effort to develop and establish
the synthetic value of this new method for construction
of complex carbocyclic and heterocyclic ring systems,
we describe here the synthesis and photochemical
lized anion generated from 7a under the treatment with
t-BuOK in t-BuOH at 0°C gave the spiro compound 8a
as a 7:1 mixture of two diastereomers.9 Analogous
synthesis afforded the dienone 8b from 4b.
Initially both thermal and photochemical techniques
were examined on 8a to screen for the best reaction
conditions. Pyrolysis of 8a (7:1 diastereomeric mixture)
dissolved in xylene in a sealed tube at 200°C afforded
very complicated product mixtures. The product analy-
ses revealed that the spiro-fused tetracycles 10 were
formed with other cyclopropane ring-opened products.
Direct irradiation of 8a in dry benzene at room temper-
ature at 366 nm for 1 h provided much cleaner product
mixtures. Optimum results were obtained by addition
of a drop of piperylene as a triplet quencher.10 Thus,
photolysis of 8a in benzene for 2.0 h generated biradical
species 9 which underwent intramolecular 1,3-biradical
cycloaddition to the tethered olefin to provide spiro-
fused tetracycles 10 (1.7:1 ratio of diastereomers) in
77% yield.11 The diastereomers could easily be sepa-
rated by flash column chromatography and were fully
characterized. The mechanism of photocycloaddition
most likely to involves: (1) homolytic cleavage of the
cyclopropane ring to provide the intermediate sulfone-
stabilized biradical 9; (2) intramolecular cyclization of
behavior
of
benzo[a]spiro[2,5]octa-1,4-dien-3-one
derivatives 8a and 8b.
The synthesis of dienones 8a and 8b is shown in Scheme
1.5 Metalation of 2-methyl-1-naphthoic acid 3 with 2.0
equiv. of s-BuLi and quenching the dianion with allylic
bromide followed by esterification of the corresponding
acid with potassium carbonate and dimethyl sulfate
provided the ester 4a. Birch reduction–alkylation of 4a
with chloro-methylphenylsulfide afforded the diene 5a.6
Reduction of 5a with lithium aluminum hydride fol-
lowed by mesylation of the corresponding alcohol gave
the mesylate 6a. Selective oxidation of the sulfide to
sulfone was then accomplished by reaction of 6a with
OXONE in methanol–water solution (1:1) without over
oxidation of the tethered olefin.7 Treatment of the
sulfone with pyridinium dichromate (PDC) and t-
BuOOH in benzene provided the dienone 7a.8
Intramolecular cyclopropanation of the sulfone-stabi-
O
O
O
5-exo-trig
hυ
PhO2S
H
SO2Ph
SO2Ph
10, 77%, 1.7:1 diastereomers
8a, 7:1 diastereomers
9

X. Zhang, A. G. Schultz / Tetrahedron Letters 43 (2002) 3239–3242
3241
the phenoxydiradical 9 to the tethered olefin via 5-exo-
trig process to yield a new diradical; (3) subsequent ring
closure of the diradical to give spiro-fused tetracycle 10.
The formation of the bicyclo[3.3.0]-product, in keeping
with the ‘rule of five’, was predominant in the photocy-
cloaddition pathway. Isomeric interconversion of
spirooctadienone to the photo-stationary state was
observed in the photolysis of spiro[2,5]octa-1,4-dien-3-
one 1.4 We have also monitored the photochemical
(ratio: 1.7:1). This result suggests that the rate of addi-
tion of the diradical to olefin is not competitive with
that of the diastereomeric interconversion of 8a. The
photoreaction was terminated after 2 h because most of
the starting material 8a disappeared and prolonged
reaction time resulted in some decomposition.
Photolysis of the analog dienone 8b (8:1 diastereomers)
under the same conditions surprisingly afforded only
spiro-fused adduct 11 without any bridged adduct 12.12
1
process of 8a in d-benzene by H NMR. Interestingly,
isomeric interconversion of 8a could be clearly seen
while photocycloaddition of diasteromeric 8a to form
10 was taking place. The results of the time-dependent
diastereomeric interconversion of 8a are graphically
portrayed in Fig. 1. The ratio of two diastereomers of
8a could be obtained by integration of the characteristic
vinyl proton at l 6.25 in one diastereomer and l 6.07 in
the other. It is assumed that isomerization of 8a
occurred through a phenolic diradical intermediate 9.
Photolysis of 8a as a 7:1 mixture of diastereomers at the
beginning of the reaction resulted in rapid isomeriza-
tion until the diastereomeric ratio of 8a became con-
stant at ꢀ1.6:1 after 1 h irradiation. The diastereomeric
interconversion of 8a was accompanied by the process
of photocycloaddition of the diradical 9 to the tethered
olefin for the formation of 10 as a pair of diastereomers
1
The structure of 12 was excluded by a decoupling H
NMR study. Irradiation of the methine proton appear-
ing at l 3.76 caused collapses of four upfield multiplets
to two AB quartets resulting from geminal coupling in
the two adjacent methylene groups. This result demon-
strated that no 6-endo-trig cyclization process was
involved in the photocycloaddition pathway, which
suggested that the cycloaddition might proceed under
kinetic control.
In summary, we have demonstrated that complex car-
bocyclic skeletons can be formed by intramolecular
1,3-biradical cycloaddition of olefin-tethered benzo[a]-
spiro[2,5]octa-1,4-dien-3-one derivatives 8a and 8b. It is
expected that remarkable diversity will be achieved
Figure 1. aPhotolysis of 6.0×10−3 M solution of 8a in benzene in a Pyrex NMR tube. The light source was a Hanovia 450-W
medium pressure mercury arc lamp fitted with a uranyl glass filter. bThe sample was irradiated for the indicated time. At each time
1
interval, the light was shut down and a H NMR of the sample was recorded to determine the diastereomeric ratio of 8a.
O
O
O
hυ
no
5-exo-trig
Me
PhO2S
SO2Ph
Me
11, 65%
Me
PhO2S
12
8b, 8:1 diastereomers

3242
X. Zhang, A. G. Schultz / Tetrahedron Letters 43 (2002) 3239–3242
by simple changes in tethered-olefin position and
composition.
NMR (500 MHz, d-benzene) major diasteromer: 7.96 (d,
J=9.3 Hz, 1H), 7.37 (m, J=8.1 Hz, 1H), 6.96 (t, J=8.6
Hz, 1H), 6.89 (m, J=6.4 Hz, 2H), 6.78 (m, 2H), 6.61 (t,
J=8.3 Hz, 2H), 6.07 (s, 1H), 5.35 (m, 1H), 4.83 (d,
J=9.8 Hz, 1H), 4.76 (d, J=17.5 Hz, 1H), 2.84 (t, J=6.8
Hz, 1H), 2.62 (t, J=7.6 Hz, 1H), 1.60 (m, 2H), 1.58 (t,
J=6.6 Hz, 1H), 1.35 (m, 1H), 1.20 (m, 1H); minor
diastereomer: 8.21 (d, J=8.1 Hz, 1H), 7.42 (m, 2H), 7.05
(m, 1H), 6.98 (m, 3H), 6.75 (m, 2H), 6.25 (s, 1H), 5.60
(m, 1H), 4.96 (d, J=9.5 Hz, 1H), 4.92 (d, J=17.5 Hz,
1H), 2.63 (t, J=6.8 Hz, 1H), 2.50 (t, J=7.0 Hz, 1H), 2.42
(t, J=6.9 Hz, 1H), 1.95 (m, 1H), 1.90 (t, J=6.5 Hz, 1H),
1.38 (m, 1H), 1.17 (m, 1H). IR (film, cm−1) 1654, 1312,
1151. MS (CI) 365, (M++1, 100).
Acknowledgements
This work was supported by a grant from the National
Institutes of Health (Grant Number GM 26568). We
thank Dr. Arthur G. Taveras for initial effort on this
project.
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1H), 1.50 (dd, J=13.9, 7.1 Hz, 1H), 1.38 (t, J=5.4 Hz,
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1
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7.10 (m, 1H), 6.07 (s, 1H), 5.91 (m, 1H), 5.14 (d, J=17.4
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3.69 (s, 3H), 3.60 (d, J=22.4 Hz, 1H), 2.37 (m, 1H), 2.34
(m, 1H), 2.22 (m, 1H), 2.02 (m, 1H); 13C NMR (125
MHz, CDCl3) 30.1, 30.6, 31.4, 44.0, 52.4, 55.0, 114.7,
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