Radical cyclization reactions of 4-bromo vinylogous-esters, vinylogous-amides
and enones
Chin-Kang Sha,* Wei-Hong Tseng, Kuan-Tsau Huang, Kuan-Miao Liu, Herng-Yih Lin and San-Yan Chu*
Department of Chemistry, National Tsing Hua University, Hsinchu 300, Taiwan, R.O.C.
Radicals generated from 4-bromo vinylogous-esters, vinylo-
gous-amides and enones cyclize to a tethered acetylene side-
chain preferentially at the g-position; theoretical calcula-
tions of the spin density of the radicals and the relative
stability of the radical intermediates are performed to
rationalize the experimental observations.
acceptable yields. 4-Bromo enone 22 underwent radical cycliza-
tion with some difficulty to give both the cyclized product 23
and the reduction product 21 in equal amounts. 4-Bromo enone
25 did not cyclize to 26 but gave only the reduction product 24.
In general, radicals generated from 4-bromo cyclohexenones 6,
12 and 22 were found to cyclize in better yields than the radicals
generated from 4-bromo cyclopentenones 9, 15 and 25.
However, it is interesting to note that most of radical
cyclizations occurred at the g-carbon. Only in entry 5, the
radical generated from compound 18 with a highly hindered g-
position cyclized both at the g- and a-positions to give 19 and
20 (1:2.5). Exocyclic double bonds formed after cyclization
were isomerised into conjugated systems under the reaction
condition (entries 1, 2 and 4, Table 1). In entry 6, the enone
double bond was deconjugated after cyclization to give 23.
To understand this unusual regioselectivity of radical cycliza-
Radical reactions have emerged as one of the most useful
synthetic methodologies in the formation of carbon–carbon
1
bonds. Previously we have described intramolecular cycliza-
2
3
tion reactions of a-ketone and a-enone radicals. As an
extension to our work in this area, we investigated the
intramolecular cyclization reactions of allylic enone radicals 2,
Scheme 1. Both from theoretical and experimental points of
view, it is of special interest to discover whether radicals 2,
generated from 4-bromo cycloalkenones 1, would cyclize at the
a- or g-position due to delocalization of the radical. Here we
report the preliminary results of this investigation.
8
tion at the g-carbon, we performed PM3 calculations on model
radical systems 27 and 28. Spin densities at the a- and g-
positions, expressed as the square of atomic orbital coefficients
in SOMO, are 0.34 and 0.49 for 27, and 0.33 and 0.53 for 28.
For the reaction under kinetic control, these coefficients are in
accordance with the experimental observations. It is noteworthy
that HOMO electron densities at the a- and g-positions of the
corresponding anionic species 29 are 0.47 and 0.32, which are
opposite to the radical species. It is well known that reactions of
Vinylogous-esters 5 and 8 and vinylogous-amides 11, 14 and
4
1
7 were prepared by literature methods. Thus, 3-trimethylsilyl-
prop-2-yn-1-ol5 was condensed with cyclohexane-1,3-dione
and cyclopentane-1,3-dione to afford vinylogous-esters 5 and 8.
6
Condensation of 3-trimethylsilylpropynylamine with the cor-
responding cycloalkane-1,3-diones, followed by reaction with
di-tert-butyl dicarbonate and 4-dimethylaminopyridine gave
tert-butoxycarbonyl (Boc) protected vinylogous-amides 11, 14
and 17. Enones 21 and 24 were synthesized by treatment of the
corresponding 3-ethoxycycloalkenones with 4-trimethylsilyl-
but-3-ynylmagnesium bromide followed by treatment with
9
anion 29 usually occur at the a-position. We also calculated the
relative stability of intermediates 30 and 31 which were formed
via the a- or g-cyclization (pathway a or b in Scheme 1). We
2
1
found that 31 is 4.5 kcal mol (1 cal = 4.184 J) more stable
than 30. This probably reflects that cyclization at the g-position,
maintaining the conjugate enone p system in the transition state,
is the pathway having the lower activation energy.
We gratefully acknowledge a grant (NSC 85-2113-M-
007-016) from the National Science Council of the Republic of
China.
7
dilute HCl. Bromination of 5, 8, 11, 14, 17, 21 and 24 with N-
bromosuccinimide (NBS) and AIBN in refluxing CCl
the corresponding 4-bromo compounds 6, 9, 12, 15, 18, 22 and
5. Radical cyclizations were then carried out using tin
4
afforded
2
2
hydride, the results of which are summarized in Table 1.
-Bromo vinylogous-esters and vinylogous-amides cyclized in
4
O
O
a
•
O
O
O
X
X
0.34
0.33
0.47
Br
SiMe3
SiMe3
1
a X = N-Boc
b X = O
c X = CH2
b
•
•
–
2
pathway b
O
0
.49
0.53
0.32
O
27
28
29
pathway a
SiMe3
O
•
•
O
SiMe3
O
X
X
SiMe3
SiMe3
31
3
4
30
Scheme 1
Chem. Commun., 1997
239