Radical cyclisations to arenes for the synthesis of phenanthrenes

Article abstract of DOI:10.1016/S0040-4039(02)00505-1

6-exo/endo-Trig intramolecular additions of aryl radicals to electron-rich, unsubstituted and electron-deficient arenes have all been shown to proceed efficiently to give the corresponding phenanthrenes in high yield.

Full text of DOI:10.1016/S0040-4039(02)00505-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3185–3187
Radical cyclisations to arenes for the synthesis of phenanthrenes
David C. Harrowven,a,* Michael I. T. Nunna and David R. Fenwickb
aDepartment of Chemistry, The University, Southampton SO17 1BJ, UK
bDiscovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK
Received 22 January 2002; revised 28 February 2002; accepted 7 March 2002
Abstract—6-exo/endo-Trig intramolecular additions of aryl radicals to electron-rich, unsubstituted and electron-deficient arenes
have all been shown to proceed efficiently to give the corresponding phenanthrenes in high yield. © 2002 Elsevier Science Ltd. All
rights reserved.
Phenanthrenes are commonly prepared by photocycli-
sation of stilbenes. When 3,3%-substituted stilbenes are
employed, several regiochemical courses may be fol-
lowed leading to as many as four regioisomeric prod-
ucts. The process is useful because electronic factors
generally bias the outcome to favour one product over
the other possibilities. However, little can be done to
promote cyclisation via an unfavourable transition
further extension of the methodology to electron-rich,
unsubstituted and electron-deficient arenes.4,5
The first cyclisation examined involved cis-4-cyano-2%-
iodo-3%,4%,5%-trimethoxystilbene 1 which, on treatment
with tributyltin hydride under standard radical forming
conditions, was smoothly transformed into 3-cyano-
5,6,7-trimethoxy-phenanthrene 2 in 85% yield (Scheme
1). Cyclisations were equally facile for the 2- and
3-cyano derivatives 3 (Scheme 2) and 5, in the latter
case giving rise to an easily separable 1:1 mixture of 2-
and 4-cyano-5,6,7-trimethoxyphenanthrenes 6 and 7
(Scheme 3).
state, representing
a
severe limitation of the
methodology.1
We recently faced such a problem during a total synthe-
sis of the alkaloid toddaquinoline. Photolysis of a 3-
aza-stilbene promoted cyclisation to C-4 of the pyridine
moiety, whereas we required cyclisation to occur to
C-2. Our means of biasing the reaction for the desired
regiochemical course was to employ an intramolecular
radical addition reaction mediated by cobalt.2 Subse-
quently we have shown that all manner of radical
cyclisation reactions to electron deficient nitrogen het-
eroaromatics are facile.3 In this letter we report a
Our focus next turned to cyclisations involving the
addition of an aryl radical to unsubstituted and elec-
tron-rich arenes. Pleasingly, cyclisation to a phenyl ring
proved facile with cis-2%-iodo-3%,4%,5%-trimethoxystilbene
8 being transformed into the corresponding phenan-
threne 9 in excellent yield (Scheme 4).6
Cyclisations to electron-rich arenes were equally
efficient.
Thus,
when
cis-2%-iodo-3,3%,4%,5%-tetra-
OMe
OMe
methoxystilbene 10 was treated with tributyltin hydride
under standard radical forming conditions, a 1:1 mix-
ture of 2,3,4,7-tetramethoxyphenanthrene 11 and
2,3,4,5-tetramethoxyphenanthrene 12 resulted (Scheme
5)7 suggesting that substitution at C-3 plays only a
minor role in determining the regiochemical course of
such reactions.
I
OMe
OMe
OMe
OMe
Bu3SnH
AIBN, PhMe
90 °C, 36 h, 85%
CN
CN
1
2
Scheme 1.
In light of these experiments, it was curious to find
that a combination of electron donating groups at
C-3 and C-4 in the acceptor ring had a marked influ-
ence on the regiochemical course of the reaction. For
example, when cis-2%-iodo-3,4-methylenedioxy-3%,4%,5%-
Keywords: radicals and radical reactions; aromatic chemistry;
phenanthrenes.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00505-1

3186
D. C. Harrow6en et al. / Tetrahedron Letters 43 (2002) 3185–3187
trimethoxystilbene 13 was subjected to standard tin
OMe
OMe
mediated radical cyclisation conditions, the dominant
product, formed in 72% yield, was 2,3-methylenedioxy-
3%,4%,5%-trimethoxyphenanthrene 14 with 3,4-methylene-
dioxy-3%,4%,5%-trimethoxyphenanthrene 15 accounting
for just 14% of the total mass balance (Scheme 6).
I
OMe
OMe
OMe
OMe
Bu3SnH
AIBN, PhMe
90 °C, 8 h, 90%
NC
NC
At this juncture it is worth noting that Aidhen and
Narasimhan reported the conversion of trans-bromo-
stilbene 16 into phenanthrene 14 in 32% yield by reac-
tion with tributyltin hydride.8 This is in stark contrast
to the reaction of trans-iodostilbene 17 which gave 14
in less than 5% yield and trans-stilbene 18 in 68% yield.
The dichotomy suggests that for 2-halostilbenes carbon
to iodine bond homolysis outpaces addition of the
tributyltin radical to the alkene, which in turn outpaces
carbon to bromine bond homolysis.3,9
3
4
Scheme 2.
MeO
OMe
MeO
CN
I
5
Bu3SnH AIBN
PhMe, 90 °C 24 h, 78%
In conclusion, we have shown that intramolecular 6-
exo/endo-trig radical cyclisations of cis-2-iodostilbenes
are facile processes providing a rapid and predictable
method for the synthesis of phenanthrenes in high
yield. Cyclisations follow the non-reducing radical
cyclisation pathway, with aromaticity in the radical
acceptor being re-established through overall loss of a
hydrogen atom.5 The radical acceptor may be electron-
rich, unsubstituted or electron-deficient and when this is
substituted at C-2, cyclisation occurs to C-6 exclusively.
By contrast, substitution at C-3 appears to have little
influence on the regiochemical course of the reaction
unless a substituent is also present at C-4. We are
presently exploring further facets of this chemistry in
the hope of delineating the origin of that effect and are
seeking to apply the methodology in target oriented
synthesis.
OMe
OMe
OMe
OMe
OMe
OMe
CN
+
CN
6
1 : 1
7
Scheme 3.
OMe
OMe
I
OMe
OMe
OMe
OMe
Bu3SnH
AIBN, PhMe
90 °C, 6 h, 89%
MeO
MeO
OMe
O
O
8
9
I
13
Scheme 4.
Bu3SnH AIBN
PhMe, 90 °C 8 h, 86%
OMe
OMe
MeO
MeO
OMe
OMe
OMe
OMe
OMe
OMe
O
+
I
10
O
Bu3SnH AIBN
PhMe, 90 °C 8 h, 82%
O
O
14
5 : 1
15
OMe
OMe
OMe
OMe
OMe
Scheme 6.
OMe
OMe
OMe
+
MeO
MeO
X
O
O
OMe
16 X = Br
17 X = I
18 X = H
11
1 : 1
12
Scheme 5.

D. C. Harrow6en et al. / Tetrahedron Letters 43 (2002) 3185–3187
3187
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