A remarkably simple and efficient benzannulation reaction

Article abstract of DOI:10.1002/anie.200603416

(Chemical Equation Presented) On a short fuse: Although fused aromatic rings are common structural motifs in natural products, there are relatively few direct methods for the preparation of such systems from acyclic precursors. An atom-transfer radical cyclization carried out under microwave (MW) irradiation has now been developed which gives rapid access to functionalized aromatic compounds from readily available starting materials (see scheme).

Full text of DOI:10.1002/anie.200603416

Angewandte
Chemie
DOI: 10.1002/anie.200603416
Fused-Ring Systems
A Remarkably Simple and Efficient Benzannulation Reaction**
James A. Bull, Michael G. Hutchings, and Peter Quayle*
Dedicated to Professor E. J. Thomas on the occasion of his 60th Birthday
Whereas the application of atom-transfer radical cyclization
reactions[1] (ATRC reactions) to the synthesis of g-butyro-
lactams and g-butyrolactones is now reasonably well estab-
lished,[2] the same cannot be said of this approach to the
synthesis of medium-sized rings.[3] Previously[4d] we had shown
that the trichloroacetate 1 (Scheme 1) undergoes sequential
5-exo,6- exo ATRC reactions to provide rapid access to the
2-oxabicyclo[4.3.0]nonane ring system. Alternate modes
of cyclization (by 9-exo or 10-endo pathways[5]) were not
observed. As a continuation of our interest[4] in this area we
investigated the cyclization of trichloroacetate 3 (Scheme 1)
under ATRC conditions. The synthesis of benzoxocins by
radical cyclization reactions has received scant attention,[6,7]
and at the outset we wished to determine if ATRC of 3 would
occur by a 7-exo or 8-endo pathway[8] and whether structural
features could be incorporated into the substrate to modify
the regiochemical outcome of the reaction.[9] Furthermore,we
Scheme 1. ATRC and benzannulation sequences catalyzed by CuCl in
the presence of ligand 2. a) 2 (5 mol%), CuCl (5 mol%), DCE, 808C,
3.5 h; b) SiO2, CH2Cl2, 75%; c) 2 (5 mol%), CuCl (5 mol%), DCE,
808C, 48 h, quantitative; d) 2 (5 mol%), CuCl (5 mol%), DCE, micro-
wave, 2008C, 2 h, 84%. DCE=1,2-dichloroethane.
also believed that this potentially problematic cyclization[10]
reaction would also serve as a suitable test case for the
development and evaluation of more efficient catalysts for
ATRC reactions.[11]
Cyclization (CuCl,5 mol%; 2,[12,13] 5 mol%; toluene;
reflux) of the readily available ester 3 proved to be rather
sluggish (95% completion after 48 h) and afforded the
labile[13] lactone 4 through an 8-endo-trig reaction.[7] This
cyclization was also accompanied by the formation of a minor,
wholly aromatic,by-product whose generation lagged behind
the formation of lactone 4. Repeating the ATRC reaction of 3
for 120 h in refluxing toluene resulted in the total consump-
Wishing to establish the synthetic generality of this
reaction,we subjected a variety of readily available aryl
trichloroacetates (8, 10, 12a–12 f; Scheme 2) to the same
experimental protocol and found that,in each case,benz-
annulation proceeded smoothly over two hours at 2008C to
produce their respective naphthalene derivatives. The requi-
site ortho-allyl phenols used in this study are themselves
readily available from an ortho-Claisen rearrangement[19] of
their respective allyl aryl ethers,a process which in many
cases can also be efficiently accomplished in a microwave
reactor.[20]
Of note is the observation that the benzannulation
reaction proceeds with complete regiochemical control to
afford an aryl chloride as a single regioisomer in each case.
For example,subjecting the isomeric naphthyl esters 8 and 10
separately to our standard reaction conditions affords the
known[21] chlorophenanthrenes 9 and 11 as the sole benz-
annulation products,an observation which is in agreement
with the supposition that the aryl–oyxgen bond of the ester
undergoes ipso substitution by Ca during the course of the
benzannulation sequence.[22] The incorporation of potentially
reactive,yet useful,functionality (esters,enolizable ketones)
is also accommodated (Scheme 2). Generally speaking both
electron-releasing and electron-withdrawing substituents are
tolerated in the cyclization sequence,although the lower yield
in the case of 12e (55%) may be attributed to a competing
deacylation reaction during the course of the benzannulation.
tion of both ester 3 and the lactone 4,and the formation of 1-
[14]
chloronaphthalene (6),which was isolated
in 23% yield
after column chromatography. Moreover we were delighted
to observe that irradiation[15–17] of a solution of the ester 3 in
1,2-dichloroethane containing our standard catalyst system in
a microwave reactor[18] afforded 6 in 84% yield after a much
reduced reaction time of two hours (Scheme 1).
[*] J. A. Bull, Dr. P. Quayle
School of Chemistry
University of Manchester
Manchester M139PL (UK)
Fax: (+44)161-275-4598
E-mail: peter.quayle@manchester.ac.uk
Dr. M. G. Hutchings
DyStar UK Ltd
School of Chemistry
University of Manchester
Manchester M139PL (UK)
[**] We thank DyStar for generous funding of this research program and
Dr. A. J. Lawrence for helpful discussions.
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diester 12l,in 34% yield. Benzannulation of substrates
containing substituents in the allyl fragment also appears
viable,as indicated by the cyclization of 12m into 13m.
The potential synthetic utility of our benzannulation
sequence is illustrated by a four-step synthesis of the novel
steroids 16a and 16b from estrone (14,Scheme 3). Allylation
Scheme 3. Application of the benzannulation reaction to the synthesis
of novel steroidal systems. a) CH2CHCH2Br (1.2 equiv), K2CO3
(1.2 equiv), 568C; b) microwave, 2158C; c) Et3N (1.2 equiv), Cl3CCOCl
(1.2 equiv), Et2O, 08C; d) 2 (5 mol%), CuCl (5 mol%), DCE, micro-
wave, 2008C, 2 h.
of 14 as reported by Miescher and Scholtz[23] followed by
ortho-Claisen rearrangement[24] and trichloroacetylation
afforded a 2:1 mixture of the trichloroacetates 15a and 15b,
which proved to be inseparable on a preparative scale.
However microwave irradiation of the 2:1 mixture of crude
esters 15a,b in the presence of our standard catalyst system
afforded the benzannulated steroid derivatives 16a,b again as
a 2:1 mixture of regioisomers in 67% yield.
Plausible pathways for the conversion of 3 into 6 are
outlined in Scheme 4. Initially we considered that the initial
product of the ATRC reaction,lactone 4,could suffer double
dehydrochlorination under the reaction conditions employed
for the diene 17. Electrocyclic ring closure[25] of 17 to the
b-lactone 18 would then lead to the observed product 6 by loss
of CO2.[26]
However,whilst control experiments confirmed that the
formation of 6 proceeds via the intermediacy of lactone 4,
microwave irradiation of 4 for two hours at 2008C in the
absence of either CuI ions or ligand resulted in quantitative
recovery of starting material 4. Addition of our catalyst
system to the reaction mixture at this stage followed by
Scheme 2. Benzannulation sequences. a) 2 (5 mol%), CuCl (5 mol%),
DCE, microwave, 2008C, 2 h. Yields are of purified products. MW=mi-
crowave.
The synthesis of 1,8-disubstituted naphthalenes 13g–k is also
amenable by this route from the corresponding esters 12g–k.
Again the introduction of a nitro substituent (12k) appears to
be limiting in terms of the yield of the isolated product. We
have also briefly investigated the possibility of multiple
benzannulation reactions,as exemplified by the preparation
of 4,10-dichlorochrysene (13l),from the readily available
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Chemie
Keywords: cyclization · fused-ring systems ·
.
microwave irradiation · radical reactions · synthetic methods
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Scheme 4. Proposed mechanism for the conversion of 3 into 6.
irradiation as above then resulted in the quantitative con-
version of 4 into 6.
The fact that control reactions show that lactone 4 is
thermally stable militates against the formation of the diene
17 and its subsequent rearrangement.[27,28] The finding that the
copper catalyst appears to be intimately involved in the
transformation of 4 into 6 leads us to suggest that the reaction
proceeds via the spirocyclic lactone 20,the product of a 4- exo
radical cyclization onto the aromatic ring.[29] Once spiro-
cyclization has taken place,presumably via the intermediacy
of radical 19,we envisage that lactone 20 suffers a rapid loss of
CO2 to produce the vinyl chloride 21.[26] Finally double
dehydrochlorination of 21 ultimately affords 1-chloro-
naphthalene (6).
Whatever the detailed mechanism[30] of this new benz-
annulation sequence,its ease of operation and potential
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[12] Ligand 2 was prepared according to the method in: A. M. Magill,
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Experimental Section
A solution of the trichloroacetate 3 (640 mg,2.4 mmol) in degassed
1,2-dichloroethane (10 mL) containing CuCl (11 mg, 0.11 mmol) and
the ligand 2 (33 mg,0.11 mmol) was sealed under nitrogen in a
reaction vial and irradiated in a microwave reactor[18] for 2 h at 2008C.
On cooling the reaction to ambient temperature the solvent was
removed in vacuo and the black residue purified by column chroma-
tography (silica gel; eluent 10% EtOAc/petroleum ether) to afford
1-chloronaphthalene (6) (yield 327 mg,84%).
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effectiveness of other catalyst systems in this reaction.
[13] Lactone 4 (1H NMR (300 MHz,CDCl 3,25 8C,tetramethylsilane
(TMS)): d = 2.75 (dd, J = 15,11 Hz, 1H), 3.15 (dd, J = 16,5 Hz,
1H),3.23 (dd, J = 15,4 Hz,1H),3.35 (dd,
J = 16,4 Hz,1H),
Received: August 21,2006
4.54–4.53 (m,1H),7.25–7.45 ppm (m,4H); 13C NMR (125 MHz,
Revised: November 11,2006
Published online: January 23,2007
[D]CHCl3,TMS): d = 163.7,151.6,132.3,129.7,126.1,124.9,
120.0,82.1,54.9,54.2,37.9 ppm; IR (film):
n˜1766 (s),1487 (m),
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1453 (m) 1217 (m),1179 (m) cm À1) readily undergoes hydrolytic
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[30] Mechanistic studies are currently underway,the results of which
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À
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