Iodine-Induced Reaction Cascades for the Rapid Construction of Variously Substituted Benzothiophenes

Article abstract of DOI:10.1021/ol035663a

(Equation presented) Readily accessible propynols with a 2-thioxyphenyl substituent selectively undergo 5-exo-iodocyclization followed by tandem rearrangement and elimination or substitution processes to give selective access to either 2-acyl- or 2-(1-iod

Full text of DOI:10.1021/ol035663a

ORGANIC
LETTERS
2003
Vol. 5, No. 23
4377-4380
Iodine-Induced Reaction Cascades for
the Rapid Construction of Variously
Substituted Benzothiophenes†
Karl O. Hessian and Bernard L. Flynn*
Department of Medicinal Chemistry, Victorian College of Pharmacy,
Monash UniVersity, 381 Royal Pde, ParkVille, Victoria 3052, Australia
bernard.flynn@Vcp.monash.edu.au
Received August 31, 2003
ABSTRACT
Readily accessible propynols with a 2-thioxyphenyl substituent selectively undergo 5-exo-iodocyclization followed by tandem rearrangement
and elimination or substitution processes to give selective access to either 2-acyl- or 2-(1-iodoalkeny)-benzo[b]thiophene systems.
In our ongoing efforts to maximize the molecular diversity
available from a limited set of substrates using a minimal
set of optimized protocols, we have focused on the syner-
gistic relationship of processes such as metalation, halogena-
tion, iodocyclization, and palladium-mediated coupling (di-
rect, carbonylative, and heteroannulative).1 In this regard we
and others have been involved in the synthesis of various
benzofused heterocycles 2 through 5-endo-digonal cycliza-
tion reactions of arylalkynes bearing ortho related hetero-
atomic nucleophiles (X) 1 (Scheme 1).1-3 These cyclizations
† Some aspects of this work were conducted at the Department of
Chemistry, Australian National University, Canberra, ACT, 0200, Australia.
(1) Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002, 45, 2670.
(b) Flynn, B. L.; Flynn, G. P.; Hamel, E.; Jung, M. K. Bioorg. Med. Chem.
Lett. 2001, 11, 2341. (c) Chaplin, J. H.; Flynn, B. L. J. Chem. Soc., Chem.
Commun. 2001, 1594. (d) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org.
Lett. 2001, 3, 651. (e) Banwell, M. G.; Flynn, B. L.; Wills, A. C.; Hamel,
E. Aust. J. Chem. 1999, 52, 767 (f) Banwell, M. G.; Flynn, B. L.; Hamel,
E.; Hockless, D. C. R. Chem. Commun. 1997, 207.
Scheme 1
(2) For reviews see a-e: (a) Cacchi, S. J. Organomet. Chem. 1999,
576, 42. (b) Cacchi, S.; Arcadi, A. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., de Meijere, A., Eds.; Wiley-
Interscience: New York, 2002; Vol. 2, p 2193. (c) Cacchi, S.; Arcadi, A.
In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., de Meijere, A., Eds.; Wiley-Interscience: New York, 2002; Vol. 2, p
2227. (d) Cacchi, S.; Fabrizi, G.; Goggiomani, A. Heterocycles 2002, 56,
613. (e) Battistuzzi, G.; Cacchi, S.; Fabrizi, G. Eur. J. Org. Chem. 2002,
2671. (f) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett
1999, 1432. (g) Dai, G.; Larock, R. C. J. Org. Chem. 2002, 67, 7042. (h)
Dai, G.; Larock, R. C. Org. Lett. 2001, 3, 4035. (i) Yue, D.; Larock, R. C.
J. Org. Chem. 2002, 67, 1905. (j) Yue, D.; Larock, R. C. Abstracts of
Papers, 223rd ACS National Meeting; Orlando, Florida, USA, April 7-11;
American Chemical Society: Washington, DC, 2002. (k) Liao, Y.; Reitman,
M.; Zhang, Y.; Fathi, R.; Yang, Z. Org. Lett. 2002, 4, 2607. (l) Arcadi, A.;
Cacchi, S.; Di Guiseppe, S.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4,
2409. (m) Barluenga, J.; Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew.
Chem., Int. Ed. 2003, 42, 2406.
are generally mediated by an electrophile (E), such as iodine
(iodocyclization) or a catalytic palladium(II) intermediate
(heteroannulative coupling). We have utilized these reactions
10.1021/ol035663a CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/23/2003

in the efficient synthesis of potent new analogues, 7-10, of
the tubulin polymerization inhibitor combretastatin A4, 6
(Figure 1).1,4,5
Scheme 2a
Figure 1. IC50 ) concentration required to inhibit the extent of
tubulin polymerization by 50%.
To further extend upon this efficient access to benzofused
heterocyclic analogues of combretastatin A4, 6, we have
investigated the capacity of homologated systems, 3, to
selectively undergo related 6-endo- or 5-exo-digonal cycliza-
tions reactions (Scheme 1). In the course of this ongoing
study, we have uncovered a remarkably efficient and
effective means of preparing variously substituted benzo[b]-
thiophenes through selective iodine-induced reaction cascades
where L in 3 is a readily accessible secondary or tertiary
alcohol. We report these findings herein.
The iodocyclization precursor, propynol 14, was prepared
from the isopropyl-protected isovanillin 11 via a sequence
involving bromination (12), nucleophilic aromatic substitu-
tion with sodium benzylthiolate (13), and reaction with
lithium 4-methoxyphenylacetylide (Scheme 2). Iodocycliza-
tion of 14 was expected to proceed in a 5-exo-fashion with
concomitant loss of the benzyl group to provide 15 (Scheme
2).6 However, this product was not isolated; instead the
2-aroylbenzo[b]thiophene 18 was obtained in good yield
(90%). Formation of this product was rationalized as resulting
from a reaction cascade that commences with initial iodo-
cyclization of the benzyl sulfide 14 to give 15, which
undergoes immediate 1,3-hydroxyl migration, proceeding
through allylic cation 16, to give 17, followed by elimination
HI to give 18, in a self-catalyzing process.
a Reagents and conditions: (a) N-bromosuccinimide, DMF, 80
°C; (b) NaH, BnSH, THF, 40 °C; (c) 2 × nBuLi, â,â-dibromo-4-
methoxystyrene, THF, -78 to 18 °C; (d) I2, CH2Cl2, 18 °C.
of 191e with 2 equiv of n-butyllithium (Scheme 3). Alcohol
20 was oxidized to the ketone 21 using manganese oxide
and reacted with 3,4,5-trimethoxyphenyllithium 22 to give
the 1,1,3-triarylpropynol 23. This material was iodocyclized
to give the 2-aroyl-3-arylbenzo[b]thiophene 24 in good yield.
In this and subsequent reactions (see below) involving 1,1,3-
triarylpropynols of the type 23, the intermediate alcohol was
Scheme 3a
The preparation of 3-substituted analogues of 18 simply
requires the use of tertiary rather than secondary propynols,
and several approaches to these were explored (Schemes 3
and 4). The 1,3-diarylpropynol 20 was prepared from 13 by
reaction with the lithium acetylide obtained from treatment
(3) For a review on related cyclization not involving benzofused
heterocycles, see: Knight, D. W. In Progress in Heterocyclic Chemistry;
Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon: Oxford, 2002; Vol. 14,
Chapter 2, p 19.
(4) For a review on combretastain A-4, see: Griggs, J.; Metcalfe, J. C.;
Hesketh, R. Lancet Oncol. 2001, 2, 82.
(5) For structurally related TPI compounds, see: Pinney, K. G.; Bounds,
A. D.; Dingeman, K. M.; Mocharla, V. P.; Pettit, G. R.; Bai, R.; Hamel, H.
W. Bioorg. Med. Chem. Lett. 1999, 9, 1081.
(6) Ren, X-F.; Turos, E.; Lake, C. H.; Churchill, M. R. J. Org Chem.
1995, 60, 6468.
a Reagents and conditions: (a) 19, 2 × nBuLi, THF, -78 to 18
°C, then 13, -78 to 18 °C; (b) MnO2, CH2Cl2, 18 °C; (c) 22 (3,4,5-
trimethoxyiodobenzene, nBuLi), THF, then 21, -78 to 18 °C; (d)
crude 23, I2, CH2Cl2, 18 °C.
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Org. Lett., Vol. 5, No. 23, 2003

We next sought to extend this protocol to alkyl-substituted
cyclization precursors (Scheme 6). It soon became apparent
Scheme 4a
Scheme 6a
a Reagents and conditions: (a) 25, nBuLi, THF, then 26, -78
to 18 °C; (b) 19, 2 × nBuLi, THF, then 27, -78 to 18 °C; (c)
crude 28, I2, CH2Cl2, 18 °C.
not isolated but converted directly to the benzothiophene by
addition of iodine to a dichloromethane extract of the
protonated reaction mixture.
Another approach to a 1,1,3-triarylpropynol cyclization
precursor involved lithiation of o-iodophenylsulfide 251d and
reaction with the acid chloride 26, giving the ketone 27,
which was reacted with the lithium acetylide generated from
19, and the crude propynol 28 iodocyclized to give 29
(Scheme 4).
a Reagents and conditions: (a) 1-pentyne, nBuLi, THF, then 13,
-78 to 18 °C; (b) same as (a) except Ac2O is added to reaction
prior to workup. Method A: 33, I2, CH2Cl2, 18 °C. Method B: 34,
I2, CH2Cl2, 18 °C. Method C: 33, I2, 1:1 H2O/CH3CN, 18 °C.
Method D: 33, I2, EtOH, 18°C. Method E: 34, I2, dry EtOH, 18
°C.
that iodocyclization of alkyl-substituted systems bearing
R-hydrogens on the alkyne 33 produce 2-[(Z)-1-iodoalkenyl]-
benzo[b]thiophenes 36 selectively (Method A, Scheme 6).
Minor quantities of the ketone 37 were formed but could be
avoided altogether if the corresponding acetate 34 was used
in the iodocyclization, so as to remove any possibility of a
hydroxyl migration (Method B). This alkenyl group presum-
ably forms from elimination of a proton from the intermediate
allylic cation 35 or by a concerted elimination of H2O or
AcOH (not shown). The Z-stereochemistry was assigned on
the basis of the strong nuclear Overhauser enhancement
(NOE) observed between the two hydrogens shown. Notably,
similar 2-alkenylbenzo[b]thiophenes have proven valuable
as diene systems in Diels-Alder cycloaddition chemistry.8
Although this access to 2-[(Z)-1-iodoalkenyl]-benzo[b]-
thiophenes, such as 36, represents an exciting adjunct to our
access to the 2-aroyl systems, we were keen to maximize
the scope of the ketone-forming process so that it also
included R-hydrogen-containing systems. Several experi-
ments were performed in acetonitrile/water mixtures in the
expectation that we might trap 35 with water prior to
elimination of the R-proton and obtain 37 selectively.
Although this was partially successful, substantial amounts
As an alternative to halogen for metal exchange, isopropyl
sulfides can be utilized as ortho-directing groups in directed
metalation.7 This possibility was exploited in a single-step
preparation of 32 from the diarylpropynone 30 (Scheme 5).
Scheme 5a
a Reagents and conditions: (a) isopropyl benzenesulfide, nBuLi,
TMEDA, THF, then 30, -78 to 18 °C, NH4Claq and extraction
with CH2Cl2 and addition of I2, 18 °C.
This involved initial coupling of 30 (prepared in a manner
similar to that for diarylpropynone 20) with ortho-lithiated
isopropyl phenylsulfide 31 and iodocyclization of the crude
1,1,3-triarylpropynol (not shown) to give benzothiophene 32
(Scheme 5). Thus, this process provides for a single-step
access to 2-acyl(or aroyl)benzothiophenes from isopropyl
phenyl sulfides and propynones or propynals.
(7) Sato, R.; Ohyama, T.; Kawagoe, T.; Baba, M.; Nokajo, S.; Kimura,
T.; Ogawa, S. Heterocycles 2001, 55, 145. (b) Cabidda, S.; Fattaoni, C.;
Floris, C.; Gelli, G.; Melis, S.; Sotgia, F. Tetrahedron 1990, 46, 861.
(8) Marrocchi, A.; Minuti, L.; Taticchi, A.; Scheeren, H. W. Tetrahedron
2001, 57, 4959.
Org. Lett., Vol. 5, No. 23, 2003
4379

of iodoalkene (1:1 36:37) were still formed even with large
amounts of water (1:1 acetonitrile/water) (Method C). We
next attempted the reaction in ethanol to further increase the
concentration of the trapping agent. The anticipated enolether
and/or the diethylketal (not shown) could then be hydrolyzed
to the ketone 37. To our pleasant surprise, reaction of 33
with iodine in ethanol gave the ketone 37 directly with
excellent selectivity over the elimination product 36 (not
observed). This product was also achieved even when the
acetate 34 was iodocyclized in dry ethanol and a basic
workup employed so as to avoid any in situ hydrolysis. It
was concluded then that the ketone 37 most likely results
from iodide cleavage of the ethyl ether of the oxonium
intermediate 39 (Scheme 7).9
Scheme 8a
a (a) MeSNa, THF; (b) 1-pentyne, nBuLi, CeCl3 THF, then 41,
-78 to 18 °C. Method A: I2, CH2Cl2, 18 °C. Method B: I2, EtOH,
18°C.
Scheme 7. Proposed Mechanism for the Conversion of 33 and
34 to 37
the anti-addition product shown) the presence of the donor-
acceptor relationship between the carbonyl and aromatic ring
in 45 induces a slow isomerization (equilibration achieved
after approximately 8 h) leading to a 1:1 thermodynamic
mixture of E/Z-isomers.
Scheme 9
These cyclization processes were also extended to alkyl-
substituted tertiary alcohols (Scheme 8). The bromo group
in 2-bromoacetophenone 40 was subject to nucleophilic
aromatic substitution with sodium methiolate to give the
sulfide 41. This product was converted to the tertiary alcohol
42 using a 1-pentynylcerium species in order to avoid the
enolization of the acetophenone 41, which was observed
when the equivalent lithiumacetylide was used. In this case,
iodocyclization of the tertiary alcohol 42 gave exclusive
formation of the 2-iodoalkenyl system 43. Also, as with the
secondary alcohol 33, tertiary alcohol 42 also provided
exclusive formation of the ketone 44 in ethanol.
The concise, convergent nature of these reaction protocols,
their chemoselectivity, and their capacity to be integrated
with related protocols in a complimentary fashion underscore
the potential of these new methodologies in the diversity-
orientated synthesis of benzothiophene cores. A more
extensive investigation into the effects of the various groups
L, X, and Y and the reaction conditions on the cyclization
of systems 3 (Scheme 1) is currently underway.
We also explored the iodocyclization of the sulfide
containing diarylpropynone 21, which afforded the 5-exo-
cyclization product, R-iodothioaurone 45, selectively over
the 6-endo-cyclization product, 3-iodothioflavone 46. Al-
Supporting Information Available: Experimental details
and spectroscopic data on all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
though H NMR of the crude reaction mixture initially
revealed the formation of only one isomer of 45 (presumably
(9) Smith, C. A.; Grutzner, J. B. J. Org. Chem. 1976, 41, 367.
OL035663A
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