Facile dearomatizing radical arylation of furan and thiophene

Article abstract of DOI:10.1021/ol051027w

(Chemical Equation Presented) In the presence of catalytic diphenyl diselenide, reduced in situ to benzeneselenol, tributyltin hydride and V-70 promote the addition of aryl iodides to furan and thiophene. The adduct radicals are trapped by the selenol to give the 2-aryl-2,3-dihydro and 2-aryl-2,5-dihydro heterocyclic products. When the iodide is an o-iodophenol, a cyclization follows the radical addition and provides bridged bicyclic acetals.

Full text of DOI:10.1021/ol051027w

ORGANIC
LETTERS
2
005
Vol. 7, No. 17
625-3628
Facile Dearomatizing Radical Arylation
of Furan and Thiophene
David Crich* and Mitesh Patel
3
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061
dcrich@uic.edu
Received May 4, 2005
ABSTRACT
In the presence of catalytic diphenyl diselenide, reduced in situ to benzeneselenol, tributyltin hydride and V-70 promote the addition of aryl
iodides to furan and thiophene. The adduct radicals are trapped by the selenol to give the 2-aryl-2,3-dihydro and 2-aryl-2,5-dihydro heterocyclic
products. When the iodide is an o-iodophenol, a cyclization follows the radical addition and provides bridged bicyclic acetals.
Some time ago we showed how benzeneselenol, produced
in situ stoichiometrically by the reduction of diphenyl
through chain-terminating dimerization of radicals, and a
significant reduction in the amount of initiator required.2
a,b
1
diselenide with tributyltin hydride, facilitates the propagation
We also have found the selenol catalysis trick to be
applicable to the trapping of cyclohexadienyl radicals arising
from the addition of aryl radicals to benzene, when a four
propagation step chain sequence (Scheme 1, eqs 1-4) takes
2
of stannane-mediated radical chain reactions. Although the
Sn-H and Se-H bond dissociation energies are very
3
similar, the selenol traps alkyl radicals some 500 times faster
4
than the stannane because of the operation of a polarity
5
effect. The quenching of aryl or vinyl radicals, on the other
hand, is barely accelerated by the presence of the selenol,
Scheme 1. Mechanism of Dearomatizing Aryl Radical
as trapping of such σ-type radicals by the stannane alone
Addition to Arenes
6
already approaches the diffusion controlled limit. The
selenol-accelerated process offers significant advantages in
chain sequences involving allyl and benzyl radicals when it
effectively increases the propagation efficiency leading to
higher substrate conversion, less formation of byproducts
(
1) (a) Crich, D.; Yao, Q. J. Org. Chem. 1995, 60, 84-88. (b) Crich,
D.; Jiao, X.-Y.; Yao, Q.; Harwood, J. S. J. Org. Chem. 1996, 61, 2368-
373. (c) Crich, D.; Hwang, J.-T.; Gastaldi, S.; Recupero, F.; Wink, D. J.
J. Org. Chem. 1999, 64, 2877-2882.
2) (a) Crich, D.; Mo, X.-S. J. Org. Chem. 1997, 62, 8624-8625. (b)
Crich, D.; Mo, X.-S. J. Am. Chem. Soc. 1998, 120, 8298-8304.
2
(
7
3) BDE Me3Sn-H, 78 kcal mol ; BDE PhSe-H, 78 ( 4 kcal mol-1.
a) Laarhoven, L. J. J.; Mulder, P.; Wayner, D. D. M. Acc. Chem. Res.
999, 32, 342-349. (b) Leeck, D. T.; Li, D. T.; Chyall, L. J.; Kenttamaa,
H. I. J. Phys. Chem. 1996, 100, 6608-6611.
4) The rate constants for trapping for primary alkyl radicals by Bu3-
-
1
place. In the absence of the selenol, as is well-known for
(
(
1
the cyclization of aryl radicals onto arenes, the cyclohexa-
dienyl radical does not propagate the chain and suffers
rearomatization, perhaps at the hands of the initiator. The
failed propagation step inevitably results in the need for
greater quantities of initiator if high conversion is to be
achieved.
8
(
6
9
-1 -1
SnH and PhSeH at 25 °C are, respectively, 2 × 10 and 1 × 10 M
a) Chatgilialoglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc. 1981,
03, 7739-7742. (b) Newcomb, M.; Choi, S.-Y.; Horner, J. H. J. Org.
s .
(
1
9
Chem. 1999, 64, 1225-1231.
(
5) Roberts, B. P. Chem. Soc. ReV. 1999, 28, 25-36.
(6) Garden, S. J.; Avila, D. V.; Beckwith, A. L. J.; Bowry, V. W.; Ingold,
K. U.; Lusztyk, J. J. Org. Chem. 1996, 61, 805-809.
(7) Crich, D.; Hwang, J.-T. J. Org. Chem. 1998, 63, 2765-2770.
1
0.1021/ol051027w CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/21/2005

Table 1. Aryl Radical Addition to Furan, Thiophene, and Pyrrole
When the aryl radical employed in eqs 1-4 (Scheme 1)
is substituted at the ortho-position by a suitable functional
group, such as a phenol, the chain sequence may be followed
up by a cyclization reaction providing a very facile entry
10
into tetrahydrodibenzofurans and the like. Indeed, we have
successfully applied this chemistry in syntheses of carbazo-
1
1
12
mycin B and of a dibenzofuran peptide â-sheet initiator,
(8) (a) Beckwith, A. L. J.; Bowry, V. W.; Bowman, W. R.; Mann, E.;
with the two key building blocks in each case being an
o-functionalized iodobenzene and benzene itself. We now
report that this chemistry is also effective with the simple
Parr, J.; Storey, J. M. D. Angew. Chem., Int. Ed. 2004, 43, 95-98. (b)
Curran, D. P.; Yu, H.; Liu, H. Tetrahedron 1994, 50, 7343-7366. (c)
Curran, D. P.; Liu, H. J. Chem. Soc., Perkin Trans. 1 1994, 1377-1393.
(
d) Engel, P. S.; Wu, W.-X. J. Am. Chem. Soc. 1989, 111, 1830-1835.
(
9) A recent study on the intermolecular addition of aryl radicals to
benzene with isolation of fully aromatic biaryls. Mart ´ı nez-Barrasa, V.; Garcia
(10) Crich, D.; Sannigrahi, M. Tetrahedron 2002, 58, 3319-3322.
(11) Crich, D.; Rumthao, S. Tetrahedron 2004, 60, 1513-1516.
(12) Crich, D.; Grant, D. J. Org. Chem. 2005, 70, 2384-2386.
de Viedma, A.; Burgos, C.; Alvarez-Builla, J. Org. Lett. 2000, 2, 3933-
3
935.
3626
Org. Lett., Vol. 7, No. 17, 2005

aromatic heterocycles furan and thiophene, thereby permit-
ting the very straightforward synthesis of 2-aryl 2,3-dihy-
drofurans and thiophenes and their 2,5-dihydro isomers.
Scheme 2. Aryl Radical Addition to Furan and Thiophene
Radical addition of aryl radicals to both furan and
thiophene has been studied previously. However, under the
non-chain conditions applied the isolated products were either
fully aromatic aryl furans and thiophenes or dihydro systems
carrying a triphenylmethyl substituent resulting from com-
bination of the adduct radical with the triphenylmethyl
radical.13 Nevertheless it was determined, using phenyl
radicals derived from the benzenediazonium ion, that the
relative rates of addition to furan, thiophene, and benzene
1
3a
are 11.5:2.6:1.
In the chemistry described in eqs 1-4, benzene functions
as reagent and solvent and the reactions are run at reflux.
Under these conditions azobisisobutyronitrile (AIBN) with
t
1/2 ) 2 h at 80 °C14 is a suitable initiator. Not surprisingly,
oxygen leading to preferential formation of the 2,3-dihydro
product (Scheme 2).
when we attempted to conduct a similar reaction in furan
bp 32 °C) at reflux, little or no reaction was observed.
(
When thiophene (bp 84 °C) was employed as solvent and
the reactions conducted at an oil bath temperature of 50 °C
using V-70 as initiator, comparable adducts were obtained,
albeit with reduced yield and a reversed selectivity in the
quenching step favoring the formation of the 2,5-dihydro
rather than the 2,3-dihydro system (Table 1, entries 6-9).
The difference in the regioselectivity of the hydrogen atom
transfer step between the furan and thiophene series is
consistent with a change in spin delocalization in the
intermediate heteroatom-substituted allyl radicals as the
heteroatom is changed from oxygen to sulfur. Indeed, it has
previously been found from the magnitudes of the electron
spin resonance hyperfine splitting constants in the 1-tert-
butylthioallyl and the 1-tert-butoxyallyl radicals that alkylthio
groups are much more effective at localizing spin than the
Switching, however, to 2,2′-azobis(4-methoxy-2,4-dimeth-
ylvaleronitrile) (V-70) as initiator, with a lower decomposi-
tion temperature (t1/2 30 °C ) 10 h in toluene for the
commercial (/meso isomer mixture)15 brought immediate
results. Thus, a 0.01 M solution of o-iodophenol in furan
containing 20 mol % of diphenyl diselenide was heated to
reflux under argon and treated with a solution of 175 mol
16
%
tributylstannane (0.05 M) and 20mol % of initiator V-70
in furan dropwise over 16 h. After heating to reflux for a
further 1 h, the furan was stripped off, and after partitioning
between hexanes and acetonitrile, the products 2 and 3 were
isolated by chromatography over silica gel (Table 1, entry
1
1
). Examination of the crude reaction mixture by H NMR
spectroscopy revealed that the 2,3,4,5-tetrahydro-2,5-epoxy-
-benzoxepin 2 is formed directly in the reaction mixture
1
7,18
1
corresponding alkoxy groups.
Minor products arising
and not on passage over silica gel. Presumably, the phenol
itself or the catalytic benzeneselenol promotes cyclization
of the initial 2-(2,3-dihydro-2-furanyl)phenol. When o-
iodovanillin was employed as substrate a more highly
functionalized epoxybenzoxepin 5 was obtained in 51% yield
together with the 2,5-dihydrofuran 6 in 14% yield (Table 1,
entry 2). Other iodoarenes lacking the phenolic hydroxyl
group in the o-position also underwent smooth addition to
furan giving mixtures of the 2,3- and 2,5-dihydro-2-aryl-
furans (Table 1, entries 3-5).
All additions to furan (Table 1, entries 1-5) were clean
and showed no indication of the alternative mode of addition
at the furan C3-position, an observation that is in keeping
with the previous work in the area.13a The additions to furan
show a preference of between 2/1 and 3.6/1 for quenching
of the intermediate 1-oxyallyl radicals distal to the ring
from aryl attack at the thiophene 3-position also were
discernible in the crude reaction mixture of all thiophene
additions, even if only isolated in one case (Table 1, entry
7). Again, the formation of minor amounts of the 3-aryl
addition product in the thiophene series is consistent with
the results of an earlier study in which phenylazotriphenyl-
methane was employed as aryl radical source.1 In the
3b
addition of the 2-hydroxyphenyl radical to thiophene (Table
1
1
, entry 6) the H NMR spectrum of the crude reaction
mixture revealed two significant products in a ratio of 2.6:1
favoring the 2,5-dihydro system 17. The second product was
the corresponding 2,3-dihydro system, but this could not be
isolated pure and underwent slow decomposition on standing
to the 2,3,4,5-tetrahydro-2,5-epithio-1-benzoxepin 16 iso-
lated, the fully aromatic 2-(2-thienyl)phenol, and a number
of unidentified substances. This observation stands in contrast
(
17) (a) Griller, D.; Nonhebel, D. C.; Walton, J. C. J. Chem. Soc., Perkin
(
13) (a) Benati, L.; La Barba, N.; Tiecco, M.; Tundo, A. J. Chem. Soc.
Trans. 2 1984, 1817-1821. (b) Korth, H.-G.; Sustmann, R. Tetrahedron
Lett. 1985, 26, 2551-2554. (c) Korth, H.-G.; Lommes, P.; Sustmann, R. J.
Am. Chem. Soc. 1984, 106, 663-668. (d) Edge, D. J.; Kochi, J. K. J. Chem.
Soc., Perkin Trans. 2 1973, 182-190.
(18) The recommended BDEs of the C-H bonds in methanol, methyl-
amine, and methanethiol are 96.06 ( 0.15, 93.9 ( 2, and 93.9 ( 2
kcal‚mol , respectively, suggesting that bond strength is not the dominating
factor here. Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic
Compounds; CRC Press: Boca Raton, 2003.
B 1969, 1253-1256. (b) Camaggi, C. M.; Leardini, R.; Tiecco, M.; Tundo,
A. J. Chem. Soc. B 1969, 1251-1253 and references therein.
(
(
14) Walling, C. Tetrahedron 1985, 41, 3887-3900.
15) (a) Kita, Y.; Gotanda, K.; Sano, A.; Oka, M.; Murata, K.; Suemua,
M.; Matsugi, M. Tetrahedron Lett. 1997, 38, 8345-8348. (b) Kita, Y.;
Matsugi, M. In Radicals in Organic Synthesis; Sibi, M. P., Renaud, P.,
Eds.; Wiley-VCH: Weinheim, 2001; Vol. 1, pp 1-10.
-1
(
16) Commercial V-70 from Wako Chemicals was employed.
Org. Lett., Vol. 7, No. 17, 2005
3627

to entries 1 and 2 of Table 1 in which, as noted above,
addition of the phenolic OH bond across the corresponding
dihydrofuran undergoes addition of the O-H bond across
the enol ether in the reaction mixture to provide a very
convenient one-pot synthesis of 2,3,4,5-tetrahydro-2,5-epoxy-
2,3-dihydrofuran could not be suppressed and is no doubt
2
5,26
indicative of the reduced reactivity of vinyl sulfides as
opposed to their ether counterparts.
Finally, we briefly investigated arylation of pyrrole (bp
1-benzoxepins.
The analogous chemistry is found with
thiophene, although the 2-aryl-2,5-dihydrothiophene is pre-
ferred over the 2,3-dihydro-isomer. Unlike furan and thiophene,
pyrrole provides complex reaction mixtures from which fully
aromatized 2-aryl pyrroles could only be obtained in low
131 °C) employing a reaction temperature of 50 °C and V-70
as initiator. Unfortunately, complex reaction mixtures were
2
7
obtained and only a rearomatized product 25 could be
yield.
19
isolated pure in low yield (Table 1, entry 10). Our inability
to suppress rearomatization in the pyrrole additions parallels
our earlier observations on radical addition to pyridine under
the benzeneselenol-catalyzed conditions when rearomatized
products were also formed, albeit in significantly better
Acknowledgment. We thank the University of Illinois
at Chicago for partial support of this work.
Supporting Information Available: Full experimental
details and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
2
0,21
yields.
In conclusion, 2-aryl-2,3-dihydrofurans, some of which
have previously found application in mutlicomponent cou-
OL051027W
22
pling reactions, can be readily accessed in a single step
via a selenol-catalyzed aryl radical addition to furan. The
(23) (a) Lee, T. D.; Dawes, G. D. J. Org. Chem. 1983, 48, 399-402.
(
1
1
b) Ozawa, F.; Kubo, A.; Hayashi, T. Tetrahedron Lett. 1992, 33, 1485-
2,5-dihydroisomers are byproducts of these reactions as they
488. (c) Ozawa, F.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 1417-
419.
are in the alternative approach employing the Heck reaction
23,24
of arylmercuric salts and aryl triflates with dihydrofuran.
When the substrate is an o-iodophenol the 2-aryl-2,3-
(24) In contrast, we are not aware of any reports of Heck reactions with
either 2,3- or 2,5-dihydrothiophene.
25) The 2,3,4,5-tetrahydro-2,5-epoxy-1-benzoxepin skeleton is found in
(
Nature at the core of the spiroxins, a series of marine-derived potent
antitumor antibiotics, and in averufin, an intermediate in the biosynthesis
of aflatoxin B. (a) Miyashita, K.; Saki, T.; Imanishi, T. Org. Lett. 2003, 5,
2683-2686. (b) Townsend, C. A.; Christensen, S. B.; Davis, S. G. J. Chem.
Soc., Perkin Trans. 1 1988, 839-861 and references therein.
(26) Interestingly, the 2,3,4,5-tetrahydro-2,5-epoxy-1-benzoxepin skeleton
is also formed on Heck reaction of o-hydroxyarylmercuric salts with
dihydrofuran. Holzapfel, C. W.; Williams, D. B. G. Synth. Commun. 1994,
24, 2139-2146.
(
19) We note that the amino group is even better at localizing spin density
than the alkylthio group and that 1-aminoallyl radicals are more localized
on the heteroatom than the corresponding alkylthio and alkoxyallyl
radicals. Griller, D.; Nonhebel, D. C.; Walton, J. C. J. Chem. Soc., Perkin
Trans. 2 1983, 1373-1379.
(
17a
20) Crich, D.; Patel, M. Heterocycles 2004, 64, 499-564.
21) A parallel study of aryl radical addition to pyridine in the absence
(
of selenol. N u´ n˜ ez, A.; S a´ nchez, A.; Burgos, C.; Alvarez-Builla, J.
Tetrahedron 2004, 60, 6217-6224.
(27) 2-Aryl pyrroles may be conveniently accessed by rhodium-catalyzed
arylation of pyrrole. Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc.
2005, 127, 4996-4997.
(22) Ghosh, A. K.; Xu, C.-X.; Kulkarni, S. S.; Wink, D. Org. Lett. 2005,
7
, 7-10.
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