Iodine-Promoted Metal-Free Aromatization: Synthesis of Biaryls, Oligo p-Phenylenes and A-Ring Modified Steroids

Article abstract of DOI:10.1002/adsc.201500303

We describe efficient procedures based on the use of iodine for the synthesis of biaryls from arylcyclohexenols or arylcyclohexanols using sub-stoichiometric/catalytic iodine and dimethyl sulfoxide (DMSO) as oxidant. Heteroarylcyclohexanols also produced the corresponding biaryl products. It was proven that biphenyl can also be efficiently obtained when the quantity of iodine was reduced to 0.05 equiv. The method is compatible with different functional groups in the aromatic ring (either electron-donating or electron-withdrawing groups). For substrate scope, apart from cyclohexanone and cyclohexenone, some substituted cyclohexanones were also used to synthesize the starting arylcyclohexanols. The process was applied to the synthesis of oligo p-phenylenes and A-ring aromatized steroids, where the combined use of I₂/DMSO not only provoked the necessary migration of the methyl group at C-10, but also further extended the conjugation.

Full text of DOI:10.1002/adsc.201500303

UPDATES
DOI: 10.1002/adsc.201500303
Iodine-Promoted Metal-Free Aromatization: Synthesis of Biaryls,
Oligo p-Phenylenes and A-Ring Modified Steroids
Victoriano Domingo,a Consuelo Prieto,a Alexis Castillo,a Lucia Silva,b
JosØ F. Quílez del Moral,a,* and Alejandro F. Barreroa,*
a
Department of Organic Chemistry, Institute of Biotechnology, University of Granada, Avda. Severo Ochoa, s/n, 18071
Granada, Spain
Fax: (+34)-958-243318; phone: (+34)-958-243318; e-mail: jfquilez@ugr.es or afbarre@ugr.es
Department of Chemistry, University of Beira Interior, Rua MarquÞs d’vila e Bolama, 6200 Covilh¼, Portugal
b
Received: March 27, 2015; Revised: July 13, 2015; Published online: October 14, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500303.
Abstract: We describe efficient procedures based
on the use of iodine for the synthesis of biaryls
from arylcyclohexenols or arylcyclohexanols using
sub-stoichiometric/catalytic iodine and dimethyl
sulfoxide (DMSO) as oxidant. Heteroarylcyclohexa-
nols also produced the corresponding biaryl prod-
ucts. It was proven that biphenyl can also be effi-
ciently obtained when the quantity of iodine was re-
duced to 0.05 equiv. The method is compatible with
different functional groups in the aromatic ring
(either electron-donating or electron-withdrawing
groups). For substrate scope, apart from cyclohexa-
none and cyclohexenone, some substituted cyclo-
hexanones were also used to synthesize the starting
arylcyclohexanols. The process was applied to the
synthesis of oligo p-phenylenes and A-ring aromat-
ized steroids, where the combined use of I2/DMSO
not only provoked the necessary migration of the
methyl group at C-10, but also further extended the
conjugation.
gence of methods for the construction of biaryls
[4]
À
based on the activation of aromatic C H bonds or
decarboxylative coupling.[5] However, most of these
processes require the use of transition metals, which
in certain cases is considered undesirable, mainly in
terms of purification of the final products.
Favored by the rapid emergence of green chemistry,
metal-free strategies such as those published by Shi
and others[6] are being reported for the achievement
of different aromatizations. In this regard, iodine
proved to play a key role in the development of
modern synthetic methodologies including some de-
hydrogenative processes.[7] Furthermore, the com-
bined use of substoichiometric iodine and DMSO was
also reported to mediate processes leading to aromat-
ic compounds.[8]
Concerning these iodine-mediated aromatization
processes, and having in mind the known capability of
iodine to dehydrate tertiary alcohols,[9] we reasoned
that iodine could catalyze both the dehydration and
subsequent aromatization of arylcyclohexenols, aryl-
cyclohexanols or heteroarylcyclohexanols to produce
the corresponding biaryl products (Scheme 1). To the
best of our knowledge, to date, no examples of such
a transformation have been reported. Herein we pres-
ent the results reached when this strategy was imple-
mented.
Keywords: aromaticity; biaryls; iodine; metal-free
reaction; steroids
Biaryls are “privileged structures” that occur widely
For operational simplicity, precursors 1, 3, 5, 7 and
in different forms in such areas as the pharmaceutical 9 were obtained by 1,2 addition over cyclohexenone
industry, natural products and electronic materials.[1] (25 mL, ca. E60) or cyclohexanone (500 mL, ca. E29)
An increase in the number of aromatic rings origi-
nates p-polyphenes, substances that are considered to
possess interesting applications in molecular electron-
ics and other related emerging areas.[2]
A number of methods for the synthesis of biaryls
have been reported, among which the palladium-cata-
lyzed cross-coupling reactions are the most widely ap-
plied.[3] Also worthy of being underlined is the emer- Scheme 1. Working hypothesis.
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Victoriano Domingo et al.
of the corresponding aryllithium or magnesium coun- duced, we treated 1 with 0.05 equiv. of iodine and
terpart. Using arylcyclohexanol 1 as model, extensive DMSO and, remarkably, biphenyl 2 was generated in
work was performed in order to find the optimal reac- 82% yield after 3 h.
tion conditions. Thus, it was found that the combined
The results summarized in Scheme 2 show that the
use of 0.2 equiv. of iodine and DMSO as oxidant ena- iodine-DMSO method is compatible with the elec-
bled the aromatization of 1 to proceed efficiently, and tron-withdrawing group CF3 in 4, an important group
a 93% yield of biphenyl 2 was obtained after 1 h of in medicinal chemistry. Electron-donating groups
reaction in refluxing toluene (Scheme 2). No dry sol- gave positive results as well (6, 8 and 10). The me-
vent was required and the reaction took place without thoxy group was perfectly tolerated and no demethy-
an inert atmosphere. The starting material remained lation was observed. Finally, the reaction could be
unaltered with polar solvents such as methanol or successfully applied to the generation of heterobiaryls
water due essentially to the lack of solubility of our 12, 14 and 16.[11] Although the results obtained with
starting material. When the quantity of I2 added to the pyridine derivative 12 were only modest, it de-
1 was 100 mol%, only decomposition of the starting serves to be noticed that no trace of this biaryl deriva-
material was observed, which could be attributable to tive was obtained in a protocol described recently by
the generation of HI in the reaction medium. The use Li using DDQ.[12]
of other iodine species such as KI produced no aro-
Encouraged by these results, we applied this sub-
matization of the starting material. Finally, it was also stoichiometric in iodine protocol to the generation of
found that no positive results were found with other biaryls from the corresponding arylcyclohexanols
oxidants such as O2 or TBHP.[10] In order to ascertain (Scheme 2). Gratifyingly, excellent yields were also
to what extent the quantity of iodine could be re- obtained for the synthesis of biaryls 2, 4, 8, 10, 16 and
23 although more prolonged reaction times were re-
quired for the reactions to be completed, when com-
pared with the arylcyclohexenol derivatives. The pres-
ence of a bromo substituent in the aromatic ring was
also tolerated in this aromatization process (23),
À
which facilitates further C C bond forming processes.
With the aim of checking if the overall transforma-
tion could be achieved in one pot, we treated the in
situ prepared p-methoxyarylcyclohexenol 9 with I2-
DMSO, and no reaction was observed. No evolution
was also observed after addition of 1 equiv. of H2O
(added to protonate the alkoxy intermediate). The de-
sired transformation was only produced when 1 equiv.
of p-TsOH was added to the reaction media, and the
expected biaryl 10 was thus obtained in 78% yield
after 10 h.
A plausible mechanism that rationalizes the genera-
tion of biaryls using the iodine-DMSO system is
shown in Scheme 3, although the involvement of car-
bocationic intermediates (e.g., I) whose generation at
the benzylic position is favored should not be discard-
ed.
The detection of the corresponding arylcyclohex-
enes during the formation of these biaryls supports
the suggested mechanism. Furthermore; it was noted
that the aromatization can take place even when the
double bond was not placed at the benzylic position,
which could be considered as an expansion of the
scope on this protocol. Thus, commercial 3-cyclohex-
en-1-ylbenzene was converted into biaryl 2 in 65%
yield when treated with the I2/DMSO system
(Scheme 4).[13] This fact was confirmed when the can-
nabinoid derivative 24 was found to give 25 in a 72%
yield after 65 h (Scheme 4). The inertness of different
functions is an additional advantage of this dehydro-
genation reaction. In a related process, Stahl has re-
Scheme 2. Scope of iodine-promoted aromatization: synthe-
sis of biaryls.
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Iodine-Promoted Metal-Free Aromatization: Synthesis of Biaryls
Scheme 5. Iodine/DMSO-based aromatizations of fluoro,
chloro and cyano derivatives.
needed to promote the dehydration step. However,
whereas the cyano derivative 28 evolved to the corre-
sponding cyanobiaryl 29, the halo derivatives 26 and
27 produced biaryl 2. This result can be rationalized
on the basis of the mechanism proposed for this
iodine-promoted formation of biaryls (Scheme 3),
thus the elimination of HCl and HF is postulated in
the generation of biphenyl 2.
Scheme 3. Mechanism proposed for the iodine-promoted
formation of biaryls.
At this point, and taking profit of the ready com-
mercial availability of 4-phenylcyclohexanone and dif-
ferent aryl dibromides o diaryl bromides, we reasoned
that this iodine-catalyzed process could be easily ap-
plied to the synthesis of oligo p-phenylenes and other
polyaromatic structures.[15] As with biaryls, most of
the methods reported for the synthesis of these sys-
tems are mediated by metals.[2c,16]
Starting 30, 33, 35 and 37 were obtained as mixture
of diatereomers.[17] Treatment of these mixtures with
the I2/DMSO system led to the production of terphen-
yl (31), quaterphenyl (34), sexiphenyl[18] (36) and bi-
phenylnaphthalene 38 in good yields (Scheme 6). Fi-
nally, it should be noted that the synthesis of 31 and
36 involved a double dehydration-dehydrogenation
process.
Scheme 4. Iodine-promoted aromatization of substituted ar-
ylcyclohexenes.
The recent interest of organic chemists in modified
cently reported the Pd-catalyzed dehydrogenation of steroids[19] to evaluate their pharmaceutical relevance
cyclohexenes to afford the corresponding arenes.[14]
prompted us to study the behavior of the arylcyclo-
To gain more data about the scope and limitations hexanol 39 generated by addition of aryllithium to
of the work, we tested arylcyclohexanols 26–28 with testosterone. Although the aromatization of cyclohex-
functional groups fluoro, chloro and cyano anol 39 should involve a migration of the methyl
(Scheme 5), prepared from the corresponding cyclo- group at C-10, some examples including iodine-medi-
hexanones. In all three cases, catalytic p-TsOH was ated rearrangement in the aromatization of friedoo-
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Victoriano Domingo et al.
Scheme 6. Synthesis of oligo p-phenylenes and biphenylnaphthalene 38.
leadienes or labdanes were previously reported.[20] the action of I2 on diene I would provoke to the gen-
Gratifyingly, the treatment of 39 with I2/DMSO not eration of 1,3,5-trienic intermediate IV. A new addi-
only provoked the necessary migration of the methyl tion of I2 would cause methyl rearrangement from C-
group at C-10, but also further extended the conjuga- 10 to C-1 via carbocation VI to give VII. Then, VII
À
tion to C-6 C-7 to produce the biaryl 40 in acceptable would evolve to biphenyl derivative 40 via HI elimi-
yield (Scheme 7). The migration to C-1 supports the nation.
previously suggested intermediacy of carbocationic
species.
Finally, we were intrigued to invesitagte the behav-
ior of allylic alcohol 41 – obtained from direct reduc-
A plausible mechanism for the formation of 40 is tion of testosterone, when treated with I2/DMSO. In
depicted in Scheme 8. Once starting 39 is dehydrated, the event, aromatization of the A-ring took placed
again after migration of the methyl group at C-10,
and compound 42 was produced as major product
(Scheme 7). Most remarkably the fully conjugated al-
dehyde 43 was also generated in this process, although
in very low yield (8%). The production of aldehyde
43, where up to eight new unsaturations were formed,
supports the high potentiality of this method.
In conclusion, we have found a new metal-free way
of constructing biaryls or heterobiaryls from both ar-
ylcyclohexenols and arylcyclohexanols,
a process
which also has a potentially wide range of applica-
tions in the construction of molecular electronics or
drug design. Thus, the method was applied to the for-
mation of different oligo p-phenylenes. Experimental
conditions using 0.2 equiv. of iodine and DMSO as
oxidant were obtained for the preparation of these
biaryls, although it was found that biphenyl 2 can also
be efficiently obtained from
1 by using only
0.05 equiv. of iodine. Finally, iodine also proved to
mediate the dehydrogenation of testosterone deriva-
tives 39 and 41 to afford A-ring aromatized steroids.
Scheme 7. Iodine/DMSO-based aromatizations of testoster-
one derivatives.
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Iodine-Promoted Metal-Free Aromatization: Synthesis of Biaryls
Scheme 8. Mechanism proposed for the iodine-promoted formation of biphenyl 40.
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General Procedure for the Aromatization Promoted
by Iodine/DMSO
To
a solution of the corresponding starting material
(1 mmol, 1 equiv.) in toluene (0.1M) heated under reflux
was added iodine (0.2 equiv.) and DMSO (5 equiv.). The so-
lution was stirred at reflux and monitored by thin-layer
chromatography analysis. Upon consumption of the starting
material the reaction was diluted in t-BuOMe (100 mL),
washed with a saturated solution of sodium thiosulfate (1”
100 mL), and brine (1”100 mL). The organic layer was
dried over sodium sulfate and evaporated under vacuum.
Purification was performed by silica gel chromatography to
yield chromatographically and spectroscopically pure prod-
uct.
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Acknowledgements
Financial support for this work was provided by the Junta de
Andalucia (P08-FQM-3596) and Ministerio de Economía y
Competitividad (CTQ-2010-16818). Marta Torres is thanked
for the preparation of 24.
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