A dehydrative arylation and thiolation of tertiary alcohols catalyzed by in situ generated triflic acid - Viable protocol for C–C and C–S bond formation

Article abstract of DOI:10.1016/j.tet.2018.09.009

The title paper discusses a mild strategy for an efficient C–C and C–S bond formation through ortho-quinone methide intermediate. A total of 29 examples (23 tetrasubstituted methanes with a quaternary carbon center and 6 triarylmethyl thioarenes) with diverse substitution patterns could be prepared in high yields (up to 82%). Use of indium triflate allowed the transformation to be carried out in an open flask without taking special care leaving water as the only by product. Control experiments revealed that the triflic acid generated in situ from indium triflate, probably through the coordination with substrate, acted as the actual catalyst for the transformation. Further this protocol can be utilized for the synthesis of promising bioactives such as CDRI-830 analogues, dihydrochromeno[2,3-b]indoles and 9-(1H-indol-3-yl)-9-phenyl-9H-xanthen-1-ol.

Full text of DOI:10.1016/j.tet.2018.09.009

Accepted Manuscript
A dehydrative arylation and thiolation of tertiary alcohols catalyzed by in situ
generated triflic acid - Viable protocol for C-C and C-S bond formation
Deblina Roy, Gautam Panda
PII:
S0040-4020(18)31064-0
10.1016/j.tet.2018.09.009
TET 29781
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 May 2018
Revised Date: 1 August 2018
Accepted Date: 4 September 2018
Please cite this article as: Roy D, Panda G, A dehydrative arylation and thiolation of tertiary alcohols
catalyzed by in situ generated triflic acid - Viable protocol for C-C and C-S bond formation, Tetrahedron
(2018), doi: 10.1016/j.tet.2018.09.009.
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ACCEPTED MANUSCRIPT
A dehydrative arylation and thiolation of tertiary alcohols catalyzed by in situ generated
Triflic Acid - Viable protocol for C-C and C-S Bond Formation
Deblina Roy and Gautam Panda*
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sitapur Road,
Jankipuram Extension, Lucknow-226031, UP, India
Abstract
The title paper discusses a mild strategy for an efficient C-C and C-S bond formation through
ortho-quinone methide intermediate. A total of 29 examples (23 tetrasubstituted methanes with a
quaternary carbon center and 6 triarylmethyl thioarenes) with diverse substitution patterns could
be prepared in high yields (up to 82 %). Use of indium triflate allowed the transformation to be
carried out in an open flask without taking special care leaving water as the only by product.
Control experiments revealed that the triflic acid generated in situ from indium triflate, probably
through the coordination with substrate, acted as the actual catalyst for the transformation.
Further this protocol can be utilized for the synthesis of promising bioactives such as CDRI-830
analogues, dihydrochromeno[2,3-b]indoles and 9-(1H-indol-3-yl)-9-phenyl-9H-xanthen-1-ol.
Introduction
Compounds having unsymmetrical 1,1-diaryl motif have been found to be very important class
1
of molecules from medicinal chemistry perspective. These types of molecules have shown wide
1
,2
3
4
variety of bioactivities like analgesics, (1) antiarrhythmics (4), anticancer (3), antitubercular
(
5
6
6), antifungal (5), etc (Fig. 1). Moreover, the thioether compounds (5) and triarylmethane (6)
having such unsymmetrical 1,1-diaryl motif developed by us, showed significant antimalarial
5
,7
and antitubercular activity respectively. Also, tetraaryl methanes, another class of molecules
having the unsymmetrical 1,1-diaryl motif have been found to be important molecules for drug
8
9
delivery and been used to detect protein translocation. As the pharmaceutical industry ventures
into new disease areas and new target classes, unexplored molecules having unique shape and
1

ACCEPTED MANUSCRIPT
1
0
binding properties like tetra substituted methanes and thioethers with such unsymmetrical 1,1-
diaryl motif might be found useful.
Figure-1 Some bioactive compounds with unsymmetrical 1,1-diarylmethyl groups.
1
1
The methods used to synthesize the tetraarylmethanes involve Friedel Crafts arylation,
1
2
nucleophilic addition of organometallic reagents to benzophenone derivatives, transition metal
catalyzed C-H arylation of 4-benzyl pyridines, triarylmethanes and heteroarylmethanes, cross
dehydrogenative coupling between triarylmethanes and an arene . However, the reported
protocols suffer from various limitations like harsh reaction conditions, providing mixture of
inseparable regioisomeric products as well as multistep organic synthesis etc.
1
3
14
1
5
From green chemistry perspective, alcohols are ideal electrophiles since most of them are
nontoxic, cheap, readily available, air, light and moisture stable and on substitution leave water
1
6
as the sole by product. Recently we reported indium triflate as a mild Lewis acid catalyst for
the Friedel Crafts alkylation of bis-benzylic alcohols with electron rich arenes for the synthesis
2

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1
7
of unsymmetrical triarylmethanes with water as by product. Continued research to develop
biologically important scaffolds derived from tetrasubstituted methanes and triarylmethyl
thioarenes, we report here an efficient C-C and C-S bond formation strategy with indium triflate
as a mild Lewis acid catalyst through the intermediate formation of ortho-quinone methides
(Scheme 1).
Scheme 1 Synthesis of Tetraarylmethanes. (a) sequential C-H arylation, (b) arylation of 4-benzyl
pyridine and (heteroaryl)diphenylmethanes to yield tetraarylmethane derivatives, (c) Friedel-crafts
arylation through “O”-quinone methide intermediate.
Results and Discussions
Initially, we investigated the C-C bond formation reaction between the tertiary alcohol (7a) with
1
8
indole (8) using various reaction conditions (Table-1). Interestingly, along with the desired
triarylethane product (9(i)), the corresponding elimination product (10) was also obtained albeit
in moderate amounts. We further screened various mild Lewis acid catalysts like copper (II)
halides (chloride, bromide, iodide), copper (II) triflate, copper(II) acetate, indium(III) triflate,
scandium triflate in different types of solvents like dichloromethane, toluene, water, ethanol,
THF (Table-1) for this C-C and C-S bond formation reaction. However, most of the applied
catalysts proved to be ineffective (Table-1 entries1-7). However, scandium (III) triflate and
indium (III) triflate showed some catalytic activity with indium (III) triflate was found to be a
3

ACCEPTED MANUSCRIPT
superior one. Next the catalyst loading was optimized and it was found 10 mol% of the Lewis
acid to be optimal. Applying both lower and higher loadings of indium (III) triflate resulted in
decreased yields. Further, various other reaction parameters like solvent, temperature etc. were
optimized. Of all the solvents screened, THF was found to be the best. Interestingly, the reaction
could be carried out at room temperature, in an open flask without taking any special care and
when it was carried out in THF at room temperature, the desired tetraaryl methane with the
quaternary center could be obtained in very good yield (82% yield). Reaction at higher
temperature probably promotes the elimination reaction.
a
Table -1 Optimization Studies
Entry
Lewis Acid
used (mol %)
Solvent
Temp.
Time
% Yield (isolated
through PTLC)
b
1
CuBr
2
(10)
Dichloromethane
RT
2h
n.r.
b
2
3
4
CuCl (10)
Dichloromethane
Toluene
RT
RT
RT
2h
2h
2h
n.r.
2
b
CuBr
2
(10)
n.r.
b
CuCl
2
(10)
Toluene
n.r.
b
5
6
CuI (10)
Toluene
Toluene
RT
RT
2h
2h
n.r.
2
b
Cu(OAc)
2
(10)
n.r.
b
7
8
9
Cu(OTf) (10)
Toluene
Toluene
Toluene
RT
RT
RT
RT
2h
2h
n.r.
2
In(OTf) (10)
60%
Trace
65%
3
Sc(OTf) (10)
2h
3
1
0
In(OTf) (10) Dichloromethane
30min
3
b
1
1
1
2
In(OTf) (10)
Water
EtOH
RT
RT
2h
2h
n.r.
3
In(OTf) (10)
50%
82%
70%
3
1
3
In(OTf) (10) Tetrahydrofuran
RT
15min
3
o
1
4
In(OTf) (10)
Tetrahydrofuran
55 C
15min
3
4

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a
Reaction Conditions : All reactions were performed with 0.089 mmol of 7a in solvent and
.098 mmol of 8. RT = Room Temperature. THF = Tetrahydrofuran. n.r. = No Reaction.
b
0
Under the optimized reaction conditions, the desired C-C and C-S bond formation with various
arenes and thiol nucleophiles were attempted (Scheme-2).
As evident from Scheme-2, both electron rich as well as electron poor carbinols were well suited
for the C-C and C-S bond formation giving a wide array of tetraarylmethanes and triarylmethyl
thioarenes respectively. Gratifyingly, we could prepare the indole derivatives with bulky phenyl
group at the second position like in (9xviii) to (9xxiii), thus highlighting the protocol to be
tolerant to the steric effects of the nucleophile. Importantly, the reaction of the carbinol (7) with
5
-fluoroindole and 4-fluorothiophenol gave the corresponding 1,1,1-triarylethanes and
triarylmethyl thioarenes respectively having the important fluoro substituents in good yields;
thus highlighting the applicability of the products in the drug discovery regime. Fluoro
compounds provide additional point of binding to the receptor protein and are considered to be
1
9
an important substituent in the drug discovery program. Furthermore, the reaction of the
carbinol (7) with 4-bromothiophenol gave the corresponding triarylmethyl thioarene with a
handle for further diversification with various iterative metal catalyzed cross-coupling reaction.
After the successful preparation of the indole derivatives and the triarylmethyl thioarenes, we
became interested in the preparation of more challenging 1,1,1-triarylethanes, tetraarylmethanes
containing all arene rings and also other heteroaromatic arenes. Though, we were successful in
preparing furan containing triarylethanes and teraarylmethanes (compound (9(xi)) and (9(xx) in
Scheme 2), less nucleophilic arenes like 1,3,5-trimethoxy benzene, cresol, thiophene, pyrrole,
benzothiophene, benzofuran did not give rise to the desired 1,1,1-triarylethanes,
tetraarylmethanes and instead gave the corresponding elimination product as the sole product or
were unchanged during the course of the reaction when we treated the carbinol (7) with those
respective arenes.
*
Substrate scope
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Me
NH
CH3
NH
NH
CH3
NH
N
Br
MeO
Br
CH3
CH3
CH3
HO
OH
9(v),79%
HO
HO
HO
9(iv),75%
9(ii),60%
9
(iii),70%
9(i),82%
MeO
NH
NH
CH3
F
O
NH
CH3
O
CH3
NH
Me
CH3
OH
OH
9(ix),80%
OH
OH
9(vii),74%
9
(viii),79%
9(vi),75%
CH3
NH
CH3
NH
CH3
Br
NH
O
3HC
CH3
H C
3
MeO
OH
HO
OMe
MeO
OH
HO
OMe
9(xiii),80%
9(x)79%
9(xi), 73%
9(xii), 79%
CH3
NH
CH3
NH
NH
CH3
MeO
MeO
N
O
F
Br
CH3
CH3
OH
MeO
MeO
OH
9(xv), 78%
OH
(xvii) 75%
MeO
OH
9
9
(xiv), 75%
9
(xvi),72%
*
Isolated yields; reactions conducted on a 0.1mmol scale using In(OTf) (10 mol%), 7(1 eqiv)
3
8
(1 equiv) in THF at Room temperature.
6

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Scheme 2 Scope of synthesis of the proposed dehydrative arylation and thiolation of ortho-
hydroxy tertiary alcohols with indoles, arenes, and heteroarenes.
During further elaboration of the methodology towards C-N bond formation using nitrogen
containing nucleophiles like piperidines, morpholines, we observed though the addition of Lewis
acid catalyst to the starting carbinol generated the ortho-quinone methide, further addition of
nitrogen nucleophile did not give any product. Further, treatment of the starting carbinols with
the Lewis acid catalyst and the indole nucleophile in presence of the sterically hindered nitrogen
base also did not give any product. Intrigued with such observations, we put various control
reactions to gain insights into the reaction pathway. At first we investigated whether the metal
triflates acted as Lewis acid catalysts or generated traces of proton which acted as Bronsted acid
2
0,21,22
catalyst for the title transformation (“hidden Bronsted acid” catalysis).
Towards that goal
we first carried out the reaction of carbinol (7c) with 10 mol% triflic acid in otherwise similar
reaction conditions with (8) as the nucleophile to obtain the tetraarylmethane 9(xviii) with
7

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similar yield in the same reaction time. This indicates that the reaction could be carried out with
Bronsted acid catalysis also. The reaction of the carbinol (7c) with 10 mol% triflic acid in
presence of a non coordinating proton scavenger 4-methyl 2,6-ditertbutyl pyridine (11) with
indole (8) as the nucleophile gave the triarylethane 9(xviii) in much lower yield and requires
prolonged reaction time. Further, the reaction of the carbinol (7c) with 10 mol% indium triflate
in presence of the proton scavenger 4-methyl 2, 6-ditertbutyl pyridine with (8) as the nucleophile
did not give the desired tetraarylmethane product. These results strongly indicated traces of triflic
2
3
acid generated from metal triflates acted as the active catalysts for the reaction. Furthermore,
with the tertiary carbinol (7d) {the methoxy analogue of the carbinol (7c)} and indole
nucleophile under otherwise similar reaction conditions, no product was observed (Scheme 3)
indicating the important role of the hydroxy group in the coordination of the indium triflate with
the substrate. Furthermore, when we added in situ generated benzyne to the mixture of the
tertiary carbinol (22) and indium triflate; the Diels Alder cycloaddition product (12) could be
generated (Scheme 3) and characterized. Recently, the Diels Alder cycloaddition of
orthoquinone methides and benzynes have been established as a viable strategy for the
2
4
preparation of 9-aryl xanthenes. This indicated the intermediate formation of the ortho-quinone
intermediate during the course of the reaction. So mechanistically the reaction may follow the
following route, at first coordination of the carbinol with indium triflate may result in the
generation of triflic acid which acted as the active catalyst and protonated the carbinol to
generate the quinone methide intermediate. The o-quinone methide intermediate, thus generated
participated in 1,4-Michael type addition reaction sequence to give the observed product
(Scheme 3).
8

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"
In(OTf)3
R2
TfOH as active catalyst" (hidden Bronsted acid catalysis)
HO R2
Ph
Ph
R2
OH
R2
R1
OH
OH
OTf
OH
TfOH
R1
O
R1
In(OTf)2
Int-1
In(OTf)2
OTf
TfOH
Ph
OH
Ph
R2
R2
OH2
OTf
Ph
+
H O
2
O
R1
O
O
R1
R1
In(OTf)2
In(OTf)3
In(OTf)2
R2
R2
Nu
Ph
Ph
NuH
R1
O
R1
OH
With Bronsted Acid
HN
With Lewis acid
Indole(8)
Indole(8)
10 mol% In(OTf)3
TfOH (10 mol%)
Ph
9
(xviii)
THF, RT, 30 min
THF, RT, 30 min
MeO
8
2 % yield
OH
OH
(xviii)
OMe
Ph
9
MeO
OH
OMe
Indole(8)
In(OTf)3
7c
Indole(8)
(10 mol%)
TfOH (10 mol%)
No reaction
Trace
THF, RT, 30 min
-Methyl 2,6-
tertbutyl pyridine
THF, RT, 30 min
4-Methyl 2,6-
tertbutyl pyridine
(10 mol%)
4
(10 mol%)
OH
Ph
H
N
In(OTf) (10 mol%)
3
No reaction
+
THF, RT, 30 min
MeO
O
OMe
8
7d
In(OTf) (10
3
TMS
OTf
O
CsF (4eq)
THF
mol%)
O
Ph
OH
Ph
THF
Ph
OH
2
O
O
2
12
(
ortho-quinone methide
intermediate)
9

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Scheme 3 Plausible reaction mechanism.
To further demonstrate the applicability of the protocol towards development of new bioactive
molecules, we subsequently converted the tetraaryl methane compound (16) into an analogue of
CDRI-S-006-830 through synthetic steps (Scheme 4a). Thus 16 was reacted with triflic
anhydride using pyridine as a base in DCM to give (16) in moderate yield (60%). The triflated
compound (17) was then subjected to a global deprotection strategy involving debenzylation and
removal of triflate group to give compound (18) in 55% yield which was converted to the CDRI-
S-006-830 analogue (19) in overall yield 9% (total 6 steps) by treating with the dialkyl
aminoethyl chain in presence of a base in refluxing acetone. Also few tetraaryl methanes were
converted to biologically important indole containing compound dihydrochromeno[2,3-b]indole
(20) derivatives in one step using the selective flourinating agent F-TEDA in 50% yield and the
tetraarylmethane 9,9-diarylxanthene (23) in 80% yield (Scheme 4b and 4c).
10

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Scheme 4 Synthesis of bioactive molecules [a) Synthesis of S-006-830, b) Synthesis of
dihydrochromeno[2,3-b]indole derivative, c) Synthesis of 9,9'-diarylxanthene utilizing our
protocol.
11

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Conclusion
For the synthesis of tetraaryl methanes and triarylmethylthioarenes having quaternary benzylic
stereocenters, we have developed an efficient strategy using tertiary benzylic alcohols as the
starting material involving the intermediate formation of the ortho-quinone methide. The method
is operationally simple, occurs in an open flask leaving behind water as the sole by product
giving a diverse set of unsymmetrical tetraarylmethanes in high yields. The prepared
tetraarylmethanes could further be converted to some interesting biologically important
molecules like CDRI-S-006-830 analogue, dihydrochromeno[2,3-b]indole derivative and 9,9'-
diarylxanthene. Preliminary mechanistic studies proved triflic acid generated in situ from metal
triflates acted as the active catalyst for the generation of an orthoquinone methide intermediate,
which takes part in the arylation/thiolation reaction. Application of this protocol for the
synthesis of various other bioactive natural and unnatural products are currently underway in our
lab and will be reported in due course.
Acknowledgements
This work was supported by MoES (09-DS/3/201P5C –IV), New Delhi, India. Instrumental
facilities from SAIF, CDRI are highly acknowledged (CDRI Communication No. xx)
1
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