Synthetic approach towards trisubstituted methanes and a chiral tertiary α-hydroxyaldehyde, a possible intermediate for tetrasubstituted methanes

Article abstract of DOI:10.1039/c3ra41826j

A series of trisubstituted methanes containing aryl and heteroaryl rings, as well as a sulfur spacer between the central methano-carbon and benzene ring, is reported. In an approach towards asymmetric tetrasubstituted methane with high enantioselectivity,

Full text of DOI:10.1039/c3ra41826j

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Synthetic approach towards trisubstituted methanes
and a chiral tertiary a-hydroxyaldehyde, a possible
intermediate for tetrasubstituted methanes3
Cite this: RSC Advances, 2013, 3, 12100
Received 16th April 2013,
Accepted 29th May 2013
Priyanka Singh, Subal Kumar Dinda, Shagufta and Gautam Panda*
DOI: 10.1039/c3ra41826j
www.rsc.org/advances
A series of trisubstituted methanes containing aryl and heteroaryl
rings, as well as a sulfur spacer between the central methano-
carbon and benzene ring, is reported. In an approach towards
asymmetric tetrasubstituted methane with high enantioselectiv-
ity, chiral tertiary a-hydroxyaldehyde has been synthesized
through a Sharpless dihydroxylation on a disubstituted olefin,
followed by the chemoselective oxidation of the primary alcohol.
The tetrasubstituted methane, (1S)-1-(1H-imidazol-4-yl)-1-(6-
methoxy-2-naphthyl)-2-methyl-1-propanol 5, a novel inhibitor of
Tri- and tetrasubstituted methanes (TRSMs) are interesting targets,
which have attracted the attention of the synthetic community, not
only for their interesting chemical properties but also for their
pharmaceutical importance.1 For example, they are known to
possess a wide variety of biological activities such as anti-breast
cancer,2 antitubercular,3 antiimplantation,4 antiproliferative5 etc.
Clotrimazole (CLT) 1, a membrane-permeant triarylmethane, is
reported as having antimycotic and antiproliferative activity.6,7
Related trisubstituted methanes such as econazole 2, ketocona-
zole, nifedipine and miconazole are known to have diverse
biological activities.8 Recently, we have reported thiophene-
containing TRSMs 3 which show significant antitubercular
properties.9 The antiproliferative activity of the non-imidazole part
of clotrimazole analogs such as 4 has also been reported10
(Scheme 1). Trisubstituted methanes (TRSMs) containing sulfide,
sulfoxide or sulfone spacers have also been reported to show
various biological activities.11–14
TRSMs have also served as suitable building blocks for the
generation of dendrimers.15 Dendrimers with specific peripheral
functionalities have been used in bioconjugation,16 cross-link-
ing,17 mass spectrometry,18 fluorescence19 and optics.19
Triphenylmethyl (trityl) derivatives, which are also a class of
TRSMs, are widely used as a family of protecting groups in organic
synthesis to transiently block various functional moieties.20
C
17,20-lyase and the key enzyme involved in androgen biosynthesis,
is thought to be a promising target for the treatment of androgen-
dependent prostate cancer7 and is currently involved in clinical
trials.21,22 In spite of its potential bioactivity, only one stereocon-
trolled synthesis22b of compound 5 has been reported so far.
Kawakami and coworkers23 reported the large-scale racemic
synthesis of 5.
In a preliminary communication, we reported an approach
towards the synthesis of TRSMs.24 Herein, we report modified
trisubstituted methanes containing benzene, naphthalene, benzo-
pyran, imidazole and indole groups, and featuring a sulfur spacer
between the central methano-carbon and the other aromatic rings.
We also report a short and elegant approach towards a chiral
tertiary a-hydroxyaldehyde,
asymmetric tetrasubstituted methane 5, applying a Sharpless
dihydroxylation for the introduction of chirality.
To begin with, 4-methoxy phenyl magnesium bromide 7 was
reacted with naphthalene-1-carbaldehyde 6 at room temperature
to generate the carbinol 8 (Scheme 2). It was treated with different
a possible intermediate for the
nucleophiles,
phenol,
thiophenol,
anisole,
aniline,
N-methylaniline, N,N-dimethylaniline to yield 9, 10, 11, 12, 13,
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR,
Lucknow-226001, UP, India. E-mail: gautam.panda@gmail.com;
gautam_panda@cdri.res.in; Fax: 91-522-2623405; Tel: 91-522-2612411-18, Ext.
4385, 4603
Electronic supplementary information (ESI) available: 1H and 13C-NMR spectra for
3
Scheme 1 Biologically relevant trisubstituted methanes (TRSMs).
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all of the new compounds. See DOI: 10.1039/c3ra41826j
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Scheme 3 Reagents and conditions: (a) anisole, PPA, 100 uC, 2 h, 58%; (b) LAH,
THF, 0 uC–RT, 2 h, 83%; (c) phenol, benzene, conc. H2SO4, 55–60 uC, 30 min, 10%
(19) and 24% (20).
synthesis of the benzopyran and imidazole-based TRSMs 21 and
22.
Scheme 2 Reagents and conditions: (a) THF, RT, 30 min, 58%; (b) phenol, conc.
H2SO4, 55–60 uC, 30 min, 55%; (c) thiophenol, conc. H2SO4, 55–60 uC, 30 min, 82%;
(d) anisole, conc. H2SO4, 55–60 uC, 30 min, 59%; (e) aniline, conc. H2SO4, 55–60 uC,
30 min, 55% (13a), 7% (13b); (f) N-methylaniline, conc. H2SO4, 55–60 uC, 30 min,
59% (14a) 9% (14b); (g) N,N-dimethylaniline, conc. H2SO4, 55–60 uC, 30 min, 60%.
Treatment of compound25,26 23 with phosphorus tribromide
afforded 4-bromo-7-methoxy-2,2-dimethyl-2H-chromene 24, which
was obtained as a pale yellow oil in 62% yield. Addition of n-butyl
lithium to 4-bromo chromene 24 in THF at 278 uC under N2 for
10–15 min afforded 4-chromenyl lithium 25, which was then
reacted with para-fluoro benzaldehyde and para-methoxy benzal-
dehyde to give 26a and 26b in 51% and 70% yields respectively
(Scheme 4).
With compounds 26a–b in hand, we proceeded towards the
synthesis of the target compounds 21 and 22. It was decided to
convert the carbinols 26a–b to the bromo derivatives, where the
nucleophilic displacement of bromine by imidazole was expected
to yield 21. Unfortunately, reaction of carbinols 26a–b with
phosphorus tribromide (PBr3) at 0 uC yielded no bromo derivative,
but rearranged products, saturated ketones and exocyclic olefins,
were isolated.27
14 and 15 as the respective alkylated products. Nucleophilic attack
of the phenol and N-methyl aniline occurred through the ortho
and para carbon atoms of the benzene ring respectively to give 9
and 14a as the major products and 10 and 14b as the minor
products. We did not isolate any ortho-substituted product in the
cases of anisole and N,N-dimethylaniline. It is interesting to note
that nucleophilic attack occurred via the sulfur atom onto the
carbinol carbon atom of 8 when thiophenol was used as the
nuclephile. We did not isolate any O-alkylated product when
phenol was used, but a similar S-alkylated product was isolated in
the case of thiophenol.
Friedel–Crafts alkylation of carbinol 8 with anisole and
N,N-dimethylaniline did not give any ortho-substituted products,
possibly due to the steric hindrance between the naphthalene ring
proton and the protons of the methoxy and N,N-dimethylaniline
groups. Sulfur, being a good nucleophile, will prefer to attack the
carbinol in the Friedel–Crafts alkylation, instead of attacking
through a carbon of the benzene core.
To obtain trisubstituted methanes through an alternative
methodology, compound 16 was treated with anisole in the
presence of polyphosphoric acid (PPA) to afford the methanone
derivative 17 in 58% yield. The reduction of the carbonyl group of
methanone 17 with lithium aluminium hydride (LAH) in THF at 0
uC generated the carbinol 18 in 83% yield. Further, Friedel–Crafts
arylation with phenol in the presence of a catalytic amount of
conc. H2SO4, and benzene as the solvent, gave 19 as the minor
product and 20 as the major product by nucleophilic attack of the
phenol through the ortho and para positions respectively on the
carbon atom of carbinol 18 (Scheme 3).
When carbinols 26a–b did not yield the required products, an
alternative strategy was adopted. A literature search revealed that
the hydroxyl group can be replaced by imidazole through
treatment with 1,19-carbonyldiimidazole (CDI).28 Towards this
Since we are involved in the design and synthesis of
biologically-important TRSMs24 as possible non-steroidal aroma-
tase inhibitors, as well as anti-TB agents, we have undertaken the
Scheme 4 Reagents and conditions: (a) PBr3, benzene, 80 uC, 6 h, 62%; (b) n-BuLi,
THF, 278 uC, 15–20 min; (c)
1
h, p-fluoro benzaldehyde, 51%, p-methoxy
benzaldehyde, 70%.
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oxidation of the primary alcohol of 32 was achieved under
standard Swern oxidation conditions to furnish the asymmetric
a-hydroxyaldehyde 33 in 81% yield, which could be an advanced
intermediate for the synthesis of 5 (Scheme 7). The van Leusen
imidazole synthesis,31 a unique multicomponent reaction, may
allow access to novel imidazoles from aldehydes using substituted
TosMIC reagents in the presence of suitable amines. Other
suitable methods may also yield 5 and will be reported elsewhere.
Scheme 5 Reagents and conditions: (a) CDI, THF, reflux, 12 h, 33% (21a) and
31% (21b).
Conclusion
We have developed a very short and easy synthetic route for the
preparation of trisubstituted methanes (TRSMs) containing aryl
and heteroaryl rings, as well as featuring a sulfur spacer between
the central methano-carbon and the aromatic ring. A new
enantioselective synthesis of chiral tertiary a-hydroxyaldehyde,
which could be an advanced intermediate of asymmetric
tetrasubstituted methanes (TRSMs), is developed. Both enantio-
mers of the TRSM could be obtained by varying the ligands in the
Sharpless asymmetric dihydroxylation.
Scheme 6 Reagents and conditions: (a) i) n-BuLi, THF, 278 uC, 15–20 min, ii)
N-benzylated indole-3-carboxaldehyde, 1 h, 50%; (b) CDI, THF, reflux, 12 h, 33%.
objective, 26a–b were refluxed with CDI in THF to afford 21a and
21b in 33% and 31% yields respectively (Scheme 5).
Acknowledgements
The target compound 22 was also synthesized following the
above-mentioned route. 4-Chromenyl lithium 25 synthesized from
bromo derivative 24 was reacted with N-benzylated indole-3-
carboxaldehyde at 278 uC under N2 to give carbinol 27, which was
then converted to 22 by using CDI in THF at room temperature
with 33% yield, (Scheme 6).
This research project was supported by the Department of
Science and Technology (DST), New Delhi, India. Priyanka,
Subal and Shagufta thank CSIR for providing fellowships.
Sailaja IReddy is thanked for the preparation of some of the
starting materials. This is CDRI commn no 8468.
With the aim of accessing asymmetric TRSM-like structures,29
the synthesis of chiral tertiary a-hydroxyaldehyde was undertaken
which could be an advanced intermediate for the synthesis of 5.
The Sharpless dihydroxylation30 was envisaged as a powerful tool
to introduce chirality on disubstituted olefins, a precursor for
asymmetric TRSMs.
The synthesis was initiated with the lithiation of commercially
available 2-bromo-6-methoxy naphthalene 28 with n-BuLi at 278
uC, followed by addition of isobutyraldehyde to yield the benzyl
alcohol 29. The Swern oxidation of 29 provided ketone 30 which,
after a Wittig olefination using methylene triphenylphosphorane
(generated in situ) in THF, generated 31 in 78% yield. The
Sharpless asymmetric dihydroxylation of olefin 31 with AD-mix-
a30,32 in t-BuOH–H2O (1 : 1) at 0 uC for 28 h provided the crude
product which, on recrystallisation twice from EtOAc–petroleum
ether, gave the pure diol 32 in 72% yield with 92% ee. The selective
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