Metal-free, high yielding synthesis of unsymmetrical biaryl, bi(heteroaryl), aryl vinyl, aryl alkyl sulfones via coupling of aryne with sulfinic acid salts

Article abstract of DOI:10.1039/c4ra07370c

Here, we report a metal-free, high yielding method for the synthesis of unsymmetrical biaryl sulfones via coupling of aryne with sulfinic acid salts. The optimized condition also works efficiently for bi(heteroaryl), aryl vinyl and aryl alkyl sulfones. The present method took comparatively shorter reaction times and has good functional group compatibility. This journal is

Full text of DOI:10.1039/c4ra07370c

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Metal-free, high yielded synthesis of
unsymmetrical biaryl, bi(heteroaryl), aryl vinyl,
aryl alkyl sulfones via coupling of aryne with
sulfinic acid salts
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Sravan Kumar Aithagani,1,2 Kushalava Reddy Yempalla,1,2 Gurunadham
Munagala,1,2 Ram A. Vishwakarma1,2 and Parvinder Pal Singh1,2,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Here, we have reported metal-free, high yielded method for
Initially,
we
have
chosen
2-(trimethylsilyl)phenyl
the synthesis of unsymmetrical biaryl sulfones via coupling of trifluoromethanesulfonate 1a, the benzyne precursor and benzene
benzyne with sulfinic acid salts. The optimized condition also
works efficiently for bi(heteroaryl), aryl vinyl and aryl alkyl
sulfones. The present method took comparatively lesser
reaction times and has good functional group compatibility.
Organosulfones represent an important class of compounds
because of their presence in many bio-active molecules1 as well as
their chemical properties.2 Organosulfones are known for their; i)
medicinal properties viz., dapsone (
anti-androgen),1e eletriptan anti-migraine),1f mesotrione
herbicide);1g ii) antagonist properties
and
receptor antagonist)1h,1i and iii) enzyme inhibitory properties (
non-nucleoside reverse transcriptase inhibitor).1j Very recently, aryl
vinyl sulfones were reported as potent neuroprotective agents for
A
, as anti-bacterial),1d casodex (
B
,
(
C
,
(
D
,
(
E
F
,
serotonin 5-HT6
, HIV-1
G
H
the treatment of Parkinson’s disease.1k In addition to this, aryl alkyl
and heteroaryl alkyl sulfones are also used as synthons3 in the organic
transformations such as Julia-olefination4 and Ramberg-Backlund
rearrangement.5
Fig 1: Examples of important sulfones
-sulfinic acid sodium salt 2a as standard substrates to optimize
suitable conditions for this reaction (Table 1). The reaction of 1a with
2a in the presence of CsF in CH3CN solvent at room temperature for 12
h under nitrogen atmosphere provided biaryl sulfone 3a in 75% yield
(Table 1, entry 1). The best yield (85%) was obtained upon increasing
the temperature from rt to 80 oC in CsF (Table 1, entry 2), this effect
may be due to the rate of reaction was enhanced by increasing the
temperature. A similar result was achieved when the reaction was
performed under oxygen atmosphere (Table 1, entry 3) ruled out the
possibilities of involvement of radical intermediacy. Upon switching
the fluoride source to KF/18-crown-6 and TBAF, comparatively slightly
lesser yield of coupled product 3a was obtained (Table 1, entry 4 and
5). Keeping the fluoride sources KF/18-crown-6 and TBAF constant
and by changing the solvent CH3CN to THF, also didn’t give any
improvement (Table 1, entry 6 and 7).
Traditionally organosulfones were prepared either by oxidation of
sulphides6a or by sulfonation of arene in the presence of strong acid.6b
Keeping in view the importance of organosulfones, several metal-
catalysed methods have been developed.7 However, emergence of
metal-free synthesis is the choice of interest these days and therefore
attempts have also been made to develop metal-free synthesis of
organosulfones as shown in Fig 2.8 These methods are specific to
some particular class among the diverse range of organosulfones.
Moreover, benzyne mediated organic synthesis has attracted the
attention and have been extensively explored in last decade for the
diverse range of organic synthesis.9 In this present study, we have
explored first time the use of reactive benzyne intermediates for the
synthesis of unsymmetrical biaryl, bi(heteroaryl), aryl vinyl, aryl alkyl
sulfones.
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DOI: 10.1039/C4RA07370C
With the optimized reaction conditions established, we next proceeded smoothly and gave the corresponding diarylsulfone 3b
explored the scope of the various sulfinic acid sodium salts and all the with 88% yield. Mesitylene sulfinate gave the corresponding coupled
results are summarized in Table 2. Firstly, benzene sulfinic acid product 3c with 55% yield, the comparatively lower yield might be due
sodium salt when treated with benzyne precursor (1a) afforded the to steric hindrance. To our delight, methoxy substituted benzene
desired product in 85% yield (3a). Moreover, aryl sulfinates bearing
sulfinates gave the corresponding products in an excellent yields of
coupled
products
(
3d-3f).
Additionally,
also
sodium
2,3-
the
Maloney and Kuethe's approch 2011
dihydrobenzo[b][1,4]dioxine-6-sulfinate
provided
X
SO2R
corresponding product 3g in 80% yield. On the other hand, electron-
TBACl
DMAc
+
NaO2SR
N
N
OTf
CsF, CH3CN
Yadav's approach 2012
SO2R2
R-SO2Na
R-SO2Ph
80 oC, 2-3 h
O
LiBr
H2O
TMS
R1
+
R = Aryl, Heteroaryl, CF3, Vinyl
NaO2SR2
+
1a
SO2Ph
2
3a-p
R1
SO2Ph
SO2Ph
SO2Ph
CH3
R1
SO2R2
Manolikakes's approach 2013
H3C
I+
O
DMF
+
R2
NaO2SAr
DMSO,
Ar1-S-Ar2
O
R1
OCH3
CH3
CH3
Chen and Yu's approach 2013
(3d, 92%)
(3a, 85%)
(3b, 88%)
(3c, 55%)
Y
Y
NaO2SR2
+ NaO2SR2
R1SO2Na
R1
+
SO2R2
X
R1
SO2Ph
SO2Ph
SO2Ph
110 O
C
Z
Z
O
SO2Ph
Cl
Deng's approach 2014
OCH3
O
OCH3
I2, TBHP
SO2R2
R1
R1
N
H
N
Cl
OCH3
(3f, 95%)
SO2Ph
H
(3g, 80%)
(3e, 86%)
(3h, 55%)
Present Approach
SO2Ph
O
S
SO2Ph
CsF, CH3CN
80 oC, 2-3 h
R1
SO2Ph
+
R
R
O
R1 = Aryl, Heteroaryl, Styryl, Alkyl, CF3
CF3
F
Fig 2: Previous and present approaches for the synthesis of sulfones
NHCOCH3
(3l, 75%)
(3k, 82%)
(3i, 82%)
(3j, 80%)
SO2Ph
NO2
SO2Ph
SO2Na
SO2CF3
S
OTf
SO2Ph
SO2Ph
F
N
conditions
TMS
MeO
NO2
(3n, 0%)
1a
2
(3p, 80%)
3a
(3o, 66%)
(3m, 50%)
F- source
Solvent Temp (oC), Time (h)
Yieldb (%)
Entry
aReaction conditions: Aryne precursor 1a (0.25 mmol, 1.0 equiv), arene
sulfinic acid sodium salt 2 (0.5 mmol, 2.0 equiv), CsF (1.0 mmol, 4.0
equiv), solvent 4 ml, 80 oC, under N2.
75
rt, 12
CH3CN
CsF
1
Table 2: Coupling of different sulfinic acid salts with benzynea
85
2
CsF
80, 2
CH3CN
3c
4
82
62
CH3CN
CH3CN
CH3CN
THF
80, 3
80, 5
CsF
-withdrawing groups containing aryl sulfinates gave corresponding
coupled products with moderate to good yields. When 2,4-dichloro
benzene sulfinic acid sodium salt was subjected to the reaction, 55%
yield of the corresponding biaryl sulfones 3h obtained. 4-F and 4-CF3
benzene sulfinates were also proceeded well and afforded the desired
products 3i and 3j with 82%, 80% yield respectively. To verify the vast
substrate scope of this method we have chosen different (naphthyl,
acetamido, trifluoromethyl) sulfinates, which also gave respective
KF/18-crown-6
83
65
5
6
TBAF
80, 5
70, 5
KF/18-crown-6
80
THF
7
70, 5
TBAF
a Reaction conditions (unless otherwise stated): 1a (0.25 mmol, 1.0
equiv), 2a (0.5 mmol, 2.0 equiv), F- source (1.0 mmol, 4.0 equiv), solvent
4 ml, under N2; b Isolated yield.
coupled products 3k-3m with good yields. Nevertheless, when di-nitro
c Reaction was done in presence of oxygen.
Table 1: Optimization studiesa
substituted sulfinate 3n was used no reaction took place. The
presence of two nitro groups makes respective sulfinate 3n weak
nucleophile and responsible for non-reactivity. Encouraged by the
results obtained, we turned our interest to heterocyclics; sodium
electron-donating groups due to their high nucleophilic nature
furnished good to excellent yields of corresponding products
benzo[
d
]thiazole-2-sulfinate was also efficiently transformed to
3o with 66% yield. Additionally, it was found that
sulfone
(
)
a
(examples 3b-3g
, except 3c). p-Methyl substituted sulfinate
2 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C4RA07370C
substituted styrene sulfinate also worked well and afforded the
desired vinyl sulfone (3p) in 80% yield.
SO2Ph
H/D
SO2Na
TBAF
0 oC to rt, 3 h
OTf
The versatility of the present reaction was also explored with
substituted arynes (Table 3). Methyl ( ) substituted
at 6th position
TMS
THF/D2O
1a
benzyne precursor 1b underwent coupling with benzene sulfinic acid
sodium salt 2a and gave an unseparable mixture of coupled products
4a/a’ with 55% yield in the ration of 37:63 (ratio was determined by
GC-MS). Methoxy (at 5th position) substituted benzyne precursor 1c
when tried, also underwent coupling and gave 62% of coupled
products 4b and 4b’ in the ratio of 45 and 55 (determined by GC-MS)
which were easily separated by column chromatography. On the
other hand, methyl (at 4th position) benzyne precursor 1d also gave an
inseparable mixture of coupled products 4c/c’ with 58% yield. Further,
napthlene containing benzyne precursor 1e also underwent coupling
smoothly and gave a 2-napthyl phenyl sulfone 4d with 50% yield.
Effect of temperature on regio-selectivity was also studied by
performing all the reactions at room temperature but no
improvement in the regio-selectivity was observed, however the
reactions gave comparatively lower yields (Table 3).
2a
3a
( 20% D incorporation)
Confirmed by LC-MS
Scheme 1: Coupling in the presence of D2O.
In conclusion, we have developed an efficient and general method
for the synthesis of unsymmetrical sulfones under metal-free
condition. The optimized method works well for the synthesis of
diverse range of sulfones such as unsymmetrical biaryl, bi(heteroaryl),
aryl vinyl, aryl alkyl sulfones. The present method gave good to
excellent yields and also have a good functional group compatibility.
Further, the efforts towards the bi-functionalization as well as
sulfonation with other benzyne precursor to expand the generality are
presently underway and will be published in due course.
Acknowledgement
SO2Ph
Authors acknowledge the financial support of CSIR with research
grant # HCP 0001 and BSC 0108. SKA, KR and GM thanks UGC and
CSIR for their Fellowship. IIIM communication number:
IIIM/1697/2014.
SO2Na
OTf
CsF, CH3CN
R
R
80 oC, 2-3 h
TMS
1b-e
4
2a
Yield(%)b
Entry
1
Aryne precursor
Products
Me
Me
Me
Notes and references
2
1Medicinal Chemistry Division, Academy of Scientific and Innovative
OTf
SO2Ph
55/35c (37 : 63)d
Research, CSIRꢀIndian Institute of Integrative Medicine, Canal Road,
Jammu 180 001, India; Tel.: +91ꢀ191ꢀ2569000ꢀ010 (ext. 292), Fax: +91ꢀ
191ꢀ2569333; Eꢀmail: ppsingh@iiim.ac.in
SO2Ph
TMS
4a/a'
1b
OMe
MeO
OTf
MeO
SO2Ph
62/43c (45 : 55)
Electronic Supplementary Information (ESI) available: [Synthesis and
characterization data]. See DOI: 10.1039/c000000x/
2
TMS
SO2Ph
1c
1
For some selected references, see: (a) Hartz, R. A.; Arvanitis, A. G.;
Arnold, C.; Rescinito, J. P.; Hung, K. L.; Zhang, G.; Wong, H.;
Langley, D. R.; Gilligan, P. J.; Trainor, G. L. Bioorg. Med. Chem.
4b
Me
4b'
Me
OTf
TMS
58/55c (53 : 47)d
3
4
Lett
R.; LehwarkꢀYvetot, G.; Hansel, W.; Schaper, K. J.; Seydel, J. K. J.
Med. Chem 2004 47, 240; (c) Pal, M.; Veeramaneni, V. R.;
Nagabelli, M.; Kalleda, S. R.; Misra, P.; Casturib, S. R.;
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Me
SO2Ph
SO2Ph
1d
4c/c'
4d
.
,
SO2Ph
OTf
TMS
50
.
,
1e
aReaction conditions: Aryne precursor 1b-e (0.25 mmol, 1.0 equiv), 2a benzene sulfinic
acid sodium salt (0.5 mmol, 2.0 equiv), CsF (1.0 mmol, 4.0 equiv), solvent 4 ml, 80 oC,
under N2; bRatio was determined by GC-MS analysis; cReactions were performed at rt
for 18h; dunseparable mixtures.
.
,
.
,
.
Table 3: Coupling of benzenesulfinic acid salt with substituted benzynesa
,
To gain further insight into the reaction mechanism, the coupling
reaction was performed in the presence of D2O (Scheme 1), wherein
the corresponding coupled product 3a was formed with 20%
deuterium incorporation which was confirmed by LC-MS (Details
given in SI). Based on our finding (reactions in presence of O2 and
D2O) and literature precedent,8b,9 a plausible mechanism can be
described by the nucleophilic attack of aryl sulfnate8b on the aryne9
derived from 2a followed by proton capture resulting in the formation
of the corresponding sulfones.
.
,
Liu, K. G.; Robichaud, A. J.; Bernotas, R. C.; Yan, Y.; Lo, J. R.;
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Y.; Kowal, D. M.; Smith, D. L.; Schechter, L. E.; Comery, T. A. J.
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2011
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54, 1587; (k) Woo, S. Y.; Kim,
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VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C4RA07370C
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Graphical Abstract:
O
S R1
O
R
Metal-free
Base catalysed
High yield
O
S
S
N
Lesser reaction time
O
(Hetero)Ar, Vinyl, CF3-SO2Na
+
R
Functional group tolerance
Synthesis of unsymmetical
biaryl, bi(heteroaryl),
aryl vinyl,
O
O
O
S
R
aryl alkyl sufones
O
S
F3C
20 Examples