Direct radical sulfonylation at α-C(sp3)-H of THF with sodium sulfinates in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2019.02.021

A direct transition-metal-free, convenient and highly regioselective synthesis of 2-alkyl/aryl sulfonyl tetrahydrofurans (THFs) has been achieved from THF and sodium sulfinates using K₂S₂O₈ as a mild oxidant. This one-pot

Full text of DOI:10.1016/j.tetlet.2019.02.021

Accepted Manuscript
3
Direct radical sulfonylation at α-C(sp )-H of THF with sodium sulfinates in
aqueous medium
Manjula Singh, Lal Dhar S. Yadav, Rana Krishna Pal Singh
PII:
S0040-4039(19)30142-X
https://doi.org/10.1016/j.tetlet.2019.02.021
TETL 50615
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 January 2019
8 February 2019
9 February 2019
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Please cite this article as: Singh, M., Yadav, L.D.S., Singh, R.K.P., Direct radical sulfonylation at α-C(sp )-H of
THF with sodium sulfinates in aqueous medium, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2
019.02.021
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Graphical Abstract
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Direct radical sulfonylation at α-C(sp )-H of THF
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with sodium sulfinates in aqueous medium
Manjula Singh, Lal Dhar S. Yadav, Rana Krishna Pal Singh

1
Tetrahedron Letters
3
Direct radical sulfonylation at α-C(sp )-H of THF with sodium sulfinates in aqueous medium
a
a
Manjula Singh , Lal Dhar S. Yadav*, Rana Krishna Pal Singh *
Electrochemical laboratory, Department of Chemistry, University of Allahabad, Allahabad 211002, India
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211002, India
a
b

Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533; E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A direct transition-metal-free, convenient and highly regioselective synthesis of 2-alkyl/aryl
sulfonyl tetrahydrofurans (THFs) has been achieved from THF and sodium sulfinates using
K
2
S
2
O
8
as a mild oxidant. This one-pot simple protocol involves an efficient radical cross
coupling reaction in aqueous medium utilizing K as an inexpensive and easy to handle
radical surrogate at room temperature.
2 2 8
S O
Available online
2
009 Elsevier Ltd. All rights reserved
Keywords:
Radical reaction
Sodium sulfinates
Sulfonylation
THF derivatives
18
The establishment of mild and efficient methods for
irradiation.
In 1996,
Malanga and coworkers have
C−S bonds formation has received considerable attention
synthesized 2-phenyl sulfonyltetrahydrofuran by reacting 2,2-
because these bonds are widely found in many important
dialkyl-1,3-dioxep-4-ene with phenylsulfinic acid (Scheme
1a). Ley and coworkers have reported the synthesis of 2-
1
19
biological and pharmaceutical compounds.
Nowadays
3
free-radical-initiated sp -hybridized C–H bond activation
phenylsulfonyltetrahydrofuran from 2,3-dihydrofuran
and
3
gets much importance because the α-C(sp )-H bond in
benzenesulphinic acid in dry dichloromethane at room
2
3
4
20
many stable compounds such as alcohols, ethers, amines,
temperature under argon (Scheme 1b). To the best of our
5
and 1,3-dicarbonyl compounds could be activated by the
radical leading to the formation of a more usable C–X (X = C,
O, N, S) bond. However, the selective activation of the
knowledge, there is no report on the direct alkyl/aryl
sulfonylation of THF in the literature.
Recently, K
2 2
S
O has emerged as a suitable inorganic
8
3
inactive C(sp )–H bonds in alkanes and ethers to form
oxidant for a wide array of oxidative transformations under
6
21
C–S bonds has been a challenging task owing to their
mild conditions.
water solubility and workability at room temperature, K
is advantageneous over organic peroxides. In view of the
above discussion and our earlier studies on K -mediated
organic synthesis, we report herein a simple and efficient
protocol to access α-alkyl/arylsulfonyl THF via K O -
Owing to its low cost, easy handling,
low reactivity.
2 2
S O
8
The direct C−H functionalization is of great importance
to organic chemistry due to its high efficiency and high
2 2
S O
8
7
22
atom-economy. Substituted tetrahydrofurans (THFs) are
ubiquitous motifs present in biological, pharmaceutical and
S
2 2
8
natural products and they are useful building blocks in
mediated direct α-sulfonylation of THF with
sulfinates (Scheme 1c).
sodium
8
organic synthesis.
In general, substituted (THFs) are
3
accessible through the α-C(sp )−H functionalization of
9
10
THF via Ni-catalyzed arylation of THF, Fe(II)-catalyzed
11
CDC reaction of THF with malonates, Cu- and Ir-catalyzed
carbenoid insertion of ethyl diazoacetate into α-C–H of
1
2
13
THF, Cr-promoted reaction of alcohols with THF, AIBN
1
4
mediated alkenylation of THF with vinyl triflones, TBHP-
promoted reaction of phenylacetylene with THF and BEt
1
5
3
-
and Me Zn-mediated addition of THF with aldehydes and
2
1
6
aldimines, respectively. α-Alkynyl cyclic ethers have been
regioselectively prepared by the α-alkynylation of cyclic
16–18
ethers.
Brown and Ley have prepared α-alkynyl
tetrahydrofuran from 2-arylsulfonyl furans by treatment with
17
the corresponding organozinc agents. α-Alkynyl cyclic
ethers have also been obtained through the α alkynylation of
3
C(sp )-H bonds in cyclic ethers with acetylenic triflones
using peroxide or AIBN or under UV-
Scheme 1. Synthesis of 2-alkyl/arylsulfonyl tetrahydrofurans

2
Our investigation starts with the radical cross coupling
reaction of equimolar tetrahydrofuran (THF, 1a) and sodium
THF
1
and a wide variety of
sodium sulfinates 2
, OCH
, and CN in their aromatic ring were
showed splendid tolerance for both
incorporating various functional groups such as CH
t-Bu, Ph, Cl, Br, CF
used. The reaction
electron-donating and electron-withdrawing
3
3
,
sulfinate 2a employing K
2
S
2
O
8
(1.5 equiv) as a radical source
3
in aqueous medium at rt under a nitrogen atmosphere to
afford the product 3a in 87% yield (Table 1, entry 1).
Encouraged by this excellent result, we proceeded to
optimize the reaction conditions. Thus, we tested several
groups
to
3
produce the desired 2-alkyl/arylsulfonyl tetrahydrofurans
in good to excellent yields irrespective of their electronic
properties (Table 2). Sodium sulfinates 2 bearing an electron-
donating group in their aromatic ring appeared to react
faster and afford slightly higher yields of the corresponding
2-alkyl/arylsulfonyl tetrahydrofurans 3 in comparision to
those having an electron-withdrawing group (Table 2, 3b-
f vs 3g-p). Notably, aliphatic and alicyclic sulfinates also
worked well under the present sulfonylation conditions (Table
2, 3q and 3r). This reaction was also effective with six-
membered pyran and/or acyclic ether and worked well (Table
2, 3s-u).
solvents
Among these H
in terms of time and yield (Table 1, entry 1 vs 2-5). The
optimum amount of K was found to be 1.5 equiv
such as
H
2
O, CH CN, DCE, THF and DMF.
3
2
O was demonstrated to be the best solvent
2 2
S O
8
because the yield was considerably reduced on decreasing
its amount from 1.5 to 1.0 equiv (Table 1, entry 1 vs 6),
although on using 2.0 equiv of the oxidant, the yield
remained unchanged (Table 1, entry 2 vs 7). The other
oxidants like CAN (ceric ammonium nitrate), oxone, TBHP
and DTBP were not as effective as
entry 2 vs 8-11). No reaction occurred in the absence
of (Table 1, entry 12). The reaction was quenched
on addition of radical scavenger 2,2,6,6-
tetramethylpiperidinyl-1-oxyl (TEMPO), indicating that
K
2 2
S O
8
(Table 1
Table 2
2
K S
2
O
8
a
Substrate scope for the synthesis of 2-alkyl/arylsulfonyl
a
a
tetrahydrofuran
radical intermediate is involved in the reaction (Table 1,
entry 13).
Table1
Optimization of reaction conditionsa
Entry
Solvent
Oxidant (1.5
equiv)
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
H
2
O
K
2
S
S
S
S
S
S
S
2
2
2
2
2
2
2
O
O
O
O
O
O
O
8
8
8
8
8
8
8
(1.5)
(1.5)
(1.5)
(1.5)
(1.5)
(1.0)
(2.0)
8
87
CH
3
CN
K
2
12
12
12
12
8
79
DCE
THF
DMF
K
2
75
K
2
71
K
2
62
H
H
H
H
H
H
H
H
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
K
2
69
K
2
8
87
CAN (1.5)
Oxone (1.5)
TBHP (1.5)
DTBP (1.5)
-
12
12
12
12
8
73
65
1
1
1
1
0
1
2
3
56
71
n.d.c
Tracesd
K
2
S
2
O
8
(1.5)
8
\
a
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), oxidant (1-2
equiv), solvent (3 mL), stirred at rt
atmosphere.
for
8-12 h under an N
2
b
Isolated yield of the pure product 3a.
Without oxidant the yield was not detected.
c
d
Reaction was quenched with TEMPO (4 equiv).
Under the optimized reaction conditions, we investigated
the generality and scope of the present K -mediated
synthesis of 2-alkyl/arylsulfonyl tetrahydrofurans 3.
2 2
S O
8

3
a
For experimental procedure, see ref. 23.
Yields of isolated pure compounds 3.
All compounds gave satisfactory spectral ( H NMR, C NMR and HRMS)
(e) G. Liu, J. T. Link, Z. Pei, E. B. Reilly, S. Leitza, B.
b
Nguyen, K. C. Marsh, G. F. Okasinski, T. W. Geldern, M.
Ormes, K. Fowler, M. Gallatin, J. Med. Chem. 43 (2000) 4025;
f) S. C. Mitchell, R. M. Nickson, Waring, R. H. Sulfur Rep.
3 (1993) 279.
T. He, L. Yu, L. Zhang, L. Wang and M. Wang, Org. Lett. 13
c
1
13
(
1
data.
2
.
.
(2011) 5016
In accordance with our observations and the literature
3.
(a) Z. Xie, Y. Cai, H. Hu, C. Lin, J. Jiang, Z. Chen, Y. Pan,
21, 22
Org. Lett.15 (2013) 4600.
b) K. Cheng, L. Huang and Y. Zhang, Org. Lett. 11 (2009)
908;
precedents,
a
plausible mechanistic
pathway is
homolyzes into
(
2
proposed • in Scheme 2. First, the K
2
S
2
O
8
two KSO
4
radicals, which abstract a hydrogen atom
4
S. Pan, J. Liu, H. Li, Z. Wang, X. Guo, Z. Li, Org. Lett. 12
(2010) 1932.
3
from the α-(C-sp )-H of THF (1a) to generate an α-
oxyalkyl radical A and oxidise sodium sulfinate 2a into
a radical B via single electron transfer (SET). Subsequently,
the radical A is coupled with B to produce the final
product 3a.
5.
.
Z. Li, R. Yu, H. Li, Angew. Chem. 120 (2008)7607.
(a) C. Liu, H. Zhang, W. Shi, A. Lei Chem. Rev. 111 (2011)
6
1
780;
(
b) C.-L. Sun, B.-J. Li, Z.-J. Shi Chem. Rev. 111 (2011) 1293.
(
c) C. J. Li, Acc. Chem. Res. 42 (2008) 335;
(
d) S. Y. Zhang, F. M. Zhang, Y. Q. Tu, Chem. Soc. Rev.
2
011 (1937) 40.
(a) T. W. Lyons, M. S. Sanford, Chem. Rev. 110 (2010) 1147;
b) P. Sehnal, R. J. K. Taylor, I. J. S. Fairlamb Chem. Rev. 110
7
.
(
(2010) 824;
(
(
c)C. L. Sun, B. J. Li, Z. J. Shi, Chem. Commun. (2010) 677;
d) X. Chen, K. M. Engle, D. H. Wang, J. Q. Yu, Angew.
Chem. Int. Ed. 48 (2009) 5094;
e) Yu, J. Q. Giri, R. Chen, X. Org. Biomol. Chem. 4 (2006)
041;
f) B.
(
4
(
Sezen, D. Sames, In Handbook of
CsH
transformations; G. Dyker, Wiley- Ed. VCH Velag GmbH &
Co. KGaA: einheim, Germany, 3 (2005).
8
.
(a) I. Vilotijevic, T. F. Jamison, Angew. Chem. Int. Ed. 48
(2009) 5250;
(b) B. Figadere, G. Jalce, X. Franck, Tetrahedron: Asymmetry
2
(
0 (2009) 2537;
c) I. Larrosa, P. Romea, F. Urpì, Tetrahedron, 64 (2008) 2683;
(
(
(
d) J. P. Wolfe, M. B. Hay, Tetrahedron 63 (2007) 261;
e) P. A. Clarke, S. Santos, Eur. J. Org. Chem. (2006) 2045;
f) K. S. Yeung, I. Paterson, Chem. Rev. 105 (2005) 4237;
Scheme 2. A plausible mechanism for the formation of 2-alkyl/aryl-
sulfonyltetrahydrofurans
(
g) T. Nakata, Chem. Rev. 105 (2005) 4314;
h) J. Muzart, Tetrahedron, 61 (2005) 5955;
(
(i) A. Bermejo, B. Figadere, M. C. Zafra-Polo, I. Barrachina, E.
In conclusion, we have developed an operationally simple,
Estornell and D. Cortes, Nat. Prod. Rep. 22 (2005) 269;
(
(
j) C. J. Dutton, B. J. Banks, C. B. Cooper, Nat. Prod. Rep. 12
1995) 165
one-pot, efficient, transition-metal-free
and
highly
regioselective synthetic method for 2-alkyl/arylsulfonyl
9
.
S.-Y. Zhang, F.-M. Zhang, Y.-Q. Tu, Chem. Soc. Rev. 40
2011)1937.
tetrahydrofurans. This new protocol involves efficient radical
(
3
sulfonylation at the α-C (sp )-H bond of THF with
10. D. Liu, C. Liu, H. Li, A. Lei, Angew. Chem. Int. Ed. 52 (2013)
4453.
1. Z. Li, R. Yu, H. Li, Angew. Chem. Int. Ed., 47 (2008) 7497.
2. (a) H. Suematsu, T. Katsuki, J. Am. Chem. Soc. 13 (2009)
sodium sulfinates using
agent. Advantageously, the present efficient cross coupling
reaction utilizes as a readily available,
2 2
K S O
8
as a mild oxidizing
1
1
2
K S
2
O
8
1
(
4218.
b) J. M. Fraile, J. I. García, J. A. Mayoral, M. Roldán, Org.
Lett. 9 (2007) 731;
c) M. M. Díaz-Requejo, T. R. Belderraín, M. C. Nicasio, S.
Trofimenko and P. J. Pérez, J. Am. Chem. Soc. 124 (2002)
96;
d) H. M. L. Davies, T. Hansen, M. R. Churchill, J. Am.
Chem. Soc. 122 (2000) 3063;
e) H. M. L. Davies, T. Hansen, J. Am. Chem. Soc. 119 (1997)
inexpensive and easy to handle radical source in aqueous
medium at room temperature.
(
Acknowledgments
8
(
We sincerely thank the SAIF, Punjab University, Chandigarh,
for providing spectra. M.S. is grateful to the UGC, New Delhi,
for a research fellowship.
(
9075;
1
1
3. R. Baati, A. Valleix, C. Mioskowski, D. K. Barma, J. R. Falck,
Org. Lett. 2 (2000) 485.
References
4.
J. Xiang, W. Jiang, J. Gong and P. L. Fuchs, J. Am. Chem.
Soc. 119 (1997) 4123.
1
.
(a) X.-B. Xu, J. Liu, J.-J. Zhang, Y.-W. Wang, Y. Peng, Org.
Lett. 15 (2013) 550;
1
5. Z.-Q. Liu, L. Sun, J.-G. Wang, J. Han, Y.-K. Zhao, B. Zhou,
Org. Lett. 11 (2009) 1437.
1
(
b) N. D. D Angelo, T.-S. Kim, K. Andrews, S. K. Booker, S.
Caenepeel, K. Chen, D. D’Amico, D. Freeman, J. Jiang, L. Liu,
J. D. McCarter, T. S. Miguel, E. L. Mullad, M. Schrag, R.
Subramanian, J. Tang, R. C. Wahl, L. Wang, D. A. Wu, T.
Whittington, N. Xi, Y. Xu, P. Yakowec, K. Yang, L. P.
Zalameda, N. Zhang, P. Hughes, M. H. Norman, J. Med. Chem.
6. (a) T. Yoshimitsu, T. Makino, H. Nagaoka, J. Org. Chem., 68
(
(
(
(
(
2003) 7548;
b) T. Yoshimitsu, Y. Arano, H. Nagaoka, J. Org. Chem. 68
2003) 625;
c) K.-I. Yamada, Y. Yamamoto, K. Tomioka, Org. Lett.
2003) 1797.
5
5
(
4 (2011) 1789;
c) M. I. Konaklieva, B. J. Plotkin, Recent Pat. Anti- Infect.
Drug Discovery 1 (2006) 177;
d) M. D. McReynolds, J. M. Dougherty, P. R. Hanson,
Chem. Rev. 104 (2004) 2239;
1
1
7. D. S. Brown, S. V. Ley, Tetrahedron Lett. 29 (1988) 4869.
8. (a) J. Gong, P. L. Fuchs, J. Am. Chem. Soc. 118 (1996) 4486;
(
(
b) J. Xiang, P. L. Fuchs, J. Am. Chem. Soc. 118 (1996) 11986;
(
1
c) T. Hoshikawa, S. Kamijo, M. Inoue, Org. Biomol. Chem.
1 (2013) 164.

4
1
2
2
9. C. Malanga, L. A. Aronica, L. Lardicci Synth. Commun. 26
1996) 2317.
0. D. S. Brown, M. Bruno, R. J. Davenport, S. V. Ley
Tetrahedron 45 (1989) 4293.
1. (a) S. Mandal, T. Bera, G. Dubey, J. Saha, J. K. Laha ACS
Catal. 8 (2018) 5085;
(
(
(
(
b) A. Ilangovan, A. Polu, G. Satish Org. Chem. Front. 2
2015) 1616;
c) D. Yang, K. Yan, W. Wei, G. Li, S. Lu, C. Zhao, L. Tian,
H. Wang, J. Org. Chem. 80 (2015)11073;
d) X. Chen, X. Li, X.-L. Chen, L.-B. Qu, J.-Y. Sun, Z. D.
(
Liu, W.-Z. Bi, Y.-Y. Xia H.-T. Wua, Y.-F. Zhao Chem.
Commun. (2015) 3846;
(
(
(
e) J. Y. Wang, Q. Jiang, C. C. Guo Synth. Commun. 44
2014) 3130;
f) H. Rao, P. Wang, J. Wang, Z. Li, X. Sun, Cao, S. RSC Adv.
4
(2014) 49165;
g) Q. Jiang, W. Shenga, C. Guo, Green Chem. 15 (2013)
(
2
175;
(h) Y. Fujiwara, V. Domingo, I. B. Seiple, R. Gianatassio, M.
D. Bel, P. S. Baran J. Am. Chem. Soc. 133 (2011) 3292;
i) Z. Yang, X. Chen, S. Wang, J. Liu, K. Xie, A. Wang, Z.
Tan J. Org. Chem. 77 (2012) 7086;
j) J. W. Lockner, D. D. Dixon, R. Risgaard, P. S. Baran Org.
Lett. 13 (2011) 5628;
k) I. B. Seiple, S. Su, R. A. Rodriguez, R. Gianatassio Y.
Fujiwara, A. L. Sobel, P. S. Baran J. Am. Chem. Soc. 132
2010) 13194.
(
(
(
(
2
2. (a) M. Singh, A. K. Yadav, L. D. S. Yadav, R. K. P. Singh
Synlett. 29 (2018) 2306;
(
5
(
b) A. K. Singh, R. Chawla, L. D. S. Yadav, Tetrahedron Lett.
5 (2014) 4742;
c) A. K. Singh, R. Chawla, T. Keshari, V. K. Yadav, L. D. S.
Yadav, Org. Biomol. Chem. 12 (2014) 8550;
d) R. Chawla, A. K. Singh, L. D .S. Yadav Eur. J. Org.
Chem. (2014) 2032;
e) A. K. Singh, R. Chawla, L. D. S. Yadav, Tetrahedron Lett.
5 (2014) 2845.
(
(
5
2
3. General procedure for the synthesis of 2-alkyl/arylsulfonyl
tetrahydrofurans 3: A mixture of tetrahydrofuran 1 (1.0
mmol), sodium sulfinate 2 (1.0 mmol), K
O (3 mL) was taken in a flask and stirred at rt for 8-12 h
Table 2). After completion of the reaction (monitored by
2 2 8
S O (1.5 equiv), and
H
2
(
TLC), water (5 mL) was added and the mixture was extracted
with ethyl acetate (3 × 5 mL). The combined organic phase
was dried over anhydrous Na
under reduced pressure. The resulting crude product was
purified by silica gel chromatography using mixture of
2 4
SO , filtered and evaporated
a
hexane/ethyl acetate (4:1) as eluent to afford an analytically
pure sample of product 3. All the compounds 3 were
1
13
characterized by comparison of their spectral ( H NMR,
C
NMR and HRMS) data.
1
Compound 3a: H NMR (400 MHz, CDCl
3
) δ: 7.56 (d, J = 7.2
Hz, 2H), 7.37-7.32 (m, 2H), 7.27-7.19 (m, 1H), 5.69-5.68 (m,
1
1
1
H), 4.09-3.99 (m, 2H), 2.46-2.38 (m, 1H), 2.09-1.98 (m, 2H),
1
3
.88-1.79 (m, 1H); C NMR (100 MHz, CDCl
30.98, 128.71, 126.69, 87.06, 67.18, 32.57, 24.77. HRMS
S 212.0507, found 212.0504.
Compound 3g: H NMR (400 MHz, CDCl ) δ: 7.47-7.36 (m,
H), 5.63-5.59 (m, 1H), 4.06-3.97 (m, 2H), 2.39-2.36 (m, 1H),
3
) δ: 135.65,
12 3
(EI): calcd for C10H O
1
3
4
2
1
1
3
.05-1.89 (m, 3H); C NMR (100 MHz, CDCl
32.47, 131.74, 120.79, 87.03, 67.22, 32.54, 24.73. HRMS
S 289.9612, found 289.9616.
Compound 3n H NMR (400 MHz, CDCl ) δ: 7.74-7.69 (m,
H), 7.37 (d, J = 7.6 Hz, 1H), 7.27-7.24 (m, 1H), 7.18-7.15 (m,
H), 5.79-5.76 (m, 1H), 4.09-3.97 (m, 2H), 2.49-2.38 (m, 1H),
3
) δ: 134.93,
10 3
(EI): calcd for C H11BrO
1
3
1
1
2
1
3
.17-2.05 (m, 2H), 1.96-1.87 (m, 1H); C NMR (100 MHz,
) δ: 135.51, 133.99, 130.83, 129.53, 127.19, 127.18,
5.52, 76.49, 32.59, 24.78. HRMS (EI): calcd for C10 S:
46.0117; found: 246.0113.
CDCl
8
2
3
H11ClO
3

5
Highlights


Transition-metal-free one-pot approach
to 2-alkyl/aryl THFs at rt.
The direct radical sulfonylation at α-
C(sp )-H of THF in aqueous medium.
3


Sodium sulfinates as a radical source.
K
2
S
2
8
O as a mild radical initiator.