Direct sulfonylation of anilines mediated by visible light

Article abstract of DOI:10.1039/c7sc03891g

Sulfones feature prominently in biologically active molecules and are key functional groups for organic synthesis. We report a mild, photoredox-catalyzed reaction for sulfonylation of aniline derivatives with sulfinate salts, and demonstrate the utility of the method by the late-stage functionalization of drugs. Key features of the method are the straightforward generation of sulfonyl radicals from bench-stable sulfinate salts and the use of simple aniline derivatives as convenient readily available coupling partners.

Full text of DOI:10.1039/c7sc03891g

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Direct sulfonylation of anilines mediated by visible
light†
Cite this: DOI: 10.1039/c7sc03891g
Tarn C. Johnson,a Bryony L. Elbert,‡a Alistair J. M. Farley,‡a Timothy W. Gorman,‡a
Christophe Genicot,b Benedicte Lallemand,b Patrick Pasau,b Jakub Flasz,c
´ ´
a
a
Jose L. Castro,c Malcolm MacCoss,d Darren J. Dixon,
Robert S. Paton,
*
*
´
a
a
a
*
*
*
Christopher J. Schofield,
Martin D. Smith
and Michael C. Willis
Sulfones feature prominently in biologically active molecules and are key functional groups for organic
synthesis. We report a mild, photoredox-catalyzed reaction for sulfonylation of aniline derivatives with
sulfinate salts, and demonstrate the utility of the method by the late-stage functionalization of drugs. Key
features of the method are the straightforward generation of sulfonyl radicals from bench-stable
sulfinate salts and the use of simple aniline derivatives as convenient readily available coupling partners.
Received 5th September 2017
Accepted 7th November 2017
DOI: 10.1039/c7sc03891g
rsc.li/chemical-science
a suitable directing group.6 There remains, however, an unmet
need for new methods that enable access to complex, highly
Introduction
functionalized aryl-sulfones, that employ mild conditions, have
wide functional group tolerance, and which are broad in scope.
We proposed that a photoredox-catalyzed process, utilizing the
redox chemistry of an aromatic substrate in combination with
a sulfonyl radical, would enable us to achieve this goal.
Sulfonyl radicals are transient intermediates that undergo
a range of reactions, including with alkenes7 and alkynes.8
However, examples of their reactivity with aromatic rings are
scarce:1 the groups of Deng and Kuhakarn have independently
reported sulfonylation of indoles at the C-2 position using
sodium sulnate salts under oxidative conditions,9 Li and
Sulfones are an important class of organosulfur compounds
that have uses ranging from polymers and solvents to synthetic
intermediates.1 Sulfones display diverse biological activities,
making them of major interest in the pharmaceutical and
agrochemical industries; they have been used for the treatment
of a variety of conditions, ranging from leprosy to skin cancer,
and are included in antibiotic and herbicidal treatments
(Fig. 1). The most common method for preparing sulfones is by
oxidation of suldes; this oen requires the use of odorous
thiols and strongly oxidizing conditions which limits functional
group compatibility.2 Electrophilic aromatic substitution of
(hetero)arenes with sulfonyl chlorides or sulfonic acids are
other classical methods for sulfone synthesis. However, these
methods normally employ harsh conditions, such as the use of
stoichiometric Lewis or Brønsted acids and high temperatures,
and the (hetero)arene reaction partner is oen required in large
excess.3 More recent methods for sulfone synthesis include
transition-metal-catalyzed coupling reactions between sulnate
salts and aryl halides,4 three-component methods utilizing SO2
surrogates,5 and C–H activation approaches employing
aDepartment of Chemistry, University of Oxford, Chemical Research Laboratory,
Manseld Road, Oxford, OX1 3TA, UK. E-mail: darren.dixon@chem.ox.ac.uk;
robert.paton@chem.ox.ac.uk; christopher.schoeld@chem.ox.ac.uk; martin.smith@
chem.ox.ac.uk; michael.willis@chem.ox.ac.uk
bGlobal Chemistry, UCB New Medicines, UCB BioPharma sprl, 1420 Braine-L'Alleud,
Belgium
cGlobal Chemistry, UCB, 261 Bath Road, Slough, SL1 3WE, UK
dBohicket Pharma Consulting LLC, 2556 Seabrook Island Road, Seabrook Island,
South Carolina 29455, USA
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7sc03891g
Fig. 1 Biologically active sulfones, and the reaction targeted in this
‡ These authors contributed equally to this work.
work.
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coworkers have reported on hypervalent iodine-mediated sul- commercially available photoredox catalysts (entries 1–5) identi-
fonylation of anilides with aryl sulfonyl chlorides,10 and sulfonyl ed [Ir(dF(CF3)ppy)2(dtbpy)]PF6 as the optimal catalyst with
radicals have been implicated in transition-metal-catalyzed potassium persulfate serving as the oxidant to drive the desired
directed C–H sulfonylations.11 Here we report on the develop- reaction under irradiation with visible light (blue LEDs).
ment of a mild and robust sulfonylation protocol that is appli-
The addition of water or triuoroacetic acid (TFA) as a co-
cable to the late-stage functionalization of aniline containing solvent (entries 4, 7–11) enabled high yields, with 10 : 1
drug-molecules. To the best of our knowledge the reaction acetonitrile/water providing the optimal solvent combination.
described herein represents the rst example of a photoredox- The optimized conditions employ a modest excess of the sul-
catalyzed aryl C–H sulfonylation process (Fig. 1).
nate salt and oxidant, and a reaction time of 72 h to reach full
conversion with the expected sulfone 1 being isolated in 85%
yield (entry 13). By way of control reactions, three different
protocols to achieve the formation of sulfone 1 from N,N-
dimethyl-p-toluidine via electrophilic aromatic sulfonylation
were performed; all three were unsuccessful, with no trace of
sulfone 1 being observed (see the ESI† for details).3a,3b,13
Results and discussion
Anilines were targeted as substrates because they are present in
many pharmaceuticals and natural products, and possess an
accessible oxidation potential (N,N-dimethylaniline 0.74 V vs.
SCE).12 N,N-Dimethyl-p-toluidine and sodium methanesulnate
were chosen as a test system, with selected optimization experi-
ments presented in Table 1 (see ESI† for details). Evaluation of
With optimised conditions established, the scope of the
reaction with respect to the aniline substrates was investigated
(Table 2a). We found that both alkyl and aryl substituents on the
aromatic ring were well tolerated, affording the corresponding
sulfones in high yields (1, 7–12). Electron-rich substrates per-
formed well, with methoxy groups in the ortho-, meta- and para-
positions all proceeding in high yields (13–15). Pleasingly,
a substrate bearing an unprotected hydroxyl group underwent
sulfonylation in high yield to give sulfone 16 featuring a meta
relationship with the dimethylamino group.14 Diamine-
containing sulfones could be accessed in moderate to good
yields from the corresponding phenylene diamine derivatives (17,
18). Halide substituents were also tolerated under the photoredox
conditions (19–21). More complex anilines preferentially under-
went sulfonylation at the least hindered ortho position, delivering
sulfones 22 and 23. Pyridines and fused heterocycles were also
compatible substrates (24–27). A survey of aniline derivatives with
differing substituents at the nitrogen atom revealed that
although aromatic groups performed very well, different alkyl
groups were prone to competing dealkylation processes, resulting
in lower yields (28–34). It was observed that, in most cases, sul-
fonylation occurs predictably at the ortho- and para-positions
with respect to the amino substituent.
Table 1 Selected optimization studies for the preparation of sulfone 1a
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
2
3
4
5
6
5
5
5
5
5
5
5
5
10 : 1 MeCN/H2O
10 : 1 MeCN/H2O
10 : 1 MeCN/H2O
10 : 1 MeCN/H2O
10 : 1 MeCN/H2O
10 : 1 MeCN/H2O
5 : 1 MeCN/H2O
MeCN
10 : 1 MeCN/TFA
10 : 1 CH2Cl2/H2O
10 : 1 acetone/H2O
10 : 1 MeCN/H2O
10 : 1 MeCN/H2O
22
12
60
67
60
60
59
27
58
52
63
76
5
6c
7
8
9c
10
11
12d
13d,e
Sulnate salts were also evaluated under the reaction
conditions and a broad range of substituents were found to be
tolerated (Table 2b). Thus, cycloalkyl (35–37), as well as linear
(38, 39) and branched alkyl (40) sulnates provided the corre-
sponding sulfones in good to moderate yields. Sulnates
featuring both saturated O- and N-heterocycles were compatible
(41, 42). Aryl sulnates were also suitable substrates, and
85(85)
a
range of electron-donating and electron-withdrawing
substituents could be included on the aromatic rings (43–46).
To investigate the robustness of the reaction we carried out
the synthesis of sulfone 1 on a preparative scale (10 mmol). Due
to the high cost of iridium catalyst 5 we sought a suitable metal-
free replacement. Recently, DiRocco and coworkers15 disclosed
the acridinium photocatalyst
6 (Table 1) and achieved
a comparable performance to 5 in a decarboxylative conjugate
addition. Replacing iridium catalyst 5 with acridinium 6 under
our optimal conditions provided the expected sulfonylation
product in 76% isolated yield. Performing the reaction on
a 10 mmol scale provided 1.55 g of sulfone 1 in a 73% yield.
a
Reaction conditions: catalyst (1 mol%), sodium methanesulnate (3
equiv.), K2S2O8 (2 equiv.), Bu4NHSO4 (20 mol%), 0.2 M, blue LEDs,
24 h. b 1H NMR yield vs. trimethoxybenzene internal standard.
c
d
Isolated yield in parentheses. No Bu4eNHSO4. 5 equiv. sodium
methanesulnate, 3 equiv. K2S2O8, 0.1 M. 72 h.
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Table 2 Scope of the direct sulfonylation of aniline derivativesa
a
Reaction conditions: 5 (1 mol%), sodium methanesulnate (5 equiv.), K2S2O8 (3 equiv.), Bu4NHSO4 (20 mol%), 10 : 1 MeCN/H2O, 0.1 M, blue
b
c
d
LEDs, 72 h. Minor regioisomer labelled with the corresponding carbon number. cLog P values of starting materials in parentheses. 40 W
blue LED, 40–56 h.
The broad applicability of this process to various anilines of drugs (Table 2c). Initial studies were encouraging, with sul-
and sulnate salts has potential for introducing diversity at fonylation being observed in all cases. Changing the light
a late stage; to demonstrate this we examined functionalization source from blue LED strips (approximately 6 W, see ESI†) to
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a 40 W LED lamp was used to achieve complete conversion. substrates bearing electron-withdrawing groups were gener-
The antibiotic linezolid was fully converted aer 40 h ally unreactive, consistent with a mechanism requiring
providing two regioisomeric sulfones in 91% combined yield oxidation of the aniline to the radical cation, as electron-
(47). Promethazine, a neuroleptic medication, underwent withdrawing groups will raise the oxidation potential. A
sulfonylation with high regioselectivity providing 48 in 92% detailed mechanistic investigation is ongoing.
yield. The precursor to the antidepressant imipramine was
Finally, to demonstrate the utility of our methodology
also sulfonylated, giving products of reaction at the 2- and 4- a diverse range of derivatives of sulfone 1 were prepared
positions in 16% and 33% yield, respectively (49). The incor- (Scheme 2). Thus, minor modication of a literature proce-
poration of a methylsulfone (MeSO2–) group can substantially dure18 led to the generation of sulnate salt 50 (62%). Further
lower the lipophilicity of a molecule and provide a potential transformations were straightforward, providing access to
site for biological interaction as a hydrogen-bond acceptor. products at the sulde (51) and sulfoxide (52) oxidation levels,
The successful late-stage sulfonylation of these complex in addition to the sulfonamide (53). The dimethylamino group
molecules bearing sensitive and reactive functionalities could be modied by methylation to provide quaternary
demonstrates the potential utility of the method for medicinal ammonium salt 54, which could be further converted to aryl
chemistry.
uoride 55 and subsequently to ether 56 or protected aniline 57
One plausible mechanistic proposal is illustrated in by nucleophilic aromatic substitution.
Scheme 1. The oxidation potentials of the aniline (N,N-
dimethylaniline 0.74 V vs. SCE)12 and the sulnate salt
(sodium methanesulnate 0.46 V vs. SCE)7a are both acces-
sible by the iridium catalyst such that both oxidative and
reductive quenching cycles can operate simultaneously
(Ir(III)*/Ir(II) 1.21 V vs. SCE, Ir(IV)/Ir(III) 1.69 V vs. SCE).16
Oxidation of the aniline to the radical cation and its reaction
with the sulfonyl radical, generated by oxidation of the sul-
nate salt, provides the sulfone product following proton loss.
The addition of neutral and anionic nucleophiles to arene
radical cations has been demonstrated,17 so nucleophilic
attack of the sulnate anion cannot be ruled out; however,
addition of 1-phenylstyrene as a sulfonyl radical trap ablates
the reaction making this pathway seem less likely (see ESI† for
details). In addition, application of reported sulfonyl-radical
generating conditions (I2, MeOH) to our test substrate
combination, failed to deliver any sulfone product. We also
explored the possibility of a thiosulfonate intermediate;
however, the use of S-methyl methanethiosulfonate in place
of sodium methanesulnate, did not deliver the sulfone
product. Unsuccessful aromatic substrates include 1,4-
dimethoxybenzene, 1-methylindole and 1-methylimidazole,
with no reaction occurring in each case. These observations
make an electrophilic aromatic substitution pathway
involving a sulfur-based electrophile unlikely. In addition,
Scheme 2 Efficient and flexible derivatization of sulfone 1. (a) 1, BnBr,
KOtBu, Et2O, 62%. (b) 50, indole, I2, PPh3, EtOH, 78 ꢀC, 83%. (c) 50,
SOCl2, MeOH, then CyMgCl, THF, 71%. (d) 50, N-chloromorpholine,
iPrOH, 70%. (e) 1, MeOTf, 79%. (f) 54, TBAF, NMP, 200 ꢀC, 60%. (g) 55,
NaOEt, EtOH, 78 ꢀC, quant. (h) 55, BnNH2, DMSO, 130 ꢀC, 78%.
Scheme 1 A plausible reaction mechanism for photoredox mediated aryl sulfonylation showing the iridium ion enabled oxidative quenching
cycle.
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´
¨
7 (a) A. U. Meyer, K. Strakova, T. Slanina and B. Konig, Chem.–
Eur. J., 2016, 22, 8694–8699; (b) X. Liu, T. Cong, P. Liu and
P. Sun, Org. Biomol. Chem., 2016, 14, 9416–9422; (c)
H. Wang, G. Wang, Q. Lu, C.-W. Chiang, P. Peng, J. Zhou
and A. Lei, Chem.–Eur. J., 2016, 22, 14489–14493.
Conclusions
In conclusion, we have developed a new and scalable method
for the introduction of the sulfone functional group to anilines
under mild conditions, without the need for pre-
functionalization of the aromatic ring. The mild reaction
conditions and consequent excellent functional group tolerance
are exemplied by the late-stage functionalization of important
biologically active compounds, suggesting the method will be
a valuable tool in discovery chemistry.
8 (a) W. J. Hao, Y. Du, D. Wang, B. Jiang, Q. Gao, S. J. Tu and
G. Li, Org. Lett., 2016, 18, 1884–1887; (b) H. Wang, Q. Lu,
C.-W. Chiang, Y. Luo, J. Zhou, G. Wang and A. Lei, Angew.
Chem., Int. Ed., 2016, 55, 595–599.
9 (a) F. Xiao, H. Chen, H. Xie, S. Chen, L. Yang and G. Deng,
Org. Lett., 2014, 16, 50–53; (b) P. Katrun, C. Mueangkaew,
M. Pohmakotr, V. Reutrakul, T. Jaipetch, D. Soorukram
and C. Kuhakarn, J. Org. Chem., 2014, 79, 1778–1785.
10 Y. Wang, Y. Wang, Q. Zhang and D. Li, Org. Chem. Front.,
2017, 4, 514–518.
Conflicts of interest
There are no conicts to declare.
11 (a) O. Saidi, J. Marae, A. E. W. Ledger, P. M. Liu,
Acknowledgements
¨
M. F. Mahon, G. Kociok-Kohn, M. K. Whittlesey and
C. G. Frost, J. Am. Chem. Soc., 2011, 133, 19298–19301; (b)
We are grateful to UCB Pharma, the Wellcome Trust ISSF
(097813/Z/11/Z#) and the John Fell Fund of the University of
Oxford, for support of this work.
´
P. Marce, A. J. Paterson, M. F. Mahon and C. G. Frost,
Catal. Sci. Technol., 2016, 6, 7068–7076; (c) J. Xu, C. Shen,
X. Zhu, P. Zhang, M. J. Ajitha, K. W. Huang, Z. An and
X. Liu, Chem.–Asian J., 2016, 11, 882–892; (d) C. Xia,
K. Wang, J. Xu, Z. Wei, C. Shen, G. Duan, Q. Zhu and
P. Zhang, RSC Adv., 2016, 6, 37173–37179; (e) S. Liang and
G. Manolikakes, Adv. Synth. Catal., 2016, 358, 2371–2378.
12 H. G. Roth, N. A. Romero and D. A. Nicewicz, Synlett, 2016,
27, 714–723.
Notes and references
1 N.-W. Liu, S. Liang and G. Manolikakes, Synthesis, 2016, 48,
1939–1973.
2 (a) M. Jereb, Green Chem., 2012, 14, 3047–3052; (b)
K. Bahrami, M. M. Khodaei and M. Sheikh Arabi, J. Org.
Chem., 2010, 75, 6208–6213.
13 A. Alizadeh, M. M. Khodaei and E. Nazari, Tetrahedron Lett.,
2007, 48, 6805–6808.
3 (a) D. O. Jang, K. S. Moon, D. H. Cho and J. G. Kim,
Tetrahedron Lett., 2006, 47, 6063–6066; (b) G. A. Olah,
T. Mathew and G. K. Prakash, Chem. Commun., 2001, 1696–
14 (a) S. A. Konovalova, A. P. Avdeenko, A. A. Santalova,
V. V. D'yakonenko, G. V. Palamarchuk and O. V. Shishkin,
Russ. J. Org. Chem., 2014, 50, 1757–1762; (b) K. Bailey,
B. R. Brown and B. Chalmers, Chem. Commun., 1967, 618–
619.
´
1697; (c) S. Repichet, C. Le Roux, P. Hernandez and
J. Dubac, J. Org. Chem., 1999, 6479–6482.
4 E. J. Emmett, B. R. Hayter and M. C. Willis, Angew. Chem., Int.
Ed., 2013, 52, 12679–12683.
´
15 A. Joshi-Pangu, F. Levesque, H. G. Roth, S. F. Oliver,
L. C. Campeau, D. Nicewicz and D. A. DiRocco, J. Org.
Chem., 2016, 81, 7244–7249.
16 M. S. Lowry, J. I. Goldsmith, J. D. Slinker, R. a. Pascal,
G. G. Malliaras, S. Bernhard and R. Rohl, Chem. Mater.,
2005, 17, 5712–5719.
5 (a) A. S. Deeming, C. J. Russell, A. J. Hennessy and
M. C. Willis, Org. Lett., 2014, 16, 150–153; (b) E. J. Emmett,
B. R. Hayter and M. C. Willis, Angew. Chem., Int. Ed., 2014,
53, 10204–10208; (c) A. S. Deeming, C. J. Russell and
M. C. Willis, Angew. Chem., Int. Ed., 2016, 55, 747–750; (d)
B. N. Rocke, K. B. Bahnck, M. Herr, S. Lavergne,
V. Mascitti, C. Perreault, J. Polivkova and A. Shavnya, Org.
Lett., 2014, 16, 154–157; (e) A. Shavnya, S. B. Coffey,
K. D. Hesp, S. C. Ross and A. S. Tsai, Org. Lett., 2016, 18,
5848–5851; (f) A. Shavnya, S. B. Coffey, A. C. Smith and
V. Mascitti, Org. Lett., 2013, 15, 6226–6229.
17 (a) N. A. Romero, K. A. Margrey, N. E. Tay and D. A. Nicewicz,
Science, 2015, 349, 1326–1330; (b) A. Meyer, A. L. Berger and
¨
B. Konig, Chem. Commun., 2016, 52, 10918–10921; (c)
Y. W. Zheng, B. Chen, P. Ye, K. Feng, W. Wang,
Q. Y. Meng, L. Z. Wu and C. H. Tung, J. Am. Chem. Soc.,
2016, 138, 10080–10083.
18 D. R. Gauthier and N. Yoshikawa, Org. Lett., 2016, 18, 5994–
5997.
6 S. Shaaban, S. Liang, N.-W. Liu and G. Manolikakes, Org.
Biomol. Chem., 2017, 15, 1947–1955.
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