Communications
doi.org/10.1002/cctc.202100803
ChemCatChem
redox active esters as alkylating reagents (Figure 1B). This
process does not require the use of transition metal catalysts or
strong acids, presenting a key advantage over several tradi-
reaction. At least 10 mol% lithium tetrafluoroborate was
required to guarantee high reaction efficiency (Table 1, en-
tries 5–7). The desired product was not obtained with the use
of other solvents, such as ethyl acetate, acetone and acetonitrile
(entries 8–10). When 2a was used as a limiting reagent, a
comparable yield was noted (entry 11).
tional equivalent methods.
A broad array of N-alkylated
sulfonamides were prepared with high functional group
compatibility.
After our initial screening of nitrogen-based nucleophiles,
sulfonamides were found to be amenable to our organo-
photoredox-catalyzed decarboxylative alkylation. To establish
the protocol for N-alkylation of sulfonamides, conditions screen-
ing was performed on the representative reaction between p-
toluenesulfonamide (1a) and pivalic acid-derived redox active
ester (2a). Based on our results from similar decarboxylative
cross-couplings, we started our screening with catalytic
amounts of N-phenyl benzo[b]phenothiazine (PTH1)[13] and
lithium tetrafluoroborate, with dichloromethane as the solvent,
stirring under blue LED light. The trial reaction proceeded well
to furnish the desired N-alkylated product (3aa) in 83% isolated
yield without the formation of the N,N-dialkylated by-product
(Table 1, entry 1).
With the optimal reaction conditions established, the scope
of applicable sulfonamides was examined with tert-butyl redox
active ester 2a (Scheme 1, top). The reactions with o- and m-
toluenesulfonamide gave the corresponding N-alkylated prod-
ucts in moderate yields (3ba and 3ca). Various halogen
substituents were well-tolerated under the optimized reaction
conditions (3da–3fa). Further to this, neither electron-deficient
nor electron-donating groups significantly affected the reaction
efficiency (3ha–3ja). Aliphatic sulfonamides were also suitable
substrates to yield C(sp3)-rich sulfonamide scaffolds with this
organophotoredox catalysis (3ka and 3la). Our protocol also
allowed the functionalization of the sulfonamide-containing
pharmaceutical drug substrates, zonisamide and celecoxib
(3ma and 3na).
The structure of photocatalyst was critical to drive the
desired reaction (Table 1, entries 2–4). For example, the use of
PTH2, bearing a benzo[a]phenothiazine scaffold, resulted in low
conversion of substrate (entry 2).[14] The product yield dramati-
cally decreased when a simple phenothiazine-based catalyst
(PTH3) was used instead of PTH1 (entry 3). A poor yield was
also observed when using N-phenyl benzo[b]phenoxazine
(POX1) as a photoredox catalyst (entry 4).
Next, we evaluated the scope of redox active esters with 1a
as a coupling partner (Scheme 1, bottom). It was possible to
synthesize alternative acyclic N-alkyl sulfonamides using our
protocol (3ab). Notably, aliphatic rings of various sizes could be
readily installed with moderate efficiencies. (3ac–3ae). Redox
active esters containing a tetrahydropyranyl group or an
adamantyl group participated in the reaction as good alkylating
reagents (3af and 3ag, respectively). An α-alkoxy derived
substituent was well tolerated under these reaction conditions.
(3ah). This alkylation protocol was applicable not only to
aromatic sulfonamides but equally to aliphatic sulfonamides
(3li and 3lg). The reactions with tertiary and secondary benzylic
redox active esters also proceeded well to afford the corre-
sponding alkylated products in moderate to high yields (3aj–
3al). We also demonstrated how our photocatalyzed sulfonami-
dation transformation could be applied to carboxylic acid-
containing druglike molecules, such as loxoprofen and gemfi-
brozil (3am and 3an). Additionally, two sulfonamide-containing
drugs were shown to react with 2o to furnish the desired
alkylated products (3mo and 3no). Although the yields were
low, these results display the potential application of our
reaction to high-throughput organic synthesis of drug-like
molecules.
To gain insight into the reaction mechanism, we carried out
the stoichiometric reaction of PTH1 and the 1-adamantanecar-
boxylic acid-derived redox active ester 2g in the presence of
lithium tetrafluoroborate salt (Figure 2A). After blue light
irradiation for 6 h, a peak corresponding to the alkylsulfonium
intermediate PTH1-2g was detected by direct analysis in real
time - high resolution mass spectrometry (DART-HRMS). This
result provided evidence towards the presence of the proposed
alkylsulfonium intermediate in this organophotoredox-catalyzed
reaction. The same trial with 2a instead of 2g was unsuccessful,
likely due to the instability of the tertiary butyl cation or the
corresponding alkylsulfonium species.
The additive and solvent were also noted to play a
significant role in this catalysis. As in our previous report,
lithium tetrafluoroborate salt was essential to promote the
Table 1. Optimization of Reaction Conditions for Coupling between 1a
and 2a[a]
Entry Change from standard conditions
Yield of 3aa
[%])[b]
1
2
3
4
5
6
7
8
none
99 (83)
22
3
28
10
32
99
0
PTH2 instead of PTH1
PTH3 instead of PTH1
POX1 instead of PTH1
without LiBF4
LiBF4 (5 mol%)
LiBF4 (20 mol%)
EtOAc instead of DCM
Acetone instead of DCM
MeCN instead of DCM
9
10
11
0
0
1a (0.6 mmol), 2a (0.2 mmol) and DCM (0.3 mL) 87 (64)
for 18 h
[a] The reaction was carried out with 1a (0.2 mmol), 2a (0.3 mmol), PTH1-
3 or POX1 (0.01 mmol, 5 mol%), and LiBF4 (0.02 mmol, 10 mol%) in DCM
(0.5 mL, 0.4 M) under blue LED irradiation for 24 h. [b] 1H NMR yield based
on 3aa. Yield of the isolated product is in parentheses.
The proposed mechanism is outlined in Figure 2B. Based on
our previous report, PTH1 and a redox active ester (2) form an
ChemCatChem 2021, 13, 1–5
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Nakagawa, Masanari
