Journal of the American Chemical Society
Page 2 of 6
We began our investigations by establishing suitable reaction
pyridine as an electron-mediator,22 these substrates became
competent coupling partners allowing the conversion of 4-
aminopyridine (22), 3-amino-4-methylisoxazole (23), as well as
imidazole (24) and pyrazole (25) to the corresponding sulfonamide.
As a further demonstration of the utility of this method, we
considered functionalizing amino acids, which would allow the
preparation of non-proteinogenic building blocks for the discovery
of new therapeutic peptides. The preparation of a diverse set of
sulfonamides derived from glycine (26), proline (27),
phenylalanine (28), serine (29), and tyrosine (30) was successful
and further demonstrates the functional group tolerance of this
electrochemical method. Notably, no racemization of the chiral
centra was observed under these reaction conditions (See
Supporting Information).
1
2
3
4
5
6
7
8
conditions for the coupling between thiophenol and cyclohexyl
amine (Fig 1C). We used an electrochemical microflow reactor to
rapidly screen the different reaction variables.15 Due to the small
interelectrode gap (250 μm), the high mass transfer and the large
electrode surface to volume ratio, intensified reaction conditions
are observed in this reactor.16-17 Indeed, after extensive screening
of conditions, the reaction could be completed in only 5 minutes
furnishing the targeted sulfonamide in good isolated yield as shown
in entry 1. The reaction requires only a small excess of amine (1.5
equiv), 10 mol% of Me4NBF4 as electrolyte and can be carried out
in a 3:1 (v/v) mixture of CH3CN/0.3M HCl at room temperature
using a combination of inexpensive graphite/stainless steel
electrodes. In the absence of acid or at lower concentrations, lower
isolated yields are obtained (entries 2 and 3). Switching to sulfuric
acid gave slightly lower yields compared to hydrochloric acid
(entry 4). Interestingly, a higher electrolyte concentration led to
lower yields, presumably due the formation of an electrolyte film
on the graphite electrode (entry 5).18 Other anode materials were
less efficient (entry 6). Notably, carrying out the new
transformation in a batch electrochemical cell was also possible but
required longer reaction times (24 h) and an increased electrolyte
loading (1 equivalent). The increase in electrolyte loading is
required to compensate for the higher ohmic drop with increasing
interelectrode distances, while the longer reaction times can be
attributed to a lower electrode-to-volume ratio and mass transfer
limitations.19
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Similarly, we investigated the breadth of thiols that are
compatible with the reaction conditions by coupling them with
cyclohexylamine. Thiophenols bearing electron-neutral (31-33), -
donating (34) and -withdrawing substituents (35-37) were all
tolerated. The reaction is not particularly sensitive to sterical
hindrance as ortho-substituted thiophenols (33, 36 and 37)
displayed similar yields to those with meta- (32) or para-
substituents (e.g. 31, 34-35). Interestingly, halogenated thiophenols
(36, 38-40) were viable substrates as well, providing functional
handles for further modification using classical cross-coupling
methods. Heterocyclic thiols, such as 2-mercaptopyridine (41),
methimidazole (42), 2-mercapto-4,6-dimethylpyrimidine (43), and
pyrazineethanethiol (44), were adequate coupling partners
furnishing the targeted compounds in good to excellent yields.
Notably, while methanethiol is a colorless, flammable and toxic gas
with a repulsive smell, we could use the corresponding disulfide as
alternative input feed to furnish the desired sulfonamide (45) in
75% isolated yield. Other aliphatic thiols were equally effective,
including ethanethiol (46), octanethiol (47), 2-ethyl-hexanethiol
(48), cyclohexylthiol (49), benzylthiol (50), and allylthiol (51). The
use of cysteine furnished the targeted compound in 49% yield (52).
While previous examples kept one of the reaction partners constant,
random variations are possible as shown by examples 53-57.
Biologically interesting amines, such as azetidine (54) and
nortropinone (55), displayed excellent reactivity. Interestingly, we
were able to couple cysteine with phenylalanine via the
electrochemical sulfonylative coupling in good isolated yield (56,
51%) providing opportunities for peptide modification. We also
found that lysine (57) functioned well as a coupling partner in our
electrochemical sulfonamide protocol.
With optimal conditions established, we examined the generality
of our electrochemical transformation. In most cases we used flow
processing to obtain optimal yields. However, in certain
circumstances, e.g. when longer reaction times are required or
when insoluble starting materials are used, conventional batch
techniques proved effective to obtain the targeted sulfonamide. As
shown in Fig. 2, a wide variety of structurally and electronically
distinct amines and thiols can be engaged in this transformation.
Free amine sulfonamides can be prepared with ammonia (1); these
compounds have great value in drug discovery programs but can
also be readily modified through arylation using a C–N cross
coupling strategy or more traditional coupling alkylation
reactions.20 Furthermore,
a variety of primary amines are
competent coupling partners in this protocol, including
methylamine (2), butylamine (3), tert-butylamine (4),
cyclopropanemethylamine
(5),
cyclopropylamine
(6),
cyclobutylamine (7), cyclopentylamine (8), cyclohexylamine (9)
and benzylamine (10), delivering the targeted products in good
isolated yields. The reaction conditions are readily scaled in flow
as demonstrated for sulfonamide 9, which was carried out on a 10
mmol scale. Allylamine (11) and propargylamine (12) are also
amenable to the reaction conditions and gave synthetically useful
yields. These sulfonamides are particularly interesting for further
synthetic diversification and use in bioconjugation processes using
strategies such as click chemistry.21 The coupling of more
structurally complex primary amines, such as (+)-
dehydroabietylamine (13), is also readily accomplished using this
electrochemical method. In addition, a diverse set of secondary
amines, such as dipropylamine (14), methylethylamine (15),
pyrrolidine (16), piperidine (17), morpholine (18), N-
methylpiperazine (19), 4-piperidone (20) and 4-chloropiperidine
(21), were effective substrates for this protocol. In contrast,
heteroarylamines proved to be challenging substrates resulting only
in trace amounts of product. However, by adding an equivalent of
A number of additional experiments were carried out to elucidate
the reaction mechanism of the electrochemical sulfonamide
synthesis (Fig.3). Kinetic experiments revealed that within the first
20 seconds of the reaction the thiol substrate is completely
converted via anodic oxidation to the corresponding disulfide
(Fig.3A).23 Indeed, we found that disulfides were equally
competent coupling partners compared to the parent thiol
substrates, providing opportunities to circumvent the use of some
of the most odorous thiols (Fig.3C). The disulfide is consumed
within 5 minutes and the corresponding sulfonamide is formed,
albeit at a slightly different rate. This hints to the fact that the
sulfonamide formation occurs via several intermediate steps.
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