In Situ Activation of Disulfides for Multicomponent Reactions with Isocyanides and a Broad Range of Nucleophiles

Article abstract of DOI:10.1021/acs.orglett.9b00275

Activation of disulfides with N-halogen succinimide in the presence of TEMPO allows insertion reaction by an isocyanide, the product of which can further accept a wide range of nucleophiles for the generation of isothioureas and related molecular moieties. This new procedure overcomes previous methods that accept essentially only aryl amines as the third nucleophilic component. The diverse nucleophiles usable in our new protocol make this approach a general method for de novo synthesis of many S-containing heterocycles.

Full text of DOI:10.1021/acs.orglett.9b00275

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
In Situ Activation of Disulfides for Multicomponent Reactions with
Isocyanides and a Broad Range of Nucleophiles
Xiaofang Lei,† Yuanyuan Wang,† Erkang Fan,‡ and Zhihua Sun*,†
†College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science 333 Longteng Road, Shanghai
201620, China
‡Department of Biochemistry, University of Washington, 1705 NE Pacific Street, Seattle, Washington 98195, United States
S
* Supporting Information
ABSTRACT: Activation of disulfides with N-halogen succi-
nimide in the presence of TEMPO allows insertion reaction
by an isocyanide, the product of which can further accept a
wide range of nucleophiles for the generation of isothioureas
and related molecular moieties. This new procedure over-
comes previous methods that accept essentially only aryl
amines as the third nucleophilic component. The diverse
nucleophiles usable in our new protocol make this approach a
general method for de novo synthesis of many S-containing
heterocycles.
he isothiourea moiety is an important feature present in
many small molecules used in chemical and biological
some heterocyclic compounds such as those S-alkyl or S-aryl
sulfanyl substituted [1,2,4]triazoles found in compounds 1 or
2, fused rings in compound 5, or aminothiazoles in compound
6 can be a challenge. For example, large-scale synthesis of
compound 1 requires the handling of 4-aryl-[1,2,4]triazole-3-
thiol-related intermediates,4 which was reported to have toxic
effects on skin, eyes, and the respiratory track.5 It is therefore
very desirable to develop a general and efficient synthetic
methodology for the construction of an isothiourea moiety in
many different forms. In this regard, we aim to develop such
synthetic methodology based on a multicomponent reaction of
isocyanides with an electrophilic sulfur center and a broad
range of nucleophiles.
T
applications. Figure 1 shows select examples of molecules
(compounds 1−7) that contain the isothiourea moiety in
various forms as an approved drug,1 as potent inhibitors of
biological targets/pathways,2 or as a chiral catalyst.3 While
synthetic procedures for a standard isothiourea such as that
present in compound 3 are straightforward,2b synthesis of
While three-component reactions involving isocyanides and
electrophilic sulfur centers have been reported by us6 and the
Maes group,7 both published procedures (Scheme 1) have the
limitation that generally the third nucleophilic component has
to be aromatic amines or special aliphatic amines with low pKa.
Using our reported protocol, a broader range of nucleophiles
are acceptable only when the reaction is carried out in an
intramolecular fashion. As a consequence, our sulfenic acid
based protocol is more useful in the construction of
heterocycles with fused ring systems.6 In order to expand the
application of such three-component reactions, we thought to
change the reaction pathway so that the limitations on the
nucleophilic component can be overcome.
Our previously reported method was thought to proceed
through isocyanide addition to sulfenic acid to form an
iminomethylene sulfornium intermediate after loss of water,
which allows further reaction with a nucleophile (Scheme 1).6
Figure 1. Select examples of molecules that contain the isothiourea
moiety.
Received: January 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00275
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Comparison of the Present Reaction Pathway
That Can Accept a Wide Variety of Nucleophiles to Earlier
Reports with Limited Aryl Amine Nucleophiles
Table 1. Using a Model Reaction To Explore Reaction
Conditions
ratio (a/b/c/d/
e)
yield
(%)
entry
initiator
oxidant
solvent
1
2
3
4
5
6
7
8
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
none
AIBN (60 °C)
none (60 °C)
BPO (40 °C)
TEMPO
NCS
NCS
NCS
NCS
NCS
NCS
NBS
NCS
NCS
NCS
NCS
NCS
toluene
THF
DMF
CH3CN
DCM
DCE
DCM
DCM
DCE
1/0.2/2/2/2
1/0.2/2/2/2
1/0.2/2/2/2
1/0.2/2/2/2
1/0.2/2/2/2
1/0.2/2/2/2
1/0.2/2/2/2
1/0/2/2/2
1/0.2/2/2/2
1/0/2/2/2
1/0.2/2/2/2
1/0.2/1/2/2
trace
83
45
75
85
82
55
none
82
9
10
11
12
DCE
DCM
DCM
none
14
a
58
a
We reasoned that if we start with a corresponding sulfenyl
halide instead of sulfenic acid, one may expect that an
isocyanide can be inserted to form a S-substituted
thiomethylimidoyl halide similar to that of isocyanide insertion
to an acyl halide.8 Reactions of isocyanides with sulfenyl
halides followed by intramolecular trapping or solvent-assisted
transformation were reported before.9 If we can identify
conditions compatible with a third nucleophile, potentially this
reaction pathway can accept a wide variety of nucleophiles for
multicomponent transformations (Scheme 1).
Reaction time: 24 h.
spectroscopic evidence of both sulfenyl chloride and N-
sulfenyl succinimide related intermediates in the reaction
mixture (see the Supporting Information). We also found that
the isolated N-sulfenyl succinimide can react with benzyl
amine to give the final desired product (see the Supporting
Information).
With the success of the model reaction, we proceeded to
explore the scope of tolerance for the various disulfides and the
final nucleophiles while keeping the isocyanide constant
(benzyl isocyanide). The results are summarized in the
following schemes (Schemes 2 and 3). In Scheme 2, the first
12 examples used aniline or substituted anilines as the
nucleophile while exploring a range of aryl and alkyl disulfides.
In most cases, isolated yields of >70% were achieved for aryl or
Preparation of sulfenyl halides was well documented through
reaction of N-halogen succinimide or halogen with thiols10 or
sulfuryl halides with disulfides.11 For ease of starting material
access and consideration of compatibility to multicomponent
reaction settings, we sought to achieve the preparation of
sulfenyl halides using disulfides and N-halogen succinimide.
We found that in the presence of 0.2 equiv of TEMPO,
sulfenyl chloride can be readily obtained with a disulfide and 2
equiv of NCS. We then used this condition to explore a model
reaction of activating phenyl disulfide with NCS, followed by
addition of benzyl isocyanide, and then by addition of aniline
as the nucleophile. As shown in Table 1, high yields of the
desired final product were obtained in several solvent systems
such as THF, DCM, DCE, or acetonitrile, but toluene was not
good while DMF produced moderate yield (entries 1−6 in
Table 1). Under similar reaction conditions, using NBS was
slightly less effective than NCS, giving 55% yield (entry 7).
It seems that the generation of sulfenyl halide went through
a radical pathway because eliminating TEMPO from the
system gave no final product (entry 8) while using a radical
initiator AIBN at 60 °C produced the desired product with
82% yield (entry 9 and control reaction omitting AIBN as
entry 10). Another radical initiator benzoyl peroxide (BPO)
was less effective (14% yield, entry 11). If the reaction indeed
goes through a radical pathway, one may expect that not only
sulfenyl halide is generated during the reaction but also N-
sulfenyl succinimide may also be formed (see Scheme 1) and
only 1 equiv of NCS or NBS is necessary to carry out the
reaction. A reaction using 1 equiv of NCS was performed, and
after 24 h of reaction, more than 50% yield was achieved (entry
12), indicating both sulfenyl halide and N-sulfenyl succinimide
were involved in the reaction, although the condition using 2
equiv of NCS is more efficient (entry 5). We have
Scheme 2. Substrate Scope for Reactions of Disulfides with
Isocyanides and Nitrogen-Based Nucleophiles
B
DOI: 10.1021/acs.orglett.9b00275
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Organic Letters
Letter
succinimide. We now can turn our attention to demonstrate
the application of our method in the construction of diverse S-
containing heterocycles (particularly single-ring examples) that
are important in chemical and biological research. As shown in
Table 2, in this preliminary study, we have successfully formed
several different S-containing ring systems with readily
accessible starting materials and high efficiency.
Scheme 3. Substrate Scope for Reactions of Disulfides with
Isocyanides and O-, S-, or C-Based Nucleophiles
Table 2. Construction of Several Important S-Containing
Heterocyclic Moieties
a
b
The disulfide is 1,2-diphenyldisulfane. The disulfide is 1,2-
c
d
dibutyldisulfane. The nucleophile is sodium methoxide. The
nucleophile is sodium isopropoxide. The nucleophile is sodium
trifluoroacetate. The nucleophile is thiophenol. The nucleophile is
phenyl magnesium bromide. The nucleophile is 1H-indole. The
nucleophile is 5-methoxy-1H-indole. The nucleophile is 5-bromo-1H-
indole. The nucleophile is 1-methyl-1H-pyrrole. The nucleophile is
e
f
g
h
i
j
k
l
m
N-methylaniline. The nucleophile is 4-fluoro-N-isopropylaniline.
n
The ortho-position product was isolated at 18%.
alkyl disulfides while 4-nitrophenyl and 2-pyridyl disulfides
gave yields around 53−55% (compound 11 and 14). Then the
next eight examples in Scheme 2 explored the use of
nonaromatic amines as nucleophiles. It shows that ammonia,
alkyl amines, and hydrazines are all good nucleophiles for the
intended reactions with 75−86% isolated yields of the final
products. These results showed that our new protocol met our
goal of overcoming the limitation of using aryl amines as
nucleophiles for multicomponent reactions of electrophilic
sulfurs and isocyanides. It thus opens up new general
methodologies for the de novo construction of S-containing
heterocycles (see the later results).
Scheme 3 contains examples with non-nitrogen nucleo-
philes. The first five examples cover oxygen-based nucleophiles
in the form of alkoxides. The isolated yields were in the range
of 25−62% and in general worse than examples of nitrogen-
based nucleophiles as shown in Scheme 2. This indicates that
additional work is needed to improve our procedures for
reactions with alcohols/alkoxides. On the other hand, PhSH or
PhMgBr gave acceptable results with, respectively, 75% and
65% isolated yields and demonstrated the general acceptance
of S- or C-based nucleophiles (compounds 33 and 34).
Compounds 35−38 shows special indole-based carbon
nucleophiles with excellent isolated yields (all >80%), and
the result with N-alkyl pyrrole (compound 39, 71% yield) is
also good. The last two examples are N-substituted anilines.
The reduced reactivity of the aniline nitrogen due to N-
substitution allows the carbon at the ortho- or para-position to
act as a nucleophile for the intended reaction, and good yields
were obtained (63−81%, compounds 40 and 41).
Because our protocol can use hydrazine as a nucleophile, the
first examples in Table 2 attempted to synthesize sulfanyl-
substituted [1,2,4]triazoles. In entry 1, the desired triazole final
product was obtained in 86% isolated yield. Entry 2 in Table 2
shows an example of synthesizing 2-sulfanyl-substituted
imidazole. The final product was obtained in 78% isolated
yield.
Examples in the preceding tables demonstrate that our new
sulfenyl halide/succinimide route is suitable for a wide range of
nucleophiles after isocyanide insertion to the sulfenyl halide/
Starting from entry 3, the examples cover compounds with
the S atom resides within the ring system (single or fused). In
C
DOI: 10.1021/acs.orglett.9b00275
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
entry 3, an example of nonaromatic isothiourea ring was shown
with 73% isolated yield. Entries 4−6 contain the same core 2-
amino thiazole ring moiety while altering the 4-position
substitution with an alkoxy group (entry 4, 68%), a phenyl
group (entry 5, 76%), or an alkyl group bearing additional
leaving groups that led to the formation of a fused ring (entry
6, 56%). Finally, entry 7 shows an example for the construction
of the benzotetramisole (BTM) moiety present in an
important class of organic catalysts with 71% isolated yields.
Overall, examples in Table 2 demonstrate that our new
multicomponent protocol can serve as a general synthetic
method for de novo construction of many important S-
containing heterocycles.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: sungaris@gmail.com.
ORCID
Zhihua Sun: 0000-0003-2407-6010
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the Science and
Technology Commission of Shanghai Municipality
(17ZR1412000).
We also use this new protocol to synthesize the FDA
approved drug lesinurad (Scheme 4). The ester precursor to
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the drug lesinurad (compound 1 in Figure 1) can be
synthesized in one step from the corresponding isocyanide
using our three-component protocol in 52% isolated yield.
Note that in this protocol NBS was used as the activator and
was in excess so that direct bromination of the triazole at its 5-
position can occur after ring formation. In comparison, patent
literature revealed several synthetic procedures of lesinurad
with four or more steps from 2-amino-7-cyclopropylnaph-
thalene, and those procedures generally involve the formation
and handling of the toxic [1,2,4]triazole-3-thiol intermediates
(Scheme 4). The overall yield of our procedure is about 36%,
well above the 4−21% range based on patent literatures.
In summary, we developed a sulfenyl halide (and
succinimide) based multicomponent protocol that involves S-
electrophilic center and isocyanide through in situ activation of
disulfides. The procedure is suitable to a wide range of
nucleophiles for the formation of isothiourea or analogous
moieties. Inparticular, when our procedure is employed in the
synthesis of S-containing heterocycles, the advantages of mild
reaction conditions, reduced purification steps, and ease of
starting material accessibility will make our method a useful
addition to existing methodologies.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00275.
General methods; experimental procedures and spectral
1
data; H and 13C NMR spectra; and references (PDF)
D
DOI: 10.1021/acs.orglett.9b00275
Org. Lett. XXXX, XXX, XXX−XXX