Thermolysis-Induced Two- or Multicomponent Tandem Reactions Involving Isocyanides and Sulfenic-Acid-Generating Sulfoxides: Access to Diverse Sulfur-Containing Functional Scaffolds

Article abstract of DOI:10.1021/acs.orglett.7b03593

Direct reaction of isocyanides with some sulfenic-acid-generating sulfoxides led to the effective formation of the corresponding thiocarbamic acid S-esters in good to high yields. A multicomponent reaction involving isocyanide, sulfoxide, and a suitable nucleophile has also been developed, providing ready access to a diverse range of sulfur-containing compounds, including isothioureas, carbonimidothioic acid esters, and carboximidothioic acid esters.

Full text of DOI:10.1021/acs.orglett.7b03593

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Thermolysis-Induced Two- or Multicomponent Tandem Reactions
Involving Isocyanides and Sulfenic-Acid-Generating Sulfoxides:
Access to Diverse Sulfur-Containing Functional Scaffolds
Shengfeng Wu,† Xiaofang Lei,† 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: Direct reaction of isocyanides with some
sulfenic-acid-generating sulfoxides led to the effective for-
mation of the corresponding thiocarbamic acid S-esters in
good to high yields. A multicomponent reaction involving
isocyanide, sulfoxide, and a suitable nucleophile has also been
developed, providing ready access to a diverse range of sulfur-
containing compounds, including isothioureas, carbonimido-
thioic acid esters, and carboximidothioic acid esters.
ne of the driving forces behind the development of
modern synthetic methodology is the demand for ever-
center and isocyanide. To the best of our knowledge, to date
there were very limited reports on such reactions (Scheme 1).
O
increasing molecular diversity in chemical, biological, and
medical research. In this regard, multicomponent reactions1
represent a set of unique synthetic tools to meet the diversity
demand because of their efficient transformation of several
functional groups into a new one. Traditional multicomponent
reactions without transition-metal catalysis mostly involve the
use of at least one carbonyl group (aldehyde or ketone) as a
reacting component.2 Multicomponent reactions can move
beyond carbonyl group with transition-metal catalysis.3 Among
all multicomponent reactions reported, reactions that involve
isocyanides probably attracted the most attention because of the
dual nucleophilic and electrophilic properties of the reactive
carbon center. However, from the early studies of the Passerini
reaction4 or Ugi reaction5 to the more recent developments,6
most of the isocyanide-involved multicomponent reactions still
use a carbon-based electrophilic center. Therefore, expanding the
general scope of multicomponent reactions to incorporate
isocyanides and noncarbon electrophiles would represent a
significant advance in the field.
Scheme 1. Multicomponent Reactions Involving Isocyanides
and Electrophilic Sulfur Centers
We recently demonstrated the application of tert-butyl
sulfoxides as stable surrogates to sulfinyl halides for the synthesis
of sulfinic acid derivatives and other sulfoxides,7 and for the
synthesis of aryl[4,5]isothiazoles through an all-heteroatom
Wittig process.8 As an effort to further explore tert-butyl sulfoxide
chemistry, we have recently examined the reaction of benzyl
isocyanide with phenyl tert-butyl sulfoxide in toluene. Intrigu-
ingly, after 2 h of reaction, N-benzyl S-phenyl thiocarbamate was
isolated as the major product (89% yield). Because it is well-
known that sulfenic acid can be generated in situ via thermolysis
of a tert-butyl sulfoxide or other alkyl sulfoxides with β-
hydrogen,9 we surveyed the literature for documented examples
of multicomponent reactions between an electrophilic sulfur
Maes et al. reported a three-component reaction using
isocyanides, aryl amines, and thiosulfonates under Cu(I)
catalysis, which was thought to proceed through an imino-
methylene sulfonium intermediate.10 Martens et al. reported that
when certain 2,2- and 5,5,-tetraalkylated 2,5-dihydro-1,3-thiazole
S-monoxides were treated with isocyanides in alcoholic solvents
in the presence of benzoic acid, isothiourea derivatives were
Received: November 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03593
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Letter
generated, and the reaction was supposed to proceed through a
sulfenic acid related reaction pathway.11 These reports are
supportive of our hypothesis that the reaction between benzyl
isocyanide and phenyl tert-butyl sulfoxide may also go through
sulfenic acid and form an iminomethylene sulfornium
intermediate (Scheme 1). Water molecules released in the
formation of the sulfonium ion can act as a nucleophile to trap
the iminomethylene sulfonium, hence leading to the formation of
thiocabamate. If one can utilize this reaction pathway in a general
way, then many important classes of molecules such as those
shown in Scheme 1 could be conveniently accessed.12
temperature (lower than the threshold value for thermolysis of
1a).
Further examples of reactions of isocyanides with tert-butyl
sulfoxides are listed in Table 2. The first eight examples are
Table 2. Substrate Scope for Reactions of Isocyanides with
tert-Butyl Sulfoxides
On the basis of this proposed mechanism, the formation of the
iminomethylene sulfornium intermediate also requires a proton
source. This can be furnished from another sulfenic acid
molecule. Alternatively, an externally provided proton source
should facilitate the reaction, as observed when 0.1 equiv of acetic
acid was used (see the Supporting Information). To gather
evidence that supports the sulfenic acid pathway, we tested some
other sulfoxides, known to generate the corresponding sulfenic
acids upon treatment under thermolytic conditions, for their
reactions with benzyl isocyanide in toluene under heating
conditions. The results are listed in Table 1. These five phenyl
Table 1. Reactions of Benzyl Isocyanide with Alkyl Phenyl
Sulfoxides That Can Generate Sulfenic Acids
reactions using phenyl tert-butyl sulfoxides; various alkyl and aryl
isocyanides gave satisfactory isolated yields (76−89%) of the
expected products. For reactions with benzyl isocyanide,
substituted phenyl sulfoxides were tested. Para-methoxy- or
fluoro-substitution gave excellent results (products 3i and 3j).
But nitro- and cyano-substitutions lowered the isolated yield to
∼40% (3k and 3l). For alkyl tert-butyl sulfoxides, the yields were
generally low and were in the 40−50% range (3m, 3n, and 3o).
Subsequently, we proceeded to examine the multicomponent
reactions of benzyl isocyanide with a tert-butyl sulfoxide and an
amine or alcohol as the extra nucleophile. Among the various
alcohols and amines tested, only aryl amines gave satisfactory
results. For reactions with added alcohols, small amounts of the
corresponding products, usually less than ca. 10%, were detected
by LC-HRMS, with the major products being identical to the
thiocarbamates from the two-component reactions. For
reactions with added alkyl amines, no desired multicomponent
nor two-component reaction products were isolated, and the tert-
butyl sulfoxide as starting material was consumed. This can
probably be explained by the requirement of acidic conditions for
the desired reaction to proceed. Addition of conventional
alkylamine with high pKa will produce ammonium ion and
deplete sulfenic acid. A similar outcome was observed in the
multicomponent reaction using isocyanides, thiosulfonates, and
amines.10 Successful examples of reactions involving aryl amines
are listed in Table 3.
Mechanistically, the intermolecular multicomponent reactions
potentially face the issue of competing addition to the sulfenic
acid by an amine nucleophile instead of the intended isocyanide.
We performed control experiments in the absence of isocyanide.
Heating a toluene solution of phenyl tert-butyl sulfoxide in the
presence of either aniline or benzyl amine did not lead to
isolatable amine adducts. Instead, a sulfonyl S-ester was obtained
(see the Supporting Information). When a less than stoichio-
metric amount of isocyanide was used in the reaction with
aniline, both the isothiourea (three-component) and the sulfonyl
S-ester products were isolated. These results indicated that under
alkyl sulfoxides were heated in toluene at temperatures reported
to efficiently generate sulfenic acid.13 Among these sulfoxides,
tert-butyl- and methoxycarbonylethyl sulfoxides gave the
targeted product 3a in very good yields (88−89%), while others
gave much inferior results (25−45% isolated yield of 1b, 1d, 1e).
Furthermore, LC-HRMS spectra of the reaction mixture of 1a, 2a
and 4 or 8 equiv of H218O indicated 15% or 48% of 18O-labeled
3a, respectively, well above the natural abundance of that for 3a
(see the Supporting Information). The 18O-labeling experiment
supports water’s nucleophilic attack to the proposed inter-
mediate, rather than a direct oxygen migration from sulfur to the
carbon center. Taken together, these results are consistent with
the mechanism outlined in Scheme 1.
Given that tert-butyl sulfoxides produced high yield and that
their synthesis in general would be easier to handle than the
methoxycarbonylehtyl sulfoxides, all subsequent investigations
were focused on the use of tert-butyl sulfoxides. Commonly used
solvents were screened for the reaction of benzyl isocyanide with
phenyl tert-butyl sulfoxide. Toluene was still found to be the best,
as compared to other aprotic high-boiling polar solvents
(dioxane, DMF, or DMSO) that gave 65−28% isolated yields
for 3a. Using THF, methanol, acetonitrile, or dichloromethane as
solvent, no desired product 3a was detectable under refluxing
conditions, presumably as a result of inadequate reaction
B
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Table 3. Successful Examples of Intermolecular
Multicomponent Reactions
Table 4. Successful Examples of Tandem Reactions with a
Third Intramolecular Nucleophile
those reaction conditions amines could not effectively attack
sulfenic acid but isocyanides could.
To overcome the above limitations in intermolecular multi-
component reactions, we sought to investigate intramolecular
versions of the reaction by incorporating the extra nucleophilic
functional group within the molecular skeleton of either the
sulfoxide or the isocyanide. While the intramolecular cases may
be classified more properly as tandem reactions, success in such
an approach will result in many different heterocyclic scaffolds.
To our satisfaction, intramolecular tandem reactions of
isocyanides and tert-butyl sulfoxides, bearing an extra nucleo-
philic moiety within either reactant, are generally successful with
high yields. A collection of examples are listed in Table 4. In those
examples, the first two are with alcohols as intramolecular
nucleophiles that produced carbonimidothioic acid esters. When
a hydroxyl group is present at the γ-position relative to the
isocyanide, the produced carbonimidothioate moiety is a
sulfanyl-5,6-dihydro-4H-[1,3]oxazine derivative (product 5a,
entry 1, Table 4). When a hydroxyl group is at the β-position
to the sulfoxide, the carbonimidothioate moiety is formed as
[1,3]oxathiolan-2-ylideneamine (product 5b, entry 2, Table 4).
Entry 3 in Table 4 is an example of carbon nucleophile. Phenyl
tert-butyl sulfoxide was reacted with isocyanide 2c that contained
an indol-2-yl group. The formed carboximidothioate moiety is
present in the product 5c as a fused quinoline ring with a
phenylsulfanyl substitution. Note that the sulfanyl group can be
turned into a good leaving group (sulfone) after oxidization.
Further transformation to displace the sulfone with propylenedi-
amine led to a key intermediate for a class of MV4-11
inhibitors12b for cancer drug development (Scheme 1 and the
Supporting Information). In entry 4, the sulfoxide contained an
ortho- primary amide group, which led to efficient formation of
the acyl isothiourea moiety present in a class of inhibitors against
type-I 11ß-hydroxysteroid dehydrogenase for potential diabetes
treatment (Scheme 1).12c Note that intramolecular trapping of
sulfenic acid by an amide group was reported before.14 In our
case of entry 4 reaction, only 5% of amide-trapped product was
obtained, indicating that addition of isocyanide to sulfenic acid is
faster than intramolecular amide trapping (see the Supporting
Information). Entry 5 is an example of aryl amine at the β-
position to the sulfoxide. The formed isothioureas is represented
as 2-amino-benzothiozole (product 5e). Entries 6−12 in Table 4
are examples with starting materials that contain an alkyl amine
three carbon atoms away from the sulfoxide group. These
produced benzene-fused 2-amino-[1,3]thiazines with respect-
able yields (68−91%). Because many examples in Table 4 involve
chiral centers in addition to the sulfoxide group, an evaluation of
the preservation of nonsulfur chiral center was performed using
the reaction of entry 6. Both the racemic and the optically
enriched (97.1% de) starting 1i were used. Little racemization
could be observed under this thermolytic procedure, as the
optically enriched material produced 5f with 96.6% ee (see the
Supporting Information).
Finally, we sought to further expand the scope of the
isocyanide-sulfoxide tandem reaction by using starting materials
that contained a fourth functional group, which could potentially
lead to more complex heterocycles. As shown in Table 5,
interesting results were obtained with these trials. Entry 1 in
Table 5 used an intermolecular three-component reaction where
the aryl amine contained an ortho-methoxycarbonyl group. The
formed isothiourea then reacted further with the methyl ester to
form a heterocyclic product 6a. From entries 2−5 in Table 5,
sulfoxides with an amino group were reacted with isocyanides
containing an aliphatic carboxylic acid methyl ester, which could
be conveniently prepared from the corresponding amino acids.
These methyl aliphatic carboxylates did not go through tandem
transformation as expected, and the final products retained the
ester group for further manipulation. In contrast, entries 6 and 7
are examples with benzyl aliphatic carboxylates. In these cases,
C
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ORCID
Table 5. Examples of Tandem Reactions with Additional
Functional Group
Zhihua Sun: 0000-0003-2407-6010
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the Science
and Technology Commission of Shanghai Municipality
(17ZR1412000). We acknowledge Dr. Zheng Wang from the
Shanghai Institute of Organic Chemistry for helpful discussions.
DEDICATION
In memory of Professor Changqi Hu (1940−2017).
■
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ASSOCIATED CONTENT
* Supporting Information
■
(14) Sivaramakrishnan, S.; et al. J. Am. Chem. Soc. 2005, 127, 10830.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03593.
Procedures and characterization data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: sungaris@gmail.com
D
DOI: 10.1021/acs.orglett.7b03593
Org. Lett. XXXX, XXX, XXX−XXX