C-H functionalization of terminal alkynes towards stereospecific synthesis of (E) or (Z) 2-methylthio-1,4-ene-diones

Article abstract of DOI:10.1039/c4cc10438b

An efficient metal free self-sorting tandem protocol for stereospecific synthesis of 2-thio-1,4-enediones involving C-C double bond formation via direct coupling of terminal alkynes has been developed. The method was also extended to the first synthesis of β-thio-γ-keto-α,β-unsaturated esters via a cross coupling reaction with ethyl glyoxylate. The reaction relies on a first of its kind use of Bronsted and Lewis acids to switch selectivity for the synthesis of an E or a Z-isomer respectively.

Full text of DOI:10.1039/c4cc10438b

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C–H functionalization of terminal alkynes towards
stereospecific synthesis of (E) or (Z) 2-methylthio-
1,4-ene-diones†
Cite this: Chem. Commun., 2015,
51, 5013
Received 31st December 2014,
Accepted 11th February 2015
Shekaraiah Devari,‡ Arvind Kumar,‡ Ramesh Deshidi and Bhahwal Ali Shah*
DOI: 10.1039/c4cc10438b
www.rsc.org/chemcomm
An efficient metal free self-sorting tandem protocol for stereo- has no precedence in the literature. Thus, in continuation of
specific synthesis of 2-thio-1,4-enediones involving C–C double our interest,12 herein we report a mild and self-sorting tandem
bond formation via direct coupling of terminal alkynes has been reaction13 with terminal alkynes employing the first use of
developed. The method was also extended to the first synthesis of Bronsted and Lewis acids for stereoselective synthesis of (E)- or
b-thio-c-keto-a,b-unsaturated esters via a cross coupling reaction (Z)-2-methylthio-1,4-dicarbonyls respectively. The method presents
with ethyl glyoxylate. The reaction relies on a first of its kind use a simple, effective, and interesting approach to 1,4-diketones as
of Bronsted and Lewis acids to switch selectivity for the synthesis of well as an attractive way to introduce the methylthio group14 into
an E or a Z-isomer respectively.
these molecules from inexpensive dimethylsulfoxide (Fig. 1).15
The 1,4-dicabonyl moiety is not only a key component of many
Unarguably synthesis of geometrically defined E/Z-isomers repre- bioactive compounds16 such as thiaplakortone A,17 lignans, and
sents one of the most interesting and challenging areas in organic mitomycin C but also a versatile building block for the synthesis
synthesis.1 They are not only pervasive structural motifs in biologi- of various heterocycles such as furans, pyrroles and thiophenes
cally relevant molecules but also serve as a foundation for a broad by Paal–Knorr synthesis.18 The main appeal of the method lies in
range of chemical transformations.2 Also, their orientation can hitherto unreported cross coupling products of alkynes with
greatly impact the bioactivity of the resultant molecule.3 For ethyl glyoxalate to generate b-methylthio-a,b-unsaturated-g-keto
synthesis of these geometrical isomers mostly classical approaches esters. Having an ester group at the terminal position opens up
like Julia-Lythgoe olefination,4 Horner–Wadsworth–Emmons plenty of avenues as it can be coupled to a broad range of
(HWE) reaction,5 catalytic ring closing metathesis (RCM),6 Peterson bioactive molecules. For example b-methylthio-a,b-unsaturated-
olefination,7 Wittig reaction8 are followed, but drawback with all g-keto esters may well be used as new side chains for the
these methods is non-availability of simple starting materials. Over synthesis of novel paclitaxel and bestatin analogues.
the past few decades many excellent methods have been reported
We started with iodine (1 equiv.) mediated reaction of phenyl-
for synthesis of thermodynamically more stable E-alkenes,9 acetylene (1 equiv.) as a model substrate at 80 1C. Pleasingly
whereas the synthesis of less stable isomeric Z-alkenes is often the reaction gave product 2 as an E/Z-isomeric mixture in the
problematic.10 To the best of our knowledge, no single method
can provide a universal solution to their stereo-specific synthesis.
Hence development of a general stereospecific method for the
synthesis of these isomers from simple and commercially
available starting materials is of great intrigue and challenge
to synthetic organic chemists.
In this regard, despite the fact that various olefination methodol-
ogies have been developed recently,11 direct functionalization of two
sp C–H bonds to generate a CQC bond with high selectivity still
Academy of Scientific and Innovative Research (AcSIR), Natural Product Microbes,
CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-Tawi, 180001,
India. E-mail: bashah@iiim.ac.in
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra.
See DOI: 10.1039/c4cc10438b
Fig. 1 Synthesis of 2-thio-1,4-enediones.
‡ These authors contributed equally.
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Table 1 Optimization studies for the oxidative coupling of phenylacetylenea
Entry
Iodine source
Promoter
Equiv.
Yield (%)
E/Zb (%)
1
2
3
4
I2
I2
I2
KI
—
—
—
—
1
0.5
0.2
1
75
50
20
—
52 : 48
ND
ND
—
5
6
NIS
CuI
—
—
1
1
40
—
ND
—
7
8
9
10
11
12
13
14
15
16
PhI(OAc)2
—
1
Trace
58
70
72
74
56
62
10
—
—
I2
I2
I2
I2
I2
I2
I2
I2
I2
TMSOTf
TMSOTf
TMSOTf
BF3ÁOEt2
BF3ÁOEt2
BF3ÁOEt2
Cu(OAc)2
FeCl3
AlCl3
1 : 0.5
1 : 1
2 : 1
1 : 1
1 : 0.3
1 : 0.5
1 : 0.3
1 : 0.3
1 : 0.3
60 : 40
73 : 27
E only
Z only
57 : 43
72 : 28
—
—
—
—
a
b
Reactants: 1 (1 mmol), DMSO (3 ml), 18 h, 80 1C. Calculated by
comparing with reported values. ND: not determined.
52 : 48 ratio and 75% yields (Table 1, entry 1), showing that the
phenylacetylene can engage in the oxidative self cross coupling
Scheme 1 Substrate scope with different alkynes. Reaction conditions: 1
reaction. Decreasing the amount of molecular iodine to 0.5 and (1 mmol), DMSO (3 ml); path I-I2 : TMSOTf (2 : 1), 18 h, 80 1C; path II-I2 : BF3Á
Et2O (1 : 1), 18 h, 80 1C.
0.2 equiv. resulted in loss of yields (Table 1, entries 2 and 3).
Further to establish the role of iodine we performed the
reaction with KI, NIS, CuI and PhI(OAc)2, while the use of NIS
resulted in the formation of a product in 40% yield, KI, CuI and
Having conditions optimized the scope of the reaction was
PhI(OAc)2 failed to promote the reaction (Table 1, entries 4–7). expanded to various terminal alkynes. The reaction proceeded
Though we obtained the desired product with iodine but still the efficiently with a range of alkynes maintaining high selectivity
critical issue of selectivity remained unaddressed. In this regard (Scheme 1). All the alkynes with path-I using TMSOTf lead to
we thought of using a promoter like TMSOTf in conjunction with the predominant formation of an E-isomer (2aa–i), whereas
iodine. The use of TMSOTf: I2 in the 0.5 : 1 ratio in reaction with path-II employing BF3ÁEt2O gave products (2ba–i) with
showed a slight improvement in E-selectivity to 60 : 40, which Z-configuration. The reaction of p-methyl, p-tert-butyl, and p-ethyl
further increased to 73: 27 upon increasing the amount of phenylacetylene proceeded smoothly with excellent yields and
TMSOTf to 1 equiv. (Table 1, entries 8 and 9). We next changed stereoselectivity with path I (2aa–d) as well as path II (2ba–d).
the ratio of TMSOTf: I2 to 1 : 2, which to our delight leads to the We further extended the substrate scope to halo substituted
formation of an E-isomer exclusively (Table 1, entry 10).
phenylacetylenes like p-bromo and p-chloro phenylacetylene, to
Having conditions established for the selective formation of get corresponding products in good yields and selectivity with
an E-isomer, the next challenge was the stereospecific synthesis both path I (2ae–f) and path II (2be–f). The bicyclic system like
of a Z-isomer, which we understand was difficult to synthesize at 1-naphthylacetylene and o-chloro phenylacetylene also gave
higher temperatures as it is thermodynamically less stable. To our good yields and selectivity in both path I and path II (2ag–h and
surprise the use of Lewis acid, BF3ÁEt2O, in combination with 2bg–h). These results demonstrate the versatility and tolerability
iodine in the 1 : 1 ratio resulted in complete inversion of selectivity of the present methodology to a wide range of substrates. The
of the product to the Z-isomer. Changing the ratio of BF3ÁEt2O reaction of p-nitro phenylacetylene also provided the corre-
to 0.5 : 1 and 0.3 : 1 leads to the loss of selectivity as well as yields. sponding products with good yields and selectivity with path I
We also tried to investigate the effect of other Lewis acids such as (2ai) and path II (2bi).
Cu(OAc)2, FeCl3 and AlCl3 in combination with molecular iodine,
Encouraged by the results obtained with terminal alkynes, we
only to find negligible or no desired product formation. The turned our attention to the cross coupling of terminal alkynes
configuration of both the isomers (2aa & 2ba) was elucidated by with ethyl glyoxylate, as we realized the mechanism involves the
comparing the chemical shifts to that of the reported values.13
formation of 2-oxoaldehyde (2-OA) as an intermediate. Thus, we
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carried out the reaction of phenylacetylene with ethyl glyoxylate probably gets protonated by triflic acid, which is released in situ
as a model reaction under optimized conditions (Table 1, entry 10) by TMSOTf, followed by loss of water resulting in generation of
to successfully obtain the desired product (4) in good yields carbocation E, which can undergo stabilization through rearrange-
but as a mixture of E and Z isomers. Then we again optimized ment to give intermediate F. The stabilized intermediate F further
the conditions and found that a further increase in the iodine undergoes loss of protons to give 2aa. To further corroborate
ratio to 3 equiv. i.e., I2 : TMSOTf in the 3 : 1 ratio, was ideal for the role of TfOH we carried out a reaction using TfOH : I2 in the
the selective formation of an E-isomer (4aa, Table S1, ESI†). 0.5 : 2 ratio. As anticipated the reaction gave product 2aa in
To examine the scope of reaction the reaction of ethyl glyoxylate good selectivity but comparably less yields. Whereas, in path II,
was carried out with different terminal alkynes. The reaction BF3 possibly leads to the formation of Z-enolate C1 from
with electron-donating alkynes like 4-Me, 4-t-Bu and 4-OMe intermediate C, which in turn favors the formation of diastereo-
phenylacetylene smoothly gave the desired product in good selective syn-aldol intermediate G.21 The intermediate G is sub-
yield as well as selectivity (4ab–d). The reaction with an electron sequently stabilized through the formation of cyclic transition
withdrawing substituent i.e., 4-Ph, also proceeded smoothly state H with carbonyl oxygen, and promotes dehydration
under the optimized conditions to give the corresponding simultaneously to give only Z product 2ba. To further establish
product (4ae) in good stereoselectivity. The optimized condi- that S–Me migrates from DMSO, we carried out the reaction with
tions were also compatible with terminal alkynes bearing a DMSO-d6 as a solvent to successfully synthesize the corresponding
halogen substituent i.e., 2-Cl, with the corresponding products product with a deuterated methyl group (Scheme 3).
being obtained in good yield and selectivity. After obtaining
In conclusion we have developed an efficient strategy for the
the selective E-products, we were interested to synthesize the stereospecific synthesis of (E) or (Z)-2-methylthio-1,4-diones
Z-product, so we used BF3ÁEt2O in combination with I2, and tried the via self coupling of terminal alkynes as well as cross coupling
different ratios (Table S1, ESI†) but unfortunately we were not able to with ethyl glyoxylate. A simple experimental procedure, without
get the desired selectivity. The reaction using BF3ÁEt2O with a range using any metal source and a wide substrate scope are some of
of terminal alkynes and ethyl glyoxylate gave the corresponding the advantages of the process. Notably this is the first report
product (4ba–f) though in good yields but as isomeric mixtures. wherein the exclusive Z-isomer of 2-methylthio-1,4-diones has
Nevertheless the Z-isomers (4ba–f) could be easily separated through
column chromatography. The configuration of E and Z isomers was
determined through NOESY (Scheme 2).
The reaction possibly proceeds via the formation of phenacyl
iodine A directly from phenylacetylene under acidic conditions,12
which can either undergo Kornblum oxidation by dimethyl sulf-
oxide to provide phenylglyoxal B,19 or react with dimethyl sulfide
(DMS), formed by reduction of DMSO,20 to give dimethyl (phenacyl)-
sulfonium iodine C. The B in turn condenses with C in an aldol-type
reaction to produce intermediate D. In path I, the intermediate D
Scheme 2 Reaction of alkynes with ethyl glyoxylate. Reaction conditions:
reactants: 1 (1 mmol), 3 (1 mmol), DMSO (3 ml); path I-I2 : TMSOTf (3 : 1), 18
h, 80 1C; path II-I2 : BF3ÁEt2O (1 : 1), 18 h, 80 1C.
Scheme 3 Plausible mechanism.
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