(: Z)-Selective anti-Markovnikov or Markovnikov thiol-yne-click reactions of an internal alkyne by amide hydrogen bond control

Article abstract of DOI:10.1039/d0cc00702a

Herein, we show exclusive control of stereo and regioselective thiol-yne click (TYC) reactions of internal alkynes via amide hydrogen bond control. By exploiting appropriate hydrogen bonding interactions like N-H?S, N-H?N and C-H?O, either (Z)-selective anti-Markovnikov or Markovnikov products could be obtained for an internal alkyne, exclusively.

Full text of DOI:10.1039/d0cc00702a

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(Z)-Selective anti-Markovnikov or Markovnikov Thiol-Yne-Click
Reactions of an Internal Alkyne by Amide Hydrogen Bond Control
Milan Pramanik, Khokan Choudhuri, Subhayan Chakraborty, Arindam Ghosh and Prasenjit Mal*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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Herein, we show an exclusive control on stereo and regioselective bonding interaction by amides is known in dipeptides and
Thiol Yne Click (TYC) reactions of internal alkynes via amide amide H-bonding is essential to control conformation and build
hydrogen bond control. By exploiting appropriate hydrogen of secondary or tertiary structure of proteins.13 The concept of
bonding interactions like N-H…S, N-H…N and C-H…O, either (Z)- H-bonding in secondary amide linkage is found to be important,
selective anti-Markovnikov or Markovnikov products could be however, more attention has been paid to the tertiary amide
obtained for an internal alkyne, exclusively.
linkage.14 To the best of our knowledge, the utilization of N-H…S
H-bonding in controlling chemical reaction is unexplored and
might be a desirable topic in organic synthesis.
The major aspect of living being is the capability of executing
their bio-molecular mechanism to create very complex set of
molecular structures from the available relatively simpler units.1
However the chemical reactions controlled by weak or non-
covalent interactions are important to synthesize complex
molecules with functions.2 Among the weak interactions,
hydrogen bonding (H-bonding) is one of the most important
noncovalent interactions which play a pivotal role to control
many physical and chemical properties of molecules.3 It is
known in literature that H-bond donor or acceptor can make a
stereo defined environment within a system via inter- or
intramolecular fashion.4 Thus many challenging reactions could
easily be performed by exploiting suitable H-bonding
interactions. Few examples of H-bonding initiated reactions are
Diels-Alder reaction by Rawal,5 electrophilic activation reaction
to synthesize 1,2-disubstituted benzimidazoles by Chakraborti
and co-workers,6 HFIP assisted para-selective C-H amination
reaction by Crousse and coworkers,7 synthesis of heterocycles
indolines by Jeffrey and Wu et al.,8 (Radio)fluoroclick reaction
by Hammond and Xu with co-workers,9 etc.
The alkyne hydrothiolation or “Thiol-Yne Click” (TYC)
reaction is one of the promising approaches for making organo-
sulfur compounds in research areas like supramolecular,15
polymer,16 medicinal,17 materials,18 etc. Vinyl sulfides produced
from TYC reaction are omnipresent in bioactive molecules19 and
are generally obtained as regioisomers via Markovnikov or anti-
Markovnikov pathways.20 For TYC reaction, many methods by
using of photoredox catalyst,21 organoactinide,22 ionic-liquids,23
UV-light,24 etc. are reported in literature. These reactions are
performed either by initiation through radical25 or ionic26
pathways, however, they have poor selectivity. Recently, Lei
and coworkers reported electrochemical synthesis of
substituted vinyl sulfide from enamines and thiophenols.27
Due to stronger electronegativity by the oxygen atom of
carbonyls, the amide N-H bonds are generally not available for
any H-bonding (Scheme 1a). It has been found that the internal
alkynes like diphenyl acetylene was found to be unreactive with
thiophenol under neat condition. Herein, we show that by
introduction of an amide group adjacent to the alkyne of
diphenyl acetylene not only activates the alkyne for reaction but
also makes the amide hydrogen available for H-bonding.
(E)-Alkenes are thermodynamically more stable and are
predominantly formed during addition reactions of alkynes. So,
tuning of stereo-selectivity from thermodynamically more
stable (E)-alkenes to high energy and less stable (Z)-alkenes is
challenging. By exploiting appropriate cooperative weak
interactions or soft forces, we demonstrate here a simple and
efficient approach to synthesize (Z)-selective anti-Markovnikov
vinyl sulfides exclusively via simple mixing of internal alkynes
N,3-diphenylpropiolamide (1a) and thiophenol (2a) under neat,
In spite of low electronegativity of sulfur,10 N-H…S type of
hydrogen bond is one of the strongest H-bond among
commonly observed hydrogen bonds.11 Limited reports are
available on H-bond in which sulfur atom acts as either
hydrogen bond donor (S-H) or acceptor (S).12 The N-H…S H-
a.School of Chemical Sciences, National Institute of Science Education and
Research (NISER), HBNI, PO Bhimpur-Padanpur, Via Jatni, District Khurda,
Bhubaneswar, Odisha 752050, India. E-mail: pmal@niser.ac.in.
† Electronic supplementary information (ESI) available: Contains experimental
details. CCDC 1910745 and 1965122. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/x0xx00000x
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room temperature and open air condition (Scheme 1b). Also vinylic hydrogen with bond distance and angle of C7-H7…O1 =
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DOI: 10.1039/D0CC00702A
switching of reactivity towards synthesis of (Z)-selective 2.374 Å and 106.72 , respectively. In addition, the bond distance
…
Markovnikov vinyl sulfide could be achieved by using 2-amino and angle were found to be, N11-H11 S12 = 2.469 Å and 119.08º,
thiophenol (2k) as the TYC partner instead of thiophenol (2a). between sulfur and amide proton respectively. Thus expected,
Importantly, we anticipate that H-bonding between amide C-H…O and N-H…S interactions during the formation of 3aa
proton and sulfur of thiophenol accelerated the reactions to helped to establish (Z)-selectivity.
move forward with exclusive control on regioselectivity.28 We
have also used the terms ‘Markovnikov’ and ‘Anti-Markovnikov’
by following literature report.29
Scheme 1. a) Making the amide proton available for H-bonding via alkyne
activation. b) Our current approach helped to obtain (Z)-selective either anti-
Markovnikov (top) or Markovnikov (bottom) vinyl sulfides.
Addition of thiophenol to N,3-diphenylpropiolamide (1a) led to
the formation of anti-Markovnikov (Z)-selective product 3aa.
Scheme 2. Control experiments. a) No product formation when amide hydrogen
The intramolecular H-bonding interactions like C-H…O and N-
H…S also helped to attain (Z)-selectivity in the product 3aa
Moreover, when amino group was introduced at the ortho-
was unavailable. b) Mixture of product was observed on reaction with phenyl 3-
phenylpropiolate derivative
6 and 4-bromo thiophenol (2f). c) X-Ray structure of
3aa. d) Expanded region of the 1H-1H 2D ROESY spectra of 3ak
.
.
position of the thiophenol, Markovnikov addition was the The (Z)-selective Markovnikov product (3ak) was confirmed by
preferred one which might be due to stronger preference of N- 1H-1H 2D ROESY NMR experiment (Scheme 2d). To get the bond
H…N H-bonding shown in Scheme 1b.
connectivity, required for 2D ROESY assignment, 13C-1H HMBC
Experiments shown in Scheme 2 helped to understand the and 13C-1H HSQC NMR were performed (ESI, Figure S8-S16). In
role of H-bonding towards synthesis of either (Z)-selective anti- the expanded region of the 2D ROESY spectra of 3ak, a strong
Markovnikov or Markovnikov vinyl sulfides (Scheme 1b). When correlation of Hb (6.18 ppm) with Ha at 7.64 ppm stands for the
amide N-H was substituted with methyl group, compound N- formation of Markovnikov selective product. And another
methyl-N,3-diphenylpropiolamide was found to be unreactive strong correlation with Hc resonating at 7.20 ppm stands for (Z)-
with thiophenol under standard condition (Scheme 2a). This selectivity of the compound (3ak) (Scheme 2d). However a very
observation clearly indicated that amide H-bonding played a weak correlation of Hb was observed with Hd. This is primarily
crucial role for the TYC reaction. Secondly, reaction between because of the large distance between Hb and Hd and was
phenyl 3-phenylpropiolate 11 and thiophenol (2a) led to an confirmed from the geometry optimization of the compound
inseparable mixture of products (ESI, Scheme S3). Similarly, 3ak through DFT shown in ESI, Fig. S14.
when compound
with 4-bromothiophenol (2f) with EtOH (few drops) as an progressive addition of thiophenol (2a) to 1a (1.0 equiv) in CDCl3
additive, mixture of compound and were isolated separately also supported for the involvement of N-H...S than S-H...O
6
, a derivative of phenylpropiolate was mixed
Variable temperature (low temp) 1H NMR analysis with
7
8
(Scheme 2b). This lack of regioselectivity indicates that hydrogen bonding interactions (ESI, Figure S3). When 0.5 equiv
availability of N-H for H-bonding is the key factor for the of thiophenol was added at 0 ºC, a significant shift of NH signal
transformation. X-Ray structure analysis of 3aa also helped to was observed at 7.93 ppm. This fact clearly indicated that the
understand the origin of (Z)-selectivity in the anti-Markovnikov shift of NH signal was due to the formation of N-H…S hydrogen
product (Scheme 2c). The crystal structure revealed a strong bonding between 1a and 2a. On the other hand this significant
intra-molecular H-bonding in between carbonyl oxygen and shift of NH signal was witnessed with no chemical shift for S-H
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of 2a, could rule out for the S-H...O hydrogen bonding by the solvent rather than neat condition was of no help for
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DOI: 10.1039/D0CC00702A
improvement of the yield of product 3aa (entries 5-9).
carbonyl group of 1a
.
Mechanistically we have shown in Scheme 1b for the Furthermore, when the reaction was performed under argon
formation of either (Z)-selective anti-Markovnikov or atmosphere, the yield was not affected. This fact indicated non-
Markovnikov products. The H-bonding interactions like N-H…S involvement of molecular oxygen in the reaction (entry 10) and
and N-H…N might have helped towards the click reactions of anticipated that reaction did not follow radical pathway.30 Also,
thiophenols and alkynes. We could easily rule out any Michael EPR experiment with DMPO (5,5-dimethyl -1-pyrroline N-oxide
type of 1,4-addition reactions because carbonyl groups cannot as spin trapping agent) under standard condition did not show
be utilized as 1,4-acceptor (Scheme 1a). Preferable N-H…S and any EPR signal (ESI, Fig. S4), which confirmed the non-
N-H…N hydrogen bonding interactions of 1a with 2a and 2k
,
involvement of radical intermediate.
respectively, could also determine the regioselectivity as shown
Substrate scope of the proposed methodology was verified
in Scheme 1b. We believe that the reaction proceeded via and shown in Tables 1 and 2. Thiophenols having electron
concerted and non-radical pathway. donating group such as -Me, -OMe offered 3ab and 3ac in 98%
The reactions were stopped at the mono-addition because, and 66%, respectively within 1.5 h of reaction time (Table 1).
electron rich vinyl sulfides may not react further with Also, p-methoxy thiophenol led to 82% of 3ac in EtOH. Solvent
nucleophilic thiols. This fact also support for the non- EtOH led to efficient mixing of the components. Halogen (X = -
involvement of carbonyl group as a Michael acceptor.
High exothermicity and cooperative weak interactions like corresponding vinyl sulfides (3ad
H-bonding could bring the components in close proximity for 91% yields. Electron deficient -CF3 group in para position
F, -Cl, -Br) containing thiols reacted smoothly and produced
,
3ae 3af) with a range of 81-
,
the reactions to be achievable at ambient condition.
substituted thiophenol also resulted in 3ag in excellent yield
(91%) after 1 h. Meta substituted thiophenols (-OMe, -Cl) have
efficiently produced the corresponding sulfides in 78% and 90%
yields, respectively. The ortho-fluorothiophenol afforded 79%
yield of 3aj at 30 min. However, no product formation could be
Table 1. Substrate Scope with various thiophenols.
observed with aliphatic thiols (3al, 3am).
Table 2. Substrate scope with various internal alkynes.
Reaction Conditions: aunder neat condition; bin 1 mL EtOH.
Using diphenylpropiolamide (1a) and thiophenol (2a) as model
substrates, the reaction condition was optimized (ESI, Table S1).
Maximum yield of product 3aa was obtained when the reaction
was performed by simply mixing of 1a and 2a (reactants) under
neat condition, at room temperature and open atmosphere.
When 1a and 2a were taken in 1:1 ratio, within 30 min of
reaction time 3aa was isolated in 50% yield (entry 1). However,
the yield of 3aa was increased significantly on increasing the
ratio of thiophenol (entry 2-4). To our delight, the reaction
worked best using 3 equiv of thiophenol and 3aa obtained in
97% yield. Possibly, the use of 3.0 equiv of thiophenol helped to
make a homogeneous reaction mixture. Interestingly, no by-
product could be detected and excess of thiophenol was
recovered after the reactions by column chromatography.
Generally, for 60 mg (0.271 mmol) of 1a, 0.814 mmol (89 mg) of
2a was used and after reaction 51 mg of 2a was recovered,
which is approximately 1.5 equiv in each case. Use of any
Substrates for various internal alkynes are shown in Table 2.
Phenylpropiolamide having -Me substituents at ortho and para
positions led to exclusive (Z)-selective vinyl sulfides (3ba, 3ca
and 3da) with moderate to excellent yields (88-96%). Similarly,
phenyl group of the phenylpropiolamide having -Et, -iPr, -tBu, -
OMe group also resulted in the corresponding products (3ea
,
3fa 3ga and 3ha) in 79-97% yield within 2 h of reaction time.
,
Biphenyl substituted propiolamide yielded only 43% of 3ia
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within 1 h. Optimized reaction time for synthesis of compound
3ia was found to be 1 h. No improvement of yield could be
observed even for 6 h of reaction time. The halogen substituted
derivatives (X= -F, -Cl, -Br, -I), were able to produce
Notes and references
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DOI: 10.1039/D0CC00702A
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NO2 and -CN groups, respectively. Furthermore, N-(3-
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and
N-(4-chloro-2-
methylphenyl)-3-phenylpropiolamide afforded, 3pa and 3qa as
the vinyl sulfides in near quantitative yield within 1.5 h. We have
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7.
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9.
and compounds 3sa, 3ta and 3ua were isolated in 78%, 62% and
48% yields, respectively. Again, primary propiolamide was
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Towards synthetic applications, 3aa was synthesized in 87%
yield at 1 g scale (Table 1). Following, N-Benzamide derivative
also led to corresponding anti-Markovnikov product 3ra with
88% yield (Scheme 3a) and signifies non-involvement of N-
benzamide part in the reactivity control of amide group with
thiol (Scheme 3a). Similarly, the vinyl sulfide 3aa was converted
to corresponding vinyl sulfoxide 4 by mCPBA oxidation (Scheme
3b). Suzuki coupling reaction with vinyl sulfide 3la led to
5 in
98% yield (Scheme 3c).
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Scheme 3. Synthetic utilization. a) Synthesis of anti-Markovnikov selective
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In conclusion, we have shown here that by implementation of
appropriate amide H-bonding interactions, a particular product
could selectively be obtained from a TYC reaction system.
Selectively, these products were obtained either as (Z)-selective
anti-Markovnikov or Markovnikov from an internal alkyne.
Therefore, using our approach, the unprecedented synthesis of
highly (Z)-selective vinyl sulfides were achieved in good to
excellent yield under a mild and convenient approach.
We thank CSIR for funding (Project No. 02(0338)/18/EMR-II
dated 24-04-2018). MP, KC and SC thank NISER for fellowships
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Conflicts of interest
“There are no conflicts to declare”
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