Pd/PTABS: Low-Temperature Thioetherification of Chloro(hetero)arenes

Article abstract of DOI:10.1021/acs.joc.9b00840

The thioetherification of heteroaryl chlorides is an essential synthetic methodology that provides access to bioactive drugs and agrochemicals. Due to their (actual or potential) industrial importance, the development of efficient and low-temperature protocols for accessing these compounds is a requirement for economic and ecologic reasons. A particular highly effective catalytic protocol using the Pd/PTABS system at only 50 °C was developed accordingly. The coupling between chloroheteroarenes and a variety of less reactive arylthiols and alkylthiols was carried out with a high efficiency. Heteroarenes of commercial relevance such as purines and pyrimidines were also found to be useful substrates for the reported transformation. The commercial drug Imuran (azathioprine) was synthesized as an example, and its preparation could be optimized. DFT studies were performed to understand the electronic effects of the tested ligands on the catalytic reaction.

Full text of DOI:10.1021/acs.joc.9b00840

Subscriber access provided by ALBRIGHT COLLEGE
Article
Pd/PTABS: Low Temperature Thioetherification of Chloro(Hetero)Arenes
Siva Sankar Murthy Bandaru, Shatrughn Bhilare, Jesvita Cardozo, Nicolas Chrysochos,
Carola Schulzke, Yogesh S. Sanghvi, Krishna Chaitanya Gunturu, and Anant R. Kapdi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00840 • Publication Date (Web): 10 Jun 2019
Downloaded from http://pubs.acs.org on June 11, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Pd/PTABS: Low Temperature Thioetherification of
Chloro(Hetero)Arenes
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
c
a
a
c
Siva Sankar Murthy Bandaru , Shatrughn Bhilare , Jesvita Cardozo , Nicolas Chrysochos ,
c,*
d
e
ab,*
Carola Schulzke , Yogesh S. Sanghvi , Krishna Chaitanya Gunturu , Anant R. Kapdi
aDepartment of Chemistry, Institute of Chemical Technology, Nathalal Parekh road, Matunga,
Mumbai-400019, India.
b
Institute of Chemical Technology-Indian Oil Odisha Campus, IIT Kharagpur extension centre,
MouzaSamantpuri, Bhubaneswar-751013, Odisha, India.
cInstitut für Biochemie, Universität Greifswald, Felix-Hausdorff-Straße 4, D-17487 Greifswald,
Germany
d
Rasayan Inc., 2802, Crystal Ridge Road, Encinitas, California, 92024-6615, USA
e
School of Chemical Sciences, SRTM University, Nanded-431606, India.
KEYWORDS PTABS, Thioetherification, ChloroHeteroarenes, Low-Temperature Catalysis,
Azathioprine.
ABSTRACT:The thioetherification of heteroaryl chlorides is an essential synthetic methodology
providing access to bio-active drugs and agrochemicals. Due to their (actual or potential)
industrial importance the development of efficient and low-temperature protocols for accessing
these compounds is a requirement for economic and ecologic reasons. A particular highly
ACS Paragon Plus Environment
1

The Journal of Organic Chemistry
Page 2 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
effective catalytic protocol using the Pd/PTABS system at only 50 °C was developed
accordingly. The coupling between chloroheteroarenes and a variety of less reactive arylthiols
and alkylthiols was carried out with high efficiency. Heteroarenes of commercial relevance such
as purines and pyrimidines were also found to be useful substrates for the reported
transformation. The commercial drug Imuran (azathioprine) was synthesized as an example, and
its preparation could be optimized. DFT studies were performed to understand the electronic
effects of the tested ligands on the catalytic reaction.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
. Introduction:
1
The formation of a C─S bond is a synthetically challenging reaction having commercial
relevance due to the occurrence of thioethers as important structural motifs in pharmaceutical
2
3
4
drugs , insecticides and generally bio-active molecules . Derivatives of thioethers namely,
sulfones5,6 and sulfoximines which can be easily accessed from thioethers, also find a wide
7,8
9
10
11
variety of applications as cell proliferation inhibitors , insecticides , ATR kinase inhibitors ,
Prostacydin receptor agonist12,13 etc. (Figure 1). Traditional synthetic approaches to prepare
1
4
thioethers are numerous but suffer from drawbacks such as long reaction times, moderate
reactivity, and poor results with aryl thiols synthons15–18
.
One of the earliest examples addressing these issues was provided by Migita and co-workers
who introduced the first respective transition metal-catalyzed C─S bond formation reaction19,20
.
The employment of [Pd(PPh
3
4
) ] by Migita, laid the foundation for a plethora of palladium-based
21
catalytic systems to be explored for such a synthetically valuable transformation . Many
research groups, which are active in this research area have focussed on the coupling of aryl
chlorides as the electrophilic coupling partners with aryl or alkyl thiols.22–24 Reports showing
using aryl thiols with chloro(hetero)arenes are having various limitations in reactivity25,26. The
ACS Paragon Plus Environment
2

Page 3 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ability of thiols and sulfur containing compounds to acts as catalyst poison by actively
coordinating the catalysts metal centre constitutes a significant problem associated with their
employment as coupling partners27,28. The poor compatibility of the available catalytic protocols
with different functional groups and competing for disulfide formation represent further
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
9
problems, which have plagued the synthesis of thioether in the past . Even though modified
transition metal-based catalytic systems have been tested for carrying out such synthetic
3
0
transformation no fully satisfying solution to the existing problems could be reached as of yet.
The functionalization of chloroheteroarenes31,32 is one crucial aspect that has been mostly
unexplored with only a very few examples for respective thioetherification available in
literature33–35. Very recently, Hierso and co-workers significantly advanced this field when they
reported an excellent protocol utilizing their previously developed ferrocene-based phosphines in
combination with a Pd-precursor for the thioetherification of chloroheteroarenes. The high
efficiency of the developed catalytic protocol accomplished the thioetherification at low catalyst
concentration with consequently rather good turn-over-numbers.
36
ACS Paragon Plus Environment
3

The Journal of Organic Chemistry
Page 4 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
A) Bio-active molecules and Commercial drugs having C-S bond on Heteroarenes
O
Me
Me
N
N
N
O
O
O
S
Me
N
N
Me
N
Me
O
H
N
N
N
S
N
O
HN
O
O
NH
N
S
S
Me
Me Insecticide
N
Me
Me
O
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Cell proliferation inhibitor
AZD6738
Ph
Ph
N
NH
O
N
N
S
S
O
CO H
2
O
O
N
N
Prostacydin receptor agonist
N
Cl
N
2
H N
B) Previous reports
TM Catalyst
Aryl/Alkyl-SH
Aryl/Heteroaryl
S Aryl/Alkyl
Aryl/Heteroaryl Chlorides
• High Catalyst loading
• Moderate Yields
• High temperature reactions
•
Limited substrate scope
C) This work: C-S coupling of Aryl/Heteroaryl chlorides
Pd/PTABS
HetAr
Cl
Aryl/Alkyl-SH
HetAr
S Aryl/Alkyl
P
N
N
PTABS
N
SO
3
•
•
•
Low catalyst loading (1.0 mol% Pd)
Large substrate scope
Facile synthesis of thiolated purine and pyrimidine analogs (ribose )
• Good to Excellent yields
• Low Temperature
Figure 1: A) Bio-active molecules and Commercial drugs having a C–S bond on Heteroarenes.
B) Previous reports of C–S bond formation processes using Pd or other transition metals and
limitations. C) Current work.
However, on closer inspection of the published protocol, it is evident that the substrates cope is
°
very limited and the required high reaction temperature (115 C) economically and
ecologically unfavorable. The operating temperature might also be detrimental to temperature-
sensitive functional groups of the reactants. These disadvantages of the known procedures
provided the incentive to develop a milder, hence better, protocol for thioetherification reactions.
In the following, we report the catalytic thioetherification of a variety of chloroheteroarenes
3
7
using the Pd/PTABS catalyst system, which is highly efficient even at low temperature. The
employment of both, aryl as well as alkylthiols provided good to excellent yields of the targeted
ACS Paragon Plus Environment
4

Page 5 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
thioethers while a wide variety of chloroheteroarenes could be utilized. Even purine and
pyrimidine structural motifs bearing temperature-sensitive ribose and deoxyribose sugars were
well tolerated and gave good yields of the desired products. Commercially useful sulfones and
sulfoximine analogues of selected thioether derivatives were prepared from those to highlight
further the endless potential and significance of the reported approach as thioethers constitute not
only targets but also valuable synthons in industrial synthesis. The unique reactivity of the
PTABS system in this context was explored by Density Functional Theory (DFT) methods, and a
catalytic mechanism is proposed based on the respective computational results.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
. Results and Discussion
The significance of thioetherification reactions relates to the occurrence of the
particularstructural C-S-C motif in commercially relevant compounds motivating researchers
3
8
to develop sustainable solutions for accessing these moieties . Our research groups have been
interested in the development of efficient, ambient to low-temperature palladium-catalysed
protocols for a variety of synthetically challenging substrates, e.g. nucleoside modification via
3
9
40
or etherification41 as well as
cross-coupling processes , chloroheteroarene-amination
4
2
oxadiazole C─H bond functionalization . The success of all these protocols is based on the
discovery and development of the highly efficient Pd/PTABS catalytic system by the Kapdi
group, which was found to promote various reactions under (relatively) mild conditions. To
provide a catalytically efficient solution to the problems associated with thioetherification, the
exceptionally successful Pd/PTABS catalytic system was now investigated in the context of
these challenging transformations.
4
3
At first, as standard transformation, the thioetherification of 2-chloropyrazine wasperformed
with thiophenol as coupling partner and different catalyst systems including the Pd/PTABS
ACS Paragon Plus Environment
5

The Journal of Organic Chemistry
Page 6 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
system were assessed(Table1). Screening studies were carried out at a relatively lower
°
44
temperature (50 C) compared to what is specified in the available literature reports .
Table 1.Screening studies for low-temperature thioetherification of chloroheteroarenes.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
S.No.
Catalyst
1.0 mol%)
Ligand
(2.0 mol%)
Base
(eq.)
Solvent
Temperature
Yield
(%)
(
(°C)
1
2
3
4
5
6
7
8
9
-
-
-
K
3
PO
4
PO
PO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
NR
38%
62%
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
K
K
K
3
3
3
4
4
2
PTA
2
PTABS
PTAPS
PTABI
PTABBr
PTABCl
PTABBn
XPhos
SPhos
Xantphos
PTABS
PTABS
PTABS
PTABS
PTABS
PTABS
PO
4
91%
85%
85%
80%
76%
82%
53%
62%
68%
85%
42%
68%
27%
22%
68%
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
K
K
K
K
K
K
K
K
3
PO
PO
PO
PO
PO
PO
PO
PO
4
2
3
3
3
3
3
3
3
4
2
2
2
2
2
2
4
4
4
4
4
4
10
11
12
13
14
15
16
PdCl
2
K
3
K
3
K
3
K
3
PO
PO
PO
PO
4
4
4
4
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
CH CN
3
Dioxane
THF
DMF
17
18
Na
Cs
KOtBu
K
K
K
2
CO
CO
3
2
3
DMF
19
20
21
22
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
PTABS
PTABS
PTABS
PTABS
DMF
DMF
DMF
DMF
50
rt (25°C)
60
54%
25%
88%
73%
3
3
3
PO
PO
PO
4
4
4
80
Reaction conditions: 1.0 mmol of 1a, 1.5 mmol of 2a, 1.0 mol % of Pd(OAC)
mol% of PTABS/ligand, 3.0 mL of solvent, DMF stirring at 50 °C for 2 hours, isolated yields.
2
or PdCl , 2.0
2
a
ACS Paragon Plus Environment
6

Page 7 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
°
Initially, a background reaction was performed in DMF at 50 C in the absence of any Pd-
precursor or ligand using only the base K PO (Entry1, Table1). No reaction was observed
3
4
under these conditions. Next, the feasibility of employing Pd(OAc)
ligand-free conditions was tested (Entry 2, Table1). As the desired product was formed in only
8% yield, it was then investigated whether the incorporation of an activating ligand could
2
on its own under
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
improve the outcome. Previously, we have reported on the application of
triazaphosphaadamantane (PTA, I) and its derivatives (PTABS, II and PTAPS, III) as ligands in
a variety of catalytic processes39–41,45. As expected, the addition of PTA as an activating ligand
supported product formation and raised the yield to 62% (Entry3, Table1), while the sulfonated
PTA derivatives, PTABS and PTAPS even reached 91% and 85% product yield, respectively
(
Entries 4 and 5, Table1). As it was observed that the utilized PTA derived ligand had at least a
small impact on the resulting quantity of product,further derivatives were prepared by
synthetically convenient alkylations of the PTA ligand. The change from covalently attached
SO −
to unbound counterion X (X = I, Br or Cl) results in a minor decrease in catalytic
−
3
efficiency under the tested/optimised conditions (Entries 6-8, Table 1). The alternative
introduction of a benzyl moiety on the PTA ligand led to similarly decent yields of the
thioetherproduct (82%, Entry 9, Table 1). Among all seven tested PTA-based derivatives,
however, PTABS constitutes the ligand of choice as was observed previously for other
transformations.
Highly electron-rich phosphines46,47 and N-heterocyclic carbenes48,49 have in the past found
5
0
51
broad applications in the thioetherification of aryl halides with the groups of Hartwig , Itoh and
5
2
Nolan utilizing sterically bulky activating ligands effectively. Considering their role in the aryl
halides (including chlorides), bulky phosphines such as XPhos, SPhos and Xantphos were
ACS Paragon Plus Environment
7

The Journal of Organic Chemistry
Page 8 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
employed to obtain a better yield of the desired product (Entries 10-12, Table 1). Lower yields as
compared to PTABS in all the cases further confirmed our initial findings of the product yield
enhancing capabilities of PTABS. Change in the palladium precursor from Pd(OAc)
PdCl also failed to bring about any improvement in the product yield (Entry 13, Table 1).
Furthermore, solvent and base studies performed provided conclusive evidence supporting the
employment of K PO as the base in DMF as solvent (Entries 14-19, Table 1). Through
2
to
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
4
optimization of conditions for the thioetherification of chloroheteroarenes provides us with a
°
mild and low-temperature protocol as any further reduction in temperature (rt or 25 C) was
found to be less effective (Entry 20, Table 1). Same was the case with any further increase in the
reaction temperature proving detrimental for the thioetherification to proceed (Entries 21-22,
Table 1).
With a highly efficient thioetherification protocol in hand, substrate scope for the reaction of
different chloroheteroarenes with arylthiols was undertaken (Scheme 1). 2-Chloropyrazine was
the first to be coupled with a sterically hindered 2,6-dimethyl thiophenol providing a good yield
of the coupled product (72%, 3b, Scheme 1). Presence of electron-deficient substituents such as
4-Cl or 4-F or 4-CO Me was found to have a negligible impact on the reactivity as good to
2
excellent yields were obtained (3c-88%, 3d-84%, 3e-88%, respectively). Free-amine groups
present in the 2- or 4- position of the thiophenol moiety were also well tolerated giving 92% (3f)
and 87% (3g) of the thioether products, respectively. The introduction of heteroaryl thiols
(pyridine-2-thiol) was also found to be compatible with the developed protocol providing the
coupled product in 76% yield (3h, Scheme 1).
Next, 2-chloroquinoxaline was coupled with different aryl and heteroaryl thiols under the
optimized conditions. In most cases good to excellent yields of the targeted quinoxaline-derived
ACS Paragon Plus Environment
8

Page 9 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
thioethers were obtained (Entries 3i-l, Scheme1). An electron-poor arylthiolbearing an ester
functionality as well as a heteroarylthiol (benzothiazole-2-thiol), presumed to be challenging
synthons, were successfully employed as reactants without any noticeable reduction in yield of
the coupled products (3m-n, Scheme 1).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 1: Scope for thioetherificationofchloroheteroarenes with thiophenols.a
Pd(OAc)
PTABS (2.0 mol %)
2
(1.0 mol %)
R
Cl
SH
P
S
Het
PTABS
N
N
K PO (2.5 equiv)
DMF, 50 oC, 2.0 h
3
4
Het
N
SO3
R
Me
CO Me
NH
2
2
N
N
S
N
N
S
N
N
S
N
N
S
N
N
S
N
S
Me
Cl
F
N
3a (88%)
3b (72%)
3c
3d (84%)
3f (92%)
(88%)
3e (88%)
Me
N
N
S
N
S
N
N
S
N
S
N
N
S
NH2
N
N
N
Me
NH2
3i (93%)
3j (88%)
3k (91%)
3g (87%)
3h (76%)
Cl
OMe
NH
2
2
CO Me
N
N
S
N
N
S
N
S
N
N
N
S
S
S
S
N
S
3l (84%)
3m (87%)
3n (75%)
3o (85%)
3p (88%)
NH
2
F
N
S
N
S
N
S
S
S
S
O
N
S
N
S
N
S
S
S
N
3r
(81%)
3s (85%)
3t
(75%)
3u (93%)a
3
q (89%)
F
F
F
F
F
S
N
S
OPent
N
N
S
F
N
N
S
F
N
S
N
N
N
3y (85%)
F
F
S
S
F
N
S
S
N
NH2
N
S
F
F
(91%)b
3w (96%)b
3x
3v (81%)
N
F
3
z (81%)
Reaction conditions: 1.0 mmol of chloroheteroarene, 1.5 mmol of thiol, 1.0 mol % of Pd(OAc)
2
, 2.0
a
mol% of PTABSligand, 3.0 mL of solvent, DMF is stirring at 50 °C for 2 hours, 2.2 equivalent thiol
b
used, 3.2 equivalent thiol used, isolated yields.
ACS Paragon Plus Environment
9

The Journal of Organic Chemistry
Page 10 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
With 2-chlorobenzothiazole as substrate, a similar catalytic reactivity was observed and good to
excellent yields of the desired thioethers were obtained (3o-t, Scheme1). It has to be emphasized,
though that with the high efficiency of the catalytic system towards etherification (reported
earlier50–52) as well asthioetherification, the reactions exhibit comparably poorer (or) no
respective chemo-selectivity (example 3r, Scheme1).In the case of the thioetherification of 2,6-
dichloropyrimidine, as another example for the occasional disadvantages of high reactivity, the
formation of doubly thioetherified product highlights the loss of regioselectivity (3u, Scheme1).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
,4,6-Trichloropyrimidine underwent efficient triple thioetherification with phenylthiol or 4-
fluorophenylthiol to provide the respective products (3w or 3x, Scheme1) in excellent yields.
All available Cl substituent of the precursors are similarly activated in the course of
the coupling reactions without any discrimination. As the pentafluorophenyl
substituent is known to enhance the bioactivity of drug molecules,
pentaflurophenylthiol was coupled with heteroarenes showing excellent reactivity, which further
confirms the exceptional synthetic utility of the developed protocol (3y and 3z, Scheme1). A
couple of the synthesized thioetherified products (3i and 3u) could be isolated as crystalline
solids and were characterized with single crystal X-ray diffraction (see supporting for detailed X-
ray crystallography data).
The coupling of arylthiols is synthetically challenging for their comparably lower activity as
coupling partners.53 The developed protocol has shown exceptional reactivity towards the
thioetherification of chloroheteroarenes with a variety of arylthiols in easily controllable
reactions. Encouraged by these results, it was further envisaged to employ the alkylthiols as
coupling partners in order to test whether they would also lead to well-defined products despite
their higher reactivity. Notably, only a somewhat limited number of reports are available,
ACS Paragon Plus Environment
1
0

Page 11 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
which detail examples of alkylthiol coupling. 2-Chloropyrazine was f i r s t coupled under the
optimized conditions to a variety of alkylthiols such as ethylthiol, dodecanethiol,
adamantanethiol, 2-butanethiol and 2-chlorobenzylthiol resulting in excellent yields of the
thioetherified products in all investigated cases (5a-e, Scheme 2). Next, 2-chloroquinoxaline was
similarly employed as chloroheteroarenes to quantitative yields of the products (5f-h, Scheme 2).
Finally, benzothiazole was chosen to couple with dodecanethiol and tert-butyl(2-
mercaptoethyl)carbamate as coupling partners resulting in >80% yield (5i-j, Scheme 2). The
alkylthiols, despite their inherent higher reactivity, behave just as well as coupling partners under
the optimized conditions as the initially investigated arylthiols.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2: Scope for thioetherification of chloroheteroarenes with alkanethiols.a
Reaction conditions: 1.0 mmol of chloroheteroarene, 1.5 mmol of thiol, 1.0 mol % of Pd(OAc)
2
, 2.0
mol% of PTABS ligand, 3.0 mL of solvent, DMF is stirring at 50 °C for 2 hours, isolated yields.
The pyrimidine structural motif is a feature in a large number of bio-active molecules most
prominently in nucleosides such as uracil and cytidine.45,54 Chemical modifications of these
molecules are highly desirable as these could lead to the development of fluorescent DNA/RNA
ACS Paragon Plus Environment
1
1

The Journal of Organic Chemistry
Page 12 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
55
probes and useful drug candidates . Subjecting 6-chlorouracil to thioetherification under
optimized conditions with 4-methoxyphenylthiol or 2-chlorobenzylthiol as coupling partners
gave the respective products, 7a and 7b in excellent yields (Scheme3). Protecting the uracil-
based precursor did not impair the coupling reactions as was shown by the thioetherification of
N-methylprotected 6-chlorouracil with similarly high yields (7c, Scheme3).The important
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
6
anti-diabetic drug Alogliptin, which is marketed by Takeda Pharmaceuticals, constitutes a
three-fold substituted uracil nucleobase, and reasonable modifications of its molecular
structure might help enhance its biological activity necessarily. T h e thioetherification
of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)yl)methyl)benzonitrile with
phenylthiol or 2-butanethiol yields derivatives of Alogliptin in which the amino-piperidinyl
substituent on the ene carbon atom is replaced by an RS-substituent in good yields (7d-e,
Scheme 3). It shows that several modifications can be facilitated by the optimized protocol very
conveniently. Determining whether the novel compounds do indeed have improved biological
reactivity is out of the scope of this study but shall be investigated in future experiments.
Scheme 3:Thioetherification of synthons with chloropyrimidine structural motifs.
O
O
Pd(OAc)2 (1.0 mol %) R1
PTABS (2.0 mol %)
R1
N
N
Alkyl/Aryl SH
P
K PO (2.5 equiv)
3
4
O
N
R2
S
Alkyl/Aryl
O
O
N
R2
Cl
o
DMF, 50 C, 2.0 h
N
N
1
R = H or Me
R = H or CNPhCH
N
SO3
2
2
PTABS
O
O
O
O
Me
N
Me
N
Me
OMe
HN
Me
HN
N
Cl
O
N
S
O
N
S
O
N
H
S
O
N
H
S
O
N
H
S
Me
7d (78%)
7a (88%)
7c (72%)
7
b (82%)
7
e (76%)
CN
CN
Reaction conditions: 1.0 mmol of chloroheteroarene, 1.5 mmol of thiol, 1.0 mol % of Pd(OAc)
2
, 2.0
mol% of PTABS ligand, 3.0 mL of solvent, DMF is stirring at 50 °C for 2 hours, isolated yields.
ACS Paragon Plus Environment
1
2

Page 13 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Synthetically challenging substrates, which have found fullapplications as fluorescent probes57,
anti-cancer58 and anti-viral59,60 drugs are the purines bases (adenine and guanine) in
nucleobase and nucleoside forms, i.e. with or without the respective sugars
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
59
(
ribose and deoxyribose) . A thiomethylation of purines was recently reported by Jiang and co-
6
1
workers . However, the operatinghigh-temperature conditions of the developed protocol
render it synthetically less attractive. The thioetherification with the Pd/PTABS catalytic
system at moderate temperature was first applied to 6- chloroguanine with pyridine-
2
-thiol, dodecanethiol and 4-chlorophenylthiol as coupling partners furnishing the desired
products in good to excellent yields (9a-c, Scheme 4). Similarly, 6-chloroguanosine (ribose)
reacted efficiently to give the thioether product without any de-glycosylation observed (9d,
Scheme 4). The second purine nucleobase was similarly subjected to the
optimized reaction conditions employing 6-chloroadenine, which was thioetherified
with a variety of thiols, namely ethanethiol, dodecanethiol, thiobenzene, pyridine-2-thiol, 4-
chlorophenylthiol and adamantanethiol (9f-j, Scheme 4). The reactivity, though, was found to be
slightly lower than with the guanine analogue, which was also observed when 6-chloroadenosine
(ribose, 9m and 9o) and 6-chloroadenosine were employed as coupling partners (9k-p, Scheme
4
). Deazapurine is a related structural motif, which comprises a common feature of a wide
6
2
63
variety of drugs and bio-active molecules such as Tubercidin , Toyocamycin and
6
4
Sangivamycin . As a respective example, 6-chloro-7-deazapurine was tested and shown
to be efficiently coupled to dodecanethiol with the optimized protocol resulting in good
yields of the product (9e, Scheme 4).
Scheme 4: Scope for thioetherification of purines and ribonucleosides.a
ACS Paragon Plus Environment
1
3

The Journal of Organic Chemistry
Page 14 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Cl
N
R-SH
SR
Pd(OAc)
2
(1.0 mol %)
HO
R' = H or
N
N
N
N
N
PTABS (2.0 mol %)
N
O
K3PO4 (2.5 equiv)
DMF, 50 oC, 2.0 h
N
OH OH
R'
R'
Cl
C12H25
S
N
C12H25
S
S
N
N
N
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
S
N
N
N
N
N
N
N
NH2
HO
N
N
H
N
NH2
NH
N
H
2
H
N
NH2
O
9
a (83%)
9b (85%)
9c (92%)
9d (79%)
OH OH
Me
C12H25
C12H25
S
N
S
N
S
N
S
S
N
N
N
N
N
N
N
N
N
N
N
H
N
H
N
N
H
N
H
N
H
N
9e (85%)
9f (67%)
9g (65%)
C12H25
9h (89%)
9i (86%)
S
N
S
N
N
S
N
Cl
N
N
N
N
N
N
N
N
S
N
HO
N
HO
HO
N
O
O
O
N
H
9m (69%)
OH OH
OH OH
OH OH
9j (88%)
9
k (76%)
9l (79%)
Me
S
N
N
S
N
Me
S
N
N
N
N
N
N
N
N
N
HO
HO
HO
O
O
O
OH OH
OH OH
9p (71%)
OH OH
n (86%)
9o (66%)
9
Reaction conditions: 1.0 mmol of chloroheteroarene, 1.5 mmol of thiol, 1.0 mol % of Pd(OAc) , 2.0
2
mol% of PTABS ligand, 3.0 mL of solvent, DMF is stirring at 50 °C for 2 hours, isolated yields.
The thioetherification of purine derivatives provided crystalline material for 9h, which could be
analyzed using single crystal X-ray diffraction confirming the proposed molecular structure (see
supporting for detailed X-ray crystallography data). Having successfully synthesized a large
ACS Paragon Plus Environment
1
4

Page 15 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
variety of thioethers, the question was raised whether it was possible to convert these coupled
products into molecules of even further synthetic significance. Sulfones are important synthetic
6
5
66
intermediates readily made available from thioethers via simple oxidation . A structural feature
having commonly been found in a variety of drugs and, at the same time, providing easy access
to a large number of chemically and biologically active molecules increases the appeal of
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
7,68
sulfones . A f e w selecte d synthesized thioethers were subsequently converted into their
44
sulfones in good yields by oxidation with meta-chloroperbenzoicacid (mCPBA) in
dichloromethane as solvent (11a-e, Scheme 5).
6
9,70
As derivatives of sulfones, sulfoximines
constitute another class of compounds obtained from
7
1
thioethers. They are commonly found as critical structural motifs in medicinal and
7
2,73
pharmaceutical chemistry . Their occurrence in commercially relevant anti-cancer drugs such
7
4
75,76
as pan-CDK inhibitor BAY1000394 from Bayer , and the ATR inhibitor AZD6738
from
Astra-Zeneca underlines the importance of the developed thioetherifcation protocol, as a wide
variety of respective precursor compounds is now easily accessible. As proof of principle, a
one-pot N- and O-transfer reaction for the formation of NH-sulfoximines from thioethersas
7
3
earlier reported by Bull and Luisi was employed to obtain good to excellent yields of the
sulfoximine products (12a-d, Scheme 5).
Scheme5: Conversion of sulfides to sulfones and sulfoximines.
ACS Paragon Plus Environment
1
5

The Journal of Organic Chemistry
Page 16 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Reaction conditions for sulfone synthesis: 1.0 mmol of thioether, 2.5 mmol of mCPBA, 0 °C, 5.0 mL of
DCM, isolated yields. Reaction conditions for sulfoximines synthesis: 1.0 mmol of thioether, 3.0 mmol of
PhI(OAc) , 2.0 mmol of ammonium acetate, 4 ml of MeOH, room temperature.
2
The immediate synthetic utility of the developed thioetherification protocol with the Pd/PTABS
catalytic system was, lastly, demonstrated with the efficient synthesis of an important
77
immunosuppressant: Imuran (Azathioprine) . Azathioprine is a purine-based drug bearing a
thioether linkage, which exhibits excellent immuno-suppressant properties. It is administered
commonly to patients undergoing kidney or liver transplantation asithelpsto decrease the body
7
8
immunity, which subsequently leads to better acceptance of the transplanted organ . Using the
ACS Paragon Plus Environment
1
6

Page 17 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Pd/PTABS derived catalytic system, we envisaged the synthesis of Azathioprine via the coupling
of 5-chloro-4-nitro-N-methylimidazole and 7-H purine-6-thiol resulting in the formation of the
desired product in good yield (Scheme 6).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 6: Synthesis of Imuran (Azathioprine 15).
Reaction conditions: 1.0 mmol of chloroheteroarene, 1.5 mmol of thiol, 1.0 mol % of Pd(OAc) , 2.0
2
mol% of PTABS ligand, 3.0 mL of solvent, DMF is stirring at 50 °C for 2 hours, isolated yield.
3
. Density functional theory studies:
In order to understand the mechanistic aspects of the present work, density functional theory
DFT) studies were carried out, and the relevant results are presented in Table 2. A total of
seven P-ligand derivatives including PTA, PTABS, PTAPS, ionic derivatives like PTAB
representing PTABBr, PTABCl and PTABI) and PTABBn were computationally investigated
alongwith XPhos and SPhos to correlate the respective structures to the observed experimental
(
(
−
−
−
−
reactivity. The effect of t h e halogen counter ion X (Cl , Br and I ) was not addressed when
the ionic PTABX and PTABBn derivatives were analyzed. Instead, these were considered as
cationic species. The geometry optimizations for all derivatives were carried out at the B3LYP/6-
79
3
1G(d,p) level of theory using the Gaussian16 program suit and all positive second-order
energy gradients confirmed the resulting structures as minima on the potential energy surfaces.
The optimized geometries were further treated for natural population analysis (NPA) and the
ACS Paragon Plus Environment
1
7

The Journal of Organic Chemistry
Page 18 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
obtained molecular electrostatic potential (MEP) mapped to the total electronic density of the
same. The calculated NPA charges on the phosphorous centers of the derivatives reveal the
electropositivity of the P atom to be lowest of all derivatives in PTA. The respective charge,
for instance, is 0.715 e in PTA while ca. 0.822 e are found for PTABS and PTAPS derivatives
and the ionic derivatives PTAB and PTABBn exhibit a charge of ca. 0.837 e on P.
Table 2: Computational data derived from the DFT study analyzing the electronic structures of
the phosphorus ligands.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Sl.No Molecule
NPA on P-center (e)
Mapped MEPa
1
2
PTA
0.715
PTABS
PTAPS
0.822
3
4
0.822
0.838
PTABX
X =
Cl,Br,I
5
PTABBn
0.837
ACS Paragon Plus Environment
1
8

Page 19 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
6
7
XPhos
SPhos
0.864
0.874
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
aThe MEP plotting ranges from -0.028 to 0.028 for PTA, XPhos and SPhos, 0 to 0.160 for PTAB
and PTABBn, -0.128 to 0.128 for PTABS and -0.114 to 0.114 for PTAPS. In the MEP drawings
red indicates an electronegative and blue an electropositive nature.
The most substantial positive charges were obtained for XPhos and SPhos with 0.864 e and
0
.874 e respectively. With PTA and SPhos at both ends of the range but equal catalytic
efficiency, the charge on P cannot be directly related to the catalytic performance observed in the
experimental thioetherifications. The computational study was therefore extended beyond the
phosphorous atom. In order to explain the better performance (higher yields) in the C-S coupling
reactions of PTA derivatives compared to PTA, XPhos and SPhos, the MEPs were plotted.
Notably, a small electronegative centre (-0.028 au) is located around the phosphorous atom in
PTA whereas for allof the PTA derivatives this region is electropositive,i.e. 0.026 au, 0.015au,
0
.027 au and 0.080 au for PTABS, PTAPS, PTAB and PTABBn respectively. This can be
attributed to the presence of the positive charge introduced to the PTA scaffold by substituting
−
−
−
−
one of its nitrogen atoms (countered by halogen ions Cl , Br , I or the SO substituent)inthe PTA
3
derivatives. This marked difference suggests better π-accepting abilities of the phosphorus atom
in the PTA derivatives while in case of the parent PTA, phosphorus and its vicinity are found to
be electron-richer (i.e. P a better donor of electron density). This subtle change in the electronic
structure around the phosphorus atom is hypothesized to have a profound effect on the
coordination properties with the palladium centre which invariably affects the catalytic activity.
ACS Paragon Plus Environment
1
9

The Journal of Organic Chemistry
Page 20 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Figure 2: Correlation between electronic on the phosphorus atom and catalytic reactivity.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Similarly to PTA, in case of XPhos and SPhos a small negative potential of-0.035au was
observed around the P-centre, which is by the relatively lower yields in the catalyzed reaction.
Thus, not only the charge directly at the phosphorous P-center but also the electrostatic
potentials around it influences the interaction between P-ligand and Pd pre-catalyst. These
relations as depicted in Figure 2 provide an insight into the subtle effects of the ligand’s
electronic structure on the catalytic activity where it involves the phosphorus donor atom.
A derived model of the potential coordination characteristics of the various phosphines with
the palladium center80,81 and the respective effect on the catalytic activity is represented in
Figure 3. We propose that the more electron-rich phosphines (PTA, XPhos and SPhos), in which
the phosphorous atoms possess more electron density, would further enhance the nucleophilicity
of the palladium centre. Rather than insertion into the C─Cl bond of the chloroheteroarene
reactants, the nucleophilic palladium might become stably coordinated by the heteroatoms of
electron-poor heteroarenes (pyrazines, pyrimidines and others), which is in accordance, with the
observed lower reactivity exhibited by these ligands. The electron-poorer phosphines (PTABS,
PTAPS, PTABBn and PTABX), on the other hand, in which phosphorous possesses less electron
density, could act as stronger π-accepting ligands decreasing the nucleophilic character of the
ACS Paragon Plus Environment
2
0

Page 21 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
palladium centre. With slightly less nucleophilic palladium, the consequently weaker
coordination by the heteroatom cannot compete permanently with the insertion into the C─Cl
bond, which now takes place more efficiently providing the desired products.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3: Effect of phosphine electronics on the thioetherification of chloroheteroarenes.
The heteroatom, in this case, acts as a directing group providing the required weak coordination
site to attract palladium, eventually allowing the oxidative addition to taking place via C─Cl
bond cleavage. Such a proposition is particularly relevant in the case of heteroarenes bearing the
nd
C─Cl bond next to the heteroatom (2 position relative to heteroatom). Any change in the
position of the C─Cl bond results in either weak or negligible reactivity highlighting the crucial
role of the directing group effect of the heteroatom in such catalytic reactions.
4. Conclusion
In conclusion, we have developed a highly efficient catalytic protocol involving the Pd/PTABS
system for the very reliable coupling of a wide variety of chloroheteroarenes to less reactive
arylthiols and more reactive alkylthiols. It is possible to couple substrates even bearing labile
functional groups as the reaction temperature couldbe kept much lower (50 °C) than in
previously reported related reactions. The novel protocol facilitates access to a
considerable variety of thioethers including the thioether-analogue of the commercially
available Alogliptin. The mild reaction conditions further allow the employment of temperature
labile substrates such as purine and pyrimidines (as nucleobases and nucleosides) to be modified
with high yields and without any de-glycosylation observed. To demonstrate the synthetic
ACS Paragon Plus Environment
2
1

The Journal of Organic Chemistry
Page 22 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
utility of the developed catalytic protocol, Imuran (azathioprine)- an immunosuppressive agent
was synthesized in good yields. Some of the synthesized thiols were also converted into sulfones,
and sulfoximines as their f r e q u e n t occurrence in bio-active molecules emphasize the
importance of respective reliable synthetic routes. The developed procedures expected to permit
mild syntheses resulting in various target compounds and the assembly of respective libraries
for combinatorial medicinal chemistry screening programs. Finally, to ascertain the influence of
the ligand’s electronic structures on the palladium-catalyzed coupling process, DFT studies
were performed on different ligands with the most reactive PTABS and related ionic ligands
distinguishing themselves with a comparably more electropositive character by providing better
reactivity than the electron-richer PTA, XPhos and SPhos.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
. Experimental Section
5
.1 General: All the reactions were performed under a nitrogen atmosphere using oven dried
standard Schlenk glassware. The completely dried N,N-dimethylformamide (DMF, 99.8%, extra
dry, stored over molecular sieves) was purchased from Acros organics was used as received for
1
13
all air or moisture sensitive reactions. H NMR (300 MHz) and C NMR (75 MHz) spectra were
recorded either on NMR EMAU Avance II-300 spectrometer or Agilent-400 MHz spectrometer.
1
13
Chemical shifts δ are given in ppm and the solvent residual peak (CDCl : H, δ = 7.27; C, δ =
3
1
7
7.0 and DMSO-d6: H, δ = 2.50; 13C, δ = 40) was used as an internal standard. Peak
multiplicities are specified as followed: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet;
br, broad. APCI-MS (m/z) spectra were recorded on an Advion MS. Mechenary-Nagel silica gel
6
0 F-254 plates were used for thin layer chromatography (TLC), and detection was achieved by
UV light. Column chromatography was performed on silica gel 60 (40-63 μm) or Acros Organics
silica gel 60 (35-70 μm). The Single X-ray crystal structure experiments conducted by using
“
STOE IPDS2T” and diffraction source with fine-focus sealed molybdenum tube.
ACS Paragon Plus Environment
2
2

Page 23 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
“
ElementarVario MICRO cube” was used for the experimental determination of elemental
configurations of final pure products.HRMS did by using Q-TOF mass analyzer and by using
ESI method.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
.2 Crystal structures and Crystallographic information: Suitable single crystals of 3i, 3u
and 9h were mounted on a thin glass fiber coated with paraffin oil. X-ray single-crystal structural
data were collected at low temperature (170 k) equipped with a normal-focus, 2.4 kW, sealed-
tube X-ray source with graphite-monochromatic MoKα radiation (λ =0.71073 Å). The program
X-Area was used for integration of diffraction profiles; numerical absorption correction was
3
1
29
made with the programs X-shape and X-red; the structures were solved by SIR9 and refined
29
by full-matrix least-squares methods using SHELXL-2013 . All other hydrogen atoms were
refined with a constraint on the displacement parameter but freely concerningthe position.
All calculations were carried out using SHELXL-201329 and the WinGX GUI, Ver2013.230.
Crystallographic data are summarized in supporting information.
5
.3 General procedure (GP1): A 25 mL of oven dried Schlenk tube was given with 1 mol% of
Pd(OAc) , 2 mol% of PTABS (ligand, Phosphoadamantinebutylsaltone) and 1 mmol of a
chloroheteroarene derivative under N atmosphere and the resultant mixture dissolved in 3 mL of
dry DMF. The reaction mixture stirred for 5 minutes and added by 1.2-1.5 equiv. of the
corresponding thiophenol, 2.0-2.5 eq. of K PO followed by stirring at 50 °C for 1-2 hrs. After
2
2
3
4
consumption of starting material (monitored by TLC / TLC-MS), the solvent was removed in
vacuum and the resultant residue obtained was purified by column chromatography in Hexane:
Ethyl Acetate (10% to 50%) solvent system to afford the desired product. In the case of
ACS Paragon Plus Environment
2
3

The Journal of Organic Chemistry
Page 24 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
nucleoside derivatives of purine and pyrimidine substrate (7a-e and 9a-9p) CHCl : MeOH (9:1)
3
was used as a mobile phase for column chromatography.
5
.4 General Procedure for thioethers oxidation to sulfones (GP2): In a clean and dry Schlenk
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
tube, thioether (1 mmol) was dissolved in DCM (5 mL). The solution cooled to 0 °C, and then
mCPBA (2.5 equiv. in 3 mL of DCM) was added dropwise at 0 °C. The reaction was then stirred
at room temperature until the complete conversion is reached (progress checked by TLC). The
mixture was washed with a saturated aqueous solution of Na
2
S
2
O
3
(3 x 10 mL). After separation,
the organic layers were washed with a saturated aqueous solution of sodium bicarbonate (3 x 5
mL). The organic phase was dried over Na
corresponding sulfones.
2
SO . The organic solvent was evaporated to get
4
5.5 General Procedure for thioethers oxidation to sulfoximine (GP3): In a clean Schlenk
tube, thioether (1 mmol), PhI(OAc) (3 mmol) and ammonium acetate (2 mmol) were diluted in
2
MeOH (4 mL) at room temperature. The mixture was stirred until the complete conversion is
reached (progress checked by TLC). The solvent was evaporated under reduced pressure by
using rota evaporator. The residue was then purified by silica gel column chromatography to get
the corresponding sulfoximine.
5.6 Substrate Scope for Palladium-Catalyzed thioetherification of Chloroheteroarenes:2-
(
(
(
phenylthio)pyrazine (3a): General procedure (GP1) was followed by using 2-chloropyrazine
0.89 mL, 1 mmol) and thiophenol (0.123 mL, 1.2 mmol, 1.2 eq.) yielded a desired 2-
phenylthio)pyrazine (165 mg, 0.88 mmol, 88%) as a pale pink oil. Hexane: Ethyl Acetate (7:3)
1
was used as a mobile phase for column chromatography. H NMR (300 MHz, CHLOROFORM-
d) δ: 7.37 - 7.50 (m, 3 H), 7.56 - 7.66 (m, 2 H), 8.21 (dd, J=5.96, 2.02 Hz, 2 H), 8.29 - 8.36 (m, 1
ACS Paragon Plus Environment
2
4

Page 25 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
1
H); C NMR{ H} (75 MHz, CHLOROFORM-d) δ: 129.3 (s, 1 C), 129.9 (s, 1 C), 130.1 (s, 2 C),
1
35.3 (s, 2 C), 140.4 (s, 1 C), 143.0 (s, 1 C), 144.1 (s, 1 C), 158.9 (s, 1 C);APCI-MS m/z =
188.04 m/z calcd. for C10
H
8
N
2
S [M]; found : 189.12[M+H]. The compound exhibited identical
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
82
H and C NMR data to the previous reports .
2
-(2,6-dimethylphenylthio)pyrazine(3b): General procedure (GP1) was followed by using 2-
chloropyrazine (0.89 mL, 1 mmol) and 2,6-dimethylbenzenethiol (0.2 mL, 1.5mmol, 1.5 eq.)
yielded a desired 2-(2,6-dimethylphenylthio)pyrazine (156 mg, 0.72mmol, 72%) as a pale yellow
1
oil. Hexane: Ethyl Acetate (7:3) was used as a mobile phase for column chromatography. H
NMR (300 MHz, CHLOROFORM-d) δ: 2.44 (s, 6 H), 7.17 - 7.24 (m, 2 H), 7.24 - 7.31 (m, 1
1
3
1
H), 7.98 (d, J=1.56 Hz, 1 H), 8.18 (d, J=2.57 Hz, 1 H), 8.27 - 8.34 (m, 1 H); C NMR { H}(75
MHz, CHLOROFORM-d) δ: 21.7 (s, 2 C), 127.1 (s, 1 C), 128.6 (s, 2 C), 130.0 (s, 1 C), 139.5 (s,
2
C), 141.3 (s, 1 C), 143.6 (s, 1 C), 143.8 (s, 1 C), 158.0 (s, 1 C); (+ve)APCI-MS m/z = 216.07
1
m/z calcd. for C12
H
12
N
2
S [M]; found : 217.82 [M+H]. The compound exhibited identical H and
13C NMR data to the previous reports83.
2
-(4-chlorophenylthio) pyrazine(3c): General procedure (GP1) was followed by using 2-
chloropyrazine (2 mmol, 1 equiv.) and 4-chlorothiophenol (2.4 mmol, 1.2 eq.) yielded a desired
product (392 mg, 88%) as a pale colorless liquid. Hexane: Ethyl Acetate (7:3) was used as a
1
mobile phase for column chromatography. H NMR (500 MHz, CDCl
3
) δ: 8.32 – 8.28 (m, 1H),
13
1
8
.23 (ddd, J = 5.9, 3.4, 2.1 Hz, 2H), 7.51 – 7.47 (m, 2H), 7.40 – 7.35 (m, 2H); C NMR{ H}
126 MHz, CDCl ) δ: 157.6 (s), 143.9 (s), 142.8 (s), 140.5 (s), 136.2 (s), 135.9 (s), 130.0 (s),
127.4 (s). ESI-MS m/z = 222.69 m/z calcd. for C10
(
3
H
7
ClN
2
S [M]; found : 223.71[M+H]. The
1
13
84
compound exhibited identical H and C NMR data to the previous reports .
ACS Paragon Plus Environment
2
5

The Journal of Organic Chemistry
Page 26 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
-(4-fluorophenylthio)pyrazine(3d): General procedure (GP1) was followed by using 2-
chloropyrazine (2 mmol, 1 equiv.) and 4-fluorothiophenol (2.4 mmol, 1.2 eq.) yielded the desired
product (346 mg, 84%) as a colourless liquid.Hexane: Ethyl Acetate (7:3) was used as a mobile
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
phase for column chromatography. H NMR (500 MHz, CDCl
3
) δ: 8.29 (dd, J = 2.6, 1.6 Hz, 1H),
8
.21 (d, J = 2.6 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H), 7.58 – 7.55 (m, 2H), 7.13 – 7.10 (m, 2H). 13C
1
NMR{ H} (126 MHz, CDCl
37.4 (d, J = 8.5 Hz), 123.9 (s), 117.0 (d, J = 24.0 Hz). ESI-MS m/z = 206.24m/z calcd. for
FN S [M]; found : 207.20 [M+H].
3
) δ 163.7 (d, J = 240.8 Hz), 158.3 (s), 143.9 (s), 142.8 (s), 140.2 (s),
1
C
10
H
7
2
Methyl 2-(pyrazin-2-ylthio)benzoate(3e):General procedure (GP1) was followed by using 2-
chloropyrazine (2 mmol, 1 equiv.) and methyl-2-thiosalicylate (2.4 mmol, 1.2 eq.) yielded a
desired product (433 mg, 88%) as a colorless liquid. Hexane: Ethyl Acetate (7:3) was used as a
1
mobile phase for column chromatography. H NMR (500 MHz, CDCl
3
) δ: 8.44 (d, J = 3.4 Hz,
1
H), 8.40 (dd, J = 2.4, 1.5 Hz, 1H), 8.32 (dd, J = 4.2, 2.9 Hz, 1H), 7.96 – 7.91 (m, 1H), 7.45 –
1
3
1
7.37 (m, 3H), 3.84 (d, J = 1.4 Hz, 3H). C NMR { H}(126 MHz, CDCl
3
) δ: 166.7 (s), 156.5 (s),
45.4 (s), 144.3 (s), 141.3 (s), 133.8 (s), 132.8 (d, J = 16.0 Hz), 132.3 (s), 131.0 (s), 128.1 (s),
2.4 (s). ESI-MS m/z = 246.05m/z calcd. for C12 S [M]; found : 246.05 [M+H].
S: C, 58.52; H, 4.09; N, 11.37; S, 13.02. Found: C, 58.62; H, 4.25;
1
5
H
10
N
2
O
2
Anal.Calcd.for C12
N, 11.25; S,13.20.
H
10
N
2
O
2
2
-(pyrazin-2-ylthio)benzenamine (3f): General procedure (GP1) was followed by using 2-
chloropyrazine (0.89 mL, 1 mmol) and 2-aminobenzenethiol (0.160 mL, 1.5 mmol, 1.5 eq.)
yielded a desired 2-(pyrazin-2-ylthio)benzenamine (186 mg, 0.92 mmol, 92%) as a pale yellow
1
oil. Hexane: Ethyl Acetate (7:3) was used as a mobile phase for column chromatography. H
NMR (300 MHz, CHLOROFORM-d) δ: 4.38 (br. s., 2 H), 6.72 - 6.90 (m, 2 H), 7.23 - 7.34 (m, 1
ACS Paragon Plus Environment
2
6

Page 27 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
H), 7.49 (dd, J=7.70, 1.56 Hz, 1 H), 8.08 (d, J=1.56 Hz, 1 H), 8.23 (d, J=2.57 Hz, 1 H), 8.34 (dd,
1
3
1
J=2.57, 1.56 Hz, 1 H); C NMR { H}(75 MHz, CHLOROFORM-d) δ: 115.6 (s, 1 C), 119 (s, 2
C), 132.2 (s, 2 C), 137.5 (s, 1 C), 140.0 (s, 1 C), 141.9 (s, 1 C), 143.7 (s, 1 C), 149.2 (s, 1 C);
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(+ve)APCI-MS m/z = 203.05m/z calcd. for C10
H
9
N
3
S [M]; found : 204.1 [M+H]. The compound
1
13
85
exhibited identical H and C NMR data to previous reports .
4
-(pyrazin-2-ylthio)benzenamine (3g): General procedure (GP1) was followed by using 2-
chloropyrazine (2 mmol, 1 equiv.) and 4-aminothiophenol (2.4 mmol, 1.2 eq.) yielded a desired
product (353 mg, 87%) as a pale yellow solid. Hexane: Ethyl Acetate (7:3) was used as a mobile
1
phase for column chromatography. H NMR (500 MHz, CDCl
3
) δ 8.31 – 8.28 (m, 1H), 8.16 (d, J
= 2.6 Hz, 1H), 8.08 (d, J = 1.3 Hz, 1H), 7.38 – 7.35 (m, 2H), 6.71 (dd, J = 8.9, 2.2 Hz, 2H), 3.99
13
1
(
s, 2H). C NMR { H}(126 MHz, CDCl
3
) δ: 160.5 (s), 148.3 (s), 143.5 (s), 141.9 (s), 139.4 (s),
37.2 (s), 116.0 (s), 115.1 (s). ESI-MS m/z = 203.26 m/z calcd. for C10 S [M]; found :
04.25 [M+H]. HRMS calcd for C10 S (M + H), 204.0589; found, 204.0589.
1
2
H
9
N
3
H
10
N
3
2-(pyridin-2-ylthio)pyrazine (3h):General procedure (GP1) was followed by using 2-
chloropyrazine (2 mmol, 1 equiv.) and 2-thiopyridine (2.4 mmol, 1.2 eq.) yielded a desired
product (287 mg, 76%) as a solid. Hexane: Ethyl Acetate (7:3) was used as a mobile phase for
1
column chromatography. H NMR (500 MHz, CDCl
3
) δ: 8.58 (d, J = 1.5 Hz, 1H), 8.46 – 8.43
(m, 1H), 8.39 (dd, J = 3.7, 2.1 Hz, 1H), 8.33 – 8.29 (m, 1H), 7.59 (tdd, J = 6.5, 4.2, 2.3 Hz, 1H),
13
1
7
.43 – 7.39 (m, 1H), 7.15 – 7.11 (m, 1H). C NMR { H}(126 MHz, CDCl ) δ: 154.6 (s), 154.5
3
(s), 150.4 (s), 146.3 (s), 144.3 (s), 141.8 (s), 137.3 (s), 126.2 (s), 122.4 (s). ESI-MS m/z = 189.04
1
m/z calcd. for C
9
H
7
N
3
S [M]; found : 190.06[M+H]. The compound exhibited identical H and
13C NMR data to previous reports86.
ACS Paragon Plus Environment
2
7

The Journal of Organic Chemistry
Page 28 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
-(phenylthio)quinoxaline (3i):General procedure (GP1) was followed by using 2-
chloroquinoxaline (146 mg, 1 mmol) and thiophenol(0.154 mL, 1.5 mmol, 1.5 eq.) yielded a
desired 2-(phenylthio)quinoxaline (222 mg, 0.93 mmol, 93%) as colorless needles. Hexane:
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Ethyl Acetate (7:3) was used as a mobile phase for column chromatography. H NMR (300 MHz,
CHLOROFORM-d) δ: 7.45 - 7.51 (m, 3 H), 7.63 - 7.73 (m, 4 H), 7.88 - 7.92 (m, 1 H), 7.97 -
1
3
1
8.03 (m, 1 H), 8.44 (s, 1 H); C NMR{ H}(75 MHz, CHLOROFORM-d) δ: 128.2 (s, 1 C), 128.7
s, 2 C), 128.9 (s, 1 C), 129.1 (s, 1 C), 129.6 (s, 2 C), 129.7 (s, 1 C), 130.4 (s, 1 C), 134.9 (s, 1
C), 139.83 (s, 1 C), 142.1 (s, 1 C), 143.4 (s, 1 C), 157.1 (s, 1 C); (+ve)APCI-MS m/z = 238.06
m/z calcd. for C14 S [M]; found : 239.09[M+H]. Anal.calcd. for C14 S:C, 70.56; H,
4.23; N, 11.76; S, 13.46; Found: C, 70.51; H, 4.19; N, 11.71, S, 13.41; X- ray Single crystal
(
H
10
N
2
H
10
N
2
1
13
87
measured. The compound exhibited identical H and C NMR data to previous reports .
2
-(2,6-dimethylphenylthio)quinoxaline (3j): General procedure (GP1) was followed by using 2-
chloroquinoxaline (146 mg, 1 mmol) and 2,6-dimethylbenzenethiol (0.2 mL, 1.5 mmol, 1.5 eq.)
yielded a desired 2-(2,6-dimethylphenylthio)quinoxaline (234 mg, 0.88 mmol, 88%) as colorless
1
solid. Hexane: Ethyl Acetate (7:3) was used as a mobile phase for column chromatography. H
NMR (300 MHz, CHLOROFORM-d) δ: 2.49 (s, 6 H), 7.23 - 7.28 (m, 2 H), 7.30 - 7.36 (m, 1 H),
7.68 (dd, J=8.21, 1.70 Hz, 1 H), 7.64 (dd, J=8.12, 1.60 Hz, 1 H), 7.88 - 7.92 (m, 1 H), 7.97 - 8.03
13
1
(m, 1 H), 8.26 (s, 1 H); C NMR { H}(75 MHz, CHLOROFORM-d) δ : 21.9 (s, 2 C),127.1 (s, 1
C),128 (s, 2 C), 128.2 (s, 1 C), 128.6 (s, 1 C), 129.0 (s, 2 C), 130.1 (s, 1 C), 130.3 (s, 1 C), 139.6
(s, 1 C), 142.2 (s, 1 C), 142.3 (s, 1 C), 143.8 (s, 1 C), 156.7 (s, 1 C); (+ve)APCI-MS m/z =
2
66.09m/z calcd. for C16
H
14
N
2
S [M]; found : 267.1 [M+H]. Anal.Calcd.for C16
H
14
2
N S: C, 72.15;
H, 5.30; N, 10.52; S, 12.04. Found: C, 72.09; H, 5.26; N, 10.59; S, 12.34.
ACS Paragon Plus Environment
2
8

Page 29 of 62
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4
-(quinoxalin-2-ylthio)benzenamine (3k):General procedure (GP1) was followed by using 2-
chloroquinoxaline (2 mmol, 1 equiv.) and 4-aminothiophenol (2.4 mmol, 1.2 eq.) yielded a
desired product (461 mg, 91%) as a pale yellow solid. Hexane: Ethyl Acetate (7:3) was used as a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
mobile phase for column chromatography. H NMR (500 MHz, CDCl
3
) δ: 8.36 (d, J = 1.4 Hz,
1
H), 7.96 (d, J = 8.2 Hz, 1H), 7.90 (dd, J = 8.4, 1.4 Hz, 1H), 7.70 – 7.66 (m, 1H), 7.63 – 7.60 (m,
1H), 7.47 – 7.45 (m, 1H), 7.44 (t, J = 1.7 Hz, 1H), 6.77 – 6.76 (m, 1H), 6.75 (t, J = 1.7 Hz, 1H),
1
3
1
3
.96 (s, 2H). C NMR { H}(126 MHz, CDCl
s), 137.1 (s), 130.3 (s), 129.1 (s), 128.2 (s), 128.0 (s), 116.0 (s), 115.3 (s);(+ve)APCI-MS m/z =
53,07m/z calcd. for C14 S[M] found : 254.2 [M+H]; Anal. calcd. for C14 S: C, 66.38;
H, 4.38; N, 16.59; S, 12.66. Found: C, 66.44; H, 4.30; N, 16.50; S, 12.51.
3
) δ: 159.0 (s), 148.2 (s), 142.8 (s), 142.0 (s), 139.5
(
2
H
11
N
3
H
11
N
3
2
-(quinoxalin-2-ylthio)benzenamine (3l): General procedure (GP1) was followed by using 2-
chloroquinoxaline (146 mg, 1 mmol) and 2-aminobenzenethiol (0.160 mL, 1.5 mmol, 1.5 eq.)
yielded a desired 2-(quinoxalin-2-ylthio)benzenamine (212.5 mg, 0.84 mmol, 84%) as yellow
1
oil. Hexane: Ethyl Acetate (7:3) was used as a mobile phase for column chromatography. H
NMR (300 MHz, CHLOROFORM-d) δ: 4.46 (s, 2 H), 6.62 - 6.71 (m, 1 H), 6.74 - 6.86 (m, 2 H),
7
.18 - 7.35 (m, 1 H), 7.56 - 7.71 (m, 2 H), 7.86 - 7.93 (m, 1 H), 7.94 - 7.99 (m, 1 H), 8.27 - 8.35
1
3
1
(m, 1 H); C NMR { H}(75 MHz, DMSO-d6) δ: 115.5 (s, 1 C), 117.8 (s, 1 C), 118.7 (s, 1 C),
27.8 (s, 1 C), 128.4 (s, 1 C), 129 (s, 1 C), 130.2 (s, 1 C), 131.3 (s, 1 C), 132 (s, 1 C), 139.6 (s, 1
C), 142.3 (s, 1 C), 149.3 (s, 1 C), 156.3 (s, 1 C); (+ve)APCI-MS m/z = 253.07m/z calcd. for
S [M]; found : 254.62 [M+H]. Anal.Calcd.for C14 S: C, 66.38; H, 4.38; N, 16.59;
S, 12.66. Found: C, 66.42; H, 4.28; N, 16.45; S, 12.66.
1
C
14
H
11
N
3
H
11
N
3
methyl 2-(quinoxalin-2-ylthio)benzoate (3m):General procedure (GP1) was followed by using 2-
chloroquinoxaline (2 mmol, 1 equiv.) and methyl-2-thiosalicylate (2.4 mmol, 1.2 eq.) yielded a
ACS Paragon Plus Environment
2
9