HFIP Promoted Low-Temperature SNAr of Chloroheteroarenes Using Thiols and Amines

Article abstract of DOI:10.1021/acs.joc.9b02371

A highly efficient and an unprecedented hexafluoro-2-propanol, promoting low-temperature aromatic nucleophilic substitutions of chloroheteroarenes, has been performed using thiols and (secondary) amines under base-free and metal-free conditions. The developed protocol also provides excellent regio-control for the selective functionalization of dichloroheteroarenes, while the utility of the protocol was demonstrated by the modification of a commercially available drug ceritinib.

Full text of DOI:10.1021/acs.joc.9b02371

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Article
HFIP Promoted Low Temperature SNAr of
ChloroHeteroarenes Using Thiols and Amines
Yuvraj B. Bhujabal, Kamlesh Shashikant Vadagaonkar, Aniket
Gholap, Yogesh S. Sanghvi, Rambabu Dandela, and Anant R. Kapdi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02371 • Publication Date (Web): 15 Nov 2019
Downloaded from pubs.acs.org on November 15, 2019
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HFIP Promoted Low Temperature SNAr of ChloroHeteroarenes Using Thiols and Amines
Yuvraj B. Bhujabal,a Kamlesh S. Vadagaonkar,a Aniket Gholap,a Yogesh S. Sanghvi,b Rambabu
Dandela,c and Anant R. Kapdia,c*
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aDepartment of Chemistry, Institute of Chemical Technology, Nathalal Parekh road,
Matunga, Mumbai-400019, India.
bRasayan Inc., 2802, Crystal ridge road, Encintas, California, 92024-6615, USA.
cDepartment of Chemistry, Institute of Chemical Technology-Indian Oil Odisha Campus,
IIT Kharagpur extension centre, MouzaSamantpuri, Bhubaneswar-751013, Odisha,
India.
E-mail: ar.kapdi@ictmumbai.edu.in
OH
F
F
F
F
R
Cl
X
F
F
+
R-XH
 Ambient or low temperature
 Wide substrate scope
 Drug modification
Het
Het
X = S or N
 Nucleoside modifications
HFIP
ABSTRACT
A highly efficient and an unprecedented HFIP promoted low temperature aromatic nucleophilic
substitutions of chloroheteroarenes has been performed using thiols and (secondary) amines
under base-free and metal-free conditions. The developed protocol also provides excellent regio-
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control for the selective functionalisation of dichloroheteroarenes, while the utility of the
protocol was demonstrated by the modification of a commercially available drug Ceritinib.
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INTRODUCTION
Heteroarenes are important structural motifs commonly found in a variety of drugs,1
agrochemicals2 and functional materials3 of commercial relevance. Presence of certain
functionalities on the heteroarene backbone has been found to greatly enhance the bioactivity of
the derived molecules. Thioethers4 and amine functionalities when incorporated onto the
heteroarene has found applications as fungicide (TCMTB),5 immunosuppressive agent (Imuran,
Azathioprine),6 anti-breast cancer agent (Buparilsib),7 anti-neoplastic agent (ZSTK474),8 anti-
hypertension agent (Uptravi)9 and many others (Figure 1).
O
SCN
S
N
N
N
S
CF3
N
N
TCMTB (Fungicide)
NO2
N
N
O
N
O
H2N
N
S
Buparilsib
(Anti breast cancer agent)
H
N
N
N
N
N
N
N
N
N
F
N
Imuran
(Azathioprine,
Immunosuppressive agent)
O
F
Ph
N
ZSTK474
(Anti-neoplastic agent)
Me
O
O
O
O
S
Ph
N
N
N
H
Me
Me Uptravi (Anti hypertension agent)
Figure 1.Thioether and amine functionality containing commercial heteroarene-based drugs and
agrochemicals.
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Access to these molecules in the past has been through a variety of general synthetic procedures
(less efficient, time-consuming and suffering from tedious work-up procedures),10 metal-
mediated processes11,12 (low reactivity and expensive) as well as metal-free (or/and base-
free)SNAr-type reactions13 (commonly carried out at very high temperatures and poor reactivity).
The problems listed with the above synthetic procedures make it highly desirable to develop
simple, efficient and scalable protocol for addressing these issues. A possible solution to this
problem could be achieved by taking into consideration the rate-enhancing effects of certain
solvents that have been reported in literature.14
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A) Previous reports
Y
Pd/Ni or Cu
X
Ar
HetAr
HetAr
HY
Ar
X = Br, I, Cl
High temperature
Limited substrate scope
Metal-mediated
Employment of expensive ligands
Moderate yields





B) This work: Thioetherification and amination of chloroheteroarenes
Y
HFIP
HetAr
HetAr
Ar
X
HY
Ar
OH
F
F
F
F
F
F
Low temperature (rt or 50 oC) Large substrate scope





Chloroheteroarenes
Metal-free
Drug modification

Base-free

Nucleoside modification
Figure 2.Prior art and current work for thioetherification and amination.
Hexafluoro-2-propanol15 (HFIP) is a highly versatile compound that has found applicability as
additive, co-solvent and most importantly a promoting solvent in a variety of synthetic
transformations under metal-mediated16 or metal-free conditions.17 Its role as a promoter could
be envisaged due to the several unique properties, such as strong hydrogen bond donor,fairly
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acidic nature and the ability to ionise substrates. A combination of these properties has
contributed immensely to its employment as a promoting solvent in processes such as Friedel
Crafts reactions,18 Diels Alder reactions,19 C─H bond functionalizations,20Aza-Michael
reactions,21Passerini reaction,22 Halogenation reactions23 and many others involving aliphatic as
well as aromatic substrates. In spite of the tremendous success obtained with HFIP in different
reactions, its applicability to promote aromatic nucleophilic substitutions on aromatic or
heteroaromatic substrates remains to date unexplored. The current report discusses in detail the
unprecedented promoting effect of HFIP as a sole solvent for ambient temperature
thioetherification and low temperature amination of chloroheteroarenes under metal-free and
base-free conditions (Figure 2).
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RESULTSAND DISCUSSION
At the outset of the studies, optimisation of conditions for the thioetherification of
chloroheteroarenes was performed with different solvents. Thioetherification via metal-mediated
processes suffers from a major drawback of catalyst poisoning that has limited their synthesis at
ambient temperature.
Table 1.OptimisationTable for Room Temperature Thioetherificationa
N
N
Cl
N
N
S
HS
Solvent
rt (28 oC), 12 hrs
3a
entry solvent catalyst
base
(equiv.)
--
solvent time
yield
(%)
(mL)
2
(h)
12
1
DMF
--
Trace
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2
3
IPA
Toluene
Ethanol
DMF
TFA
--
--
--
2
2
2
2
2
2
2
1
3
2
12
12
12
12
12
12
12
12
12
12
Trace
NR
--
4
--
--
Trace
Trace
79
5b
6
HFIP
--
--
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--
7
TFE
--
--
65
8
HFIP
HFIP
HFIP
HFIP
--
--
87
9
--
--
--
94
10
11c
--
86
--
Na2CO3(2.0)
Trace
aReaction conditions: 2-chloropyrazine (1.0 mmol), thiophenol (1.2 mmol) and solvent
(1-3 mL) were stirred at rt (28 oC)for 12 h in a pressure vial. bReactionin the presence of
catalytic amount of HFIP. cReactionin the presence of Na2CO3 (2.0 equiv.) as a base.
To address this problem, it was decided to explore the possibility of performing the
metal-free thioetherification at ambient temperature between 2-chloropyrazine and
thiophenol (Table 1). Polar solvents such as dimethylformamide and isopropanol (Table
1, entries 1 and 2) failed to provide any product as was the case with toluene and ethanol
(Table 1, entries 3and 4). The employment of HFIP as an additive to DMF also failed to
provide any product (Table 1, entry 5). Fluorinated alcohols in the past have shown
promising results in promoting substitution reactions in different substrates. With this in
mind, trifluoroacetic acid (TFA), trifluoroethanol (TFE) and HFIP were employed as the
solvents without the addition of any base. Interestingly, fluorinated solvents provided
good to excellent yield of the desired thioetherified product with best results obtained
with HFIP (Table 1, entries 6-8 respectively). Quantity of HFIP used for the reaction also
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had a pronounced effect on the nucleophilic substitution reaction as 1.0 mL of HFIP was
found to be the optimum concentration for obtaining maximum yield (Table 1, entry 9),
while addition of base failed to provide any product with deprotonation of HFIP as the
possible reason for the loss in activity (Table 1, entry 11).
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With a simple, metal-free and base-free protocol in hand, we explored the substrate scope for
thioetherification with a wide variety of chloroheteroarenes and aryl as well as alkyl thiols.With
good to excellent yields obtained for simple heteroarenes at ambient temperature (3a-q, Scheme
1) the thioetherification protocol was also extended to 6-chloropurine with similar results (3r-t,
Scheme 1). Modification of 6-chloro purine riboside is a synthetically challenging prospect given
the lability of the glycosidic bond due to its temperature sensitivity. Thioetherification of 6-
chloro purine riboside at ambient temperature would therefore be ideal and unprecedented.24This
was achieved in good yields using the developed protocol promoted by HFIP (3u-w, Scheme 1).
Besides arylthiols, the developed protocol also was tested for the employment of alkylthiols as
nucleophilic partners with very good yields obtained for their coupling with 2-chloroquinoxaline
(3x-z, Scheme 1). Oxygen containing heterocycles such as 2-chlorobenzoxazole was also
thioetherified efficiently under the developed reactions conditions (3aa, Scheme 1).Successful
development of room temperature thioetherification protocol allowed us to explore the
possibility of carrying out amination of chloroheteroarenes.
Scheme 1.Scope Studies for Thioetherificationof Chloroheteroarenes at Low Temperature
in HFIP
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S
HFIP (1.0 mL)
rt (28 oC), 12-48 hrs
Aryl/Alkyl
N
Aryl/Alkyl-SH
HetAr
Cl
HetAr
7
8
9
N
N
S
N
N
S
N
N
S
N
N
S
N
S
Cl
OMe
S
N
3e
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3a
3b
3c
3d
(75%)
(94%)
(86%)
(89%)
(91%)
N
N
N
S
N
N
S
N
N
N
S
N
N
N
N
OMe
N
Cl
H3C
3f
3j
3g
(90%)
S
(80%)
3i
(85%)
3h
(89%)
S
N
N
S
N
N
N
S
N
N
N
N
F
N
S
N
N
S
Me
S
3k
(86%)
CO2Me
(94%)
S
3m
3l (87%)
(87%)
3n
(79%)
Cl
N
S
N
S
N
S
S
N
S
S
S
OMe
Cl
N
N
N
3o
(81%)
OMe
3p
(83%)
3q
(80%)
N
H
(71%)
N
H
N
N
F
MeO
3r
3s
(65%)
N
S
N
S
N
S
S
N
N
N
N
C10H21
N
N
N
N
N
N
S
N
Cl
3x
(95%)
N
N
N
H
N
HO
HO
HO
N
N
S
N
N
O
O
3t
(67%)
O
3y
(93%)
S
OH OH
3v
OH OH
3u
OH OH
3w
3z
(92%)
(71%)
(59%)
N
O
(67%)
S
3aa
(86%)
Amination of chloroheteroarenes was next to be undertaken and at the outset it was observed that
as compared to thioetherification, which proceeds at ambient temperature, amination requires
o
slightly higher temperature (50 C). Firstly, 2-chlorobenzoxazole was subjected to amination
conditions with wide variety of secondary amines as it was observed initially that the primary
amines provided poor reactivity. Secondary amines ranging from diethylamine, methyl
benzylamine, azetidine, pyrrolidine, 3-methyl piperidine, 4-(2-methoxyphenyl)piperazine and
azepanewere coupled efficiently with 2-chlorobenzoxazole (5a-g, Scheme 2). Next, 2-
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chlorobenzothiazole was employed as the substrate, however in comparison to benzoxazole it
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was found to be less reactive providing lower yields of the aminated product (5h-m, Scheme 2).
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Scheme 2.Scope Studies for Amination of Chloroheteroarenes at Low Temperature in
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HFIP
R
N
R
N
R
HFIP (1.0 mL)
50 oC, 12 hrs
R
Cl
N
HetAr
H
HetAr
N
OMe
N
N
O
N
N
N
O
N
O
N
O
N
O
N
N
N
N
N
O
O
Me
5a
(80%)
5c
(69%)
5b
(79%)
5g
(74%)
5d
5f
(81%)
(86%)
5e
(83%)
OMe
N
N
S
N
S
N
S
N
S
N
S
N
S
N
N
N
N
O
N
N
5m
(45%)
5h
(43%)
5i
5l
(48%)
(49%)
O2N
5j
5k
(36%)
(41%)
N
N
N
N
N
N
N
N
N
N
OMe
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
H
N
H
N
N
5s
(57%)
5o
5n
(73%)
Boc
5r
(68%)
(59%)
5p
(78%)
5q
(76%)
5u
(75%)
5t
(63%)
O
N
O
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
HO
HO
HO
HO
N
H
N
H
N
H
N
N
N
O
O
O
O
5v
(77%)
5w
(71%)
5x
(59%)
OH OH
5aa
OH OH
5y
OH OH
5z
OH OH
5ab
(60%)
(64%)
(92%)
(90%)
Improved yields were obtained with pyrimidine as 5 different secondary amines were coupled
efficiently under the developed reaction conditions (5n-r, Scheme 2). Although, 2-
chloropyridine was also subjected to amination, negligible product formation due to the possible
protonation of pyridine N atom was observed. To address this issue, we envisaged the
introduction of an electron-withdrawing group that would help promote the amination to proceed
in the forward direction. Accordingly, 2-chloro-5-nitropyridine when reacted with secondary
o
amines in HFIP at 50 C yielded decent amount of the desired product (5s, Scheme 2). Purine
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was next to be submitted to the amination conditions with different secondary amines providing
good yields of the product (5t-x, Scheme 2), an observation which was also achieved in the case
of 6-chloroadenosine providing molecules of synthetic relevance (5y-z, 5aa-ab, Scheme 2).
Regioselectivity in synthesis is an important synthetic challenge that in the past has been
explored extensively using metal-mediated processes.25 Solvent-assisted regioselective reactions
are rare and development of selective processes without the incorporation of metal is highly
desirable. In literature, polyhalogenated heteroarenes have been effectively functionalized in a
selective manner.26We envisaged HFIP to promote the selective mono-amination or
thioetherification of dichloro or trichloroheteroarenes. 2,6-Dichloropurine, 2,4-
dichloropyrimidine and 2,4,6-trichloropyrimidine were selected as substrates and amination as
well as thioetherification was performed to provide mono-functionalised heteroarenes in good
yields by the employment of a stoichiometric amount of nucleophiles (7a-f, Scheme 3A).
Scheme 3. Regioselective Modification of Polyhalogenated Heteroarenes
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SR/NR2
or
Amines/sulfides
1.0 equiv.
(or 3.0 equiv.)a
HFIP (1.0 mL)
Cl
HetAr
HetAr
HetAr
Temp, 12 hrs
rt or 50 oC
Cl
Cl
SR/NR2
SR/NR2
9
A) Mono amination (thioetherification)
OMe
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S
N
N
N
N
S
N
N
N
N
N
Cl
N
N
H
Cl
Cl
N
N
H
N
Cl
7d
(88%)
7c
(85%)
7a
(70%)
7b
(78%)
O
Cl
N
N
N
N
S
Cl
N
Cl
7e
(88%)
7f
(78%)
B) Diaminationa
O
N
N
N
N
N
N
N
N
O
a
8b
(94%)
a
8a
(85%)
Buparilsib intermediate
However, the employment of excess amount of amine (piperidine or morpholine) with dichloro
heteroarenes provided diaminated products of which one was an important Buparilsib
intermediate7 (Buparlisib is a pan-class 1 phosphoinositide 3-kinase inhibitor) 8b (8a-b, Scheme
3B). The above result suggests that the employment of HFIP as a promoter solvent has beneficial
effect for obtaining selectivity in the given transformations. This was further exploited for the
synthesis
of
unsymmetrically
substituted
heteroarenes
via
simultaneous
thioetherification/amination protocol performed at different temperatures (9a-b, Scheme 4). The
strategy employed involves an initial regioselective thioetherification carried out at ambient
o
temperature followed by amination performed at an elevated temperature of 50 C. Such a
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synthetic strategy presents researchers with an easy and efficient method for accessing such
diverse structural motifs.
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Scheme
4.
Unsymmetrically
Substituted
Heteroarenes
via
Simultaneous
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Thioetherification/AminationProtocol
SR
SR
HFIP (1.0 mL)
rt (28 oC), 12 hrs
R2-NH
Cl
HetAr
HetAr
HetAr
Cl
(1.0 equiv.)
50 o
C
Cl
NR2
Arylsulfides
1.0 equiv.
S
N
S
N
N
N
N
N
O
9a
(84%)
9b
(87%)
Synthetic utility of the developed protocol was demonstrated with the modification of a
commercial anti-cancer drug, Ceritinib (10).27
Me
O
O
S
Me
H
N
N
HN
Me
O
N
Cl
Me
Me
N
H
10
The secondary amine (piperidine) structural feature under the HFIP promoted amination
conditions coupled with 6-chloropurine and 2,6-dichloropurine in good yields (11a-b, Scheme
5).
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Scheme 5. Commercial Secondary Amine-Based Drug Modification
5
6
7
8
N-Drugs
HFIP (1.0 mL)
55 oC, 12 hrs
Amine-based
drugs
Cl
HetAr
HetAr
9
Me
Me
O
O
O
O
S
10
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Me
S
Me
H
H
N
N
N
N
O
N
O
HN
O
HN
F
Me
N
Me
O
N
O
Cl
Cl
Me
Me
N
Me
N
Me
N
N
O
N
N
N
N
11c
(50%)
N
N
N
H
N
N
H
Cl
(63%)
11b
11a
(69%)
Similarly, another commercial drug, Norfloxacin could easily be modified using the developed
protocol with chlorobenzoxazole interacting with the secondary amine of the drug (11c, Scheme
5).
The development of a synthetically useful thioetherification and amination protocol for
chloroheteroarenes allowed for the possibility to perform scale-up studies. With a 10 mmol
reaction of 2-chloropyrazine carried out with 12 mmol thiophenol in 10 mL of HFIP at ambient
temperature provided 94% of the desired product (Scheme 6). On completion of the reaction,
HFIP was recovered up to 80% providing an opportunity to reuse the solvent for further
application.
Scheme 6. Scale-up studies
N
N
Cl
N
N
S
HS
HFIP (10 mL)
rt (28 oC), 12 hrs
3a
(94%)
(10 mmol)
(12 mmol)
80% recovery of HFIP
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Based on the results obtained with HFIP as a solvent and promoter a plausible mechanism has
been put forth (Scheme 7). Initially, the reaction between chloroheteroarenes and HFIP wherein
the proton interacts strongly28 with the nitrogen atom could be seen as a crucial step in bringing
about the possible weakening of the otherwise strong C─Cl bond. Approach of the nucleophile
to the electrophilic carbon next to the heteroatom is therefore assisted by the HFIP coordinated
complex releasing HCl molecule, eventually leading to the formation of the desired product.
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Scheme 7. Plausible Mechanism for HFIP Promoted Thioetherification or Amination of
Chloroheteroarenes
OH
CF3
N
N
Nu
Cl
N
N
N
N
+
Cl
F3C
-

N
O
N
O
Nu
Nu
Cl
H
H
F3C
CF3
F3C
CF3
CONCLUSION
In conclusion, we have developed a highly efficient and synthetically attractive HFIP promoted
thioetherification (aryl and alkylthiols) and amination (secondary amines) of chloroheteroarenes
under base-free and metal-free conditions. An attractive feature of the developed protocol is the
low temperature conditions (ambient temperature for thioetherification) promoting the
functionalisation of temperature sensitive substrates such as 6-chloropurine riboside. With a
large substrate scope providing an easy access to synthetically useful molecules, the developed
protocol was also found to be highly regioselective in promoting the mono-thioetherification or
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amination of dichloroheteroarenes in good to excellent yields. We have also demonstrated the
usefulness of the developed synthetic strategy with the synthesis of a Buparilsib intermediate as
well as for the modification of a commercially available anti-cancer drug, Ceritinib. A plausible
mechanism highlighting the unprecedented promoting effect of HFIP in the given synthetic
transformation has also been provided.
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EXPERIMENTALSECTION
General Information.All the chemicals and solvents were obtained from commercial sources.
All the reactions were performed using oven-dried 20 mL pressure vials. All reactions were
monitored by TLC performed on aluminum plates (0.25 mm, E. Merck) precoated with silica gel
Merck 60 F-254. Developed TLC plates were visualized under a short wavelength UV lamp.
13
Yields refer to spectroscopically (1H, C NMR) homogeneous material obtained after column
chromatography. Column chromatography was performed on silica gel (100:200 mesh size)
supplied by S. D. Fine Chemicals Limited, India. 1H NMR (400 MHz, 500 MHz) and 13C NMR
(101 MHz, 126 MHz) spectra were recorded in CDCl3 and DMSO-d6 on Agilent 400 MHz and
500 MHz spectrometers. Chemical shifts (δ) are reported in ppm, relative to SiMe4 (δ = 0.0) as
an internal standard. The number of protons (n) for a given resonance are indicated by nH. Peak
multiplicities are designated by the following abbreviations: s, singlet; d, doublet; t, triplet; m,
multiplet; dd, doublet of doublet; ddd, doublet of doublet of doublet; td; triplet of doublet; br;
broad. Coupling constant (J) values are reported in hertz (Hz). Elemental analysis was performed
using an Elementar Vario MICRO cube instrument. High resolution mass spectra were obtained
by using positive electrospray ionization (ESI) by time of flight (TOF) method. Melting points
were recorded on a standard melting point apparatus and are uncorrected.
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General Procedure for Thioetherification of Chloroheteroarenes.A 20 mL oven-dried
pressure vial was charged with chloroheteroarene (1, 1.0 mmol) and HFIP (1.0 mL). The mixture
was stirred at room temperature for 10 min. and to it was added 1.2 equiv. of corresponding
thiophenol(2,1.2 mmol). The resulting mixture was stirred at room temperature (28 °C) for 12-48
h. After completion of the reaction (monitored by TLC), the solvent was removed under vacuum
and the residue obtained was purified by column chromatography on 100:200 mesh silica gel by
using ethyl acetate:n-hexane (1-15%) solvent system to afford the corresponding products 3a-3q
and 3x-3aa.In the case of purine derivatives(3r-3t) and riboside derivatives (3u-3w),
MeOH:CHCl3 (1-5%) was used as a mobile phase for column chromatography. Mono
thioetherification of polyhalogenated chloroheteroarenes (6) was carried out using 1.0 equiv. of
corresponding thiophenol(2,1.0 mmol) by using above procedure to afford corresponding
products 7b, 7d and 7f.
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General procedure for amination of chloroheteroarenes.A 20 mL oven-dried pressure vial
was charged with chloroheteroarene (1,1.0 mmol) and HFIP (1.0 mL). The mixture was stirred at
0 oC for 10 min. and to it was slowly added 1.2 equiv. of corresponding secondary amine (4, 1.2
mmol). The resulting mixture was stirred at 50 °Cin an oil bath for 12 h. After completion of the
reaction (monitored by TLC), the solvent was removed under vacuum and the residue obtained
was purified by column chromatography on 100:200 mesh silica gel by using ethyl acetate: n-
hexane (5-10%) solvent system to afford the corresponding products 5a-5s.In the case of purine
derivatives (5t-5x) and riboside derivatives (5y-5ab), MeOH:CHCl3 (1-5%) was used as a
mobile phase for column chromatography.Mono amination of polyhalogenated
chloroheteroarenes (6) was carried out using 1.0 equiv. of corresponding secondary amine (4, 1.0
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mmol) by using above procedure to afford corresponding products 7a, 7c and 7e.Diamination of
polyhalogenated chloroheteroarenes (6) was carried out using 3.0 equiv. of corresponding
secondary amine (4, 3.0 mmol) by using above procedure to afford corresponding products 8a
and 8b. Unsymmetrically substituted heteroarenes 9a and 9b were obtained by simultaneous
mono thioetherification of dichloropyrimidine at room temperature followed by amination of
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o
mono thioetherication product at 50 C by using above procedures.Products 11a and 11b were
obtained via amination of di and monochloropurine by using Ceritinib (commercially available
o
drug) at 55 C. Product 11c was obtained via amination of 2-chlorobenzoxazole by using
Norfloxacin methyl ester at 55 oC.
Characterization data of the products
1
2-(Phenylthio)pyrazine (3a).29Yellow oil(177 mg, 94%);Time: 12h; H NMR (500 MHz,
CDCl3) δ8.34 (dd, J = 2.4, 1.6 Hz, 1H), 8.23 (d, J = 2.5 Hz, 1H), 8.19 (d, J = 1.4 Hz, 1H), 7.63–
7.59 (m, 2H), 7.46-7.44 (m, 3H).13C{1H} NMR (126 MHz, CDCl3) δ 158.7(s, 1C), 143.8 (s, 1C),
142.7 (s, 1C),140.1(s, 1C),135.1 (s, 2C), 129.9 (s, 2C), 129.7 (s, 1C),128.9 (s, 1C).Anal.Calcd
(%) for C10H8N2S: C, 63.80; H, 4.28; N, 14.88; S, 17.03.Found: C, 63.94; H, 4.07; N, 14.96; S,
17.21.
2-((4-Chlorophenyl)thio)pyrazine (3b).30Yellow oil(192 mg, 86%); Time: 12h;1H NMR (500
MHz, CDCl3) δ 8.37 (dd, J = 2.5, 1.6 Hz, 1H), 8.27 (distorted t, J = 2.9, 2.0 Hz, 2H), 7.53 (d, J =
8.5 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H).13C{1H} NMR (126 MHz, CDCl3) δ 158.1 (s, 1C), 144.2 (s,
1C), 142.4 (s, 1C), 140.0 (s, 1C), 136.3 (s, 2C), 136.2 (s, 1C), 130.1 (s, 2C), 127.2 (s,
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1C).Anal.Calcd (%) for C10H7ClN2S: C, 53.94; H, 3.17; N, 12.58; S, 14.40.Found: C, 53.68; H,
3.39; N, 12.72; S, 14.66.
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2-((4-Methoxyphenyl)thio)pyrazine (3c).Yellow oil(195 mg, 89%); Time: 12h;1H NMR (500
MHz, CDCl3) δ 8.32 (dd, J = 2.5, 1.6 Hz, 1H), 8.20 (d, J = 2.6 Hz, 1H), 8.12 (d, J = 1.5 Hz, 1H),
7.54 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H).13C{1H} NMR (126 MHz, CDCl3)
δ161.0 (s, 1C), 159.7 (s, 1C), 143.7 (s, 1C),142.2 (s, 1C), 139.7 (s, 1C), 137.2 (s, 2C), 118.9(s,
1C),115.5 (s, 2C),55.4 (s, 1C). Anal.Calcd (%) for C11H10N2OS: C, 60.53; H, 4.62; N, 12.83; S,
14.69. Found: C, 60.73; H, 4.42; N, 12.97; S, 14.91.HRMS (ESI-TOF): m/z [M + H]+calcd for
C11H11N2OS: 219.0592; found: 219.0598.
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2-(Pyridin-2-ylthio)pyrazine (3d).30Yellow oil(142 mg, 75%); Time: 12h;1H NMR (500 MHz,
CDCl3) δ 8.65 (d, J = 1.3 Hz, 1H), 8.53 (d, J = 4.6 Hz, 1H), 8.46 (distorted t, J = 2.2, 1.5 Hz,
1H), 8.39 (d, J = 2.5 Hz, 1H), 7.66 (td, J = 7.7, 1.9 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.21 (ddd,
J = 7.5, 4.9, 1.0 Hz, 1H).13C{1H} NMR (126 MHz, CDCl3) δ 154.7 (s, 1C), 154.7 (s, 1C), 150.5
(s, 1C), 146.4 (s, 1C), 144.4 (s, 1C), 141.8 (s, 1C), 137.3 (s, 1C), 126.4 (s, 1C), 122.5 (s,
1C).Anal.Calcd (%) for C9H7N3S: C, 57.12; H, 3.73; N, 22.21; S, 16.94.Found: C, 57.34; H,
3.91; N, 22.43; S, 16.82.
1
2-(Phenylthio)quinoxaline (3e).13c Off white solid(217 mg, 91%); Time: 12h; H NMR (400
MHz, CDCl3) δ8.42 (s, 1H), 7.97 (dd, J = 8.3, 1.2 Hz, 1H), 7.88 (dd, J = 8.3, 1.2 Hz, 1H), 7.70–
7.60 (m, 4H), 7.49–7.43 (m, 3H).13C{1H} NMR (101 MHz, CDCl3) δ157.1 (s, 1C),143.4 (s, 1C),
142.1 (s, 1C), 139.8 (s, 1C),135.0 (s, 2C), 130.4 (s, 1C), 129.8 (s, 2C), 129.6 (s, 1C), 129.1(s,
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1C), 128.9 (s, 1C), 128.7 (s, 1C), 128.3 (s, 1C).Anal.Calcd (%) for C14H10N2S: C, 70.56; H, 4.23;
N, 11.76; S, 13.45. Found: C, 70.72; H, 4.07; N, 11.82; S, 13.53.
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2-((4-Chlorophenyl)thio)quinoxaline (3f).White solid(246 mg, 90%); mp 66-68 C; Time:
12h;1H NMR (500 MHz, CDCl3) δ8.48 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.86 (d, J = 8.1 Hz,
1H), 7.70–7.62 (m, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H).13C{1H} NMR (126
MHz, CDCl3) δ156.1 (s, 1C), 143.4 (s, 1C), 142.2 (s, 1C), 140.0 (s, 1C), 136.2 (s, 2C), 135.9 (s,
1C), 130.5 (s, 1C), 129.9 (s, 2C), 129.2 (s, 1C), 128.9 (s, 1C), 128.3 (s, 1C), 127.3 (s,
1C).Anal.Calcd (%) for C14H9ClN2S: C, 61.65; H, 3.33; N, 10.27; S, 11.75. Found: C, 61.83; H,
3.12; N, 10.41; S, 11.63. HRMS (ESI-TOF): m/z [M + H]+calcd for C14H10ClN2S: 273.0253;
found: 273.0257.
2-(Pyridin-2-ylthio)quinoxaline (3g).Yellow oil(192mg, 80%); Time: 12h;1H NMR (500 MHz,
CDCl3) δ 8.79 (s, 1H), 8.54–8.53 (m, 1H), 8.05 (dd, J = 7.3, 2.4 Hz, 1H), 7.97 (dd, J = 7.8, 1.9
13
Hz, 1H), 7.75–7.67 (m, 3H), 7.61 (d, J = 8.0 Hz, 1H), 7.25–7.22 (m, 1H). C{1H} NMR (126
MHz, CDCl3) δ 154.7 (s, 1C), 153.9 (s, 1C), 150.5 (s, 1C), 146.3 (s, 1C), 142.5 (s, 1C), 140.4 (s,
1C), 137.3 (s, 1C), 130.4 (s, 1C), 129.6 (s, 1C), 129.2 (s, 1C), 128.7 (s, 1C), 126.4 (s, 1C), 122.5
(s, 1C).Anal.Calcd (%) for C13H9N3S: C, 65.25; H, 3.79; N, 17.56; S, 13.40.Found: C, 65.44; H,
3.97; N, 17.40; S, 13.52.HRMS (ESI-TOF): m/z [M + H]+calcd for C13H10N3S: 240.0595; found:
240.0589.
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2-((4-Methoxyphenyl)thio)quinoxaline (3h).Light green solid(239 mg, 89%); mp 63-65 C;
Time: 12h;1H NMR (500 MHz, CDCl3) δ8.37 (s, 1H), 7.97 (dd, J = 8.1, 0.8 Hz, 1H), 7.88 (dd,
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J= 8.3, 0.8 Hz, 1H), 7.70–7.67 (m, 1H), 7.63 (dd, J = 8.2, 1.2 Hz, 1H), 7.60 (d, J = 8.8 Hz, 2H),
7.00 (d, J = 8.8 Hz, 2H), 3.87 (s, 3H).13C{1H} NMR (126 MHz, CDCl3) δ161.0 (s, 1C), 158.2 (s,
1C),142.9 (s, 1C), 142.1 (s, 1C), 139.7 (s, 1C),137.1 (s, 2C),130.4 (s, 1C), 129.1 (s, 1C), 128.5
(s, 1C), 128.2 (s, 1C), 118.9 (s, 1C),115.5 (s, 2C), 55.5 (s, 1C).Anal.Calcd (%) for C15H12N2OS:
C, 67.14; H, 4.51; N, 10.44; S, 11.95. Found: C, 67.32; H, 4.39; N, 10.56; S, 11.83.HRMS (ESI-
TOF): m/z [M + H]+calcd for C15H13N2OS: 269.0749; found: 269.0755.
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2-((1-Methyl-1H-tetrazol-5-yl)thio)quinoxaline (3i).Pale yellow solid(208 mg, 85%); mp 158-
160 oC; Time: 12h;1H NMR (500 MHz, CDCl3) δ8.82 (s, 1H), 8.09–8.05 (m, 1H), 7.79–7.71 (m,
3H), 4.15 (s, 3H).13C{1H} NMR (126 MHz, CDCl3) δ 149.8 (s, 1C), 147.2 (s, 1C), 142.9 (s, 1C),
142.3 (s, 1C), 140.8 (s, 1C), 131.3 (s, 1C), 130.3 (s, 1C), 129.4 (s, 1C), 128.3 (s, 1C), 34.8 (s,
1C).Anal.Calcd (%) for C10H8N6S: C, 49.17; H, 3.30; N, 34.40; S, 13.12.Found: C, 49.35; H,
3.09; N, 34.58; S, 13.20. HRMS (ESI-TOF): m/z [M + H]+calcd for C10H9N6S: 245.0609; found:
245.0613.
o
2-(Naphthalen-1-ylthio)quinoxaline (3j).Off white solid(272 mg, 94%); mp 120-122 C; Time:
12h;1H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 8.2 Hz, 1H), 8.14 (s, 1H), 8.02 (distorted t, J =
8.5, 7.1 Hz, 2H), 7.94 (dd, J = 8.1, 3.9 Hz, 2H), 7.87 (d, J = 8.4 Hz, 1H), 7.69–7.66 (m, 1H),
7.63–7.60 (m, 1H), 7.58–7.50 (m, 3H).13C{1H} NMR (126 MHz, CDCl3) δ 157.5 (s, 1C), 142.8
(s, 1C), 142.1 (s, 1C), 139.7 (s, 1C), 135.8 (s, 1C), 134.6 (s, 1C), 134.5 (s, 1C), 131.4 (s, 1C),
130.5 (s, 1C), 129.1 (s, 1C), 128.8 (s, 1C), 128.7 (s, 1C), 128.2 (s, 1C), 127.7 (s, 1C), 126.8 (s,
1C), 126.0 (s, 1C), 125.7 (s, 1C), 125.6 (s, 1C).Anal.Calcd (%) for C18H12N2S: C, 74.97; H, 4.19;
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N, 9.71; S, 11.12.Found: C, 74.73; H, 4.07; N, 9.63; S, 11.22. HRMS (ESI-TOF): m/z [M +
5
6
H]+calcd for C18H13N2S: 289.0799; found: 289.0791.
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Methyl 2-(quinoxalin-2-ylthio)benzoate (3k).30White solid(255 mg, 86%); Time: 12h;1H NMR
(400 MHz, CDCl3) δ 8.59 (s, 1H), 8.00 (distorted t, J = 9.2, 8.7 Hz, 2H), 7.90 (d, J = 8.1 Hz,
1H), 7.71–7.64 (m, 2H), 7.58 (d, J = 7.5 Hz, 1H), 7.49–7.42 (m, 2H), 3.80 (s, 3H).13C{1H} NMR
(101 MHz, CDCl3) δ 166.9 (s, 1C), 155.7 (s, 1C), 145.1 (s, 1C), 142.3 (s, 1C), 140.2 (s, 1C),
134.4 (s, 1C), 133.4 (s, 1C), 132.3 (s, 1C), 131.8 (s, 1C), 131.1 (s, 1C), 130.4 (s, 1C), 129.1 (s,
1C), 129.1 (s, 1C), 128.5 (s, 1C), 128.4 (s, 1C), 52.3 (s, 1C).Anal.Calcd (%) for C16H12N2O2S: C,
64.85; H, 4.08; N, 9.45; S, 10.82.Found: C, 64.97; H, 4.03; N, 9.62; S, 10.78.
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2-((4-Fluorophenyl)thio)quinoxaline (3l).White solid(223 mg, 87%); mp 50-52 C; Time:
12h;1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 7.99 (dd, J = 8.2, 1.4 Hz, 1H), 7.86 (dd, J = 8.0,
1.4 Hz, 1H), 7.70–7.62 (m, 4H), 7.20–7.15 (m, 2H).13C{1H} NMR (126 MHz, CDCl3) δ 163.7
(d, JC,F = 251.4 Hz, 1C), 156.7 (s, 1C), 143.1 (s, 1C), 142.2 (s, 1C), 139.9 (s, 1C), 137.4 (d, JC,F
=
8.6 Hz, 2C), 130.5 (s, 1C), 129.2 (s, 1C), 128.8 (s, 1C), 128.2 (s, 1C), 123.8 (d, JC,F = 3.4 Hz,
1C), 117.0 (d, JC,F = 22.2 Hz, 2C).Anal.Calcd (%) for C14H9FN2S: C, 65.61; H, 3.54; N, 10.93;
S, 12.51.Found: C, 65.79; H, 3.68; N, 10.78; S, 12.70. HRMS (ESI-TOF): m/z [M + H]+calcd for
C14H10FN2S: 257.0549; found: 257.0545.
2-(Phenylthio)benzo[d]thiazole (3m).31Yellow oil(212 mg, 87%); Time: 48h;1H NMR (400
MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 6.6 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.53–
7.45 (m, 3H), 7.39 (distorted t, J = 8.0, 7.4 Hz, 1H), 7.26 (distorted t, J = 8.0, 6.8 Hz,
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1H).13C{1H} NMR (101 MHz, CDCl3) δ 169.6(s, 1C), 153.9 (s, 1C),135.5 (s, 1C),135.3 (s,
2C),130.4 (s, 1C),130.0 (s, 1C),129.9 (s, 2C),126.1 (s, 1C), 124.3 (s, 1C), 121.9 (s, 1C), 120.8 (s,
1C).Anal.Calcd (%) for C13H9NS2: C, 64.17; H, 3.73; N, 5.76; S, 26.35. Found: C, 64.33; H,
3.61; N, 5.90; S, 26.47.
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2-((1-Methyl-1H-tetrazol-5-yl)thio)benzo[d]thiazole (3n).White solid(197 mg, 79%); mp 96-98
oC; Time: 48h;1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H),
7.46 (distorted t, J = 8.2, 7.2 Hz, 1H), 7.39 (distorted t, J = 8.0, 7.2 Hz, 1H), 4.16 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ 157.4 (s, 1C), 152.7 (s, 1C), 147.8 (s, 1C), 136.2(s, 1C),
126.8 (s, 1C), 125.9 (s, 1C), 122.9 (s, 1C), 121.3 (s, 1C), 34.8 (s, 1C).Anal.Calcd (%) for
C9H7N5S2: C, 43.36; H, 2.83; N, 28.09; S, 25.72. Found: C, 43.50; H, 2.70; N, 28.26; S,
25.84.HRMS (ESI-TOF): m/z [M + H]+calcd for C9H8N5S2: 250.0221; found: 250.0229.
2-((4-Methoxyphenyl)thio)benzo[d]thiazole (3o).31White solid(222 mg, 81%);Time: 48h;1H
NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.62 (d, J = 8.7
Hz, 1H), 7.38 (t, J = 7.1 Hz, 1H), 7.23 (distorted t, J = 7.3, 6.7 Hz, 1H), 6.99 (d, J = 8.9 Hz, 2H),
3.86 (s, 3H).13C{1H} NMR (101 MHz, CDCl3) δ 171.8 (s, 1C), 161.7 (s, 1C), 154.2 (s, 1C),137.5
(s, 2C),135.4 (s, 1C), 126.0 (s, 1C), 124.0 (s, 1C), 121.7 (s, 1C), 120.7 (s, 1C), 120.2 (s, 1C),
115.5 (s, 2C), 55.4 (s, 1C).Anal.Calcd (%) for C14H11NOS2: C, 61.51; H, 4.06; N, 5.12; S, 23.46.
Found: C, 61.63; H, 4.02; N, 5.26; S, 23.60.
2-((4-Chlorophenyl)thio)benzo[d]thiazole (3p).32White solid(231 mg, 83%); Time: 48h;1H
NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.2 Hz, 1H), 7.66 (distorted t, J = 8.5, 6.3 Hz, 3H), 7.44
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(d, J = 8.6 Hz, 2H), 7.40 (d, J = 7.2 Hz, 1H), 7.28 (t, J = 8.2 Hz, 1H). 13C{1H} NMR (101 MHz,
CDCl3) δ 168.2 (s, 1C), 153.8 (s, 1C), 136.9 (s, 1C), 136.4 (s, 2C), 135.6 (s, 1C), 130.1 (s, 2C),
128.4 (s, 1C), 126.3 (s, 1C), 124.5 (s, 1C), 122.1 (s, 1C), 120.8 (s, 1C).Anal.Calcd (%) for
C13H8ClNS2: C, 56.21; H, 2.90; N, 5.04; S, 23.08. Found: C, 56.37; H, 2.74; N, 5.16; S, 23.20.
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2-(Naphthalen-1-ylthio)benzo[d]thiazole (3q).33White solid(235 mg, 80%); Time: 48h;1H NMR
(400 MHz, CDCl3) δ 8.52–8.43 (m, 1H), 8.06 (d, J = 7.6 Hz, 2H), 7.96–7.90 (m, 1H), 7.88 (d, J
= 8.1 Hz, 1H), 7.61–7.53 (m, 3H), 7.51 (d, J = 8.0 Hz, 1H), 7.37 (distorted t, J = 8.0, 7.4 Hz,
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1H), 7.20 (distorted t, J = 7.9, 7.3 Hz, 1H). C{1H} NMR (101 MHz, CDCl3) δ 170.0 (s, 1C),
153.9 (s, 1C), 136.3 (s, 1C), 135.6 (s, 1C), 134.5 (s, 1C), 134.3 (s, 1C), 132.1 (s, 1C), 128.8 (s,
1C), 127.9 (s, 1C), 126.9 (s, 1C), 126.9 (s, 1C), 126.1 (s, 1C), 125.9 (s, 1C), 125.5 (s, 1C), 124.1
(s, 1C), 121.8 (s, 1C), 120.7 (s, 1C). Anal.Calcd (%) for C17H11NS2: C, 69.59; H, 3.78; N, 4.77;
S, 21.85. Found: C, 69.73; H, 3.62; N, 4.61; S, 21.95.
6-(Phenylthio)-9H-purine (3r).34White solid(162 mg, 71%); Time: 12h;1H NMR (500 MHz,
DMSO-d6) δ 13.59 (s, 1H), 8.52 (s, 1H), 8.49 (s, 1H), 7.63–7.60 (m, 2H), 7.49–7.46 (m,
3H).13C{1H} NMR (126 MHz, DMSO-d6) δ 158.5 (s, 1C), 152.1 (s, 1C), 150.1 (s, 1C), 143.9 (s,
1C),135.9 (s, 2C),130.1 (s, 1C), 129.9 (s, 2C), 129.8(s, 1C), 127.4 (s, 1C).Anal.Calcd (%) for
C11H8N4S: C, 57.88; H, 3.53; N, 24.54; S, 14.04. Found: C, 57.96; H, 3.39; N, 24.68; S, 14.18.
6-((4-Chlorophenyl)thio)-9H-purine (3s).35White solid(171 mg, 65%);Time: 12h;1H NMR (500
MHz, DMSO-d6) δ13.61 (s, 1H), 8.54 (s, 1H), 8.50 (s, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.54 (d, J =
8.5 Hz, 2H).13C{1H} NMR (101 MHz, DMSO-d6) δ 157.8 (s, 1C), 152.0 (s, 1C), 150.1(s, 1C),
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144.1 (s, 1C), 137.6 (s, 2C), 135.0 (s, 1C), 129.9 (s, 1C), 129.8 (s, 2C), 126.5 (s, 1C).Anal.Calcd
(%) for C11H7ClN4S: C, 50.29; H, 2.69; N, 21.33; S, 12.20. Found: C, 50.44; H, 2.56; N, 21.45;
S, 12.36.
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6-((4-Methoxyphenyl)thio)-9H-purine (3t).35White solid(173 mg, 67%); Time: 12h;1H NMR
(500 MHz, DMSO-d6) δ 13.54 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 7.51 (d, J = 8.7 Hz, 2H), 7.04
(d, J = 8.7 Hz, 2H), 3.80 (s, 3H). 13C{1H} NMR (126 MHz, DMSO-d6) δ 160.9 (s, 1C), 159.2 (s,
1C), 152.1 (s, 1C), 149.9 (s, 1C), 143.8 (s, 1C), 137.8 (s, 2C), 130.0 (s, 1C), 117.4 (s, 1C), 115.5
(s, 2C), 55.8 (s, 1C).Anal.Calcd (%) for C12H10N4OS: C, 55.80; H, 3.90; N, 21.69; S, 12.41.
Found: C, 55.94; H, 3.78; N, 21.80; S, 12.55.
(2R,3S,4R,5R)-2-(Hydroxymethyl)-5-(6-((4-methoxyphenyl)thio)-9H-purin-9-
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yl)tetrahydrofuran-3,4-diol (3u).White solid(262 mg, 67%); mp 74-76 C; Time: 18h;1H NMR
(400 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.54 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.7 Hz,
2H), 5.96 (d, J = 5.4 Hz, 1H), 5.48 (d, J = 5.9 Hz, 1H), 5.19 (d, J = 4.9 Hz, 1H), 5.07 (t, J = 5.4
Hz, 1H), 4.57 (dd, J = 10.5, 5.3 Hz, 1H), 4.16 (t, J = 4.1 Hz, 1H), 3.94 (d, J = 3.4 Hz, 1H), 3.80
(s, 3H), 3.71–3.62 (m, 1H), 3.60–3.50 (m, 1H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 161.0 (s,
1C), 160.4 (s, 1C), 152.1 (s, 1C), 148.9 (s, 1C), 144.0 (s, 1C), 137.8 (s, 2C), 130. 9 (s, 1C), 117.2
(s, 1C), 115.5 (s, 2C),88.3 (s, 1C), 86.1 (s, 1C), 74.2 (s, 1C), 70.7 (s, 1C), 61.7 (s, 1C), 55.8 (s,
1C).Anal.Calcd (%) for C17H18N4O5S: C, 52.30; H, 4.65; N, 14.35; S, 8.21. Found: C, 52.42; H,
4.47; N, 14.49; S, 8.35. HRMS (ESI-TOF): m/z [M + H]+calcd for C17H19N4O5S:
391.1076;found: 391.1084.
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(hydroxymethyl)tetrahydrofuran-3,4-diol (3v).White solid(224 mg, 59%); mp 64-66 C; Time:
18h;1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.57 (s, 1H), 7.66 (dd, J = 8.4, 5.5 Hz, 2H),
7.33 (t, J = 8.7 Hz, 2H), 5.97 (d, J = 5.4 Hz, 1H), 5.49 (d, J = 5.8 Hz, 1H), 5.19 (d, J = 5.0 Hz,
1H), 5.06 (t, J = 5.4 Hz, 1H), 4.57 (dd, J = 10.7, 5.4 Hz, 1H), 4.15 (dd, J = 8.3, 4.3 Hz, 1H), 3.95
(d, J = 3.6 Hz, 1H), 3.70–3.62 (m, 1H), 3.58–3.51 (m, 1H).13C{1H} NMR (101 MHz, DMSO-d6)
δ 163.5 (d, JC,F = 249.5 Hz, 1C), 159.4(s, 1C), 152.1 (s, 1C),149.1 (s, 1C), 144.2 (s, 1C),138.5 (d,
JC,F = 9.1 Hz, 2C),131.0 (s, 1C),122.7 (d, JC,F = 3.0 Hz, 1C),117.0 (d, JC,F = 22.2 Hz, 2C),88.3 (s,
1C), 86.1 (s, 1C), 74.2 (s, 1C), 70.7 (s, 1C), 61.6 (s, 1C).Anal.Calcd (%) for C16H15FN4O4S: C,
50.79; H, 4.00; N, 14.81; S, 8.47. Found: C, 50.91; H, 3.87; N, 14.73; S, 8.34. HRMS (ESI-
TOF): m/z [M + H]+calcd for C16H16FN4O4S: 379.0876; found: 379.0882.
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(2R,3S,4R,5R)-2-(Hydroxymethyl)-5-(6-(phenylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol
(3w).30 White solid(256 mg, 71%); Time: 18h;1H NMR (400 MHz, DMSO-d6) δ8.74 (s, 1H),
8.56 (s, 1H), 7.65–7.56 (m, 2H), 7.52–7.42 (m, 3H), 5.97 (d, J = 5.4 Hz, 1H), 5.50 (d, J = 5.9 Hz,
1H), 5.21 (d, J = 4.9 Hz, 1H), 5.09 (t, J = 5.4 Hz, 1H), 4.58 (dd, J = 10.6, 5.3 Hz, 1H), 4.16 (dd,
J = 8.2, 4.6 Hz, 1H), 3.95 (d, J = 3.5 Hz, 1H), 3.70–3.63 (m, 1H), 3.59–3.51 (m, 1H). C{1H}
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NMR (101 MHz, DMSO-d6) δ 159.5 (s, 1C), 152.1 (s, 1C), 149.1 (s, 1C), 144.2 (s, 1C),135.9 (s,
2C), 131.0 (s, 1C), 130.0 (s, 1C), 129.8 (s, 2C), 127.1 (s, 1C), 88.3 (s, 1C), 86.1 (s, 1C), 74.2 (s,
1C), 70.7 (s, 1C), 61.6 (s, 1C).Anal.Calcd (%) for C16H16N4O4S: C, 53.32; H, 4.48; N, 15.55; S,
8.90. Found: C, 53.51; H, 4.32; N, 15.47; S, 8.71.
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2-(Decylthio)quinoxaline (3x).White solid(288 mg, 95%); mp 88-90 C; Time: 12h;1H NMR
(400 MHz, CDCl3) δ 8.56 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.67 (t, J =
7.6 Hz, 1H), 7.59 (t, J = 7.6 Hz, 1H), 3.32 (t, J = 7.3 Hz, 2H), 1.81–1.73 (m, 2H), 1.51–1.44 (m,
2H), 1.36–1.24 (m, 12H), 0.86 (t, J = 6.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.5 (s,
1C), 144.9 (s, 1C), 142.8 (s, 1C), 139.7 (s, 1C), 130.0 (s, 1C), 129.2 (s, 1C), 127.8 (s, 1C), 127.8
(s, 1C), 31.9 (s, 1C), 29.6 (s, 1C), 29.6 (s, 1C), 29.5 (s, 1C), 29.3 (s, 1C), 29.1 (s, 1C), 29.0 (s,
1C), 28.9 (s, 1C), 22.6 (s, 1C), 14.1 (s, 1C).Anal.Calcd (%) for C18H26N2S: C, 71.48; H, 8.66; N,
9.26; S, 10.60.Found: C, 71.56; H, 8.84; N, 9.38; S, 10.48.HRMS (ESI-TOF): m/z [M + H]+calcd
for C18H27N2S: 303.1895; found: 303.1887.
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2-((2-Chlorobenzyl)thio)quinoxaline (3y).White solid(267 mg, 93%); mp 52-54 C; Time:
12h;1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 8.01 (dd, J = 7.8, 5.4 Hz, 2H), 7.72 (t, J = 7.7
Hz, 1H), 7.66–7.62 (m, 2H), 7.39 (d, J = 7.2 Hz, 1H), 7.21–7.16 (m, 2H), 4.72 (s, 2H). 13C{1H}
NMR (126 MHz, CDCl3) δ155.3 (s, 1C), 144.6 (s, 1C), 142.5 (s, 1C), 140.0 (s, 1C), 135.2 (s,
1C), 134.5 (s, 1C), 131.3 (s, 1C), 130.3 (s, 1C), 129.6 (s, 1C), 129.3 (s, 1C), 128.9 (s, 1C), 128.1
(s, 1C), 127.8 (s, 1C), 126.8 (s, 1C), 31.2 (s, 1C).Anal.Calcd(%) for C15H11ClN2S: C, 62.82; H,
3.87; N, 9.77; S, 11.18. Found: C, 62.90; H, 3.71; N, 9.60; S, 11.36. HRMS (ESI-TOF): m/z [M
+ H]+calcd for C15H12ClN2S: 287.0410; found: 287.0416.
2-(Cyclohexylthio)quinoxaline (3z).Off white solid(225 mg, 92%); mp 54-56 C; Time: 12h;1H
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NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.3 Hz, 1H), 7.66
(t, J = 7.0 Hz, 1H), 7.58 (t, J = 6.9 Hz, 1H), 4.13–4.05 (m, 1H), 2.20–2.10 (m, 2H), 1.79 (dd, J =
8.7, 3.8 Hz, 2H), 1.67–1.49 (m, 5H), 1.40–1.31 (m, 1H). 13C{1H} NMR (101 MHz,CDCl3) δ
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156.4 (s, 1C), 145.1 (s, 1C), 142.8 (s, 1C), 139.7 (s, 1C), 129.9 (s, 1C), 129.2 (s, 1C), 127.8 (s,
1C), 127.8 (s, 1C),42.7 (s, 1C),32.9 (s, 2C),25.9 (s, 1C),25.7 (s, 2C).Anal.Calcd (%) for
C14H16N2S: C, 68.82; H, 6.60; N, 11.46; S, 13.12. Found: C, 68.92; H, 6.44; N, 11.30; S, 13.26.
HRMS (ESI-TOF): m/z [M + H]+calcdfor C14H17N2S: 245.1112; found: 245.1120.
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2-(Phenylthio)benzo[d]oxazole (3aa).31Colorless oil(196 mg, 86%); Time: 12h; H NMR (400
MHz, CDCl3) δ 7.69 (dd, J = 5.8, 2.9 Hz, 2H), 7.59 (dd, J= 6.0, 1.6 Hz, 1H), 7.50–7.38 (m, 4H),
7.27–7.21 (m, 2H). C{1H} NMR (101 MHz, CDCl3) δ 163.3 (s, 1C), 151.8 (s, 1C), 141.9 (s,
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1C),134.4 (s, 2C), 129.8 (s, 1C), 129.6 (s, 2C), 127.2 (s, 1C), 124.3 (s, 1C), 124.3 (s, 1C), 119.1
(s, 1C), 110.0 (s, 1C).Anal.Calcd (%) for C13H9NOS: C, 68.70; H, 3.99; N, 6.16; S, 14.11.
Found: C, 68.82; H, 3.95; N, 6.30; S, 14.21.
N,N-Diethylbenzo[d]oxazol-2-amine (5a).36Yellow oil(153 mg, 80%);Time: 12h;1H NMR (400
MHz, CDCl3) δ 7.32 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.12 (td, J = 7.6, 0.9 Hz, 1H),
6.95 (td, J = 7.8, 1.0 Hz, 1H), 3.56 (q, J = 7.1 Hz, 4H), 1.26 (t, J = 7.1 Hz, 6H).13C{1H} NMR
(101 MHz, CDCl3) δ 162.2 (s, 1C), 148.8 (s, 1C), 143.6 (s, 1C), 123.7 (s, 1C), 119.9 (s, 1C),
115.8 (s, 1C), 108.4 (s, 1C), 42.9 (s, 2C), 13.4 (s, 2C). Anal.Calcd (%) for C11H14N2O: C, 69.45;
H, 7.42; N, 14.73. Found: C, 69.57; H, 7.50; N, 14.81.
N-Benzyl-N-methylbenzo[d]oxazol-2-amine (5b).37Off white solid(189 mg, 79%); Time: 12h;1H
NMR (400 MHz, CDCl3) δ7.42–7.21 (m, 7H), 7.16 (t, J = 7.6 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1H),
4.75 (s, 2H), 3.12 (s, 3H).13C{1H} NMR (101 MHz, CDCl3) δ163.0 (s, 1C), 149.0 (s, 1C), 143.5
(s, 1C), 136.4 (s, 1C), 128.7 (s, 2C), 127.7 (s, 1C), 127.6 (s, 2C), 123.9 (s, 1C), 120.3 (s, 1C),
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116.1 (s, 1C), 108.7 (s, 1C), 53.8 (s, 1C), 35.1 (s, 1C).Anal.Calcd (%) for C15H14N2O: C, 75.61;
H, 5.92; N, 11.76. Found: C, 75.73; H, 5.98; N, 11.86.
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2-(Azetidin-1-yl)benzo[d]oxazole (5c).White solid(121 mg, 69%); mp 88-90oC; Time: 12h;1H
NMR (400 MHz, CDCl3) δ7.35 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 7.6 Hz,
1H), 7.00 (t, J = 7.7 Hz, 1H), 4.26 (t, J = 7.6 Hz, 4H), 2.50–2.43 (m, 2H).13C{1H} NMR (101
MHz, CDCl3) δ162.7 (s, 1C), 149.1 (s, 1C), 143.1 (s, 1C), 123.9 (s, 1C), 120.7 (s, 1C), 116.5 (s,
1C), 108.8 (s, 1C), 51.4 (s, 2C), 17.4 (s, 1C).Anal.Calcd (%) for C10H10N2O: C, 68.95; H, 5.79;
N, 16.08. Found: C, 68.87; H, 5.91; N, 16.20.HRMS (ESI-TOF): m/z [M + H]+calcd for
C10H11N2O: 175.0871; found: 175.0877.
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2-(Pyrrolidin-1-yl)benzo[d]oxazole (5d).37White solid(153 mg, 81%); Time: 12h;1H NMR (400
MHz, CDCl3) δ7.33 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.95
(t, J = 7.7 Hz, 1H), 3.62 (t, J = 6.5 Hz, 4H), 2.00 (t, J = 6.5 Hz, 4H).13C{1H} NMR (101 MHz,
CDCl3) δ 161.0 (s, 1C), 149.0 (s, 1C), 143.6 (s, 1C), 123.7 (s, 1C), 120.0 (s, 1C), 115.9 (s, 1C),
108.5 (s, 1C), 47.4 (s, 2C), 25.5 (s, 2C).Anal.Calcd (%) for C11H12N2O: C, 70.19; H, 6.43; N,
14.88.Found: C, 70.31; H, 6.30; N, 14.96.
2-(3-Methylpiperidin-1-yl)benzo[d]oxazole (5e).38White solid(180 mg, 83%); Time: 12h;1H
NMR (400 MHz, CDCl3) δ7.31 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 7.6 Hz,
1H), 6.96 (t, J = 7.7 Hz, 1H), 4.16 (t, J = 11.4 Hz, 2H), 3.00 (td, J = 12.6, 2.9 Hz, 1H), 2.68 (dd,
J = 12.6, 11.0 Hz, 1H), 1.83 (d, J = 12.0 Hz, 1H), 1.78–1.68 (m, 2H), 1.65–1.54 (m, 1H), 1.18–
1.08 (m, 1H), 0.94 (d, J = 6.6 Hz, 3H).13C{1H} NMR (101 MHz, CDCl3) δ 162.3 (s, 1C), 148.6
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(s, 1C), 143.3 (s, 1C), 123.8 (s, 1C), 120.2 (s, 1C), 115.9 (s, 1C), 108.5 (s, 1C), 53.0 (s, 1C), 46.0
(s, 1C), 32.6 (s, 1C), 30.6 (s, 1C), 24.7 (s, 1C), 18.9 (s, 1C). Anal.Calcd (%) for C13H16N2O: C,
72.19; H, 7.46; N, 12.95. Found: C, 72.33; H, 7.36; N, 12.83.
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2-(4-(2-Methoxyphenyl)piperazin-1-yl)benzo[d]oxazole (5f).39White solid(267 mg, 86%);Time:
12h; 1H NMR (400 MHz, CDCl3) δ 7.36 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.16 (t, J =
7.7 Hz, 1H), 7.05–6.99 (m, 2H), 6.97–6.92 (m, 2H), 6.88 (d, J = 7.9 Hz, 1H), 3.87 (distorted d, J
= 7.1 Hz, 7H), 3.16 (t, J = 4.9 Hz, 4H).13C{1H} NMR (101 MHz, CDCl3) δ 162.2 (s, 1C), 152.3
(s, 1C), 148.8 (s, 1C), 143.1 (s, 1C), 140.8 (s, 1C), 124.0 (s, 1C), 123.6 (s, 1C), 121.1 (s, 1C),
120.6 (s, 1C), 118.5 (s, 1C), 116.3 (s, 1C), 111.4 (s, 1C), 108.7 (s, 1C), 55.5 (s, 1C), 50.2 (s, 2C),
45.9 (s, 2C). Anal.Calcd (%) for C18H19N3O2: C, 69.88; H, 6.19; N, 13.58.Found: C, 69.96; H,
6.31; N, 13.70.
2-(Azepan-1-yl)benzo[d]oxazole (5g).37Off white solid(160 mg, 74%); Time: 12h;1H NMR (400
MHz, CDCl3) δ 7.32 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.95
(t, J = 7.7 Hz, 1H), 3.68 (t, J = 5.8 Hz, 4H), 1.82 (br s, 4H), 1.59 (br s, 4H). 13C{1H} NMR (101
MHz, CDCl3) δ 162.6 (s, 1C), 148.8 (s, 1C), 143.7 (s, 1C), 123.7 (s, 1C), 119.8 (s, 1C), 115.7 (s,
1C), 108.4 (s, 1C), 48.0 (s, 2C), 28.2 (s, 2C), 27.4 (s, 2C). Anal.Calcd (%) for C13H16N2O: C,
72.19; H, 7.46; N, 12.95. Found: C, 72.34; H, 7.32; N, 12.81.
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2-(Azetidin-1-yl)benzo[d]thiazole (5h).Pale yellow solid(82 mg, 43%); mp 96-98 C; Time:
12h;1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 7.8 Hz, 2H), 7.27 (t, J = 7.6 Hz, 1H), 7.04 (t, J =
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7.6 Hz, 1H), 4.18 (t, J = 7.4 Hz, 4H), 2.51–2.43 (m, 2H). C{1H} NMR (101 MHz, CDCl3) δ
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168.4 (s, 1C), 153.0 (s, 1C), 131.4 (s, 1C), 125.9 (s, 1C), 121.3 (s, 1C), 120.9 (s, 1C), 119.1 (s,
1C), 53.0 (s, 2C), 17.4 (s, 1C). Anal.Calcd (%) for C10H10N2S: C, 63.13; H, 5.30; N, 14.72; S,
16.85. Found: C, 63.27; H, 5.44; N, 14.59; S, 16.93. HRMS (ESI-TOF): m/z [M + H]+calcd for
C10H11N2S: 191.0643; found: 191.0651.
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2-(Pyrrolidin-1-yl)benzo[d]thiazole (5i).40Pale yellow solid(98 mg, 48%); Time: 12h;1H NMR
(400 MHz, CDCl3) δ7.56 (d, J = 7.8 Hz, 2H), 7.26 (t, J = 7.9 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H),
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3.56 (t, J = 6.4 Hz, 4H), 2.05 (t, J = 6.7 Hz, 4H). C{1H} NMR (101 MHz, CDCl3) δ 165.3 (s,
1C), 153.3 (s, 1C), 130.7 (s, 1C), 125.8 (s, 1C), 120.6 (s, 2C), 118.6 (s, 1C), 49.4 (s, 2C), 25.6 (s,
2C). Anal.Calcd (%) for C11H12N2S: C, 64.67; H, 5.92; N, 13.71; S, 15.69. Found: C, 64.83; H,
5.80; N, 13.85; S, 15.81.
2-(Piperidin-1-yl)benzo[d]thiazole (5j).41White solid(90 mg, 41%); Time: 12h;1H NMR (400
MHz, CDCl3) δ 7.56 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 7.03
(t, J = 7.6 Hz, 1H), 3.59 (br s, 4H), 1.68 (br s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 168.9 (s,
1C), 152.9 (s, 1C), 130.6 (s, 1C), 125.8 (s, 1C), 121.0 (s, 1C), 120.5 (s, 1C), 118.8 (s, 1C), 49.6
(s, 2C), 25.3 (s, 2C), 24.2 (s, 1C). Anal.Calcd (%) for C12H14N2S: C, 66.02; H, 6.46; N, 12.83; S,
14.69. Found: C, 66.20; H, 6.30; N, 12.68; S, 14.61.
4-(Benzo[d]thiazol-2-yl)morpholine (5k).41White solid(80 mg, 36%); Time: 12h;1H NMR (400
MHz, CDCl3) δ 7.60 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.30 (t, J = 7.7 Hz, 1H), 7.08
(t, J = 7.6 Hz, 1H), 3.82 (t, J = 4.8 Hz, 4H), 3.61 (t, J = 4.8 Hz, 4H). 13C{1H} NMR (101 MHz,
CDCl3) δ 169.0 (s, 1C), 152.5 (s, 1C), 130.6 (s, 1C), 126.1 (s, 1C), 121.6 (s, 1C), 120.7 (s, 1C),
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