Efficient synthesis of unsymmetrical heteroaryl thioethers and chalcogenides by alkali hydroxide-mediated SNAr reactions of heteroaryl halides and dichalcogenides

Article abstract of DOI:10.1039/c6ra10517c

An efficient alkali hydroxide-mediated S_NAr reaction of heteroaryl halides has been developed for the practical synthesis of the useful unsymmetrical heteroaryl thioethers and chalcogenides. The usually odorless, easily available, lowly toxic, and easily stored and handled diorganyl dichalcogenides can be used as safer and convenient chalcogen nucleophile precursors and diverse unsymmetrical heteroaryl chalcogenides can be obtained in good to high yields by the method.

Full text of DOI:10.1039/c6ra10517c

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Efficient Synthesis of Unsymmetrical Heteroaryl Thioethers and
Chalcogenides by Alkali Hydroxide-Mediated SNAr Reactions of
Heteroaryl Halides and Dichalcogenides
Received 00th January 20xx,
Accepted 00th January 20xx
Xiantao Ma,a,b Quan Liu,b Xiaojuan Jia,b Chenliang Sua* and Qing Xub*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient alkali hydroxide-mediated SNAr reaction of heteroaryl develop greener and more efficient methods for heteroaryl
halides has been developed for practical synthesis of the useful thioethers especially by using odorless and more easily-
unsymmetrical heteroaryl thioethers and chalcogenides. The handled sulfur reagents instead of the thiols.
usually odorless, easily available, lowly toxic, and easily stored
Known methods:
and handled diorganyl dichalcogenides can be used as the safer
cat. TM
ligand, base
and convenient chalcogen nucleophile precursors and a diverse
N
N
N
N
RSH
N
FG
FG
FG
FG
FG
FG
X
X
+
+
SR (1)
unsymmetrical heteroaryl chalcogenides can be obtained in good
to high yields by the method.
excess base
SNAr reaction
RSH
N
(2)
SR
FG
Thioethers are significant structural motifs abounding in
natural products, biological, pharmaceutical, and agrichemical
compounds.1 They are also good ligands in transition metal (TM)
catalyzed reactions,2 key intermediates for the synthesis of the
corresponding sulfoxides and sulfones,3 and even effective
organocatalysts themselves in synthesis.4 Therefore, numerous
methods have been developed for symmetrical and
unsymmetrical thioethers, which can be mainly classified into
TM-catalyzed Buchwald-Hartwig5 and copper-catalyzed
Ullmann6 coupling reactions of aryl halides with thiols, TM-free
super base media-promoted coupling of aryl halides and thiols
via benzyne intermediates,7 as well as the TM-free nucleophilic
aromatic substitution (SNAr)reactions of the more reactive
electron-withdrawing groups (EWG)-activated aryl halides and
thiols.8 As to heteroaryl thioethers, although TM-catalyzed
(Scheme 1, eq. 1)9 and SNAr (eq. 2)10 methods have also been
reported in recent years, the currently available methods are
obviously much less than those for the usual aryl thioethers.5-8
Besides, these methods still employ thiols as the starting
material, which are smelly and toxic, sensitive and not easy to
handle. Therefore, there is still a great need in the field to
TBAX (10 mol%)
(3)
SPh
PhS-SiMe
N
X +
3
- TMSX (recoverable)
X = Cl, Br
(RS)2
R'M
N
FG
M
(4)
X
N
FG
SR
(5)
- RSM
M = Li, MgX', ZnX'
This work:
MAOH/DMSO
N
FG
N
X + (RY)2
FG
YR
Y = S, Se, Te
MA = Na, K, Cs
Scheme 1. Methods for heteroaryl thioether synthesis.
We have been engaged in the preparation and synthetic and
catalytic applications of organochalcogen compounds11-12 and
heterocycle compounds12 including the heteroaryl thioethers13
and chalcogen heterocycles.14 We have previously described a
waste-free TBAX (X = Cl, Br)-catalyzed SNAr reaction of
heteroaryl halides with phenylthiotrimethylsilane(PhS–SiMe3)
via a fluorine-free halide ion-catalyzed S-Si bond activation
process (Scheme 1, eq. 3).13 However, this method is mainly
limited to heteroaryl phenyl thioethers due to the lower
availability of other RS–SiMe3 reagents than PhS-SiMe3. We
a.SZU-NUS Collaborative Innovation Center for Optoelectronic Science
Technology, Key Laboratory of Optoelectronic Devices and Systems of Ministry of
&
Education and Guangdong Province, College of Optoelectronic Engineering, then considered using diorganyl disulfides as the alternative
Shenzhen University, Shenzhen 518060, China. E-mail: chmsuc@szu.edu.cn; Fax:
sulfur nucleophile precursors since they are not only as
(+)-86-755-26536206; Tel: (+)-86-130-66870440
b.College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou,
Zhejiang 325035, China. E-mail: qing-xu@wzu.edu.cn; Fax: (+)-86-577-86689302;
Tel: (+)-86-138-57745327
available as the corresponding thiols, but usually odourless,
much lower in toxicity, and more easily stored and handled
than the thiols. To our knowledge, although disulfides have
Electronic Supplementary Information (ESI) available: Experimental details,
product characterization, and copies of 1H NMR and 13C NMR spectra of the been frequently used in aryl thioether synthesis by TM-
products. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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catalyzed coupling reactions with aryl halides,15 by benzyne- Table 1. Base screening and reaction condition optimization.a
type reactions with aryl halides in super basic media,16 or by
aromatic radical nucleophilic substitution (SRN1) reaction with
aryl halides in the presence of SmI2 and NaBH4,17,18 they have
not been adopted in SNAr reactions for heteroaryl thioether
synthesis so far. Although heteroaryl thioethers could also be
obtained from multi-step reactions of disulfides and heteroaryl
halides,18,19 in these known methods the heteroaryl halides
have to be converted first into the corresponding reactive and
sensitive organometallic nucleophiles such as lithium,
magnesium, and zincate reagents, which were then trapped by
using disulfides as the sulfur electrophile (Scheme 1, eq. 4).
Clearly, these methods have severe drawbacks such as the
requirement of low temperature, strict anhydrous conditions,
low tolerance of functional groups, and generation of wastes.
Hence there is still much room for improvements in the
synthsis of heteroaryl thioethers from disulfides and
heteroaryl halides. As an ongoing interest in organochalcogen
compounds11-13 and based-mediate/catalyzed synthesis of
heterocycle derivatives,14 herein we report a new method for
the synthesis of unsymmetrical heteroaryl thioethers by an
efficient and practical NaOH-mediated SNAr reaction of
heteroaryl halides with disulfides (Scheme 1, eq. 5). This
method can also be extended to the synthesis of
unsymmetrical heteroaryl selenides and tellurides from the
corresponding diselenides and ditellurides under similar
conditions.
base
(PhS)2
+
solvent, N2, T, 24 h
N
X
N
SPh
2a
1
3a
run
X
base (equiv.)
Na2CO3 (2.0)
NaOH (2.0)
KOH (2.0)
T(oC)
150
150
150
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
3a%b
56
95
94
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
1
2
3
CsOH·H2O (2.0)
none
99
trace
96
4
5
6
150
150
120
120
120
120
120
120
120
120
120
NaOH (2.0)
NaOH (1.5)
NaOH (2.0)
NaOH (2.0)
NaOH (2.0)
NaOH (2.0)
NaOH (1.5)
NaOH (1.5)
NaOH (1.5)
96 (80)
79
7
8
9
Toluene
DMF
64
94
54
10
11c
12
13
14
DMSO
DMSO
DMSO
DMSO
87 (68)
96 (75)
99 (70)
Br
I
a
Unless otherwise noted, the mixture of
and base in a solvent (1.0 mL) was sealed under N2 in a Schlenk tube,
1 (0.5 mmol), 2a (0.3 mmol),
b
heated for 24 h, and monitored by TLC and/or GC-MS. GC yields
(isolated yield in parenthesis) based on 1
. c Under air.
The optimized conditions (Table 1, run 7) were then
employed to extend the scope of the method. As shown in
Table 2, both electron-donating and electron-withdrawing
groups substituted 2-chloropyridines, including those with
reactive groups such as amino, cyano, nitro, and chloro (runs 2,
5-8) that may undergo side reactions under strong basic
conditions,7,8,21 could all react with 2a efficiently to give the
Various bases (2 equiv.) were initially evaluated in the model
reaction of 2-chloropyridine (1a) and diphenyl disulfide (2a) in
o
DMSO at 150 C under nitrogen (Table 1).20 Except the weak
desired pyridyl phenyl thioethers 3a-3h in moderate to good
yields (runs 2-8). This suggested that, in above reactions with
reactive groups (runs 2, 5-8), the potential side reactions in the
NaOH/DMSO super base media7,16 might have been effectively
avoided by the generation of the phenylthio anion (PhS-) from
(PhS)2 and NaOH/DMSO, which in turn should be a rather
efficient process to afford PhS-, a more nuleophilic but less
basic than the corresponding O- and N- nuleophiles.
basic Na2CO3 that gave only a moderate yield of target product
3a (run 1), strong basic alkali hydroxide bases all gave high
yields of 3a (runs 2-4). No obvious product formation was
observed in the reaction without base (run 5), suggesting that
base is crucial for the generation of the nucleophilic phenylthio
anion (PhS-) from (PhS)2.15,16,20 Since NaOH is more economic,
more available, lower in molecular weight, and easier to
handle, it was used in further optimization of the reaction
conditions. The reaction temperature and the amount of
In the cases of dichloropyridines with unreactive chloro
groups at the 3- or 5-position (runs 7-8), the reactions were
regiospecific and gave only the mono-substituted products
under the standard conditions. While in reactions of
dichloropyridines with reactive chloro groups at the 4- or 6-
position (runs 9-12), a mixture of mono- and disubstituted
products could be obtained under the standard conditions,
with the mono-substituted product being the major one under
the standard conditions (runs 9,11). When doubled amounts of
2a and NaOH were used, the di-substituted products were
obtained in high selectivities and in good yields (runs 10,12). In
the case of 4-iodopyridine (1k), it also reacted smoothly with
2a to give a moderate yield of the target 3k (run 13), which
may be attributed to the instability of the substrate. The same
method could also be extended to other active heteroaryl
halides such as 2-chloroquninoline, 2-chloropyrimidine, 2-
chlorobenzothiazole, which gave good to high yields of the
products (runs 14-16). Different to previous TBAX-catalyzed
method that mainly limited to PhS-SiMe3 and for the
preparation of phenyl thioethers,13 the advantage of the
o
NaOH loaded could be reduced to 120 C and 1.5 equiv. but
still maintaining the high reaction efficiency (runs 6-7); while
the reactions performed at lower temperatures or using even
less amounts of NaOH only led to lower yields of 3a. Solvent
effect was also investigated at 120 oC using other usual
solvents such as acetonitrile, toluene, DMF, etc. The results
showed that DMSO is still the best one (runs 6, 8-10). For a
control reaction under air, only a moderate yield of 3a was
obtained (run 11), most possibly because the in situ generated
PhS- is sensitive with air.15 The optimized conditions (run 7)
could also be applied to 2-fluoro-, 2-bromo, and 2-
iodopyridines, giving moderate to good yields of the product
(runs 12-14). These results not only showed that all the
heteroaryl halides are suitable substrates, but also suggested
that the economic heteroaryl chlorides such as 2-
choloropyridine (1a) are the most preferable ones.
2 | J. Name., 2012, 00, 1-3
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present methods is that various disulfides including diaryl, as electron-rich 5-methyl 2-chloropyridine (run 2), electron-
diheteroaryl, or dialkyl disulfides even dichalcogenides (R2Se2, deficient 2,3-dichloropyridine (run 3), and 4-iodopyridine (run
R2Te2) are all promising nucleophiles in the method. Thus, 4) all reacted efficiently with (PhSe)2 to give the target
electron-rich disulfides without sterically bulky groups products. Similarly, other heteroaryl halides such as 2-
afforded good yields of the products (run 17, 19). In contrast, chloroquninoline (run 5) and 2-chlorobenzothiazole also gave
the reaction of di(2-aminophenyl) disulfide with steric the target unsymmetrical heteroaryl phenyl selenides in good
hindrance from the ortho-amino group required a higher yields under the same conditions (run 5-6). Finally, the
temperature to ensure a smooth reaction (run 18). The reactions of diphenyl ditelluride (PhTe)2 was investigated,
reaction of di(2-nitrophenyl) disulfide was not efficient at which gave only a very low yield of the target heteroaryl
present most possibly due to its weak nucleophilicity telluride under the above conditions (run 7). Using CsOH·H2O
attributed to the strong electron-withdrawing ortho-nitro as the base instead of KOH and conducting the reaction at 150
group (run 20). Finally, diheteroaryl and dialkyl disulfides oC improved the product yield to 29% (run 8).
reacted efficiently with 2-chloropyridine to give good to high
yields of the target thioethers under the standard conditions Table 3. Unsymmetrical heteroaryl chalcogenide synthesis.a
KOH (1.5 equiv.)
(runs 21-22).
N
FG
(PhY)2
X
+
YPh
N
FG
DMSO, N2, 120 oC, 24 h
Y = Se, Te
4
1
Table 2. Unsymmetrical heteroaryl thioether synthesis.a
5
NaOH (1.5 equiv.)
DMSO, N2, 120 oC, 24 h
(RS)2
FG
N
N
SR
X +
FG
run
1
1
5
Yield (%)b
88
2
1
3
(1) 3a: H, 80%
N
Cl 1a
N
SePh 5a
Cl
N
SPh
(2) 3b: 3-NH2, 67%b
(3) 3c: 4-Me, 66%
(4) 3d: 5-Me, 51%;
(5) 3e: 5-CN, 57%c
(6) 3f: 5-NO2, 77%c
(7) 3g: 3-Cl, 79%
(8) 3h: 5-Cl, 75%
Me
Me
2
88
86
FG
N
SePh 5b
N
Cl
Cl 1d
SPh
N
SPh
N
SPh
Cl
3i
3i'
3
3
4
(9) 3i: 4-Cl, 69% (3i/3i' 90/10)
(10) 3i': 4-SPh, 79% (3i/3i' <1/99)d
N
SePh
SePh 5c
N
I
Cl 1g
42
SPh
N
5d
PhS
N
SPh
N
1k
Cl
N
SPh
3j
N
SPh
3j'
5
6
77
70
N
(11) 3j: 6-Cl, 80% (3j/3j' 99/1)
(12) 3j': 6-SPh, 78% (3j/3j' <1/99)d
(13) 3k: 45%e
N
S
Cl 1l
Cl
N
S
SePh 5e
SePh
(14) 3l: 90%
NH2
S
N
N
1n
5f
N
H2N
SPh
7
9
N
SPh
N
N
S
N
S
N
Cl 1a
N
TePh 5g
(18) 3p: 52%f
(15) 3m: 61%
(16) 3n: 88%
(17) 3o: 61%
8c
29
1a
5g
O2N
OMe
S
a Unless otherwise noted, the mixture of
1 (0.5 mmol), 4 (0.3 mmol),
N
S
N
S
Ph
N
S
N
S
and KOH (0.75 mmol, 1.5 equiv.) in DMSO (1 mL) were stirred under N2
o
(19) 3q: 75%
(21) 3s: 66%
(20) 3r: trace
(22) 3t: 88%
at 120 C for 24 h. Isolated yield based on 1.c CsOH
·H2O (0.75 mmol,
b
1.5 equiv.), 150 oC.
a Unless otherwise noted, see run 7 of Table 1 for reaction conditions and X
= Cl. FG = substituted functional group. Isolated yields of 3 were based on 1.
b
Ratios of the products in some reactions were determined by GC. 60 h. c
Based on above results and the literatures on SNAr reactions of
EWG-activated aryl halides and heteroatom-activated
heteroaryl halides,8,10,13 a mechanism depicted in Scheme 2
was proposed for the present SNAr reactions of heteroaryl
150 oC, 60 h. d 1 (0.5 mmol), 2a (0.6 mmol, 2.4 equiv.), NaOH (3.0 equiv.). e
= I. f 150 oC.
X
The reactions of diorganyldichalcogenides were then tested
to extend the scope of the method for the synthesis the
corresponding unsymmetrical heteroaryl chalcogenides (Table
3). When the above standard conditions were initially applied
to the reaction of 2-chloropyridine (1a) and diphenyldiselenide
halides with dichalcogenides.22 Thus, dichalcogenides
was first transformed into the corresponding RY- anion
2
or
4
6
by
the bases.15,16,20 6 then added to the heteroaryl halides to form
dearomatized anion 7, which is relatively stable due to the
stablization of the anionic charge on the ring by the
electronegative heteroatoms in the ring.8 The final leaving of
(PhSe)2 (4), the reaction was found not complete and gave only
a moderate yield of the target 2-pyridyl phenyl selenide (5a).
Base screening showed that, by simply replacing NaOH with
KOH, the same reaction could proceed more efficiently to
ensure full conversion of the reactants to give a high 88%
isolated yield of 5a (Table 3, run 1). Other halopyridines such
halide anion and rearomatization of
reaction to give the target unsymmetrical thioethers
chalcogenides
7
completes a typical SNAr
3
or
5
.
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heteroaryl compound synthesis are still in progress in this
group.
N
YR
FG
(RY)2 (Y = S, Se, Te)
2 or 4
3 or 5
MAOH
(MA = Na, K, Cs)
- MAX
YR
Acknowledgment
X
X = F, Cl, Br, I
N
MA
RY MA
We thank NNSFC (51502174), Science and Technology Project
of Shenzhen (JCYJ20150324141711616), and ZJNSF for
Distinguished Young Scholars (LR14B020002) for financial
support.
6
N
FG
X
FG
7
Scheme 2. Proposed mechanism for MAOH-mediated SNAr reaction
of heteroaryl halides with dichalcogenides.
Notes and references
However, how dichalcogenides are transformed into the
corresponding RY- anions
1
(a) L. Liu, J. E. Stelmach, S. R. Natarajan, M.-H. Chen, S. B.
Singh, C. D. Schwartz, C. E. Fitzgerald, S. J. O’Keefe, D. M.
Zaller, D. M. Schmatz and J. B. Doherty, Bioorg. Med. Chem.
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II., B. V. Shetty, J. E. Fritz, K. Appelt, J. A. Burgess, K. M.
Campanale, N. Y. Chirgadze, D. K. Clawson, B. A. Dressman, S.
D. Hatch, D. A. Khalil, M. B. Kosa, P. P. Lubbehusen, M. A.
Muesing, A. K. Patick, S. H. Reich, K. S. Su and J. H. Tatlock, J.
Med. Chem., 1997, 40, 3979; (c) G. Liu, J. R. Huth, E. T.
Olejniczak, R. Mendoza, P. DeVries, S. Leitza, E. B. Reilly, G. F.
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Y. Kim, E. Wang, N. Z. Baturay and C.- H. Kwon, J. Med. Chem.,
2000, 43, 4160.
6
by the alkali bases and the
stoichiometry between dichalcogenides and anions 6 are still
not clear. Previous reports on the reactions of disulfides and
bases provided no more insights on this subject.15,16 Whereas,
a seminal work reported by Danehy and Hunter suggested that
alkali treatment of aryl and alkyl disulfides may lead to 75%
thiol and 25% sulfonic acid (eq. 6).18,22 However, although we
tried many times on slightly different reactions under the
standard conditions, and performed and analyzed the
reactions with great care by means of NMR, GC-MS, TLC
comparison with the authentic sample of sulfonic acid, even
purification of the reaction residue containing the potential
sulfonic acid, we could not isolate even merely observe any
trace of sulfonic acid in these reactions.23 In contrast, trace
2
3
amounts of PhSMe (8) and PhSCH2SPh (9) that are most
possibly produced from the reactions of DMSO was detected
in the reactions (eq. 7).24,25 This may suggest that in the media
of alkali base and DMSO,15,16 generation of the thio anions
does not follow Danehy and Hunter’s proposal (eq. 6).22,23
Therefore, no more amounts of dichalcogenides than 0.3
mmol is needed in the reactions and usually good yields of the
products could be obtained under the standard conditions.20
4
5
E. M. McGarrigle, E. L. Myers, O. Illa, M. A. Shaw, S. L. Riches
and V. K. Aggarwal, Chem. Rev., 2007, 107, 5481.
(a) J. F. Hartwig, Acc. Chem. Res., 2008, 41, 1534; (b) D. S.
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Andrioletti, Tetrahedron, 2002, 58, 2041; (f) S. Van de Jeught
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P.Beletskaya and A. V. Cheprakov, Coord. Chem. Rev., 2004,
248, 2337.
-
2 R2S2 + 4 OH-
3 RS-
+
RSO2 + 2 H2O
(6)
NaOH/DMSO
standard conditions [PhSH]
PhS
SPh
(PhS)2
+ PhSMe +
(7)
with or without 1a
or 3a
8
trace
9
after acidic workup
trace
(PhSO2H not observed)
6
(a) F. Ullmann, Chem. Ber., 1904, 37, 853; (b) A. A. Moroz
and M. S. Shvartsberg, Russ. Chem. Rev., 1974, 43, 679; (c) J.
Lindley, Tetrahedron, 1984, 40, 1433; (d) A. W. Thomas and
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M. Sevignon, C. Gozzi, C. Schul and M. Lemaire, Chem. Rev.,
2002, 102, 1359; (f) J. S. Sawyer, Tetrahedron, 2000, 56, 5045;
(g) R. Frlan, D. Kikelj, Synthesis, 2006, 2271.
In summary, an efficient NaOH-mediated SNAr reaction of
heteroaryl halides and disulfides has been developed for a
practical synthesis of the useful unsymmetrical heteroaryl
thioethers. The advantage of the method is that the usually
odorless, easily available, lowly toxic, and easily stored and
handled diorganyl disulfides can be used as the safer and more
convenient sulfur nucleophile precursors instead of the
7
8
(a) Y. Yuan, I. Thomé, S. H.Kim, D. Chen, A. Beyer, J.
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smelling and toxic thiols, and
a diverse unsymmetrical
heteroaryl thioethers can be obtained in good to high yields by
this method. Moreover, this method could also be extended to
diselenides and ditellurides for the synthesis of unsymmetrical
heteroaryl selenides and tellurides, largely extended the scope
of the method in unsymmetricalheteroaryl chalcogenide
synthesis. Further applications of the SNAr method in
4 | J. Name., 2012, 00, 1-3
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Journal Name
COMMUNICATION
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generated, 25% yield of the sulfonic acid PhSO2H is not a
small amount. As a white solid, it should be isolatable from
the reaction mixtures if it has been produced in ca. 25% yield,
at least being detectable by means of NMR, GC-MS, or TLC
comparison with the authentic sample. On the contrary, we
did not observe any trace of PhSO2H in the reaction mixtures
by these means. All these results only suggested that it could
not be produced in the present reaction systems.
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transformed into the corresponding thio anions by
treatment with bases and how many thio anions (at least 1
equiv., up to 2 equiv.) could be generated in present
reactions are still not clear yet (see mechanism section and
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Table of Contents
Efficient Synthesis of Unsymmetrical Heteroaryl Thioethers and Chalcogenides by Alkali
Hydroxide-Mediated SNAr Reactions of Heteroaryl Halides and Dichalcogenides
Xiantao Ma, Quan Liu, Xiaojuan Jia, Chenliang Su* and Qing Xu*
MAOH/DMSO
N
FG
X + (RY)2
N
FG
YR
Y = S, Se, Te
MA = Na, K, Cs
X = F, Cl, Br, I
29 examples
up to 90% isolated yield
An efficient SNAr reaction of heteroaryl halides and diorganyl dichalcogenides is developed for practical synthesis of the
useful unsymmetrical heteroaryl thioethers and chalcogenides.