Palladium-catalyzed difluoromethylthiolation of heteroaryl bromides, iodides, triflates and aryl iodides

Article abstract of DOI:10.1039/c6sc00082g

A palladium-catalyzed difluoromethylthiolation of heteroaryl halides and triflates under mild conditions was described. A vast range of heteroaryl halides such as pyridyl, quinolinyl, benzothiazolyl, thiophenyl, carbazolyl and pyazolyl halides could be difluoromethylthiolated efficiently, thus providing medicinal chemists with new tools for their search of new lead compounds for drug discovery. Likewise, aryl iodides were difluoromethylthiolated in high yields under a modified reaction condition.

Full text of DOI:10.1039/c6sc00082g

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DOI: 10.1039/C6SC00082G
Journal Name
ARTICLE
Palladium-Catalyzed Difluoromethylthiolation of Heteroaryl
Bromides, Iodides,Triflates and Aryl Iodides
Received 00th January 20xx,
Accepted 00th January 20xx
Jiang Wu, Yafei Liu, Changhui Lu and Qilong Shen*
A palladium-catalyzed difluoromethylthiolation of heteroaryl halides and triflates under mild conditions was described. A
vast range of heteroaryl halides such as pyridyl, quinolinyl, benzothiazolyl, thiophenyl, carbazolyl and pyazolyl halides were
able to be difluoromethylthiolated efficiently, thus providing the medicinal chemists new tools for their search of new lead
compounds for drug discovery. Likewise, aryl iodides were difluoromethylthiolated in high yields under a modified
reaction conditions.
DOI: 10.1039/x0xx00000x
www.rsc.org/
difluoromethylation of simple heteroaryl thiolates with a
difluorocarbene precursor, a difluoromethyl radical reagent or
an electrophilic difluoromethyl reagent have been reported.5
Introduction
Heteroarenes are common structural motifs and generally play
key roles in pharmaceuticals and agrichemicals, as evidenced
by the fact that 640 out of 1086 small molecules approved by
the U.S. Food and Drug administration (FDA) are heterocycles.1
On the other hand, the advantageous impact of the fluorine
and fluoroalkyl groups in the field of medicinal and agro-
chemistry has also been well-recognized and practised.2 Very
recently, one of the fluoroalkyl groups, difluoromethylthio
group (SCF2H), has attracted increasingly attention.3
Difluoromethylthio group (Hansch parameter R = 0.68)4 is
slightly more lipophilic than the methyl group (R = 0.56), but
much less lipophilic than its analog trifluoromethylthio group
(CF3S, R = 1.44), providing the medicinal chemists the
opportunity in fine-tuning the drug molecule’s lipophilicity. In
addition, the electron-withdrawing nature of the
difluoromethylthio group would increase the drug molecule’s
metabolic stability. Furthermore, the difluoromethylthio group
bearing an acidic proton that can act as hydrogen bonding
donor to interact with the enzyme could enhance the drug
molecule’s binding selectivity.3b Thus, if the beneficial effects
of the difluoromethylthio groups could be combined with the
appreciated heteroarene structural motif, a synergistic effect
would be achieved that would improve on the drug molecule’s
overall efficacy.
Nevertheless, various base-sensitive functional groups were
not compatible with the strong basic conditions in these
reactions. Furthermore, except for some structurally simple
heteroarylthiols, few methods are available for the formation
of structurally more complicated heteroarylthiols. More
recently, we3e and Goossen’s group3c-d independently reported
that the heteroaryldifluoromethylthioether could be accessed
from heteroaryldiazonium salts under mild conditions. Yet, the
explosive nature of the heteroaryldiazonium salts requires
extreme care for handling that limits their pratical
applications.6 Alternatively, we recently discovered an
electrophilic difluoromethylthiolating reagent-difluoromethyl-
thiophthalimide that was able to direct difluoromethylthiolate
electron-rich heteroarenes such as indoles, pyrroles,
imidazo[1,2-a]pyridine, aminothiazole and isoxazole in the
presence of
a
Lewis acid.[3f] However, no desired
difluoromethylthiolated heteroarenes were observed when
other less electron-rich or electron-poor heteroarenes such as
benzothiophene, benzofuran or pyridine were subjected to the
reaction conditions. Thus, new and efficient methods that
allow for difluoromethylthiolation of a broad range of common
heteroarenes are highly desirable.
Palladium-catalyzed cross-coupling reactions7 represent as
one of the most utilized synthetic tools for the formation of
carbon-carbon and carbon-heteroatom bonds.8 In this respect,
several palladium-catalyzed coupling of aryl halides with
Despite the potential of the difluoromethylthioheteroarene
unit on the drug molecule’s properties, its widespread
application in medicinal studies remains rather limited due to a
lack of efficient synthetic methods. A limited examples for the
fluoroalkylated
difluoromethylation,
nucleophiles
for
trifluoromethylation,
and
monofluoromethylation
formation
of
heteroaryldifluoromethylthioether
via
trifluoromethylthiolation under significantly different reaction
conditions9 have been developed, while the analogous
difluoromethylthiolation has not been reported. One main
reason behind the fluoroalkyl group’s different behavior is due
to the unique properties of fluoroalkyl groups. One subtle
change in the structure of fluoroalkyl groups may lead to
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032.
E-mail: shenql@sioc.ac.cn
† Electronic Supplementary Information (ESI) available. CCDC 1436785. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/x0xx00000x.
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dramatic stability and reactivity differences. For instance, Scheme 1 Optimization of the Palladium-Catalyzed Difluoromethylthiolation
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DOI: 10.1039/C6SC00082G
AgSCF3 is a stable solid and is known to be a good coupling of 3-Iodopyridine.a
partner for aryl and heteroaryl iodides and bromides, while its
analog AgSCF2H or other nucleophilic difluoromethylthiolating
reagent is an unknown species and many efforts to synthesize
it all failed. Since we recently discovered that a bulky N-
heterocyclic carbene (SIPr) can stabilize AgSCF2H,3e we
wondered whether this reagent [(SIPr)Ag(SCF2H)] can be
utilized in the palladium-catalyzed difluoromethylthiolation of
various heteroaryl halides. Herein, we report the realization of
such a new cross-coupling reaction under mild reaction
conditions. A vast range of different difluoromethylthiolated
hereroarenes could then be accessed, thus providing the
medicinal chemists new tools for their search of new lead
compounds for drug discovery. In addition, under a modified
condition, the difluoromethylthiolation of aryl iodides were
also equally achieved.
Results and discussion
One
concerning
for
the
palladium-catalyzed
difluoromethylthiolation of heteroaryl halides is the reductive-
elimination step of the commonly proposed catalytic cycle
since it is well-known that reductive-elimination from
heteroaryl-palladium complexes proceeded much more
difficult than those of aryl-palladium complexes.10 To probe
whether the reductive-elimination from the putative
a Reaction conditions: 3-iodopyridine (0.05 mmol), (SIPr)Ag(SCF2H)
2 (0.05 mmol),
palladium precursor (10 mol %), ligand (15 mol %) in different solvent (1.0 mL) at
50 oC for 12 h; bYields were determined by 19F NMR analysis of the crude reaction
mixture with trifluorotoluene as an internal standard; c1.2 equiv of
(SIPr)Ag(SCF2H)
2
was used; dPd(dba)2 (10 mol %), Xantphos (10 mol %) were
intermediate [L2Pd(heteroaryl)(SCF2H)]
3 is problematic, we
synthesized Xantphos11-ligated complex [(Xantphos)Pd(3- used as the catalyst; ePd(dba)2 (10 mol %), Xantphos (20 mol %) were used as the
f
catalyst; Pd(dba)2 (7.5 mol %), Xantphos (11.3 mol %) were used as the catalyst;
Py)(I)]
1 and studied its reaction with [(SIPr)Ag(SCF2H)] 2 at
gPd(dba)2 (5.0 mol %), Xantphos (7.5 mol %) were used as the catalyst.
various solvent and temperature. To our surprise, reaction of
[(Xantphos)Pd(3-Py)(I)] with 1.5 equivalents of [(SIPr)Ag(SCF2H)]
in toluene occurred smoothly at room temperature after 1.0 h
generated the corresponding product in 55% yield, while
reactions using other bidentate ligands such as DPPE, DPPB,
DPPF occurred in less than 2% yields (Scheme 1, entries 2-6).
Interestingly, electron-rich, monodentate alkyl phosphines
such as BrettPhos or XPhos that can be used efficiently in the
palladium-catalyzed trifluoromethylthiolation were not
effective at all9d (Scheme 1, entries 7-9). We then further
studied the effect of solvent and the temperature. It turned
out that the reaction in other solvents such as THF or dioxane
gave comparable yields (Scheme 1, entries 10-11). The
reaction conducted at room temperature occurred in much
lower conversion (Scheme 1, entries 14-15). Further studies
indicated that the ratio of the palladium to ligand is very
important for the reaction. Using a combination of 10 mol%
Pd(dba)2 and 10 mol% Xantphos as the catalyst was much less
effective while reaction with 10 mol% Pd(dba)2 and 20 mol%
Xantphos occurred in slightly lower yield (Scheme 1, entries
17-18). Finally, reactions in lower catalyst loading resulted in
35-42% yields (Scheme 1, entries 19-20).
to
afford
the
reductive-elimination
product
3-
difluoromethylthiopyridine as the only product in 73% yield, as
determined by 19F NMR spectroscopy of the reaction mixture
(Figure 1). These results indicate that reductive-elimination to
form heteroaryldifluoromethylthioether is a fast process and
would not likely be the turnover limiting step of the possible
palladium-catalyzed difluoromethylthiolating reaction.
Figure
[(SIPr)Ag(SCF2H)]
1
Stoichiometric reaction of complex [(Xantphos)Pd(3-Py)(I)]
at room temperature.
1 with
2
The
reaction
conditions
optimized
for
The observed stoichiometric reaction was successfully
translated into the catalytic reaction. Reaction of 3-
difluoromethylthiolation of 3-iodopyridine turned out to be
rather effective for difluoromethylthiolation of a variety of
heteroaryl iodides, as summarized in Scheme 2. In general,
pyridyl iodides bearing the halogen in the 2, 3, or 4-position
with electron-donating or withdrawing groups underwent
iodopyridine with reagent
2 in the presence of 10 mol%
Pd(dba)2 and 15 mol% Xantphos occurred smoothly after 12 h
at 50 oC to give 3-difluoromethylthiopyridine in 72% yield
(Scheme 1, entry 1). Reaction using DPEPhos as the ligand
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Scheme 2 Scope of the Palladium-Catalyzed Difluoromethylthiolation of benzofuran, thiophene, or dibenzothiophene occurred in good
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Heteroaryl Iodides.a
DOI: 10.1039/C6SC00082G
to excellent yields (Scheme 1, 4r-4aa). In addition, iodo-
substituted heteroarenes with two hetero-atoms such as
pyrimidine, pyrazine, quinazoline, indazole, thieno[3,2-
b]pyridine, benzothiazole all can be difluoromethylthiolated in
high yields (Scheme 1, 4ab-ak). Interestingly, in most cases,
when a heteroarene containing both an iodo group and
another halogen such as fluoride, chloride or bromide was
subjected to the reaction conditions, the iodo group was
preferentially difluoromethylthiolated (Scheme 2, 4a
-
b,
4g
-
i
,
4m 4t 4ab ad 4ah 4aj). However,
-
p
,
-
u
,
-
,
,
the
bisdifluoromethylthiolated pyrazine was obtained as the only
product when 2-bromo-5-iodopyrazine was used (4af). Notably,
a variety of functional groups other than halogens such as
nitro, cyano, ester, enolizable ketone or protected phenolic
hydroxyl group were compatible with the reaction conditions
(Scheme 2, 4c-e, 4k-l, 4u, 4z, 4ag, 4aj). These compounds are
of great interesting since they allow further functional group
transformation or derivatization. Interestingly, the isolated
complex [(Xantphos)Pd(3-py)(Br)] could also served as the
catalyst for the same transformation. In these cases, the
catalyst loading could be decreased to 5.0 mol% (Scheme 2, 4d
,
4f
,
4m
,
4r
,
4x,
4aa and 4ad).
Scheme
3
Scope
of
the
Palladium-Catalyzed
Difluoromethylthiolation of Heteroaryl Bromides.a
aReaction conditions A: heteroaryl iodine (0.5 mmol), (SIPr)Ag(SCF2H)
2 (0.6
mmol), Pd(dba)2 (10 mol %), Xantphos (15 mol %) in toluene (2.5 mL) at 50 oC for
12 h; Isolated yields; bReaction conditions B: heteroaryl iodine (0.5 mmol),
(SIPr)Ag(SCF2H) 2 (0.6 mmol), (XantPhos)Pd(3-py)(Br) (5.0 mol %), XantPhos (2.5
mol %) in toluene (5.0 mL) at 50 oC for 6 h; Isolated yields; cYields were
determined by 19F NMR analysis of the crude reaction mixture with
trifluorotoluene as an internal standard; dPd(dba)2 (10 mol%), DPEPhos (10 mol%)
aReaction conditions A: heteroaryl bromides (0.5 mmol), (SIPr)Ag(SCF2H)
2 (0.6
mmol), Pd(dba)2 (10 mol %), Xantphos (15 mol %) in toluene (2.5 mL) at 50 oC for
6 h; Isolated yields; bReaction conditions B: heteroaryl bromides (0.5 mmol),
(SIPr)Ag(SCF2H)
2 (0.6 mmol), (XantPhos)Pd(3-py)(Br) (5.0 mol %), XantPhos (2.5
mol %) in toluene (5.0 mL) at 50 oC for 6 h; Isolated yields; cYields were
determined by 19F NMR spectroscopy using trifluorotoluene as the internal
standard.
were used; e2-Bromo-5-iodopyrazine and 2.4 equiv of (SIPr)Ag(SCF2H)
used.
2 were
difluoromethylthiolation in high yields (Scheme 2, 4a
-
q
). For
with
Since we observed that heteroaryl bromide can also be
difluoromethylthiolated in the case of 4af, we studied the
example,
[(SIPr)Ag(SCF2H)]
reaction
of
2-chloro-5-iodopyridine
2
occurred after 12 h at 50 oC to give 2-
reaction of heteroaryl bromides with [(SIPr)Ag(SCF2H)]
detail, as summarized in Scheme 3. Reactions of various
activated heteroaryl bromides could be
2 in
chloro-5-difluoromethylthiopyridine in 87% yield (4g), while
the same reaction with 4-iodo-2-methoxypyridine occurred in
91% yield (4q). Not only pyridyl iodides, but also reactions of
iodine-substituted quinoline, isoquinoline, indole, carbazole,
difluoromethylthiolated in high yields, while reactions of the
electron-rich heteroaryl bromides occurred in less than 5%
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conversion. Heteroaryl bromides bearing two bromo groups at yields were obtained when DPEPhos was used tVhieew lAirgtiaclnedO,nlianes
different positions reacted preferentially at the activated summarized in Scheme 5. In the presencDeOoI:f1100.10m39o/lC%6SPCd0(0d0b8a2)G2
carbon-bromide bond. For example, reaction of 2,4- and 10 mol% DPEPhos, a variety of aryl iodides were able to
dibromopyridine gave 4-bromo-2-difluoromethylthiopyridine difluoromethylthiolated in excellent yields. The catalyst
exclusively in 50% yield (Scheme 3, 4ao). Nevertheless, various loading can be decreased to 5-7.5 mol% when activated aryl
heteroaryl bromides such as bromo- pyridine, quinoline, iodides with electron-withdrawing groups were subjected to
isoquinoline, pyrazine, and bipyridine were successfully the reaction conditions (Schmeme 5, 5i
difluoromethylthiolated in good to excellent yields. Likewise, Noteworthily, common functional groups such as halides, ester,
when isolated palladium complex [(Xantphos)Pd(3-py)(Br)] ketone, nitro and cyano group were compatible (Scheme 5, 5i
(5.0 mol%) was used as the catalyst, the reactions also ). Nevertheless, reactions of aryl bromides occurred in low
occurred in comparable yields, as demonstrated in the cases of yields under current reaction conditions and further
, 5j, 5p, 5s) .
-
s
4an
,
4ap
,
4at in Scheme 3.
optimization of the conditions are needed.
Heteroaryl phenols are common in naturally occurring
Scheme 5. Scope of the Palladium-Catalyzed Difluoromethylthiolation of Aryl
organic molecules and the corresponding triflic esters are
valuable coupling partners for transition metal-catalyzed cross-
Iodidess.a
coupling reactions.12
Having establishing a general and
for the formation of
excellent
protocol
heteroaryldifluoromethylthioether, we next tried to extend
this method to the easily available heteroaryl triflates. Yet, less
than 10% conversion was observed when 5-bromo-2-pyridyl
triflates was subjected to the standard conditions for
heteroaryl bromides and iodides. After a quick screening of the
reaction conditions, we found that the addition of 2.0
equivalents of NaBr dramatically improved the yields of the
reaction. It is likely that the bromide anion could stabilize
[(XantPhos)Pd(heteroaryl)(OTf)] by forming stable palladium
intermediate [(XantPhos)Pd(heteroaryl)(Br)](OTf). Under these
conditions,
successfully
a
variety of heteroaryl triflates could be
converted into their corresponding
difluoromethylthiolated compounds in moderate to good
yields, as summarized in Scheme 4.
Scheme
4 Scope of the Palladium-Catalyzed Difluoromethylthiolation of
Heteroaryl Triflates.a
aReaction conditions: aryl iodides (0.5 mmol), (SIPr)Ag(SCF2H) 2 (0.6 mmol), Pd(dba)2
b
(10 mol %), DPEPhos (10 mol %) in toluene (2.5 mL) at 50 oC for 12 h; Isolated yields;
Pd(dba)2 (7.5 mol%), DPEPhos (7.5 mol%) was used; c Pd(dba)2 (5.0 mol%), DPEPhos (5.0
mol%) was used.
To
demonstrate
the
protocol,
applicability
we
of
studied
this
the
difluoromethylthiolating
difluoromethylthiolation of two medicinally important
compounds. Compound 6, a difluoromethylthiolated analog of
Imiquimod,13 a medicine that acts as an immune response
modifier to treat genital warts, was generated in 88% yield.
aReaction conditions A: heteroaryl triflates (0.5 mmol), (SIPr)Ag(SCF2H) 2 (0.6 mmol),
Pd(dba)2 (10 mol %), Xantphos (15 mol %) and NaBr (2.0 equiv) in toluene (2.5 mL) at
Likewise, compound 7, a difluoromethylthiolated derivative of
b
50 oC for 6 h; Isolated yields; Reaction conditions B: heteroaryl triflates (0.5 mmol),
herbicide safener Cloquintocet-mexyl,14 was formed in 84%
yield under standard reaction conditions.
(SIPr)Ag(SCF2H) 2 (0.6 mmol), (XantPhos)Pd(3-py)(Br) (6.0 mol %), XantPhos (3.0 mol %)
and NaBr (2.0 equiv) in toluene (5.0 mL) at 50 oC for 6 h; Isolated yields; cPd(dba)2 (20
mol%), XantPhos (30 mol%) was used.
Encouraged by the broad scope of the palladium-
catalyzed difluoromethylthiolation of heteroaryl substrates,
we would like to further extend this protocol to
difluoromethylthiolation of aryl iodides. However, only
moderate yields were observed when a combination of
Pd(dba)2/Xantphos was used as the catalyst. Instead, high
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1494-1497; g) L.-C. Li, F. Wang, C.-F. Ni and J.-B. Hu, Angew.
Chem. Int. Ed., 2013, 52, 12390-12394D; Oh)I: 1V0..1P0.3VM9i/eCew6hAStrCtaic0lae0nO0d8nl2iMnGe.
F. Greaney, Org. Lett., 2013, 15, 5036-5039; i) K. Fuchibe, M.
Bando, R. Takayama and J. Ichikawa, J. Fluorine Chem., 2015,
171, 133-138.
6
7
8
a) D. S. Wulfmann, in The Chemistry of Diazonium and Diazo
Groups, Part 1, S. Patai, Ed.; Wiley, New York, 1978; b) B. J.
Deadman, S. g. Collins and A. R. Maguire, Chem. Eur. J., 2015,
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Conclusions
Chem. Front., 2015, 2, 590-614.
a) A. Milnar, Ed., Palladium-Catalyzed Coupling Reactions:
Practical Aspects and Future Development, Wiley-VCH,
Weinheim, 2013; b) A. de Meijere, F. Diederich, Eds. Metal-
Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim,
2010.
In summary, we have developed the first palladium-catalyzed
direct difluoromethylthiolation of heteroaryl bromides, iodides,
triflates and aryl iodides. The reactions were conducted under
mild reaction conditions and many common functional groups
were tolerant. Thus, the current method provides an
alternative and attractive strategy for the preparation of the
difluoromethylthiolated heteroarenes. In detailed mechanistic
studies including isolation of the difluoromethylthiolated
palladium intermediate, investigation of the reaction kinetics
and expansion the reaction scope to other common aryl
halides/triflates are undergoing currently in our laboratory.
Selected examples for Pd-catalyzed functionalization of
heteroaryl halides: a) X. Wu, C. Lei, G. Yue and J. Zhou Angew.
Chem. Int. Ed., 2015, 54, 9601-9605; b) X. Wu, J. See, K. Xu, H.
Hirao, J. Roger, J.-C. Hierso and J. Zhou, Angew. Chem. Int.
Ed., 2014, 53, 13573-13577; c) L. Ackermann, R. Vicente and
A. R. Kapdi, Angew. Chem. Int. Ed., 2009, 48, 9792-9826; d) P.
Xi, F. yang, S. Qin, D. Zhao, J. Lan, G. Gao, C. Hu and J. You, J.
Am. Chem. Soc., 2010, 132, 1822-1824; e) D. Mandal, A. D.
Yamaguchi and K. Itami, J. Am. Chem. Soc., 2010, 132, 1822-
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Zhao, M. A. Huffman and J. M. Mcnamara, Org. Lett., 2002, 4,
The authors thank the financial support from National Basic
Research Program of China (2012CB821600), National Natural
Science Foundation of China (21372247/21572258/21421002)
and SIOC.
3481-3484.
9
a) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Z. hang, D. A. Watson
and S. L. Buchwald, Science, 2010, 328, 1679-1681; b) Y. Gu,
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11 Xantphos was chosen initialy as the ligand for the Pd-
catalyzed difluoromethylthiolation of 3-iodopyridine because
,
reductive-elimination
trifluoromethylated
from
palladium
Xantphos-ligated
complex
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