Copper-promoted sandmeyer difluoromethylthiolation of aryl and heteroaryl diazonium salts

Article abstract of DOI:10.1002/anie.201502113

An efficient copper-promoted difluoromethylthiolation of aryl and heteroaryl diazonium salts is described. The reaction is conducted under mild reaction conditions and various functional groups were compatible. In addition, reactions of heteroaryl diazonium salts such as pyridyl, quinolinyl, benzothiazolyl, thiophenyl, carbazolyl, and pyrazolyl diazonium salts occurred smoothly to afford the medicinally important difluoromethylthiolated heteroarenes. Furthermore, a more practical one-pot direct diazotization and difluoromethylthiolation protocol was developed, and it converts the aniline derivatives into difluoromethylthiolated arenes. The utility of the method is demonstrated by difluoromethylthiolation of a number of natural products and drug molecules. A dose of salt: The title reaction is conducted under mild reaction conditions and various functional groups are compatible. (Hetero)aryl diazonium salts reacted smoothly to afford the medicinally important difluoromethylthiolated (hetero)arenes. A practical one-pot direct diazotization and difluoromethylthiolation protocol was developed for aniline derivatives to generate difluoromethylthiolated arenes.

Full text of DOI:10.1002/anie.201502113

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502113
German Edition: DOI: 10.1002/ange.201502113
Synthetic Methods
Copper-Promoted Sandmeyer Difluoromethylthiolation of Aryl and
Heteroaryl Diazonium Salts**
Jiang Wu, Yang Gu, Xuebing Leng, and Qilong Shen*
Abstract: An efficient copper-promoted difluoromethylthiola-
tion of aryl and heteroaryl diazonium salts is described. The
reaction is conducted under mild reaction conditions and
various functional groups were compatible. In addition,
reactions of heteroaryl diazonium salts such as pyridyl,
quinolinyl, benzothiazolyl, thiophenyl, carbazolyl, and pyra-
zolyl diazonium salts occurred smoothly to afford the medic-
inally important difluoromethylthiolated heteroarenes. Fur-
thermore, a more practical one-pot direct diazotization and
difluoromethylthiolation protocol was developed, and it con-
verts the aniline derivatives into difluoromethylthiolated
arenes. The utility of the method is demonstrated by difluoro-
methylthiolation of a number of natural products and drug
molecules.
several different difluorocarbene precursors such as HCF2Cl
(F22), BrCF2P(O)(OEt)2, ClCF2CO2Na, TMSCF2Br,
HCF2OTf, and PhS(O)(NTs)CF2H have been developed.[4]
In addition, three reports for difluoromethylation of aryl
thiolates by either an electrophilic or radical substitution
pathway have been independently reported by the groups of
Prakash, Hu, and Baran.[5] Nevertheless, the methods men-
tioned above typically require strong basic conditions to
deprotonate the thiol and are incompatible with many base-
sensitive functional groups. In addition, these methods
require the preformation of the aryl thiols and the formation
of structurally complicated aryl thiols is an intricate task.
Thus, a new strategy which can form difluoromethylthiolated
arenes and heteroarenes under mild reaction conditions is
highly desirable.
O
rganofluorine compounds, which generally serve as
The Sandmeyer reaction[6] represents one of the funda-
mental functional-group transformations routinely practiced
in research laboratories and applied in industry to efficiently
convert the NH2 group of ArNH2 into a variety of functional
groups such as halogen (F, Cl, Br, I), hydroxy, cyano, and
boryl groups.[7] More recently Sandmeyer-type trifluorome-
thylation[8] and trifluoromethylthiolation[9] of aryl diazonium
salts have also been developed. Although it is still elusive, the
mechanism of the Sandmeyer reaction was generally believed
to be initiated with a single-electron transfer (SET) from CuX
to the diazonium group to form a diazo radical and CuIIX. The
diazo radical then releases a molecule of nitrogen to form an
aryl radical, which reacts with CuIIX to from the final ArX
product.
Inspired by the mechanism of the Sandmeyer reaction and
the recent advances in this field, we envisioned that if
a CuSCF2H species could be generated in situ, a similar
Sandmeyer-type difluoromethylthiolation reaction could be
developed. Thus, an alternative strategy for the formation of
aryl and heteroaryl difluoromethylthiolation could be created
and would allow incorporation of the difluoromethylthio
group at a later stage of the synthesis of drug candidates
(Figure 1).
potent active ingredients in drugs and crop protecting
agents, are of great interest in the field of pharmaceuticals
and agrichemicals.[1] Fluorine and trifluoromethyl groups
represent two prominent, well-developed structural motifs
which effectively enhance the drugꢀs pharmacokinetics,
metabolic stability, and binding selectivity, whereas the effects
of other fluoroalkyl groups, such as difluoromethyl and
difluoromethylthio groups, are less recognized. However,
interests in these fluoroalkyl groups are increasing rapidly.[2]
More specifically, the difluoromethylthiolated arenes and
heteroarenes (ArSCF2H) represent promising structural units
which might bring desirable changes to the physical and
biological properties of drug molecules since the difluorome-
thylthio group is generally considered a highly lipophilic
hydrogen-bonding donor.[3] Therefore, the development of
new and efficient methods for the formation of difluorome-
thylthiolated arenes and heteroarenes is of great current
interest.
The most well-known strategy for the formation of
difluoromethylthiolated arenes and heteroarenes is based
on the nucleophilic reaction of aryl thiolates with difluoro-
carbene with subsequent protonation. Toward this end,
Herein, we report the preparation and characterization of
the thermally stable N-heterocyclic carbene (NHC) ligated
[*] J. Wu, Y. Gu, Dr. X.-B. Leng, Prof. Dr. Q. Shen
Key Laboratory of Organofluorine Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (China)
E-mail: shenql@sioc.ac.cn
[**] We thank the National Basic Research Program of China
(2012CB821600), National Natural Science Foundation of China
(21172245/21172244/21372247/21421002), the Syngenta PhD fel-
lowship (Y.G.) and sioc for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502113.
Figure 1. Proposed Sandmeyer difluoromethylthiolation of diazonium
salts.
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Table 1: Optimization of the copper-catalyzed difluoromethylthiolation
difluoromethylthiolated silver complex [(SIPr)Ag(SCF2H)]
[1; SIPr= 1,3-bis(2,6-diisopropylphenyl)imidazolin-2-yli-
of a phenyl diazonium salt.[a]
dene].[10] In the presence of one equivalent of [Cu-
(CH3CN)4]PF6/bpy, the reaction of 1 with a variety of aryl
and heteroaryl diazonium salts occurred smoothly to generate
difluoromethylthiolated arenes and heteroarenes in good to
excellent yields under mild reaction conditions. Furthermore,
a one-pot sequence for diazotization/difluoromethylthiola-
tion of aniline derivatives was developed. The broad range of
substrates, mild reaction conditions, and operational simplic-
ity make the method very attractive as the method of choice
for the formation of difluoromethylthiolated arenes and
heteroarenes.
[(SIPr)Ag(SCF2H)] (1) could be easily synthesized from
the reaction of [(SIPr)Ag(CF2H)], a complex previously
discovered in our own laboratory,[11] with sulfur in THF for
50 minutes at ambient temperature.[12] The reaction can be
readily scaled up to 4.8 grams and 1 was isolated as a white
solid in 82% yield. The complex 1 was fully characterized by
1H, 13C, and 19F NMR spectroscopy and elemental analysis.
CuX
Ligand
–
Solvent Yield
[%][b]
1
2
3
4
5
6
7
8
9
Cu(CH3CN)4PF6
Cu(CH3CN)4PF6 2,2’-bipyridine
CuI
CuCl
CuSCN
CuCN
Cu(CH3CN)4PF6 2,2’-bipyridine
Cu(CH3CN)4PF6 2,2’-bipyridine
Cu(CH3CN)4PF6 2,2’-bipyridine
CH3CN 27
CH3CN 65
CH3CN 62
CH3CN 43
CH3CN 43
CH3CN 32
2,2’-bipyridine
2,2’-bipyridine
2,2’-bipyridine
2,2’-bipyridine
DMF
THF
CH2Cl2
<5
<5
10
10 Cu(CH3CN)4PF6 2,2’-bipyridine
toluene <5
CH3CN 43
CH3CN 50
CH3CN 47
CH3CN 55
CH3CN 52
11 Cu(CH3CN)4PF6 1,10-phenanthroline
12 Cu(CH3CN)4PF6 bathophenanthroline
13 Cu(CH3CN)4PF6 4,4’-dimethyl-2,2’-bipyridyl
14 Cu(CH3CN)4PF6 5,5’-dimethyl-2,2’-bipyridyl
15 Cu(CH3CN)4PF6 4,4’-dimethoxy-2,2’-bipyridyl
16 Cu(CH3CN)4PF6 4,4’-di-tert-butyl-2,2’-bipyridyl CH3CN 48
17 Cu(CH3CN)4PF6 2,2’-bipyridine
18 Cu(CH3CN)4PF6 2,2’-bipyridine
19 Cu(CH3CN)4PF6 2,2’-bipyridine
CH3CN 72[c]
CH3CN 76[d]
CH3CN 79[e]
[a] Reaction conditions: phenyl diazonium salt (0.05 mmol),
1 (0.05 mmol), CuX (40 mol%), ligand (40 mol%) in different solvent
(1.0 mL) at 508C for 24 h. [b] Yields were determined by 19F NMR
analysis of the crude reaction mixture with trifluorotoluene as an internal
standard. [c] [Cu(CH3CN)4]PF6 (80 mol%) and bpy (80 mol%) were used
as the catalyst. [d] [Cu(CH3CN)4]PF6 (100 mol%) and bpy (100 mol%)
were used as the catalyst. [e] [Cu(CH3CN)4]PF6 (100 mol%) and bpy
(100 mol%) as the catalyst and 1.2 equiv of 2a were used. DMF=N,N-
dimethylformamide.
2,2’-bipyridine (bpy) significantly increased the yield of the
reaction to 65% (entry 2). Switching the copper salt from
[Cu(MeCN)4]PF6 to CuI resulted in a slightly lower yield, and
reactions with other copper salts such as CuCl, CuSCN, and
CuCN occurred in much lower yields (entries 3–6). Using
CH3CN as the solvent is important for the conversion of the
reaction since reactions conducted in other solvents, such as
DMF, THF, CH2Cl2, and toluene, generated the desired
difluoromethylthiolated product in less than 10% yield
(entries 7–10). Other dinitrogen ligands such as 1,10-phenan-
throline, bathophenanthroline, 4,4’-dimethyl-2,2’-bipyridine,
5,5’-dimethyl-2,2’-bipyridine, 4,4’-dimethoxy-2,2’-bipyridine,
and 4,4’-di-tert-butyl-2,2’-bipyridine were tested, but reactions
under these conditions formed less than 55% of the
difluoromethylthiolated benzene (entries 11–16). Finally, the
yields of the desired products were improved to 72% and
76% when 0.8 and 1.0 equivalentsof [Cu(CH3CN)4]PF6/bpy,
respectively, were used as the catalyst (entries 17 and 18). The
yield was further increased to 79% when 1.2 equivalents of
the phenyl diazonium salt were used (entry 19).
The structure of 1 was further unambiguously confirmed by
X-ray analysis of its single crystals (see the Supporting
Information for details).[16] The compound 1 is not sensitive to
either moisture, light, or air. No detectable decomposition
was observed after more than one week storage on the shelf at
ambient temperature. The compound 1 is stable in solvents
such as MeCN, CH2Cl2, 1,4-dioxane, THF, DMF, and CHCl3
at room temperature for at least 12 hours as determined by
19F NMR spectroscopy.
With 1 in hand, we initially chose the reaction of phenyl
diazonium tetrafluoroborate (2a) with 1 as a model reaction
to identify reaction conditions for the conversion of aryl
diazonium salts into difluoromethylthiolated arenes. Consid-
ering that the halogen anion may involve in the Sandmeyer
reaction, we tried the reaction using [Cu(CH3CN)4]PF6 as the
catalyst and the product 3a was observed in 27% yield after
24 hours at 508C (Table 1, entry 1). Interestingly, unlike the
classic Sandmeyer reaction, addition of the dinitrogen ligand
A variety of aryl diazonium salts were subjected to the
reaction conditions used in entry 19, Table 1, and the reac-
tions occurred smoothly to give the corresponding difluoro-
methylthiolated arenes in good to excellent yields, as
2
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Scheme 2. Difluoromethylthiolation of heteroaryl diazonium salts.
Reaction conditions: heteroaryl diazonium salt (0.6 mmol),
1 (0.5 mmol), [Cu(CH3CN)4]PF6 (1.0 equiv), and bpy (1.0 equiv) in
CH3CN (2.0 mL) at 508C for 24 h. Yield is that of the isolated product.
[a] Reaction was conducted in 10.0 mL of CH3CN. [b] Yield was
determined by 19F NMR spectroscopy using trifluorotoluene as the
internal standard.
ethers, we tried to extend this method to heteroaryl diazo-
nium salts. As illustrated in Scheme 2, we found that this new
protocol also allowed the efficient conversion of heteroaryl
diazonium salts into difluoromethylthiolated heteroarenes in
good to excellent yields. More specifically, difluoromethyl-
thiolation of six-atom pyridyl or quinoliny diazonium salts
occurred in 55–75% yields (3ai–ao). Reactions of five-atom
heteroaryl diazonium salts such as diazonium salts of
benzothiazole, thiophene, carbazole, and pyrazole were less
efficient but acceptable yields of the desired products were
obtained (3ap–at). It is worth mentioning that these difluoro-
methylthiolated heteroarenes are not easily accessible by the
conventional methods.
In general, aryl diazonium salts are not commercially
available and are usually prepared by the reaction of anilines
with a source of nitrite before use.[7] Thus, if difluorome-
thylthiolated arenes could be directly accessed from readily
available aniline derivatives through diazotization and
difluoromethylthiolation, a more practical and attractive
one-pot protocol that circumvents the isolation of the
diazonium salts could be developed. Indeed, it was found
that treatment of a mixture of aniline derivatives and HBF4 in
CH3CN with tBuONO[14] at 08C for 30 minutes formed the
aryl diazonium salts. After evaporation of the solvent and
volatiles, the residue was directly treated with the copper
catalyst and 1 in CH3CN at 508C and after 24 hours generated
the desired difluoromethylthiolated arenes in good to excel-
lent yields (Scheme 3). Again, many functional groups were
compatible with this one-pot protocol.
Scheme 1. Scope of the copper-promoted difluoromethylthiolation of
aryldiazonium salt. Reaction conditions: aryl diazonium salt
(0.6 mmol), 1 (0.5 mmol), [Cu(CH3CN)4]PF6 (1.0 equiv), and bpy
(1.0 equiv) in CH3CN (10.0 mL) at 508C for 24 h. Yield is that of the
isolated product. [a] Reaction was conducted in 2.0 mL of CH3CN.
summarized in Scheme 1. In general, both electron-rich and
electron-poor aryl diazonium salts reacted in high yields.
Sterically hindered ortho-substituted diaryl diazonium salts
also underwent efficient difluoromethylthiolation to give the
ortho-substituted difluoromethylthioether in high yields (3o–
s, 3v, 3aa, and 3ag). A variety of functional groups such as
ester, amide, enolizable ketone, alkene, alkyne, cyano, nitro,
chloro, bromo, iodo, and heteroaryl pyridyl and oxazolyl
functional groups were compatible with the reaction condi-
tions (3 f–n, 3p–v, 3x–z, 3ac–ad, 3af–ag). Notably, aryl
diazonium salts with a halogen group such as chloride,
bromide, and iodide all reacted under the standard reaction
conditions to give the corresponding products in 79, 71, and
45% yield, respectively (3h–j). These products are of interest
since they could be further functionalized through well-
known cross-coupling reactions.[13]
Fluoroalkylated heteroarenes are valuable synthons for
medicinally important compounds or crop-protecting agents
and there is an urgent need for new efficient methods to
access these compounds.[2] Encouraged by the general and
excellent protocol for the formation of difluoromethylthio-
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thoxy pyridazine and sulfamethazine[15] are all compatible
with copper-mediated difluoromethylthiolation conditions
(Scheme 4). These results demonstrate the utility of the
copper-mediated reaction for late-stage difluoromethylthio-
lation to access compounds which are not easily accessible by
conventional methods.
In summary, we have demonstrated the first copper-
mediated Sandmeyer-type difluoromethylthiolation of aryl
and heteroaryl diazonium salts.[17] The reactions were con-
ducted under mild reaction conditions and a variety of
functional groups were compatible. The advantage of this
method was further demonstrated by application in a number
of biologically active molecules. Thus, the current method
provides an alternative and attractive strategy for the
formation of the difluoromethylthiolated arenes and hetero-
arenes. Mechanistic studies and synthetic applications of
these transformations are ongoing in our laboratory.
Scheme 3. One-pot diazotization/difluoromethylthiolation of aniline
derivatives. Reaction conditions: aniline derivative (1.0 mmol), HBF4
(2.0 mmol), tBuONO (2.0 mmol), MeCN (1.0 mL) at 08C–room tem-
perature for 30 min; 1 (0.5 mmol), [Cu(CH3CN)4]PF6 (1.0 equiv), and
bpy (1.0 equiv) in CH3CN (2.0 mL) at 508C for 24 hours. Yield is that
of the isolated product.
Keywords: copper · diazo compounds · fluorine · heterocycles ·
synthetic methods
Late-stage modification of natural compounds or drug
candidates is a valuable strategy for medicinal chemists
attempting to fine-tune the activity of the leading compounds.
We selected several natural compounds and drug molecules to
illustrate the advantage of the current difluoromethylthiola-
tion protocol. Amino derivatives of biologically active
molecules such as coumarin 120/151, isonicotinic acid, (1s)-
(+)-camphoric acid, vitamin B3, and drug molecules sulfame-
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Scheme 4. Difluoromethylthiolation of diazonium salts of natural com-
pounds or drug molecules. Yield is that of the isolated product.
Conditions for 4a–c and 4e–g: aryl diazonium salt (0.6 mmol),
compound 1 (0.5 mmol), [Cu(CH3CN)4]PF6 (1.0 equiv), bpy (1.0 equiv)
in CH3CN (10.0 mL) at 508C for 24 h; for 4d: aniline derivative
(1.0 mmol), HBF4 (2.0 mmol), tBuONO (2.0 mmol), MeCN (1.0 mL),
08C to room temperature, 30 min; compound 1 (0.5 mmol), [Cu-
(CH3CN)4]PF6 (1.0 equiv), bpy (1.0 equiv) in CH3CN (2.0 mL) at 508C
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[10] a) Y. Gu, X.-B. Leng, Q. Shen, Nat. Commun. 2014, 5, 5405,
DOI: 10.1038/ncomms6405; b) D.-L. Chang, Y. Gu, Q. Shen,
Chem. Eur. J. 2015, 21, 6074.
[11] Reactions of AgF, S8, and TMSCF2H under various conditions
did not generate AgSCF2H.
Received: March 5, 2015
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Synthetic Methods
J. Wu, Y. Gu, X.-B. Leng,
Q. Shen*
&&&& — &&&&
Copper-Promoted Sandmeyer
Difluoromethylthiolation of Aryl and
Heteroaryl Diazonium Salts
A dose of salt: The title reaction is
(hetero)arenes. A practical one-pot direct
diazotization and difluoromethylthiola-
tion protocol was developed for aniline
derivatives to generate difluoromethyl-
thiolated arenes.
conducted under mild reaction condi-
tions and various functional groups are
compatible. (Hetero)aryl diazonium salts
reacted smoothly to afford the medici-
nally important difluoromethylthiolated
6
www.angewandte.org
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!