Pd-catalyzed synthesis of Ar-SCF3 compounds under mild conditions

Article abstract of DOI:10.1002/anie.201102543

Good to excellent yields of aryl trifluoromethyl sulfides, which are an important class of compounds in both the pharmaceutical and agrochemical areas, can be achieved under mild conditions by the Pd-catalyzed reaction of aryl bromides with a trifluoromethylthiolate nucleophile (see scheme). Copyright

Full text of DOI:10.1002/anie.201102543

Communications
DOI: 10.1002/anie.201102543
À
C S Bond Formation
À
Pd-Catalyzed Synthesis of Ar SCF3 Compounds under Mild
Conditions**
Georgiy Teverovskiy, David S. Surry, and Stephen L. Buchwald*
The unique chemical properties of aryl trifluoromethyl
sulfides (ArSCF3) have been known for over 60 years.[1] The
capacity of SCF3 to act as a lipophilic electron-withdrawing
group has resulted in the incorporation of ArSCF3 compo-
nents into a number of pharmaceutical and agrochemical
agents.[2] Unfortunately, direct access to this important class of
compounds is complicated by a lack of efficient, safe, and
general methods.[1a,3]
Scheme 1. Various ligands used in Pd-catalyzed cross-coupling reactions.
Significant advances in Pd-catalyzed cross-coupling pro-
cesses have allowed efficient access to a diverse array of
functionalized aromatic products, such as aryl sulfides.[4]
While the coupling of many aromatic or aliphatic thiols with
aryl halides has been achieved with very high efficiency,[5] the
analogous transformation to form aryl trifluoromethyl sul-
fides has not been reported. As gaseous CF3SH (b.p.
À368C)[6] can be difficult to handle in a laboratory setting,
several SCF3 salts have been developed, however, most of
these decompose under standard cross-coupling conditions.[3c]
results, we hypothesized that a similar Pd-based system might
À
allow the formation of a Caromatic SCF3 bond.
As we suspected that reductive elimination from putative
intermediate 11 would be rate limiting in any catalytic
process, we began our investigation by attempting its prep-
aration from oxidative addition complex 10 by treatment with
AgSCF3 (Scheme 2). We were surprised when this procedure
did not provide the expected transmetalation complex but
À
À
It has been postulated that reductive elimination of Ar
SR from a palladium center is initiated by a nucleophilic
instead led directly to the Ar SCF3 product 12 (presumably
via 11).
attack on the electrophilic hydrocarbyl group by the metal-
bound thiolate.[7] Thus, metal-catalyzed Ar SCF3 coupling
À
might be complicated by the reduced nucleophilicity of the
SCF3 anion[2b] as compared to a standard thiolate.
Recent reports from our group regarding novel ligands
including BrettPhos (1), tBuBrettPhos (2), XPhos (3), and
3,4,5,6-tetramethyl(tBu)XPhos (4; Scheme 1), have allowed
the successful coupling of weak nucleophiles traditionally
thought to be reluctant participants in the transmetalation or
reductive elimination steps of a typical Pd0/PdII catalytic cycle.
Specifically, using these catalyst systems has allowed the
direct formation of diaryl ether,[8] aryl fluoride,[9] aryl
trifluoromethyl,[10] and aryl nitro compounds[11] from their
corresponding aryl halides or pseudo halides. In light of these
Scheme 2. Formation of ArSCF3 by transmetalation and reductive
elimination from an isolated LPdAr(Br) complex.
Given this finding, we attempted to convert 4-(4-bromo-
phenyl)morpholine to the corresponding trifluoromethyl
sulfide using AgSCF3 and a catalytic quantity of 1 and
[(cod)Pd(CH2TMS)2] (Table 1). However, under these con-
ditions, none of 13 was observed. We surmised that failure to
observe the coupled product might be due to the inefficient
transfer of ÀSCF3 to 10 under catalytic conditions. Thus, we
elected to examine the use of a number of alternative
previously reported ÀSCF3 sources (Table 1).[3c,e]
[*] G. Teverovskiy, Dr. D. S. Surry, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Clark and Adamsꢀ[3d] work on the use of (Bu)4NI and
AgSCF3 for SNAr reactions with aryl halides indicated to us
that the addition of a quaternary ammonium salt might be
beneficial. Consistent with this hypothesis, the addition of one
equivalent of (Bu)4NI to the reaction mixture increased the
yield of 13 from 0% to 55% (Table 1). Further examination
of different ammonium salts revealed that Ph(Me)3NI was
more effective than (Bu)4NI and that switching to a more
soluble ammonium salt, Ph(Et)3NI, provided a nearly quan-
titative yield of the desired product (Table 1). Based on work
Fax: (+1)617-253-3297
E-mail: sbuchwal@mit.edu
[**] We thank the National Institutes of Health (NIH) for financial
support of this project (GM-58160). We thank BASF for a gift of Pd
compounds, FMC Lithium for a gift of tBu2PCl, and Nippon
Chemical for a gift of Cy2PCl and unrestricted support. G.T. would
also like to thank the DoD for a NDSEG Fellowship (32 CFR 168a).
The Varian NMR instrument used was supported by the NSF (CHE-
980861).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102543.
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Angew. Chem. Int. Ed. 2011, 50, 7312 –7314

Table 1: Examination of different SCF3 sources.[a]
and electron-rich substrates were coupled more efficiently
than their electron-poor analogues. This effect has previously
been noted in the coupling of aryl halides with NaNO2.[11]
Substrates containing acid-sensitive functional groups, such as
tert-butyoxycarbonyl(BOC)-protected anilines and nitriles,
were tolerated and coupled in high yield along with substrates
containing ketones, esters, and free NH groups of anilines
(Table 3). Aryl bromides containing bulky ortho groups, for
example, o-cyclohexyl and o-phenyl groups, could also be
coupled successfully, although they required the use of the
smaller ligand XPhos (3) (Table 3).
Entry
SCF3 source
Additive
Yield [%]
1
2
3
4
5
6
7
8
9
CsSCF3
AgSCF3
(Me)4NSCF3
AgSCF3
AgSCF3
AgSCF3
AgSCF3
AgSCF3
AgSCF3
none
none
None
(Me)4NI
(Bu)4NCl
(Bu)4NBr
(Bu)4NI
Ph(Me)3NI
PhEt3NI
10
0
20
0
0
56
55
80
>99
Table 3: Pd-catalyzed coupling of aryl bromides.[a]
[a] [(cod)Pd(CH2TMS)2] (2.5 mol%), PhMe (4 mL); all reactions were
run on 0.2 mmol scale and all reported yields are based on GC data.
done by Clark and Adams, it is presumed that the iodide
anion binds to AgSCF3 to generate an anionic “ate” complex.
We hypothesize that a large diffuse cation further aids in the
solubility of this complex. It is worth noting that while the use
of quaternary ammonium iodides and bromides allowed
catalytic turnover, the corresponding chloride analogues were
ineffective.
With the optimal combination of Ph(Et)3NI and AgSCF3
realized, we re-examined various other previously reported
ligands, which have enjoyed a measure of success in Pd-
catalyzed cross-coupling reactions (Table 2).[12] Our survey
revealed that only dialkylbiarylphosphine-based ligands were
successful at carrying out this transformation, while other
ligands such as 5 or 6 did not perform well even with higher
catalyst loadings.
98%[b]
98%[c]
93%[d]
97%
97%[c]
96%
96%[d]
96%[c]
97%
>99%
83%[c]
98%[c]
91%
Accordingly, we were successful in converting electron-
rich, -neutral, and -deficient aryl bromides to their respective
aryl trifluoromethyl sulfides in 2 h at 808C using 1.5–
3.5 mol% of Pd and 1.65–3.85 mol% of 1. Electron-neutral
[a] ArBr (1 mmol), PhMe (5 mL); yield of isolated product, average of
two runs. [b] 3.0 mol% Pd, 3.3 mol% 1. [c] 2.0 mol% Pd, 2.2 mol% 1.
[d] 3.0 mol% Pd, 3.3 mol% 3.
Heteroaryl bromides, such as those containing indoles,
pyridines, quinolines, thiophenes, and furans, were also viable
substrates (Table 4). Unfortunately, attempts to extend this
methodology to the coupling of aryl chlorides or aryl triflates
were unsuccessful. We are currently working to understand
and overcome these limitations.
Table 2: Examination of various ligands commonly employed in Pd-
catalyzed reactions.[a]
Finally, to demonstrate the utility of this method, we
prepared an intermediate in the reported synthesis of
Toltrazuril,[13] an antiprotozoal agent. Intermediate 14 can
be assembled from readily available starting materials in an
Entry
Ligand
t [h]
Yield [%]
1
2
3
4
5
6
7
8
9
1
2
3
7
8
5
6
9
4
1
1.5
1
2
2
2
2
2
2
>99[b]
60[b]
84[b]
36[c]
3[c]
À
overall yield of 88%. The key C SCF3 bond-forming process
proceeded in 95% yield (Scheme 3).
In summary, we have developed a general method for the
29[d]
0[d]
À
Pd-catalyzed Ar SCF3 bond-forming reaction. Using this
0[d]
method, a wide range of aryl bromides were converted into
their corresponding aryl trifluoromethyl sulfides. Addition-
ally, we have been successful in generating a variety of
heterocyclic aryl trifluoromethyl sulfides from heteroaryl
<1[c]
[a] PhMe (4 mL); all reactions were run on 0.2 mmol scale and all
reported yields are based on GC data. [b] 1.15 mol% Pd, 1.27 mol% L.
[c] 1.5 mol% Pd, 1.65 mol% L. [d] 2.5 mol% Pd, 2.75 mol% L.
À
bromide precursors. Due to the utility of Ar SCF3 com-
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Communications
[a]
À
Table 4: Pd-catalyzed formation of heteroaryl SCF3 compounds.
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94%
93%[c]
81%[c]
96%[b]
96%
98%
98%[b]
[a] ArBr (1 mmol), PhMe (5 mL); yield of isolated product, average of two runs.
[b] 1.5 mol% Pd, 1.65 mol% 1. [c] 3.5 mol% Pd, 3.85 mol% 1.
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Scheme 3. Synthesis of Toltrazuril intermediate.
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pounds as biologically active agents, and the mild reaction
conditions employed, we expect this method to be immedi-
ately implemented in the discovery of novel compounds with
pharmaceutical and agrochemical applications.
Received: April 12, 2011
Published online: June 20, 2011
[13] A. Gꢃnther, K.-H. Mohrmann, M. Stubbe, H. Ziemann (Bayer
AG), DE3516630, 1986.
À
Keywords: C S bond formation · P ligands · palladium · sulfur ·
synthetic methods
.
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Angew. Chem. Int. Ed. 2011, 50, 7312 –7314