Palladium-Catalyzed C-H Arylation of (Benzo)oxazoles or (Benzo)thiazoles with Aryltrimethylammonium Triflates

Article abstract of DOI:10.1021/acs.orglett.5b02458

The C-H arylation of (benzo)oxazoles or (benzo)thiazoles with aryltrimethylammonium triflates was carried out via Pd-catalyzed C-H/C-N cleavage. Oxazoles, thiazoles, benzoxazole, and benzothiazole were arylated using activated and deactivated aryltrimethylammonium triflates to give 2-aryl(benzo)oxazoles or 2-aryl(benzo)thiazoles in reasonable to excellent yields.

Full text of DOI:10.1021/acs.orglett.5b02458

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed C−H Arylation of (Benzo)oxazoles or
(Benzo)thiazoles with Aryltrimethylammonium Triflates
Feng Zhu,† Jian-Long Tao,† and Zhong-Xia Wang*,†,‡
†CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry, University of Science and Technology of China,
Hefei, Anhui 230026, P. R. China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, P. R. China
S
* Supporting Information
ABSTRACT: The C−H arylation of (benzo)oxazoles or
(benzo)thiazoles with aryltrimethylammonium triflates was
carried out via Pd-catalyzed C−H/C−N cleavage. Oxazoles,
thiazoles, benzoxazole, and benzothiazole were arylated using
activated and deactivated aryltrimethylammonium triflates to
give 2-aryl(benzo)oxazoles or 2-aryl(benzo)thiazoles in reasonable to excellent yields.
tudies on synthetic methods of 2-aryl(benzo)oxazoles or
carried out.10 It is of interest to explore the possibility of using
S(benzo)thiazoles have attracted considerable attention aryltrimethylammonium salts as arylating reagents in the direct
C−H arylation of (benzo)oxazoles and (benzo)thiazoles.
The reaction of 1-naphthyltrimethylammonium triflate with
benzoxazole was used to screen catalysts and reaction
conditions, and the results are listed in Table S1 (Supporting
Information). The combination of Ni(COD)2 and dcype, PCy3,
or IPr·HCl was, respectively, tested in DMF at 120 °C in the
presence of NaO-t-Bu as base, and the results showed that the
above catalyst systems were not very effective for this reaction
(Table S1, entries 1−3). By contrast, a combination of
Pd(OAc)2 and dcype gave higher yield under the same
conditions (Table S1, entry 4). This improvement encouraged
us to test combinations of Pd(OAc)2 and other didentate
phosphine ligands, including dppm, dppe, dppb, dppp,
Xantphos, and DPEphos (Table S1, entries 5−10). However,
application of these didentate phosphines did not further
improve the reaction in comparison with Pd(OAc)2/dcype
system. This made us switch to monodentate phosphine and N-
heterocyclic carbene ligands such as Xphos, P(t-Bu)3, PCy3, IPr,
and IMes (Table S1, entries 11−15). Both PCy3 and IPr were
demonstrated to be excellent ligands in the palladium-catalyzed
reaction, whereas Xphos, P(t-Bu)3, and IMes were less effective.
Different palladium compounds also affected the reaction to
some extent. PdCl2 was less active than Pd(OAc)2, but the
activities of Pd2(dba)3 and [Pd(π-allyl)Cl]2 were comparable
with that of Pd(OAc)2 when PCy3 was employed as the ligand
(Table S1, entries 16−18). We also screened bases and solvents
using [Pd(π-allyl)Cl]2/PCy3 as catalyst (Table S1, entries 19−
23). NaO-t-Bu was superior to other bases such as LiO-t-Bu,
Cs2CO3, and K3PO4. Toluene and dioxane proved to be less
effective solvents than DMF. It was also noted that the amount
of the catalyst could be decreased. A combination of 2.5 mol %
of [Pd(π-allyl)Cl]2 and 10 mol % of PCy3 resulted in the
because the compounds are important structural units in
natural products, functional materials, agrochemicals, and
pharmaceutically active compounds.1 Among the synthetic
approaches explored, cross-coupling is one of the most
powerful and reliable methods. Compared with traditional
cross-couplings, the C−H arylation of (benzo)oxazoles or
(benzo)thiazoles avoids the need to prepare stoichiometric
amounts of aryl-metal reagent.2 On the other hand, it was
reported that C2-lithiated benzothiazole is very unstable even at
−50 °C.3 This leads to difficult to prepare 2-arylated
benzothiazole derivatives through cross-coupling of 2-metalated
benzothiazoles such as benzothiazolato magnesium reagents
and benzothiazolato zinc reagents with an aryl electrophilic
reagent. Hence, the C−H arylation of (benzo)oxazoles or
(benzo)thiazoles is receiving increasing attention. A variety of
electrophilic reagents including aryl halides, sulfides, and
phenol derivatives such as triflates, tosylates, mesylates,
sulfamates, esters, and carbamates have been employed for
the transformation.4−9 However, developing new arylating
reagents for the coupling reaction is still an active research
subject.
Aryltrimethylammonium salts are easily prepared from
arylamines, and the latter are widely available in nature and
industry. Compared with corresponding arylamines, the
ammonium salts show much higher C−N reactivity due to
strong C−N bond polarity and release of electronically neutral
amine in the process of reaction. Hence, aryltrimethylammo-
nium salts are promising arylation reagents in organic
transformations. A disadvantage of using this arylation reagent
is the presence of competing reactions of Csp3−N and Csp2−N
cleavages. However, the choice of suitable catalysts and
optimization of reaction conditions can overcome the draw-
backs. Several transition-metal-catalyzed cross-coupling reac-
tions using aryltrimethylammonium salts as the electrophiles,
such as Suzuki, Kumada, and Negishi couplings, have been
Received: September 10, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02458
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Letter
desired product in 92% yield. The combination of 2.5 mol % of
[Pd(π-allyl)Cl]2 and 10 mol % of IPr·HCl gave a slightly lower
yield (Table S1, entries 24 and 25). In addition, we noted that a
small amount of homocoupling species of 1-naphthyltrimethy-
lammonium triflate were often obtained in the reactions.
Hence, we tried to carry out the reaction using excess 1-
naphthyltrimethylammonium triflate. The result showed that
the yield of the desired product could be increased to 97%
(Table S1, entry 26). We also tested the counterion effect using
Table 1. Reaction of Aryltrimethylammonium Triflates with
Benzoxazole
a
1-naphthyltrimethylammonium salts with I− and BF4 as the
−
counterions under the optimized conditions (Table S1, entries
27 and 28). The results clearly showed that the iodide and
tetrafluoroborate salts were less reactive than the triflate salt.
Finally, we examined the reaction in the absence of catalyst.
The result showed that only a trace amount of coupling
product was observed (Table S1, entry 29), accompanied by
formation of N,N-dimethylnaphthalen-1-amine.
With the optimized reaction conditions in hand, the scope of
the aryltrimethylammonium triflates was tested using benzox-
azole as the nucleophilic precursor, and the results are listed in
Table 1. Compared with 1-naphthyltrimethylammonium
triflate, more electron-rich (4-methoxynaphthyl)trimethyl-
ammonium triflate exhibited somewhat lower reactivity. This
is reasonable because (1) more electron-rich (4-methoxy-
naphthyl)trimethylammonium triflate has a stronger C−N
bond which is more difficult to cleave in the oxidative addition
step and (2) the C−Pd bond between more electron-rich 4-
methoxynaphthyl group and palladium is stronger, which is
disadvantageous to the reductive elimination in the catalytic
cycle. Surprisingly, 2-naphthyltrimethylammonium triflate and
2-anthryltrimethylammonium triflate showed lower reactivity
than both (4-methoxy-1-naphthyl)trimethylammonium triflate
and 1-naphthyltrimethylammonium triflate (Table 1, entries 1−
3). Further, phenyltrimethylammonium triflate and (4-
methylphenyl)trimethylammonium triflate were discovered to
have lower reactivity than (2-methylphenyl)trimethyl-
ammonium triflate (Table 1, entries 4−6). The former required
higher catalyst loadings and led to lower product yield. In these
examples, it seems that the ammonium salts with more
sterically hindered aryl groups have higher reactivity. The
same phenomenon was also observed by other researchers.7e,11
We deduced that in these reactions the reductive elimination
step is the rate-determining step and a bulky aryl group can
promote the reductive elimination due to steric repulsion.
However, the methoxy-substituted phenyltrimethylammonium
triflates exhibited different reactivity trends. Both (p-methox-
yphenyl)- and (m-methoxyphenyl)trimethylammonium triflates
exhibited higher reactivity than (o-methoxyphenyl)trimethyl-
ammonium triflate under the same conditions (Table 1, entries
7−9). The o-methoxy-substituted substrate may form a C,O-
chelate intermediate through coordination of the oxygen atom
to the central palladium atom in the process of catalysis. The
chelation plays a leading role in the reductive elimination step
and makes the reductive elimination of the o-methoxyphenyl-
substituted intermediate more difficult compared with meta-
and para-substituted ones. [p-(Dimethylamino)phenyl]trimeth-
ylammonium triflate exhibited reactivity similar to that of (p-
methoxyphenyl)trimethylammonium triflate. Its reaction with
benzoxazole under the same conditions gave 40% product yield
(Table 1, entry 10). For installing the phenyl groups with
electron-withdrawing substituents onto benzoxazole, we found
that IPr is a more suitable ligand than PCy3. All electron-
deficient aryltrimethylammonium triflates gave moderate to
a
Unless otherwise specified, the reactions were carried out according
to the conditions indicated by the above equation; 0.5 mmol of
benzoxazole and 0.75 mmol of aryltrimethylammonium triflate were
employed. Isolated yield. 10 mol % of [Pd(π-allyl)Cl]2 and 40 mol %
of PCy3 were employed.
b
c
high product yields (Table 1, entries 11−14). Meanwhile, the
functional groups on the aromatic rings such as CF3, CN,
COPh, and CONEt2 were well tolerated. However, reaction of
p-EtO2CC6H4NMe3 OTf− with benzoxazole under the stand-
+
ard conditions could not give the desired product. In addition,
(2-pyridyltrimethyl)ammonium triflate was proved to be a good
reaction partner. Its reaction with benzoxazole resulted in
desired product in 82% isolated yield (Table 1, entry 15).
B
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We next examined the range of azoles using 1-naphthyl-
trimethylammonium triflate as the electrophile. As can be seen
from Table 2, various azoles including oxazoles, thioazoles, 5-
Benzothiazole displayed excellent reactivity under the opti-
mized conditions, and its reaction resulted in the cross-coupling
product in 97% yield (Table 2, entry 6). Both thiazole and 5-
methylthiazole showed much lower reactivity compared with
benzothiazole. Reaction of the former gave the corresponding
products in 53% and 43% yields, respectivity (Table 2, entries 7
and 8). Meanwhile, some demethylation products of 1-
naphthyltrimethylammonium triflates, 1-(N,N-dimethylamino)-
naphthalene, were observed. Finally, we found that 2-
(naphthalen-1-yl)-1,3,4-oxadiazole could also be arylated
using 1-naphthyltrimethylammonium triflate, but the product
yield was lower than those using oxazoles (Table 2, entry 9).
To further demonstrate the utility of this method for organic
synthesis, we examined the reaction of benzoxazole with 1-
naphthyltrimethylammonium triflate on a 10 mmol scale under
the conditions as shown in Table S1, entry 26. The
corresponding product was isolated in 95% yield. In addition,
the direct C−H bond arylation can also be performed in a
convenient one-pot procedure. Thus, N,N-dimethylnaphthalen-
1-amine was treated with MeOTf in CH2Cl2 at room
temperature. After removal of CH2Cl2, the resultant ammo-
nium salt was reacted directly with benzoxazole under the
optimized conditions to afford the arylated product in 92%
overall yield (Scheme 1). This result showed that the one-pot
reaction is as effective as the reaction between an aryltrimeth-
ylammonium salt and benzoxazole under identical conditions.
Table 2. Reaction of Azoles with 1-
a
Naphthyltrimethylammonium Triflate
Scheme 1. One-Pot Reaction for the C−H Arylation of
Benzoxazole
To gain preliminary mechanistic information about this
transformation, several control experiments were carried out
under the standard conditions. When an equimolar amount of
free-radical inhibitor 1,1-diphenylethylene or TEMPO was
added to the reaction mixture of benzoxazole and 1-
naphthyltrimethylammonium triflate, the product yields were
not affected. The experimental facts ruled out the possibility of
a free-radical reaction. As shown in Table S1, entry 17, the
Pd2(dba)3/PCy3 system exhibited comparable catalytic activity
with the combination of [Pd(π-allyl)Cl]2 or Pd(OAc)2 and
PCy3. Hence, the active catalyst in the catalytic cycle may be a
Pd(0) species. On the basis of the above observations and the
previous reports,2h,11 a plausible catalystic cycle is outlined in
Scheme 2. It is believed that this process is initiated from a
Pd(0) species (A) generated under the reaction conditions.
a
Unless otherwise specified, the reactions were carried out according
to the conditions indicated by the above equation; 0.5 mmol of
oxazole or thiazole and 0.75 mmol of aryltrimethylammonium triflate
were employed. Isolated yield. 0.5 mmol of 1-naphthyltrimethy-
lammonium triflate and 0.75 mmol of oxazole or thiazole were
employed.
b
c
methylbenzoxazole, and benzothiazole could be used for the
reaction and gave the arylated products in reasonable to
excellent yields. Compared with benzoxazole, 5-methylbenzox-
azole exhibited lower reactivity (Table 2, entry 1). Oxazole
reacted smoothly with 1-naphthyltrimethylammonium triflate
under the same conditions to give corresponding product in
89% yield (Table 2, entry 2). Reaction of 5-aryloxazoles was
demonstrated to proceed smoothly using [Pd(π-allyl)Cl]2/IPr
as the catalyst, leading to the desired products in modest yields
regardless of the electron-deficient or electron-rich properties
of the aryl groups on the oxazole rings (Table 2, entries 3−5).
The Pd(0) species reacts with ArNMe3 OTf− to form an
+
oxidative addition species LPd(OTf)Ar (B) and release NMe3,
which was monitored by GC−MS. Next, the C−H palladation
of azoles with LPd(OTf)Ar (B) in the presence of a base gives
aryl(heteroaryl) palladium intermediate (C), which undergoes
C
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Letter
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reductive elimination to form the cross-coupling product along
with regeneration of the Pd(0) complex (A).
In summary, we report the first example of palladium-
catalyzed direct C−H arylation of oxazoles and thiozaoles using
aryltrimethylammonium triflates as the arylating reagents. This
methodology displays a broad substrate scope. Various
aryltrimethylammonium triflates including electron-rich and
-poor ones can be used as arylating reagents. A variety of azoles
or thiazoles can be arylated with aryltrimethylammonium
triflates under the optimal reaction conditions. The reaction
gives reasonable to excellent yields in most cases and shows
good compatibility of functional groups. We believe that this
methodology would provide a valuable complement to the
direct C−H arylation of azoles and thiozaoles and enrich the
utilization of aromatic amines in organic synthesis chemistry.
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̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02458.
■
S
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Experimental details of the coupling reaction, character-
ization data, and NMR spectra of the cross-coupling
products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(11) (a) Muto, K.; Yamaguchi, J.; Lei, A.-W.; Itami, K. J. Am. Chem.
Soc. 2013, 135, 16384. (b) Hachiya, H.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2009, 11, 1737.
*E-mail: zxwang@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Natural Science
Foundation of China (Grant No. 21372212) and the National
Basic Research Program of China (Grant No. 2015CB856600)
is greatly acknowledged. Ms. Fang He of the Department of
Chemistry, University of Science and Technology of China, is
thanked for her help with sample purification.
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DOI: 10.1021/acs.orglett.5b02458
Org. Lett. XXXX, XXX, XXX−XXX