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plementary protocols for TAM-assisted CÀH activation that
would allow for the use of user-friendly organic electrophiles
as the arylating reagents and, thus, avoid the use of terminal
oxidants. To this end, we developed highly step- and atom-
economical ruthenium-catalyzed CÀH arylations, with aryl hal-
ides,[26–30] of arenes, heteroarenes, and alkenes (Scheme 1b), re-
ported herein. Notable features of our findings include the use
of a highly modular removable triazole-based auxiliary, chemo-
selective direct arylations with easily accessible aryl bromides,
and ample substrate scope.
Results and Discussion
Optimization
We initiated our studies by preparing a representative set of
novel benzamides, 1, displaying substituted 1,2,3-triazoles, by
means of the copper-catalyzed 1,3-dipolar Huisgen cycloaddi-
tion under mild reaction conditions (see the Supporting Infor-
mation). With diversely decorated substrates, 1, in hand, we
subsequently probed different reaction conditions for the de-
sired CÀH arylation of TAM-amide 1a with aryl bromide 2a
(Table 1 and Tables S1–S3 in the Supporting Information). Pre-
Scheme 2. Variation of the auxiliary substitution pattern. [a] NMR conversion
with CH2Br2 as internal standard.
With the optimized reaction conditions in hand, we subse-
quently explored the effect exerted by the substituents of the
auxiliary on the performance of the ruthenium catalyst
(Scheme 2). A gem-dimethyl substitution pattern in the amide
backbone of substrate 1a was found to be beneficial for ensur-
ing high catalytic efficacy (3aa versus 3ba and 3ca). Moreover,
electron-donating N-substituents on the 1,2,3-triazole proved
to be suitable, whereas N-aryl-substituted derivatives 1e and
1 f did not deliver the desired products. With these less-elec-
tron-donating N-aryl substituents on the triazole moiety only
the starting materials, 1e and 1 f, were isolated. It is particular-
ly noteworthy that significantly inferior results were obtained
when using the hitherto “gold standard”, namely, a pyridyl-
substituted amide or the substrate derived from 8-aminoqui-
noline (4aa and 5aa, respectively). This observation is a strong
testament to the superior directing-group power of our tria-
zole auxiliary for ruthenium(II)-catalyzed CÀH functionalization.
Thereafter, we put the proposed bidentate binding motif of
the triazolyl-substituted amides, 1, to the test (Scheme 3). Terti-
ary amide 1g failed to deliver desired arylated product 3ga,
highlighting the importance of the acidic NH-free functionality.
In accordance with this finding, the corresponding ester, 1h,
was not a viable substrate for the ruthenium(II)-catalyzed
direct arylation. Likewise, simple primary or secondary amides
1i–1k, being devoid of the second Lewis basic nitrogen, were
not converted by the ruthenium catalyst.
Table 1. Optimization of ruthenium-catalyzed CÀH arylation of amide
1a.[a]
Entry
Variation from standard conditions
Yield [%]
1
2
3
4
5
6
7
–
98
–
–
PCy3, X-Phos, or dppf instead of PPh3
HIPrCl instead of PPh3
P(p-Tol)3 or P(4-FC6H4)3 instead of PPh3
[Ru3(CO)12] instead of [RuCl2(p-cymene)]2
1408C
86 or 91
–
96
99
[RuCl2(PPh3)3] instead of [RuCl2(p-cymene)]2/PPh3
[a] Reaction conditions: 1a (0.50 mmol), 2a (0.60 mmol), base
(0.75 mmol), [RuCl2(p-cymene)]2 (2.5 mol%), catalyst, ligand, o-xylene
(2.0 mL), 22 h, 120–1408C. Cy = cyclohexane, dppf = 1,1’-bis(diphenyl-
phosphino)ferrocene; Tol = tolyl.
liminary experiments identified ruthenium(II) complex [RuCl2(p-
cymene)]2 as a highly effective catalyst, particularly when
being coordinated by phosphine ligands (Table 1, entries 1–5).
However, well-defined ruthenium(II) complex [RuCl2(PPh3)3]
outperformed the in situ generated catalytic system (Table 1,
entries 1, and 7). Among a variety of bases (K2CO3, K3PO4,
KOAc, NaOAc, or CsOPiv; Piv= pivaloyl), Na2CO3 furnished op-
timal results. Furthermore, ortho-xylene allowed for more effi-
cient catalysis compared with reactions being conducted with
H2O[29,31–33] or in toluene, N-methyl-2-pyrrolidone (NMP), or
DMF as the solvent.
Scope
Having identified the secondary N-benzyl-substituted TAM-
amide as the most effective auxiliary, we explored the scope of
the ruthenium(II)-catalyzed CÀH arylation with diversely deco-
rated substrates 1 (Scheme 4). The direct arylation efficiently
proceeded with the parent substrate 1l, as well as with differ-
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Chem. Eur. J. 2014, 20, 1 – 6
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