Table 2. Zinc-catalyzed dehydrogenative N-silylation of indoles with hy-
drosilanes.[a]
fective, demonstrating that the use of ZnACTHNURTGNENG(U OTf)2 and pyridine
in EtCN is ideal for the reaction (Table 1, entries 21–24).
The use of a catalytic amount of pyridine is feasible, but this
decreased the reaction rate slightly (Table 1, entry 25). The
catalyst loading can be reduced further to 1 mol% without
significantly lowering the yield (Table 1, entry 26). As
Table 1 shows, there seems to be an interesting correlation
between the basicity of the organic base and the reaction
rate, which tends to increase with decreasing a pKa value of
the organic base.[9] Thus, an organic base with a pKa value of
approximately 5.3 is likely to be suitable for this reaction.
Stronger bases might impair the catalytic activity of the zinc
Lewis acid, possibly by strong coordination to the zinc
center.
After identifying the promising reaction conditions, the
substrate scope was explored (Table 2). Indoles 1 with an
alkyl, alkoxy, or functionalized alkyl group at any of the six
possible positions (R1–R6) coupled with 2a or HSiMe2Ph in
a dehydrogenative manner, invariably giving yields over
90% (Table 2, 3a–3j and 3r–3t). Aryl and heteroaryl substi-
tuted indoles 1 also reacted well with 2a to give 3k and 3l.
The N-
silylation can be readily extended to indoles 1 containing an
electron-withdrawing functionality (Table 2, 3m–3q); how-
ever, 3-benzoylindole did not couple with 2a even under rel-
atively harsh conditions [ZnACHTNUGRTENUNG(OTf)2 (10 mol%), 1108C, 30 h
in PrCN]. Some indoles 1 successfully reacted with a range
of trialkylsilyl groups with different steric natures (Table 2,
3u–3x). The compatibility of the functional groups OMe,
CH2CN, Cl, phthalimidoyl (in 3j), Br, I, CO2Me, and B(pin-
ACHTUNGTRENNUNG
uations, in which pyrrole (5) and carbazole (6) are used in-
stead of indoles;[10] or in which H2SiMePh is employed as
the silane (Scheme 1). The use of H2SiMePh led to double
dehydrogenative coupling, giving 9 and 10 in high yields.[11]
In all cases, the avoidance of partial reduction of the nitro-
gen-containing heteroarenes and the achievement of yields
over 88% demonstrate the high validity and reliability of
this strategy. Importantly, a practical application can be
demonstrated by synthesis on a preparative scale. For exam-
ple, 3a, 3n, and 7 were prepared on 10, 4, and 5 mmol
scales, respectively, to provide 2.98 g of 3a (95% yield),
1.69 g of 3n (93% yield), and 1.21 g of 7 (92% yield).
To our knowledge, the synthesis of N-(SiMePh2)indoles,
which has mainly been demonstrated herein, has no prece-
dent.[12] Therefore, to evaluate their utility in organic synthe-
sis, a carbon–carbon bond formation reaction on 3n and
a subsequent desilylation were performed as a preliminary
inquiry (Scheme 2). The Negishi cross-coupling of 3n with
a series of organozinc bromides proceeded smoothly at
room temperature to give 11a–11c in good to high yields.[13]
The removal of the SiMePh2 group from 11a, for instance,
was then readily achieved by using Bu4NF, and provided 12
in 91% yield.[12] This is the first case to demonstrate that N-
(SiMePh2)indoles can serve as useful synthetic intermediates
for further transformations.
[a] Reagents (unless otherwise specified):
1 (0.40 mmol), 2 (0.48–
0.80 mmol), Zn(OTf)2 (20–60 mmol), pyridine (0.20–0.40 mmol), EtCN
AHCTUNGTRENNUNG
(0.40 mL). Yields of isolated 3, based on 1, are shown here. See the Sup-
porting Information for further details. [b] PrCN instead of EtCN was
used as the solvent. [c] Performed with a 2m solution of the indole
(0.80 mmol) in EtCN (0.40 mL), containing 2a (1.2 mmol), Zn
(40 mmol), and pyridine (0.80 mmol). [d] Performed with a 2m solution of
the indole (0.80 mmol) in PrCN (0.40 mL), containing HSi(iPr)3
(1.6 mmol), Zn(OTf)2 (0.12 mmol), and pyridine (0.40 mmol).
ACHTUNGTRENNUNG(OTf)2
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
NMR spectroscopy studies gave us significant insight into
the mechanistic aspects of the reaction. By monitoring a 1:1
mixture of ZnACHTUNGTRNEG(UN OTf)2 and HSiMePh2 (2a) in CD3CN with
1H NMR spectroscopy, a new broad singlet appeared at
A
1
4.64 ppm (0.35H) in the H NMR spectrum and can be at-
&
2
&
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!