Angewandte
Communications
Chemie
with a more Lewis basic carbonyl-oxygen atom for the highly
scaled-up using a lower catalyst loading without any detri-
reactive and Lewis acidic cobalt(III) catalyst. Upon switching
from the acetyl hydrazide (Ia) and the bulkier, non enolizable
pivaloyl hydrazide (Ib) to the benzoyl hydrazide (II), traces of
product could be observed. To our delight, the introduction of
a carbamate group, such as the ethyl hydrazinecarboxylate
(IIIa) and the tert-butyl hydrazine carboxylate (IIIb), enabled
the formation of the desired product (Scheme 1b, see the
Supporting Information).
mental impact on its efficiency (3a).
Then, we investigated the scope of several internal
alkynes (Scheme 3). Different symmetrical disubstituted
diarylalkynes led to the corresponding indole products in
good yields (4a–4e). Gratifyingly, the reaction also tolerated
Comparing the ethyl-2-phenylhydrazine-1-carboxylate
IIIa with Boc-phenylhydrazine IIIb, we found that IIIb led
to a completely selective formation of the desired product.
Therefore Boc-phenylhydrazine was used for optimization
with diphenylacetylene as standard substrate. After intensive
screening, the annulation reaction afforded the desired
unprotected indole (3a) in 83% yield, using [Cp*Co(CO)I2]
(10 mol%), AgSbF6 (20 mol%), and KOAc (10 mol%) in
HFIP (0.2m) at 808C (Scheme 2). Note that the standard
Scheme 3. Variation of several internal alkynes with 2-Boc-1-phenyl
hydrazine. Yields of isolated product are given. 1a (0.8 mmol), 2
(0.4 mmol), [Cp*Co(CO)I2] (10 mol%), AgSbF6 (20 mol%), and KOAc
(10 mol%) in HFIP (0.2m) at 808C for 22 h. [a] 1008C. [b] 0.2 mmol
scale, 1a (0.8 mmol), 1008C.
a diheteroarylalkyne and a multisubstituted diarylalkyne (4i,
4 f) in synthetically useful yields. Moreover, only one
regioisomer could be isolated when unsymmetrical alkyl–
aryl and alkyl–ester alkynes were employed (4g–4h, 4l),[16]
whereas the unsymmetrical ethyl-3-phenyl propiolate
afforded the desired product in a 6:1 mixture of regioisomers
(4j).
For the analysis of the reaction mechanism further
experiments were carried out (Scheme 4). In a competition
experiment the p-chloro-Boc-phenylhydrazine showed
a higher reactivity compared to the p-methyl-Boc-phenyl-
hydrazine (see the Supporting Information) and therefore
a CMD-type mechanism is proposed for the reaction reported
herein.[3c,15] Furthermore the 15N-isotope-labeled Boc-phenyl-
hydrazine 15N-1a was synthesized to determine which nitro-
gen atom of the hydrazine is placed in the corresponding
indole product. The pure isotope-labeled indole product 15N-
3a was isolated in 77% yield containing 100% of the labeled
nitrogen atom as analyzed by 15N-NMR spectroscopy and
ESI-MS. The kinetic-isotope effect (KIE) was studied in
parallel and competition experiments. A kH/kD value of 2.2
for the parallel experiment and a KIE of 2.8 for the
competition experiment were observed. These results indi-
Scheme 2. Variation of different substituted 1-Boc-arylhydrazines with
diphenylacetylene. Yields of isolated product are given. 1 (0.8 mmol),
2a (0.4 mmol), [Cp*Co(CO)I2] (10 mol%), AgSbF6 (20 mol%), and
KOAc (10 mol%) in HFIP (0.2m) at 808C for 22 h. [a] 5.0 mmol scale
using [Cp*Co(CO)I2] (5 mol%), AgSbF6 (20 mol%), and KOAc
(10 mol%) in HFIP (0.2m) at 808C for 46 h. [b] 1008C. [c] 0.3 mmol
scale. [d] [Cp*RhCl2]2 instead of [Cp*Co(CO)I2] (optimized conditions
of Ref. [15a] used). HFIP=hexafluoro isopropanol.
reaction is finished within 6 h on an 0.1 mmol scale. However,
for a more general methodology, the reaction time was
increased to 22 h. With these conditions in hand, the substrate
scope of Boc-protected arylhydrazines was investigated.
Various electron-donating (3a–3c, 3h, 3l–3m) and elec-
tron-withdrawing (3d–3g, 3i–3k, 3n) functional groups are
tolerated by this catalytic methodology. Meta-substituted
Boc-arylhydrazines led to a regioselective formation of the
desired product (3g–3i). We were delighted to observe
a superior reactivity of the cobalt(III) catalyst compared to
the rhodium(III) catalyst when ortho-substituted Boc-arylhy-
drazines were applied (3j–3l). In this particular reaction
excellent yields could be obtained for several ortho-substi-
tuted Boc-arylhydrazines, which can only be rarely utilized in
rhodium(III) catalysis.[15a] Pleasingly, the reaction could be
À
cate that the C H bond activation presumably occurs in the
rate-determining step of the reaction. Moreover the partic-
ular difference in reactivity of the cobalt(III)-catalyst system
regarding our directing group was investigated in competition
Angew. Chem. Int. Ed. 2016, 55, 3208 –3211
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