Organic Letters
Letter
the two vicinal hydrogen atoms was crucial for the
dehydrogenation.
Scheme 4. Synthesis of Pharmacologically Active Molecules
Importantly, various N-substituents were tolerated in the
indoline scaffold (2g−2p). Even in the presence of β-hydrogen
atoms in the N-alkyl substituent as in Et, n-Bu, i-Bu, and Cy
groups, the dehydrogenation occurred at the indoline ring with
exclusive site-selectivity. It is also noteworthy that branching
was tolerated at the positions α or β to the N atom. Thus, this
protocol is useful for the synthesis of N-alkylindoles since the
direct N-alkylation of indole derivatives under basic conditions
often suffers from competitive elimination reactions of the
alkylating reagents.13 Moreover, the reaction of 1k bearing a 4-
methoxybenzyl group at the N atom, which should be sensitive
to the oxidation conditions, occurred cleanly to give 2k in high
yield, while the oxidation with stoichiometric DDQ (in THF at
40 °C for 12 h) produced 2k in only 57% yield along with
unidentified byproducts. A phenyl group on the N atom was
also tolerated (2m).
The indoline (1n) with a strongly electron-withdrawing N-
tosyl group underwent efficient dehydrogenation to give 2n in
89% yield, whereas Fujita’s catalyst cat.1 did not promote the
reaction. N-Trifluoromethylsulfonyl or N-acyl-substituted
indolines were also suitable substrates (1o and 1p) although
the yields were moderate.
a
The (PS-DPPBz)-Ir catalyst system is also applicable to the
acceptorless dehydrogenation of NH-heterocycles (1q−1ab).
The reaction of 1q was conducted on the gram scale with a
reduced catalyst loading of 0.08 mol % (10 mmol scale, 94%
NMR yield, TON 1175) with reasonable hydrogen gas release
(∼210 mL, 94% based on H2). Two- or 3-fold dehydrogen-
ation occurred from tetrahydroquinoline-, tetrahydroisoquino-
line-, tetrahydroquinoxaline-, and piperazine-type substrates to
give the corresponding N-heteroarenes. 2-Phenyl-2,3-dihydro-
benzothiazole (1ab) also participated in this reaction.
To demonstrate the utility of this catalytic acceptorless
dehydrogenation, we applied the protocol to the synthesis of
pharmacologically active molecules having N-substituted
indoline scaffolds. The dehydrogenation of indolines 1ac and
1ad proceeded smoothly to provide CDK4/cyclin D1
inhibitors 2ac and 2ad, respectively, in high yields (Scheme
4a,b). When the corresponding dehydrogenative transforma-
tions were conducted using a large excess of activated MnO2,
the yields were only moderate.14 Compound 1ae, having
piperidine and pyridine moieties, was transformed to the
precursor of enzastaurin (2ae)15 in 37% yield (5 mol % Ir, 43%
conv. of 1ae, Scheme 4c).
Scheme 5. Deuterium Isotope Experiments
a
Conditions: 1 (0.2 mmol), [IrCl(cod)]2 (2 mol % Ir), PS-DPPBz (2
mol %), p-xylene (1 mL), 130 °C, 2 h. Yield was determined by H
1
NMR analysis of the crude product.
Scheme 6. Plausible Reaction Pathway
To gain insights into the mechanism, the reactions of
deuterated N-methylindolines were conducted. The dehydro-
genation of 2,2- and 3,3-dideuterated N-methylindolines [2
mol % (PS-DPPBz)-Ir, 130 °C, for 2 h] proceeded at only
slightly reduced rates compared to that of nondeuterated N-
methylindoline (61% and 53% 1H NMR yields vs 78%,
Scheme 5a−c). A deuteration effect in the reaction of 2,2,3,3-
tetradeuterated N-methylindoline (3%, Scheme 5d) was much
more significant than expected from the combination of the
effects of the deuteration at the C2 and C3 positions.
A possible reaction pathway for the (PS-DPPBz)-Ir-
catalyzed acceptorless dehydrogenation of N-substituted indo-
lines (1) is given in Scheme 6, which is distinct from the well-
established pathway for the acceptorless dehydrogenation of
NH-heterocycles, in which metal−ligand cooperation is
essential for NH deprotonation and H2 release from the
catalyst as in Fujita’s Cp*Ir(III) catalyst system.16 The reaction
starts from a coordination of the N atom of 1 to bisphosphine-
Ir(I) complex A. Oxidative addition of an N-adjacent C(sp3)−
H bond to the indoline-bound Ir(I) center in B gives Ir(III)
monohydride C.17,18 Subsequent β-hydrogen elimination
provides dehydrogenated product 2 and Ir(III) dihydride
species D.19 The stereochemical requirement of the cis-
arrangement of the two hydrogen atoms at the C2 and C3
positions evidenced by the reaction of cis- and trans-1f
(Scheme 3) is supportive of the involvement of this step.
Finally, H2 is released from D with the regeneration of A.
C
Org. Lett. XXXX, XXX, XXX−XXX