Communication
hydrazones could react efficiently to furnish the desired prod-
ucts 2o–q in high yields, while a lower yield was observed in
the reaction of N-acyl hydrazone, presumably because of a de-
crease in the electron density at the nitrogen atom. The keto-
hydrazone is also compatible with this reaction, with the for-
mation of 2-substituted indole 2s in 93% yield. Furthermore,
the ester moiety was not essential for this reaction. Thus, the
substrates carrying the hydrogen atom, the methyl group and
the phenyl group at R4, instead of the ester, provided the cor-
responding products 2t–v in good yields, indicating that the
reaction has a broad substrate scope. It should be noted that
not only substrates bearing electron-rich or -poor aryl groups
at R4, but also heteroaryl groups were well tolerated to give
3-arylmethyl indoles 2w–y.
Scheme 6. Synthesis of indomethacin.
The 3-methyl-conjugated hydrazone 12 readily participated
in the indolization reaction to form the indolenine 13 bearing
a quaternary carbon, which was treated with MeNH2 or NaOH,
affording pyrroloindoline 14 and furoindoline 15 in 50 and
52% yields, respectively (Scheme 7).[21] Subsequently, N-methyl-
A plausible mechanism for the reductive Fischer indolization
is shown in Scheme 5. The tert-butyl iodide initially reacts with
MeCN to form hydrogen iodide and isobutene via the genera-
tion of the nitrilium ion D.[14,15] The regioselective protonation
of 1 would then proceed by hydrogen iodide to form
the azonium ion E, which would be subsequently
converted to the intermediate F through the addition
of an iodide anion to the N=N bond.[16,17] Then, F
would be reduced by hydrogen iodide to form the
enamine G along with one equivalent of molecular
iodine, which was confirmed by titration with sodium
thiosulfate. Finally, the HI-promoted [3,3]-sigmatropic
rearrangement, cyclization and aromatization with
the loss of the ammonium iodide provides the indole
2.[18]
Scheme 7. Synthesis of esermethole.
To demonstrate the synthetic utility of this reduc-
tive Fisher indolization, syntheses of biologically
active compounds were performed (Schemes 6 and 7). A non-
steroidal anti-inflammatory drug, indomethacin,[19] was synthe-
sized on a gram scale in three steps from 4-methyl conjugated
hydrazone 9. The indolization reaction of 9 with tBuI efficiently
proceeded to give indole 10 in 95% yield. Subsequent N-acyla-
tion to give 11, followed by demethylation led to indometha-
cin (Scheme 6).[20]
ation and reduction of the pyrroloindoline 14 afforded eser-
methole, which is a key intermediate in the synthesis of the
cholinesterase inhibitor, physostigmine.[22] The furoindoline 15
could also be converted into physostigmine by a reported
protocol.[23,24]
In summary, we have shown the utility of tert-butyl iodide as
an anhydrous hydrogen iodide source and developed a novel
reductive Fischer indolization of N-aryl conjugated hydrazones.
The reductive Fischer indolization is applicable to various sub-
strates to give the corresponding indole derivatives, and can
also be applied to the synthesis of biologically active
compounds. Further investigations on this methodology are
ongoing in our laboratory.
Experimental Section
General procedure for the reductive Fischer indolization
To a solution of conjugated hydrazone 1 (0.2 mmol) in MeCN
(2 mL) was added tBuI (71 mL, 0.6 mmol, 3.0 equiv) at reflux. After
being stirred for 0.5 h, the reaction mixture was quenched with
10% Na2S2O3 solution and extracted with CHCl3 (3). The organic
phase was dried over MgSO4 and concentrated under reduced
pressure. The crude product was purified by preparative thin-layer
chromatography (hexane/AcOEt=3:1) to afford the corresponding
indole 2.
Scheme 5. A plausible reaction mechanism.
Chem. Eur. J. 2016, 22, 2616 – 2619
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Ito, Yuta
