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rearrangements enjoy much less success owing to the
instability of the resultant imine, the weak driving force,
and unpredictable side reactions.[7] While the scattered known
examples mainly focus on extremely strained substrates, aza-
pinacol and aza-semipinacol rearrangements involving ring
expansion from a 5-membered ring to a 6-membered ring, as
shown in Scheme 1, have been challenging. Mechanistically
related to our design is the inventive work of the Driver
group, which utilizes transition-metal-catalyzed ester migra-
tion for the synthesis of indolenines.[8]
A model reaction of 1a was carried out first (Table 1) to
produce an indoline with a fused lactone (2a), which
represents the core structure of alstolactine A and lancifer-
Table 1: Optimized reaction conditions.[a]
Entry
Acid
Solvent
Yield [%][b]
1
2
3
4
5
6
7
TFA
TFA
TFA
TFA
DMF
1,4-dioxane
THF
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
0
0
0
70
97[c]
88
90[d]
TFA
4.0 M HCl in dioxane
TFA
Scheme 2. Synthesis of indolines and indolenines based on the hydro-
carbazole framework via aza-pinacol rearrangements.
[a] Reaction conditions: The specified acid (0.4 mL) was added to
a solution of 1a (0.15 mmol) in 3.0 mL solvent. The resulting mixture
was stirred at RT for 5 min and then heated to 408C for 5 h. [b] The yields
were calculated by 1H NMR using 1,3,5-trimethoxyl-benzene as the
internal standard. [c] Yield of isolated product after silica-gel chroma-
tography. [d] Yield of isolated product for the gram-scale synthesis
(1.43 g, 2a). TFA=trifluoroacetic acid, Boc=tert-butoxycarbonyl.
nitrile, aryl, and alkyl) proved to be efficient substrates
(Scheme 2). The deprotection/aza-pinacol rearrangement
cascade sequence proceeded smoothly, generating indolines
with different fused rings (2a–d) and indolenines with rich
functionality (2e–2i), which represent the core structures of
alstolactine A, aspidophylline A, vincorine, minfiensine, and
many other akuammiline natural products. In addition,
substrates bearing a bromide substituent on the phenyl ring
were also investigated, furnishing products with synthetic
handles for further elaboration (2j–2l). Moreover, the related
aza-pinacol rearrangements with substrates containing an
additional fused phenyl ring at the 5-membered ring were
accompanied by automatic aerobic oxidation,[11] thereby
affording the ketones 2m and 2n with good yields. Further
decoration of the 5-membered ring and related transforma-
tions are reported in Scheme 4.
Besides using Boc as the protecting group, which was
cleaved during the reaction, an alkyl substituent or other
protecting groups, such as a methyl carbamate, on the
nitrogen atom were also well tolerated (Scheme 3a), and
the corresponding reactions furnished protected indolines
(2o, 2p) in high yields. Besides tertiary alcohols, trisubstituted
alkenes also turned out to be suitable substrates, and the
related aza-semipinacol rearrangements (upon protonation)
proceeded very well, generating 2a and 2e in comparable
yields to those obtained by aza-pinacol rearrangement.
ine[9] (structure not shown in Figure 1) and has been
challenging to access by other approaches. We envisioned
that in the presence of a suitable acid, the cascade sequence
involving cleavage of both protecting groups, aza-pinacol
rearrangement, and cyclization of the carboxylic acid onto the
resulting imine could occur in a single operation, thereby
generating 2a with remarkable efficiency. To our delight, after
several attempts, we observed the formation of the desired
product 2a in 70% yield when using TFA as the acid and
acetonitrile as the solvent (entry 4). Further optimization in
terms of solvents, acids, concentration, and temperature led to
the identification of optimized reaction conditions: the
reaction was carried out in dichloromethane at 408C in the
presence of TFA, delivering 2a in 97% yield (entry 5). The
structure of 2a was unambiguously confirmed by X-ray
structure analysis.[10] It should be noted that the reaction can
be carried out on a gram scale with excellent yield (entry 7).
Under optimized reaction conditions, the substrate scope
was investigated. Avariety of tertiary alcohols 1 with different
side chains (carboxylic ester, alcohol, protected amines,
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 12627 –12631