Angewandte
Chemie
indolizidines and consequently provide easy access to many
types of natural products (Scheme 1). Herein we report, to the
best of our knowledge, the first high-yielding and completely
regioselective and asymmetric hydrogenation of challenging
N-bridged heterocycles, represented by substituted indolizine
and 1,2,3-triazolo[1,5-a]pyridine derivatives.
Our study started with the hydrogenation of 3-butyl-5-
methylindolizine (2a) as a model substrate, with the ultimate
goal of a direct synthesis of the alkaloid monomorine. When
we applied our catalytic system to this aromatic precursor
under 60 bar of hydrogen and at 808C, we observed that the
six-membered ring was selectively reduced, giving 3a with
81% yield and 94:6 e.r. Even though the fully reduced
indolizidine core III (Scheme 2) was not observed, we
envisioned that the completely hydrogenated system could
be obtained by a second hydrogenation using a heterogeneous
catalyst (vide infra). The reaction reached full conversion and
a good e.r. of 97:3 was obtained when the reaction was
performed at room temperature and 100 bar of hydrogen.[15]
Solvent screening revealed that n-hexane is best suited for this
reaction. Other solvents such as toluene and t-amyl alcohol
are also suitable, but yields and e.r. values were not highly
reproducible. The use of an unsaturated NHC derivative led
to similar results in conversion and regioselectivity but
a significant decrease in the enantiomeric ratio. Other
NHCs were tested, but in all cases either no reaction occurred
or only the racemic product was formed.
Scheme 3. Scope for the asymmetric hydrogenation of indolizines 2a–
Having established the optimized reaction conditions, we
tested a variety of indolizines. As shown in Scheme 3, when
we increased the length of the substituent in position 5, the
enantiomeric ratio decreased slightly, while perfect conver-
sion to the desired product (3b,c) was maintained. The
reaction tolerates the presence of esters. Thus, 2d reacts
smoothly, yielding 3d with full conversion and 91:9 e.r.
without any reduction of the ester. In order to investigate the
effect of the position of the substituent in the six-membered
ring, we prepared a series of methyl-2-phenylindolizines (2e–
h). With these substrates, the best e.r. was obtained for 5-
methyl-2-phenylindolizine (2e). Surprisingly, 6-methyl-2-phe-
nylindolizine (2 f) did not react, even when we applied
harsher conditions like higher pressure, temperature, and
catalyst loading. In the case of the 7-methyl-2-phenylindoli-
zine (2g) we obtained full conversion to the desired product
only when the temperature was increased to 408C, albeit the
e.r. was only 75:25. Changing the position of the methyl group
to position 8 (2h) led to a drop in the enantioselectivity to
62:38, but perfect regioselectivity and complete conversion
were still maintained. We also observed that the electronics of
the phenyl ring in position 2 play a key role for the hydro-
genation.[16] While the unsubstituted phenyl ring of substrate
2e has no adverse effects on the hydrogenation in terms of
reactivity and enantioselectivity, when a fluorine atom is
present in the para position (2i), partial over-reduction of the
substrate was observed, yielding a mixture of products
impossible to separate for characterization. However,
HPLC analysis of the mixture indicates that enantiomeric
ratio (94:6) is almost the same as that observed for 3e. In
contrast, the p-methoxyphenyl-substituted indolizine 2j gave
no hydrogenation product; the starting material was com-
j. General conditions: [Ru(cod)(2-methylallyl)2] (0.015 mmol; cod=cy-
clooctadiene), KOtBu (0.045 mmol), and 1 (0.03 mmol) were stirred at
708C in n-hexane (2 mL) for 12 h, after which the reaction mixture was
added to 2a–j (0.30 mmol), and hydrogenation was performed at
100 bar and room temperature for 24 h. Yields of isolated products are
given. Enantiomeric ratios were determined by HPLC on a chiral
stationary phase. The absolute configuration of 3a was determined by
hydrogenation to monomorine (see Scheme 5). [a] Reaction carried out
at 100 bar and 408C. [b] 3i was obtained accompanied with over-
reduction products and was impossible to purify for characterization.
pletely recovered, even under higher pressure, temperature,
and catalyst loading.
We also explored the asymmetric hydrogenation of 1,2,3-
triazolo-[1,5-a]pyridines (Scheme 4). This core can be found
in many biologically active compounds. The selective reduc-
tion of 1,2,3-triazolo-[1,5-a]pyridines could be an easy way to
access new and more active derivatives, and therefore is
highly interesting for medicinal chemistry research.[17] The
hydrogenation of different alkyl-substituted substrates pro-
ceeded with perfect conversion and moderate enantioselec-
tivity (4a–d). We noticed that the enantiomeric ratio
decreased slightly when the length of the alkyl chain was
increased, while perfect conversion to the desired product was
maintained. The reaction of 7-phenethyl-1,2,3-triazolo[1,5-
a]pyridine (4e) also gave the desired product with an e.r.
value of 83:17.
In the transformation presented here the regioselectivity
of the hydrogenation reaction can be explained by the
unusual aromatic structure of the fused N-bridged hetero-
cycle: While the five-membered ring still corresponds to an
intact pyrrole unit, the six-membered ring resembles a diene
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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