Angewandte
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were also well established by using various transition-metal
catalysts and proper oxidants (Scheme 1b).[7,8] However, the
redox-neutral [4+2] annulations of imines and alkynes to give
3,4-dihydroisoquinolines remain elusive. Herein, we describe
À
the first redox-neutral [4+2] cyclization of N H imines and
internal alkynes to access cis-3,4-dihydroisoquinolines by
employing iron carbonyls as catalysts (Scheme 1c). This
reaction also represents the first iron-carbonyl-catalyzed
À
C H transformation of arenes since its parent cycloferration
reaction was reported in 1965.[5]
Recently, we reported a manganese-catalyzed dehydro-
À
genative [4+2] annulation of N H imines and alkynes, thus
affording isoquinolines with the evolution of dihydrogen.[8]
During the evaluation of various transition-metal catalysts,
we serendipitously found that the cis-3,4-dihydroisoquinoline
3ca, rather than the isoquinoline 4ca, was selectively formed
1
À
in 78% yield ( H NMR) from the reaction of the N H imine
1c and diphenylacetylene (2a) in diethyl ether when [Fe3-
(CO)12] was used as a catalyst instead of [MnBr(CO)5]
[Eq. (2); PMP = para-methoxyphenyl].[9] Of note, no trans-
3,4-dihydroisoquinoline product was detected during the
optimization process.
Scheme 2. Scope with respect to the imines and alkynes. Reaction
conditions: 1 (0.5 mmol), 2 (0.75 mmol), [Fe3(CO)12] (5 mol%), Et2O
(1.6 mL), 1208C, 24 h. Yield are those of the isolated products. [a] Et2O
(0.25m). [b] Yield of the pure isolated isomer. [c] Determined by
1H NMR analysis of the crude reaction mixture.
We next investigated the substrate scope (Scheme 2).
Both electron-donating and electron-withdrawing groups on
À
N H imines were tolerated successfully (3aa-da). An ortho-
substituted diarylimine showed good reactivity despite its
was run (Scheme 3b). No reaction occurred with 1c and
[Fe3(CO)12], whereas the trinuclear iron complexes Fe-I and
Fe-II were selectively generated from reactions of [Fe3(CO)12]
and 2a at 60 and 1208C, respectively.[10] Although no reaction
took place with 1c and either Fe-I or Fe-II, they did catalyze
the annulation of 1c with 2a to afford 3ca in comparable
yields (Scheme 3c). Furthermore, different alkynes, 2g and
2b, were reacted with 1c under the catalysis of either Fe-I or
Fe-II and only 3cg and 3cb were formed. Therefore 3ca was
not detected, and suggests that the alkyne moieties in Fe-I and
Fe-II were not involved in the final product. Third, the
increased steric hindrance (3ea). The less sterically congested
À
C H bond was preferably annulated in the meta-substituted
imine, albeit in lower yield (3 fa). The di(naphthalenyl)me-
thanimine 1g was also a suitable substrate (3ga), and an
excellent level of regiocontrol was obtained when an unsym-
metrical diarylimine was used (3ha). Alkyl aryl imines
bearing electronically varied groups were also applicable to
this reaction (3ia–pa). A series of aromatic alkynes contain-
ing functional groups like F, Cl, Br, and CF3 in different
substitution patterns was all compatible with the reaction
conditions (3cb–k), which allowed further synthetic elabo-
rations. Unfortunately, the reactions of other alkynes such as
4-octyne did not proceed and phenylacetylene failed to give
the expected product.[9] Two regioisomers were formed when
an unsymmetrical diaryl alkyne was used, and fortunately
could be separated by simple chromatography (3cl, 3cl’).
To probe the possible reaction intermediates, a series of
mechanistic experiments was carried out. First, the intercon-
version between 3 and 4 was tested (Scheme 3a). It was
shown that no formation of 4ca was observed from 3ca under
the standard reaction conditions. Meanwhile, only 3ca was
obtained without 3cg detected when 4cg was added to the
reaction of 1c and 2a, and thus ruled out the intermediacy of
4cg for the formation of 3cg. Second, a stoichiometric
reaction of either the imine 1c or alkyne 2a with [Fe3(CO)12]
À
dinuclear ferracycle Fe-III was synthesized by C H activation
from the aldimine 1q and [Fe3(CO)12][5] and it mainly
decomposed to 1q under the reaction conditions even in the
presence of either 2a or 1c, which implies the reversibility of
À
the C H activation and H-migration steps (Scheme 3d).
Interestingly, Fe-III could also catalyze the annulation of 1c
and 2a, albeit with lower reactivity. Finally, two possible
reaction intermediates, 6aa and 7aa,[11] formally arising from
À
À
the C H and N H addition of 1a to 2a, respectively, were
synthesized and examined under the reaction conditions
(Scheme 3e). It turned out the former could deliver product
3aa with or without [Fe3(CO)12], thus indicating its possible
involvement in the reaction.
À
To shed light on the nature of the C H activation step,
several deuterium-labeling experiments were carried out. The
reaction of the deuterated imine [D10]-1a with 2a was first
Angew. Chem. Int. Ed. 2016, 55, 5268 –5271
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