Manganese-catalyzed dehydrogenative [4+2] annulation of N-H imines and alkynes by C-H/N-H activation

Article abstract of DOI:10.1002/anie.201402575

Described herein is a manganese-catalyzed dehydrogenative [4+2] annulation of N-H imines and alkynes, a reaction providing highly atom-economical access to diverse isoquinolines. This transformation represents the first example of manganese-catalyzed C-H activation of imines; the stoichiometric variant of the cyclomanganation was reported in 1971. The redox neutral reaction produces H₂ as the major byproduct and eliminates the need for any oxidants, external ligands, or additives, thus standing out from known isoquinoline synthesis by transition-metal-catalyzed C-H activation. Mechanistic studies revealed the five-membered manganacycle and manganese hydride species as key reaction intermediates in the catalytic cycle.

Full text of DOI:10.1002/anie.201402575

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DOI: 10.1002/anie.201402575
Heterocycles
À
Manganese-Catalyzed Dehydrogenative [4+2] Annulation of N H
Imines and Alkynes by C H/N H Activation**
À
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Ruoyu He, Zhi-Tang Huang, Qi-Yu Zheng, and Congyang Wang*
Abstract: Described herein is a manganese-catalyzed dehy-
À
drogenative [4+2] annulation of N H imines and alkynes,
a reaction providing highly atom-economical access to diverse
isoquinolines. This transformation represents the first example
À
of manganese-catalyzed C H activation of imines; the stoi-
chiometric variant of the cyclomanganation was reported in
1971. The redox neutral reaction produces H2 as the major
byproduct and eliminates the need for any oxidants, external
ligands, or additives, thus standing out from known isoquino-
À
line synthesis by transition-metal-catalyzed C H activation.
Mechanistic studies revealed the five-membered manganacycle
and manganese hydride species as key reaction intermediates
in the catalytic cycle.
À
O
ver the past two decades, the strategy based on C H
activation has evolved as a powerful tool to construct
functional molecules, and offers an atom- and step-economic
alternative to traditional organic synthesis which relies
heavily on transformations of various functional groups.[1]
So far, second- and third-row transition-metal (e.g., Rh, Pd,
À
À
Scheme 1. Manganese-catalyzed C C bond formation by C H activa-
tion.
Ir, and Ru) catalysts have played a leading role in the area of
[2]
À
À
C H activation. However, from the viewpoint of sustain-
further develop new types of C H transformations beyond
the stoichiometric ones. Thus, considerably rare examples of
able development, it is desirable for chemists to develop more
economic alternatives to these precious metals. In line with
this, first-row transition metals are naturally abundant and
À
À
manganese-catalyzed C C bond-forming reactions by C H
activation have been disclosed recently.[6] Kuninobu and
Takai et al. demonstrated a manganese-catalyzed insertion of
an aldehyde into a C(sp ) H bond (Scheme 1a).
group latter reported a manganese-catalyzed addition of an
inexpensive, and can be promising candidates for catalyst
[3]
2
[6a,b]
À
À
development in C H activation reactions.
Our
Manganese is a first-row early transition metal and has
[6c]
À
À
been far less studied in the activation of inert C H bonds,
except for the exceptional work on manganese oxo complex
promoted C H oxidation. Despite the fact that stoichio-
metric cyclometalation reactions of [MnR(CO)5] (R = CH3,
Bn, etc.) have been well documented,[5] significant challenges
still remain to achieve an efficient catalytic turnover and
aromatic C H bond to a terminal alkyne (Scheme 1b).
Inspired by the stoichiometric cyclomanganation of benzyli-
deneaniline described by Bruce et al. in 1971,[7] we set out to
[4]
À
À
explore manganese-catalyzed C H transformations of imines.
Herein we report a dehydrogenative [4+2] annulation of N-
unsubstituted imines and alkynes to expediently furnish
À
À
isoquinolines by manganese-catalyzed C H/N H activation
(Scheme 1c). Remarkably, the reaction produces H2 as the
predominant byproduct and eliminates the need for an
oxidant. Though rhodium-, ruthenium-, palladium-, and
nickel-catalyzed isoquinoline syntheses from imines (or its
[*] R. He, Prof. Dr. Z.-T. Huang, Prof. Dr. Q.-Y. Zheng, Prof. Dr. C. Wang
Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences
À
structural analogues) and alkynes by C H activation have
Beijing 100190 (China)
E-mail: wangcy@iccas.ac.cn
Homepage: http://wangcy.iccas.ac.cn/
been reported,[8–11] an external or internal oxidant is generally
needed in the reaction to induce catalytic turnover. In
principle, the extrusion of H2 is the most atom-economic,
arguably ideal, and unprecedented feature among the
reported annulations. Therefore, this manganese-catalyzed
reaction provides an important complementary method for
isoquinoline synthesis.
[**] Financial support provided by the National Natural Science
Foundation of China (21322203, 21272238) and the National Basic
Research Program of China (973 Program; No. 2012CB821600) is
gratefully acknowledged. We thank Prof. Chao Chen (Tsinghua
University) for GC analysis of the gas composition of the reaction
mixture. We also thank the Alexander von Humboldt Foundation for
the Equipment Subsidy.
Initially, bis(4-methoxyphenyl)methanimine (1a) and
diphenylacetylene (2a) were chosen as model substrates
and extensive investigations were carried out to define the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402575.
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a meta-methyl or meta-trifluoromethyl group allowed C H
activation to take place predominantly or exclusively on the
less sterically hindered positions (3ma, na). However, reverse
regioselectivities were observed with meta-methoxy- and
meta-fluoro-substituted imines (3oa’, pa’). This result could
be attributed to the secondary directing effect of OMe and F
groups.[13]
Next, the scope of alkynes was explored using 1a as the
reaction partner (Scheme 4). Various aromatic and aliphatic
acetylenes reacted with 1a readily to form the corresponding
isoquinolines in high yields (3ab–g, 3ar, as). It is noteworthy
Scheme 2. The model reaction. [a] Yield determined by 1H NMR spec-
troscopy. [b] Yield of the isolated product. PMP=para-methoxyphenyl.
optimal reaction conditions.[12] In the end, treatment of 1a
with 1.5 equivalents of 2a in the presence of 10 mol%
[MnBr(CO)5] gave the isoquinoline 3aa in 92% yield, and
cis-stilbene (4a) was formed in 14% (Scheme 2). GC analysis
of the atmosphere above the reaction mixture clearly showed
the existence of H2 and CO. Importantly, only 1.0 equivalent
of 2a was sufficient to achieve as high as an 88% yield
(determined by NMR spectroscopy) of 3aa and that of 4a
decreased to 6%.
With the optimized reaction conditions established, the
scope of imines was first examined (Scheme 3). Both diaryl
and aryl alkyl ketimines with a wide array of functional
groups and varied substitution patterns reacted readily to give
isoquinolines in good yields (3aa–la, 3qa, ra). The presence of
Scheme 4. Scope of the alkynes. Reaction conditions: 1a (1.0 mmol),
2 (1.5 mmol), [MnBr(CO)5] (0. 1 mmol), 1,4-dioxane (1 mL), 1058C,
12 h. Yields of the isolated 3 are shown. [a] 15 mol% [MnBr(CO)5].
[b] 1508C. [c] Using 1h in place of 1a. [d] Major isomer was shown.
PMP=p-methoxyphenyl.
that terminal alkynes, which are often challenging substrates
for rhodium-, palladium-, nickel-, and ruthenium-catalyzed
isoquinoline synthesis,[8–11,14] proved to be amenable to the
current system. A broad range of terminal alkynes including
aromatic (2h–k), aliphatic (2l,m), silylated (2n), and hetero-
aromatic (2o,p) alkynes, participated smoothly in the reaction
to generate 3ah–ao and 3hp as single regioisomers in
moderate to excellent yields. The terminal alkyne 2q,
containing alcohol functionality, was also suitable for the
reaction (3aq).
To probe the reaction mechanism, a set of experiments
was carried out (Scheme 5).[12] First, the annulation of 1c with
2h cleanly produced the isoquinoline 3ch in 88% yield
(Scheme 5a). As a potential intermediate of this reaction, the
2-styryl imine 5a was prepared and then subjected to the
reaction conditions in either the absence or the presence of
2h. In the first case, unreacted starting material largely
remained and only a trace amount of 3ch as well as 27% of
the 3,4-dihydroisoquinoline 5b was formed (Scheme 5b). In
Scheme 3. Scope of imines. Reaction conditions: 1 (1.0 mmol), 2a
(1.5 mmol), [MnBr(CO)5] (0. 1 mmol), 1,4-dioxane (1 mL), 1058C,
12 h. Yields of the isolated 3 are shown. [a] 15 mol% [MnBr(CO)5].
[b] 24 h.
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Scheme 6. KIE experiments. [a] Determined by 1H NMR spectroscopy.
Conditions: [MnBr(CO)5] (10 mol%), 1,4-dioxane, 1058C
bond cleavage might be directly involved in the rate-
determining step.[17]
Based on the above results, a plausible catalytic cycle is
proposed in Scheme 7. The reaction commences with cy-
clomanganation of the imine 1a with [MnBr(CO)5] to
generate the five-membered manganacycle A. Insertion of
À
2a into the Mn Caryl bond of A via the manganese alkyne
Scheme 5. Probe for possible reaction intermediates. Yields were
determined by H NMR spectroscopy unless otherwise noted. [a] Yield
1
of the isolated product. [b] Based on 1a.
the latter case, a complicated mixture of products was
generated (Scheme 5c). It can be seen that the conversion
of 5a into 3ch exhibited very low efficiency and was
accompanied by competitive formation of several side
products (5b–d), which were not detected in the reaction of
1c with 2h (Scheme 5a). Therefore, the mechanism involving
an alkene intermediate such as 5a might not be operative in
the dehydrogenative annulation.
Second, the stoichiometric reaction of [MnBr(CO)5] with
1a afforded the five-membered manganacycle A in 30% yield
À
upon isolation (Scheme 5d). The ease of C H activation here
with [MnBr(CO)5] was striking and contrasted with conven-
tional cyclomanganation achieved by the general use of
manganese hydrocarbyls, which were tediously synthesized
from [Mn2(CO)10] and Na/Hg.[5,15] Treatment of A with the
alkyne 2a gave 3aa and 4a in 85% and 14% yields,
respectively, possibly via the intermediacy of the seven-
membered manganacycle C (Scheme 5e).[16] It is likely that
a Mn-H species was responsible for the formation of 4a.
Moreover, a catalytic amount of A efficiently promoted the
dehydrogenative cyclization of 1a with 2a (Scheme 5 f), thus
affording 3aa in comparable yield. Collectively, these results
indicate the involvement of A in the catalytic reaction.
Third, three types of kinetic isotope effect (KIE) experi-
ments were conducted and the KIE values were measured to
be 1.9, 2.0, and 2.2 respectively (Scheme 6a–c). In addition,
the deuterated ketone [D5]-6c from hydrolysis of the uncon-
verted imine was isolated and no deuterium loss was detected,
Scheme 7. A proposed catalytic cycle.
complex B forms the seven-membered manganacycle C,
which is directly transformed into 3aa with concomitant
formation of the manganese hydride species [HMn(CO)4].
There are two possible rationales for this process: 1) meta-
2
À
À
thesis between C(sp ) Mn and N H bonds, and 2) oxidative
À
À
addition of the N H bond followed by C N reductive
elimination. Then the coordinatively unsaturated complex
D combines with 1a and subsequently regenerates A along
with elimination of H2 (Path a). Alternatively, D could react
with 2a and 1a to eventually regenerate A and release 4a
through a series of sequential steps (Path b). The H2-
producing pathway (Path a) is deemed to be the major one
according to the low yields of 4a (Scheme 2).
À
thus indicating the C H activation step might be an irrever-
In conclusion, a manganese-catalyzed dehydrogenative
À
À
sible process. These experiments suggested that the C H
[4+2] annulation of N H imines and alkynes has been
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tion on manganese catalysis in the field of C H activation is
currently underway in our laboratory.
Experimental Section
General procedure: In an oven-dried Schlenk tube under N2
atmosphere,
a mixture of the imine 1 (1.0 mmol), alkyne 2
(1.5 mmol), [MnBr(CO)5] (0.1 mmol), and anhydrous 1,4-dioxane
(10 mL) was stirred at 1058C for 12 h. The solvent was then removed
in vacuo and the product 3 was isolated by column chromatography
on silica gel.
Received: February 19, 2014
Published online: April 2, 2014
À
Keywords: alkynes · C H activation · heterocycles · manganese ·
.
synthetic methods
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