Manganese(I)-Catalyzed Substitutive C?H Allylation

Article abstract of DOI:10.1002/anie.201601560

The first manganese(I)-catalyzed C?H allylations with ample scope were achieved by carboxylate assistance. The highly selective C?H/C?O functionalizations proved viable with densely substituted allyl carbonates, and the organometallic C?H allylation strategy set the stage for expedient late-stage diversification with excellent levels of positional selectivity.

Full text of DOI:10.1002/anie.201601560

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International Edition: DOI: 10.1002/anie.201601560
German Edition: DOI: 10.1002/ange.201601560
À
C H Activation
À
Manganese(I)-Catalyzed Substitutive C H Allylation
Weiping Liu, Sven C. Richter, Yujiao Zhang, and Lutz Ackermann*
À
Abstract: The first manganese(I)-catalyzed C H allylations
with ample scope were achieved by carboxylate assistance. The
We initiated our studies by exploring reaction conditions
À
for the envisioned C H allylation of the ketimine 1a with the
[16]
À
À
À
À
highly selective C H/C O functionalizations proved viable
with densely substituted allyl carbonates, and the organome-
tallic C H allylation strategy set the stage for expedient late-
stage diversification with excellent levels of positional selectiv-
ity.
carbonate 2a (Table 1). The desired C H/C O cleavage
failed to proceed in the absence of a manganese catalyst or
when employing simple manganese(II) salts, such as MnCl2
and Mn(OAc)2 (entries 1–3). To our delight, [MnBr(CO)5],
À
À
was identified as competent catalyst, thus delivering the C H
allylation product 3aa in 76% yield upon hydrolytic work-up
(entry 4). Among a set of co-catalytic additives, carboxy-
lates[17] proved optimal (entries 4–10), with best results
accomplished when using the sterically hindered KO2CMes
(entry 10). Likewise, the dimeric complex [Mn2(CO)10] dis-
played a considerable catalytic efficacy, with NaOAc being
the co-catalytic additive of choice here (entries 11–15). In
addition to allyl carbonates, the manganese(I) catalysis
proved amenable to allyl phosphates and carbamates.[18]
À
T
he functionalization of otherwise inert C H bonds has been
recognized as a transformative platform in molecular synthe-
ses,[1] with enabling applications to inter alia material
sciences,[2] drug development,[3] and natural product syn-
thesis.[4] While the vast majority of C H functionalizations
À
was realized with precious 4d transition metals,[5] recent years
have witnessed the emergence of increasingly powerful earth-
abundant 3d transition-metal catalysts.[6] Particularly, organ-
ometallic[7] C H functionalizations by manganese catalysis
À
have gained significant momentum recently[8] with key
contributions from the groups of Kuninobu and Takai,[9]
Wang,[10] and Ackermann,[11] among others.[12] Despite these
undisputable advances,[8–12] the manganese(I) catalysis regime
has thus far largely been limited to hydroarylations by
[a]
À
Table 1: Optimization of C H allylation with the carbonate 2a.
À
À
À
additions of C H bonds onto C C or C Het multiple
bonds. Within our program on sustainable C H functional-
Entry
Catalyst
Additive
Yield [%][b]
À
izations with inexpensive 3d transition metals,[13] we have now
devised reaction conditions for unprecedented manganese(I)-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
–
NaOAc
NaOAc
NaOAc
NaOAc
–
NaOMe
KOAc
LiOAc
NaOPiv
KO2CMes
–
–
–
–
MnCl2
catalyzed intermolecular substitutive C H allylations[14]
À
Mn(OAc)2
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[Mn2(CO)10]
[Mn2(CO)10]
[Mn2(CO)10]
[Mn2(CO)10]
[Mn2(CO)10]
(Figure 1),[15] which we report on herein.
76
11
78
78
34
83
86
67
51
75
81
88
Notable aspects of our approach include a) efficient
manganese(I)-catalyzed C H allylations with differently
substituted electrophiles, b) excellent levels of positional
and diastereocontrol, c) versatile late-stage diversification,
and d) key mechanistic insights into the organometallic C H
À
À
manganesation manifold.
KO2CMes
NaOPiv
KOAc
NaOAc
[a] Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), [Mn] (10 mol%),
additive (20 mol%), 1,4-dioxane (1.0 mL), 14 h. [b] Yield of isolated
product. Mes=mesityl, Piv=pivaloyl, PMP=4-methoxyphenyl.
With the optimized catalytic system in hand, we explored
its versatility in the carboxylate-assisted manganese(I)-cata-
À
Figure 1. Substitutive C H allylations by manganese(I) catalysis.
À
lyzed C H allylation of imines 1 with differently substituted
[*] W. Liu, S. C. Richter, Y. Zhang, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
electrophiles 2 (Scheme 1). The chemoselectivity of the
broadly applicable manganese(I) catalyst was reflected by
fully tolerating valuable electrophilic functional groups, such
as amino, fluoro, chloro, bromo, iodo, and cyano substituents.
Tammannstraße 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
À
The positional selectivity of the C H allylation process was
largely governed by steric interactions (3ma and 3na), with
the exception of substrates featuring a meta substituent which
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201601560.
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Scheme 2. Manganese(I)-catalyzed C H allylation of heteroarenes 4.
[a] E/Z ratio given in parentheses. [b] [Mn2(CO)10] (10 mol%), NaOAc
(40 mol%), 1208C. [c] The diallylated product 5ia’ (20%) was also
isolated.
À
Scheme 1. Manganese(I)-catalyzed C H allylation of imines 1.
[a] 1208C. [b] Major regioisomer shown. Regioisomeric ratio given
within parentheses. [c] [Mn2(CO)10] (10 mol%), NaOAc (40 mol%).
[d] E/Z ratio in parentheses.
have a secondary directing-group capacity (3oa). The robust
nature of the manganese(I) catalysis enabled the efficient
À
C H allylation of the ketimines 1k–l as well as the challeng-
ing use of highly substituted allylic carbonates 2b–e with
excellent levels of diastereocontrol.[19] For all studied C H
À
allylations, potential double-bond isomerizations to the
thermodynamically more stable styrene derivatives were not
observed. These findings render the formation of manganese
hydride intermediates less likely, thus providing support for
À
an isohypsic, that is, redox-neutral, C H manganesation
mode of action.
À
The manganese(I)-catalyzed direct C H allylation by
À
À
C H/C O cleavage was not restricted to arenes 1. Indeed,
biologically relevant indole heterocycles 4[20] also underwent
À
the step-economical C H allylation with high catalytic
efficacy and ample substrate scope (Scheme 2). The chemo-
À
selectivity of the manganese(I)-catalyzed C H activation set
À
the stage for the high-yielding C H allylation of the indole 4 f
at the heteroaromatic moiety. Thus, the less stable formyl
À
C H bond remained untouched, again highlighting the
À
organometallic nature of the C H manganesation process.
Notably, the optimized catalytic system was not limited to
À
indole substrates, but also allowed the step-economical C H
allylation of the pyrrole 4g and thiophenes 4h,i.
In consideration of the unique features of the substitutive
Scheme 3. Key mechanistic findings.
À
manganese(I)-catalyzed C H allylation, we were interested
in delineating the mode of action of the catalyst. To this end,
we performed reactions with isotopically labeled substrates
(Scheme 3). Hence, we conducted competition experiments
and a manganese-catalyzed H–D exchange (Scheme 3a,b),
and both observations were in good agreement with a base-
intermolecular (Scheme 3c,d) studies with the isotopically
labeled substrates [D1]-1b and [D5]-1b, respectively. These
À
observations are indicative of a fast C H manganesation
process.
Further evidence for the organometallic activation mani-
assisted electrophilic substitution (BIES) type[21] of C H
fold was gathered by successful manganese(I)-catalyzed C H
À
À
activation.[18] In agreement with the latter finding, minor
kinetic isotope effects (KIEs) were determined by intra- and
functionalizations in the presence of stoichiometric amounts
of typical radical scavengers (Scheme 4).
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Scheme 4. Support for an organometallic C H activation mode of
action. BHT=2,6-di-tert-butyl-4-methylphenol, and TEMPO=2,2,6,6-
tetramethylpiperidine-N-oxyl radical.
Scheme 6. Proposed catalytic cycle.
À
Scheme 5. C H allylations with cyclometalated complex 8a.
Subsequently, we independently prepared the cyclometa-
À
lated complex 8a by stoichiometric C H manganesation
(Scheme 5a). Notably, the manganese(I) complex 8a proved
to be highly competent in both the catalytic (Scheme 5b) as
À
well as the stoichiometric (Scheme 5c) C H allylation pro-
tocol.
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Scheme 7. Diversification of C H activation products. Reagents and
conditions: a) 1. LiAlH4, Et2O, 238C, 12 h. 2. KOtBu, NMP, 1008C, 1 h.
b) AlMe3, [Ni(cod)2] (20 mol%), PCy3 (20 mol%), THF, 238C, 15 min.
c) 1. 9-BBN, THF, 238C, 24 h. 2. aq. H2O2, NaOH, THF, 238C, 2 h.
d) 1. LDA, TMSCl, THF, À788C, 2 h. 2. Grubbs-II (7.0 mol%), PhH,
658C, 1.5 h. e) 1. HONH2·HCl, NaOAc, MeOH/H2O, 1008C, 1 h.
2. cyanuric chloride (5.0 mol%), ZnCl2 (10 mol%), MeCN, 908C, 2 h.
cod=1,5-cyclooctadiene, LDA=lithiumdiisopropyl amide, NMP=
N-methylpyrrolidone, THF=tetrahydrofuran.
Our mechanistic studies are suggestive of a facile organ-
ometallic C H manganesation by isohypsic carboxylate
À
assistance, along with a subsequent migratory insertion of
the electrophile 2 (Scheme 6). Alternatively, the activation of
the allyl carbonate 2 could proceed by an oxidative addition.
Finally, b-hydride elimination is proposed to liberate the
desired product 3, while decarboxylation and salt metathesis
regenerate the catalytically active manganese(I) complex.
The unique transformative power of the manganese(I)-
Acknowledgments
À
catalyzed C H functionalization strategy was illustrated by
Generous support by the European Research Council under
the European Communityꢀs Seventh Framework Program
(FP7 2007–2013)/ERC Grant agreement no. 307535, and the
Chinese Scholarship Program (fellowship to W.L.) is grate-
fully acknowledged.
the late-stage diversification[22] of the ketones 3, thereby
offering efficient access to a synthetically useful ether (9),
indanol (10), alcohol (11), indanone (12), or anilide (13;
Scheme 7).
In summary, we have reported on the first organometallic
À
manganese(I)-catalyzed substitutive C H activation for the
step-economical allylation of arenes. The optimized
manganese(I) catalyst is highly functional-group tolerant
À
Keywords: C H activation · electrophiles · heteroarenes ·
manganese · reaction mechanisms
À
and allows C H functionalizations on synthetically useful
heteroarenes with ample scope. Detailed mechanistic studies
How to cite: Angew. Chem. Int. Ed. 2016, 55, 7747–7750
Angew. Chem. 2016, 128, 7878–7881
À
provide strong support for an organometallic C H manga-
nesation regime by redox-neutral carboxylate assistance,
which proved instrumental for applications to late-stage
diversification in a step-economical fashion.
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Received: February 13, 2016
Published online: April 20, 2016
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