Manganese-catalyzed synthesis of cis-β-amino acid esters through organometallic C-H activation of ketimines

Article abstract of DOI:10.1002/anie.201411808

Manganese-catalyzed C-H functionalization reactions of ketimines set the stage for the expedient synthesis of cis-β-amino acid esters through site- and regioselective alkene annulations. The organometallic C-H activation occurred efficiently with high fun

Full text of DOI:10.1002/anie.201411808

Angewandte
Chemie
DOI: 10.1002/anie.201411808
ꢀ
C H Activation
Manganese-Catalyzed Synthesis of cis-b-Amino Acid Esters through
ꢀ
Organometallic C H Activation of Ketimines**
Weiping Liu, Daniel Zell, Michael John, and Lutz Ackermann*
ꢀ
Abstract: Manganese-catalyzed C H functionalization reac-
tions of ketimines set the stage for the expedient synthesis of cis-
b-amino acid esters through site- and regioselective alkene
alkene annulation process as well as a versatile cascade
transformation with unusual cis diastereoselectivity.
At the outset of our studies, we tested various reaction
ꢀ
ꢀ
annulations. The organometallic C H activation occurred
conditions for the envisioned C H functionalization of
ketimine 1a (Table 1). Interestingly, catalytic amounts of
[Mn2(CO)10] directly furnished the cis-b-amino acid ester 3aa
efficiently with high functional group tolerance, delivering
densely functionalized b-amino acid derivatives with ample
scope.
[a]
ꢀ
Table 1: Optimization of manganese-catalyzed C H activation.
A
s b-amino acids are key structural motifs of non-natural
b-peptides and versatile intermediates in organic synthesis,[1]
methods for the efficient preparation of substituted deriva-
tives continue to be in high demand. In recent years, catalyzed
ꢀ
C H activation reactions have emerged as an increasingly
viable method for improving the step economy of organic
syntheses.[2] During the past decade, progress has largely
relied on complexes of expensive 4d or 5d noble metals, such
as palladium, iridium, or rhodium. In stark contrast, the
Entry
Catalyst
Solvent
T [8C]
Yield [%]
1
2
3
4
5
6
7
8
9
[Mn2(CO)10]
[Mn2(CO)10]
[Mn2(CO)10]
[MnBr(CO)5]
MnCl2
[Mn2(CO)10]
[Mn2(CO)10]
–
toluene
toluene
toluene
toluene
DCE
DCE
1,4-dioxane
DCE
100
140
120
120
120
120
120
120
120
120
59
45
87
11[b]
potential of naturally abundant 3d metal complexes as
catalysts for C H functionalizations is largely untapped.
[b]
[3]
–
ꢀ
94
77
–
Despite of recent advances with nickel, cobalt, and iron
catalysts,[3] manganese complexes are still scarcely employed
[4]
ꢀ
as catalysts in organometallic C H activations, although
[Co2(CO)8]
[Ni(cod)2]
DCE
DCE
<3
–
[b]
manganese is the third most abundant transition metal after
iron and titanium. Thus far, manganese catalysis has been
dominated by outer-sphere radical oxygenations or halogen-
ations by high-valent manganese species.[5–7] As a conse-
10
[a] Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), catalyst
(5.0 mol%), solvent (1.0 mL), 1208C, 18 h, yields of isolated products
given. [b] Catalyst (10 mol%). cod=cyclooctadiene, DCE=1,2-
dichloroethane, PMP=para-methoxyphenyl.
ꢀ
quence, only sporadic examples of organometallic C H
activation reactions with inexpensive manganese catalysts
have been described, with pioneering reports by the groups of
Kuninobu and Takai,[8] as well as elegant recent contributions
from Wang and co-workers.[9] Within our program on
sustainable C H functionalization processes,
developed a novel manganese-catalyzed direct synthesis of
b-amino acid derivatives from easily available imines by
organometallic C H activation. Notable features of our
approach include an excellent functional-group tolerance,
an unprecedented manganese-catalyzed C H activation/
(entries 1–3), and additional amines or metal acetate addi-
tives were not required for an efficient alkene annulation
process. The unusual cis configuration of product 3aa was
unambiguously established by detailed two-dimensional
NMR spectroscopy.[11] Subsequent optimization studies high-
lighted the unique activity of the [Mn2(CO)10] catalyst
(entries 3–5) with optimal results being obtained in toluene
or DCE as the solvent (entries 3, 6, and 7). Intriguingly,
representative cobalt or nickel complexes did not deliver the
desired product 3aa, and unreacted starting materials were
reisolated (entries 9 and 10). In stark contrast to a trans-
formation of ketones into indenes that is catalyzed by the
expensive 5d rhenium complex [ReBr(CO)3(THF)2] at 150–
1808C,[12] the new manganese-catalyzed process occurs under
considerably milder[13] reaction conditions, thereby allowing
for the general assembly of the sensitive b-amino acid motif.
With the optimized catalytic system in hand, we explored
[10]
ꢀ
we have
ꢀ
ꢀ
[*] M. Sc. W. Liu, M. Sc. D. Zell, Dr. M. John, Prof. Dr. L. Ackermann
Institut fꢀr Organische und Biomolekulare Chemie
Georg-August-Universitꢁt Gçttingen
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
[**] Generous support by the European Research Council under the
European Community’s Seventh Framework Program (FP7 2007–
2013/ERC Grant 307535) and the Chinese Scholarship Program
(fellowship to W.L.) is gratefully acknowledged.
ꢀ
its scope for the manganese-catalyzed C H functionalization
of imine 1a (Scheme 1). A variety of alkenes 2a–d proved to
be suitable substrates, affording the desired cis-b-amino esters
3 with excellent regio- and diastereoselectivity. Notably, the
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201411808.
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Scheme 1. Manganese-catalyzed C H functionalization with alkenes 2.
[a] In toluene. [b] With [Mn2(CO)10] (10 mol%).
manganese-catalyzed transformation was not limited to
terminal alkenes 2, but the considerably more challenging
internal alkene (E)-2e was also efficiently converted. Here,
the desired product 3ae was selectively formed with excellent
control over all three contiguous stereocenters. In contrast,
a (Z)-crotonate, a cinnamic acid ester, and a methacrylate
gave only traces of the desired products. The robustness of the
manganese-catalyzed alkene annulation was reflected by
a reaction performed on a 5 mmol scale that gave a compa-
rably high yield.
ꢀ
Scheme 2. Manganese-catalyzed C H functionalization with imines 1.
[a] In toluene. [b] With [Mn2(CO)10] (10 mol%). [c] Major regioisomer
shown; regioisomeric ratios in parentheses.
A broad range of substituted imines 1 were suitable
substrates for the manganese-catalyzed transformation
(Scheme 2). The catalytic system tolerates a wide range of
functional groups, including cyclopropyl, ester, fluoro, chloro,
or bromo substituents, which should prove instrumental for
further derivatizations of compounds 3. Generally, both alkyl
and aryl ketimines 1 underwent the alkene annulation with
comparable levels of efficacy, whereas an aldimine (not
shown) furnished only traces of the corresponding product.
Particularly, the chemoselective conversion of ethyl-substi-
tuted ketimine 1g at the arene ring is a strong testament to an
ꢀ
organometallic C H activation (see below) as radical trans-
ꢀ
formations would occur at the weaker Csp3 H bonds. Intra-
molecular competition experiments of meta-substituted
arenes 1n and 1o were controlled by steric interactions,
leading to the predominant formation of regioisomers 3na
and 3oa, respectively. In contrast, the meta-dioxolane sub-
ꢀ
stitution pattern of arene 1p led to site-selective C H
functionalization at the C2 position,[14] which can be ration-
alized in terms of a secondary directing group effect.
Considering the unique chemo- and stereoselectivity of
ꢀ
the new manganese-catalyzed C H activation, we became
intrigued by delineating its mode of action. To this end, we
performed intra- and intermolecular competition experi-
ments with arenes 1 bearing different substituents, which
showed that the electronic nature of the substituent exerts
only a minor influence on the reactivity (Scheme 3).
Scheme 3. Intra- and intermolecular competition experiments. For 3oa
and 3ra, the major regioisomer is shown, and the regioisomeric ratios
are given in parentheses.
H/D exchange reaction, as was corroborated by the isolation
of the partially labeled acetophenone [D]n-4a after acidic
work-up, along with the labeled product [D]n-3aa (Sche-
ꢀ
C H functionalization reactions conducted in the pres-
ence of D2O as the co-solvent were suggestive of a reversible
2
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Scheme 6. Proposed mechanism.
ꢀ
tory insertion of the latter into the Mn C bond. Through the
assistance of the weakly coordinating[16,17] alkyloxycarbonyl
group manganese enolate 6 is generated, which thereafter
undergoes an intramolecular nucleophilic attack at the carbon
atom of the imine moiety, thereby affording complex 7. The
chelation of the imino group and the ester enolate motif by
the manganese ion is suggested to facilitate this key cycliza-
tion, which in turn leads to the exclusive cis diastereoselec-
tivity. Finally, proto-demetalation of amide 7 affords the
desired cis-b-amino ester 3 and regenerates the catalytically
active manganese complex.
Scheme 4. H/D exchange experiment and determination of KIEs.
me 4a). The intramolecular kinetic isotope effect (KIE) of
ꢀ
the manganese-catalyzed C H functionalization was found to
be kH/kD ꢁ 2.4 (Scheme 4b). Moreover, the intermolecular
KIE of kH/kD ꢁ 2.7 was investigated by means of the initial
rates for independent reactions of substrates 1b and [D]5-1b
(Scheme 4c). These experimental results are indicative of
ꢀ
a kinetically relevant C H metalation step.
It is noteworthy that the working mode of the organome-
tallic catalyst (see below) was clearly shown by successful
To illustrate the synthetic utility of the obtained b-amino
esters 3 we explored their further diversification (Scheme 7).
Thus, compound 3aa was selectively converted into b-amino
ester 8, which displays the free amino group (Scheme 7a). The
ꢀ
manganese-catalyzed C H functionalizations under an
atmosphere of air or in the presence of the radical scavenger
ꢀ
ꢀ
TEMPO (Scheme 5). The successful C H activation of
power of the manganese-catalyzed C H activation approach
ketimine 1a in ambient air furthermore highlights the
robust nature of the operationally simple manganese-cata-
lyzed transformation.
was finally demonstrated by the step-economical synthesis of
the useful building block 9 (Scheme 7b) as well as the
versatile b-lactam scaffold of compound 10 (Scheme 7c).
ꢀ
Scheme 5. C H functionalization in the presence of radical scaveng-
ers.
Based on these mechanistic studies, we propose a plausible
catalytic cycle for the formation of b-amino esters 3
ꢀ
(Scheme 6). The initial C H metalation of ketimine 1 is
Scheme 7. Diversification of product 3aa. Reagents and conditions:
a) CAN (2.5 equiv), CH3CN/H2O (1:1), 238C, 3 h. b) Toluene, 1608C,
14 h. c) LiHMDS (1.5 equiv), THF, 08C!238C, 10 h. CAN=ceric
ammonium nitrate, LiHMDS=lithium bis(trimethylsilyl)amide.
proposed to proceed by base assistance[15] and leads to
intermediate 5. Subsequently, the metallacycle 5 carboman-
ganates the a,b-unsaturated ester 2 by regioselective migra-
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Received: December 8, 2014
Revised: December 23, 2014
Published online: && &&, &&&&
ꢀ
Keywords: amino acids · C H activation · manganese ·
ꢀ
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Communications
ꢀ
C H Activation
W. Liu, D. Zell, M. John,
L. Ackermann*
&&&& — &&&&
Manganese-Catalyzed Synthesis of cis-b-
Amino Acid Esters through
ꢀ
Organometallic C H Activation of
Ketimines
An operationally simple manganese-cat-
mation was studied, and its utility proven
by further modifications of the syntheti-
cally useful b-amino acid esters into
attractive compounds.
ꢀ
alyzed C H functionalization of keti-
mines provides access to b-amino acid
esters. The mechanism of this transfor-
6
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