Manganese-Catalyzed C?H Annulation of Ketimines with Allenes: Stereoselective Synthesis of 1-Aminoindanes

Article abstract of DOI:10.1002/adsc.201800465

A manganese-catalyzed C?H annulation of ketimines with poly-substituted ester-activated allenes toward the synthesis of 1-aminoindanes bearing two vicinal all-substituted carbon stereocenters and an exocyclic double bond was developed. The reaction featur

Full text of DOI:10.1002/adsc.201800465

Title: Manganese-Catalyzed C-H Annulation of Ketimines with Allenes:
Stereoselective Synthesis of 1-Aminoindanes
Authors: Chong Lei, Lijie Peng, and Ke Ding
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10.1002/adsc.201800465
Advanced Synthesis & Catalysis
UPDATE
Manganese-Catalyzed C-H Annulation of Ketimines with
Allenes: Stereoselective Synthesis of 1-Aminoindanes
Chong Lei, Lijie Peng,* Ke Ding*
School of Pharmacy, Jinan University, Guangzhou 510632, China;
Guangzhou City Key Laboratory of Precision Chemical Drug Development, Guangzhou 510632, China;
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development,
Ministry of Education (MOE) of People’s Republic of China, Guangzhou 510632, China
E-mail: elva_0916@jnu.edu.cn, dingke@jnu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
catalyzed C-H activation reaction led to the
ketimines with poly-substituted ester-activated allenes hydroarylation prodoucts, whereas the employment
Abstract. A manganese-catalyzed C-H annulation of
toward the synthesis of 1-aminoindanes bearing two vicinal
all-substituted carbon stereocenters and an exocyclic
double bond was developed. The reaction features high
diastereoselectivity, high E/Z selectivity, 100% atom-
economy, broad substrate scope and good functional group
tolerance.
of poly-substituted allenyl esters in the same reaction
gave cyclized products via C−H
a
alkenylation/Smiles rearrangement cascade, featuring
a migration of the heterocyclic directing group
(Scheme 1c). The latter reaction, together the
reported Mn(I)-catalyzed C-H addition reactions to
C-heteroatom
unsaturated
bonds
(including
aldehydes,[14] ketones,[14a] imines,[15] isocyanates,[16]
and nitriles[14b]) and oxiranes,[17] highlight the strong
nucleophilicity of C-Mn bond. Herein, we report our
realization of a Mn(I)-catalyzed [3+2] cyclization of
aromatic ketimines with allenyl esters by taking
advantage of the high nuelcophilicity of C-Mn bond
and the unique regioselectivity of the allenes (Scheme
1d). The reaction provides a simple access to 1-
aminoindanes[18] bearing two vicinal all-substituted
carbon stereocenters and an exocyclic double bond
with high diastereoselectivity and E/Z selectivity. It
should be noted the cycloaddition of aromatic
ketimines with allene was known with Re(I)[19] or
Rh(I)[20] catalyst. The scope of these reactions was
limited to mono-alkyl-substituted allenes.
Keywords: allene; C-H activation; indane; ketimine;
manganese
The recent years have witnessed great advances in
metal-catalyzed C-H activation reactions, which
enable an efficient assembly of complex molecules
from simple starting materials in an atom- and step-
economic fashion.[1] So far, however, these catalytic
reactions have been arguably over-reliant on precious
metals such as palladium, rhodium, iridium, platinum,
and ruthenium.[1] For the sake of sustainability,
recently, significant efforts have been paid on the
employment of earth abundant metals in lieu of those
precious metals.[2] In this regard, the manganese-
based catalysts show great promise due to their low
toxicity, low cost and sometimes, unique working
modes.[3] On the other hand, the multi-fold
reactivities of allene[4] in metal catalysis have
rendered it an intriguing synthon in C-H activation
reactions, leading to diverse alkenylation,[5]
allylation,[6] allenylation[7] or cyclization[8] products.
For instance, under the catalysis of manganese, Wang
reported an atom-economic aromatic C-H allylation
reaction by using 1,1-disubstitued allenes as coupling
partner (Scheme 1a).[9] When N-aryl ketimines were
used as substrates, an interesting Mn(I)/Ag(I)-cascade
catalysis allowed an C-H allylation/Povarov reaction
in one-pot to form the complex polycyclic products
(Scheme 1a).[10] Glorius recently disclosed an elegant
Mn(I)/BPh3-cocatalyzed direct C-H propargylation
using bromoallenes (Scheme 1b).[11] The electron-
withdrawing group-activated allenes showed unique
reactivity and different regioselectivity. As such,
Rueping[12] and Wang[13] independently found that the
use of 1,3-disubstituted allenyl esters in Mn(I)-
Scheme 1. Manganese-catalyzed C-H activation with
allenes.
1
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10.1002/adsc.201800465
Advanced Synthesis & Catalysis
At the outset of our studies, we tested the reaction
Table 2. Mn(I)-catalyzed C-H annulation ketimines with
of aromatic ketamine 1a with 1,1,3-trisubstituted
allenyl ester 2a (1.5 equiv.) with MnBr(CO)5 (10
mol %) as catalyst in 1,4-dioxane at 100 °C (Table 1).
Interestingly, an annulated 2,3-dihydro-1H-indene
product 3aa was furnished in 23% yield as a single
stereoisomer in the presence of NaOAc (40 mol %) as
additive (entry 1). The cis configuration and E
geometry of the product was unambiguously
identified by X-ray crystallography analysis.[21] No
reaction took place without NaOAc, indicating the
important role of base for C-H activation (entry 2).
While KOAc showed comparable reactivity (entry 3),
HOAc was ineffective for the reaction (entry 4). The
screening of solvents demonstrated that the originally
used 1,4-dioxane was optimal (entries 5-7).
Increasing the loading of 2a to 2.0 equivalents led to
a better yield of 39% (entry 8). The yield could be
further improved to 68% by elevation of the
temperature to 120 °C (entry 9). A good yield of 82%
was obtained by doubling the loading of manganese
catalyst (entry 10).
allensa
Table 1. Optimization of Mn(I)-catalyzed C-H annulation
reactiona
entr
y
2a
(eq)
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
2.0
2.0
Mn
(mol %)
10
T
Yield
[%]
23%
0
additive
Solvent
[oC]
100
100
100
100
100
100
100
100
120
120
1
NaOAc
-
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DCE
2
10
3
10
KOAc
HOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
22%
0
4
10
5
10
3%
0
6
10
toluene
7
10
CH3CN
12%
39%
68%
82%
8
10
1,4-dioxane
1,4-dioxane
1,4-dioxane
9
10
ageneral conditions:
MnBr(CO)5 (0.2 equiv.), NaOAc (0.4 equiv.), 1,4-dioxane
1 (0.2 mmol), 2 (0.4 mmol),
10
20
a1a (0.2 mmol), 2a, cat. MnBr(CO)5, additive (0.4 equiv.),
solvent (1.0 mL), T, 21 h, isolated yield.
b
(1.0 mL), 120 °C, 21 h, isolated yield. NaOAc (1 equiv.)
was used, 130 °C. c48 h. dMnBr(CO)5 (0.1 equiv.), 100 °C.
With the optimized catalytic system in hand, we
firstly explored the generality of the reaction by
reacting 2a with a broad range of ketimines 1 (Table
2). Ketimines bearing either electron- donating (3ba
and 3ca) or withdrawing groups (3da and 3ea) on the
N-aryl ring were applicable for cyclization, giving the
corresponding products in good to excellent yields.
The para-halogen functional groups (3fa-3ia)
substituted on the benzene ring of C-H activation
were all well tolerated. Stronger electron-
withdrawing groups such as cyano (3ja) and ester
(3ka), however, gave significantly lower yields.
Interestingly, the electron-donating groups did deliver
the cyclization products (3la-3na) as expected. A
minor amount of amino-eliminated products (4la-4na)
were also observed, which could be rationalized by
the stabilization of benzylic cation by para electron-
donating groups (see Scheme 3b). The meta-Cl
substitution led to two regioisomers (3oa:3oa’ =
2.6:1), with cyclization occurring preferationally at
the sterically less crowded position. The 3,5-
dimethoxy-substituted substrate gave the desired
product (3pa) without difficulty, although both of the
ortho C-H bonds were sterically shielded. In addition
to alkyl aryl ketimines (3aa-3qa), the diaryl ketimine
was also a suitable substrate for the reaction (3ra).
However, the aldimine only gave trace amount of the
corresponding product (3sa). The scope on the allene
part was also examined. Besides the iso-propyl group,
2
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10.1002/adsc.201800465
Advanced Synthesis & Catalysis
other aliphatic substituents at C3 position of allene,
such as ethyl (3ab) and benzyl (3ac), were also well
tolerated, but a phenyl substituent (3ad) resulted in
no reaction. With an additional methyl group at the
C3 position, however, the reactivity was completely
shut down probably for steric reasons (3ae). A
decreased reactivity was also observed with a more
sterically demanding C1-benzyl substituent (3af).
The 1,3-disubstituted allenyl esters were good
substrates as well, delivering the cis-products in good
yields with 10 mol % catalyst loading at 100 °C (3ag,
3bg, 3dg, 3ah).[21] The use of terminal allene did give
the desired product, but in low yield (3ai). The
exocyclic double bond-migrated product 3ai’ was
also found.
To showcase the synthetic utility of the obtained
products, we explored their further diversifications
(Scheme 2). The attempt to deprotect the 4-
methoxyphenyl group on nitrogen with DDQ resulted
in an elimination reaction, giving the corresponding
dienes in good yields (Scheme 2a and 2b). The
reduction of the ester group in 3bg with DIBAL-H
gave a free alcohol 5 in 64% yield (Scheme 2c).
Finally, the hydrogenation of 3bg with the Pd/H2
protocol delivered the reduced product 6 bearing
stereoselectity in this step. Specifically, the C-Mn
bond in B attacks the more electron-deficient central
carbon of allene from the less sterically hindered face,
thereby forming the observed E-type exocyclic
double bond in the final product. The profound
nucleophilicity of the formed C-Mn bond would then
trigger an intramolecular nucleophilic addition to the
imine moiety, wherein the steric repulsion between
the ester and R groups causes a trans orientation of
these two groups in the final cyclized product. Upon
protonation with HOAc, the desired cyclization
product 3 is formed and the active catalyst is
regenerated. For substrates (3la-3ma) bearing
electron-donating substituent at the para position, the
ligation of manganese with the amine group in the
initially formed products will trigger an elimination
reaction to form the second exocyclic double bond
(Scheme 3b).[22]
three consecutive chiral centers as
distereroisomer (Scheme 2d).
a
single
Scheme 3. A proposed Mechanism.
In summary,
a
manganese-catalyzed C-H
activation/annulation reaction with ester-activated
allenes was developed. The protocol offers a simple
and efficient method toward the synthesis of 2,3-
dihydro-1H-indenes bearing two vicinal all-
substituted carbon stereocenters and an exocyclic
double bond with high diastereoselectivity and E/Z
selectivity. Good functional group tolerance and
100% atom-economy was observed. A possible
reaction mechanism was proposed to account for the
reaction outcomes. Synthetic transformations of the
products were conducted, showcasing their utility.
We hope this chemistry will find applications in 1-
aminoindane derivative synthesis.
Scheme 2. Derivatization of the products.
The following mechanistic scenario was proposed
to rationalize the observed reaction outcome (Scheme
3a). Initially, the ligation of manganese to the
nitrogen atom of imine promotes a C-H activation to
form a metallacycle B. This process is believed to be
assisted by acetate anion present in the reaction
mixture. Thereafter, the allene coordination and a
subsequent migratory insertion lead to the formation
of complex D. The unique electronic and steric
properties of allene dictate the observed regio- and
Experimental Section
General Procedure for manganese-catalyzed C-H
annulation of ketimines with allenes: Ketimine (0.2 mmol),
MnBr(CO)5 (11 mg, 20 mol%), NaOAc (6.6 mg, 40
mol %), 1,4-dioxane (1.0 mL) and allene (0.4 mmol) were
placed in a 15 mL Schlenk tube under N2. The mixture was
stirred at 120 °C for 21 h. After cooled to ambient
temperature, the reaction mixture was diluted with EtOAc
(8 mL). Then H2O (4 mL) was added, and the resulting
mixture was extracted with EtOAc (3×10 mL). The
3
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10.1002/adsc.201800465
Advanced Synthesis & Catalysis
combined organic layer was washed with brine (10 mL),
and then dried over Na2SO4. After concentration under
reduced pressure, purification by column chromatography
on silica gel afforded the desired products 3.
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Acknowledgements
Financial support by the National Natural Science Foundation of
China (81502907) is gratefully acknowledged.
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10.1002/adsc.201800465
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201800465
Advanced Synthesis & Catalysis
UPDATE
Manganese-Catalyzed C-H Annulation of
Ketimines with Allenes: Stereoselective Synthesis
of 1-Aminoindanes
Adv. Synth. Catal. Year, Volume, Page – Page
Chong Lei, Lijie Peng,* Ke Ding*
6
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