Iron-Catalyzed Aerobic Dehydrogenative Kinetic Resolution of Cyclic Secondary Amines

Article abstract of DOI:10.1021/jacs.9b00615

A nonenzymatic iron-catalyzed dehydrogenative kinetic resolution of cyclic secondary amines using air as an oxidant has been reported. The economical and practical method is applicable to a series of cyclic benzylic amines, including 5,6-dihydrophenanthridines and 1,2-dihydroquinolines, with diverse functional groups at the α position in high yields with excellent enantioselectivities. The direct dehydrogenative kinetic resolution of advanced intermediates of bioactive molecules that are difficult to access using existing catalytic asymmetric synthetic strategy was also demonstrated.

Full text of DOI:10.1021/jacs.9b00615

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Article
Iron-Catalyzed Aerobic Dehydrogenative
Kinetic Resolution of Cyclic Secondary Amines
Ran Lu, Liya Cao, Honghao Guan, and Lei Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00615 • Publication Date (Web): 27 Mar 2019
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Iron-Catalyzed Aerobic Dehydrogenative Kinetic Resolution of Cy-
clic Secondary Amines
Ran Lu,†,§ Liya Cao,†,§ Honghao Guan,‡,§ Lei Liu*,†,‡
†School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China
‡School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China
Supporting Information Placeholder
5,6-Dihydrophenanthridines with diverse α substituent patterns
ABSTRACT: A nonenzymatic iron-catalyzed dehydrogenative
are present in a number of bioactive molecules possessing a wide
range of pharmacological activities.14 However, surprising few
catalytic enantioselective methods to access enantiopure com-
pounds have been reported, and each method is typically suitable
A) KR via N-acylation approach (Fu, Hou, Bode, Kozlowski)
kinetic resolution of cyclic secondary amines using air as an
oxidant has been reported. The economical and practical method
is applicable to a series of cyclic benzylic amines, including 5,6-
dihydrophenanthridines and 1,2-dihydroquinolines, with diverse
functional groups at the α position in high yields with excellent
enantioselectivities. The direct dehydrogenative kinetic resolution
of advanced intermediates of bioactive molecules that are difficult
to access using existing catalytic asymmetric synthetic strategy
was also demonstrated.
n
n
n
cat*, R'COX
FG
FG
FG
+
R
R
R
N
N
N
H
H
COR'
H
B) Organocatalytic ODKR via transfer hydrogenation to imine (Akiyama)
cat. chiral
phosphoric acid
R
H
R
R
+
N
N
N
H
H
H
Ar
Ar
INTRODUCTION
N
HN
Ph
Catalytic nonenzymatic kinetic resolution (KR) of racemic start-
ing materials represents a powerful and practical alternative to
prepare valuable optically pure targets, especially in cases where
other methods are not possible or provide insufficient enantiocon-
trol.1 Enantiomerically pure α-substituted cyclic amines are key
constituents of bioactive natural products and synthetic pharma-
ceuticals. Present nonenzymatic KR of cyclic amines dominantly
focused on enantioselective N-acylation strategy (Figure 1A).2-5
Ph
H
C) Iron-catalyzed ODKR using air as oxidant (This work)
Fe cat*, air
additive
+
N
R
N
R
N
R
H
H
H
challenges: NH moiety prone to oxidation and deactivation of chiral metal catalyst
Dehydrogenation of secondary amines to imines is one of the
most common transformations in chemistry.6 Transition-metal
catalyzed dehydrogenative KR of secondary alcohols to furnish
prochiral ketones has been well studied.7 In sharp contrast, pure
chemically catalytic dehydrogenative KR of secondary amines
remains scarce, principally due to two essential features of the NH
moiety including the susceptibleness to oxidation and potential
deactivation of chiral transition metal catalysts.8 To avoid such
two issues, Akiyama developed a delicate chiral phosphoric acid
catalyzed dehydrogenative KR of cyclic secondary amines based
on transfer hydrogenation to imines (Figure 1B).9 However, no
example of metal catalyzed dehydrogenative KR of secondary
amines has been disclosed to date. On the other hand, the devel-
opment of eco-friendly oxidative transformations using earth-
abundant metal catalyst is a broad goal in chemistry.10 In this
context, molecular oxygen in air is the most ideal oxidant, and
iron is the second most abundant metal in the earth’s crust.11,12
Seminal work from the Katsuki group demonstrated the possibili-
ty of iron(salan)-catalyzed asymmetric aerobic oxidation.13 Herein
we communicate the first nonenzymatic iron-catalyzed dehydro-
genative KR of cyclic amines using air as an oxidant (Figure 1C).
Figure 1.Overview of KR of cyclic secondary amines
for a specific substituent pattern of functionalities in the α-
position as well as the heterocyclic skeleton.15 Therefore, dehy-
drogenative KR of 5,6-dihydrophenanthridine 1a under air at
ambient temperature was selected as the model reaction for the
search of chiral iron catalyst system (Table 1). No reaction was
observed when Fe(salen) (R,R)-C1 was used as the catalyst (entry
1). Delightedly, Fe(salan) (R,R)-C2 showed oxidation catalysis
reactivity, though no enantioselectivity was obtained (entry 2).16
Binuclear iron complex appeared to be a better catalyst than the
parent monomer, and Fe(salan) (R,R)-C3 catalyzed dehydrogena-
tive KR reaction proceeded providing recovered (R)-1a with 10%
ee at the conversion of 30% (entry 3). An extensive investigation
of additive effect revealed that catalytic amount of electron-rich
phenol was beneficial for improving the reaction efficiency, and
4-methoxy-1-naphthol A5 was found to be optimal (entries 4-9).
Further fine-tuning the binuclear iron complex identified (R,R)-
C9 bearing a diphenylethylenediamine unit to be the superior
catalyst, furnishing recovered (R)-1a in 46% yield with 98% ee
(entries 10-16). Using pure oxygen as the terminal oxidant pro-
vided a comparable result to that of the reaction with air (entry
17).
RESULTS AND DISCUSSION
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Table 1. Reaction condition optimizationa
ring of 5,6-dihydrophenanthridine was well tolerated, and 1a-1h
were recovered in high efficiency with 97%-99% ee. Substrates
1i-1n bearing a variety of electronically varied aryl groups at the
α position with different substituent patterns participated in the
dehydrogenative KR process, providing the remaining amines
with high efficiency and excellent selectivity factors. Substrates
bearing α-heteroaryl substituents, such as 2-furanyl 1o and 2-
thiophenyl 1p, were well compatible with the dehydrogenative
KR. Other common functionalities, including alkyl (1q-1s), ben-
zyl (1t), and phenethyl (1u), at the α position were also well tole-
rated, thus demonstrating the capacity of dehydrogenative KR
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conv.
ee
entry
catalyst
additive
krel
(%)b
< 5
16
30
32
44
53
55
52
53
51
52
56
55
46
54
53
55
(%)c
1
2
–
n.d.
0
n.d.
n.d.
1.8
C1
C2
C3
C3
C3
C3
C3
C3
C3
C4
C5
C6
C7
C8
C9
C10
C9
–
Scheme
1.
Dehydrogenative
KR
of
5,6-
dihydrophenanthridinesa
3
–
10
9
4
1.6
A1
A2
A3
A4
A5
A6
A5
A5
A5
A5
A5
A5
A5
A5
R2
C9 (2.5 mol%)
R2
R2
A5 (15 mol%)
R1
R1
R1
+
5
15
26
31
40
32
60
73
< 5
82
30
98
0
1.7
air, toluene, rt
R3
R3
N
H
R3
N
N
H
H
6
2.0
2
rac-1
(R)-1
7
2.2
variant of 5,6-dihydrophenanthridine (Ar = 4-MeOC6H4)
OMe
8
3.1
OMe
9
2.4
N
Ar
10
11
12
13
14
15
16
17d
6.7
N
Ar
N
Ar
H
H
H
1c, 28 h, 45%
1a, 24 h, 46%
1b, 30 h, 47%
11.0
n.d.
12.6
2.7
99% ee, krel = 49.0
98% ee, krel = 50.2
99% ee, krel = 80.1
Me
MeO
N
Ar
MeO
N
Ar
N
H
Ar
H
H
50.2
n.d.
49.0
1f, 30 h, 45%
99% ee, krel = 49.0
1d, 29 h, 46%
99% ee, krel = 60.9
1e, 32 h, 47%
97% ee, krel = 55.4
99
Me
Cl
N
Ar
N
H
Ar
H
H
H
N
N
O
N
O
N
O
1h, 20 h, 48%
98% ee, krel = 91.3
1g, 26 h, 44%
99% ee, krel = 40.8
Fe
Fe
tBu
O
tBu
tBu
tBu
Cl
Cl
tBu
tBu
tBu
tBu
C1
C2
Ph
H
Ph
N
H
H
H
N
O
N
N
O
Fe
Fe
R1
R1
O
O
R2
R2
Br
Br
H
2
2
HO
HO
C9
C3: R1 = R2 = tBu
C4: R1 = tBu, R2 = Br
Ph
H
Ph
N
: R1 = R2 = Br
: R1 = Br, R2 = H
C5
C6
N
O
C7: R1 = H, R2 = Br
Fe
C8: R1 = H, R2 = OMe
O
Cl
C10
Br
Br
aReaction condition: rac-1a (0.1 mmol), (R,R)-catalyst (2.5 mol%),
and additive (10mol%) in toluene (0.5 mL) under air at rt for 24-
36 h, unless otherwise noted. bConversion was calculated from the
isolated yield of recovered (R)-1a. cDetermined by HPLC analysis
on a chiral stationary phase. dPure oxygen used instead of air.
Under the optimized conditions, the scope of iron-catalyzed
aerobic dehydrogenative KR of 5,6-dihydrophenanthridines was
then explored (Scheme 1). In general, a substituent on either arene
aYield of recovered 1.
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strategy for asymmetric access to diversely functionalized mole-
Scheme 3. Synthetic applications
cules.17 Notably, previously reported catalytic asymmetric me-
thods are limited to either α-aryl or α-alkyl substituted 5,6-
dihydrophenanthridines.15
8
The dehydrogenative KR technology was next applied to α-
substituted 1,2-dihydroquinolines not only owing to their fascinat-
ing biological activities, but also because of the capability of the
alkene moiety as a reactive handle for rapid preparation of struc-
turally and stereochemically diverse tetrahydroquinolines
(Scheme 2).18 Delightedly, when Fe(salen) C5 was used as the
catalyst, the dehydrogenative KR of 1,2-dihydroquinoline (rac-3a)
proceeded to afford (S)-3a in 46% yield with 96% ee.19 1,2-
Dihydroquinolines bearing electron-withdrawing or -donating
groups at the 5-, 6-, and 7-positions were suitable substrates, fur-
nishing respective enantiopure 3b-3h in high yields with excellent
enantioselectivities. Substrate 3i bearing a substituent at the 4-
position was also compatible with the dehydrogenative KR
process, providing (S)-3i in 45% yield with 90% ee. The dehydro-
genative KR reactions of 1,2-dihydroquinolines bearing electron-
neutral and -deficient aryl groups at the α position proceeded
smoothly, furnishing respective 3j and 3k with good selectivity
factors. Substrates 3l bearing an α-heteroaryl substituent and 3m
with an α-alkyl moiety were also well tolerated. Notably, the KR
process exhibited excellent chemoselectivity, and potential alkene
epoxidation process was not detected for all the studied 1,2-
dihydroquinoline substrates.
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activity (Scheme 3).14b Under the standard conditions, aerobic
dehydrogenative KR of rac-6 proceeded, and (R)-6 was recovered
in 49% yield with 72% ee (Krel
=
11.6). 5,6-
Dihydrophenanthridine 7 was proved to be a potent in vivo bra-
dykinin B1 receptor antagonist.14c When (S,S)-C7 was used as
catalyst, rac-8 bearing an ester moiety underwent dehydrogenative
KR process, furnishing (S)-8 in 46% yield with 99% ee (Krel
=
60.9).
Mechanistic Studies. Control experiments were conducted to
get a preliminary understanding of Fe(salan)-catalyzed aerobic
dehydrogenative KR of cyclic secondary amines. No reaction was
observed under the standard conditions in the absence of either
Fe(salan) complex or molecular oxygen. The reaction without 1-
naphthol additive haltered at a 40% conversion, and (R)-1a was
recovered with 35% ee, suggesting that the additive is crucial to
the enantiocontrol as well as catalysis reactivity (eq 1, Scheme 4).
While the monomeric Fe(salan) C10 catalyzed the dehydrogena-
tion process, no enantiocontrol was achieved, suggesting that the
monomer might not be the catalyst species in our dehydrogenative
KR of amines (entry 16, Table 1). Treatment of complex C9 with
Scheme 2. Dehydrogenative KR of 1,2-dihydroquinolinesa
Scheme 4. Control experiments
aYield of recovered 3.
We envisioned that one of the most remarkable demonstration
of its utility is direct dehydrogenative KR of advanced interme-
diates of bioactive molecules that would be difficult to access
using existing catalytic asymmetric synthetic strategy. 5,6-
Dihydrophenanthridine 5 was identified as a potent and selective
estrogen receptor (ER) ligand that inhibits NF-κB transcriptional
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1-naphthol provided a new species C11, which was determined to
Scheme 5. A plausible mechanistic pathway
be a μ-(1-naphthoxo)-μ-hydroxo iron dimer by X-ray structure
analysis (eq 2).20 Complex C11 exhibited asymmetric catalysis
reactivity identical to that of the combination of C9 and A5, im-
plying that C11 might be the reactive catalyst species in the dehy-
drogenative KR of amines (eq 3). The relationship between the
enantiomeric excesses of the recovered 1d and the catalyst C9
was investigated, and a negative nonlinear relationship was ob-
served, further suggesting the possible intervention of a dimeric
complex (Figure 2).21
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the oxidation potentials of Fe(III)(salan) dimer complexes was
observed. The first oxidation potential of C12 (+ 0.50 V vs.
Fc+/Fc), which has an electron-rich 1-naphtholate ligand, is
slightly lower than that of C9 possessing a hydroxo ligand (+ 0.66
V vs. Fc+/Fc). C11 bearing an electron-neutral 1-naphtholate li-
gand and C13 with an electron-deficient one exhibit significantly
higher first oxidation potentials (+ 0.95 V and + 0.96 V vs. Fc+/Fc)
than that of C9. Reaction rates were found to be positively corre-
lated with the electronic property of naphtholate ligands, and the
reaction with electron-rich 1-naphtholate was faster than those
with electron-neutral and -deficient ones (Figure 3). The
Table 2. The first oxidation potentials of Fe(III)salan dimer
complexes
Fe(III)salan
C9
the first oxidation potential (V vs. Fc+/Fc)
Figure 2. Plot of the enantiomeric excess of recovered 1d ver-
sus the enantiomeric excess of C9 at 50% conversion. The
dotted line symbolizes the linear correlation.
+ 0.66
+ 0.95
+ 0.50
+ 0.96
C11
According to the above control experiments and literature sur-
vey, Fe(III)(salan) complex catalyzed aerobic dehydrogenative
KR of amines might proceed through two plausible mechanisms.
The first one might involve Fe(III) to Fe(II) cycle initiated either
by single-electron oxidation of amine or by hydrogen atom ab-
straction from amine.22 The second one might involve Fe(III) to
Fe(IV) cycle.13b-13d Control experiments were conducted to distin-
guish these two catalytic cycles. The oxidation potential of amine
1a was measured to be + 0.43 V vs. Fc+/Fc, while the first reduc-
tion potential of Fe(III)(salan) dimer complex C9 was measured
to be -1.36 V vs. Fc+/Fc (see the Supporting Information for de-
tails). Accordingly, the Fe(III) to Fe(II) cycle initiated by single
electron oxidation might be excluded. The experiment of 1a with
one equivalent of complex C11 and TEMPO under N2 atmosphere
was performed (eq 4, Scheme 4). However, no reaction was ob-
served, implying that the Fe(III) to Fe(II) cycle initiated by the
hydrogen atom abstraction pathway also might not be viable.
C12
C13
In the Fe(III) to Fe(IV) catalytic cycle, complex C11 is oxi-
dized by molecular oxygen furnishing radical cation 9, which then
oxidizes 1 via single-electron transfer (SET) producing amine
radical cation 10 (Scheme 5).23 10 underwent proton and hydrogen
atom abstraction to give imine 2, regenerating C11 for catalytic
cycle. The intermolecular KIE for 1a is 2.4, implying that the C–
H bond cleavage might be involved in the rate-determining step
(eq 7, Scheme 4). According to the absolute configuration of re-
covered 5,6-dihydrophenanthridines, we envisioned that amine
(S)-1 was oxidized more preferentially than (R)-1, and therefore
unreacted (R)-1 was obtained with high enantioselectivity.
Naphthol additives were found to be beneficial for improving
the reactivity and enantioselectivity (entries 3 and 6-9, Table 1).
Therefore, cyclic voltammetry (CV) of a series of Fe(III)(salan)
dimer complexes were measured to investigate their electrochem-
ical properties (Table 2). An obvious ligand effect on
Figure 3. Time versus substrate conversion in the aerobic KR
with different 1-naphthol additives. Each data point is an av-
erage of three runs.
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selectivity factors exhibited a similar correlation with the elec-
dev, D. A.; Levit, G. L. Nonenzymatic acylative kinetic resolution
of racemic amines and related compounds. Eur. J. Org. Chem.
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tion of saturated N‑heterocycles by enantioselective amidation
with chiral hydroxamic acids. Acc. Chem. Res. 2016, 49, 2807.
(3) Selected examples on nonenzymatic acylative KR of primary
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ic resolution of amines by a nonenzymatic acylation catalyst.
Angew. Chem. Int. Ed. 2001, 40, 234. (b) Arseniyadis, S.; Valleix,
A.; Wagner, A.; Mioskowski, C. Kinetic resolution of amines: a
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a unique solvent-induced reversal of stereoselectivity. Angew.
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Valleix, A.; Mathew, S. P.; Blackmond, D. G.; Wagner, A.; Mi-
oskowski, C. Tuning the enantioselective N-acetylation of racemic
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philic and hydrogen bonding catalysis: an anion binding approach
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Merging nucleophilic and hydrogen bonding catalysis: an anion
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De, C. K.; Kundu, D. S.; Döhring, A.; Garczynski, A.; List, B.
Asymmetric catalysis of the carbonyl-amine condensation: kinetic
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(4) Selected examples on nonenzymatic acylative KR of cyclic
secondary amines, see: (a) Arp, F. O.; Fu, G. C. Kinetic resolu-
tions of indolines by a nonenzymatic acylation catalyst. J. Am.
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Bode, J. W. Catalytic kinetic resolution of cyclic secondary
amines. J. Am. Chem. Soc.2011, 133, 19698. (d) Kreituss, I.; Mu-
rakami, Y.; Binanzer, M.; Bode, J. W. Kinetic resolution of nitro-
gen heterocycles with a reusable polymer-supported reagent. An-
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Gutierrez, O.; Kozlowski, M. C.; Bode, J. W. Catalytic kinetic
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resin for decagram scale resolution of (±)-mefloquine and other
chiral N-heterocycles. Angew. Chem. Int. Ed. 2016, 55, 1553.
(5) Selected examples on nonenzymatic acylative KR of amides,
see: (a) Birman, V. B.; Jiang, H.; Li, X.; Guo, L.; Uffman, E. W.
Kinetic resolution of 2-oxazolidinones via catalytic, enantioselec-
tive N-acylation. J. Am. Chem. Soc. 2006, 128, 6536. (b) Fowler,
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lution of formamides and thioformamides as an entry to nonra-
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tioselective N‑acylation of lactams and thiolactams using amidine-
based catalysts. J. Am. Chem. Soc. 2012, 134, 17605.
tronic property of naphtholate ligand (Krel= 50.2 for 4-methoxy-1-
naphthol, Krel = 38.6 for 1-naphthol, Krel = 17.6 for 4-nitro-1-
naphthol, and Krel = 2.0 without naphthol additive). While we
cannot rationalize the exact role of naphthol additives at this point,
we envisioned that the reassembled (μ-1-naphthoxo-μ-
hydroxo)Fe(salan) dimer catalyst might afford more advantages
than the mother (di-μ-hydroxo)Fe(salan) dimer for the occurrence
and stereoselective differentiation of aerobic KR of cyclic amines.
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CONCLUSION
In summary, the first nonenzymatic iron-catalyzed dehydrogena-
tive KR of cyclic secondary amines using air as an oxidant has
been developed. The economical and practical method is applica-
ble to a series of cyclic benzylic amines, including 5,6-
dihydrophenanthridines and 1,2-dihydroquinolines, with diverse
functional groups at the α position in high yields with excellent
enantioselectivities. The direct dehydrogenative KR of advanced
intermediates of bioactive molecules that are difficult to access
using existing catalytic asymmetric synthetic strategy was also
demonstrated. Further study of the mechanism of the aerobicde-
hydrogenative KR is in progress.
ASSOCIATED CONTENT
Supporting Information.
The Supporting Information is available free of charge on the
ACS Publications website.
X-ray crystallographic data for C9 (CIF)
X-ray crystallographic data for C11 (CIF)
Experimental procedures, control experiments, cyclic vol-
tammogarms, and spectra data (PDF)
AUTHOR INFORMATION
Corresponding Author
*leiliu@sdu.edu.cn
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support was provided by the National Science
Foundation of China (21722204, 21432003).
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SI.
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