Copper-Catalyzed Asymmetric Arylation of N-Heteroaryl Aldimines: Elementary Step of a 1,4-Insertion

Article abstract of DOI:10.1002/anie.201812646

Copper complexes of monodentate phosphoramidites efficiently promote asymmetric arylation of N-azaaryl aldimines with arylboroxines. DFT calculations and experiments support an elementary step of 1,4-insertion in the reaction pathway, a step in which an aryl-copper species adds directly across four atoms of C=N?C=N in the N-azaaryl aldimines.

Full text of DOI:10.1002/anie.201812646

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: Copper-Catalyzed Asymmetric Arylation of N-Heteroaryl
Aldimines via an Elementary Step of 1,4-Insertion
Authors: Jianrong Steve Zhou, Xurong Qin, Chunlin Wu, Hajime Hirao,
and Adhitya Mangala Putra Moeljadi
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812646
Angew. Chem. 10.1002/ange.201812646
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http://dx.doi.org/10.1002/ange.201812646

10.1002/anie.201812646
Angewandte Chemie International Edition
COMMUNICATION
Copper-Catalyzed Asymmetric Arylation of N-Heteroaryl
Aldimines via an Elementary Step of 1,4-Insertion
†a
†a
b
b
Chunlin Wu, Xurong Qin, Adhitya Mangala Putra Moeljadi, Hajime Hirao and Jianrong Steve
a
Zhou *
Abstract: Copper complexes of monodentate phosphoramidites
efficiently promote asymmetric arylation of N-azaaryl aldimines with
arylboroxines. DFT calculations and kinetic isotopic experiments
support an elementary step of 1,4-insertion in the reaction pathway,
in which an aryl-copper species adds directly across four atoms
C=N-C=N in N-azaaryl aldimines.
mechanistic standpoint, both rhodium and palladium catalysts
use 1,2-insertion of arylmetal species to imines.[14] In most cases,
imines activated with N-sulfonyl and N-sulfamoyl groups were
used. Recently, chiral 1,1'-biphenols and thioureas were also
used in asymmetric addition of arylborons to reactive α-
iminoesters.[15]
Me
.
CuOTf 0.5 tol 10 mol%
ligand 12 mol%
3-pic
HN
Ph
(p-toyl-BO)3
N
N
Chiral alkylamines are important motifs in modern medicines
and they are present in about 15% of blockbuster drugs.
Therefore, efficient stereoselective synthesis of these
compounds has received much attention amongst synthetic
chemists.[1] Of particular interest to us, chiral N-azaaryl
alkylamines are present in quite a number of medicines and
drug candidates (Figure 1). For example, ontazolast is a drug
currently used for the treatment of inflammation.[2] Chiral amine-
substituted thiazole, pyrazole and imidazopyridazine are also
found in many therapeutic agents that target depression,
Alzheimer’s disease and malaria.[3] Moreover, aminopyrimidines
are present in an isocitrate dehydrogenase (IDH) inhibitor[4] and
difulmetorim. The latter is a new-generation fungicide to protect
wheat and barley.[5]
KOAc, toluene
110 oC, 24 h
p-tolyl
Ph
H
1a
2a (0.5 equiv)
3a
Ph
Ph
Ph
Me
Me
Me
Me
O
O
O
O
O
N
N
P
P
N
P
O
Ph
L
S1
S2
90% ee, 90% yield
85% ee, 95% yield
56% ee, 80%(12)yield
OMe
Ph
O
Ph
Me
Me
Me
O
O
O
N
P
N
N
P
P
O
Me
O
Me
Ph
(12)
OMe
S3
L'
S4
82% ee, 90% yield
-84% ee, 80% yield
77% ee, 85% yield
OMe
Cl
Ph
O
Ph
O
O
Me
Me
Me
OMe
N
N
Et HN
N
Me
HN
N
N
S
N
P
F
F
N
N
N
P
Me
Me
O
Me
Me
O
Me
N
Ph
Ph
N1
F
N2
F
Ontazolast
(inflammation)
CRF1 receptor antagonist
(depression)
-65% ee, 90% yield
γ-secretase modulator
(Alzheimer’s disease)
-55% ee, 90% yield
CN
Scheme 1. Screening of chiral phosphoramidites for model arylation.
Cl
H
Ph
Et
N
CH3
HN
O
O
H
H
Initially, we attempted copper-catalyzed arylation of
aldimines with arylboroxines and searched for chiral ancillary
ligands (Scheme 1).[16] Among a dozen of aldimines carrying
different groups on the nitrogen atom that we have tested (see
Schemes 5 and 6c), aldimine 1a bearing an N-3-picolyl ring
afforded the desired product in both good yield and excellent
stereoselectivity. Thus, 10 mol% copper catalyst ligated by
spiro-1,1'-diindanyl phosphoramidite L[17] promoted arylation of
p-tolylboroxine 2a to deliver benzhydryl amine 3a in 90% ee and
90% yield. Modification of the amine fragment of L failed to
improve the stereoselectivity further unfortunately (S1-4). Later,
we prepared ligand L' with inverted spiro chirality, which led to
the opposite enantiomer of 3a as the major isomer (-84% ee).
Therefore, the spiro-backbone is the dominant stereo-
determining element in the catalyst. Furthermore, two Feringa
ligands N1-2 only provided 3a in moderate ee values. 0.5 equiv
of p-tolylboroxines also gave 3a in 85% yield after 2 days. Other
arylboron regents were also tested such as PhB(OH)2, PhBF3K,
PhBpin and PhB(cat), which provided no desired product. As a
note of caution, the reaction was sensitive to trace amounts of
added water, so dry solvents must be used.
N
N
N
N
N
N
HO
Me
N
N
Me
N
N
Me
OMe
OCHF2
Difulmetorim
(fungicide)
kinase PfPK7 inhibitor
(malaria infection)
IDH inhibitor
(cancer)
Figure 1. Examples of chiral medicines and agrochemicals containing N-
azaaryl amines.
Catalytic asymmetric arylation of imines using benchtop-
stable arylboron reagents is a simple, convergent method to
prepare chiral benzylic and benzhydryl amines from readily
available reagents.[6] For this reaction, noble metal catalysts,
mostly based on rare and expensive rhodium[7] and palladium,[8]
proved to be particularly effective, owing to efforts of Hayashi,[9]
Lin and Xu,[10] Zhang,[11] Manolikakes,[12] and others.[13] From a
[a]
Dr. C. Wu, Dr. X. Qin, Prof. Dr. J. S. Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, 21 Nanyang Link, SPMS-CBC-
06-06, Singapore 637371
E-mail: jrzhou@ntu.edu.sg
[†]
[b]
CW and XQ are co-first authors
Dr. A. M. P. Moeljadi, Prof. Dr. H. Hirao
Department of Chemistry, City University of Hong Kong, Tat Chee
Avenue, Kowloon, Hong Kong, China
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812646
Angewandte Chemie International Edition
COMMUNICATION
CuOAc 10 mol%
ligand L 12 mol%
3-pic
R1
boroxine (Scheme 3). Moreover, heterocycles such as thiophene,
furan and benzofuran (3n'-q') were tolerated. We found that sec-
and tert-alkyl aldimines (3r'-s') also reacted well, but linear
aliphatic aldehydes led to a complex mixture during aldimine
formation. A brominated product 3e' was suitable for single-
crystal X-ray diffraction and its configuration was determined to
be 1S.[18] In a scale-up reaction, 2 mol% of the copper catalyst
was sufficient to produce one gram of 3a when the reaction
temperature was raised from 80 to 100 °C (Scheme 3b). A
simple crystallization readily improved optical purity of 3a’ to
99%. N-picolylamine 3a’ can be easily converted to the N-Boc
amine via a reported procedure.[19]
3-pic
H
HN
Ph
(R1-BO)3
N
KOAc, toluene
80 oC, 24 h
Ph
1a
2 (0.7 equiv)
3
R1=
Me
Br
Cl
MeO
F
3e 93% yield
93% ee
3d 81% yield
90% ee
3b 91% yield
92% ee
3c 91% yield
95% ee
3a 90% yield
95% ee
F
F3C
Ph
F3C
F
CF3
3f 87% yield
90% ee
3h 87% yield
94% ee
3g 86% yield
3j 89% yield
50% ee, 40 o
3i 85% yield
92% ee
93% ee
C
Scheme 2. Organoboroxines in asymmetric addition to 1a.
To streamline the synthesis of benzhydryl amines, we
condensed 3-picolyl-2-amine and aryl aldehydes in the presence
of a catalytic amount of tosylic acid together with molecular
sieve (Scheme 4). The resulting aldimines were used directly,
without purification, in the next step of catalytic arylation.[20] At
110 °C, we found that 1 mol% copper catalyst was sufficient to
achieve full conversion in all cases, which was accompanied by
a slight drop of ee values.
CuOAc 10 mol %
ligand L 12 mol %
3-pic
3-pic
HN
N
(a)
(PhBO)3
KOAc, toluene
80 oC, 48 h
Ph
R
R
H
1
2b (0.7 equiv)
3
R =
Cl
F
Me
MeO
3c' 88% yield
95% ee
3d' 84% yield
95% ee
3a' 93% yield
93% ee
3b' 94% yield
93% ee
CuOAc 1 mol%
ligand L 1.2 mol%
3-pic-NH2
O
3-pic
Ph
3-pic
cat. p-TsOH
HN
N
F
(PhBO)3 0.7 equiv
KOAc 2 equiv
110 oC, 48 h
MS 4Å, toluene
140 oC, 30 h
R
R
H
R
H
F3C
no isolation
3
Br
F
3e' 81% yield
95% ee (X-ray)
3f' 86% yield
94% ee
3g' 86% yield
95% ee, 90 o
3h' 95% yield
95% ee
R =
MeO
C
F
Br
F3C
O
O
3e' 80% yield
3f' 83% yield
93% ee
3b' 83% yield 3c' 85% yield
87% ee
90% ee
90% ee
Me
F
3k' 92% yield
90% ee, 100 oC
3l' 93% yield
94% ee
3m' 85% yield
97% ee
Cl
MeS
Ph
3h' 87% yield
89% ee
3v' 84% yield
3t' 70% yield
3u' 82% yield
92% ee
S
O
S
92% ee
88% ee
O
3n' 81% yield
90% ee
3o' 86% yield
94% ee
3p' 80% yield
78% ee
3q' 65% yield
74% ee, 110 oC
Me
Me
Me
Me
Me
Me
3a' 1.3 gram
3w' 82% yield
3x' 77% yield
3r' 89% yield
3s' 87% yield
93% ee, 90 o
C
92% yield, 91% ee
71% ee
86% ee
86% ee, 50 o
C
Scheme 4. Streamlined arylation of aromatic aldimines.
CuOAc 2 mol%
ligand L 3 mol%
3-pic
HN
3-pic
H
(Ph-BO)3
0.7 equiv
N
(b)
KOAc, toluene
100 oC, 24 h
p-tolyl
Ph
p-tolyl
3a' 1.07 gram
92% ee, 93% yield
99% ee after crystallization
Scheme 3. (a) Examples of arylation of aldimines. (b) A gram-scale
arylation of an aldimine.
The optimized copper catalyst of ligand L was applicable to
asymmetric arylation of aldimine 1a using both electron-rich and
poor aryl boroxines (3a-i) (Scheme 2). In particular, aryl fluorides,
chlorides and bromides were well tolerated (3c-e and 3g), but
aryl iodides inhibited the desired transformation. In the reaction
of o-tolyl boroxine, the corresponding product was obtained in
good yield, albeit in moderate 66% ee. 4-Pyridyl boroxine did not
react at all whiles 3-pyridyl analogues led to about 10% yield.
Methyl boroxine did not react at all. Unfortunately, the addition of
trans-styryl boroxine (3j) resulted in only moderate 50% ee.
Many aromatic aldimines of different electronic and steric
properties on aryl rings also reacted smoothly with phenyl
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10.1002/anie.201812646
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COMMUNICATION
Y
Y
N
X
X
R
enantiomer as the major, in contradiction with experimental
results.
CuOAc 5 mol%
ligand L 6 mol%
Y
O
X
MgSO4, toluene
140 oC, 30 h
N
N
HN
Ar
Ar
H
H2N
N
(RBO)3 0.7 equiv
KOAc 2 equiv
110 oC, 48 h
Ar
H
The 1,4-insertion step led to immediate product Prod with a
partially dearomatized pyridine, which helped to disperse the
negative charge on the iminyl nitrogen. Wiberg bond index
analysis revealed that from GS to Prod, the bond order of N1-C2
decreased from 1.29 to 1.15, while that of N2-C2 increased
significantly from 1.16 to 1.52.
1 equiv
4
N
N
N
N
N
N
HN
N
HN
N
HN
HN
Me
Br
OMe
Cl
4a
4b
4c
4d
80% yield, 92% ee
72% yield, 89% ee
75% yield, 85% ee
70% yield, 97% ee
The new 1,4-insertion mechanism also received some
experimental support (Scheme 6). (a) The 3-methyl group on N-
picolyl aldimines reinforced the s-cisoid reactive conformation of
aldimines by exerting A1,3-type strain and thus accelerated the
insertion process. Its omission or replacement at other positions
on the N-pyridine resulted in much slower conversions (3a2-4).
(b) The N-3-picolyl ketimine of acetophenone failed to react,
because the iminyl methyl group disfavors the s-cisoid
conformation. (c) All of other aldimines carrying N-anisyl (3a5),
N-1-naphthyl, N-benzyl, N-Boc and N-Cbz groups lacked the
ability to bind to the copper center, so did not react. (d) In a
competition experiment leading to the formation of 3a6 and 3a7
carrying 4-CF3 and 4-OMe groups on the N-pyridine ring, the
former was formed much faster than the latter (42% yield versus
6% yield after 6 h), consistent with the important role played by
the N-pyridine in stabilizating the developing negative charge
during insertion. (e) All aldimines carrying other types of N-
N
N
N
N
HN
N
F
HN
N
HN
N
HN
N
F
N
Br
N
MeO
N
4e
4f
4g
4h
62%% yield, 90% ee
68% yield, 91% ee
61% yield, 94% ee
64% yield, 93% ee
N
N
HN
N
HN
N
HN
N
S
Me
Me
MeO
N
4k
80% yield, 89% ee
4j
4i
75% yield, 84% ee
70% yield, 86% ee
NMe
Me
N
NMe
O
N
N
HN
HN
N
N
HN
HN
Me
Me
Me
Br
Me
4l
4m
65% yield, 90% ee
4n
4o
65% yield, 89% ee
72% yield, 88% ee
68% yield, 91% ee
Scheme 5. Streamlined arylation of other N-azaaryl aldimines.
azacycles in Scheme
5
can easily undergo partial
dearomatization to accommodate the negative charge. (f) A
stoichiometric reaction between mesitylcopper(I), aldimine 1a
and ligand L (1 equiv) was performed in toluene (20 h at 110 oC).
It resulted in 74% conversion and an adduct in <2% ee. In a
background reaction, only 22% conversion was detected
indicating ligand acceleration effect. (g) A Hammett plot was
constructed for phenylation of several analogues of aromatic
aldimine 1b with different para-substituents on the aryl rings
(OMe, Me, F, Cl and CF3). A relatively large ρ value of +1.04
revealed a strong correlation between electron-deficient nature
of aldimines and insertion rates.
Furthermore, a streamlined procedure was established for
asymmetric synthesis of biarylmethylamines from other
heteroaryl amines derived from pyrazine (4a-i), pyrimidine (4j),
quinoline (4k), pyrazole (4l-m), 2-indazole (4n) and 2-
benzoisoxazole (Scheme 5). Herein, magnesium sulfate was
used instead of molecular sieve, to improve the reproducibility of
aldimine condensation. We found that the reactions in Scheme 5
were generally slower than those of N-2-picolyl aldimines;
therefore, 5 mol% copper catalyst was needed to achieve good
conversion at 110 °C, owing to relatively weak binding of these
azacycles to the copper catalyst. Unfortunately, derivatives of
azolyl amines of 1,3-oxazole, imidazole and 1,3-benzothiazole
led to desired amines in good yields, but in 0-10% ee, probably
because of competitive binding of these azoles to generate
achiral copper catalysts.
We studied the insertion of phenylcopper(I) complex[21] with
a single phosphoramidite L into bound aldimine 1b, using DFT
calculations (B3LYP-D3(BJ)(SCRF)//B3LYP-D3(BJ)/B1 level)
(Scheme 6a). In ground state GS, the coordination geometry
around the copper center was trigonal planar. The three-
coordinate organocopper(I) centers have been reported by
others previously as key intermediates or as key fragments in
copper-catalyzed reactions.[22] Instead of classical 1,2-
insertion,12 we identified that 1,4-insertion of the copper-carbon
bond into the core fragment of C=N2-C=N1 of 1b was the more
energetically favored pathway (Scheme 6a).[23] The activation
barrier leading to the major (S)-isomer was
7
kcalmol-1.
Moreover, the energy gap between two transition states TS-S
and TS-R was 1.7 kcalmol-1, in good agreement with the
observed 93% ee. We also calculated 1,2-insertion pathways,
which had much higher insertion barriers (21 and 23 kcalmol-1
leading to (R)- and (S)-isomer), but it predicted the (R)-
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10.1002/anie.201812646
Angewandte Chemie International Edition
COMMUNICATION
(a) 1,4-insertion pathway for the model arylation
Acknowledgement
R
R
CuOAc 10 mol %
ligand 12 mol %
NH Me
N
N
N
Me
Ph
(PhBO)3
+
We thank financial support from Nanyang Technological
University, GSK-EDB Trust Fund (GSK-EDB Green and
Sustainable Manufacturing Award 2017), A*STAR Science &
Engineering Research Council (AME IRG A1783c0010), City
University of Hong Kong (7200534 and 9610369) and National
Science Foundation of China (21502157). CW and XQ
contributed equally to the experiments. AMP and HH contributed
DFT calculations of reaction pathways.
KOAc, toluene
80 o
C
3a' 93% ee (S)
1b R = p-tolyl
2b 0.7 equiv
R
H
Me
N2
Me
R
N2
C2
N1
C6
Me
N2
R
H
Ph
N1
N1
Ph
L
Cu
Cu
Cu
L
L
GS
TS-S
Prod
Insertion barrier of TS-S: 7.3 kcal/mol.
Energy gap between TS-S and TS-R: 1.7 kcal/mol
Keywords: copper catalysis • imine addition • chiral alkylamines
(b) Effect of N-directing groups on arylation of aldimines (10 mol% Cu, 80 oC, 48 h in Scheme 2)
• asymmetric arylation • heteroaromatic amines
Me
OMe
HN
Ph
N
HN
Ph
N
Me
HN
Ph
N
HN
Ph
References
p-tolyl
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p-tolyl
p-tolyl
p-tolyl
3a3 32% yield
80% ee
3a4 48% yield
91% ee
3a5 0% yield
3a2 44% yield
87% ee
[2] P. R. Farina, C. A. Homon, E. S. Lazer, T. P. Parks, "Discovery of BIRM
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(c) Competition experiment between two aldimines
OMe
N
CF3
OMe
CF3
CuOAc 10 mol %
ligand 12 mol %
+
+
HN
Ph
HN
Ph
N
N
N
N
N
(o-tolylBO)3 0.7 equiv
KOAc, toluene
110 oC, 6 h
p-tolyl
p-tolyl
Ph
0.1 mmol
Ph
3a7 6% yield
84% ee
3a6 42% yield
88% ee
0.1 mmol
Scheme 6. (a) 1,4-addition transition state TS-S leading to the major (S)-
isomer. (b) Effect of different N-directing groups in aldimines on arylation
and (c) substituents on N-pyridine group.
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The DFT-optimized transition states indicated that the
copper catalyst ligated with a single bulky phosphoramidite L[24]
was sufficient for excellent enantiofacial induction during
arylation. Ligand L adopted a specific baseball glove-like
conformation, by minimizing steric interaction between its two
large 1-phenylethyl groups (Figure 2). Consequently, one of
them shielded the bottom-right quadrant (front view), whereas
an aromatic ring of the spiro-diindanyl backbone pointed into the
top-left space. Thus, the bottom-left quadrant was left widely
open to house the reacting partners.
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Figure 2. Transition state TS-S (left) and disfavored TS-R (right) for
phenylation of (L)(phenyl)Cu(I) complex and bound aldimine 1b. L is
shown in space-filling representation and copper and other reacting
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ligand in green, nitrogen and carbon of aldimine 1b in blue and pink.
In summary, we report the first example of catalytic
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COMMUNICATION
R
R
NH
N
M
N
N
Me
copper catalyst
Ph
N-heterocyclic
nitrogen of
Chunlin Wu, Xurong Qin, Adhitya Mangala Putra Moeljadi,
Hajime Hirao and Jianrong Steve Zhou*
(Ph-BO)3
ligand:
aryl boroxine
monodentate phosphoramidite
>90% ee
aldimines is
directly involved
in 1,4-insertion
of aryl-copper
species
Me
H
N
Ph
Page No. – Page No.
Me
R
R
N
R
H
N
N
Ph
N
N
Cu
Cu
L
Copper-Catalyzed Asymmetric Arylation of N-Heteroaryl
Aldimines via an Elementary Step of 1,4-Insertion
Cu
L
L
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