Copper-Catalyzed Umpolung of Imines through Carbon-to-Nitrogen Boryl Migration

Article abstract of DOI:10.1021/acscatal.9b00777

We report a general strategy for the catalytic umpolung of imines, which was enabled by an unprecedented 1,2-boryl carbon-to-nitrogen migration. Based on the discovery of a rearrangement of an α-borylalkylamido copper intermediate to an α-borylaminoalkyl

Full text of DOI:10.1021/acscatal.9b00777

Subscriber access provided by CAL STATE UNIV BAKERSFIELD
Letter
Copper-Catalyzed Umpolung of Imines
through Carbon-to-Nitrogen Boryl Migration
Zhenghua Li, Liang Zhang, Masayoshi Nishiura, and Zhaomin Hou
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b00777 • Publication Date (Web): 15 Apr 2019
Downloaded from http://pubs.acs.org on April 15, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 7
ACS Catalysis
1
2
3
4
5
6
7
8
9
Copper-Catalyzed Umpolung of Imines through Carbon-to-Nitrogen
Boryl Migration
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Zhenghua Li,† Liang Zhang,*,†,‡ Masayoshi Nishiura,†,‡ and Zhaomin Hou*,†,‡
†Advanced Catalysis Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako,
Saitama 351-0198, Japan
‡Organometallic Chemistry Laboratory, RIKEN Cluster for Pioneering Research, 2-1 Hirosawa, Wako, Saitama
351-0198, Japan
ABSTRACT: We report a general strategy for the catalytic umpolung of imines which was enabled by an
unprecedented 1,2-boryl carbon-to-nitrogen migration. Based on the discovery of a rearrangement of an -
borylalkylamido copper intermediate to an -borylaminoalkyl copper species through 1,2-migration of a boryl group
from carbon to nitrogen and copper migration from nitrogen to carbon, we have developed a copper-catalyzed selective
allylation of a wide range of aldimines and ketimines with allyl electrophiles in the presence of B2(pin)2 and LiOtBu. We
expect this catalytic imine-umpolung strategy may derive useful methodologies for the synthesis of various
functionalized amines.
KEYWORDS: allylation, amine synthesis, imine umpolung, boryl migration, copper catalysis
The polarity-reversed (umpolung) reactions open up new
vistas for the development of synthetic methodologies.1
Compared with carbonyl umpolung chemistry, which has
made tremendous success in organic synthesis, the
umpolung reactions of imines are still largely
underdeveloped.2 Inverting the inherent polarity of
imines may enable novel reaction patterns and provide
access to useful synthetic protocols that are
complementary to the reactions using imines as
electrophilic precursors for the preparation of valuable
amines.3 Previously, limited types of imine umpolung
have been reported. A benzoin-type aromatic aldimine
coupling afforded diamines in the presence of NaCN.4
The umpolung reactions of N-benzyl imines have been
achieved via 2-azaally anion intermediates in the
presence of a base.5,6 N-heterocyclic carbenes (NHC)
have been reported to facilitate the addition of aromatic
aldimines to Michael acceptors through the aza-Breslow
intermediates.7 Under photoredox catalysis conditions,
the generation of either nucleophilic radicals8 or
carbanionic intermediates9 have been observed, some of
which have been trapped with electrophiles in several
catalytic reactions. Despite these recent advances, the
development of a general strategy for the umpolung of
simple imines remains an attractive and important
research subject.
aza-Brook rearrangement and a boryl migration from a
carbon atom to an oxygen atom in bora-Brook
rearrangement have been reported.12 The current
discovery represents a novel carbon-to-nitrogen boryl
migration.
Scheme 1. Cu-Catalyzed Imine Umpolung via 1,2-
Boryl Migration
R
H
X
R
N
N
R'
R''
[Cu], B2(pin)2, LiOtBu
R'
R''
X
LCu-B(pin)
R
B(pin)
CuL
R
CuL
Cu/B rearrangement
N
N
R'
R''
R'
R''
B(pin)
new strategy for imine umpolung and transformation
novel 1,2-boryl migration from C to N
catalytic generation of -borylaminoalkyl copper
broad substrate scope for valuable amine synthesis
Envisaging that the resulting -aminoalkyl anion
could be trapped by an electrophile, we have developed
an efficient catalytic umpolung of simple imines, which
has led to the selective allylation of a wide range of
aldimines and ketimines with allyl electrophiles in the
presence of a copper catalyst, bis(pinacolato)diboron
(B2(pin)2), and LiOtBu. This work features several
advantages, including: a) providing a novel strategy for
umpolung of simple imines; b) revealing a novel boryl
migration from carbon to nitrogen; c) catalytically
generating a nucleophilic -borylaminoalkyl copper
During our previous studies on the reactions of
borylcopper species with alkynes and aldehydes,10 we
became interested in the transformation of imines by
borylcopper complexes.11 Herein, we report an
unprecedented intramolecular rearrangement of an -
borylalkylamido copper intermediate to an -
borylaminoalkyl copper species via 1,2-boryl migration
from carbon to nitrogen and copper migration from
nitrogen to carbon (Scheme 1). Previously, the migration
of a silyl group from a carbon atom to a nitrogen atom in
ACS Paragon Plus Environment

ACS Catalysis
species; d) proving a model reaction design for amine
Page 2 of 7
spontaneously as identified by the  C―H signal at 5.02
ppm. DFT calculations revealed that is
1
2
3
4
5
6
7
8
synthesis from imines and potential electrophiles.
At first, we examined the reaction of N-
benzylideneaniline 1a with a borylcopper complex
Scheme 2. Sequential Reactions of a Boryl
Copper Complex with an Imine and Allyl
Bromide
4
thermodynamically favorable over 3 by about 8.6
kcal/mol. To the best of our knowledge, this is the first
example of direct observation of 1,2-boryl migration
from carbon to nitrogen.12
α C-H in 4
[(IPr)Cu-B(pin)]
+
[(IPr)CuBr]
+
 C-H in 3
240 mins
Ph
N
Ph
H
9
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
180 mins
150 mins
120 mins
90 mins
60 mins
50 mins
40 mins
30 mins
20 mins
10 mins
5 mins
Ph
Ph
1a
2a
C6H6
Br
rt, 20 h
rt, 10 min
Ph
Ph
Cu(IPr)
Ph
N
B(pin)
N
B(pin)
Ph
Cu(IPr)
3
4
[(IPr)CuB(pin)]
diisopropylphenyl)imidazol-2-ylidene),
(IPr
=
1,3-bis(2,6-
which was
prepared from [(IPr)CuOtBu] and B2(pin)2,13,14 at room
temperature in benzene. To our surprise, an -
borylaminoalkyl copper complex 4 (rather than a
straightforward, nucleophilic addition product such as 3)
was isolated in 78% yield (Scheme 2). The molecular
structure of 4 was unambiguously confirmed by the X-
ray crystallographic analysis (Figure 1). When allyl
bromide was added to a benzene solution of 4 at room
temperature, [(IPr)CuBr] was isolated in 99% yield along
with the homoallylic amine 2a in 95% yield after
treatment with silica gel.
5.0
4.5
4.0
3.5
f1 (ppm)
3.0
2.5
2.0
1
Figure 2. H NMR monitoring of transformation of 3 to 4
(see Supporting Information for details).
Based on the stoichiometric reactions described above,
we envisioned that a catalytic allylation of imines with
allyl electrophiles may be achieved through the copper-
catalyzed imine umpolung. Table 1 summarizes the
results of our examination of the reaction of N-
benzylideneaniline 1a with allyl bromide in the presence
of a catalytic amount of a copper compound, B2(pin)2,
and LiOtBu. It was found that [(SIMes)CuCl] (SIMes =
1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene)
showed higher catalytic activity than [(IPr)CuCl] (entry
1)
and
[(IMes)CuCl]
(IMes
=
1,3-bis(2,4,6-
trimethylphenyl)imidazol-2-ylidene) (entry 2), affording
the desired homoallylic amine 2a almost quantitatively
at 80 C in 18 h (entry 3). The NHC-free CuCl also served
as an excellent catalyst (entry 4). However, the
CuCl/PCy3 combination or CuCl/bipy combination gave
lower yields (entry 5, 6). The formation of 2a was not
observed in the absence of a copper catalyst (entry 7). A
systematic screening of base and solvent showed that
LiOtBu and dioxane were the best combination for this
catalytic transformation (Table 1).
Figure 1. ORTEP drawing of 4 with thermal ellipsoids set
at 30% probability. H atoms have been omitted for clarity.
Selected bond lengths (Å) and angles (deg): Cu1−C1,
1.897(6); Cu1−C20, 1.898(5); N1−C1, 1.392(8); N1−B1,
1.483(9); C1−Cu1−C20, 169.9(3); N1−C1−Cu1, 124.4(5).
We then monitored the reaction of 1a with
[(IPr)CuB(pin)] in C6D6 by H and 13C NMR analyses. In
1
1
With the optimized reaction conditions in hand, we
first investigated the umpolung allylation of various
aldimines with allyl bromide by using [(SIMes)CuCl] as
the catalyst (Table 2).15 Aldimines derived from aniline
the H NMR monitoring, the instant formation of an -
carbon-borylated species assignable to 3 was identified
as shown by the typical  C―H signal at 4.26 ppm
(Figure 2). The transformation of 3 to 4 occurred almost
ACS Paragon Plus Environment

Page 3 of 7
ACS Catalysis
and benzaldehydes bearing electron-donating groups
such as Me and MeO performed well in the current
reaction, affording the desired products such as 2b and
2c, respectively, in good yields. Thioanisole-containing
steric hindrance vs. its aldimine counterparts, the
ketimine substrate 5a derived from acetophenone
worked well in this reaction at 100 C, affording the
desired homoallylic amine 6a in 81% isolated yield.
Electron-rich ketimines
1
2
3
4
5
6
7
8
Table
1.
Cu-Catalyzed
Allylation
of
N-
Benzylideneaniline with Allyl Bromidea
Table 2. Catalytic Umpolung Allylation of
Aldiminesa
Ph
H
Ph
N
catalyst (5 mol%)
N
R
H
R
[(SIMes)CuCl] (5 mol%)
N
+
N
Br
+
B2(pin)2 (1.0 equiv)
Br
Ph
B2(pin)2 (1.0 equiv)
Ph
R'
base (1.1 equiv)
R'
LiOtBu (1.1 equiv)
2a
1a
solvent, 80 o
C
9
dioxane, 80 o
C
1
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
yield
(%)b
H
H
H
H
entry
catalyst
base
solvent
N
N
N
N
1
[(IPr)CuCl]
[(IMes)CuCl]
[(SIMes)CuCl]
CuCl
LiOtBu
LiOtBu
LiOtBu
LiOtBu
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
THF
25
85
MeO
Me
MeS
2
2d
, 60%
N
2c
, 81%
2b
2a
, 78%
, 86%
3
97 (86)
H
H
N
H
H
4
99 (88)
56
79
0
N
N
5
CuCl/PCy3 (1:3) LiOtBu
CuCl/bipy (1:2) LiOtBu
F3C
F
F
Br
6
2g
, 61%
2f
2h
, 89%
, 92%
2e
, 73%
N
7
-
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
NaOtBu
KOtBu
LiOMe
H
N
H
8
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
68
53
10
H
N
9
DME
10
11
12
13
14
toluene
hexane
dioxane
dioxane
dioxane
MeO
Ph
2k
2j
, 71%
, 93%
2i
, 73%
Ph
12
H
H
H
N
15
N
N
O
18
N
2n
, 70%
2m
, 72%
4
2l
, 87%
F
aReaction conditions: catalyst (5 mol%), 1a (0.5 mmol), allyl
bromide (1.0 equiv), B2(pin)2 (1.0 equiv), base (1.1 equiv),
solvent (3 mL), 80 C, 18 h. NMR yield with CH2Br2 as an
internal standard. Isolated yields are shown in parentheses.
tBu
H
N
F5
H
N
Me
H
3
H
N
N
b
2q
, 89%
2p
2r
, 58%
2o
, 73%
, 87%
aldimine was compatible with the reaction conditions to
give the corresponding homoallylic amine product 2d
efficiently. Halides such as Br and F were also tolerated
and the corresponding products 2e-g were isolated in
high yields. Aldimines bearing trifluoromethyl, biphenyl
or naphthyl group worked efficiently to deliver the
desired amines 2h-j in very high yields. Remarkably,
aldimine bearing an alkyne unit, which is generally
sensitive towards a borylcopper species, functioned well
in this reaction and afforded 2k selectively. Oxygen and
nitrogen-containing heteroaromatic cycles also survived
the reaction conditions, leading to the isolation of
functionalized amines 2l and 2m in high yields. It is
noteworthy that cyclic imine 1n which was originated
from aliphatic aldehyde is also a suitable substrate,
affording the corresponding product 2n in good yield.
Besides, aldimines derived from benzaldehyde and
electron-rich or electron-poor anilines could also be used
in this reaction, affording 2o-q in high yields.
Furthermore, the reaction of relatively less reactive N-
alkyl aldimine 1r also worked well to yield the N-hexyl
substituted homoallylic amine 2r.
aReaction conditions: [(SIMes)CuCl] (5 mol%), 1 (0.5
mmol), allyl bromide (1.0 equiv), B2(pin)2 (1.0 equiv),
LiOtBu (1.1 equiv), dioxane (3 mL), 80 C, 18 h. Isolated
yields are shown.
containing isopropyl, methoxyl, or thioether groups are
also good substrates, yielding the corresponding
products 6b-d efficiently. Chloride could tolerate the
current conditions to give 6e selectively. The reactions of
ketimine substrates bearing biphenyl or naphthyl group
also occurred smoothly to generate products 6f or 6g in
good yields, respectively. The reaction of ketimine 5h
which is derived from electron-rich aniline afforded 6h
in 88% yield. Less reactive N-butyl ketimine 5i also
worked well to yield the N-alkyl substituted homoallylic
amine 6i. Besides the methyl phenyl ketone-originated
ketimines, ethyl, iso-propyl, and benzyl substituted
ketimine substrate 5j-l could also be used in our
reaction. Despite increased steric hindrance, products
6j-l could be obtained efficiently. Particularly, the
reaction of more sterically demanding benzophenone
imine 5m yielded the desired product 6m selectively,
albeit in moderate yield. It’s worth noting that a primary
amine 6n could be obtained selectively from
benzophenone imine. Remarkably, ketimine prepared
Considering the importance of generation of
quaternary carbon centers from the allylation of
ketimines, we then investigated the umpolung allylation
of a series of ketimines (Table 3). Despite the increased
ACS Paragon Plus Environment

ACS Catalysis
Page 4 of 7
Ph
Ph
Ph
H
from 1-methylisatin also worked well to deliver the
R1
R1
[(SIMes)CuCl] (5 mol%)
N
N
+
R2
1
2
3
4
5
6
7
8
heterocycle containing homoallylic amine 6o in good
yield. Furthermore, a cyclic ketimine 5p which was
derived from aliphatic ketone could also afford the
corresponding product 6p in good yield. To the best of
our knowledge, this protocol represents a rare example
of umpolung allylation of simple ketimines.6,8a
X
R2
B2(pin)2 (1.0 equiv)
LiOtBu (1.1 equiv)
dioxane, 80 oC, 18 h
Ph
1a
R1 = H
R1 = H
R1 = H
R2 = H
2a
2a
2a
X = MeOCO2
, 86%
, 56%
, 78% (at 100 oC)
69% (at 100 oC)
63% (at 100 oC)
R2 = H
X = (EtO)2PO2
R2 = H
R1 = Me R2 = H
R1 = H R2 = Ph
X = Cl
X = Br
X = Br
7
,
8
,
Table 3. Catalytic Umpolung Allylation of
Ketiminesa
9
R
H
R
A
possible reaction mechanism of the catalytic
N
[(SIMes)CuCl] (5 mol%)
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
Br
B2(pin)2 (1.0 equiv)
allylation of imines with allyl bromide is shown in
Scheme 4. The nucleophilic addition of a borylcopper
species LCuB(pin) to the C=N double bond of an imine
substrate should give a carbon-borylated amidocopper
species like A. The subsequent copper/boron
rearrangement through the migration of the boryl group
from carbon to nitrogen and migration of the copper unit
from nitrogen to carbon would afford an -
borylaminoalkyl copper species B. This rearrangement
may be driven by the formation of a strong B−N bond.
The cross-coupling reaction between the nucleophilic -
aminoalkyl copper species and the electrophilic allyl
bromide gives the N-borylated homoallylamine products,
which are converted to the corresponding amines after
protonolysis.
R'
R''
R'
N
R''
LiOtBu (1.1 equiv)
dioxane, 100 o
C
6
5
H
H
H
N
Me
H
N
N
Me
Me
Me
iPr
MeS
MeO
6d
, 85%
6c
, 80%
6b
, 78%
6a
, 81%
Me
H
H
H
N
N
N
H
Me
N
Me
Me
Me
Cl
Ph
6g
, 61%
6h
6f
, 88%
, 69%
N
6e
, 66%
H
H
N
Me
H
Et
H
N
Me
Scheme 4. Proposed Mechanism of Cu-Catalyzed
Umpolung Reaction of Imines
N
iPr
Bn
6j
6k
, 50%
, 72%
6l
, 51%
H
6i
, 51%
LCuCl
LiOtBu
H
N
H
H
R
H
H
N
N
N
N
N
Ph
Ph
LCu(OtBu)
LiBr
LiOtBu
Me
Me
B2(pin)2
R'
R''
Me
6p
O
Me
, 79%
6o
, 75%
6n
, 52%
6m
, 54%
tBuOB(pin)
aReaction conditions: [(SIMes)CuCl] (5 mol%), 5 (0.5
mmol), allyl bromide (1.0 equiv), B2(pin)2 (1.0 equiv),
LiOtBu (1.1 equiv), dioxane (3 mL), 100 C, 18 h. Isolated
yields are shown.
H
LCuBr
LCuB(pin)
R
B(pin)
N
R
N
R'
R''
Under the current reaction conditions, we further
investigated the reactions of 1a with other allyl
electrophiles (Scheme 3).16 The reaction employing allyl
methyl carbonate efficiently afforded product 2a in 86%
isolated yield. Allyl diethylphosphate could also be used
as an allylation reagent for 1a, although the yield of 2a
was lower under the same conditions. Besides, the
reaction of allyl chloride afforded 2a in 78% yield at 100
C. Furthermore, both 3-bromo-2-methylpropene and
cinnamyl bromide worked well in the current reaction to
afford the corresponding allylation product 7 and 8,
respectively.
R'
R''
Br
R
B(pin)
CuL
R
CuL
N
N
R'
R''
R'
R''
B(pin)
B
A
In summary, we have discovered that the
intramolecular 1,2-migration of the boryl group from
carbon to nitrogen in an -borylalkylamido copper
species can take place to generate a carbon-nucleophilic
-borylaminoalkyl copper complex. Based on this
discovery, we have developed a novel strategy for the
catalytic umpolung of simple imines, which has enabled
the selective formation of homoallylic amines in the
reaction of a wide range of imines with allyl electrophiles
such as allyl bromide, chloride, carbonate and phosphate
in the presence of a copper catalyst, B2(pin)2, and
LiOtBu. Both aldimines and ketimines are suitable for
this transformation. Good functional tolerance has been
observed. This strategy may open the door to a wide
Scheme 3. Cu-Catalyzed Umpolung Allylation of
N-Benzylideneaniline
Electrophiles
with
Other
Allyl
ACS Paragon Plus Environment

Page 5 of 7
ACS Catalysis
13320. (d) Hu, L.; Wu, Y.; Li, Z.; Deng, L. Catalytic
Asymmetric Synthesis of Chiral γ-Amino Ketones via
Umpolung Reactions of Imines. J. Am. Chem. Soc. 2016,
138, 15817-15820. (e) Hu, B.; Deng, L. Catalytic
Asymmetric Synthesis of Trifluoromethylated γ-Amino
Acids through the Umpolung Addition of Trifluoromethyl
Imines to Carboxylic Acid Derivatives. Angew. Chem. Int.
Ed. 2018, 57, 2233-2237. (f) Li, M.; Gutierrez, O.; Berritt,
S.; Pascual-Escudero, A.; Yeşilçimen, A.; Yang, X.; Adrio,
J.; Huang, G.; Nakamaru-Ogiso, E.; Kozlowski, M. C.
range of umpolung reactions of imines with various
electrophiles for the synthesis of diversified functional
amines.
1
2
3
4
5
6
7
8
ASSOCIATED CONTENT
Supporting Information
Experimental details, spectroscopic and analytical data for
new compounds, and crystallographic data of complex 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Transition-Metal-Free
Chemo-and
Regioselective
Vinylation of Azaallyls. Nat. Chem. 2017, 9, 997-1004. (g)
Li, Z.; Hu, B.; Wu, Y.; Fei, C.; Deng, L. Control of
Chemoselectivity in Asymmetric Tandem Reactions: Direct
Synthesis of Chiral Amines Bearing Nonadjacent
Stereocenters. Proc. Natl. Acad. Sci. U. S. A. 2018, 115,
1730-1735. (h) Niwa, T.; Yorimitsu, H.; Oshima, K.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
AUTHOR INFORMATION
Corresponding Author
*houz@riken.jp
*lzhang@riken.jp
Palladium-Catalyzed
Benzylic
Arylation
of
N-
Benzylxanthone Imine. Org. Lett. 2008, 10, 4689-4691.
(i) Liu, X.; Gao, A.; Ding, L.; Xu, J.; Zhao, B. Aminative
Umpolung Synthesis of Aryl Vicinal Diamines from
Aromatic Aldehydes. Org. Lett. 2014, 16, 2118-2121. (j) Li,
M.; Berritt, S.; Walsh, P. J. Palladium-Catalyzed
Regioselective Arylation of 1,1,3-Triaryl-2-azaallyl Anions
with Aryl Chlorides. Org. Lett. 2014, 16, 4312-4315. (k) Li,
M.; Yucel, B.; Jiménez, J.; Rotella, M.; Fu, Y.; Walsh, P. J.
ORCID
Zhenghua Li: 0000-0002-2291-4511
Liang Zhang: 0000-0002-5661-3557
Masayoshi Nishiura: 0000-0003-2748-9814
Zhaomin Hou: 0000-0003-2841-5120
Umpolung
Synthesis
of
Diarylmethylamines
via
Palladium-Catalyzed Arylation of N-Benzyl Aldimines.
Adv. Synth. Catal. 2016, 358, 1910-1915. (l) Hu, B.; Deng,
Notes
The authors declare no competing financial interests.
L.
Direct
Catalytic
Asymmetric
Synthesis
of
Trifluoromethylated
γ-Amino
Esters/Lactones
via
ACKNOWLEDGMENT
Umpolung Strategy. J. Org. Chem. 2019, 84, 994-1005.
(m) Fields, W. H.; Chruma, J. J. Palladium-Catalyzed
Decarboxylative Benzylation of Diphenylglycinate Imines.
Org. Lett. 2010, 12, 316-319. (n) Tang, S.; Park, J. Y.;
Yeagley, A. A.; Sabat, M.; Chruma, J. J. Decarboxylative
Generation of 2-Azaallyl Anions: 2-Iminoalcohols via a
Decarboxylative Erlenmeyer Reaction. Org. Lett. 2015, 17,
2042-2045. (o) Niwa, T.; Suehiro, T.; Yorimitsu, H.;
Oshima, K. Carbon-Carbon Bond Formations at the
Benzylic Positions of N-Benzylxanthone Imines and N-
Benzyldi-1-naphthyl Ketone Imine. Tetrahedron 2009,
65, 5125-5131. (p) Chen, Y.-J.; Seki, K.; Yamashita, Y.;
Kobayashi, S. Catalytic Carbon-Carbon Bond-Forming
Reactions of Aminoalkane Derivatives with Imines. J. Am.
Chem. Soc. 2010, 132, 3244-3245. (q) Matsumoto, M.;
Harada, M.; Yamashita, Y.; Kobayashi, S. Catalytic Imine-
Imine Cross-Coupling Reactions. Chem. Commun. 2014,
50, 13041-13044. (r) Li, M.; Yücel, B.; Adrio, J.; Bellomo,
A.; Walsh, P. J. Synthesis of Diarylmethylamines via
Palladium-Catalyzed Regioselective Arylation of 1,1,3-
Triaryl-2-azaallyl Anions. Chem. Sci. 2014, 5, 2383-2391.
(s) Li, M.; González-Esguevillas, M.; Berritt, S.; Yang, X.;
Bellomo, A.; Walsh, P. J. Palladium‐Catalyzed C-H
Arylation of α,β‐Unsaturated Imines: Catalyst‐Controlled
Synthesis of Enamine and Allylic Amine Derivatives.
Angew. Chem. Int. Ed. 2016, 55, 2825-2829. (t)
Fernández-Salas, J. A.; Marelli, E.; Nolan, S. P. Synthesis
of (Diarylmethyl)amines Using Ni-Catalyzed Arylation of
C(sp3)-H Bonds. Chem. Sci. 2015, 6, 4973-4977. (u) Wu,
Y.; Deng, L. Asymmetric Synthesis of Trifluoromethylated
Amines via Catalytic Enantioselective Isomerization of
Imines. J. Am. Chem. Soc. 2012, 134, 14334-14337. (v)
Xiao, X.; Xie, Y.; Su, C.; Liu, M.; Shi, Y. Organocatalytic
Asymmetric Biomimetic Transamination: From α-Keto
Esters to Optically Active α-Amino Acid Derivatives. J. Am.
Chem. Soc. 2011, 133, 12914-12917.
This work was supported in part by JSPS KAKENHI Grant
Number JP17H06451 (Z.H.) (Hybrid Catalysis). Dr. Béatrice
Carry is gratefully acknowledged for participating in the
preliminary studies. We also greatly appreciate Dr. Zhen Liu
at East China University of Science and Technology for DFT
calculations.
REFERENCES
(1) Seebach, D. Methods of Reactivity Umpolung. Angew.
Chem. Int. Ed. 1979, 18, 239-258.
(2) (a) Romanov-Michailidis, F.; Rovis, T. Natural Polarity
Inverted. Nature 2015, 523, 417-418. (b) Waser, M.;
Novacek, J. An Organocatalytic Biomimetic Strategy Paves
the Way for the Asymmetric Umpolung of Imines. Angew.
Chem. Int. Ed. 2015, 54, 14228-14231.
(3) (a) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of
the Structural Diversity, Substitution Patterns, and
Frequency of Nitrogen Heterocycles among U.S. FDA
Approved Pharmaceuticals. J. Med. Chem. 2014, 57,
10257-10274. (b) Nugent, T. C. Chiral Amine Synthesis
Methods, Developments and Applications. Wiley-VCH,
Weinheim, 2010.
(4) (a) Reich, B. J. E.; Justice, A. K.; Beckstead, B. T.;
Reibenspies, J. H.; Miller, S. A. Cyanide-Catalyzed
Cyclizations via Aldimine Coupling. J. Org. Chem. 2004,
69, 1357-1359. (b) Ogle, J. W.; Zhang, J.; Reibenspies, J.
H.; Abboud, K. A.; Miller, S. A. Synthesis of Electronically
Diverse Tetraarylimidazolylidene Carbenes via Catalytic
Aldimine Coupling. Org. Lett. 2008, 10, 3677-3680.
(5) (a) Wu, Y.; Hu, L.; Li, Z.; Deng, L. Catalytic Asymmetric
Umpolung Reactions of Imines. Nature 2015, 623, 445-
450. (b) Zhu, Y.; Buchwald, S. L. Ligand-Controlled
Asymmetric Arylation of Aliphatic α-Amino Anion
Equivalents. J. Am. Chem. Soc. 2014, 136, 4500-4503. (c)
Chen, P.; Yue, Z.; Zhang, J.; Lv, X.; Wang, L.; Zhang, J.
Phosphine‐Catalyzed Asymmetric Umpolung Addition of
Trifluoromethyl Ketimines to Morita-Baylis-Hillman
Carbonates. Angew. Chem. Int. Ed. 2016, 55, 13316-
(6) For umpolung allylation of imines, see: (a) Liu, J.; Cao, C.-
G.; Sun, H.-B.; Zhang, X.; Niu, D. Catalytic Asymmetric
Umpolung Allylation of Imines. J. Am. Chem. Soc. 2016,
138, 13103-13106. (b) Su, Y.-L.; Li, Y.-H.; Chen, Y.-G.;
Han, Z.-Y. Ir/PTC Cooperatively Catalyzed Asymmetric
ACS Paragon Plus Environment

ACS Catalysis
Page 6 of 7
Umpolung Allylation of α-Imino Ester Enabled Synthesis
of a-Amino Boronate Esters via Organocatalytic
Pinacolboryl Addition to Tosylaldimines. Chem. Commun.
2012, 48, 3769-3771. (d) Hong, K.; Morken, J. P. Catalytic
Enantioselective One-pot Aminoborylation of Aldehydes: A
Strategy for Construction of Nonracemic α-Amino
Boronates. J. Am. Chem. Soc. 2013, 135, 9252-9254. (e)
Zhang, S.-S.; Zhao, Y.-S.; Tian, P.; Lin, G.-Q. Chiral
NHC/Cu(I)-Catalyzed Asymmetric Hydroboration of
Aldimines: Enantioselective Synthesis of α-Amido Boronic
Esters. Synlett. 2013, 24, 437-442. (f) Wen, K.; Wang, H.;
Chen, J.; Zhang, H.; Cui, X.; Wei, C.; Fan, E.; Sun, Z.
of α-Quaternary Amino Acid Derivatives Bearing Two
Vicinal Stereocenters. Chem. Commun. 2017, 53, 1985-
1988. (c) Zhan, M.; Pu, X.; He, B.; Niu, D.; Zhang, X.
Intramolecular Umpolung Allylation of Imines. Org. Lett.
2018, 20, 5857-5860. (d) Burger, E. C.; Tunge, J. A.
Synthesis of Homoallylic Amines via the Palladium-
Catalyzed Decarboxylative Coupling of Amino Acid
Derivatives. J. Am. Chem. Soc. 2006, 128, 10002-10003.
(e) Yeagley, A. A.; Chruma, J. J. C−C Bond-Forming
Reactions via Pd-Mediated Decarboxylative α-Imino Anion
Generation. Org. Lett. 2007, 9, 2879-2882. (f) Li, Z.;
Jiang, Y.-Y.; Yeagley, A. A.; Bour, J. P.; Liu, L.; Chruma, J.
J.; Fu, Y. Mechanism of the Pd‐catalyzed Decarboxylative
Allylation of α‐Imino Esters: Decarboxylation via Free
Carboxylate Ion. Chem. Eur. J. 2012, 18, 14527-14538. (g)
Qian, X.; Ji, P.; He, C.; Zirimwabagabo, J.-O.; Archibald,
M. M.; Yeagley, A. A.; Chruma, J. J. Palladium-Catalyzed
Decarboxylative Generation and Asymmetric Allylation of
α-Imino Anions. Org. Lett. 2014, 16, 5228-5231.
1
2
3
4
5
6
7
8
Improving
Carbene-Copper-Catalyzed
Asymmetric
9
Synthesis of α-Aminoboronic Esters Using Benzimidazole-
Based Precursors. J. Org. Chem. 2013, 78, 3405-3409. (g)
Wang, D.; Cao, P.; Wang, B.; Jia, T.; Lou, Y.; Wang, M.;
Liao, J. Copper(I)-Catalyzed Asymmetric Pinacolboryl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Addition of N-Boc-imines Using
a Chiral Sulfoxide-
Phosphine Ligand. Org. Lett. 2015, 17, 2420-2423.
(12) For reviews, see: (a) Brook, A. G. Molecular
Rearrangements of Organosilicon Compounds. Acc. Chem.
Res. 1974, 7, 77-84. (b) Moser, W. H. The Brook
Rearrangement in Tandem Bond Formation Strategies.
Tetrahedron 2001, 57, 2065-2084. For examples of aza-
Brook rearrangement, see: (c) Honda, T.; Mori, M. An Aza-
Brook Rearrangement of (α-Silylallyl)amine. J. Org. Chem.
1996, 61, 1196-1197. (d) Yagi, K.; Tsuritani, T.; Takami, K.;
(7) (a) Patra, A.; Mukherjee, S.; Das, T. K.; Jain, S.; Gonnade,
R. G.; Biju, A. T. N-Heterocyclic-Carbene-Catalyzed
Umpolung of Imines. Angew. Chem. Int. Ed. 2017, 56,
2730-2734. (b) Fernando, J. E. M.; Nakano, Y.; Zhang, C.;
Lupton, D. W. Enantioselective N-Heterocyclic Carbene
Catalysis Exploiting Imine Umpolung. Angew. Chem. Int.
Ed. 2019, 58, 4007-4011. (c) Patra, A.; Gelat, F.;
Pannecoucke, X.; Poisson, T.; Besset, T.; Biju, A. T.
Synthesis of 4-Difluoromethylquinolines by NHC-
Catalyzed Umpolung of Imines. Org. Lett. 2018, 20, 1086-
1089.
(8) (a) Qi. L.; Chen, Y. Polarity-Reversed Allylations of
Aldehydes, Ketones, and Imines Enabled by Hantzsch
Ester in Photoredox Catalysis. Angew. Chem. Int. Ed.
2016, 55, 13312-13315. (b) Lee, K. N.; Lei, Z.; Ngai, M.-Y.
β-Selective Reductive Coupling of Alkenylpyridines with
Shinokubo,
H.;
Oshima,
K.
Reaction
of
Silyldihalomethyllithiums with Nitriles: Formation of α-
Keto Acylsilanes via Azirines and 1,3-Rearrangement of
Silyl Group from C to N. J. Am. Chem. Soc. 2004, 126,
8618-8619. (e) Huang, Z.-A.; Tang, F.; Xu, Y.-J.; Lu, C.-D.
[1,4]-Aza-Brook Rearrangement for Efficient Formation of
Benzynes and Their Cycloaddition. Synlett. 2015, 26, 891-
896. (f) Lin, C.-Y.; Sun, Z.; Xu, Y.-J.; Lu, C.-D. Synthesis of
Aryl anti-Vicinal Diamines via Aza-Brook Rearrangement-
Initiated Nucleophilic Addition of α-Silylamines to Imines.
J. Org. Chem. 2015, 80, 3714-3722. (g) Huang, Z.-A.; Liu,
H.; Lu, C.-D.; Xu, Y.-J. Stereoselective Synthesis of
Enantioenriched 2-Chloro-2-aroylaziridines by Cascade
Reaction between Aryl Nitriles, Silyldichloromethanes, and
tert-Butanesulfinylimines. Org. Lett. 2015, 17, 4042-4045.
For a report on bora-Brook rearrangement, see: (h) Kisu,
H.; Sakaino, H.; Ito, F.; Yamashita, M.; Nozaki, K. A
Qualitative Analysis of a “Bora-Brook Rearrangement”:
The Ambident Reactivity of Boryl-Substituted Alkoxide
Including the Carbon-to-Oxygen Migration of a Boryl
Group. J. Am. Chem. Soc. 2016, 138, 3548-3552.
Aldehydes
and
Imines
via
Synergistic
Lewis
Acid/Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139,
5003-5006.
(9) (a) Wang, R.; Ma, M.; Gong, X.; Panetti, G. B.; Fan, X.;
Walsh, P. J. Visible-Light-Mediated Umpolung Reactivity
of Imines: Ketimine Reductions with Cy2NMe and Water.
Org. Lett. 2018, 20, 2433-2436. (b) Wang, R.; Ma, M.;
Gong, X.; B.; Fan, X.; Walsh, P. J. Reductive Cross-
Coupling of Aldehydes and Imines Mediated by Visible
Light Photoredox Catalysis. Org. Lett. 2019, 21, 27-31. (c)
Fan, X.; Gong, X.; Ma, M.; Wang, R.; Walsh, P. J. Visible
Light-Promoted CO2 Fixation with Imines to Synthesize
Diaryl α-Amino Acids. Nat. Commun. 2018, 9, 4936. (d)
Ju, T.; Fu, Q.; Ye, J.-H.; Zhang, Z.; Liao, L.-L.; Yan, S.-S.;
Tian, X.-Y.; Luo, S.-P.; Li, J.; Yu, D.-G. Selective and
Catalytic Hydrocarboxylation of Enamides and Imines
with CO2 to Generate α,α‐Disubstituted α‐Amino Acids.
Angew. Chem. Int. Ed. 2018, 57, 13897-13901.
(10) (a) Zhang, L.; Cheng, J.; Carry, B.; Hou, Z. Catalytic
Boracarboxylation of Alkynes with Diborane and Carbon
Dioxide by an N-Heterocyclic Carbene Copper Catalyst. J.
Am. Chem. Soc. 2012, 134, 14314-14317. (b) Carry, B.;
Zhang, L.; Nishiura, M.; Hou, Z. Synthesis of Lithium
Boracarbonate Ion Pairs by Copper-Catalyzed Multi-
Component Coupling of Carbon Dioxide, Diboron, and
Aldehydes. Angew. Chem. Int. Ed. 2016, 55, 6257-6260.
(11) Selected examples of Cu-catalyzed borylation of imines: (a)
Beenen, M. A.; An, C.; Ellman, J. A. Asymmetric Copper-
Catalyzed Synthesis of α-Amino Boronate Esters from N-
tert-Butanesulfinyl Aldimines. J. Am. Chem. Soc. 2008,
130, 6910-6911. (b) Buesking, A. W.; Bacauanu, V.; Cai, I.;
Ellman, J. A. Asymmetric Synthesis of Protected a-Amino
Boronic Acid Derivatives with an Air- and Moisture-Stable
Cu(II) Catalyst. J. Org. Chem. 2014, 79, 3671-3677. (c)
Solé, C.; Gulyás, H.; Fernández, E. Asymmetric Synthesis
(13) Neeve, E. C.; Geier, S. J.; Mkhalid, I. A. I.; Westcott, S. A.;
Marder, T. B. Diboron(4) Compounds: From Structural
Curiosity to Synthetic Workhorse. Chem. Rev. 2016, 116,
9091-9161.
(14) (a) Laitar, D. S.; Miller, P.; Sadighi, J. P. Efficient
Homogeneous Catalysis in the Reduction of CO2 to CO. J.
Am. Chem. Soc. 2005, 127, 17196-17197. (b) Zhao, H.; Lin,
Z.; Marder, T. B. Density Functional Theory Studies on the
Mechanism of the Reduction of CO2 to CO Catalyzed by
Copper(I) Boryl Complexes. J. Am. Chem. Soc. 2006, 128,
15637-15643. (c) Dang, L.; Lin, Z.; Marder, T. B. Boryl
Ligands and Their Roles in Metal-Catalysed Borylation
Reactions. Chem. Commun. 2009, 3987-3995.
(15) When CuCl was used as a catalyst in the reaction of 1e, a
lower yield of 2e (41% NMR yield) was observed.
Therefore, the substrate scope was investigated by using
[(SIMes)CuCl] as the catalyst.
(16) Under the current conditions (80 C), only trace amount of
the desired products were detected in the reactions of 1a
with benzyl bromide, ethyl bromoacetate, prenyl bromide,
or crotyl bromide. No significant improvement was
observed when the reactions were carried out at 100 C.
ACS Paragon Plus Environment

Page 7 of 7
ACS Catalysis
Table of Contents
1
2
3
R
H
R
Cu
N
N
4
5
R'
R''
X
B2(pin)2, LiOtBu
R'
R''
6
7
X
LCu-B(pin)
8
9
1,2-migration
of boryl from C to N
R
CuL
R
B(pin)
CuL
N
N
catalytic generation
of -borylaminoalkyl copper
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R'
R''
R'
R''
B(pin)

7
ACS Paragon Plus Environment