Redox-neutral: Ortho -C-H amination of pinacol arylborates via palladium(ii)/norbornene catalysis for aniline synthesis

Article abstract of DOI:10.1039/c9sc02759a

A palladium(ii)/norbornene cooperative catalysis enabled redox-neutral ortho-C-H amination of pinacol aryl- or heteroarylborates for the synthesis of structurally diverse anilines is reported. This method is scalable, robust (tolerance of air and moisture), phosphine ligand-free, and compatible with a wide range of functionalities. These practical features make this reaction amenable for industry. A plethora of synthetically very useful halogenated anilines, which often cannot be prepared via other transition-metal-catalyzed aminations, are readily produced using this method. Particularly, the orthogonal reactivity between pinacol arylborates and aryl iodides is demonstrated. Preliminary deuterium-labeling studies reveal a redox-neutral ipso-protonation mechanism of this process, which will surely inspire the future development of this field. Overall, the exceptionally broad scope (47 examples) and reliability of this procedure, together with the wide availability of pinacol arylborates, make this chemistry a valuable addition to the existing methods for aniline synthesis.

Full text of DOI:10.1039/c9sc02759a

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DOI: 10.1039/C9SC02759A
ARTICLE
Redox-Neutral Ortho-C‒H Amination of Pinacol Arylborates via
Palladium(II)/Norbornene Catalysis for Anilines Synthesis
†a
Shuqing Chen, Peng Wang, a Hong-Gang Cheng,a Chihui Yanga and Qianghui Zhou*a,b
†
Received 00th January 20xx,
Accepted 00th January 20xx
Reported is a palladium/norbornene cooperative catalysis enabled redox-neutral ortho-C‒H amination of pinacol aryl- or
heteroarylborates for the synthesis of structurally diverse anilines. This method is scalable, robust (tolerance of air and
moisture), phosphine ligand-free, and compatible with a wide range of functionalities. These practical features make this
reaction amenable for industry. A plethora of synthetically very useful halogenated anilines, which often cannot be prepared
via other transition-metal-catalyzed aminations, are readily produced using this method. Particularly, the orthogonal
reactivity between pinacol arylborates and aryl iodides is demonstrated. Preliminary deuterium-labeling studies reveal a
redox-neutral ipso-protonation mechanism of this process, which will surely inspire the future development of this field.
Overall, the exceptionally broad scope (47 examples) and reliability of this procedure, together with the wide availability of
pinacol arylborates, make this chemistry a valuable addition to the existing methods for aniline synthesis.
DOI: 10.1039/x0xx00000x
Functionalized anilines have attracted considerable attention as reagents and isopropanol as the proton source for ipso-
a result of their widely applications in the pharmaceutical termination.4 Later on, they extended this chemistry to ortho-
industry and medicinal chemistry.1 For example, the popular
marketed medicines aripiprazole (antipsychotics),1b repaglinide
A) Buchwald-Hartwig amination (Ipso amination)
R1
(anti type II diabetes),1c linezolid (antibacterial),1d and the
EphB4 kinase inhibitor1e all contain the aniline motif as the
pharmacophore (Fig. 1). Therefore, general methods for the
assembly of these motifs are highly desirable. Synthesis of
anilines through C‒N bond formation is the most widely
adopted strategy, and substantial progress has been made over
the past two decades.2-5 Among these approaches, the
palladium-catalyzed aminations play a significant role.3-5 For
example, the famous Buchwald–Hartwig ipso-amination3 that
allows the facile synthesis of anilines from aryl halides and
nucleophilic amines (Scheme 1A). In 2013, the Dong group
reported an elegant palladium(0)/norbornene (NBE)
cooperative catalysis (the Catellani reaction)6 enabled ortho-
C‒H amination of aryliodides (the Dong amination), utilizing
electrophilic O-benzoyl hydroxyamines as the amination
Pd(0), ligand
R
R
X
N
NHR1R2
R2
2008
Acc. Chem. Res.
, 41, 1534
2008
Ar
Ar
Angew. Chem. Int. Ed.
, 47, 6338
base, inert gas
H
H
(X = Cl, Br, I, OTf, OTs)
B) Dong amination (Ortho-C-H amination)
Pd(0)/NBE, ligand
BzO-NR1R2
R
R
X
H
2013
J. Am. Chem. Soc.
, 135, 18350
, 140, 8551
Ar
Ar
R1
2018
J. Am. Chem. Soc.
R'OH
H
N
R2
Cs2CO3, inert gas
(X = Br, I)
C) The speculated "borono-Catellani amination" (Redox-neutral amination) (This work)
R
R
PdII/NBE
cooperative catalysis
B(OR')2
H
H
OBz
N
Ar
Ar
+
R1
R1
R2
redox neutral
"
"
N
R2
1
2
3
PdII
"Formidable Challenges"
BH
 Selective protodepalladation
 Protolytic deboronation
 Direct ipso amination
 Homo-coupling
R
R
PdII
H
PdIIX
Ar
Ar
R1
N
Cl
Cl
O
NBE
base
R2
I
IV
O
ANP
H
N
N
N
F
N
N
N
R
N
R
NBE
H
N
N
OEt
OH
O
Ar
Ar
N
O
MeN
OBz
N
BH
PdIV OBz
N
Me
O
PdII
CO2
H
NH
R1
R2
O
O
III
II
N
O
Me
NHAc
Me
R1
R2
2
aripiprazole
(Antipsychotics)
repaglinide
(Type II diabetes)
linezolid
(Antibacterial)
EphB4 kinase inhibitor
D) Redox-neutral ortho functionalization of boroxines (Dong, 2019)
cat.PdII/NBE
BzO
R
O
O
R
N
Fig. 1 Biologically important anilines scaffold.
R
H
H
N
X
BO
H
Ar
O
Ar
Ar
Ar
1/3
Ar
Ar
AsPh3
a. Sauvage Center for Molecular Sciences, College of Chemistry and Molecular
Sciences, Wuhan University, Wuhan, 430072, China.
P(OPh)3
O
X
3
boroxines
b. The Institute for Advanced Studies, Wuhan University, 430072, Wuhan, China.
E-mail: qhzhou@whu.edu.cn.
Scheme 1 Palladium-catalyzed amination strategies for anilines
synthesis.
† These authors contributed equally to this paper.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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ARTICLE
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C‒H amination of arylbromides (Scheme 1B).5 The Dong
amination represents a nice complement to the Buchwald-
Hartwig ipso-amination for the preparation of meta-substituted
anilines, while it requires stoichiometric reductant for the
recovery of palladium(0) catalyst. Recently, the group of Zhang
and us concurrently reported the ortho-C‒H alkylation of the
arylboronic acids and their derivatives (instead of aryl halides)
via the palladium(II)-initiated Catellani-type reaction (borono-
Catellani reaction).7 Therein, stoichiometric oxidant (Cu(OAc)2,
air or oxygen) is required for regenerating the palladium(II)
catalyst. Based on these chemistry, we envisaged a redox-
neutral “borono-Catellani amination” process for the facile
preparation of anilines, with widely accessible arylboronic acids
or their derivatives and O-benzoyl hydroxyamines as the
reactants (Scheme 1C). Prior to the start of this project, redox-
neutral borono-Catellani reactions had not been reported. Until
recently, the group of Dong reported an elegant related
research (Scheme 1D).8 As shown in Scheme 1C, it is surmised
that the reaction is initiated through transmetalation between
the palladium(II) catalyst and arylboronic acid derivative 1 to
deliver the aryl palladium(II) intermediate I. The following steps
involving insertion of NBE to I and subsequent ortho-C‒H
activation, generating the aryl/NBE palladacycle complex (ANP)
II. The oxidative addition of amination reagent 2 to II gives
palladium(IV) complex III,9 which then undergoes reductive
elimination and successive release of NBE to afford palladium(II)
species IV. The final reaction termination by protonation10 of IV
provides the desired aniline 3 and regenerate the palladium(II)
catalyst. The intrinsic advantage of this “borono-Catellani
amination” lies on its “redox-neutral” property: this process
involves a Pd(II)-Pd(IV)-Pd(II) catalytic cycle,11 thus no external
oxidant and reductant is needed. This feature constitutes a nice
extension of the previous Catellani-type reactions.12 In addition,
the widely accessible arylboronic species versus aryl halides will
guarantee a promising synthetic potential of this process for
diversified anilines preparation. Although the above process is
intriguing and mechanistically feasible, multiple challenges can
be foreseeable. First, protodepalladation can occur to
arylpalladium species (I, II and IV) of the catalytic cycle, which
may result in a selectivity issue. Second, transmetalation of
arylborates as well as the following ortho-C‒H activation are
generally promoted by base, while the final protodepalladation
step necessitates an acid. Hence, the compatibility of these
paradoxical steps could be another issue. Third, other
competing side reactions related to arylboronic species (e.g.
direct ipso-amination,13 protolytic deboronation,14 and homo-
coupling15) will also constitute formidable challenges.
Table 1 Optimization of reaction conditions.a
View Article Online
DOI: 10.1039/C9SC02759A
Bpin
H
O
Pd(OAc)2 (10 mol%)
NBE (2.0 equiv)
OBz
N
N
+
O
base (2.5 equiv)
solvent, air, 70 oC, 16 h
1a
2a
3a
( 1.5 equiv)
(1.0 equiv)
Entry
[Pd]
Base
Solvent
Yield (%)b
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
K2CO3
K2CO3
K2CO3
K2CO3
KHCO3
KOH
DMF
15
toluene
1
56
3
DMSO
4
5
DMSO/dioxanec
DMSO/dioxanec
DMSO/dioxanec
DMSO/dioxanec
DMSO/dioxanec
DMSO/dioxanec
82 (84)d
46
6
7
70
K2CO3
K2CO3
K2CO3
51
8
9e
Pd(TFA)2
Pd(OAc)2
74
75
aThe reaction was performed on a 0.1 mmol scale. bGC yield with
biphenyl as an internal standard. cDMSO/dioxane = 2:5. dIsolated
yield in parentheses on a 0.2 mmol scale. eThe reaction was
performed under argon. TFA = trifluoroacetoxy, DMF = N,N-
dimethylformamide, DMSO = dimethylsulfoxide.
studies focused on screening of the reaction solvent, which was
demonstrated to play a critical role in this process (entries 1–4).
Only a trace amount of 3a was detected when nonpolar solvent
toluene was used. In contrast, while switching to the polar
solvent DMSO, a dramatic increase of yield for 3a was realized
(56%, entry 3). In addition, the screening of other polar solvents
did not provide further improvement in the reaction efficiency
(see SI for the details). The use of DMSO as the solvent was
beneficial for the desired reaction on the one side, but on the
other side, a severe protodeboronation14 side reaction to yield
naphthalene as well as quick decomposition of the amination
reagent 2a also accompanied. This was why an overall
moderate yield (56%) was obtained. To our delight, after
intensively optimizations, this problem was nicely solved by
simply employing 1,4-dioxane as the cosolvent (DMSO/dioxane
= 2:5), and the yield of 3a was improved to 82% (entry 4).
Additional optimizations regarding the base and palladium
catalyst did not provide any significant improvement (entries 5–
8). Thus, entry 4 was identified as the optimal conditions for this
transformation. It is worth mentioning that these optimization
studies were all performed in air,7b and a following control
experiment revealed that air was beneficial since a tangible
drop of yield was observed when running the reaction in argon
(entry 9). This interesting phenomenon indicates on the one
side the desired transformation is indeed a redox-neutral
process (no external oxidant is needed). On the other side, it
shows that the presence of air could prohibit the possible
palladium(0)-involved side reactions,15 thus favoring the
expected reaction. Additionally, allowing to perform the
reaction in air is very attractive from both the practical and
economic perspective. Moreover, this process does not require
any phosphine or arsine ligand7b-c which is pivotal for previous
To address the aforementioned challenges and realize this
intriguing process, a model reaction was set up for the reaction
conditions optimization, with readily available 1-
naphthylboronic acid pinacol ester (1a) and morpholino
benzoate (2a) as the reactants. Selected results were
summarized in Table 1. Initially, Pd(OAc)2 was chosen as the
catalyst (10 mol%), 2-norbornene (NBE) as the mediator, K2CO3
as the base (2.5 equiv), and DMF as the solvent. Gratifyingly,
o
when the reaction was run at 70 C in air for 16 h, the desired
product 3a was obtained in 15% yield (entry 1). The following
2 | J. Name., 2012, 00, 1-3
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ARTICLE
palladium-catalyzed aminations.3-5,7a,8 Overall, these practical
features make this reaction amenable for industry.
To illustrate the synthetic utility of this protocol, the scope of
the amination reagent 2 was then investigated, with pinacol
View Article Online
DOI: 10.1039/C9SC02759A
With the optimized conditions in hand, we first examined the arylborate 1a as the reaction partner (Table 3). O-Benzoyl
scope of pinacol arylborates, employing 2a as the reaction hydroxylamines derived from common cyclic amines, such as
partner. The results were summarized in Table 2. For ortho- morpholine (2a), piperidine (2b–2k), piperazine (2l–2n),
substituted pinacol arylborates, both electron-donating (1f–h, thiomorpholine (2o) as well as pyrrolidine (2p) and azepane (2q)
1j–k, 1q, and 1t) and electron-withdrawing substitutions (1i, 1l- can all be used in the reaction to afford the corresponding
p, 1r, 1u,) on the aromatic rings were compatible, providing products in moderate to good yields (29–84%). A gamut of
meta-substituted anilines in moderate to good yields (38–77%). functional groups beared in these amination reagents were
Polycyclic pinacol arylborates (1a–e) were also suitable tolerated during the process, such as primary alcohol (2g),
substrates to deliver the corresponding aninines in good yields secondary alcohols (2e), tertiary alcohol (2h), TBS ether (2f),
(62–84%). Notably, pinacol heteroarylborates (1x–1z) reacted ketal (2i), ester (2j and 2k), benzoylamino (2l) and carbamate
well with 2a to afford the desired heteroanilines (3x–3z) in 43%, (2m and 2n) groups. In addition, the uncyclized amination
44% and 74% yield, respectively. For pinacol arylborates reagent N-benzyl N-benzoyl hydroxymethylamine (2r) also
without ortho substituents, the diaminated products (3aa–3ad) reacted uneventfully albeit in a moderate yield, which may
were obtained in moderate yields. Especially, the tyrosine- serve as an alternative way to access the secondary aryl amines
derived pinacol arylborate (1ad) could be applied to this through a following debenzylation. It is worth mentioning that
reaction, delivering the corresponding unnatural amino acid- the incorporated heterocyclic motifs, e.g. morpholine,
type product (3ad) in 26% yield. Furthermore, this piperidine, piperazine, pyrrolidine and azepane are ubiquitous
transformation possesses excellent chemoselectivity, and a and essentially important in small molecule drug discovery.17
variety of functional groups were tolerated, including fluoro
Table 3 Substrate scope of N-benzoyl hydroxyamines.a
(3n–3o, 3s, 3u, 3x, and 3aa), chloro (3p and 3ab), bromo (3d,
Bpin
H
R1
N
3v, and 3ac), even iodo (3w), methoxyl (3c, 3j, 3t, and 3y),
trifluoromethyl (3i), trifluoromethoxyl (3k), ester (3l, 3r, 3u,
and 3ad), bis-Boc-protected amino (3ad), and nitro (3m). The
compatibility of various functional groups is intriguing, since it
would allow further manipulation of the obtained anilines. It is
especially noteworthy that a variety of halogenated anilines
(3d, 3p, 3v, 3w, 3ab-3ac), which often cannot be prepared via
other transition-metal-catalyzed aminations,3-5 enable further
metal-catalyzed cross coupling reactions.16
Pd(OAc)2 (10 mol%)
NBE (2.0 equiv)
R1
R2
H
R2
N
+
OBz
K2CO3 (2.5 equiv)
DMSO/dioxane, air, 70 o
C
1a
2ar
3A3R
( 1.5 equiv)
(1.0 equiv)
Me
Ph
OH
OTBS
O
N
N
N
N
N
N
BzO
BzO
BzO
BzO
BzO
BzO
2a
2b
2c
2d
2e
2f
: 84%
: 66%
: 70%
: 72%
CO2Et
: 73%
: 45%
OH
Ph Ph
O
CO2Et
Bz
OH
N
O
N
N
N
N
N
N
BzO
BzO
BzO
BzO
BzO
BzO
BzO
2g
2h
2i
2j
2k
2l
: 43%
: 83%
: 53%
: 57%
: 71%
: 59%
Cbz
Boc
N
N
S
CH3
N
Table 2 Substrate scope of pinacol arylborates.a
N
N
N
N
N
BzO
BzO
BzO
2p
BzO
BzO
2r
Bn
2m
2n
2o
2q
: 29%
: 50%
: 60%
: 56%
: 42%
: 35%
R
R
Pd(OAc)2 (10 mol%)
NBE (2.0 equiv)
H
N
Bpin
O
Ar
Ar
N
+
BzO
aAll reactions were performed on a 0.2 mmol scale, and 2 was
added in two portions. Isolated yields are reported.
K2CO3 (2.5 equiv)
DMSO/dioxane, air, 70 o
H
1
C
2a
(1.0 equiv)
3
O
( 1.5 equiv)
H
O
3a
: R1 = H, 84%
: R1 = Me, 70%b
3f
H
O
The practicality and robustness of this amination process are
demonstrated by the 6.0 mmol scale experiment between 1a
and 2a, as depicted in Scheme 2A, wherein application of the
standard reaction conditions afforded product 3a in a good
yield (72%, 0.92 g). Tolerance of the iodo group in current
borono-Catellani amination process prompted us to investigate
the possible orthogonal reactivity between pinacol arylborate
and aryl iodides. The bifunctional reagent 1w was chosen as the
model substrate to testify this hypothesis. Firstly, 1w reacted
with 2a under the standard borono-Catellani amination
conditions, and the product 3w was indeed afforded in 51%
yield while no classic Catellani-type product was observed.
Then, the intact iodo group in 3w enabled a traditional Catellani
reaction18 to provide the polysubstituted arene 4 in 71% yield.
In stark contrast, subjecting 1w and 2a to the traditional
H
N
: R1 = Me, 68%
: R1 = OMe, 62%
: R1 = Br, 68%
3g
3h
N
: R1 = Et, 61%b
: R1 = iPr, 44%
: R1 = CF3, 39%
3b
3c
3d
R1
N
3i
R1
O
3e
: 70%
H
O
: R1 = 3-F,54%b
: R1 = 4-F, 56%b
: R1 = 4-Cl, 62%b
3n
H
O
H
O
3j
: R1 = OMe, 67%b
F
N
3o
3p
3q
3r
R1
N
: R1 = OCF3, 38%
Me
N
3k
3l
: R1 = CO2Me, 75%
: R1 = 4-Me, 60%b
3
: R1 = NO2, 77%
3m
F
4
: R1 = 4-CO2Me, 74%
R1
3s
: 69%
H
O
H
O
H
O
H
O
Me
N
MeO2
C
N
MeO
N
N
O
N
X
F
F
OMe
3v
: X = Br, 55%
3x
: 43%
3u
3w
: X = I, 51%
: 50%
3t
N
: 52%
O
H
O
H
O
O
H
O
N
N
H
O
MeO
N
N
N
N
: R1 = F, 42%c
: R1 = Cl, 47%c
: R1 = Br, 44%c
3aa
3ab
3ac
CO2Me
NBoc2
N
Me
R1
c,d
3y
3z
: 44%
: 74%
3ad
: 26%
aAll reactions were performed on a 0.2 mmol scale. Isolated yields
Catellani
reaction
conditions,4a
the
intramolecular
b
c
were reported. 2a was added in two portions. 2.0 equiv of 2a
and 4.0 equiv of K2CO3 were applied. dThe reaction was
performed at 80 oC.
Suzuki−Miyaura coupling product 5 was isolated as the major
component, alongside the minor Catellani-type amination
product 6 formed through intramolecular Suzuki−Miyaura
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
A) Scale-up experiment
Bpin
deuterium incorporation (65%) at the ipso positiVoienw (AErtqiculeaOtniloinne
D). These experimental results indicatedDthOaI:t10b.o10th39t/hCe9SpCr0o2t7o59nAs
from ortho-C‒H of pinacol arylborate and the adventitious
water in the reaction system are the sources for the Catellani
termination step, but not from the solvent DMSO. The erosion
of deuterium incorporation ratio in equation C and D was
probably due to the facile H-D exchange with water in the
reaction system.8 Thus, these results support the redox-neutral
ipso-protonation mechanism proposed in Scheme 1C.
H
O
Pd(OAc)2 (10 mol%)
NBE (2.0 equiv)
OBz
N
N
+
O
K2CO3 (2.5 equiv)
DMSO/dioxane, air, 70 o
C
1a
2a
(6 mmol, 1.24 g)
3a
(9 mmol, 1.5 equiv)
(72%, 0.92 g)
B) Orthogonal reactivity
I
I
Classic Catellani
Amination
(1)
O
Ph
Borono-Catellani
Amination
2a
O
O
N
O
Bpin
H
N
standard
condition
2a
+
PhBpin
1w
3w
4
N
: 51%
: 71%
O
O
Classic Catellani
Amination
2a
+
iPrOH
(<0.01 D)
H/D
(2)
Pd(OAc)2 (10 mol%)
NBE (2.0 equiv)
Bpin
O
O
N
K2CO3 (2.5 equiv)
O
H
+
+
2a
2a
(A)
(B)
N
6/dioxane, air, 70 o
82%
C
DMSO-d
N
O
1a
1a
3a-d
+
Bpin
O
O
(<0.01 D)
H/D
Pd(OAc)2 (10 mol%)
NBE (2.0 equiv)
K2CO3 (2.5 equiv)
7
5
: not isolated
: 84%
Bpin
6
: 12%
O
N
C) Synthetic application
O
DMSO/
8, air, 70 o
C
O
N
dioxane-d
O
H
N
61%
N
N
3a-d
N
Ullmann-Ma amination
N
H
N
OH
(0.20 D)
H/D
Ref. 1e
NH2
Pd(OAc)2 (10 mol%)
NBE (2.0 equiv)
K2CO3 (2.5 equiv)
Ref. 20
D
D
Bpin
N
O
MeN
Me
D
O
X = Cl, 61% (90% brsm)
X = Br, 64%
X
N
D
D
D
D
D
D
N
D
O
O
2a
+
(C)
DMSO/dioxane, air, 70 o
61%
C
3ab 3ac
,
8
9
EphB4 kinase inhibitor
D
1a-d7
D
D
D
3a-d
Reagents and conditions: (1) Pd(OAc)2, (2-furyl)3P, NBE, Cs2CO3,
toluene, 80 oC, Ar, 20 h; (2) Pd(OAc)2, P(pOMe-C6H4)3, NBE, Cs2CO3,
toluene, 100 oC, Ar, 24 h.
(0.65 D)
H/D
Pd(OAc)2 (10 mol%)
NBE (2.0 equiv)
K2CO3 (2.5 equiv)
D
Bpin
O
D
D
D
D
N
D
(D)
+
2a
DMSO/dioxane, air, 70 o
D2O (4.0 equiv)
56%
C
D
D
D
D
Scheme 2 Scale-up experiment and synthetic applications
D
D
3a-d
1a-d7
termination.18 The Catellani-type ortho-C‒H amination product
7 generated by protonation termination was not isolated
(Scheme 2B). Hence, the orthogonal reactivity between these
two types of Catellani reactions was demonstrated.
Furthermore, the synthetic utility of the obtained ortho-C-H
amination products was demonstrated in Scheme 2C. The 3,5-
bisaminated aryl halides 3ab and 3ac from Table 2 were readily
transformed to 3,5-di(morpholino)aniline 8, the useful common
intermediate to prepare various potent EphB4 kinase
inhibitors,19 in good yields through the Ullmann-Ma
amination.20 It is noteworthy that 8 was previously prepared in
three steps from expensive starting materials.21
Scheme 3 Preliminary mechanistic studies.
Conclusions
In summary, we have developed a palladium(II)/norbornene
cooperative catalysis enabled redox-neutral ortho-C‒H
amination of pinacol aryl- or heteroarylborates for the synthesis
of structurally diverse anilines. This method is scalable, robust
(tolerance of air and moisture), phosphine ligand-free, and
compatible with a wide range of functionalities. These practical
features make this reaction amenable for industry. It is
especially noteworthy that a plethora of synthetically very
useful halogenated anilines, which often cannot be prepared via
other transition-metal-catalyzed aminations, are readily
produced using this method. Particularly, the tolerance of the
iodo function enables the orthogonal reactivity between
pinacol arylborate and aryl iodides. Preliminary deuterium-
Finally, to probe the proton source of the termination step
and gain mechanistic insights into this reaction, the deuterium-
labeling experiments were performed (Scheme 3). First, an
experiment regarding the reaction between 1a and 2a in DMSO-
d6 instead of normal DMSO under the standard reaction
conditions led to the isolation of product 3a without any
deuterium incorporation (Equation A); the same deuterium
results were obtained when the 1,4-dioxane-d8 instead of 1,4-
dioxane was used as the cosolvent (Equation B). These results
indicated that the termination step didn’t involve reductive
elimination of [ArPdH] species with hydride from the solvents.22
labeling studies reveal
a redox-neutral ipso-protonation
mechanism of this process, which will surely inspire the future
development of this research field. Overall, the exceptionally
broad scope and reliability of this procedure, together with the
wide availability of pinacol arylborates, make this chemistry a
valuable addition to the existing methods for anilines synthesis.
23
Then, the fully deuterated 1a-d7 was used as the substrate
(see SI for its preparation), and 20% deuterium incorporation at
the ipso position of product 3a was found (Equation C). Lastly,
when 1a-d7 reacted with 2a under the standard reaction
conditions with 4.0 equiv of D2O as the additive, 3a was isolated
in a lower yield (56%) but with a significantly increased
Conflicts of interest
The authors declare no competing financial interests
.
4 | J. Name., 2012, 00, 1-3
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Liu, Q. Gao, H.-G. Cheng and Q. Zhou, Chem. Eur. J., 2018, 24,
Acknowledgements
15461–15476; g) H.-G. Cheng, S. Chen, R. ChenViaenwdArtQic.leZOhnolinue,
DOI: 10.1039/C9SC02759A
Angew. Chem. Int. Ed., 2019, 58, 5832–5844; h) J. Wang and G.
Dong, 2019, 10.1021/acs.chemrev.9b00079; For selected
recent works, see: i) Y. Yamamoto, T. Murayama, J. Jiang, T.
Yasui and M. Shibuya, Chem. Sci., 2018, 9, 1191–1199; j) Z.-S
Liu, G. Qian, Q. Gao, P. Wang, H.-G. Cheng, Q. Wei, Q. Liu and
Q. Zhou. ACS Catalysis., 2018, 8, 4783–4788; k) R. Li and G.
Dong, Angew. Chem. Int. Ed., 2018, 57, 1697 –1701; l) Q. Zhao,
W. C. Fu and F. Y. Kwong, Angew. Chem. Int. Ed., 2018, 57,
3381–3385; m) H.-G. Cheng, C. Wu, H. Chen, R. Chen, G. Qian,
Z. Geng, Q. Wei, Y. Xia, J. Zhang, Y. Zhang and Q. Zhou, Angew.
Chem. Int. Ed., 2018, 57, 3444–3448; n) L. Bai, J. Liu, W. Hu, K.
Li, Y. Wang and X. Luan, Angew. Chem. Int. Ed., 2018, 57, 5151
–5155; o) G. Qian, M. Bai, S. Gao, H. Chen, S. Zhou, H.-G. Cheng,
W. Yan and Q. Zhou, Angew. Chem. Int. Ed., 2018, 57, 10980–
10984; p) C. Wu, H.-G. Cheng, R. Chen, H. Chen, Z.-S. Liu, J.
Zhang, Y. Zhang, Y. Zhu, Z. Geng and Q. Zhou. Org. Chem. Front.,
2018, 5, 2533–2536; q) F. Liu, Z. Dong, J. Wang, and G. Dong,
Angew. Chem. Int. Ed., 2019, 58, 2144–2148; r) Q. Gao, Z.-S. Liu,
Y. Hua, L. Li, H.-G. Cheng, H. Cong and Q. Zhou. Chem. Comm.
DOI: 10.1039/C9CC03126J.
a) G. Shi, C. Shao, X. Ma, Y. Gu and Y. Zhang, ACS Catal., 2018,
8, 3775–3779; b) S. Chen, Z.-S. Liu, T. Yang, Y. Hua, Z. Zhou, H.-
G. Cheng and Q. Zhou, Angew. Chem. Int. Ed., 2018, 57, 7161–
7165; c) P. Wang, S. Chen, Z. Zhou, H.-G. Cheng and Q. Zhou,
Org. Lett., 2019, 21, 3323–3327.
Very recently, the Dong group reported an elegant ortho
acylation of aryl boroxines via palladium/norbornene
cooperative catalysis, see: R. Li, F. Liu and G. Dong, Chem.,
2019, 5, 929–939. In their research, the pinacol arylborates are
unreactive substrates. They also reported the ortho amination
of aryl boroxines (six examples), which required triphenyl
phosphite as the ligand, CsI and benzoquinone (BQ) as the
additives.
We are grateful to the National Natural Science Foundation of
China (Grants 21602161, 21871213, 21801193), the National
“1000-Youth Talents Plan”, start-up funding from Wuhan
University, and the China Postdoctoral Science Foundation
(2016M602339, 2018M642894) for financial support. We thank
Prof. W.-B. Liu (WHU) for sharing the instruments and Ms Q.
Gao for checking the experiments. We thank Prof. D. Ma (SIOC)
for sharing the oxalamide ligands.
Notes and references
1
a) E. Vitaku, D. T. Smith and J. T. Njardarson, J. Med. Chem.,
2014, 57, 10257–10274; b) S. Basoglu, M. Yolal, A. Demirbas, H.
Bektas, R. Abbasoglu and N. Demirbas, Turk. J. Chem., 2012, 36,
37–53; c) A. Inoue, S. Miki, M. Seto, T. Kikuchi, S. Morita, H.
Ueda, Y. Misu and Y. Nakata, Eur. J. Pharm., 1997, 321, 105–
111; d) K. Prasad, K. Srinivas, A. Pallavi and K. Mukkanti, Drug.
Test. Analysis., 2018, 10, 212–221; e) B. Barlaam, R. Ducray, C.
Lambert-van der Brempt, P. Ple, C. Bardelle, N. Brooks, T.
Coleman, D. Cross, J. G. Kettle and J. Read, Bioorg. Med. Chem.
Lett., 2011, 21, 2207–2211.
For aniline synthesis through copper catalyzed C‒N bond
formation, see: a) S. V. Ley and A. W. Thomas, Angew. Chem.
Int. Ed., 2003, 42, 5400–5449; b) C. Sambiagio, S. P. Marsden,
A. J. Blacker and P. C. McGowan, Chem. Soc. Rev., 2014, 43,
3525–3550; c) S. Bhunia, G. G. Pawar, S. V. Kumar, Y. Jiang and
D. Ma, Angew. Chem. Int. Ed., 2017, 56, 16136–16179. For
anilines synthesis through nickel catalyzed C‒N bond formation,
see: d) M. Marín, R. J. Rama and M. C. Nicasio, Chem. Rec., 2016,
16, 1819–1832. For anilines synthesis through cobalt catalyzed
C-N bond formation, see: e) M. Usman, Z.-H. Ren, Y.-Y. Wang
and Z.-H. Guan, Synthesis, 2017, 49, 1419–1443; f) Y.-H. Chen,
S. Grassl and P. Knochel, Angew. Chem. Int. Ed., 2018, 57, 1108–
1111. For anilines synthesis through transition metal-free C‒N
bond formation, see: g) C. Zhu and J. R. Falck, Adv. Synth. Catal.,
2014, 356, 2395–2410.
7
8
2
9
For palladium(IV)-involved aminations, see: a) J. A. Jordan-Hore,
C. C. Johansson, M. Gulias, E. M. Beck and M. J. Gaunt, J. Am.
Chem. Soc., 2008, 130, 16184–16186; b) T. Mei, X. Wang and J.-
Q. Yu, J. Am. Chem. Soc., 2009, 131, 10806–10807. However,
another mechanism involving direct nucleophilic substitution
of the amination reagent 2 by arylpalladium(II) species (II) can’t
be excluded, see related references: c) A. M. Berman and J. S.
Johnson, J. Am. Chem. Soc., 2004, 126, 5680–5681; d) T. J.
Barker and E. R. Jarvo, J. Am. Chem. Soc., 2009, 131, 15598–
15599; e) G. Cheng, T.-J. Li and J.-Q. Yu, J. Am. Chem. Soc., 2015,
137, 10950–10953.
3
4
a) F. Paul, J. Patt and J. F. Hartwig, J. Am. Chem. Soc., 1994, 116,
5969–5970; b) A. S. Guram and S. L. Buchwald, J. Am. Chem.
Soc., 1994, 116, 7901–7902; c) J. F. Hartwig, Acc. Chem. Res.,
2008, 41, 1534–1544; d) D. S. Surry and S. L. Buchwald, Angew.
Chem. Int. Ed., 2008, 47, 6338–6361.
For seminal work, see: a) Z. Dong and G. Dong, J. Am. Chem.
Soc., 2013, 135, 18350–18353. For selected following studies,
see: b) Z.-Y. Chen, C.-Q. Ye, H. Zhu, X.-P. Zeng and J.-J. Yuan,
Chem. - Eur. J., 2014, 20, 4237–4241; c) P.-X. Zhou, Y.-Y. Ye, J.-
W. Ma, L. Zheng, Q. Tang, Y.-F. Qiu, B. Song, Z.-H. Qiu, P.-F. Xu
and Y.-M. Liang, J. Org. Chem., 2014, 79, 6627–6633; d) F. Sun
and Z. Gu, Org. Lett., 2015, 17, 2222–2225; e) H. Shi, D. J.
Babinski and T. Ritter, J. Am. Chem. Soc., 2015, 137, 3775–
3778; f) B. Luo, J.-M. Gao and M. Lautens, Org. Lett., 2016, 18,
4166–4169; g) P. Wang, G.-C. Li, P. Jain, M. E. Farmer, J. He, P.-X.
Shen and J.-Q. Yu, J. Am. Chem. Soc., 2016, 138, 14092–14099;
h) W. C. Fu, B. Zheng, Q. Zhao, W. T. K. Chan and F. Y. Kwong,
Org. Lett., 2017, 19, 4335–4338; i) L. Fan, J. Liu, L. Bai, Y. Wang
and X. Luan, Angew. Chem. Int. Ed., 2017, 56, 14257–14261.
Z. Dong, G. Lu, J. Wang, P. Liu and G. Dong, J. Am. Chem. Soc.,
2018, 140, 8551–8562.
For seminal work, see: a) M. Catellani, F. Frignani and A.
Rangoni, Angew. Chem., Int. Ed. Engl., 1997, 36, 119–122. For
selected reviews, see: b) M. Catellani, Top. Organomet. Chem.,
2005, 14, 21–53; c) M. Catellani, E. Motti and N. Della Ca’, Acc.
Chem. Res., 2008, 41, 1512–1522; d) J. Ye and M. Lautens, Nat.
Chem., 2015, 7, 863–870; e) N. Della Ca’, M. Fontana, E. Motti
and M. Catellani, Acc. Chem. Res., 2016, 49, 1389–1400; f) Z.-S.
10 For selected Catellani-type studies involving redox-neutral
protonation as the termination step, see: a) L. Jiao and T. Bach,
J. Am. Chem. Soc., 2011, 133, 12990–12993; b) L. Jiao, E.
Herdtweck and T. Bach, J. Am. Chem. Soc., 2012, 134, 14563–
14572; c) X.-C. Wang, W. Gong, L.-Z. Fang, R.-Y. Zhu, S. Li, K. M.
Engle and J.-Q. Yu, Nature, 2015, 519, 334–338; d) Z. Dong, J.
Wang and G. Dong, J. Am. Chem. Soc., 2015, 137, 5887–5890;
e) H. Zhang, H.-Y. Wang, Y. Luo, C. Chen, Y. Cao, P. Chen, Y.-L.
Guo, Y. Lan and G. Liu, ACS Catal., 2018, 8, 2173–2180. For a
review about protodepalladation, see: f) M. L. O’Duill and K. M.
Engle, Synthesis., 2018, 50, 4699–4714.
11 The oxidation state of the palladium complexes may be always
kept at two throughout the catalytic cycle. For selected
examples, see: a) Y.-H. Zhang, B.-F. Shi and J.-Q. Yu, Angew.
Chem. Int. Ed., 2009, 48, 6097–6100; and ref.9f.
12 For mechanism studies on Catellani-type reactions, see: a) M.
Catellani and B. E. Mann, J. Organomet. Chem., 1990, 390, 251–
255; b) G. Bocelli, M. Catellani and S. Ghelli, J. Organomet.
Chem., 1993, 458, C12–C15; c) B. Martín-Matute, C. Mateo, D.
J. Cárdenas and A. M. Echavarren, Chem. Eur. J., 2001, 7, 2341–
2348; d) D. J. Cárdenas, B. MartínMatute and A. M. Echavarren,
J. Am. Chem. Soc., 2006, 128, 5033–5040; e) G. Maestri, E.
5
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Motti, N. Della Ca’, M. Malacria, E. Derat and M. Catellani, J.
View Article Online
Am. Chem. Soc., 2011, 133, 8574–8585; f) D. I. Chai, P.
Thansandote and M. Lautens, Chem. Eur. J., 2011, 17, 8175–
8188.
DOI: 10.1039/C9SC02759A
13 a) S. N. Mlynarski, A. S. Karns and J. P. Morken, J. Am. Chem.
Soc., 2012, 134, 16449–16451; b) C. Zhu, G. Li, D. H. Ess, J. R.
Falck and L. Kürti, J. Am. Chem. Soc., 2012, 134, 18253–18256;
and ref. [2g].
14 D. V. Partyka, Chem. Rev., 2011, 111, 1529–1595.
15 M. Kotora and T. Takahashi in Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 1 (Ed.: E.-i. Negishi), Wiley,
New York, 2002, pp. 973–993.
16 J.-P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651–2710.
17 R. D. Taylor, M. MacCoss and A. D. G. Lawson, J. Med. Chem.,
2014, 57, 5845–5859.
18 C. Ye, H. Zhu and Z. Chen, J. Org. Chem., 2014, 79, 8900–8905.
19 a) C. Bardelle, Bernard. Barlaam, N. Brooks, T. Coleman, D.
Cross, R. Ducray, I. Green, C. Lambert-van der Brempt, A. Olivier
and Jon. Read, Bioorg. Med. Chem. Lett., 2010, 20, 6242–6245;
b) K. Ebert, J. Wiemer, J. Caballero, M. Köckerling, J. Steinbach,
J. Pietzsch and C. Mamat, Bioorg. Med. Chem., 2015, 23, 6025–
6035. And ref. 1e.
20 a) M. Fan, W. Zhou, Y. Jiang and D. Ma, Org. Lett., 2015, 17,
5934−5937; b) J. Gao, S. Bhunia, K. Wang, L. Gan, S. Xia and D.
Ma, Org. Lett., 2017, 19, 2809−2812.
21 For the general method for the synthesis of 8, see: ref. 19b.
22 For a precedent using ethers (eg. DME) as the hydride source,
see: A. Martins, D. A. Candito and M. Lautens, Org. Lett., 2010,
12, 5186−5188.
23 F. Mo, J. Yan, D. Qiu, F. Li, Y. Zhang and J. Wang, Angew. Chem.
Int. Ed., 2010, 49, 2028–2032.
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