Catalyst-Directed Chemoselective Double Amination of Bromo-chloro(hetero)arenes: A Synthetic Route toward Advanced Amino-aniline Intermediates

Article abstract of DOI:10.1021/acs.orglett.8b00646

A chemoselective sequential one-pot coupling protocol was developed for preparing several amino-anilines in high yield as building blocks for active pharmaceutical ingredients (APIs). Site (Cl vs Br on electrophile) and nucleophile (amine vs imine) selectivity is dictated by the catalyst employed. A Pd-crotyl(t-BuXPhos) precatalyst selectively coupled the Ar-Br of the polyhaloarene with benzophenone imine, even in the presence of a secondary amine, while Pd-based RuPhos or (BINAP)Pd(allyl)Cl coupled the Ar-Cl site with secondary amines.

Full text of DOI:10.1021/acs.orglett.8b00646

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalyst-Directed Chemoselective Double Amination of
Bromo-chloro(hetero)arenes: A Synthetic Route toward
Advanced Amino-aniline Intermediates
Alexandre A. Mikhailine, Gabriela A. Grasa Mannino, and Thomas J. Colacot*
Johnson Matthey, 2001 Nolte Drive, West Deptford, New Jersey 098066, United States
S
* Supporting Information
ABSTRACT: A chemoselective sequential one-pot coupling protocol was developed for preparing several amino-anilines in high
yield as building blocks for active pharmaceutical ingredients (APIs). Site (Cl vs Br on electrophile) and nucleophile (amine vs imine)
selectivity is dictated by the catalyst employed. A Pd-crotyl(t-BuXPhos) precatalyst selectively coupled the Ar−Br of the
polyhaloarene with benzophenone imine, even in the presence of a secondary amine, while Pd-based RuPhos or (BINAP)Pd(allyl)Cl
coupled the Ar−Cl site with secondary amines.
applications.14 Notable examples include new oncology drugs
ombining a multistep synthesis into a one-pot protocol dra-
Cmatically increases the process efficiency, safety, and eco- such as anaplastic lymphoma kinase (ALK) tyrosine kinase
receptor inhibitor Brigatinib14c and drug candidates such as ATP-
nomics, in addition to making the synthesis environmentally
competitivecyclin-dependent kinase (CDK)Milciclib14a and selec-
friendly by limiting the isolation, purification, and exposure of the
tive FAK inhibitor PND-118614b (Figure 1A).
intermediates.1 Despite obvious advantages, the practicality of
multicomponent reactions is limited due to challenges associated
with the selectivity, which can lead to byproduct formation.
In theory, orthogonal reactivity provided by the different catalytic
systems can be effectively utilized for selective one-pot trans-
formations with higher control over the selectivity.2 The use of
catalytic sequential multicomponent reactions was earlier demon-
strated for the selective coupling of various nucleophiles with
polyhaloarenes. Initial reports from the Heck group highlighted
the sequential alkenylation of di-iodo- and bromo-iodo-benzene.3
However, the selectivity and overall yield of the reactions were
poor. The scope of selective sequential coupling reactions was
subsequently extended to borylation−Suzuki,4 Suzuki−Suzuki,5
Heck−Suzuki,6 Heck−Sonogashira,7 and Heck−Heck7,8 cou-
pling reactions. Aromatic and heteroaromatic amines have also
been accessed by exploiting sequential amination−Sonogashira9
and amination−Suzuki−Stille reactions.10 Intra- and intermo-
lecular double-N-arylation11 were also employed for the
synthesis of carbazole12 and triaryl amines,13 respectively. Both
selectivity and efficiency of the processes were enhanced for
those reactions that utilized well-defined catalytic systems con-
taining specialty ligands.4b,c
The most common strategy to prepare amino-anilines involves
a two-step synthesis: amination of a nitro-haloarene via noncatalytic
nucleophilic aromatic substitution, followed by Pd/C-catalyzed
reduction of nitro groups (Figure1B, top).15 The utility is restricted
due to limited substrate scope, poor functional group tolerance of
the nucleophilic aromatic substitution, limited substrate availability,
and cost.16 The free amino-anilines are known to undergo oxidative
degradation during workup, isolation, and storage. These advanced
intermediates are often used toward the end of the synthesis of
complex drug molecules. Therefore, the impurity profile may
impose complications during the purification process, thereby
incurring lower overall efficiency and process economics. In order
to address these limitations, we were interested in preparing
protected amino-anilines via a sequential catalytic double
amination of dihaloarenes (Figure 1B, bottom) with secondary
amines and an ammonia generating imine. This synthetic strategy
would also provide access to a library of intermediates for quick
availability at the drug discovery stage.17
The Pd-catalyzed coupling of secondary amines is well estab-
lished in the literature.18 The direct synthesis of primary aryl amines
using ammonia with an aryl halide has not become a practical
method due to low functional group tolerance of the substrates
The amino-aniline linkage that encompasses both NH2 and
secondary amine functionalities on a single terminal aryl or hetero-
aryl ring is an important pharmaceutical core that is encountered
in new drugs and drug candidates with various therapeutic
Received: February 23, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00646
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reported to be effective for imination and secondary amination,
respectively by Buchwald and others.18a,21a,24 The selectivity of
the precatalysts was first examined in a model three-component,
4-vector reaction mixture, containing 1-bromo-3-chlorobenzene,
piperidine, and benzophenone imine (Table 1).
At room temperature, C1 showed exceptional selectivity
toward the formation of product 2, while C2 was practically
inactive at room temperature (Table 1, entries 1 and 2). The
predominant formation of product 2 was also observed when
both precatalysts were present in the reaction mixture, indicating
that C2 does not interfere with the performance of C1 (entry 3).
The reaction involving C1 at 22 °C for 90 min, followed by
heating at 80 °C, gave the desired product 6 in poor yield (entry 4).
This result shows that C1 efficiently and selectively catalyzes the
coupling of the benzophenone imine in the presence of piperi-
dine, but it is a poor catalyst for the amination with piperidine
(secondary amine) even at elevated temperatures. When the
reaction was performed in the presence of imine and piperidine
at 80 °C, precatalyst C2 showed no conversion to the desired
product 6 (entry 5). Surprisingly, when the reaction was repeated
with no imine, aminated product 3 was isolated quantitatively,
indicating that the imine is deterring the efficiency of C2 (entry 6).
The reaction, where both precatalysts were present, gave 6 in
good yield (entry 7), with major byproducts 4 and 5. These
originated from undesired amination during the first coupling
step. To determine whether the use of preisolated C2 can be
eliminated, RuPhos (L2) was added, instead of C2. Product 6 was
obtained in 83% yield, indicating that ligand exchange is taking
place at elevated temperature to provide the required metal ligand
combination for the second coupling to occur (entry 8 vs 7).25
It should be noted that the reaction conditions could be further
fine-tuned for individual substrates to gain optimal selectivity
toward the desired product.
The conditions for the one-pot sequential coupling (entry 8)
were successfully applied to various bromo-chloro(hetero)arene
electrophiles. The isolated yields of the amino-anilines after imine
cleavage are reported, with the conversions of the corresponding
imine protected anilines in parentheses (Scheme 2). The amina-
tion of unsubstituted meta- and para- bromo-chlorobenzene
resulted in selective formation of 7 and 8 in good yields, while the
ortho-substituted substrate gave no appreciable amount of 9. The
sequential coupling of methoxy- (10−12), fluoro- (13 and 14),
and methyl- (15−17) substituted bromo-chloro-arenes gave the
desired products in good to excellent yields, with exceptional
selectivity. However, higher catalyst loadings were required to
achieve full conversions for 11, 12, 14, 16, and 17.
Figure 1. (A) Examples of relevant pharmaceutical targets. (B) Synthetic
routes for the preparation of amino-anilines.
and potential overamination.19 More reliable ammonia surro-
gates such as benzophenone imine or carbamates are more
desirable,18a,20 as the deprotection process is high yielding and
scalable under mild conditions.21
A four-vector catalytic reaction involving oxidative addition,
transmetalation, and reductive elimination steps, in the presence
of a nonselective catalyst, assuming full conversion, can statis-
tically generate a complex mixture of products (Scheme 1).
Scheme 1. Possible Product Distribution Arising from 4-Vector
Coupling Reaction
The product arising from this ortho isomer (9) is a chelating
ligand, capable of replacing a phosphine ligand from the
Pd-coordination sphere. The resulting catalyst poisoning may be
responsible for the poor reactivity observed for this electrophile,
compared to para- and meta-isomers.
Finally, coupling of pyridine-based substrates was attempted
using a C1/L2 mixture as a catalytic system, which gave chloro-
iminopyridines (monocoupled) as the major product, regardless
of the amount of substrate, catalyst loading, temperature, and
reaction time. Similarly, poor reactivities have been reported
for substrates containing pyridine rings, where the catalyst is
deactivated via Pd-pyridine coordination.The catalysts contain-
ing chelating ligands, on the other hand, exhibited an increased
stability toward coordinating substrates and showed superior
activity.26 To test this concept, a precatalyst, containing a che-
lating ligand ((R-BINAP)Pd(allyl)Cl), was used in place of L1 to
obtain the desired coupling products (18−20) in excellent yields.
The reactivity has commonly been proclaimed to depend on C−X
bond dissociation energy, although the nature of the catalyst,
solvent, and other reaction parameters are also known to be
important.22,23 The selectivity of the subsequent transmetalation
and reductive elimination steps will primarily depend on the
propensity of the catalytically active species to interact with one
nucleophile over the other (e.g., amine vs imine) to generate up
to four possible products (Scheme 1). We have undertaken this
investigation with an objective of finding catalytic systems that
will be highly selective for directed, streamlined oxidative addi-
tion and transmetalation steps toward the formation of the desired
product (Scheme 1, B and/or D).
Initial selectivity tests were performed using t-BuXPhos
(L1)- and RuPhos (L2)-based catalysts, which were previously
B
DOI: 10.1021/acs.orglett.8b00646
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Organic Letters
Letter
a
Table 1. Selectivity and Activity of Palladium Precatalysts toward Sequential Double Amination of 1-Bromo-3-chlorobenzene (1)
c
c
c
c
c
c
entry
cat.
C1
t (°C)
22
1 (%)
2 (%)
3 (%)
4 (%)
5 (%)
6 (%)
1
2
3
4
5
6
7
8
1
92
0
89
4
10
4
0
0
0
0
0
0
C2
22
b
b
C1/C2
C1
22
88
68
9
12
9
0
0
0
d
d
22−80
22−80
0
10
0
0
13
0
C2
87
0
4
0
e
C2
80
0
87
0
0
13
10
8
0
d
d
C1/C2
22−80
22−80
0
0
14
9
76
83
f
C1/L2
0
0
0
a
Conditions: 2.5 mmol of NaOt-Bu, 1.0 mmol of 1, 1.1 mmol of benzophenone imine, 1.1 mmol of piperidine, 1.2 mol % of catalyst, 4 mL of THF,
b
c
d
with reaction time of 1.5 h. 1.2 mol % of C1 and 1.2 mol % of C2. Determined as relative integrations of GC peaks. Reacted for 1.5 h at 22 °C
followed by 2 h at 80 °C. Imine was not added to the reaction mixture. 1.2 mol % of C1 and 1.2 mol % of L2.
e
f
Scheme 2. Substrate Scope of Double Amination of
(Hetero)aryl-dihalides
Addition of R-BINAP as a ligand instead of C3 gave inferior
results, unlike in the earlier cases.
a
Unfortunately, only activated 2-chloro-substituted pyridines
yielded the desired products, indicating the importance of the
activated carbon−chloride vector for a successful reaction. We are
currently exploring other catalysts to resolve this limitation. It should
be noted that the products 18 and 19 are isolated as protected
anilines, because their corresponding free amines are unstable.
Particularly, decomposition was more pronounced with the aniline
derived from 19. This observation illustrates an additional advan-
tage of this method, compared to the conventional preparation
routes.
Unsubstituted para- and meta-1-bromo-chlorobenzene were
chosen to explore the reactivity of different secondary amines in
the sequential amination (Scheme 3). The coupling of important
(hetero)cyclic amines, such as N-methyl piperazine and
morpholine, gave 21, 28 and 22, 29 in good yields, respectively.
The reaction of acyclic aliphatic and aromatic secondary amines
successfully gave the desired products in good yields (23−25 and
30−32). Slightly lower yields were observed with bicyclic amines
featuring an adjacent benzene ring, when approximately 20% for-
mation of the diamine byproduct was observed (26, 27, 33, and 34).
Considering the complexity of the multicomponent or catalyst-
controlled one-pot reactions, the results of this study are quite
impressive from an academic point of view. On the other hand,
higher efficiency of the process is usually preferred for industrial
applications. To maximize the potential of these findings, exper-
iments were conducted, where the secondary amine was added
after the completion of the first coupling step. The yields of the
final products were increased by 5−25% (21, 22, 32−34), while
still enjoying the benefits of the one-pot reaction.
a
Conditions: 2.5 mmol of NaOt-Bu, 1.0 mmol of aryl-dihalide,
1.1 mmol of benzophenone imine, 1.1 mmol of amine, 1.2 mol % of
C1 and 1.2 mol % of L2, 4 mL of THF, 1.5 h at 22 °C followed by 12 h
at 80 °C. Yields reported: isolated; in parentheses GC-yield of the imine
product. 3.6 mol % of C1 and 3.6 mol % of L2. 2.4 mol % of C1 and
2.4 mol % of L2. 1.0 mol % of C1 and 2.0 mol % of C3. 2.0 mol % of
b
c
d
e
f
The practical utility of the one-pot protocol was further dem-
C1 and 4.0 mol % of C3. The product was isolated as imine protected
aniline, due to poor stability of the corresponding amino-anilline.
onstrated by synthesizing a precursor used for the preparation of
C
DOI: 10.1021/acs.orglett.8b00646
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Letter
a
Scheme 3. Reactivity of Various Amines in the Sequence
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00646.
■
S
Experimental procedures and characterization data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: thomas.colacot@jmusa.com; tcolacot@yahoo.com.
ORCID
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Thomas J. Colacot: 0000-0001-9976-1376
Notes
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The authors declare the following competing financial interest(s):
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Catalysts and organic intermediates will be made commercial.
(b) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
D
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