Synthesis of Secondary Amides through the Palladium(II)-Catalyzed Aminocarbonylation of Arylboronic Acids with Amines or Hydrazines and Carbon Dioxide

Article abstract of DOI:10.1002/ejoc.201701802

A new Pd-catalyzed aminocarbonylation of arylboronic acids with amines or phenylhydrazines has been developed. Various secondary amides were produced from readily available substrates and cheap common metal catalysts in a CO atmosphere (balloon). Remarkably, we presents the first example of aminocarbonylations between arylboronic acids and phenylhydrazines.

Full text of DOI:10.1002/ejoc.201701802

A Journal of
Accepted Article
Title: Synthesis of Secondary Amides through Palladium(II)-catalyzed
Aminocarbonylation of Arylboronic Acids with Amines /
Hydrazines and CO
Authors: Jin Zhang, Yuqiang Ma, and Yangmin Ma
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701802
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701802
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10.1002/ejoc.201701802
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of Secondary Amides through Palladium(II)-catalyzed
Aminocarbonylation of Arylboronic Acids with Amines /
Hydrazines and CO
Jin Zhang, *[a] Yuqiang Ma,[a] and Yangmin Ma *[a][b]
Dedication ((optional))
[7]
Abstract: A novel Pd-catalyzed aminocarbonylation of arylboronic
acids with amines or phenylhydrazines has been developed. Various
secondary amides were produced by the utility of readily available
substrates and cheap common metal catalysts in CO atmosphere
(balloon). Remarkably, this represents the first example of
source.
Organoboronic acids were recognized to be readily
available, nontoxic and moisture-stable sources of carbon
nucleophiles, [8] their use in the preparation of amides became
particularly convenient in recent years.
[9]
More recently, two
different approach with N-chloroamines and organoboronic acids
to prepare tertiary amides were achieved by Wu’s group under
high CO pressure. [10] Jiao’s group developed a direct approach
to tertiary amides with organoboronic acids and amines as
starting materials. [11] However, the applicability for second aryl
amides was less effective (<10% yield). Herein, we report a
direct approach to prepare secondary amides with arylboronic
acids, primary amines or phenylhydrazines in the presence of
CO (balloon). To the best of our knowledge, this represents the
first example on aminocarbonylative of organoboronic acids with
phenylhydrazines.
aminocarbonylation
phenylhydrazines.
between
arylboronic
acids
and
Introduction
Amide bonds are present in a vast array of useful molecules
including numerous industrially important compounds, as well as
a wide selection of bioactive natural products. For example, the
amide bond is found in up to 25% of all pharmaceuticals on the
[1]
market,
and it was present in 2/3 of drug candidates which
were surveyed by three leading pharmaceutical companies in
2006. [2] Traditional methods for amide synthesis include the use
of activated carboxylic acid derivatives, such as acyl chlorides or
anhydrides, as well as the use of stoichiometric amounts of
[3]
coupling agents.
Usually, most of these methodologies are
associated with significant drawbacks such as long reaction
times, harsh reaction conditions, low to moderate yields and
poor atom-economy. Due to these issues, as well as the
importance of the amide bond in the pharmaceutical industry, a
catalytic and waste-free production of amides was voted a
highlighted area of research by the American Chemical Society’s
(ACS) Green Chemistry Institute (GCI) Pharmaceutical
Roundtable (PR) in 2005. [4] Therefore, the developments of new
and more efficient methods for amides synthesis are still under
current request. [5]
Transition metal-catalyzed aminocarbonylation reactions
have already become a powerful toolbox in amides preparation.
Scheme 1. General strategies for aminocarbonylation of arylboronic acids with
amines
[6]
Amides can be effectively produced by introducing carbon
monoxide into the parent compounds with amines as the
coupling partner. However, most of the developed procedures
are facing two challenges: employing aryl halides as the
electrophiles and using high pressure CO as the carbonyl
Results and Discussion
Initially, phenylboronic acid (1a) and aniline (2a) were chosen as
the model substrates to explore the reaction conditions. These
two coupling partners were reacted with 5 mol% PdCl2, 2
equivalents of CuCl, CO (balloon) and 5 mol % PPh3 as a ligand
in anisole heated at 100 oC for 24 h, which afforded N-
phenylbenzamide (3aa) in 43% yield (Table 1, entry 1). Other
palladium catalyst such as Pd(OAc)2, Pd(PPh3)2Cl2, Pd(dppf)Cl2
were also tested (Table 1, entries 2-4), and Pd(dppf)Cl2 （5
mol %） gave the best result (60% yield). Copper sources such
as CuI, Cu, CuO and nano CuO were also investigated (Table 1,
entries 5-8). Nano CuO has been extensively studied as the
[a]
[b]
College of Chemistry & Chemical Engineering, Shaanxi University of
Science & Technology
Weiyang Campus, Xi’an 710021, People's Republic of China
E-mail: zhangjin@sust.edu.cn; mym63@sina.com
Key Laboratory of Auxiliary Chemistry & Technology for Chemical
Industry, Ministry of Education, Shaanxi University of Science and
Technology
Weiyang Campus, Xi’an 710021, People's Republic of China
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
catalyst and oxidant for its redox properties and larger, higher
[12]
reactive surface areas.
To our delight, 3aa was smoothly
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10.1002/ejoc.201701802
European Journal of Organic Chemistry
COMMUNICATION
provided (80%) by the use of 2 equiv. nano CuO as the additive
(Table 1, entry 8). Aminocarbonylation was not achieved in the
absence of Pd(dppf)Cl2 or nano CuO (Table 1, entries 9-10),
which indicated both palladium catalyst and copper additive
were indispensable in this transformation. Co2(CO)8 and
Mo(CO)6 were added into the reaction to replace CO, however,
the amide yields were decreased (Table 1, entries 11-13). A
amides yield (Table 1, entry 14). Further investigations revealed
that different solvents critically influenced the reaction efficiency.
Changing anisole with MeCN, DMSO, dioxane and DMF, the
reaction yields were obviously decreased (Table 1, entries 15-
18). To improve the efficiency, the reaction temperature and
time were also investigated. 3aa was provided in 80% yield with
o
Pd(dppf)Cl2 (5 mol %), nano CuO (2 equiv.), heated at 100 C
balloon filled with mixed gas (CO/O2 = 2:1) did not improve the
Table 1. Optimizing conditions for aminocarbonylation of phenyboronic acid
(1a) and aniline (2a)a,b
for 24 h. Further raising the temperature or extending the time
did not give an obvious improvement in amides yield (Table 1,
entries 19-22).
With the optimized reaction conditions in hand, we examined
the scope of reaction with a range of arylboronic acids. As
shown in Table 2, the reaction proceeded well with alky-
substituted phenylboronic acids, giving the corresponding
amides in moderate to high yields (3ba-3ga). A range of
phenylboronic acids bearing halogen substituents could provide
the amide products in good yields (3ha-3na). To our delight, N-
pheny-2-naphthamide was prepared in good yield with
naphthalen-2-ylboronic acid (3oa). Generally, para-substituted
phenyboronic acids seemed to be more efficient than meta- and
orth-substituted phenyboronic acids for the same group (3ba vs
3ca; 3ha vs 3ia). Meanwhile, electron-donating groups (3ba-
3ga) showed better activity than halide groups (3ha-3ma). Some
limitations to the reaction were identified such as the presence
of a nitro or hydroxyl group (3pa, 3qa), which were not
compatible with the reaction conditions.
entry
1c
catalyst
additive
CuCl
solvent
anisole
anisole
anisole
anisole
anisole
anisole
anisole
anisole
anisole
anisole
anisole
anisole
anisole
anisole
MeCN
Yield (%)b
43
PdCl2
2c
Pd(OAc)2
CuCl
35
3
Pd(PPh3)2Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
-
CuCl
53
4
CuCl
60
5
CuI
45
6
Cu
15
Table 2. Aminocarbonylation of aniline with different substituted arylboronic
acidsa,b.
7
CuO
70
8
nano CuO
nano CuO
-
80
9
0
10
11d
12e
13f
14g
15
16
17
18
19h
20i
21j
22k
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
trace
trace
30
nano CuO
nano CuO
nano CuO
nano CuO
nano CuO
nano CuO
nano CuO
nano CuO
nano CuO
nano CuO
nano CuO
nano CuO
40
65
45
DMSO
dioxane
DMF
trace
20
0
anisole
anisole
anisole
anisole
60
82
[a] Optimized conditions: 1a-1q (1.0 mmol), 2a (1.0 equiv), Pd(dppf)Cl2 (5
mol %), nano CuO (2 equiv.), anisole (5 mL), CO (balloon), 100 oC, 24 h. [b]
Yield of isolated product after column chromatography.
58
75
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.0 equiv), Pd catalyst (5
mol %), additive (2.0 equiv.), solvent (5 mL), CO (balloon), 100 oC, 24h. [b]
Yield of isolated product after column chromatography. [c] PPh3 (5 mol %).
[d] 1.5 mmol Mo(CO)6 instead of CO. [e] 1.5 mmol Co2(CO)8 instead of CO.
[f] 1 mmol Co2(CO)8 with CO balloon. [g] CO/O2 = 2:1. [h] 12 h. [i] 36 h. [j]
80 oC. [k] 120 oC.…
To further examine the substrate scope of this process, a
range of amines was screened to couple with phenylboronic acid
1a (Table 3). The reactions between 1a and amines 2b-2o with
either electron-rich of electron-deficient groups at orth-, meta-
and para-positions of phenyl ring were found to be favored in the
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10.1002/ejoc.201701802
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COMMUNICATION
reaction to afford the corresponding products 3ab-3am in
moderate to high yields. Of particular note was the utility of our
method for the preparation of N-benzylbenzamide (3am) from 1a
and benzylamine (2m) achieved an excellent yield (90%).
However, nitryl substituted aniline resulted in slightly lower yields
(3al). Moreover, the aliphatic amines, such as n-propylamine
and isobutylamine were also investigated. Satisfactorily, the
products N-propylbenzamide (3an) and N-isobutylbenzamide
(3ao) were also obtained under the standard conditions.
However, tryptamine showed non-reactivity, 3ap was not
detected.
To maximize the potential of this method, the reactivity of
phenylhydrazine with phenylboronic acid in the presence of CO
was investigated. Surprisingly, amides were obtained instead of
acylhydrazines under the optimized reaction conditions.
Moreover, various substituted phenylboronic acids and
phenylhydrazines were assembled to provide corresponding
amides in good yields (Table 4). In general, the reactivity of
phenylboronic acids with phenylhydrazines was inferior to aryl
anilines, electron-donating groups showed higher reactivity than
electron-withdrawing groups for both phenyboronic acids and
phenylhydrazines.
Several additional experiments were carried out to better
understand the mechanism and chemoselectivity of the reaction.
Radical experiments signified that this reaction did not go
through a radical mechanism (Scheme 2a). Two competition
experiments were performed to investigate the relative reactivity
of substituted phenylboronic acids and arylamines (Scheme 2b).
As shown, electron donating phenylboronic acids were
inherently more reactive, electron donating arylamines reacted
slowly. Finally, the reaction of phenylhydrazines under the
modified conditions were carried out and corresponding amines
were detected, which indicated that phenyhydrazine could be
reduced to phenylamine and then reacted with arylboronic acids
(Scheme 2c). [13]
Table 3. Aminocarbonylation of phenyboronic acid with different aminesa,b
[a] Optimized conditions: 1a (1.0 mmol), 2b-2p (1.0 equiv), Pd(dppf)Cl2 (5
mol %), nano CuO (2 equiv), anisole (5 mL), CO (balloon), 100 oC, 24 h. [b]
Yield of isolated product after column chromatography.
Table 4. Aminocarbonylation of phenyboronic acids with phenyhydrazinesa,b
.
Scheme 2. Controlling Experiments
On the basis of the experimental evidence and previous
literature reports, [10a, 11, 14] the reaction may perform through two
pathways (Scheme 3). First path (path a) started with the
transmetalation of arylboronic acids in the presence of PdII
catalyst, arylpalladium species A thus formed. Following by the
CO insertion, acylpalladium complex B was formed as the key
intermediate. At the same time, the phenylhydrazine was
reduced under this condition and the formed amine
[a] Optimized conditions: arylboconic acids (1.0 mmol), hydrazines (1.5 equiv),
Pd(dppf)Cl2 (5 mol %), nano CuO (2 equiv), anisole (5 mL), CO (balloon), 100
oC, 24 h. [b] Yield of isolated product after column chromatography.
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Conclusions
In conclusion, we have developed
aminocarbonylation of arylboronic acids with amines
a facile Pd-catalyzed
/
phenylhydrazines to give secondary amides. This method
exhibited good atom economy and showed a wide functional
group tolerance, the use of readily available substrates and
cheap common metal catalysts under ambient pressure make
this method easily operated. To the best of our knowledge, this
represents the first example on aminocarbonylative of
arylboronic acids with phenylhydrazines.
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Entry for the Table of Contents
COMMUNICATION
Key Topic*
Jin Zhang, * Yuqiang Ma, and Yangmin
Ma *
Page No. – Page No.
Title
A novel Pd-catalyzed aminocarbonylation of arylboronic acids with amines or
hydrazines in secondary amides was achieved.
Synthesis of Secondary Amides
through Palladium(II)-catalyzed
Aminocarbonylation of Arylboronic
Acids with Amines / Hydrazines
and CO
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