Boric Acid Catalyzed Direct Amidation between Amino-Azaarenes and Carboxylic Acids

Article abstract of DOI:10.1055/s-0036-1588126

A novel and facile boric acid catalyzed direct amidation between amino-azaarene compounds and carboxylic acids has been developed. The amidation proceeded cleanly and provided good to excellent yields of the desired amides. Boric acid is a green and inexpensive catalyst. We have also found that N,N,N′,N′-tetramethylpropane-1,3-diamine acted as an additive accelerating this boric acid catalyzed amidation. A mixed acid anhydride is postulated to be the active intermediate responsible for this successful amidation. This direct amidation is an atom- and step-economical reaction.

Full text of DOI:10.1055/s-0036-1588126

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–N
paper
A
F. Yun et al.
Paper
Synthesis
Boric Acid Catalyzed Direct Amidation between Amino-Azaarenes
and Carboxylic Acids
Fan Yun‡
O
Chunhui Cheng‡
B(OH)3
O
R1
R
Ar
NH
R
Ar
N
NH2
Jing Zhang
Jingxuan Li
Xia Liu
R1
N
HO
N
N
mesitylene
34 examples with isolated yields ranging from 47–82%
Rui Xie
Pingwah Tang*
Qipeng Yuan*
State Key Laboratory of Chemical Resource Engineering, Organ-
ic and Medicinal Chemistry Division, College of Life Science and
Technology, Beijing University of Chemical Technology, Beijing
100029, P. R. of China
tangpw@mail.buct.edu.cn
yuanqp@mail.buct.edu.cn
‡ These authors contributed equally to this work.
Received: 29.09.2016
Accepted after revision: 29.11.2016
Published online: 21.12.2016
rect amidations, for example, via carboxylic acid chloride or
mixed acid anhydrides as the electrophiles, which react
with amines in the presence of an acid scavenger. Despite
the vitality of amide compounds in organic chemical indus-
try and its wide scope of applications in pharmaceutical in-
dustry, many common known procedures for the prepara-
tion of amides are still inefficient. The aforementioned pro-
tocol via acid chloride intermediate suffers from serious
drawbacks. Most notable drawbacks are the limited stabili-
ty of many intermediate acid chlorides and the use of haz-
ardous reagent for their preparation (thionyl chloride, ox-
alyl chloride, etc.), which release volatile corrosive by-prod-
ucts. The environmental aspect is of primary concern in
chemical industry. Moreover, incompatible functional
groups present either in the acid molecules or in the amine
molecules with chlorinating reagents or with the resulting
acid chlorides need to be protected to ensure the chemose-
lective amide formation. In some procedures, the use of
coupling reagents such as DCC/HOBt, EDC, BOP-Cl, and oth-
ers is beneficial.13–15 However, stoichiometric quantities of
coupling reagents in the amidation formation are required.
In addition, tedious separation of the resulting by-products
in stoichiometric quantities formed by the coupling re-
agents after the completion of the amidation is generally
needed.
DOI: 10.1055/s-0036-1588126; Art ID: ss-2016-h0679-op
Abstract A novel and facile boric acid catalyzed direct amidation be-
tween amino-azaarene compounds and carboxylic acids has been de-
veloped. The amidation proceeded cleanly and provided good to excel-
lent yields of the desired amides. Boric acid is a green and inexpensive
catalyst. We have also found that N,N,N′,N′-tetramethylpropane-1,3-di-
amine acted as an additive accelerating this boric acid catalyzed amida-
tion. A mixed acid anhydride is postulated to be the active intermediate
responsible for this successful amidation. This direct amidation is an at-
om- and step-economical reaction.
Key words amidation, boric acid, azaarenes, aminopyridine,
N,N,N′,N′-tetramethylpropane-1,3-diamine
Amide compounds are present in a vast array of indus-
trial synthetic chemicals and in a wide variety of naturally
occurring bioactive products. They are very important
compounds in many fields including fine chemicals, dyes
and pigments, agricultural chemicals, photographic prod-
ucts, polymers, soft matter, new materials, and in particular
active pharmaceutical ingredients (API) and medicinal
products. Amide function containing compounds are of sig-
nificant importance. In fact, presently about 25% of the
pharmaceutical/medicinal products in the market have one
or several amide functionalities.1–10 The preparation of am-
ides is a very important synthetic transformation in organic
chemistry. ACS Green Chemistry Institute Pharmaceutical
Roundtable have expressed that amide bond formation is
one of the most important chemical reactions used in in-
dustry.11 Many well-established procedures for the prepa-
ration of amide-containing compounds are known in the
literature.12 The most widely practiced methods are indi-
Direct amidation of carboxylic acids with amines is a
well-known topic. Several mediators including organome-
tallic compounds such as Ti(OPr)4,16 Cp2ZrCl3,17 ZrCl4,18 and
boron compounds such as arylboronic acids and borates in
catalytic amount or in stoichiometric quantity or in excess
employed in direct amidations have been reported. Direct
amidation promoted by boron compounds is of high inter-
est and has been attracted considerable attention.19,20 Cur-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

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F. Yun et al.
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Synthesis
rently, there is a focus on the development of new, atom-
and step-economical, and eco-friendly methods for the di-
rect amidation of carboxylic acids with amines.
al and fungal strains.26 Recently, Sheppard et al. reported
the direct amidation using excess of B(OCH2CF3)3.20 While
the reported method using B(OCH2CF3)3 was very successful
for direct amidation of aniline compounds, the method met
with difficulty when it was applied to aminopyridine com-
pounds,. As a matter of fact, only two examples of direct
amidation of amino-azaarenes were reported: pyridin-3-
amine to 2-phenyl-N-(pyridin-3-yl)acetamide and pyridin-
2-amine to 2-phenyl-N-(pyridin-3-yl)acetamide using an
excess of B(OCH2CF3)3 in a sealed tube at 100 °C for 24
hours. The amidations were performed under harsh condi-
tions, and the yields of the amide products were low (53%
and 12%, respectively). Our continuing interests in direct
boric acid catalyzed amidation have led us to investigate
the feasibility of the amidation between a carboxylic acid
and an amino-azaarene compound.
Boric acid direct amidation is highly effective for a num-
ber of amide compounds formed directly between aliphatic
or aromatic carboxylic acids and primary or secondary ami-
no-arene derivatives.21,22 A wealth of boric acid catalyzed
amidations have been devoted to the applications of the
synthesis of active pharmaceutical ingredients (API).23–26
The aforementioned boric acid catalyzed amidation has re-
ceived many applications in green chemistry as well.19 Bo-
ric acid catalyzed direct amidation offers the advantage of
atom- and step-economy and obviates protection/deprotec-
tion steps. This methodology has the aforementioned ad-
vantages in a potentially green and sustainable setting in
chemical and pharmaceutical industries. In sharp contrast,
to the best of our knowledge, there is no report on the di-
rect amidation of amino-azaarenes catalyzed by boric acid
in the literature.
The strength of π-electron system in azaarene ring ren-
ders the exo-amine group less nucleophilic making the di-
rect amidation still challenging. During the course of our
discovery program directed towards the preparation of his-
tone deacetylase enzyme inhibitors [HDACi] comprising an
azaarene ring, potential chemotherapeutic agents against
Carboxamides containing an azaarene moiety play an
important role in medicine for the treatment of various
bacterial and fungal diseases caused by pathogenic bacteri-
Table 1 Amidation Conditions for Boric Acid Catalyzed Direct Amidation Between Pyrinin-3-amine and 8-Methoxy-8-oxooctanoic Acida
O
O
H
NH2
N
HO
B(OH)3
OMe
OMe
+
O
O
solvent, additive
N
N
Entry
B(OH)3 (mol%)
Additive (mol%)
Solvent(s)
Time (h)
Yield (%)
1
2
3
4
5
0
10
20
30
30
0
0
0
0
0
aromatic solventsb
48
48
48
48
24
0
<5
30
49
33
toluene
xylene
xylene
xylene
N
N
6
7
30
30
xylene
xylene
24
7
80
10
(30 mol%)
N
N
N
(30 mol%)
N
8
9
30
30
10
mesitylene
mesitylene
mesitylene
7
7
7
82
35
38
(30 mol%)
0
N
N
10
(30 mol%)
N
N
11
30
mesitylene
7
80
(30 mol%)
a Reaction conditions: amine (5 mmol), acid (5.5 mmol), and solvent (70 mL), temp: solvent at reflux.
b Toluene, xylene, or mesitylene.
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F. Yun et al.
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the proliferation of human cancer cells,27–29 we had reasons
to examine the feasibility of boric acid catalyzed direct ami-
dation. The rationale behind this project is the expectation
that without the use of coupling agent and any hazardous
acid chloride intermediates, the boric acid could mediate
the direct amidation of the amino group of azaarenes. In or-
der to ascertain the feasibility, we decided to concentrate
on the experimental conditions to achieve the boric acid
catalyzed direct amidation between a carboxylic acid and
an amino-azaarene compound. Of importance is that the
amidation with amino-azaarenes, if successful, will be
complementary to that seen in the boric acid catalyzed di-
rect amidation with amino-arene compounds. Thus, we de-
cided to prepare a series of precursors of HDACi comprising
pyridinylamido and quinolinylamido functionalities using
boric acid as catalyst for the direct catalyzed amidation.
Our work began with the investigation of general reac-
tion conditions for the boric acid catalyzed amidation of the
amino group of azaarenes with carboxylic acids. First, dif-
ferent reaction conditions were investigated including
amount of catalyst, solvents, temperature, and additive in
order to assess the feasibility of the amidation and eventu-
ally identify the quasi-optimal reaction conditions to
achieve the amidation of amino-azaarenes. We commenced
by screening the reaction conditions to determine the best
conditions for carrying out the boric acid catalyzed amida-
tion between pyridin-3-amine and 8-methoxy-8-oxoocta-
noic acid. To ensure the critical role of boric acid in the ami-
dation, we have first verified that the direct amidation did
not produce any desired amide in the absence of boric acid
after 48 hours of heating at reflux in aromatic solvents (tol-
uene, xylene, or mesitylene) (Table 1, entry 1). Then, a low
amount of boric acid (10 mol%) was used to carry out the
amidation of pyridin-3-amine in toluene at reflux. While
the amidation reaction with aniline derivatives in toluene
at reflux for few hours offered quantitative yield of the cor-
responding amide, we found that the same reaction with
pyridin-3-amine produced less than 5% yield of the desired
amide after 48 hours of reaction (entry 2). Increasing the
amount of boric acid to 20 mol% and elevating the reaction
temperature by shifting from toluene at reflux to xylene at
reflux brought modest improvement in amide formation
(yield: 30%, entry 3). Further increase in the loading of
B(OH)3 to 30% level did provide even higher yield (49%, en-
try 4). The results indicated that the employment of boric
acid at higher loading could effectively catalyze the direct
amidation for azaarene compound at reflux temperature of
xylene for 48 hours. However, long reaction times are not
practical in preparative chemistry. By shortening the reac-
tion time from 48 to 24 hours, a lower yield of the desired
amide (33%) was obtained (entry 5 vs entry 4). Later, we
discovered that by employing an additive such as N,N,N′,N′-
tetramethylpropane-1,3-diamine at 30 mol% level, we could
achieve effectively the catalyzed amidation (yield: 80%) af-
ter 24 hours with the same amount of boric acid (30 mol%)
(entry 6). The aforementioned additive did bring a benefi-
cial effect to this direct boric acid catalyzed amidation. Tak-
ing full advantage of the beneficial effect of the additive, it
was decided to reduce the reaction time from 24 to 7 hours
at the same time maintaining a high yield in amide. The ex-
periment was carried out but unfortunately was not suc-
cessful; only 10% of the desired amide was obtained (entry
7). We realized that merely reduction of reaction time
without raising the temperature of the reaction would not
do any benefit to the amidation. The same reaction was re-
peated as described in entry 6 with mesitylene as solvent
instead of xylene for the purpose of a higher reaction tem-
perature. By operating at higher temperature for a shorter
reaction time (7 h) the same high yield of 82% was obtained
in the reaction using xylene as solvent for 24 hours (entry 8
vs entry 6). This finding suggested that if other reaction
conditions were kept unchanged, one could be able to
Table 2 Control Experimentsa
O
O
H
N
HO
R
NH2
B(OH)3
solvent
OMe
R
OMe
+
O
O
Entry
1
RNH2
Solvent
toluene
B(OH)3 (mol%)
10
Time (h)
48
Yield (%)b
<5c
NH2
N
O
O
NH2
2
toluene
10
48
70
a B(OH)3-catalyzed amidation between a saturated carboxylic acid and an amino-azaarene and that between a saturated carboxylic acid and methyl 3-aminoben-
zoate (less nucleophilic aniline). Reaction conditions: amine (5 mmol), acid (5.5 mmol), and toluene (70 mL), reflux.
b Isolated yields.
c Entry 2 in Table 1.
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achieve the amidation in high yields for a shorter reaction
time by operating the reaction at higher temperature. Thus
far, the reaction conditions used in entry 8 appeared to be
the best conditions in our study. We still wanted to under-
stand the importance of the additive (the factor of the addi-
tive) in the amidation when operated at high temperature
(mesitylene at reflux). Thus, the same reaction was repeat-
ed as described in entry 8 without using the additive in the
amidation. Under this condition, the yield of the amidation
was reduced approximately to half (entry 9). Likewise, with
the reduction of the B(OH)3 loading to 10%, the yield of the
amidation was also reduced approximately to half (entry
10). We conclude that both 30% loading of boric acid and
additive are needed for the amidation. Finally, it is notewor-
thy that N,N,N′,N′-tetramethylethylenediamine can provide
equally the same beneficial effect (entry 11).
stating material 3-aminopyridine in the presence of
N,N,N′,N′-tetramethylpropane-1,3-diamine or N,N,N′,N′-te-
tramethylethylenediamine at 30 mol% level in mesitylene at
reflux temperature could be the quasi-optimum condition
for the direct amidation (Table 1, entry 7).
In addition, the results in Table 2 clearly indicate that
there is a significant difference in the reactivity of amida-
tion between amino-azaarene and methyl 3-aminobenzo-
ate (less nucleophilic aniline), as evidenced by the yields of
the isolated amides in the absence of any additive.
Encouraged by these findings, the aforementioned ex-
perimental conditions were used to expand the scope of
the boric acid catalyzed direct amidation of amino-
azaarene compounds including pyridinylamines and quino-
linylamines with either saturated (Table 3) or α,β-unsatu-
rated (Table 4) carboxylic acids.
The experimental results in Table 1 indicate that in an
amidation of an azaarene compound, a co-catalytic system
comprising 30 mol% of boric acid relative to the amount of
Table 3 Boric Acid Catalyzed Direct Amidation of Amino-Azaarenes with Saturated Carboxylic Acidsa
O
O
B(OH)3
R1
R
Ar
NH
R
Ar
N
NH2
additive
mesitylene
R1
N
HO
Amide
Amino-azaarenes
Amide product
Yield (%)b
61
O
NH2
NH
OMe
1
N
O
N
O
H
NH2
N
2
3
4
5
6
OMe
82
70
75
62
63
N
O
N
O
H
Me
NH2
N
Me
OMe
N
O
N
O
H
MeO
NH2
N
MeO
OMe
N
O
N
O
H
Cl
NH2
N
Cl
OMe
N
O
N
O
H
N
NH2
OMe
Cl
N
O
Cl
N
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Table 3 (continued)
Amide
Amino-azaarenes
Amide product
Yield (%)b
53
O
Br
NH2
H
N
Br
7
8
9
OMe
N
O
N
O
H
NH2
N
OMe
O
78
47
F3C
N
O
F3C
N
O
O
H
N
NH2
OMe
MeO
MeO
Cl
O
N
N
NH2
10
11
no amidation observed
–
–
Cl
Cl
N
N
NH2
no amidation observed
Br
O
H
Me
Cl
NH2
N
Me
Cl
12
13
14
OMe
OMe
86
84
–
N
O
O
N
N
O
H
N
Me
Br
NH2
Me
Br
N
NH2
no amidation observed
MeO
N
N
NH2
15
16
no amidation observed
no amidation observed
NH
–
–
N
N
N
NH2
O
NH2
17
18
OMe
74
80
O
N
N
N
O
N
NH
MeO
NH2
O
a Reaction conditions: amine (5 mmol), acid (5.5 mmol), B(OH)3 (1.5 mmol), additive (1.5 mmol) and mesitylene (70 mL), reflux, 7 h.
b Isolated yields.
A number of important generalizations emerge from
the data from Tables 3 and 4. First, our discovery that the
combination of B(OH)3 and N,N,N′,N′-tetramethylpropane-
1,3-diamine is an efficient catalyst system to promote the
direct amidation of pyridine-3-amine. The amidation is re-
giospecific in that acylation occurred only at the amino
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group. As shown in the examples in Tables 3 and 4, the bo-
ric acid catalyzed amidation works well. In fact, the amida-
tions were completed within 7 hours. First, they were clean
and provided good to excellent yields without using any en-
vironmentally toxic chemicals and/or coupling agents. Sec-
ond, activating groups such as methyl or methoxy groups in
the pyridine ring render the amidation much readily. De
facto, the amidation reactions were completed within 5
hours in the cases of products 3 and 4 (Table 3). Third, with
one deactivating group: such as Cl, Br, CF3, and ester, the
amidation proceeded normally providing acceptable yields
(51–78%) (products 5–9). Fourth, with two deactivating
groups on the pyridine ring: two Cl or one Cl and one Br
(products 10 and 11), no amidation was observed under the
studied experimental conditions. Fifth, an interesting inter-
play was found between the activating and deactivating
groups on the pyridine ring. When one of deactivation
group (for example Cl) on the pyridine ring was replaced by
an activating group (Me), the nucleophilic strength of the
amino group was restored. The amidation worked again
and good yields of the desired amides were obtained (prod-
ucts 12 and 13). Sixth, the direct amidation of pyridin-4-
amine met with failure even if there is an activating group
(for example: methoxy) on the pyridine ring (product 14).
The failure was probably due to the tautomerization of pyr-
idin-4-amine, and the formation of pyridine-4(1H)imine.
Seventh, when there are two nitrogen atoms in the same
ring, such as aminopyrazine and aminopyrimidine, no ami-
dation was achieved (products 15 and 16). This failure
might be due to the weak nucleophilic strength of the ami-
no group. Eighth, the direct amidation of the amine group
of fused arene rings such as quinoline systems sailed
smoothly without any difficulty providing excellent yields
of the desired quinolinylamides (products 17 and 18). Our
boric acid catalyzed amidation worked well with α,β-unsat-
urated carboxylic acids as well. As shown in Table 4, the di-
rect amidation offered good yields of α,β-unsaturated car-
boxamides. Sheppard et al.20 reported the use of an excess
of B(OCH2CF3)3 to promote the amidation. Our study of bo-
ric acid catalyzed amidation of aminopyridines offered ad-
vantage over the reported amidation mediated by
B(OCH2CF3)3 in that we used 30 mol% of inexpensive B(OH)3
instead of an excess of much more expensive B(OCH2CF3)3,
which is not commercially available. The preparation of
B(OCH2CF3)3 involved the employment of an excess of
CF3CH2OH and the separation required distillation.
B(OCH2CF3)3 is moisture-sensitive and special handling is
needed for its use. We have compared our method with the
one reported by Sheppard et al.20 using an excess of expen-
sive B(OCH2CF3)3. The results are given in Table 5.
Table 4 Boric Acid Catalyzed Direct Amidation of Amino Azaarenes with α,β-Unsaturated Carboxylic Acidsa
O
O
B(OH)3
R1
Ar
R2
R1
NH
Ar
N
NH2
R2
additive
mesitylene
N
HO
Amide
Amino-azaarenes
Amide product
Yield (%)b
81
NH2
H
N
19
N
O
N
NH2
H
N
20
21
60
70
Me
N
O
N
OMe
OEt
NH2
H
N
N
O
N
NH2
H
N
22
77
N
O
N
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Table 4 (continued)
Amide
Amino-azaarenes
Amide product
Yield (%)b
OPr
NH2
H
N
23
64
N
O
N
OMe
OMe
NH2
H
N
24
25
63
71
N
O
N
NH2
H
N
N
O
N
OEt
N
26
61
N
HN
NH2
NH2
O
Cl
Br
H
N
27
28
56c
51c
N
N
O
N
NH2
H
N
O
N
N
NH2
H
N
29
72c
N
O
N
a Reaction conditions: amine (5 mmol), acid (5 mmol), B(OH)3 (1.5 mmol), additive (1.5 mmol), and mesitylene (70 mL), reflux, 8 h.
b Isolated yields.
c Refluxing time: 10–12 h.
The data in Table 5 indicate that the boric acid catalyzed
amidation of 3-aminopyridine and 2-aminopyridine is su-
perior to the amidation mediated by an excess of
B(OCH2CF3)3,20 because boric acid catalyzed amidation not
only obviated the need of the harsh conditions (sealed tube
at high temperature), but did offer better yields of the ami-
dation products than that obtained from the amidation me-
diated by an excess of B(OCH2CF3)3 (products 2, 30, 31,
and 32 versus compound R1] and (products 33 and 34 ver-
sus compound R2].
intermediates, one of them could be a mixed acid anhydride
[Int. 1] formed between carboxylic acid and boric acid
(Scheme 2).30–36
In conclusion, we have developed and reported hereby a
novel and facile boric acid catalyzed direct amidation for
aminopyridines and aminoquinolines without employing
any environmentally hazard chemicals or coupling agents.
To the best of our knowledge, such catalyzed amidation has
not been previously reported in the literature. The reported
amidation methodology offers advantage of atom- and
step-economy. By virtue of the operational simplicity of
this methodology, this boric acid catalyzed amidation
might, therefore, qualify for large-scale preparation, as well
as for the excellent chemoselectivity profile, which can
make protection/deprotection sequence obsolete. There-
20
The mechanism of the boric acid catalyzed amidation
could be complicated. The reaction could involve many in-
termediates before giving rise to the final amidation prod-
uct (Scheme 1 and Scheme 2).1,30–36 Among many plausible
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20
Table 5 Comparison of Boric Acid Catalyzed Amidation with the Amidation Mediated by an Excess of B(OCH2CF3)3
Amide
Aminopyridine
Amide producta
Yield (%)b
82
O
NH2
H
N
OMe
2
N
O
N
NH2
NH
30
31
73
75
O
N
N
NH2
NH
N
O
N
NH
NH2
32
R1
59
53
O
N
N
this work, with catalyst B(OH)3
NH
NH2
O
N
R1: reported literature method using B(OCH2CF3)320
N
in a sealed tube at high temperature for 24 h
O
33
34
R2
75
57
12
N
NH
N
N
NH2
NH2
O
N
NH
this work, with catalyst B(OH)3
O
N
NH
R2: reported literature method using B(OCH2CF3)320
N
NH2
in a sealed tube at high temperature for 24 h
a Reaction conditions: amine (5 mmol), acid (5.5 mmol acid), B(OH)3 (1.5 mmol), additive (1.5 mmol), and mesitylene (70 mL), reflux, 7 h.
b Isolated yields.
O
OH
B
OH
B
fore, this direct amidation could allow organic molecule ar-
chitects for quick building of molecular complexity. We be-
lieve that the successful development and application of
this boric acid mediated direct amidation of aminopyridine
and aminoquinoline have opened up a new possibility of
practical direct amidation because many naturally existing
products and new medicinally useful compounds compris-
ing either pyridinylamido or quinolinylamido moiety could
be made by this boric acid catalyzed amidation method.
Our research projects on further the possibility of the direct
amidation of other azaarenes catalyzed by boric acid are
ongoing towards this goal.
O
[ Int-1]
+
R
O
OH
HO
OH
R
OH
N
Z
N
Z
OH
O
N
Z
B
R
O
OH
[Int-2]
Scheme 1 Plausible intermediates in the catalytic cycle
were obtained using a Waters Xevo G2 QTof mass spectrometer. TLC
on precoated plates with silica gel F254, purchased from Qingdao Hai-
yang Chemical Co. Ltd., was employed to monitor the progress of the
reaction. CH2Cl2 was purchased from Beijing Chemical Works and
dried over molecular sieves 4Å before use. EtOH was purchased from
1H NMR and 13C NMR spectra were recorded in DMSO-d6 on a Bruker
AV III 400 spectrometer (400 MHz). The chemical shifts were report-
ed in ppm relative to Me4Si as an internal standard. Mass spectra
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

I
F. Yun et al.
Paper
Synthesis
lon-coated magnet stirring bar were placed pyridin-3-amine (0.47 g,
5mmol), boric acid (0.1 g, 1.5 mmol), and mesitylene (70 mL). To the
stirred reaction mixture were added N,N,N′,N′-tetramethylpropane-
l,3-diamine (0.20 g, 1.5 mmol) and cinnamic acid (1.11 g, 7.5 mmol)
in one portion. The stirred reaction mixture was heated at gentle re-
flux at ca. 164 °C for 8 h. TLC analysis (eluent: EtOAc) indicated the
complete disappearance of the amine starting material. Upon cooling
to r.t., precipitation of an off-white solid occurred immediately, which
was filtered through a sintered glass funnel. The collected solid was
thoroughly washed with petroleum ether and H2O, and then dried in
vacuo at r.t. for 24 h, then purified by flash chromatography to afford
of N-(pyridin-3-yl)cinnamamide as an off-white solid; yield: 0.80 g
(81%); mp 175.3–176.3 °C.
N
O
O
R
N
H
HO
OH
R
OH
B
OH
N
Z
N
Z
H
O
O
B
NH2
N
H2O
Z
R
N
O
OH
1H NMR (400 MHz, DMSO-d6): δ = 10.44 (1 H, s), 8.85 (1 H, s), 8.29 (1
H, m), 8.16 (1 H, d, J = 8.52 Hz), 7.65 (3 H, t, J = 6.70 Hz), 7.45 (4 H, m),
6.85 (1 H, d, J = 15.9 Hz).
[Int. 1]
Scheme 2 The catalytic cycle of boric acid catalyzed amidation
13C NMR (100 MHz, DMSO-d6): δ = 164.01, 144.26, 140.82, 135.89,
134.51, 129.94, 129.02, 127.79, 126.11, 123.68, 121.55.
HRMS (ESI): m/z (M + H)+ calcd for C14H12N2O: 225.1029; found:
225.1030.
Beijing Chemical Works and dried over molecular sieves 4Å before
use. All reagents of analytical grade were purchased from Sigma-Al-
drich, Beijing Inno-Chem Co. Ltd., Alfa Aesar, Beijing Chemical Works,
and other commercial sources. They were used without further puri-
fication. All reactions were carried out in oven-dried glassware. Dry
N2 was used to purge the reactor and all the glass apparatus before
the reaction and to protect the reaction during the entire operation.
Preparation of Compounds Listed in Table 3
Methyl 6-Oxo-6-(pyridin-3-ylamino)hexanoate (1); Typical Proce-
dure
To an oven-dried 100 mL three-necked round-bottomed flask
equipped with two glass stoppers, a vacuum-jacketed Dean–Stark
trap topped with a reflux condenser fitted with a N2 inlet, and a Tef-
lon-coated magnet stirring bar were placed 3-aminopyridine (0.5 g,
5.3 mmol), boric acid (0.1 g,1.6 mmol), and mesitylene (70 mL). To the
stirred reaction mixture were added N,N,N′,N′-tetramethylpropane-
l,3-diamine (0.21 g, 1.6 mmol) and 6-methoxy-6-oxohexanoic acid
(1.27 g, 8 mmol) in one portion. The stirred reaction mixture was
heated at gentle reflux at 164 °C for 7 h. TLC analysis (eluent: EtOAc)
indicated the complete disappearance of the amine starting material.
After cooling to r.t., the mixture was poured into petroleum ether
(350 mL) leading to the immediate precipitation of an off-white solid.
Stirring was continued for an additional 30 min and the precipitate
was then filtered through a sintered glass funnel. The collected solid
was thoroughly washed with petroleum ether and H2O, and dried in
vacuo at r.t. for 24 h to afford methyl 6-oxo-6-(pyridin-3-ylami-
no)hexanoate as a light-brown solid; yield: 0.76 g (61%); mp 41.3–
42.5 °C.
Boric Acid Catalyzed Amidation; Methyl 8-Oxo-8-(pyridin-3-yl-
amino)octanoate (2); Typical Procedure for Products Listed in Ta-
bles 1–3
To an oven-dried 100 mL three-necked round-bottomed flask
equipped with two glass stoppers, a vacuum-jacketed Dean–Stark
trap topped with a reflux condenser fitted with a N2 inlet, and a Tef-
lon-coated magnet stirring bar were placed pyridin-3-amine (0.5 g,
5.3 mmol), boric acid (0.1 g, 1.6 mmol), and mesitylene (70 mL). To
the stirred reaction mixture were added N,N,N′,N′-tetramethylpro-
pane-l,3-diamine (0.21 g, 1.6 mmol) and 8-methoxy-8-oxooctanoic
acid (1.5 g, 8 mmol) in one portion. The stirred reaction mixture was
heated at gentle reflux at ca. 164 °C for 7 h. TLC analysis (eluent:
EtOAc) indicated the complete disappearance of the amine starting
material. After cooling to r.t., the mixture was poured into petroleum
ether (350 mL) leading to the immediate precipitation of an off-white
solid. Stirring was continued for an additional 30 min and the precip-
itate was then filtered through a sintered glass funnel. The collected
solid was thoroughly washed with petroleum ether and H2O, and
dried in vacuo at r.t. for 24 h, then purified by flash chromatography
to afford methyl 8-oxo-8-(pyridin-3-ylamino)octanoate as an off-
white solid; yield: 1.14 g (82%); mp 52.6–53.4 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.14 (1 H, s), 8.73 (1 H, s), 8.23 (1
H, d, J = 4.89 Hz), 8.02 (1 H, d, J = 8.27 Hz), 7.31 (1 H, m), 3.59 (3 H, s),
2.34 (4 H, m), 1.59 (4 H, m).
1H NMR (400 MHz, DMSO-d6): δ = 10.07 (1 H, s), 8.73 (2 H, d, J = 2.47
Hz), 8.24 (1 H, m), 8.04 (1 H, m), 7.33 (1 H, m), 3.59 (1 H, s), 2.32 (4 H,
m), 1.60 (2 H, t, J = 7.03 Hz), 1.54 (2 H, t, J = 7.41 Hz), 1.31 (4 H, m).
13C NMR (100 MHz, DMSO-d6): δ = 173.67, 172.03, 144.41, 141.16,
136.35, 126.37, 124.03, 51.68, 36.30, 33.49, 24.87, 24.50.
HRMS (ESI): m/z (M + H)+ calcd for C12H16N2O3: 237.1240; found:
237.1272.
13C NMR (100 MHz, DMSO-d6): δ = 173.31, 171.76, 143.90, 140.66,
135.88, 125.87, 123.54, 51.13, 36.12, 33.19, 28.24, 28.17, 24.74, 24.27.
HRMS (ESI): m/z (M + H)+ calcd for C14H20N2O3: 265.1553; found:
265.1557.
The syntheses of other compounds (compounds 3 to 18) were carried
out according to the aforementioned typical procedures as described
for compounds 1 and 2.
Boric Acid Catalyzed Amidation; N-(Pyridin-3-yl)cinnamamide
Methyl 8-[(5-Methylpyridin-3-yl)amino)-8-oxooctanoate (3)
(19); Typical Procedure for Products Listed in Tables 4 and 5
Prepared from 5-methylpyridin-3-amine (1.08 g, 10 mmol), boric
To an oven-dried 100 mL three-necked round-bottomed flask
equipped with two glass stoppers, a vacuum-jacketed Dean–Stark
trap topped with a reflux condenser fitted with a N2 inlet, and a Tef-
acid (0.19 g, 3 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine
(0.21 g, 3 mmol), and 8-methoxy-8-oxooctanoic acid (1.92 g, 10.2
mmol); yield: 1.94 g (70%); light-brown solid; mp 65.53–67.5 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

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F. Yun et al.
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Synthesis
1H NMR (400 MHz, DMSO-d6): δ = 10.00 (1 H, s), 8.51 (1 H, s), 8.08 (1
13C NMR (100 MHz, DMSO-d6): δ = 173.31, 172.21, 144.10, 138.93,
H, s), 7.89 (1 H, s), 3.58 (3 H, m), 2.29 (7 H, m), 1.56 (4 H, m), 1.29 (4 H,
m).
13C NMR (100 MHz, DMSO-d6): δ = 173.79, 172.21, 144.73, 138.44,
136.95, 127.75, 119.58, 51.13, 36.15, 33.18, 28.16, 24.60, 24.25.
HRMS (ESI): m/z (M + H)+ calcd for C14H19BrN2O3: 343.0658 and
345.0638; found: 343.1500 and 345.1000.
135.99, 133.25, 126.72, 51.62, 33.69, 28.73, 28.68, 24.77.
HRMS (ESI): m/z (M + H)+ calcd for C15H22N2O3: 279.1709; found:
279.1703.
Methyl 8-Oxo-8-{[6-(trifluoromethyl)pyridin-3-yl]amino}octa-
noate (8)
Prepared from 6-(trifluoromethyl)pyridin-3-amine (0.5 g, 3 mmol),
boric acid (0.06 g, 0.9 mmol), N,N,N′,N′-tetramethylpropane-l,3-di-
amine (0.12 g, 0.9 mmol), and 8-methoxy-8-oxooctanoic acid (0.87 g,
4.63 mmol); yield: 0.8 g (78%); off-white solid; mp 92.6–93.7 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.50 (1 H, s), 8.87 (1 H, d, J = 2.06
Hz), 8.33 (2 H, d, J = 8.79 Hz), 7.8 5 (1 H, d, J = 8.61 Hz), 3.59 (3 H, s),
2.39 (2 H, t, J = 7.72 Hz), 2.31 (2 H, t, J = 7.54 Hz), 1.57 (4 H, m), 1.31 (4
H, m).
Methyl 8-[(5-Methoxypyridin-3-yl)amino)-8-oxooctanoate (4)
Prepared from 5-methoxylpyridin-3-amine (0.5 g, 4 mmol), boric
acid (0.08 g, 1.2 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine
(0.16 g, 1.2 mmol), and 8-methoxy-8-oxooctanoic acid (0.90 g, 4.8
mmol); yield: 0.88 g (75%); light-brown solid; mp 72.2–73.8 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.10 (1 H, s), 8.31 (1 H, d, J = 1.62
Hz), 7.98 (1 H, d, J = 2.50 Hz), 7.76 (1 H, m), 3.81 (3 H, s), 3.59 (3 H, s),
2.32 (4 H, m), 1.56 (4 H, m), 1.30 (4 H, m).
13C NMR (100 MHz, DMSO-d6): δ = 173.30, 172.38, 140.48, 138.76,
126.25, 121.19, 51.13, 36.19, 33.17, 28.16, 24.57, 24.25.
HRMS (ESI): m/z (M + H)+ calcd for C15H19F3N2O3: 333.1427; found:
333.1430.
13C NMR (100 MHz, DMSO-d6): δ = 173.31, 171.91, 155.25, 136.56,
132.78, 131.39, 110.62, 55.39, 51.13, 36.19, 33.19, 28.23, 28.17, 24.70,
24.26.
HRMS (ESI): m/z (M + H)+ calcd for C15H22N2O4: 295.1659; found:
295.1662.
Methyl 5-(8-Methoxy-8-oxooctanamido)nicotinate (9)
Prepared from methyl 5-aminonicotinate (0.5 g, 3 mmol), boric acid
(0.06 g, 0.9 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.12 g,
0.9 mmol), and 8-methoxy-8-oxooctanoic acid (0.94 g, 5 mmol);
yield: 0.45 g (47%); off-brown solid; mp 98.8–100.8 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.33 (1 H, s), 8.91 (1 H, d, J = 2.39
Hz), 8.75 (2 H, d, J = 1.96 Hz), 8.64 (1 H, t, J = 2.39 Hz), 3.89 (3 H, s),
3.58 (3 H, s), 2.30 (4 H, m), 1.60 (4 H, m), 1.30 (4 H, m).
Methyl 8-[(5-Chloropyridin-3-yl)amino]-8-oxooctanoate (5)
Prepared from 5-chloropyridin-3-amine (0.5 g, 4 mmol), boric acid
(0.08 g, 1.2 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.16 g,
1.2 mmol), and 8-methoxy-8-oxooctanoic acid (0.94 g, 5 mmol);
yield: 0.72 g (62%); off-white solid; mp 76.5–78 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.32 (1 H, s), 8.61 (1 H, d, J = 2.44
Hz), 8.30 (1 H, d, J = 2.26 Hz), 8.26 (1 H, t, J = 2.44 Hz), 3.59 (3 H, s),
2.33 (4 H, m), 1.57 (4 H, m), 1.31 (4 H, m).
13C NMR (100 MHz, DMSO-d6): δ = 173.31, 172.17, 165.13, 144.09,
135.95, 125.81, 125.39, 52.45, 51.13, 36.15, 33.19, 28.16, 24.64, 24.25.
13C NMR (100 MHz, DMSO-d6): δ = 173.31, 172.25, 141.98, 138.71,
HRMS (ESI): m/z (M + H)+ calcd for C16H22N2O5: 323.1608; found:
136.74, 130.53, 124.99, 51.13, 36.16, 33.18, 28.18, 24.56, 24.25.
323.1604.
HRMS (ESI): m/z (M + H)+ calcd for C14H19ClN2O3: 299.1163; found:
299.1164.
Methyl 8-[(6-Chloro-5-methylpyridin-3-yl)amino]-8-oxoocta-
noate (12)
Prepared from 6-chloro-5-methylpyridin-3-amine (0.5 g, 3 mmol),
boric acid (0.07 g, 1.05 mmol), N,N,N′,N′-tetramethylpropane-l,3-di-
amine (0.14 g, 1.05 mmol), and 8-methoxy-8-oxooctanoic acid (1 g,
5.3 mmol); yield: 0.94 g (86%); off-white solid; mp 73.2–75 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.16 (1 H, s), 8.42 (1 H, d, J = 2.54
Hz), 8.04 (2 H, d, J = 2.26 Hz), 3.59 (3 H, s), 2.31 (7 H, m), 1.56 (4 H, m),
1.30 (4 H, m).
Methyl 8-[(6-Chloropyridin-3-yl)amino]-8-oxooctanoate (6)
Prepared from 6-chloropyridin-3-amine (0.5 g, 4 mmol), boric acid
(0.08 g, 1.2 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.16 g,
1.2 mmol), and 8-methoxy-8-oxooctanoic acid (0.94 g, 5 mmol);
yield: 0.75 g (63%); off-white solid; mp 99.9–100.6 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.23 (1 H, s), 8.60 (1 H, d, J = 2.67
Hz), 8.08 (1 H, d, J = 8.90 Hz), 7.46 (1 H, t, J = 8.90 Hz), 3.59 (3 H, s),
2.33 (4 H, m), 1.56 (4 H, m), 1.29 (4 H, m).
13C NMR (100 MHz, DMSO-d6): δ = 173.30, 171.81, 143.54, 137.63,
135.50, 131.80, 129.77, 51.13, 36.07, 33.18, 28.21, 24.69, 24.25, 19.18.
HRMS (ESI): m/z (M + H)+ calcd for C15H21ClN2O3: 313.1320; found:
13C NMR (100 MHz, DMSO-d6): δ = 173.31, 171.86, 143.22, 140.17,
135.49, 129.55, 124.11, 51.13, 36.10, 33.18, 28.17, 24.65, 24.25.
313.1321.
HRMS (ESI): m/z (M + H)+ calcd for C14H19ClN2O3: 299.1163; found:
299.1164.
Methyl 8-[(6-Bromo-5-methylpyridin-3-yl)amino]-8-oxoocta-
noate (13)
Methyl 8-[(5-Bromopyridin-3-yl)amino]-8-oxooctanoate (7)
Prepared from 6-bromo-5-methylpyridin-3-amine (0.5 g, 3 mmol),
boric acid (0.06 g, 0.9 mmol), N,N,N′,N′-tetramethylpropane-l,3-di-
amine (0.12 g, 0.9 mmol), and 8-methoxy-8-oxooctanoic acid (0.8 g, 4
mmol); yield: 0.8 g (84%); off-white solid; mp 71.0–71.4 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.22 (1 H, s), 8.43 (1 H, d, J = 2.55
Hz), 8.02 (2 H, d, J = 2.26 Hz), 3.62 (3 H, s), 2.31 (7 H, m), 1.58 (4 H, m),
1.31 (4 H, m).
Prepared from 5-bromopyridin-3-amine (1.42 g, 8.2 mmol), boric
acid (0.15 g, 2.46 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine
(0.32 g, 2.46 mmol), and 8-methoxy-8-oxooctanoic acid (1.57 g, 8.37
mmol); yield: 1.49 g (53%); light brown solid; mp 79.7–80.8 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.31 (1 H, s), 8.65 (1 H, s), 8.39 (2
H, d, J = 9.55 Hz), 3.59 (3 H, s), 2.33 (4 H, m), 1.57 (4 H, m), 1.28 (4 H,
m).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

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F. Yun et al.
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Synthesis
13C NMR (100 MHz, DMSO-d6): δ = 173.31, 171.85, 138.14, 136.23,
135.81, 134.37, 129.22, 51.13, 36.10, 33.18, 28.21, 24.67, 24.25, 21.46.
HRMS (ESI): m/z (M + H)+ calcd for C15H21BrN2O3: 357.0815 and
359.0794; found: 357.0818 and 359.0800.
1H NMR (400 MHz, DMSO-d6): δ = 10.33 (1 H, s), 8.83 (1 H, d, J = 2.33
Hz), 8.28 (1 H, m), 8.14 (1 H, m), 7.59 (3 H, t, J = 7.97 Hz), 7.38 (1 H,
m), 7.01 (2 H, d, J = 8.69 Hz), 6.67 (1 H, d, J = 15.80 Hz), 3.81 (3 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 164.82, 161.21, 144.58, 141.25,
141.09, 136.52, 129.96, 127.57, 126.49, 124.14, 119.44, 114.98, 55.79.
HRMS (ESI): m/z (M + H)+ calcd for C15H14N2O2: 255.1134, found:
Methyl 8-Oxo-8-(quinolin-3-ylamino)octanoate (17)
255.1136.
Prepared from quinoline-3-amine (0.5 g, 3.5 mmol), boric acid (0.07
g, 1.05 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.14 g,
1.05 mmol), and 8-methoxy-8-oxooctanoic acid (1 g, 5.3 mmol);
yield: 0.81 g (74%); light yellow solid; mp 92.1–93.3 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.35 (1 H, s), 8.90 (1 H, d, J = 2.24
Hz), 8.72 (1 H, s), 7.93 (2 H, d, J = 8.37 Hz), 7.58 (2 H, d, J = 8.07 Hz),
3.58 (3 H, s), 2.40 (2 H, t, J = 7.63 Hz), 2.30 (2 H, t, J = 7.63 Hz), 1.64 (2
H, m), 1.54 (2 H, m), 1.32 (4 H, m).
13C NMR (100 MHz, DMSO-d6): δ = 173.80, 172.58, 144.93, 144.54,
133.44, 128.98, 128.34, 128.10, 127.74, 122.20, 51.63, 33.69, 28.77,
28.70, 24.78.
HRMS (ESI): m/z (M + H)+ calcd for C18H22N2O3: 315.1709, found:
315.1712.
(E)-3-(4-Ethoxyphenyl)-N-(pyridin-3-yl)acrylamide (22)
Prepared from pyridin-3-amine (0.47 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.5
mmol), and (E)-3-(4-ethoxyphenyl)acrylic acid (0.96 g, 5 mmol);
yield: 1.03 g (77%); off-white solid; mp 208.5–210.2 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.33 (1 H, s), 8.83 (1 H, s), 8.28 (1
H, m), 8.14 (1 H, m), 7.59 (3 H, m), 7.37 (1 H, m), 6.99 (1 H, d, J = 8.38
Hz), 6.66 (1 H, d, J = 15.52 Hz), 4.09 (2 H, m), 1.34 (3 H, t, J = 7.15 Hz).
13C NMR (100 MHz, DMSO-d6): δ = 164.83, 160.50, 144.57, 141.25,
141.13, 136.53, 129.97, 127.42, 126.49, 124.14, 119.32, 115.37, 63.74,
15.04.
HRMS (ESI): m/z (M + H)+ calcd for C16H16N2O2: 269.1291; found:
269.1292.
Methyl 8-Oxo-8-(quinolin-8-ylamino)octanoate (18)
Prepared from quinoline-8-amine (0.5 g, 3.5 mmol), boric acid (0.07
g, 1.05 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.14 g,
1.05 mmol), and 8-methoxy-8-oxooctanoic acid (1 g, 5.3 mmol);
yield: 0.88 g (80%); light yellow solid; mp 92.3–95 °C.
1H NMR (400 MHz, DMSO-d6): δ = 9.99 (1 H, s), 8.92 (1 H, d, J = 4.14
Hz), 8.47 (1 H, d, J = 9.12 Hz), 7.76 (4H, m), 3.59 (3 H, s), 2.32 (4 H, m),
1.66 (4 H, m), 1.35 (4 H, m).
13C NMR (100 MHz, DMSO-d6): δ = 174.40, 173.30, 171.99, 150.35,
148.09, 133.99, 131.39, 129.00, 125.89, 121.45, 120.80, 51.13, 33.53,
33.21, 28.34, 28.21, 25.03, 24.32.
(E)-3-(4-Propoxyphenyl)-N-(pyridin-3-yl)acrylamide (23)
Prepared from pyridin-3-amine (0.47 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.5
mmol), and (E)-3-(4-propoxyphenyl)acrylic acid (1.03 g, 5 mmol);
yield: 0.90 g (64%); off-white solid; mp 189.5–190.2 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.33 (1 H, s), 8.83 (1 H, s), 8.27 (1
H, m), 8.16 (1 H, d, J = 8.62 Hz), 7.57 (3 H, m), 7.37 (1 H, m), 7.02 (2 H,
d, J = 8.50 Hz), 6.68 (1 H, d, J = 6.68 Hz), 3.99 (2 H, t, J = 6.90 Hz), 1.75
(2 H, m), 0.99 (3 H, t, J = 7.15 Hz).
HRMS (ESI) (M
315.1712.
+
H)+ calcd for C18H22N2O3: 315.1709; found:
13C NMR (100 MHz, DMSO-d6): δ = 164.34, 160.17, 144.07, 140.75,
140.62, 136.03, 129.47, 126.92, 125.99, 123.64, 118.83, 114.92, 69.09,
21.93, 10.33.
HRMS (ESI): m/z (M + H)+ calcd for C17H18N2O2: 283.1447; found:
Preparation of Compounds Listed in Table 4
283.1450.
The syntheses of compounds 20–29 were carried out according to the
aforementioned typical procedure as described for compound 19.
(E)-3-(3,4-Dimethoxyphenyl)-N-(pyridin-3-yl)acrylamide (24)
(E)-N-(Pyridin-3-yl)-3-(m-tolyl)acrylamide (20)
Pepared from pyridin-3-amine (0.47 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.5
Prepared from pyridin-3-amine (0.47 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.5
mmol), and (E)-3-(m-tolyl)acrylic acid (0.82 g, 5 mmol); yield: 0.70 g
(60%); off-white solid; mp 91.7–92.4 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.41 (1 H, s), 8.83 (1 H, d, J = 2.44
Hz), 8.29 (1 H, m), 8.16 (1 H, m), 8.14 (1 H, m), 7.61 (1 H, d, J = 16.26
Hz), 7.44 (2 H, d, J = 8.94 Hz), 7.36 (2 H, m), 7.24 (1 H, d, J = 7.56 Hz),
6.85 (1 H, J = 15.93 Hz), 2.36 (3 H, s).
mmol), and (E)-3-(3,4-dimethoxyphenyl)acrylic acid (1.04 g,
5
mmol); yield: 0.90 g (63%); off-white solid; mp 207.4–207.7 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.35 (1 H, s), 8.84 (1 H, s), 8.28 (1
H, m), 8.16 (1 H, m), 7.58 (1 H, d, J = 16.02 Hz), 7.37 (1 H, m), 7.22 (2
H, m), 7.03 (1 H, d, J = 7.64 Hz), 6.71 (1 H, d, J = 16.77 Hz), 3.82 (6 H, d,
J = 7.64 Hz).
13C NMR (100 MHz, DMSO-d6): δ = 164.01, 144.26, 140.82, 135.89,
13C NMR (100 MHz, DMSO-d6): δ = 164.02, 144.23, 140.86, 140.78,
138.19, 135.89, 134.45, 130.64, 128.92, 128.29, 126.06, 125.00,
123.68, 121.41.
134.51, 129.94, 129.02, 127.79, 126.11, 123.68, 121.55.
HRMS (ESI): m/z (M + H)+ calcd for C16H16N2O3: 285.1240; found:
285.1243.
HRMS (ESI): m/z (M + H)+ calcd for C15H14N2O: 239.1185. found:
239.1186.
N-(Quinolin-3-yl)cinnamamide (25)
Prepared from quinoline-3-amine (0.37 g, 2.5 mmol), boric acid (0.05
g, 0.8 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.10 g, 0.8
mmol), and cinnamic acid (0.37 g, 2.5 mmol) in mesitylene (70 mL);
yield: 0.48 g (71%); off-white solid; mp 219.1–219.4 °C.
(E)-3-(4-Methoxyphenyl)-N-(pyridin-3-yl)acrylamide (21)
Prepared from pyridin-3-amine (0.47 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.5
mmol), and (E)-3-(4-methoxyphenyl)acrylic acid (0.89 g, 5 mmol);
yield: 0.88 g (70%); off-white solid; mp 149.3–150.1 °C.
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1H NMR (400 MHz, DMSO-d6): δ = 10.72 (1 H, s), 9.01 (1 H, s), 8.84 (1
H, s), 7.97 (2 H, t, J = 8.34 Hz), 7.67 (5 H, m), 7.46 (3 H, m), 6.94 (1 H, d,
J = 15.89 Hz).
13C NMR (100 MHz, DMSO-d6): δ = 164.28, 144.46, 144.22, 140.89,
134.51, 132.97, 129.98, 129.04, 128.55, 127.83, 127.08, 122.08,
121.57.
1H NMR (400 MHz, DMSO-d6): δ = 10.69 (1 H, s), 8.93 (1 H, s), 8.35 (6
H, m), 7.42 (1 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 165.03, 145.46, 142.50, 138.82,
135.90, 133.01, 129.06, 127.93, 124.07, 118.72, 114.60.
HRMS (ESI): m/z (M + H)+ calcd for C13H9N3O: 224.0825; found:
224.0816.
HRMS (ESI): m/z (M + H)+ calcd for C18H14N2O: 275.1185; found:
275.1181.
Preparation of Compounds Listed in Table 5
(E)-3-(4-Ethoxyphenyl)-N-(quinolin-8-yl)acrylamide (26)
4-Phenyl-N-(pyridin-4-yl)butanamide (30)
Prepared from quinoline-8-amine (0.72 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.20 g, 1.5
mmol), and (E)-3-(4-ethoxyphenyl)acrylic acid (0.96 g, 5 mmol) in
mesitylene (70 mL); yield: 0.97 g (61%); off-white solid; mp 204.1–
205.3 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.18 (1 H, s), 8.94 (1 H, s), 8.58 (1
H, s), 7.98 (d, J = 7.15 Hz), 7.88 (1 H, d, J = 7.55 Hz), 7.79 (1 H, t, J = 7.55
Hz), 7.60 (4 H, m), 7.03 (3 H, m), 4.10 (2 H, m), 1.35 (3 H, t, J = 7.15
Hz).
Prepared from pyridin-3-amine (0.5 g, 5.3 mmol), boric acid (0.10 g,
1.6 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.6
mmol), and 4-phenylbutanoic acid (1.31 g, 8 mmol); yield: 0.92 g
(73%); off-white solid; mp 92.3–93.5 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.09 (1 H, s), 8.72 (2 H, d, J = 2.37
Hz), 8.24 (1 H, m) 8.02 (1 H, m), 7.31 (3 H, m), 7.23 (3 H, m), 2.63 (2 H,
t, J = 7.42 Hz), 2.36 (2 H, t, J = 7.42 Hz), 1.91 (2 H, m).
13C NMR (100 MHz, DMSO-d6): δ = 171.98, 144.40, 142.05, 114.18,
136.35, 128.81, 128.75, 126.41, 126.28, 124.03, 36.05, 35.04, 27.04.
HRMS (ESI): m/z (M + H)+ calcd for C15H16N2O: 241.1342; found:
241.1339.
13C NMR (100 MHz, DMSO-d6): δ = 165.16, 160.42, 150.92, 148.60,
140.89, 134.54, 131.76, 129.91, 129.62, 127.65, 126.27, 122.82,
121.35, 121.21, 119.74, 115.38, 63.74, 15.07.
HRMS (ESI): m/z (M + H)+ calcd for C20H18N2O2: 319.1447; found:
319.1443.
3-Phenyl-N-(pyridin-3-yl)propanamide (31)
Prepared from pyridin-3-amine (0.94 g, 10 mmol), boric acid (0.19 g,
3 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.39 g, 3 mmol),
and 3-phenylpropanoic acid (1.50 g, 10 mmol); yield: 1.7 g (75%);
white solid; mp 120–121.9 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.14 (1 H, s), 8.73 (1 H, m), 8.25 (1
H, m), 8.04 (1 H, d, J = 8.27 Hz), 7.29 (6 H, m), 2.94 (2 H, t, J = 7.06 Hz),
2.67 (2 H, t, J = 8.48 Hz).
13C NMR (100 MHz, DMSO-d6): δ = 170.95, 143.98, 140.99, 140.67,
135.78, 128.30, 128.20, 125.92, 125.95, 123.57, 37.76, 30.65.
HRMS (ESI): m/z (M + H)+ calcd for C14H14N2O: 227.1185; found:
227.5947.
4-Chloro-N-(pyridin-3-yl)benzamide (27)
Prepared from pyridin-3-amine (0.47 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.5
mmol), and 4-chlorobenzoic acid (0.78 g, 5 mmol), then purified by
flash chromatography; yield: 0.65 g (56%); light-brown solid; mp
146.3–147.6 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.51 (1 H, s), 8.92 (1 H, s), 8.33 (1
H, s), 8.19 (1 H, s), 8.02 (2 H, s), 7.65 (2 H, s), 7.41 (1 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 165.29, 145.19, 142.48, 137.20,
136.10, 133.50, 130.16, 129.03, 127.86, 124.02.
HRMS (ESI): m/z (M + H)+ calcd for C12H9ClN2O: 233.0482; found:
233.0476.
2-Phenyl-N-(pyridin-3-yl)acetamide (32)
Prepared from pyridin-3-amine (0.47 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.5
mmol), and 2-phenylacetic acid (0.68 g, 5 mmol), then purified by
flash chromatography; yield: 0.62 g (59%); light-brown solid; mp
107.9–108.8 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.38 (1 H, s), 8.74 (1 H, s), 8.24 (1
H, d, J = 4.07 Hz), 8.02 (1 H, d, J = 7.58 Hz), 7.33 (5 H, m), 3.68 (2 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 170.15, 144.66, 141.20, 136.28,
136.08, 129.62, 128.80, 127.08, 126.49, 124.09, 43.55.
HRMS (ESI): m/z (M + H)+ calcd for C13H12N2O: 213.1029; found:
213.1021.
4-Bromo-N-(pyridin-3-yl)benzamide (28)
Prepared from pyridin-3-amine (0.47 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.5
mmol), and 4-bromobenzoic acid (1.005 g, 5 mmol), then purified by
flash chromatography; yield: 0.70 g (51%); light-brown solid; mp
162.2–163.7 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.52 (1 H, s), 8.92 (1 H, s), 8.33 (1
H, s), 8.19 (1 H, s), 7.93 (2 H, s), 7.79 (2 H, s), 7.41 (1 H, s).
13C NMR (100 MHz, DMSO-d6): δ = 165.41, 145.20, 142.49, 136.09,
133.86, 131.97, 130.33, 127.86, 126.16, 124.02.
HRMS (ESI): m/z (M + H)+ calcd for C12H9BrN2O: 276.9977 and
278.9957, found: 276.9971 and 278.9952.
3-Phenyl-N-(pyridin-2-yl)propanamide (33)
Prepared from pyridin-2-amine (0.94 g, 10 mmol), boric acid (0.19 g,
3 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.39 g, 3 mmol),
and 3-phenylpropanoic acid (1.53 g, 10.2 mmol); yield: 1.0 g (75%);
off-white solid; mp 81.7–82.6 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.48 (1 H, s), 8.30 (1 H, d, J = 4.44
Hz), 8.10 (1 H, d, J = 8.88 Hz), 7.76 (1 H, m), 7.28 (4 H, m), 7.18 (1 H,
m), 7.08 (1 H, m) 2.91 (2 H, t, J = 7.52 Hz), 2.67 (2 H, t, J = 8.77 Hz).
4-Cyano-N-(pyridin-3-yl)benzamide (29)
Prepared from pyridin-3-amine (0.47 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.5
mmol), and 4-cyanobenzoic acid (0.73 g, 5 mmol), then purified by
flash chromatography; yield: 0.81 g (72%); light-brown solid; mp
105.2–106.2 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–N

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Synthesis
13C NMR (100 MHz, DMSO-d6): δ = 171.31, 152.04, 147.85, 141.07,
(6) Trapani, G.; Reno, A.; Laytofa, A. Synthesis 1983, 1013.
138.05, 128.26, 128.24, 125.90, 119.16, 113.37, 37.63, 30.63.
HRMS (ESI): m/z (M + H)+ calcd for C14H14N2O: 227.1185; found:
227.5945.
(7) Pelter, A.; Levitt, T. E.; Nelson, P. Tetrahedron 1970, 26, 1539.
(8) Collum, D. B.; Chen, S. C.; Ganem, B. J. Org. Chem. 1978, 43, 4393.
(9) Pelter, A.; Levitt, T. E. Tetrahedron 1970, 26, 1545.
(10) Carlson, R.; Lundstedt, T.; Nordahl, A.; Rochazka, M. P. Acta
Chem. Scand., Ser. B. 1986, 40, 522.
(11) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, L. Jr.; Lindeman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B.
A.; Wells, A.; Zhang, T. Green Chem. 2007, 9, 535.
(12) For a review on this topic, see: (a) Montalbetti, C. A. G. N.;
Falque, V. Tetrahedron 2005, 61, 10827. (b) Valeur, E.; Bradley,
M. Chem. Soc. Rev. 2009, 38, 606. (c) Pattabiraman, V. R.; Bode, J.
W. Nature 2011, 480, 471.
2-Phenyl-N-(pyridin-2-yl)acetamide (34)
Prepared from pyridin-3-amine (0.47 g, 5 mmol), boric acid (0.10 g,
1.5 mmol), N,N,N′,N′-tetramethylpropane-l,3-diamine (0.21 g, 1.5
mmol), and 2-phenylacetic acid (0.68 g, 5 mmol), then purified by
flash chromatography, yield: 0.60 g (57%); light-brown solid; mp
105.5–106.9 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.09 (1 H, s), 8.32 (1 H, s), 8.04 (1
H, s), 7.75 (1 H, s), 7.34 (4 H, m), 7.09 (1 H, s), 3.72 (2 H, s).
(13) Han, S. Y.; Kim, A. Tetrahedron 2004, 60, 2447.
(14) Joullie, M. M.; Lassen, K. M. ARKIVOC 2004, (viii), 189.
(15) Kim, Y. A.; Han, S. Y. Bull. Korean Chem. Soc. 2000, 21, 943.
(16) Lundberg, H.; Tinnis, F.; Adolfsson, H. Synlett 2012, 23, 2201.
(17) Allen, C. L.; Chhatwal, A. R.; Williams, J. M. J. Chem. Commun.
2012, 48, 666.
13C NMR (100 MHz, DMSO-d6): δ = 170.49, 152.50, 148.41, 138.61,
136.27, 129.64, 128.77, 127.03, 119.87, 113.81, 43.44.
HRMS (ESI): m/z (M + H)+ calcd for C13H12N2O: 213.1029; found:
213.1021.
(18) Lundberg, H.; Tinnis, F.; Adolfsson, H. Chem. Eur. J. 2012, 18,
3822.
Methyl 3-(8-Methoxy-8-oxooctanamido)benzoate (Table 2, entry
2)
(19) For reviews on this topic, see: (a) Lundberg, H.; Tinnis, F.;
Selander, N.; Adolfsson, H. Chem. Soc. Rev. 2014, 43, 2714.
(b) Allen, C. L.; Williams, J. M. J. Chem. Soc. Rev. 2011, 40, 3405.
(c) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew. Chem. Int. Ed.
2008, 47, 2876. (d) Maki, T.; Ishihara, K.; Yamamoto, H. Org. Lett.
2005, 7, 5043.
(20) Lanigan, R. M.; Starkov, P.; Sheppard, T. D. J. Org. Chem. 2013, 78,
4512.
(21) Tang, P. W. Org. Synth. 2005, 81, 262.
Prepared from methyl 3-aminobenzoate (0.76 g, 5 mmol), boric acid
(0.03 g, 0.5 mmol), and 8-methoxy-8-oxooctanoic acid (1.04 g, 5.5
mmol), then purified by flash chromatography; yield: 1.12 g (70%);
light-brown solid; mp 105.5–106.9 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.10 (1 H, s), 8.28 (1 H, s), 7.82 (1
H, s), 7.61 (1 H, s), 7.44 (1 H, s), 3.85 (3 H, s), 3.58 (3 H, s), 2.31 (4 H, d,
J = 6.10 Hz), 1.57 (4 H, m), 1.30 (4 H, m).
13C NMR (100 MHz, DMSO-d6): δ = 173.80, 172.01, 166.59, 140.14,
130.50, 129.62, 124.01, 123.90, 119.93, 52.64, 51.63, 33.69, 28.74,
28.68, 24.77.
(22) Tang, P. W. Org. Synth. 2012, 89, 432.
(23) Mylavarapu, R. K.; Kondaiah, G. C. M.; Kolla, N.; Veeramlla, R.;
Koilkonda, P.; Bhattacharya, A.; Bandichhor, R. Org. Process Res.
Dev. 2007, 11, 1065.
HRMS (ESI): m/z (M + H)+ calcd for C17H23NO5: 322.1655; found:
322.1650.
(24) Bhattacharya, A.; Bandichhor, R. Green Technologies in the
Generic Pharmaceutical Industry, In Green Chemistry in the Phar-
maceutical Industry; Dunn, P.; Wells, A.; Williams, M. T., Eds.;
Wiley-VCH: Weinheim, 2011, Chap. 14, 289.
Acknowledgment
(25) Anderson, J. E.; Cobb, J.; Davis, R.; Dunn, P. J.; Fitzgerald, R. N.;
Pettman, A. J. Industrial Applications of Boric Acid and Boronic
Acid-Catalyzed Direct Amidation Reactions, In Sustainable Catal-
ysis, Challenges and Practices for the Pharmaceutical and Fine
Chemical Industries; Dunn, P. J.; Hii, K. K.; Krische, M. J.;
Williams, M. T., Eds.; Wiley: Hoboken, 2013, 7398.
Financial support from National Science Foundation of China (Grant
No. 21176018) is gratefully acknowledged. We are indebted to the
staff of the Mass Spectrometry Group of the College of Science, Bei-
jing University of Chemical Technology for their courtesy in recording
the mass spectra.
(26) For reviews on this topic, see: (a) Zhang, X. X.; Teo, W. T.; Chan,
P. W. H. J. Organomet. Chem. 2011, 696, 331. (b) Glomb, M. A.;
Pfahler, C. J. Biol. Chem. 2001, 276, 41638. (c) Wang, G. W.; Yuan,
T. T.; Li, D. D. Angew. Chem. Int. Ed. 2011, 50, 1380. (d) Kung, P.
P.; Huang, B. W.; Zhang, G.; Zhou, J. Z.; Wang, J.; Digits, J. A.;
Skaptason, J.; Yamazaki, S.; Neul, D.; Zientek, M.; Elleraas, J.;
Mehta, P.; Yin, M. J.; Hickey, M. J.; Gajiwala, K. S.; Rodgers, C.;
Davies, J. F.; Gehring, R. J. Med. Chem. 2010, 53, 499. (e) Armelin,
E.; Franco, L.; Rodriguez-Galan, A.; Puiggali, J. Macromol. Chem.
Phys. 2002, 203, 48.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588126.
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