Direct amidation of non-activated carboxylic acid and amine derivatives catalyzed by TiCp2Cl2

Article abstract of DOI:10.1002/aoc.5568

This paper described a mild and efficient direct amidation of non-activated carboxylic acid and amine derivatives catalyzed by TiCp₂Cl₂. Arylacetic acid derivatives reacted with different amines to afford the corresponding amides in good to excellent yield except of aniline. Aryl formic acids failed to react with aniline but smoothly reacted with aliphatic amines and benzylamine in moderate to good yield, fatty acids reacting with benzyl and aliphatic amines give amides in good to excellent yield. Chiral amino acids derivatives were transformed into amides without racemization in moderate yield. The possible mechanism of direct amidation catalyzed by TiCp₂Cl₂ was discussed. This catalytic method is very suitable for the amidation of low sterically hindered arylacetic acid, fatty acids with different low sterically hindered amines except aniline, as well as the amidation of aryl formic acid with benzyl and aliphatic amines.

Full text of DOI:10.1002/aoc.5568

Received: 11 September 2019
DOI: 10.1002/aoc.5568
Revised: 10 January 2020
Accepted: 13 January 2020
F U L L P A P E R
Direct amidation of non-activated carboxylic acid and
amine derivatives catalyzed by TiCp2Cl2
Hui Wang | Wei Dong | Zhipeng Hou | Lidan Cheng | Xiufen Li |
Longjiang Huang
State Key Laboratory Base for Eco-
This paper described a mild and efficient direct amidation of non-activated car-
boxylic acid and amine derivatives catalyzed by TiCp2Cl2. Arylacetic acid
derivatives reacted with different amines to afford the corresponding amides in
good to excellent yield except of aniline. Aryl formic acids failed to react with
aniline but smoothly reacted with aliphatic amines and benzylamine in moder-
ate to good yield, fatty acids reacting with benzyl and aliphatic amines give
amides in good to excellent yield. Chiral amino acids derivatives were trans-
formed into amides without racemization in moderate yield. The possible
mechanism of direct amidation catalyzed by TiCp2Cl2 was discussed. This cata-
lytic method is very suitable for the amidation of low sterically hindered
arylacetic acid, fatty acids with different low sterically hindered amines except
aniline, as well as the amidation of aryl formic acid with benzyl and aliphatic
amines.
Chemical Engineering, College of
Chemical Engineering, Qingdao
University of Science and Technology,
Qingdao, 266042, P. R. China
Correspondence
Longjiang Huang, College of Chemical
Engineering, Qingdao University of
Science and Technology, Qingdao 266042,
P. R. China.
Email: huanglj@qust.edu.cn
Funding information
Shandong Province Higher Educational
Science and Technology Program, Grant/
Award Number: No.J16LC13
K E Y W O R D S
amine derivatives, chiral amino acids, direct amidation, non-activated carboxylic acid
derivatives, without racemization
1 | INTRODUCTION
cost-effective and atom economy processes with water as
the only by-product.
Amide bonds, which form proteins and polypeptides of
the cornerstone of life, exist widely in natural and syn-
thetic compounds such as drugs,[1–3] agrochemicals, bio-
macromolecules and food additives.[4–8] The high
stability of amide bonds has led to their extensive applica-
tions in materials such as nylon and artificial silk.[9,10]
Therefore, the formation of amide bonds is one of the
most important reactions for organic synthesis. Although
there are many different ways to obtain amides, most of
them suffer from complicated purification process and
poor atom economy. The formation of amides with high
atom economy process was ranked as the most challeng-
ing task in organic chemistry by the ACS Green Chemis-
try Institute.[11] Catalytic direct amidation of carboxylic
acid and amine is highly attractive as it would lead to
In the past 10 years, catalytic direct amidations by
organo-boron derivatives have emerged.[12–29] However,
the acquisition of organo-boron compounds often
requires long reaction steps, harsh reaction conditions
and tedious purification.[12,14,15,17,19,21–28] Direct ami-
dation catalyzed by Group IV metal or early transition
metal complexes have received increasing attention in
recent years. In 2015, Adolfsson et al. reported the direct
amidation of acids and amines at room temperature with
good to excellent yields by using expensive HfCp2Cl2 as
catalyst.[30] In 2012, Adolfsson et al. reported the direct
amidation by using 2–10 mol% moisture sensitive ZrCl4
with good yields and elucidated the possible mechanism
in 2017.[31,32] These methods are novel, however, zirco-
nium and hafnium are both rare metals and coexist in
Appl Organometal Chem. 2020;e5568.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5568

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WANG ET AL.
nature, which result in difficulties in separation. Their
high cost and sensitivity to humidity and air limited their
application in large scale. Using titanium compounds as
amidation catalyst is more attractive since it is cheap and
abundant in nature. Nordahl and Carlson[33] reported the
direct amidation of benzoic acid with different amines in
toluene with reflux by using a catalytic amount of TiCl4
(30 mol%). In the same year, Mader and Helquist[34]
reported that 50 mol% of Ti (Oi-Pr)4 can mediate
lactamisations of amino acids in 1,2-dichloroethane at
reflux with good yields. Adolfsson et al. reported that cat-
alytic direct amidation of non-activated carboxylic acids
with amines in good yield by using 10 mol% of Ti (Oi-
Pr)4 as catalyst.[35] However, these titanium salts or com-
plex are sensitive to moisture or air (smoke under the air)
and hard to handle in lab or industry. Developing stable
Ti complex as direct amidation's catalyst becomes critical
and meaningful. As our program to develop amidation
catalysts continues,[36] here we present a more stable
catalyst-TiCp2Cl2 which can efficiently carry out direct
amidation of non-active carboxylic acids and amines. To
the best of our knowledge, this is the first report of using
TiCp2Cl2 as catalyst for direct amidation.
FIGURE 1 The GC of amide reaction catalyzed by TiCl4, Ti
(Oi-Pr)4 and TiCp2Cl2
in 11% yield without catalyst which is similar to the result
reported by Adolfsson et al.[35] When TiCl4 was used as
catalyst, the isolated yield of the amide was 84%, the com-
petition reaction is the condensation of the phenylacetic
acid affording 1,3-diphenylpropan-2-on. The isolated
yield of the amidation reaction catalyzed by TiCp2Cl2 was
up to 96% which is higher than the reaction catalyzed by
Ti (Oi-Pr)4 (81% yield) and TiCl4. The results show that
titanium salt or complex can truly catalyze the formation
of amide bond and TiCp2Cl2 is the best among the three
catalysts.
2 | RESULTS AND DISCUSSION
Phenylacetic acid and benzylamine were selected as
model compounds to investigate the performance of the
different catalysts including Ti (Oi-Pr)4, TiCl4 and
TiCp2Cl2. To verify the role of these catalysts, control
experiment was performed in the absence of the
catalysts. Adolfsson's Ti (Oi-Pr)4 catalyzed direct ami-
dation protocol[35] was used to investigate the perfor-
mance of the different catalysts. The reaction was
monitored by Gas Chromatography-Mass Spectrometer
(GC–MS). As showed in Figure 1, only one by-product
peak was found in the reaction catalyzed by
TiCl4, whereas three by-products peaks, two of which
was identified as 1,3-diphenylpropan-2-one, N-
benzylidene-1-phenylmethan amine and one unknown
product were found in the reaction catalyzed by Ti (Oi-
Pr)4. The structures of the by-products were identified by
matching mass spectrometry libraries and confirmed by
comparing their retention time and mass spectral data
with those of standards under the same GC–MS experi-
mental conditions. Interestingly, almost no any by-
product peak was observed in the reaction of amidation
catalyzed by TiCp2Cl2. The yield of the target amide was
showed in Figure 2. The target product can be obtained
Peak 1: phenylacetic acid. Peak 2: N-
benzylidene-1-phenyl-methanamine. Peak 3:
1,3-diphenylpropan-2-one. Peak 4: target
FIGURE 2 The yield of amidation of phenylacetic acid with
benzylamine catalyzed by Ti complex

DIRECT AMIDATION OF ACID AND AMINE DERIVATIVES CATALYZED BY TICP2CL2
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amide. Peak 5: unknown by-product. Reac-
tion condition: phenylacetic acid (1.2 mmol),
benzyl-amine (1.0 mmol), cat. (10 mol%), sol-
vent (10 mL), 0.75 g 4 Å MS.
by-product 1,3-diphenylpropan-2-one, which increases
the difficulty of product purification.
The catalyst loading was evaluated by using
phenylacetic acid and benzylamine as substrates. When
the amount of catalyst was 10 mol%, the yield of ami-
dation was 96% (Table 2, entry 2). Reducing the catalyst
loading to 5 mol%, the isolated yield was significantly
reduced to 58% (Table 2, entry 1), increasing the catalyst
loading to 20 mol%, the yield is 95% (Table 2, entry 3).
The results showed that 10 mol% catalysts loading are
enough for the direct amidation.
The results also revealed that water played an impor-
tant role in the process of catalytic direct amidation, as
showed in Figure 3, the isolated yield of amide was
strictly dependent on the amounts of 4 Å powdered
molecular sieves when all other parameters are equal.
When the amount of molecular sieve was increased to
0.75 g/mmol substrate, the best yield of amide was
obtained; an increase in the amount of 4 Å powdered
molecular sieves resulted in the lower product yield. This
finding indicated the dual role of water in the reaction
which was first proposed by Adolfsson.[19,30]
In our catalytic amidation procedure, the reactants,
molecule sieves, catalyst and solvent together under Ar
were mixed in a sealed tube and heated for 24, 36 or
48 hr. This procedure is simpler than that reported by
Adolfsson using Ti (Oi-Pr)4 as catalyst.[35]
Table 1 showed the amidation yield by TiCp2Cl2 in
different solvents such as DCM, THF, tolueꢀne,
1,4-dioxane, MeCN and DMSO. In DCM under 40 C,
the yield was 50% for 36 hours and 60% for 48 hr
(Table 1, entry 1 and 2). When the temperature was
ꢀ
increased to 70 C, the yield increased to 95% and 94%
for 24 hr (Table 1, entry 3 and 4). However, when tolu-
ene, 1,4-dioxane, MeCN was used as the solvent, the
yield decreased (88%, 89% and 63%, respectively,
Table 1, entry 7, 8, 9), especially DMSO, the yield
decreased dramatically (32%, Table 1, entry 10). The
best yield by TiCp2Cl2 was obtained in THF at 24 hours
in 96% with a slight excess of the amine (Table 1, entry
5). Furthermore, the reaction was rather insensitive to
the stoichiometry of reactants because equally good
results were obtained by using either a slight excess of
the acid or of the amine and the use of an excess of the
amine was beneficial due to the yield of product
(Table 1, entries 3–4, 5–6) and the excess of the acid
may lead to the formation of a small amount of
As shown Table 3, Table 4 and Table 5, different non-
activated carboxylic acids including aryl acetic acid, aryl
formic acid, fatty acid and amine derivatives were used to
TABLE 2 Effect of the amount of catalyst on the reaction
Entry
TiCp2Cl2 (mol%)
Yield (%)
1
2
3
5
10
20
58
96
95
TABLE 1 The effects of different solvents on the direct
amidation of phenylacetic acid with benzylamine catalyzed by
TiCp2Cl2
Entry
Solventa
DCMa
DCMa
DCMa
DCMc
THFa
THFc
Toluenea
1,4-dioxanea
MeCNa
DMSOa
Time
36
Temp. (ꢀC)a
Yield (%)b
1
2
40
40
70
70
70
70
70
70
70
70
50
60
95
94
96
94
88
89
63
32
48
3
24
4
24
5
24
6
24
7
24
8
24
9
24
10
24
aReaction condition: phenylacetic acid (2 mmol), benzylamine (2.4 mmol),
cat. (10 mol%), solvent (20 mL), 1.5 g 4 Å MS.
bIsolated yields.
cPhenylacetic acid (2.4 mmol), benzylamine (2.0 mmol), cat. (10 mol%),
solvent (20 mL), 1.5 g 4 Å MS.
FIGURE 3 Effect of the amount of molecular sieve in the
reaction mixture on the amide yield

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WANG ET AL.
TABLE 3 Synthesis of amide derivatives from different substituents of phenylacetic acids and amines using TiCp2Cl2 as catalyst
aReaction condition: acid (1 mmol), amine (1.2 mmol), cat. (10 mol%), 075 g 4 Å MS, dry THF (10 mL), at 70 ꢀC in a sealed tube under Ar, 24 hr.
bcat. (20 mol%), acid (1 mmol), amine (2.0 mmol), 80 ꢀC, 36 hr.
ccat. (20 mol%), 80 ꢀC, 48 hr, determined by GC–MS.

DIRECT AMIDATION OF ACID AND AMINE DERIVATIVES CATALYZED BY TICP2CL2
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investigate the efficiency of the TiCp2Cl2-catalyzed direct
amidation.
reaction of sterically hindered 1-phenylethanamine with
phenylacetic acid afforded the amide in 28% yield
(Table 3, 3az). The amidation reaction of heteroaryl
methylamine or heteroaryl acetic acid derivatives carried
out smoothly and the corresponding amides were
obtained in good yield (Table 3, 3bi-3bm). The reaction
of more complex anti-inflammatory drug indomethacin
with benzylamine produced the corresponding amide
successfully in the yield of 85% (Table 3, 3bn).
1-Naphthaleneacetic acid reacted with benzylamine to
afford the amide in 70% yield (Table 3, 3ax). The reaction
of phenylacetic acid with aliphatic amines required
20 mol% catalyst loading, two equivalent amine and lon-
ger reaction time in order to reach good yields (Table 3,
3bd-3bh). Aniline (weak basicity) failed to react with
phenylacetic acid but p-methoxyaniline afforded the
amide in 10% yield (Table 3, 3ba-3bb), however, the yield
of 3bb was increased to 50% and the yield of 3ba was
trace under the optimized reaction condition.
According to the results in Table 3, the substitute
groups on the aromatic ring of the phenylacetic acid
derivatives played crucial roles for the direct amidation
with benzylamine. The yield was affected by the steric
and electronic effect of the substitute groups on the aro-
matic ring and the steric effect was more important. With
the same substitute on the different positions of the aro-
matic ring, the order of the amidation yield was
para>meta>ortho (Table 3, 3ab-3ad, 3ae-3ag, 3ah-3aj,
3ak-3am). The ortho substitution has strong steric bulk
effect, resulting in significantly decreased yield (Table 3,
3ab, 3ae, 3ah, 3ak). The amidation yield of the acid sub-
strate with electron-donating group (s) on the aromatic
ring is generally higher than that of the substrate with
electron-withdrawing group (s) (Table 3, 3aa-3 am). The
substitute groups on the aromatic ring of the benzyl
amine derivatives affected the amidation yield and the
electron-withdrawing group on the aromatic rings was
favorable for the reaction (Table 3, 3an-3aw). The
Under TiCp2Cl2-catalyzed direct amidation condition,
examining the aryl formic acid's reactivity is similarly
intriguing. Benzoic acid, 2-furancarboxylic acid and
2-thiophenecarboxylic acid failed to react with aniline
even using 20 mol% TiCp2Cl2 (Table 4, 4aa-4ac). The
reaction of benzoic acid with aliphatic amines and benzyl
amine derivatives required 20 mol% catalyst loading, two
TABLE 4 Synthesis of amide derivatives from aryl formic acids and amines using TiCp2Cl2 as catalyst
aReaction condition:acid (1 mmol), amine (1.2 mmol), cat. (10 mol%), 075 g 4 Å MS, dry THF (10 mL), at 70 ꢀC in a sealed tube under Ar, 24 hr.
bcat. (20 mol%), acid (1 mmol), amine (2 mmol), 80 ꢀC, 36 hr.
cacid (1 mmol), amine (1.2 mmol), cat. (10 mol%), yield was determined by GC–MS.

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WANG ET AL.
TABLE 5 Synthesis of amide derivatives from fatty acids and amino acids with amines using TiCp2Cl2 as catalyst
aReaction condition: acid (1 mmol), amine (1.2 mmol), cat. (10 mol%), 075 g 4 Å MS, dry THF (10 mL), at 70 ꢀC in a sealed tube under Ar, 24 hr.
b8 h.
ccat. (20 mol%), acid (1 mmol), amine (2 mmol), 80 ꢀC, 36 hr.
equivalent amine and longer reaction time to reach good
yields and benzylamine derivatives afforded the amides
in higher yield (Table 4, 4ad-4ap). 4-nitrobenzoic acid
with strong electron-withdrawing nitro group reacted
with benzylamine to afford the corresponding amide in
55% yield (Table 4, 4ak), 2-furancarboxylic acid reacted
with benzylamine in 45% yield (Table 4, 4al). The results
indicated that benzylamine derivatives possess higher
reactivity to aryl formic acids and this enhanced
reactivity of benzylamine- “benzylic effect” have been
also observed by Andrew Whiting[37] and André
Loupy[38] in the uncatalyzed direct amide formation
reaction.
When fatty acids with different chain lengths and
benzylamine were used as substrates, the amidation yield
was moderate to good. Moreover, the yield of amidation
increased with the increasement of the length of carbon
chains (Table 5, 5aa-5ad, 62–82%). When the acid is
dichloroacetic acid or trifluoroacetic acid with strong
acidity, the yield was over 99% in 8 hours (Table 5, 5ae-
5af). Fatty acids reacted with aliphatic amines to afford
the corresponding amides in 81–95% yield by using
20 mol% catalyst and two equivalent amine (Table 5, 5ai-
5ak). However, trifluoroacetic acid reacted with
dodecylamine to afford the amide in excellent yield with
10 mol% catalyst loading and 1.2 equivalent amine
(Table 5, 5al, >99%). Ether and thioether groups on the ɑ
position of acetic acid were unaffected by the amidation
reaction and very favorable for the amidation yields
(Table 5, 5ag >99%, 5ah 92%).
When the chiral starting materials such as L-
phenylalanine methyl ester, Boc-L-alanine, Boc-L-proline
and Boc-L-leucine were used as the substrate, the target
amides were obtained in the yield of 54%, 56%, 60% and
51%, without racemization (Table 5, 5am-5aq). By using
5 am as the example, the enantiomeric excess of the tar-
get amide was determined by comparison of chiral HPLC
of target amide with the racemic amide compound
(Figure 4, (a) and (b), 5 am).
In 2011, Whiting et al. proposed the possible mecha-
nism of uncatalyzed direct amidation through
hydrogen-bonded dimeric carboxylic acid,[37] in 2017,
Adolfsson et al. elucidated the mechanism of
zirconium-catalyzed direct amidation through a din-
uclear zirconium species.[32] The normal Lewis acid
mechanism of Ti (OBu)4-catalyzed esterification of acid
and alcohol was proposed by Bonora et al. in 1985.[39]
As showed in Figure 5, when the phenylacetic acid was

DIRECT AMIDATION OF ACID AND AMINE DERIVATIVES CATALYZED BY TICP2CL2
7 of 9
FIGURE 4 Chiral HPLC of compound
5 am (b) and racemic compound 5 am (a)
ꢀ
heated in THF under 70 C in the presence of 10 mol%
catalyst and 4 Å molecule sieves to afford a small
amount of the anhydride of phenylacetic acid after
10 hr. The result suggested that the TiCp2Cl2-catalyzed
direct amidation is possibly through anhydride interme-
diate (thermal amidation) and Lewis acid-catalyzed
mechanism simultaneously. The titanium atom in the
complex easily coordinated with oxygen atom and the
crystal structure of the adduct of titanium complex and
ester formed from ethyl lactate and acrylic acid has
been solved.[40] The possible mechanism of amidation
catalyzed by TiCp2Cl2 was proposed based on the
results mentioned above, in our Lewis acid-catalyzed
reaction, the acid reacts with catalyst TiCp2Cl2 to afford
the six member ring intermediate,[39,40] then the carbon
of carbonyl group of the acid becomes electropositive
enough in the intermediate for subsequent attack by
the amine to afford the target amide and water
(Figure 6).
Reaction condition: phenylacetic acid (1
mmol), cat. (10 mol%), 0.75 g 4Å MS, dry
THF (10 mL), at 70 ꢀC in a sealed tube under
Ar, 10 hr.
FIGURE 5 The GC of reaction of phenylacetic acid catalyzed
FIGURE 6 The possible mechanism of the direct amidation
by TiCp2Cl2 and of phenylacetic acid anhydride
catalyzed by TiCp2Cl2

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WANG ET AL.
3 | EXPERIMENTAL
FUNDING INFORMATION
Shandong Province Higher Educational Science and
Technology Program, Grant/Award Number: J16LC13.
Flame-dried 4 Å MS (0.75 g), acid derivative (1 mmol),
amine derivative (1.2 mmol), TiCp2Cl2 (10 mol% of the
acid) and dry THF (10 mL) was placed in an oven-dried
vial equipped with a stirring bar and sealed with a crimp-
on cap. The atmosphere was exchanged for Ar. The
resulting mixture was stirred at 70 ꢀC for 24 hr, after that,
the mixture was cooled to room temperature, filtered, the
filter cake was washed with dichloromethane (3 × 5 mL),
the filtrate was combined and evaporated to dryness, the
residue was purified by flash column to gain the pure
amide.
ORCID
Longjiang Huang https://orcid.org/0000-0002-8691-
8896
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
How to cite this article: Wang H, Dong W,
Hou Z, Cheng L, Li X, Huang L. Direct amidation
of non-activated carboxylic acid and amine
derivatives catalyzed by TiCp2Cl2. Appl
Organometal Chem. 2020;e5568. https://doi.org/10.
1002/aoc.5568
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