Hydroxy-Directed Amidation of Carboxylic Acid Esters Using a Tantalum Alkoxide Catalyst

Article abstract of DOI:10.1021/jacs.6b09482

We describe herein a new strategy for the chemoselective synthesis of amides by using a metal-catalyzed hydroxy-directed reaction. A hydroxy group located at the β-position of an ester group promoted the activation of a carbonyl group with a tantalum alkoxide catalyst followed by amidation reactions, leading to a wide variety of β-hydroxyamides with excellent chemeselectivity. The chemoselective amidation strategy can be extended to the catalytic synthesis of dipeptide derivatives, which remains challenging research subjects in modern organic synthesis.

Full text of DOI:10.1021/jacs.6b09482

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Communication
Hydroxy-Directed Amidation of Carboxylic Acid
Esters Using a Tantalum Alkoxide Catalyst
Hiroaki Tsuji, and Hisashi Yamamoto
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b09482 • Publication Date (Web): 16 Oct 2016
Downloaded from http://pubs.acs.org on October 16, 2016
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Hydroxy-Directed Amidation of Carboxylic Acid Esters Using a Tan-
talum Alkoxide Catalyst
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Hiroaki Tsuji* and Hisashi Yamamoto*
Molecular Catalyst Research Center, Chubu University, 1200 Matsumotoꢀcho, Kasugai, Aichi 487ꢀ8501, Japan
Supporting Information Placeholder
tion and provides remarkable synthetic tools, as exemꢀ
plified by asymmetric epoxidation4 and hydrogenation
reactions.5 Thus, these processes expand the horizon of
organic synthesis as substrateꢀcontrolled reactions. Inꢀ
deed, the directing effect of the hydroxy group in metal
catalysis has been exhibited in crossꢀcoupling reactions,6
ringꢀopening reactions,7 cyclization reactions,8 hydroacꢀ
ylation reactions,9 azirizination reactions,10 as well as Cꢀ
H bond functionalization reactions.11 Inspired by the
high efficiency of a hydroxy group in metal catalysis as
a directing group, we envisioned that a hydroxy group
ABSTRACT: We describe herein a new strategy for the
chemoselective synthesis of amides by using a metalꢀ
catalyzed hydroxyꢀdirected reaction. A hydroxy group
located at βꢀposition of an ester group promoted the acꢀ
tivation of a carbonyl group with a tantalum alkoxide
catalyst followed by amidation reactions, leading to a
wide variety of βꢀhydroxyamides with excellent chemeꢀ
selectivity. The chemoselective amidation strategy can
be extended to the catalytic synthesis of dipeptide derivꢀ
atives, which remains challenging research subjects in
modern organic synthesis.
situated at the βꢀposition of the carbonyl group would
promote the activation of the carbonyl group by metal
catalysts and subsequent amidation reactions, allowing
for the efficient and chemoselective amidation of carꢀ
boxylic acid esters with amines (Scheme 1).
Amides are the most important functional groups
found in natural products, pharmaceuticals, polymers, as
well as proteins. Owing to their importance, the develꢀ
opment of efficient amidation processes that avoid the
use of wasteful peptide coupling reagents is an urgent
research subject in synthetic organic chemistry.1 In this
context, catalytic approaches to the synthesis of amides
have been attracting considerable attention, and a numꢀ
ber of elegant catalytic methods have been established to
date.2 However, developed strategies for the chemoseꢀ
lective catalytic amidation reaction are scarce despite its
utility in the chemical ligation of peptides and proteins
and the manipulation of complex organic molecules.
Herein, we describe a new strategy for the synthesis of
amides in a metalꢀcatalyzed hydroxyꢀdirected amidation
Scheme 1. Metal-Catalyzed Hydroxy-Directed Ami-
dation of β-Hydroxy Carboxylic Acid Esters
To verify our hypothesis, we initially assessed the diꢀ
recting effect of a hydroxy group in the metalꢀcatalyzed
amidation reaction of carboxylic acid esters.12 The reacꢀ
tion of an equimolar mixture of phenyl
βꢀ
hydroxypropanoate (1a) and phenyl propanoate (2a)
with pꢀtoluidine (3a) was carried out in toluene at room
temperature for 24 h in the presence of various metal
catalysts (Table 1). Although a La(OTf)3ꢀcatalyzed amiꢀ
dation reaction of esters has been reported,12b selfꢀ
condensation reactions of 1a occurred predominantly as
a side reaction in our reaction system (Entry 1). Other
metal triflate catalysts, such as Sc(OTf)3, In(OTf)3, and
Bi(OTf)3, were also employed (Entries 2ꢀ4). In these
of
β
ꢀhydroxycarboxylic acid esters, providing the correꢀ
ꢀhydroxyamides in good yields and with high
sponding
β
chemoselectivities. The hydroxyꢀdirected amidation
approach we developed has been extended to the catalytꢀ
ic synthesis of dipeptide derivatives, which remains a
challenging research subject in modern organic syntheꢀ
sis.
Substrateꢀdirected reactions are versatile methods for
the construction of organic molecules in chemoꢀ and
stereoselective manners.3 The metalꢀcatalyzed hydroxyꢀ
directed reaction is an important substrateꢀdirected reacꢀ
cases, the desired βꢀhydroxyamide 4aa was obtained in
a moderate yield. However, the amidation reaction of
nonꢀhydroxyꢀcontaining ester 2a also took place, resultꢀ
ing in low chemoselectivity. Next, we examined severꢀ
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al metal alkoxides as catalysts. Although Parco reported With the optimized reaction conditions in hand, we
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the amidation reaction of esters catalyzed by Zr(Otꢀ
Bu)4,12a the catalyst did not effectively work under our
reaction conditions (Entry 5). Ti(OEt)4, Hf(OtꢀBu)4,
VO(OiꢀPr)3, and lanthanum isopropoxides also showed
no efficiency for the hydroxyꢀdirected amidation reacꢀ
tion (Entries 6ꢀ11). On the other hand, when Nb(OEt)5
was used as the catalyst, the yield of 4aa slightly imꢀ
proved to 54% (Entry 12). Gratifyingly, we found that
Ta(OEt)5 efficiently catalyzed the hydroxyꢀdirected amiꢀ
dation reaction to give the desired product 4aa in an
88% NMR yield (84% isolated yield) with excellent
chemoselectivity (Entry 13). We observed that the use
investigated the scope of amines in the hydroxyꢀdirected
amidation reaction of esters (Scheme. 2). A wide variety
of amines, including aromatic (3aꢀj), heteroaromatic
(3k, 3l), and aliphatic amines (3m-3s), were smoothly
reacted with
give the corresponding
β
ꢀhydroxycarboxylic acid esters (1aꢀ1c) to
ꢀhydroxyamides 4aa-4as in up
β
to a 91% yield with >98:2 chemoselectivities. The amiꢀ
dation of 1a could be conducted on a gram scale with
slightly improved yield (94%) and without loss of
chemoselectivity (>99:1). While the reaction using arꢀ
omatic amines bearing an electronꢀdonating group (3aꢀf)
proceeded well, the use of electronꢀdeficient aromatic
amine (3h) led to a slight decrease in the yield. Aniline
derivatives 3i and 3j bearing fluoro and bromo atoms on
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of phenyl
desired
β
ꢀmethoxypropanoate instead of 1a gave the
β
ꢀmethoxyamide in only 9% yield. We also
tested the other tantalum sources under the reaction conꢀ
ditions. TaCl5 and TaBr5 also showed efficient catalytic
activity for the amidation reaction, but a trace amount of
5aa was also formed (Entries 14 and 15).
Scheme 2. Scope of Amines in the Hydroxy-Directed
Amidation of Carboxylic Acid Esters
Table 1. Screening of Metal Catalysts
entry cat.
yield of
yield of
4aa:5aab
4aa (%)a 5aa (%)a
1c
2
La(OTf)3
ꢀ
ꢀ
ꢀ
Sc(OTf)3
In(OTf)3
Bi(OTf)3
53
41
47
15
12
13
<1
<1
<1
<1
ꢀ
78:22
77:23
78:22
>99:1
>99:1
>99:1
>99:1
ꢀ
3
4
5
Zr(OtꢀBu)4 11
6
Ti(OEt)4
31
9
7
Hf(OtꢀBu)4
8
VO(OiꢀPr)3 24
9c
10c
11c
12
13
14
15
La(OiꢀPr)3
Ga(OiꢀPr)3
Yb(OiꢀPr)3
Nb(OEt)5
Ta(OEt)5
TaCl5
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
54
88(84)d
<1
<1
<9e
<5e
>99:1
>99:1
>90:10
>95:5
84
TaBr5
94
1
aThe yields were determined by H NMR analyses using
1,1,2,2ꢀtetrachloroethane as an internal standard. bThe
chemoselectivities were determied by 1H NMR analyses of
crude mixtures. cComplex mixtures of 4aa, selfꢀcondensed
products of 1a, and the other unidentified byproducts were
observed in H NMR of crude mixtures. dIsolated yield.
1
aReaction conditions: 1 (0.25 mmol), 2 (0.25 mmol), 3
(0.75 mmol), Ta(OEt)5 (0.025 mmol) in toluene (1 mL) at
eWith a trace amount of impurities.
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rt or 100 ˚C for 24 h. The chemoselectivities were deꢀ
aReaction conditions: 1 (0.25 mmol), 2 (0.25 mmol), 3
(0.75 mmol), Ta(OEt)5 (0.025 mmol) in toluene (1 mL) at
rt or 100 ˚C for 24 h. The chemoselectivities were deꢀ
1
termied by H NMR analyses of crude mixtures. b1.0 g of
1
2
3
4
5
6
7
8
1a was used. cWith 1.2 equiv of amines. dMethyl butyrate
e
f
1
was used as 2b. 4br:5br = 93:7. 4as:5as = 98:2.
termied by H NMR analyses of crude mixtures. b4fa:5da
c
= 97:3. 4mn:5da = 98:2.
their phenyl rings gave ꢀhydroxyamides 4ai and 4aj in
β
β
ꢀmonoꢀ and
esters 1 were efficiently transformed into the correꢀ
sponding ꢀhydroxyamides 4da-4on in moderate to
high yields with excellent chemoselectivities. The reacꢀ
tion of phenyl ꢀhydroxy ꢀphenylpropanoate (1d) and
βꢀdisubstituted βꢀhydroxycarboxylic acid
71% and 51% yields with excellent chemoselectivities.
The amidation reaction using aniline derivatives having
heteroaromatic rings (3k, 3l) took place chemoselectiveꢀ
ly to deliver the desired products 4ak and 4al in 30%
and 52% yields, respectively. OꢀBenzylhydroxyamine
β
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β
β
(3m) underwent the reaction to afford
β
ꢀhydroxyamide
phenyl butanoate (2d) with pꢀtoluidine (3a) proceeded in
the presence of 10 mol% Ta(OEt)5 to afford the amide
4da in a 97% yield with complete chemoselectivity.
Aromatic substituents bearing methoxy, trifluoromethyl,
and bromo groups were well tolerated, giving the amides
4am in a 91% yield with perfect chemoselectivity,
which can be converted into valuable hydroxamic acids
and primary amides by a simple reduction.13 Although
the use of highly reactive aliphatic amines 3nꢀ3q and a
high reaction temperature were required, methyl ester
(1b) or isopropyl ester (1c) in place of phenyl ester (1a)
were applicable to this catalytic system, providing the
4eaꢀ4ga in high yields and chemoselectivities.
Hydroxyamides 4ha and 4ia having 2ꢀfuryl and 2ꢀ
βꢀ
thienyl substituents were obtained in 87% and 88%
corresponding βꢀhydroxyamides 4bn-4bq in high yields
and with high chemoselectivities. A free hydroxy group
in the amine substrate was compatible with the amiꢀ
yields, respectively.
hydroxycarboxylic acid esters 1j and 1k underwent the
reaction to deliver the ꢀalkyl ꢀhydroxyamides 4jn and
4kn in 79% and 88% yields, respectively. The reaction
of ꢀdiethyl ꢀhydroxycarboxylic acid ester 1l took
place to give ꢀhydroxyamide 4ln in a 68% yield.
Diphenyl ꢀhydroxycarboxylic acid ester 1m afforded
the amide 4mn in a high yield. ꢀHydroxycarboxylic
acid esters 1n and 1o bearing two different substituents
on their ꢀposition were also applicable to our reaction
The reaction of βꢀalkyl βꢀ
β
β
dation, giving
93:7 chemoselectivity.
methoxypropanoate was subjected to the reaction condiꢀ
tions instead of 1b, the desired ꢀmethoxyamide was
β
ꢀhydroxyamides 4br in 89% yield with
When methyl
β
ꢀ
β
,β
β
β
β,βꢀ
β
β
formed in 32% yield with 75:25 chemoselectivity. Morꢀ
pholine (3s) gave the desired product 4as in an 87%
yield with a slight formation of amide 5as.
β
β
conditions, giving the desired amides 4nn and 4on in
We next examined the scope with respect to
hydroxycarboxylic acid esters 1 (Scheme 3). A series of
Scheme 3. Scope of -Hydroxy Esters in the Hy-
droxy-Directed Amidation of Carboxylic Acid Esters
βꢀ
50% and 82% yields, respectively.
Next, we extended our protocol towards the amidation
of esters, which have two methyl ester groups on differꢀ
β
ent positions from the hydroxy group and also
αꢀ
hydroxyesters. The reaction of ester 6a with benzylaꢀ
mine (3n) took place chemoselectively to give amide
7an in a 76% yield (eq 1). A phenolic hydroxy group
also showed a directing effect for the amidation reaction,
thus, amide 7bn was obtained in a 72% yield (eq 2).
Furthermore, the catalyst system can be applicable to the
amidation of
α
ꢀhydroxyesters 6c, providing
αꢀ
hydroxyamide 7ca in 85% yield with excellent chemoseꢀ
lectivity (eq 3).14
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Spectral data (PDF)
To demonstrate the synthetic utility of the hydroxyꢀ
directed amidation reaction, we turned our attention to
the catalytic synthesis of dipeptide derivatives without
the use of enzymatic methods,15 which still remains
challenging in modern organic chemistry (Scheme 4).16
To our delight, the reaction of NꢀBocꢀserine methyl ester
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AUTHOR INFORMATION
Corresponding Authors
*tsuji@isc.chubu.ac.jp
*hyamamoto@isc.chubu.ac.jp
(8a) with amino acid methyl esters 9a-d derived from
Lꢀ
alanine, ꢀphenylalanine, ꢀleucine, and ꢀvaline proꢀ
L
L
L
Notes
ceeded in the presence of Ta(OEt)5 as the catalyst to
provide the corresponding dipeptide derivatives 10aa-ad
in 43ꢀ81% yields with excellent diastereoselectivities.17
Furthermore, NꢀBocꢀthreonine methyl ester (8b) was
also transformed into dipeptide derivatives 10ba and
10be in 78% and 63% yields, respectively. Fortunately,
we did not observed any epimerization of amino acid
moiety, which is due to the use of simple methyl ester
rather than highly activated carboxylic acids of the preꢀ
vious peptide coupling reagents.
The authors declare no competing financial interest.
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ACKNOWLEDGMENT
This work was supported by ACTꢀC, JST.
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Scheme 4. Catalytic Synthesis of Dipeptide Deriva-
tives
aReaction conditions: 8 (0.25 mmol), 9 (0.75 mmol),
Ta(OEt)5 (0.025 mmol) in toluene (1 mL) at 60ꢀ100 ˚C for
24 h. The diastereomeric ratios (d.r.) were determined by
1H NMR analyses of crude mixtures.
In conclusion, we have developed a new strategy toꢀ
wards the chemoselective synthesis of amides by a tantaꢀ
lum ethoxideꢀcatalyzed hydroxyꢀdirected amidation reꢀ
(11) (a) Miura, M.; Satoh, T.; Hirano, K. Bull. Chem. Soc. Jpn. 2014,
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action of
β
ꢀhydroxycarboxylic acid esters with amines,
leading to an array of
β
ꢀhydroxyamides in good yields
with high chemoselectivity. The protocol allowed for
the catalytic synthesis of dipeptide derivatives, which is
still in its infancy in modern organic chemistry. The
development of a method for the catalytic peptide synꢀ
thesis using our directed amidation strategy and its apꢀ
plication to the synthesis of peptide pharmaceuticals are
ongoing in our laboratory.
(13) Bihovsky, R.; Levinson, B. L.; Loewi, R. C.; Erhardt, P. W.;
Polokoff, M. A. J. Med. Chem. 1995, 38, 2119–2129.
ASSOCIATED CONTENT
(14) Based on reviewers’ suggestions, we examined the amidation of
γꢀ and δꢀhydroxyesters. Fortunately, these substrates were reacted
with benzylamine at 60 ˚C under our catalyst system to give the corꢀ
responding γꢀ and δꢀhydroxyamides in 23% and 27% yields, respecꢀ
tively, with >99:1 chemoselectivity. More detailed experiments of
these substrates are in due course.
Supporting Information.
The Supporting Information is available free of charge on
the ACS Publications website.
Experimental procedures (PDF)
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T.; Hayashi, Y.; Agura, K.; Fujii, Y.; Yoshiyama, A.; Mashima, K.
Chem. Commun. 2012, 48, 5434–5436. (b) Liu, S.; Yang, Y.; Liu, X.;
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16084–16087.
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(17) We also tested NꢀBocꢀcysteine methyl ester as the substrate to
assess the directing effect of a thiol group, but the desired dipeptide
derivative was not formed.
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Hydroxy-Directed Amidation of Carboxylic Acid Esters Using a Tantalum Alkoxide Catalyst
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Hiroaki Tsuji,* and Hisashi Yamamoto*
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ACS Paragon Plus Environment