Chemoselective calcium-catalysed direct amidation of carboxylic esters

Article abstract of DOI:10.1039/c5ra18288c

Unactivated carboxylic esters and primary amines undergo calcium-catalysed direct amide bond formation in excellent yields under homogeneous conditions in toluene. This green and mild reaction proceeds chemoselectively with esters, whereas related carboxylic acids and amides remain unreactive.

Full text of DOI:10.1039/c5ra18288c

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Chemoselective calcium-catalysed direct
amidation of carboxylic esters†
Cite this: RSC Adv., 2015, 5, 77658
D. Thao Nguyen, Danny C. Lenstra and Jasmin Mecinovic*
´
Received 16th July 2015
Accepted 9th September 2015
DOI: 10.1039/c5ra18288c
www.rsc.org/advances
Unactivated carboxylic esters and primary amines undergo calcium- been developed; these, however, generally require the presence
6
catalysed direct amide bond formation in excellent yields under of organocatalysts or expensive and environmentally harmful
7
homogeneous conditions in toluene. This green and mild reaction transition metal catalysts. Herein, we report the development
proceeds chemoselectively with esters, whereas related carboxylic of chemoselective calcium-catalysed amide bond formation
acids and amides remain unreactive.
between unactivated carboxylic esters and primary amines.
In order to develop a highly sustainable catalytic method for
the formation of amides from readily available carboxylic esters
and amines, we focused especially on the evaluation of cheap,
non-toxic, and abundant metal salts as potential catalysts.
Transition metals and rare earth metals have already been
Many highly useful transformations in organic chemistry are
catalysed by transition metals, such as Ru, Rh, Ir, Os, Pt, Pd, Au,
1
Cu, and Fe. Transition metal catalysis is no longer recognised
as the most optimal method for generating organic compounds,
mainly due to the increased toxicity, high cost and restricted
accessibility of such catalysts. At present, however, basic
transformations oen lack greener variations employing benign
and cheap catalysts. Calcium, as one of the cheapest, most
abundant and most non-toxic metals, is a particularly attractive
8
reported to catalyse direct amidation of esters into amides. We
reasoned that simple alkali metals and alkaline earth metals
might possess good catalytic properties for direct amidation of
carboxylic esters. Alkali metal salts were observed to act as poor
catalysts for the model reaction between methyl butyrate and
benzylamine to yield N-benzyl butyramide in anhydrous toluene
2
candidate that could replace widely used transition metals. In
ꢀ
at 110 C in 4 hours; lithium, sodium, potassium, rubidium,
the past decade, several calcium-catalysed reactions have been
reported, most of them acting on alkenes, alcohols, or carbonyl-
and cesium salts afforded the amide in <40% conversions
(
Table 1).
Alkaline earth metal salts have shown superior ability over
alkali metal salts to catalyse direct amidation of methyl buty-
rate. The conversions into the amide in the presence of MgBr
and MgI were observed to be 21% and 89%, respectively,
3
containing compounds.
This work arises from our interest in developing novel
catalytic amide bond formation reactions. Despite the ubiqui-
tous presence of amides in nature, chemists' toolbox in making
amides has remained more or less unchanged over the past
decades. Synthetic methods still heavily rely on classical stoi-
chiometric reactions between carboxylic acids and amines in
the presence of diimide-based coupling reagents or trans-
formations of acids into more reactive acyl chlorides, followed
2
2
indicating that the nature of the anion has a substantial effect
on the overall reaction (Table 1). Simple calcium salts catalysed
direct amidation of methyl butyrate in excellent conversions.
CaI , CaBr and Ca(OTf)2 all afforded the amide in 89–92%
2
2
conversions under standard conditions. In contrast, sulfate,
oxalate, chloride and carbonate salts of calcium only yielded
4
by reactions with amines. The reactions between carboxylic
acids or carboxylic esters and amines lead to corresponding
amides at elevated temperatures (>140 C) or under microwave
conditions in the absence of any catalyst. Catalytic variations of
direct amide bond formations between commonly available
carboxylic acids, esters or amides and amines have only recently
<32% of the amide product. We attribute the observed signi-
ꢀ
cant differences in catalytic properties for these calcium salts to
5
ꢀ
alterations in their solubilities in toluene at 110 C. The reac-
tions in the presence of 10 mol% of CaI , CaBr or Ca(OTf) were
2
2
2
carried out under homogeneous conditions (i.e. no solid was
observed in the reaction mixture), whereas CaSO , CaC O ,
4
2 4
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg CaCl
3
and CaCO were only partially soluble or insoluble under
2
1
35, 6525 AJ Nijmegen, The Netherlands. E-mail: j.mecinovic@science.ru.nl
the reaction conditions. In this regard, we also showed that
lower CaI
†
Electronic supplementary information (ESI) available: Reaction optimisation,
2
catalyst load resulted in decreased conversions into
background reactions, characterisation of products. See DOI: 10.1039/c5ra18288c
77658 | RSC Adv., 2015, 5, 77658–77661
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a
Table 1 Screening of catalysts for amide bond formation
Aer screening of catalysts and optimisation of reaction
conditions (Table 1, see ESI†), we used the most optimal reac-
tion conditions for the synthesis of various amides (Table 2).
Aliphatic methyl and ethyl esters reacted with benzylamine to
afford the corresponding amides in excellent yields. Reactions
with para-substituted methyl benzoates also proceeded well in
b
Entry
Catalyst
Conversion
8
4
0–84% conversions; deactivated 4-methoxy derivative gave only
5% amide. CaI -catalysed amidation also worked well with
2
1
2
3
4
5
6
7
8
9
LiI
40
36
22
11
1
other alkyl benzoates, including ethyl, benzyl and allyl (see
ESI†). Ethyl hippurate, and Boc- and Cbz-protected glycine
methyl esters yielded corresponding amides in quantitative
NaCl
NaI
KI
RbCl
CsBr
9
8–100% conversions. Cyclic g-butyrolactone underwent ami-
3
ꢀ
dation with ring-opening in 91% conversion at 50 C. Amidation
of enantiopure Boc-protected methyl esters of R- and S-alanine
gave the amide products in 85–98% conversions; we observed a
small degree (4–8%) of racemisation (see ESI†).
MgBr
MgI
2
21
89
91
92
92
90
89
32
11
10
2
71
24
92
88
14
29
7
2
CaI
CaI
CaI
CaBr
Ca(OTf)
CaSO
CaC
CaCl
CaCO
Ca(NTf)
Ca(NTf)
2
c
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
2
2
$xH
2
O
2
CaI -catalysed amidation of methyl butyrate also proceeds
2
very efficiently with other primary amines. Reactions with
substituted benzylamines, heteroaromatic amines and fully
aliphatic amines afforded corresponding amides in 84–96%
conversions (Table 2). All background reactions in the absence
2
4
2
O
4
2
3
of CaI
provided only <20% of amides (see ESI†). Interestingly,
-catalysed direct ami-
2
2
secondary amines did not undergo CaI
2
2
4 6
/Bu NPF
dation reaction. Methyl butyrate and methyl benzoate did not
react with piperidine, morpholine or N-methylbenzylamine
SrI
BaI
Et NI
2
2
4
under standard conditions as well as at harsher conditions
HI
—
ꢀ
(
20 hours at 140 C in the presence of 20 mol% CaI ). We
2
observed that all reactions with secondary amines immediately
a
Conditions: methyl butyrate (2.5 mmol), benzylamine (3.25 mmol), furnished a large amount of insoluble material (likely an
catalyst (0.25 mmol), anhydrous toluene (0.6 mL), 110 C, 4 h.
ꢀ
insoluble complex between CaI
Recent studies showed that unactivated carboxylic esters,
acids and amides all undergo Cp ZrCl -catalysed amidation
reactions under virtually the same experimental conditions
2
and secondary amine).
b
c
2
Conversion determined by GC. 99.999% pure CaI .
2
2
ꢀ
7i–k
the amide, although the reaction proceeded very well even with (toluene or cyclohexane at 80–110 C). We were pleased the
mol% of CaI (see ESI†). Ca(NTf) , and in particular Ca(NTf)
CaI -catalysed direct amidation is highly chemoselective for
Bu NPF
that is known to catalyse several transformations in carboxylic esters under our reaction conditions (Scheme 1).
organic chemistry, were found to be less active catalysts for Unlike Cp
our model amidation reaction. reaction between carboxylic acids and amines. Not surprisingly
In order to exclude any potential transition metal-catalysed and in accordance with previous report, butanoic acid under-
2
2
2
2
/
2
4
6
2
b
2 2 2
ZrCl -mediated amidation, CaI did not catalyse the
7
i
9
amide bond formation, we also used CaI
possible purity available (i.e. 99.999%); it afforded 92% amide, 64% conversion. The presence of CaI
similar to the 99.95% pure CaI
that we use in standard reac- conversion to 30%, presumably by the chelation of carboxylic
tion. This result conrms that the formation of the amide is acid by calcium cation, thus making it inaccessible for amida-
calcium-catalysed. The reaction also proceeds very well with tion reaction. Similarly, CaI -catalysed and uncatalysed amida-
2
with the highest went direct amide bond formation in the absence of CaI
2
in
2
even lowered the
2
2
very cheap CaI $xH O (x ¼ 4–6), indicating that the presence of tion of benzoic acid only afforded <10% of amide. Interestingly,
2
2
water does not affect the progress of the reaction. In addition, a recent study demonstrates that carboxylic acids, unlike ester
the CaI -catalysed amide bond formation proceeds in excellent counterparts, undergo selective amidation under mild condi-
2
7l
conversions in normal toluene and other non-polar solvents tions in the presence of catalytic amounts of Cp
under open-ask conditions (see ESI†).
2
HfCl
We have not observed transamidation of butyramide with
benzylamine in the presence of CaI (Scheme 1). CaI -catalysed
2
.
Other toluene-soluble earth alkali metal salts, such as SrI
2
2
2
and BaI
2
, also exhibited very efficient catalytic properties for the and uncatalysed background reactions only produced traces
conversion of methyl butyrate into N-benzyl butyramide (92% (1%) of the amide product. Similarly, reaction between benza-
and 88% conversion, respectively). The reaction in the presence mide and benzylamine afforded 22% and 21% of the N-benzyl
of 10 mol% of Et NI or HI yielded <30% of the amide product, benzamide product in the absence and presence of 10 mol%
4
2
indicating that iodide itself does not act as a catalyst for ami- CaI , respectively, again demonstrating that amides do not
dation reaction. It is noteworthy that the model reaction in the undergo CaI
2
-catalysed transamidation under our standard
absence of catalyst only yielded 7% of N-benzyl butyramide.
conditions.
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Table 2 Scope of the calcium-catalysed amidation of carboxylic Table 2 (Contd.)
a
esters
Entry
Amide
Conversion (yield)
96 (89)
Entry
1
Amide
Conversion (yield)
16
b
c
91 (89)
1
1
7
8
92 (70)
84 (75)
2
3
4
5
6
90 (86)
94 (68)
84 (79)
82 (64)
80 (77)
1
9
85 (66)
a
Conditions: carboxylic ester (2.5 mmol), amine (3.25 mmol), CaI
2
ꢀ
0.25 mmol), anhydrous toluene (0.6 mL), 110 C, 4 h for aliphatic
b c
(
esters, 8 h for aromatic esters. Determined by GC. Isolated yield.
d
ꢀ
e
f
5
0 C, 2 h. 96% ee. 92% ee.
7
8
9
83 (80)
45 (38)
85 (82)
a
b
Scheme
1 Calcium-catalysed and uncatalysed amidation of
a,b
aliphatic and aromatic carboxylic esters, acids and amides;
conversion (%) determined by GC.
10
11
12
13
14
15
100 (67)
100 (88)
We next applied the newly developed reaction for the rapid
synthesis of alfuzosin, an antagonist of the alpha-1 adrenergic
receptor. The rst-step CaI -catalysed reaction between the
2
methyl ester of tetrahydro-2-furanoic acid and N-methyl
ꢀ
1
,3-diaminopropane proceeded quantitatively (100%) at 25 C,
d
91 (85)
whereas uncatalysed reaction afforded only 10% of amide
(Scheme 2).
In conclusion, we have developed calcium-catalysed amide
e
98 (90)
bond formation reaction between carboxylic esters and primary
amines. The reaction is chemoselective for unactivated
carboxylic esters over related carboxylic acids and amides, and
f
85 (82)
94 (78)
Scheme 2 CaI
2
-catalysed synthesis of alfuzosin. Conversion (isolated
yield).
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demonstrates the ability of cheap and non-toxic alkaline earth
metals to catalyse an important transformation in organic
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