Triphenylphosphine-catalysed amide bond formation between carboxylic acids and amines

Article abstract of DOI:10.1039/c4cc01861c

Unactivated carboxylic acids and amines undergo organocatalytic Ph ₃P/CCl₄-mediated amide bond formation by employing in situ reduction of triphenylphosphine oxide to triphenylphosphine in the presence of diethoxymethylsilane and bis(4-nitrophenyl)phosphate. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01861c

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Triphenylphosphine-catalysed amide bond formation between
carboxylic acids and amines
Danny C. Lenstra, Floris P. J. T. Rutjes and Jasmin Mecinović*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
be reduced back to Ph3P by the appropriate reducing agent(s)
Unactivated carboxylic acids and amines undergo
organocatalytic Ph3P/CCl4-mediated amide bond formation
by employing in situ reduction of triphenylphosphine oxide
50 (Scheme 1). Such in situ reduction of phosphine oxides has been
employed in several catalytic reactions, including Appel, Wittig,
and Staudinger.23-26 Notably, related catalytic organophosphorus
reactions based on the P(V)/P(III) or P(V) cycle have also been
developed recently.27-32
into
triphenylphosphine
in
the
presence
of
10 diethoxymethylsilane and bis(4-nitrophenyl)phosphate.
The amide bond is ubiquitous in all forms of life. Amide bonds
constitute the skeleton of biologically important proteins, several
drugs, including penicillin and paracetamol, and also widely used
2
synthetic polymers, such as nylon.1, Amides are most often
15 prepared from carboxylic acids and amines, either via formation
of more reactive carboxylic acid anhydrides or acyl chlorides, or
via activation with coupling reagents. Most of the current
synthetic methods for the formation of the amide bond are,
however, limited to the use of stoichiometric amounts of reagents
20 that activate carboxylic acids.3, 4
55
Scheme 1 Proposed catalytic amide bond formation cycle.
The formation of the amide bond under catalytic conditions is
considered as one of the grand challenges of modern organic
chemistry.5, 6 Recent endeavours have demonstrated the promise
that amides can be synthesised from various readily available
Initially, we explored reaction conditions for the model
reaction between 4-nitrobenzoic acid and benzylamine to afford
the corresponding amide in toluene at 110 °C. Under
60 stoichiometric conditions in the presence of 2 equiv. of CCl4 and
1 or 2 equiv. of Ph3P, 92 and 100% of amide were obtained,
respectively (Table 1, entries 1-2). In the presence of 0.25 equiv.
of Ph3P and 2.0 equiv. of CCl4, 4-nitrobenzoic acid and
benzylamine reacted to afford 24% of amide (Table 1, entry 3).
65 Recent study by Williams et al. demonstrated that unactivated
aliphatic carboxylic acids and aliphatic amines, unlike their
aromatic counterparts, undergo direct coupling reactions in
toluene at 110 °C in the absence of catalyst, and in many cases,
the amide was formed quantitatively.13 Thus, we had to test
70 whether 4-nitrobenzoic acid and benzylamine react in the absence
of activating agents; in control experiment, only traces of amide
(5%) were formed after 20 hours at 110 °C (Table 1, entry 4).
Having shown that the model reaction gives excellent
conversions in the presence of an excess of Ph3P, and poor
75 conversion in the presence of the catalytic amounts of Ph3P, we
investigated whether the yield for the reaction that is catalytic in
Ph3P can be increased in the presence of the appropriate reducing
25 starting materials, including the most preferred pair of carboxylic
8
acids and amines.7,
For instance, direct coupling between
carboxylic acids and amines has been achieved under
organocatalytic conditions in the presence of functionalised
arylboronic acids.9-11 In addition, several metal-catalysed
30 methods for the formation of amide bonds have been established
using Zr-, Ti-, Zn-, Fe- and Sn-based catalysts.12-17
We envisaged that it might be possible to synthesise amides
from carboxylic acids and amines in the presence of catalytic
amounts of phosphines by employing in situ reduction of
35 phosphine oxides. Recently, several methods were developed for
the efficient conversion of triphenylphosphine oxide (Ph3P=O) to
triphenylphosphine
(Ph3P),
either
by
utilising
i)
diethoxymethylsilane and bis(4-nitrophenyl)phosphate,18 ii)
tetramethyldisiloxane (TMDS) and copper(II) triflate,19 or iii)
40 TMDS and indium(III) bromide.20 Early studies showed that
amides can almost quantitatively be obtained by the reaction
between carboxylic acids and amines in the presence of 2 equiv.
reagent(s).
A
combination
of
diethoxymethylsilane
of Ph3P and CCl4 under reflux in THF via a variation of the
22
Appel reaction.21,
Thus, we hypothesised that a system that
((EtO)2MeSiH) and bis(4-nitrophenyl)phosphoric acid was found
80 to improve the conversion of the model reaction. The conversion
increased significantly from 24% to above 60% (Table 1, entries
5-7). Optimisation of the ratios between (EtO)2MeSiH and bis(4-
nitrophenyl)phosphoric acid provided the most optimal reaction
45 consists of a carboxylic acid, amine, Ph3P and CCl4 could be a
good starting point to develop the ‘first generation’
organocatalytic amide bond formation. In this proposed method,
which uses catalytic amounts of Ph3P, the Ph3P=O product has to
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conditions for the formation of amide. In the presence of 1.5
Table 2 Scope of the organocatalytica and uncatalyticb amidation of
equiv. of (EtO)2MeSiH and 0.05 equiv. of bis(4-nitrophenyl)
phosphoric acid, 84% of the target amide was formed. Replacing
Ph3P by Ph3P=O under standard conditions resulted in a decrease
of the conversion to 60%, indicating that one additional reduction
step at the beginning of the catalytic cycle is not completely
quantitative (Table 1, entry 8). Moreover, control experiments for
the amidation of 4-nitrobenzoic acid and benzylamine in the
absence of PPh3/CCl4, but in the presence of (EtO)2MeSiH and
carboxylic acids and amines.
View Article Online
DOI: 10.1039/C4CC01861C
45
5
Entry
Amide
Catalytic
Uncatalytic
Conversion
(yield)
Conversion
(yield)
10 bis(4-nitrophenyl)phosphate showed that only 11% of amide was
formed (Table 1, entries 9-10). In addition, the standard reaction
in the absence of CCl4 affords only 13% of amide (Table 1, entry
11).
1
84c (64)d
81 (60)
77 (58)
72 (61)
71 (68)
90 (54)
80 (75)
52 (46)
99 (76)
72 (69)
82 (53)
71 (58)
96 (75)
65 (48)
35 (25)
81 (77)
87 (52)
98 (52)
24 (19)
2
24 (12)
21 (13)
25 (19)
20 (6)
17 (11)
22 (19)
5 (3)
Previous studies also demonstrated that Ph3P=O can be
15 reduced to Ph3P in the presence of other reducing agents.18-20 In
contrast to the (EtO)2MeSiH and bis(4-nitrophenyl)phosphoric
acid, a combination of TMDS and copper(II) triflate was not
compatible with the conditions for the catalytic amide bond
formation; only 22% of amide product was formed (Table 1,
20 entry 12). Similarly, Ph3P/CCl4-mediated amide bond formation,
coupled to putative TMDS/InBr3-catalysed reduction of Ph3P=O
to Ph3P, did not afford improved yields of the desired amide; 28%
conversion of amide was found (Table 1, entry 13). In addition to
CCl4, we evaluated two other common halogen-donor reagents;
25 under standard reaction conditions, but in the presence of CBr4
and CBrCl3, only 58 and 49% conversions to the amide were
observed, respectively (Table 1, entries 14-15).
3
4
5
6
7
Several reports showed that amides can be reduced into amines
in the presence of various reducing agents, including silanes.33-35
30 In
a control experiment, the amide did not react with
8
(EtO)2MeSiH nor with a mixture of (EtO)2MeSiH and bis(4-
nitrophenyl) phosphoric acid in dry toluene at 110 °C; 99% of the
amide was recovered.
9
28 (6)
13 (10)
14 (7)
9 (5)
35 Table 1 Optimisation of conditions for amide bond formation.a
10
11
12
13
14
15
16
17
18
Entry
Reagent
Catalyst
Conv.b
(yield)c
92 (73)
100 (87)
24 (19)
5 (1)
1
CCl4/Ph3Pd
CCl4/Ph3Pe
CCl4/Ph3Pf
-
-
2
-
3
-
28 (20)
8 (5)
4
-
5
CCl4/Ph3P
CCl4/Ph3P
CCl4/Ph3P
CCl4/Ph3POh
-
silane (1.5)/phosphate (0.05)g
silane (4.0)/phosphate (0.05)
silane (1.5)/phosphate (0.1)
silane (1.5)/phosphate (0.05)
silane (1.5)
84 (64)
63 (37)
71 (51)
60 (44)
10 (2)
6
7
8
O
9
16 (10)
17 (8)
22 (8)
20 (14)
N
H
10
11
12
13
14
15
-
silane (1.5)/phosphate (0.05)
silane (1.5)/phosphate (0.05)
TMDS (1.5)/Cu(OTf)2 (0.04)
TMDS (1.5)/InBr3 (0.02)
silane (1.5) /phosphate (0.05)
silane (1.5)/phosphate (0.05)
11 (10)
13 (11)
22 (15)
28 (21)
58 (26)
49 (18)
O2N
Ph3P (0.25)
CCl4/Ph3P
CCl4/Ph3P
CBr4/Ph3Pi
CBrCl3/Ph3Pj
a
Conditions: 4-nitrobenzoic acid (1 mmol), benzylamine (1.3 mmol), anhydrous
toluene (5 mL), 110 °C, 20 h; b Conversion determined by GC; Isolated yield;
c
d
g
e
f
CCl4 (2.0)/Ph3P (1.0);
40 silane/phosphate (EtO)2MeSiH and bis(4-nitrophenyl)phosphate;
(2.0)/Ph3PO (0.25); i CBr4 (2.0)/Ph3P (0.25); j CBrCl3 (2.0)/Ph3P (0.25).
CCl4 (2.0)/Ph3P (2.0);
CCl4 (2.0)/Ph3P (0.25);
h
=
CCl4
2
|
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the (S)-amide product (>99.9%).
In conclusion, we have successfully demonstrated the
60 feasibility of organocatalytic amide boDndOI:f1o0r.m10a3Vt9iieo/Cwn4ACrbtCicel0tew1O8en6el1innCe
unactivated aromatic carboxylic acids and amines. This reaction
proceeds in the presence of a catalytic amount of Ph3P and a two-
fold excess of CCl4, employing in situ reduction of Ph3P=O into
Ph3P using (EtO)2MeSiH and bis(4-nitrophenyl)phosphate.
65 Considering the importance of the amide bond, we hope that our
new approach may inspire researchers to develop alternative
catalytic methods for the formation of amide bonds in the coming
years.
19
91 (51)
21 (15)
a Conditions: carboxylic acid (1 mmol), amine (1.3 mmol), Ph3P (0.25 mmol), CCl4
(2.0 mmol), (EtO)2MeSiH (1.5 mmol), bis(4-nitrophenyl)phosphate (0.05 mmol),
b
anhydrous toluene (5 mL), 110 °C, 20 h; Conditions as in catalytic, but in the
absence of silane and phosphate; c Determined by GC; d Isolated yield.
5
The influence of the solvent on the conversion was then
investigated. Performing the reaction at reflux in solvents with
high boiling points could potentially allow a good recovery of
Ph3P by the reduction of Ph3P=O. Among several common
10 solvents, dry toluene gave the best yield for the model reaction.
In o-xylene, acetonitrile, 1,4-dioxane, and THF, the amide
product was formed in lower conversions relative to toluene (see
Supplementary Information). Interestingly, the amide was formed
in higher conversions when the reaction was performed at higher
15 temperature, hence suggesting the direct uncatalysed reaction.
We next explored the scope of the organocatalytic amide bond
formation. A diverse set of unactivated para-substituted benzoic
acids was reacted with benzylamine to afford the corresponding
amides in very good to excellent conversions (70-90%) (Table 2,
20 entries 1-7). Isolated yields for the amides obtained under
catalytic conditions were found to be in the range of 54-76%,
while reactions under uncatalytic conditions (i.e. in the absence
of (EtO)2MeSiH and bis(4-nitrophenyl)phosphate) afforded
amides in isolated yields below 20% (conversions 17-25%). Only
25 4-methoxybenzoic acid gave comparatively lower conversions for
the reaction with benzylamine (52%) (Table 2, entry 8). Picolinic
and quinaldic acid were also converted into amides in 99 and
72% yields, whereas under non-reducing conditions less than
10% of amides was formed (Table 2, entries 9-10). Overall, these
30 results imply that (EtO)2MeSiH and bis(4-nitrophenyl)phosphate
facilitate the Ph3P/CCl4-mediated amide bond formation reaction
by reducing the Ph3P=O product into Ph3P, which is subsequently
used in the next catalytic cycle.
In addition, 4-nitrobenzoic acid reacted with 4-methoxy
35 benzylamine under catalytic conditions to afford the
corresponding amide in 82% conversion (53% yield) (Table 2,
entry 11). 2-(Aminomethyl)thiophene, 2-phenylethylamine, and
cyclohexylamine gave 71, 96, and 65% conversions, respectively
(Table 2, entries 12-14). Aniline was found to afford only 35% of
40 amide; we attribute the relatively low reaction conversion to the
lower nucleophilic characted of aniline when compared to
aliphatic amines (Table 2, entry 15). Notably, reactions with
secondary amines, including piperidine and morpholine,
proceeded in 81-87% conversions (52-77% isolated yields),
45 demonstrating that our standard conditions are also applicable for
the synthesis of tertiary amides (Table 2, entries 16-17).
Background reactions under uncatalytic conditions for this set of
amines only gave poor conversions of amides. In all cases,
conversions and isolated yields were observed to be below 30%.
Notes and references
70 Institute for Molecules and Materials, Radboud University Nijmegen,
Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands. Fax: +31 24
3653393; Tel: +31 24 3652381; E-mail: j.mecinovic@science.ru.nl
† Electronic Supplementary Information (ESI) available: Synthetic
procedures, characterisation of compounds, and chiral HPLC data. See
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