Highly efficient and environmentally benign preparation of Weinreb amides in the biphasic system 2-MeTHF/water

Article abstract of DOI:10.1039/c3ra41262h

A straightforward chromatography-free preparation of Weinreb amides starting from acid halides has been achieved in the biphasic medium 2-MeTHF/water. Analytically pure compounds were isolated in excellent yields simply after removal of 2-MeTHF, which abs

Full text of DOI:10.1039/c3ra41262h

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Highly efficient and environmentally benign
preparation of Weinreb amides in the biphasic system
Cite this: RSC Advances, 2013, 3, 10158
2-MeTHF/water3
Received 3rd February 2013,
Accepted 12th April 2013
a
a
b
a
´
´
Vittorio Pace,* Laura Castoldi, Andres R. Alcantara and Wolfgang Holzer
DOI: 10.1039/c3ra41262h
www.rsc.org/advances
A straightforward chromatography-free preparation of Weinreb
amides starting from acid halides has been achieved in the
biphasic medium 2-MeTHF/water. Analytically pure compounds
were isolated in excellent yields simply after removal of 2-MeTHF,
which absolutely avoids the use of any contaminant organic
solvent within the whole process due to its (practically) immis-
cibility with water.
(Scheme 1, path b); however, the use of such reagents at pilot
plant scale is limited by safety concerns against the 12th
Principle.6 Moreover, these expensive activators are not always
effective in promoting the formation of Weinreb amides starting
from hindered carboxylic acid derivatives,13 so that more
sophisticated routes have been reported, such as the palladium-
catalyzed aminocarboxylation14 of aryl bromides,15 arylboronic
acids and lactam/lactone-derived vinyl triflates in a carbon
monoxide atmosphere (Scheme 1, path c),16 and the Stille-type
cross-coupling reaction between aryl and vinyl stannanes and
N-methoxy-N-methylcarbamoyl chloride (Scheme 1, path d).17
Although in general effective in promoting the amidation-type
reactions, the attractiveness of the procedures involving the
activation of a carboxylic acid is limited by the concomitant
production of undesired products derived from the active
intermediate species. As a consequence, they often require tedious
and somewhat complicated chromatographic separations13 with
contaminant solvents, thus lengthening the synthetic sequence
and producing toxic and unnecessary organic wastes, contravening
the 1st Principle of Green Chemistry.6 Evidently, the development
of general and efficient protocols for the synthesis of Weinreb
amides under more sustainable conditions is a formidable
challenge to be pursued. Thus, herein we disclose our findings
on an environmentally benign and cost-effective preparation of
N-methoxy-N-methylamides, commonly known as Weinreb
amides, are highly versatile scaffolds in organic synthesis.1,2
Since their introduction in early 1980s, their usefulness as
acylating agents upon reaction with organometallic species or
hydride donors has been continuously increased.3,4 In particular,
this motif continues to represent the ideal starting material for the
preparation of ketones and aldehydes with the above mentioned
reactants. Indeed, the formation of a strongly stabilized metal-
chelated intermediate accounts for the (almost) complete elimina-
tion of any undesired product resulting from the overaddition of
these reagents to the resulting carbonyl-type carbon atom.5
Effectively, Weinreb amides allow to shorten synthetic processes
by avoiding unnecessary protecting–deprotecting steps, thus
maximizing the chemical economy in agreement with the 2nd
and 8th Anastas’ Principles of Green Chemistry.6
Due to this paramount importance in synthesis, different
protocols have been established for their preparation. The classical
approach employs a carboxylic acid which, however needs to be
activated prior to its reaction with the commercially available
N,O-dimethylhydroxylamine
hydrochloride
(DMHA).3
Unfortunately, the activation requires the use of an excess of
hazardous reagents (e.g. DCC,7 HOBT,8 deoxo-fluor,9 PPh3-I2,10
P[NCH3(OCH3)]),11 which maybe pyrophoric or even explosive
(Scheme 1, path a). Alternatively, carboxylic esters or imides maybe
activated with organoaluminium1 or Grignard reagents12
aDepartment of Drug and Natural Product Synthesis, University of Vienna,
Althanstrasse 14, 1090, Vienna, Austria. E-mail: vpace@farm.ucm.es;
Fax: +43-1-4277-9556; Tel: +43-1-4277-55623
bDepartment of Organic and Pharmaceutical Chemistry, Complutense University of
Madrid, Pza. Ramon y Cajal s/n, 28040, Madrid, Spain
Scheme 1 Synthetic approaches to Weinreb amides.
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Table 1 Optimization of the reaction conditionsa
these valuable scaffolds without performing any purification (i.e.
chromatography, recrystallization, distillation) by means of a
Schotten–Baumann-type reaction18 in a biphasic medium water-2-
methyltetrahydrofuran (2-MeTHF)19–22 without the necessity to use
any additional organic solvent during the overall process.
At first sight, the reaction of an acid halide and DMHA
represents the conceptually simplest approach to the targets: in
this context, it should be argued that such a methodology is much
more atom efficient23 compared to those protocols using
carboxylic derivatives not always commercially available (e.g.
esters, anhydrides, imides, etc.). Unfortunately, acid halides-
mediated synthesis of Weinreb amides previously reported are
performed in halogenated or ethereal solvents in the presence of
amines such as pyridine.1,5,24 It is clear that a chemical synthesis
carried out under these conditions presents serious issues from an
environmental perspective and for the safety of the operators both
in laboratory and industrial scale. Furthermore, these methods do
not allow a straightforward approach to Weinreb amides because
purifications are often necessary. In this context, due to our
commitment to carry out chemical synthesis under more
sustainable conditions,25–30 we decided to test a biosolvent,
2-MeTHF, derived from renewable sources (corncobs and bagasse)
and whose use, as documented in the literature, fulfils 3rd, 5th
and 7th Principles.6 In fact, the search for more sustainable
solvents is a major task inside Green Chemistry,31,32 and inside
this area, the use of biosolvents is a growing tendency, especially
in Pharma Industry.33–35
As the model reaction, we selected the challenging substrate
cinnamoyl chloride 1, in which the presence of a conjugated
olefinic system renders it susceptible to the possible attack of the
nucleophilic amine also at the b-position to the carbonyl moiety.
As reported in Table 1, the use of a series of common organic
solvents (dichloromethane, diethyl ether, acetonitrile, DMF,
AcOEt, THF, 2-MeTHF) in the presence of potassium carbonate
as the base, affords the desired Weinreb amide 1a in moderate
yields (entries 1–7). Interestingly, with less than 2 equiv. of base
yields of 1a diminished sensitively (entry 8), while no reaction was
observed at all in its absence (entry 9). This behaviour may be
understood as a consequence of the deprotonating action
displayed by the bases on the hydrochloride salt of DMHA.
Interestingly, inorganic bases performed better than organic ones
(entries 11–12), while the use of a supported inorganic base (KF-
Celite)37–40 reduced remarkably the yields due to its insolubility in
both aqueous and organic phases (entry 13). Remarkably, switch-
ing to the biphasic system organic solvent- water compound 1a
could be obtained in higher yields (entries 14–17): evidently, the
use of the so-called Schotten–Baumann conditions18 allows not
only to deprotonate DMHA but, also to neutralize the hydrochloric
acid formed upon the amidation and thus, driving the reaction to
completion. In this context, the employment of immiscible solvent
systems provide the optimum results due to the fact that the so-
obtained Weinreb amide remains in the organic phase, while the
inorganic by-products move to the aqueous phase. Among the
various solvents screened, ethereal ones provided better results
compared to toxic chlorinated and hydrocarbon ones (entries 16,
17), being 2-MeTHF-water the ideal combination (entry 14). Some
Isolated Yield
Base equiv. of 1a [%]
Entry Solvent
Base
1
2
CH2Cl2
Et2O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
—
2.2
2.2
2.2
2.2
2.2
2.2
2.2
1.1
—
42
47
39
28
37
44
51
37
n.r.
43
35
33
20
97
86
81
72
3
4
5
MeCN
Toluene
AcOEt
6
7
8
9
10
11
12
13
14a
15
16
17
THF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
NaHCO3
NEt3
2.2
2.2
2.2
DIPEA
KF-Celite36 2.2
2-MeTHF–H2Ob K2CO3
2.2
2.2
2.2
2.2
Et2O–H2Ob
K2CO3
K2CO3
K2CO3
CH2Cl2–H2Ob
Toluene–H2Ob
a
Unless otherwise specified reactions were carried out during 1 h
b
from 0 uC to rt. 1 : 1 v/v mixture. (n.r. no reaction).
point merits mention: a) to minimize the possible hydrolysis of
the acyl halide, it was initially dissolved in 2-MeTHF jointly with
DMHA and subsequently the basic solution was added; otherwise
a slight decrease of the yield (ca. 10%, as a consequence of the
rapid hydrolysis to the acid) was noticed; b) reaction reached to
completion within 1 h and the isolation of the product is simply
performed after acidic wash (1 M HCl) and separation of the
phases. In this sense, the low solubility of 2-MeTHF in water (4 g
100 mL )
21 41 allows an extremely easy isolation without needing to
add any other solvent (e.g. diethyl ether, ethyl acetate, dichlor-
omethane, etc.), and in the absence of any additional purification
steps. Thus, analytically pure Weinreb amide 1a was simply
isolated after evaporation of the non-carcinogenic 2-MeTHF42
under reduced pressure.
Inspired by this success, we turned our attention towards
different acyl halides. As shown in Table 2 the protocol results of
broad application, allowing an easy preparation of these amides in
a straightforward manner. Interestingly a,b-unsaturated systems
react smoothly without any side reaction (i.e. attack of the amine
on the b-carbon), affording the Weinreb amides in high yields,
regardless of the nature of the substituents across the C–C double
bond or on the aryl systems directly connected to it (entries 1–8).
Significantly, the extended conjugation in case of chloride 6 did
not affect the outcome of the reaction (entry 5). It should be
highlighted that this protocol represents a versatile alternative for
the preparation of these particular Weinreb amides compared to
previous described ones involving Wittig-type reactions between
an unsaturated aldehyde and a phosphorane.43–45 Analogously,
both functionalized aromatic and heteroaromatic acid halides
react very well, giving the desired Weinreb amides in excellent
yields (entries 9–14). It has been reported that more reactive
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Table 2 Substrate scope of the reaction
Table 2 (Continued)
Isolated
Yield (%)
Entry
12
Substrate
Product
96
Isolated
Yield (%)
Entry
1
Substrate
Product
94
13
14
15
16
89
92
93b
90
2
92
3
4
83
86
17
18
19
88
95
97
5
97
6
92
91
89
96a
7
20
21
96
89
8
9a
10
11
94
90
a
b
Starting from the corresponding bromide 93% yield. starting
from the corresponding bromide 95% yield.
halides (i.e. aromatic) are substrates leading to lower yields in
Schotten–Baumann type amidations compared to aliphatic ones;46
however, in our hands we did not observe this pattern, probably
because the alkaline aqueous solution (responsible of the
hydrolysis) is added to the mixture of DMHA and acid halide in
2-MeTHF. Similarly, aliphatic acid halides afforded the corre-
sponding Weinreb amides regardless the presence of distinct
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the core of the acid (entries 15–21). Of particular significance is the
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available or readily obtainable acid halides in the biphasic
medium (alkaline) water/2-MeTHF. Due to the immiscibility of
this biomass derived solvent with water, there is no necessity to
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process. Pure compounds are obtained by simple removal of
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