Synthesis of tertiary amides from anionically activated aromatic trifluoromethyl groups

Article abstract of DOI:10.1021/ol100507n

Figure presented In this paper, a novel synthesis of tertiary amides from anionically activated aromatic trifluoromethyl groups is presented. Anionically activated trifluoromethyl groups react with secondary amines under aqueous conditions to afford tertiary amides. The mechanism involves initial elimination of hydrogen fluoride by an E1cB mechanism to afford an electrophilic quinone methide- or azafulvene-type intermediate that reacts with secondary amines under aqueous conditions to afford the tertiary amide in good yield (up to 99%).

Full text of DOI:10.1021/ol100507n

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2024-2027
Synthesis of Tertiary Amides from
Anionically Activated Aromatic
Trifluoromethyl Groups
Gavin O’Mahony* and Andrew K. Pitts
AstraZeneca R&D Mo¨lndal, Pepparedsleden 1, 43183 Mo¨lndal, Sweden
gaVin.omahony@astrazeneca.com
Received March 1, 2010
ABSTRACT
In this paper, a novel synthesis of tertiary amides from anionically activated aromatic trifluoromethyl groups is presented. Anionically activated
trifluoromethyl groups react with secondary amines under aqueous conditions to afford tertiary amides. The mechanism involves initial elimination
of hydrogen fluoride by an E1cB mechanism to afford an electrophilic quinone methide- or azafulvene-type intermediate that reacts with
secondary amines under aqueous conditions to afford the tertiary amide in good yield (up to 99%).
Aromatic trifluoromethyl groups are widely encountered in
medicinal chemistry.1-3 They are often employed as isosteric
replacements for methyl groups and are generally considered
chemically inert. However, under some circumstances,
aromatic trifluoromethyl groups exhibit a range of reactivities
that have been the subject of a number of review papers.4-6
It has long been known that 2-7 and 4-(trifluoromethyl)-
phenols8 are hydrolyzed under basic aqueous conditions to
afford the corresponding 2- and 4-hydroxybenzoic acids,
respectively. The mechanism involves initial elimination of
HF (via an E1cB mechanism) to give a key electrophilic
quinone methide intermediate, which can be attacked by a
range of nucleophiles, such as hydroxide.6,9 Similar reactivity
of 2- and 4-(difluoromethyl)phenols, formed by in situ
enzymatic cleavage of 2- and 4-(difluoromethyl)phenyl-ꢀ-D-
glucosides, has been exploited in the design of enzyme-
activated irreversible inhibitors of almond ꢀ-glucosidase.10
Similarly, 2-(difluoromethylphenyl) phosphate esters have
been used as suicide substrates to identify catalytic antibodies
with phosphate monoesterase activity.11
2-12 and 4(5)-(Trifluoromethyl)imidazoles13-17 are also
hydrolyzed to the corresponding carboxylic acids by heating
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10.1021/ol100507n  2010 American Chemical Society
Published on Web 03/31/2010

in aqueous sodium hydroxide. However, reaction with 5%
ammonium hydroxide affords exclusively the corresponding
2-18 and 4(5)-cyanoimidazoles.19 Both the hydrolysis and
ammonolysis reactions proceed via an electrophilic azaful-
vene intermediate (e.g., 1, Scheme 1). Interestingly, in the
Initial investigations were performed using 2-phenyl-4-
trifluoromethylimidazole 5,20 piperidine, and 1 M aqueous
sodium hydroxide at 160 °C for 1 min using microwave
irradiation (Table 1). Gratifyingly, the desired tertiary amide
was obtained.
Table 1. Tertiary Amide Formation in Microwave at 160 °Ca
Scheme 1. Ammonolysis of 2-Trifluoromethyl Imidazole
equiv
entry piperidine
equiv 1 M
aq NaOH
solvent
ratio 5:6:7:8 (%)b
1
2
3
4
5
6
1
1
1
1
1
4
4
4
3
2
1
0
water
0:70:30:0
0:73:27:0
0:87:13:0
9:66:0:25
25:33:0:42
0:30:0:70
dioxane
dioxane
dioxane
dioxane
water
a 1 equiv 5, 160 °C, 1 min, µW. b Determined by LCMS at pH 3.
Complete conversion of 5 into a mixture of amide 6 and
acid 7 was obtained with 1 equiv piperidine and 3 equiv
NaOH in water (Table 1, entry 1). The addition of dioxane
(entry 2) improved the ease of operation. Formation of
significant amounts of acid byproduct 7 was observed when
the reaction was performed at 160 °C due to competing basic
hydrolysis of 5. Reducing the amount of NaOH (entries 3-5)
led to reduced acid formation, but also to lower yields of
the amide, as water alone appeared to be insufficiently
nucleophilic to completely convert the diazafulvene to the
desired product. If NaOH was omitted and an excess of
secondary amine was used as base (entry 6), complete
conversion to a 3:7 mixture of amide 6 and diazafulvene 8,
respectively, was observed, with no acid formation (entry
6). Subsequent addition of extra sodium hydroxide followed
by heating led to complete hydrolysis of the diazafulvene to
the desired tertiary amide with no acid formation. The use
of such a two-step protocol minimized the amount of the
acid byproduct formed, but a one-step protocol that maxi-
mized the yield of the tertiary amide while minimizing
byproduct formation was considered preferable. Direct
observation of base-sensitive diazafulvene 8 by LCMS
indicates that the proposed mechanism (Scheme 2) for the
transformation is indeed in operation.
ammonolysis reactions, none of the primary amide 3 was
formed, despite the aqueous conditions and low concentra-
tions of ammonia used. It could be envisaged that trapping
of a difluoroamino intermediate 2 by hydroxide or water
could lead to formation of the primary amide. However, 1,2-
elimination of HF from 2 predominates and 2-cyanoimida-
zole is the only observed product.
It was predicted that the reaction of such anionically
activated trifluoromethyl groups with secondary amines
would furnish the corresponding tertiary amides, as 1,2-
elimination of HF from a difluoromethylamino intermediate
of type 2 would not be possible, thereby forcing elimination
of HF across the ring in a 1,4-fashion, leading to the tertiary
amide (Scheme 2). In this paper, we present a novel method
Scheme 2. Proposed Mechanism for Formation of Tertiary
Amides from Anionically-Activated Trifluoromethyl Compounds
Further experimentation on the commercially available
2-(trifluoromethyl)phenol 4a showed that acid formation was
dependent on reaction temperature. Acid formation could be
minimized (or eliminated in many cases) by performing the
reaction with conventional heating at lower temperatures
(e.g., 75 °C for 4a, Table 2). This procedure was then applied
to the synthesis of a number of salicylamides.
for the synthesis of tertiary amides from anionically activated
trifluoromethyl groups under aqueous conditions and without
the use of coupling reagents.
A total of 19 secondary amines were reacted with 4a.
Yields generally reflected the nucleophilicity of the secondary
(18) Kimoto, H.; Cohen, L. A. J. Org. Chem. 1979, 16, 2902–2906.
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Org. Lett., Vol. 12, No. 9, 2010
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(Table 1, entries 1, 3-5, 11). Branched cyclic and acyclic
aliphatic amines (entries 7-9) gave moderate yields, while
very sterically hindered amines such as diisopropylamine
(entry 11) gave a low yield (6%) of the product as expected.
A free alcohol was tolerated (entries 6, 10), as was a tertiary
amine (entry 5). Both electron-rich (entry 15) and electron-
poor (entry 14) aromatic amines gave good yields of the
desired amide. Aminopyridines gave only low yields or none
of the desired product (entries 17-19). In most cases, low
yields of the desired product were accompanied by conver-
sion of the remaining trifluoromethylphenol into salicylic
acid. Attempts to perform the reaction with Boc-protected
primary amines or secondary sulfonamides failed, with
exclusive hydrolysis of 4a to salicylic acid being observed,
which is most likely due to insufficient nucleophilicity of
the carbamate or sulfonamide. Primary amines afforded the
symmetrical amidine as the major product, as the diazaful-
vene/quinone methide intermediate in such cases is a
tautomer of the corresponding amidine.
Table 2. Synthesis of Tertiary Amides Using
2-(Trifluoromethyl)phenol 4a and 2-(Trifluoromethyl)aniline 4ba
Neither 3-(trifluoromethyl)phenol nor 1-methoxy-2-trif-
luoromethylbenzene reacted with piperidine under these
conditions, with the starting materials remaining unchanged.
This provides additional evidence (along with direct observa-
tion by LCMS of the quinone methide intermediates) that
the proposed mechanism (Scheme 2) is in operation.
2-(Trifluoromethyl)aniline 4b did not react under the
conditions (75 °C, conventional heating) employed for
reactions with the phenol 4a, with only starting material being
recovered. However, heating to 195 to 200 °C using
microwave irradiation led to conversion to the desired tertiary
amide products. This lower reactivity may be attributed to
the lower acidity of the aniline 4b compared to the phenol
4a, thus leading to a reduced rate for the initial E1cB
elimination of HF. Aliphatic amines gave good yields of the
desired tertiary amides (Table 1, entries 20 and 21). The
relatively poor nucleophile aniline gave a low yield (entry
22), while a more nucleophilic, electron-rich aromatic amine
gave a slightly better yield (entry 23).
Piperazine reacted with two equivalents of phenol 4a to
give the diamide 28 in 78% isolated yield (Scheme 3).
Scheme 3. Preparation of Diamide 28
4-(Trifluoromethyl)phenol 29 reacted, under identical
conditions, in a similar fashion to the ortho isomer 4a (Table
3), affording the desired tertiary amides. The yields were
complarable to those obtained with 4a, although the reaction
times were somewhat longer for the aliphatic amines.
a Full experimental procedures provided in Supporting Information. For
X ) O, reactions performed at 75 °C. b Isolated yields. c Performed at 200
°C. d Performed at 195 °C.
Tertiary imidazole-4(5)-carboxamides have found a range
of applications in drug discovery, for example, as cholecys-
amine. Unhindered cyclic and acyclic aliphatic amines gave
the desired tertiary amides in moderate to excellent yields
2026
Org. Lett., Vol. 12, No. 9, 2010

Table 3. Synthesis of Tertiary Amides from Secondary Amines
and 4-(Trifluoromethyl)phenol 29a
Table 4. Formation of Tertiary Amides from
2-Phenyl-4(5)-trifluoromethyl Imidazolea
a Full experimental procedures provided in Supporting Information.
b Isolated yield.
a Full experimental procedures provided in Supporting Information.
b Isolated yield.
tokinin 1 receptor21,22 and cannabinoid receptor 1 agonists,23
as protease inhibitors,24 carbonic anhydrase inhibitors,25
potassium channel inhibitors,26 and as histamine H3 receptor
modulators.27 Their precursor carboxylic acids are somewhat
difficult to isolate due to their zwitterionic nature. Therefore,
the amidation conditions used in the synthesis of the amides
from phenols 4a and 29 were then also applied to the 4(5)-
(trifluoromethyl)imidazole 5, with the desired tertiary amides
being obtained in excellent yield, thus, avoiding the use of
the carboxylic acids (Table 4).
In conclusion, we have developed a novel method for the
synthesis of tertiary amides from secondary amines and
anionically activated aromatic trifluoromethyl groups that can
be performed under aqueous conditions and that does not
require any hazardous coupling reagents beyond aqueous
sodium hydroxide. Previous syntheses of the amides of
hydroxy- and amino-benzoic acids have often required
protection of the hydroxy or amino moieties or the use of
alternative acid activation procedures.28 This method affords
a one-pot preparation of the tertiary amides of such acids
without the need for protecting groups. In addition, a novel
method for the synthesis of the pharmaceutically important
tertiary imidazole carboxamides that avoids the troublesome
isolation of the precursor carboxylic acids has been devel-
oped.
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Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 5, 9a-27a,
9b-12b, 28, and 30-37. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL100507N
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