BF3·OEt2-TFAA Mediated Tetra-Functionalization of Amino Acids-Synthesis of Di-and Tri-Substituted 2-Trifluoromethyl Oxazoles in One Pot

Article abstract of DOI:10.1021/acs.orglett.0c02484

A highly efficient, TFAA-BF3·OEt2 mediated multicomponent coupling of amino acid, TFAA, and aromatics provides a broad library of 2-Trifluoromethyl equipped 2,5-disubstituted/2,4,5-Trisubstituted oxazoles or N-(trifluoroacetyl)-β-Aminoalkyl ketones. This amino acid tetra-functionalization approach involves amidation (C-N), anhydride (C-O), Friedel-Crafts acylation (C-C), and Robinson-Gabriel annulation (C-O) followed by dehydrative aromatization. This reaction takes place under operationally simple, mild, and metal-free conditions using readily available amino acids and aromatic compounds.

Full text of DOI:10.1021/acs.orglett.0c02484

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Letter
BF ·OEt ‑TFAA Mediated Tetra-Functionalization of Amino Acids -
3
2
Synthesis of Di- and Tri-Substituted 2‑Trifluoromethyl Oxazoles in
One Pot
Velusamy Karuppusamy and Andivelu Ilangovan*
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sı Supporting Information
ABSTRACT: A highly efficient, TFAA-BF ·OEt mediated multicomponent coupling of amino acid, TFAA, and aromatics provides
3
2
a broad library of 2-trifluoromethyl equipped 2,5-disubstituted/2,4,5-trisubstituted oxazoles or N-(trifluoroacetyl)-β-aminoalkyl
ketones. This amino acid tetra-functionalization approach involves amidation (C−N), anhydride (C−O), Friedel−Crafts acylation
(
C−C), and Robinson−Gabriel annulation (C−O) followed by dehydrative aromatization. This reaction takes place under
operationally simple, mild, and metal-free conditions using readily available amino acids and aromatic compounds.
t present, about 20% of pharmaceuticals and 30% of
methods are associated with disadvantages such as multistep
13c,d
A
agrochemicals available in the market are equipped with
synthesis of starting material (Figure 1b),
need for multiple
1
13c,d
fluorine atoms. The trifluoromethyl (−CF ) group shows
reagents,
less yield of product, and involvement of harsh
3
13e
unique characteristics such as high electronegativity, metabolic
stability, lipophilicity, and bioisosteric properties for several
atoms or groups. Several pharmaceuticals, agrochemicals,
and materials containing the −CF group shows interesting
physical and biological properties. Hence, chemists are taking
reaction conditions (Figure 1c).
Thus, these limitations
prompted us to develop an efficient method.
2
3
4
Amino acids are renewable, and their racemic or natural
forms are cheap and readily available in varieties. The main
challenge in using amino acids in Friedel−Crafts acylation is
self-coupling, on activation of the acid group. Thus, only N-
5
3
3
a special interest in designing methods for synthesis of
14
compounds having the −CF group. Consequently, many
3
TFA protected α-amino acid chloride with AlCl3 and N-TFA
protected α-amino acid N-hydroxysuccinimide ester (1 equiv)
methods have been developed for the incorporation of the
+
6
−
7
•
8
−
CF group using reagents bearing CF , CF , and CF .
3 3 3 3
with AlCl (6 equiv) were used in the Friedel−Crafts acylation
3
Oxazoles are privileged motifs found among a wide variety of
15a
of aromatics (300 equiv). Interestingly, an amino acid, on
9
10a,b
10c
pharmaceuticals, natural products,
agrochemicals, and
treatment with TFAA, afforded −CF substituted oxazolone
1
0d
3
fluorescent dyes. The approaches adopted for synthesis of
functionalized oxazole could be roughly classified into three
15b
(
Figure 1a).
We envisaged that if cascade tetra-functionalization of amino
1
1
categories. The most used approach is cyclization involving
α-acylaminoketone/α-acyloxyketone/α-haloketone, primary
amide/alkyne and nitrile/amine, and α,β-unsaturated carbon-
yls. The next one is regioselective functionalization of the
oxazole core through metalations and subsequent functional-
acids, such as amidation, anhydride formation, Friedel−Craft
acylation of aromatics using the in situ generated amido
anhydride, and intramolecular cyclization of N-(trifluoroac-
ety1)-α-aminoalkyl ketones, could be performed in one pot, it
should lead to the formation of −CF armed oxazoles. In this
1
2
3
ization. The third and least explored category is the
multicomponent reactions, which are highly efficient and
11
Received: July 28, 2020
atom economical. Dehydrative condensation to form 5-
triazinyloxy) oxazoles from carboxylic acids, amino acids, and
DMT-MM, followed by Suzuki−Miyaura coupling, to provide
(
1
1
2
,4,5-trisubstituted oxazoles has already been reported.
Although −CF substituted oxazoles find promising applica-
3
13
tions, very few methods are known for their synthesis. These
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c02484
A
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Letter
treatment with 1a no reaction was observed, even after 3 h
entry 1). However, in the case of TFAA (6.0 mmol) we were
(
delighted to observe a domino reaction leading to the
formation of −CF containing disubstituted oxazole 3aa, albeit
3
in low yield (20%, entry 1).
Based on this encouraging result, efforts were made to
improve the yield of the product 3aa, and the results are
summarized in Table 1. On decreasing the quantity of AlCl3
(
1.0 mmol), the yield dropped (entry 2, 10%). The reaction
performed in CHCl medium produced 3aa in low yield (entry
3
3
, 15%). Since reaction without solvent produced a similar
yield, further experiments were performed under neat
conditions. With SnCl , only a trace amount of desired oxazole
2
3
aa (entry 4) was obtained. In the case of TiCl , multiple
4
products along with 3aa were observed and could not be
separated (entry 5). Gratifyingly, when BF ·OEt (4.0 mmol)
3
2
was used as the catalyst, oxazole 3aa was obtained in excellent
yield (entry 6, 94%). On using 1.0 mmol of BF ·OEt the yield
3
2
of 3aa did not decrease (entry 7, 94%). Further, with a
substoichiometric amount of BF ·OEt (entry 8, 65%; entry 9,
3
2
4
0%) the yield of 3aa decreased drastically. Performing the
Figure 1. Synthesis of −CF substituted oxazole.
reaction using BF ·OEt (1.0 mmol) in chlorinated solvents
3
3
2
decreased the yield (entries 10−12). Bronsted acid TfOH was
also useful, but produced oxazole 3aa in a relatively lower yield
1
6
direction, BF ·OEt2 -TFAA has been discovered as the
3
suitable reagent to mediate the cascade of all these reactions
in one pot and lead to the formation of 2-(trifluoromethyl) di-
or trisubstituted oxazoles or N-trifluoroacylamino-β-ketones.
Herein we present the results.
than BF ·OEt (entry 13, 81%; entry 14, 30%). Based on the
3 2
screening results, it was identified that the reaction of an
equimolar mixture of 1a and 2a with 6.0 mmol of TFAA in the
presence of Lewis acid BF ·OEt (1.0 mmol), under solvent-
3 2
The study began with identification of p-methylanisole (1a)
and glycine (2a) as model substrates. With the aim of
activating the acid through formation of anhydride and
protecting the amine and using it in situ in Fridel−Crafts
acylation, glycine 2a (1.0 mmol) was treated, in three separate
reactions with acetic anhydride (AA, 6.0 mmol), pivolyl
chloride (PC, 6.0 mmol), and TFAA (6.0 mmol) for 1 h,
free conditions and at room temperature, would be optimal for
further study. After establishing the optimal conditions, the
scope of the reaction of 2a with various substituted aromatics
1a−s was explored (Scheme 1).
Similar to 1a, different disubstituted aromatics were
examined. o-Methyl anisole (1b) furnished −CF bearing
3
oxazole 3ba in good yield. But m-methyl anisole (1c), as a
followed by the addition of 1a (1.0 mmol) and AlCl (4.0
3
,
a b
mmol) at room temperature (Table 1). In the case of PC and
AA, the reaction mixture was not homogeneous and on
Scheme 1. Scope of Electron-Rich Aromatics
a
Table 1. Reaction Optimization
b
entry
catalyst (mmol)
solvent
time (h)
yield 3aa (%)
,
c d
1
2
3
4
5
6
7
8
9
AlCl (4.0)
neat
neat
CHCl3
neat
neat
neat
neat
neat
3
3
3
3
4
5
5
5
5
5
5
5
3
3
20/NR
10
3
AlCl (1.0)
3
AlCl (4.0)
15
3
SnCl (4.0)
trace
ND
94
94
65
40
80
79
80
2
TiCl (4.0)
4
BF ·OEt (4.0)
3
2
BF ·OEt (1.0)
3
2
BF ·OEt (0.5)
3
2
BF ·OEt (0.1)
neat
3
2
10
11
12
13
14
BF ·OEt (1.0)
DCM
CHCl3
DCE
neat
3
2
BF ·OEt (1.0)
3
2
BF ·OEt (1.0)
3
2
CF SO H (1.0)
81
30
3
3
a
CF SO H (0.1)
neat
Reaction conditions: 1 (1.0 mmol), 2a (1.0 mmol), TFAA (6.0
3
3
b
mmol), BF ·OEt (1.0 mmol) at room temperature. Isolated yield.
3
2
a
c
d
Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), TFAA (6.0
25 g scale experiment. Regioisomeric ratio by NMR (44:40:16).
Regioisomeric ratio by NMR (42:58). No reaction (1l was
b
c
d
e
f
mmol) at room temperature. Isolated yield. Pivolyl chloride. Acetic
g
anhydride, NR = No Reaction, ND = Not determined.
completely recovered). Not detected.
B
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Letter
,
a b
result of the o- and p-directing effect, gave a regioisomeric
mixture of oxazoles, 3ca, 3ca′, and 3ca′′ (44:40:16), in 75%
yield and only oxazole 3ca could be isolated. Further, o- and p-
Scheme 2. Substrate Scope of α-Amino Acids
methoxy anisoles 1d and 1e produced the corresponding −CF
3
substituted oxazoles 3da (77%) and 3ea (83%) in very good
yield. The structure of 3ea was confirmed using single crystal
X-ray structure analysis [CCDC number: 1997398; see
Supporting Information]. p-Acetamido anisole (1f) underwent
both oxazole formation and −COCH replacement by the
3
−
COCF group to afford product 3fa in moderate yield
57%). However, o-xylene (1g) afforded an inseparable
3
(
regioisomeric mixture (41:59) of 3ga and 3ga′ in excellent
yield.
a
Reaction conditions: 1a (1.0 mmol), 2 (1.0 mmol), TFAA (6.0
Next, reactivity of monosubstituted benzenes was examined.
Anisole (1h) provided separable mixture of oxazoles 3ha
b
mmol), BF ·OEt (1.0 mmol) at room temperature. Isolated yield.
3
2
c
Not detected.
(
51%) and 3ha′ (34%) in good overall yield. In case of toluene
(
1i), formation of CF -incorporated oxazole 3ia was achieved
3
were obtained from 3-phenyl-L-alanine (2c) and L-valine (2d)
respectively in good yield. Oxazole 3ae and 3af were obtained
in good yield when 1a was treated with L-leucine (2e) and L-
isoleucine (2f) respectively. Unfortunately, methionine (2g)
and 2-amino-5-(benzyloxy)-5-oxopentanoic acid (2h) failed to
give the desired oxazoles 3ag and 3ah respectively.
Interestingly, L-proline (2i) underwent N-acylation followed
by Fridel−Craft’s C-acylation to provide optically pure α-
acylamino ketone (S)-4ai in moderate yield. Similalrly, D-
proline also provided optically pure (R)-4ai in similar yield.
This confirms no racemization occurs during the reaction.
Next, the reactivity of β-amino acids, with activated
aromatics, were examined under the standardized reaction
conditions (Scheme 3). β-Alanine (5a), on treatment with 1a,
in good yield. Similarly, oxazoles 3ja and 3ka were obtained in
good yield by using isopropylbenzene (1j) and tert-
butylbenzene (1k) respectively. Crude H NMR spectra of
1
3ja and 3ka confirm the formation of only para-substituted
oxazole. While benzaldehyde (1l) containing the electron-
withdrawing −CHO group did not undergo reaction to
provide expected oxazole 3la, biphenyl (1m) furnished
oxazoles 3ma in low yield.
Subsequently, reactivity of trisubstituted benzenes was
examined. Intriguingly, 1,3,5-trimethoxybenzene (1n), due to
remarkable electron richness, underwent trifluoroacetylation in
addition to oxazole formation to provide 3na. Unexpectedly,
mesitylene (1o) containing sterically hindering trimethyl
substituents provided α-acylamino ketone 4oa exclusively in
9
6% yield, instead of expected cyclized product 3oa.
a b
Scheme 3. Substrate Scope of β-Alanine ,
Formation of uncyclized product 4oa was in accordance with
17b
the observation by Wasserman et al. that the amide oxygen
of α-acylamino ketone should be retained in the oxazole
formation. Interestingly, although amide carbonyl in 4oa could
undergo enolization, the steric hindrance by the 2,6-dimethyl
group prevents its intramolecular nucleophilic attack on the
ketone carbonyl. Further, this also provides evidence that the
other possible reaction, the ketone carbonyl undergoing
enolization followed by intramolecular nucleophilic attack on
a
Reaction conditions: 1 (1.0 mmol), 5a (1.0 mmol), TFAA (6.0
b
17b
mmol), BF ·OEt (1.0 mmol) at room temperature. Isolated yield.
3
2
the less hindered amide carbonyl, does not take place.
Simple benzene did not undergo this reaction. Next, naphthyl
ring system compounds were studied. A separable regioiso-
meric mixture of oxazole 3pa (58%) and 3pa′ (22%) was
obtained from naphthalene (1p) in good yield. 1-Methox-
ynaphthalene (1q) provided oxazole 3qa in good yield.
Substituted oxazoles 3ra and 3sa were obtained in good
yield from corresponding 2-methoxy naphthalene (1r) and 1-
methyl naphthalene (1s) respectively.
1
7a
afforded the Mannich base N-trifluoroacetylamino-β-ketone
6aa instead of expected six-membered CF -group bearing 6-
3
aryl-2-trifluoromethyl-4H-[1,3]oxazine 7. Similarly, reaction of
1b and 1e with 5a gave the corresponding products 6ba and
6ea respectively. However, electron-rich but sterically hindered
aromatic substrate 1n on reaction with 5a provided N-
trifluoroacylamino-β-ketone 6na, albeit in low yield, in which
trifluoroacetylation occurred on the aryl ring.
In order to understand the mechanism of this cascade
reaction, control experiments were performed. Formation of
mono-functionalized amino acid (8a, 92%, Scheme 4a) as an
intermediate was confirmed by treating amino acid 2a with
We expected that employing 2.0 mmol of amino acid 2a and
.0 mmol of aryl compound 1a may yield 2-fold oxazole-
1
introduced product 3aaa. However, only single oxazole
substituted product 3aa was obtained. Compound 3aa
obtained in 93% yield (48.9 g) from reaction of 1a (25.0 g)
and 2a (15.3 g) under standard condition guarantees
applicability of this method in bulk scale (Scheme 1).
Having successfully observed oxazole formation on different
aromatic substrates 1a−s using glycine (2a), the reactivity of
different α-amino acids 2b−h were examined next. Aromatic
compound 1a was taken as standard (Scheme 2) and treated
TFAA (1.2 equiv) and quenching with H O.
2
Involvement of anhydride as an intermediate was confirmed
through formation of methyl ester (8b, 85%, Scheme 4a) by
treating amino acid 2a with TFAA (3.0 equiv) and entrapping
it with methanol. The reaction between 1e and 2a when
worked up quickly before completion (20 min) provided 25%
of keto amide 4ea, along with 40% of 3ea (Scheme 4b). This
confirms that keto amide 4ea is an intermediate in the reaction.
with L-alanine (2b) to obtain 2-CF containing trisubstituted
3
oxazole 3ab in excellent yield. Similarly, oxazole 3ac and 3ad
C
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Letter
Scheme 4. Control Experiments
acids. We strongly believe that this easily scalable new
synthetic method would find immense use in medicinal
chemistry, material science, and industry. Further, biological
studies of the synthesized compounds are underway in our
laboratory.
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02484.
Experimental procedures, characterization data, copies of
NMR spectra for all new products, and HPLC
chromatograms of 4ai (PDF)
Further, compound 4ta containing the electron-withdrawing 4-
OAc group failed to undergo cyclization to form oxazole
(Scheme 4c). The electron-withdrawing effect of the 4-OAc
due to its influence on the aromatic ring disfavors positive
polarization of ketone carbonyl carbon; hence, nucleophilic
attack by the amide carbonyl oxygen is not facilitated.
Accession Codes
CCDC 1997398 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
17b
Based on the results obtained and literature precedence,
a
plausible mechanism is proposed as shown in Scheme 5.
Scheme 5. Proposed Mechanism
AUTHOR INFORMATION
Corresponding Author
■
Andivelu Ilangovan − School of Chemistry, Bharathidasan
University, Tiruchirappalli 620024, India; orcid.org/0000-
0
001-7240-7166; Email: ilangovanbdu@yahoo.com
Author
Velusamy Karuppusamy − School of Chemistry, Bharathidasan
University, Tiruchirappalli 620024, India; Department of
Pharmaceutical Research & Development, Biocon Limited,
Bangalore 560100, India
Reaction of an α-amino acid with TFAA forms N-
trifluoroacetamide A and mixed anhydride B which ultimately
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02484
gives an amido anhydride C from steps 1 and 2. BF should
3
facilitate Friedel−Crafts acylation of aromatics with inter-
mediate C to form intermediate D. Enolisation of D to form
1
7b
Notes
E
should facilitate intramolecular Robinson Gabriel
annulation and aromatization of intermediate F to afford
CF substituted oxazole 3. As explained in the case of α-
The authors declare no competing financial interest.
−
3
ACKNOWLEDGMENTS
acylamino ketone 4oa, the other possible pathway, ketone
■
carbonyl undergoing enolization and nucleophilic attack on the
V.K. thanks Biocon and Dr. Srinivas P.V for providing research
facilities. We thank DST-FIST and DST-PURSE New Delhi,
India for NMR and HRMS facilities at School of Chemistry,
Bharathidasan University, Tiruchirappalli, India.
17b
amide carbonyl, is not favored.
In summary, we have developed a novel and simple
multicomponent approach for the formation of −CF
3
containing di- and trisubstituted oxazoles as well as N-
trifluoroacylamino-β-ketones in one pot from readily available
amino acids. The starting material, amino acids, are cheap in
racemic and natural forms, found in varieties, and renewable.
Unlike other methods, this is versatile, so that di- as well as
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