One-pot conversion of amino acids into 2,5-disubstituted oxazoles: No metals needed

Article abstract of DOI:10.1002/adsc.201400496

2,5-Disubstituted oxazoles with a variety of alkyl and aryl groups are efficiently formed from N-acylamino acids, by a one-pot radical decarboxylation- oxidation-enolization and iodine-promoted cyclization process. Remarkably, the reaction takes place under mild conditions, and no metal catalysis is needed. The process can be useful for the direct modification of small peptides.

Full text of DOI:10.1002/adsc.201400496

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DOI: 10.1002/adsc.201400496
One-Pot Conversion of Amino Acids into 2,5-Disubstituted
Oxazoles: No Metals Needed
Ivan Romero-Estudillo,a Venkateswara Rao Batchu,a and Alicia Botoa,*
a
Instituto de Productos Naturales y Agrobiologꢀa del CSIC, Avda. Astrofꢀsico Fco. Sꢁnchez 3, 38206 La Laguna, Tenerife,
Spain
Fax : (+34)-922-260-135; phone: (+34)-922-260-112; e-mail: alicia@ipna.csic.es
Received: May 19, 2014; Revised: August 7, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400496.
Abstract: 2,5-Disubstituted oxazoles with a variety
of alkyl and aryl groups are efficiently formed from
N-acylamino acids, by a one-pot radical decarboxy-
lation–oxidation–enolization and iodine-promoted
cyclization process. Remarkably, the reaction takes
place under mild conditions, and no metal catalysis
is needed. The process can be useful for the direct
modification of small peptides.
ty of some metals has prompted the search for new
metal-free methodologies.[18,19]
The combination of metal-free and cascade meth-
ods is particularly attractive for industry, since in-
creasing environmental regulations have prompted
the development of more sustainable chemical pro-
cesses.[20] Metal-free cascade reactions are less toxic,
and also save time, materials and purification of inter-
mediates, and reduce the waste. Although few of
these methods have yet been reported for the genera-
tion of oxazoles,[20] the development of new ones is an
emerging area.
Keywords: amino acids; cyclization; domino reac-
tions; heterocycles; sustainable chemistry; synthetic
methods
For these sustainable methods, the use of amino
acids as substrates would be of interest, since amino
acids are readily available, inexpensive, stable, and
non-toxic compounds. Threonine and serine units
The oxazole ring can be found in many bioactive have been used in biomimetic routes to produce 2,4-
products, from natural compounds[1] such as the disubstituted oxazoles,[1] but to our surprise, the use
potent cytotoxic agents diazonamide[2] and telomesta- of amino acid substrates to produce 2,5-disubstituted
tin,[3] to synthetic agrochemicals[4] and synthetic drugs oxazoles (present in many drugs, polymers, sensors
against cancer, microbial infections, arthritis, pain and and dyes[1–10]) is unexplored.
diabetes.[5]
We present herein a metal-free sequential process
Besides, oxazoles are components of fluorescent which efficiently transforms readily available amino
dyes,[6] sensors,[7] receptors,[7] polymers[8] and ligands acid derivatives (including a peptide model) into a di-
for catalysts.[9] Finally, they are useful synthetic inter- versity of 2,5-disubstituted oxazole rings (e.g., conver-
mediates.[10]
sion 1!2, Scheme 1 and Table 1), using low-toxicity
Therefore, the preparation[1–10] and functionaliza- hypervalent iodine reagents.
tion[11] of oxazoles has attracted much interest. The
The first steps of the process (conversion 1!5)
synthetic methods vary from modification of other were previously reported by our group.[21a] Thus, the
heterocycles, such as ring rearrangements[11] or oxazo- decarboxylation of amino acids (such as compound 1)
line oxidation,[12] to the cyclization of acyclic precur- using (diacetoxyiodo)benzene (DIB) and iodine
sors.[13] The classic methods, including the cyclodehy- under the irradiation of visible light, generated an
dration of a-acylamino ketones (Robinson–Gabriel iminium ion such as intermediate 3. Under appropri-
reaction),[14a,b] or the Hantzsch[15c] and Conforth cycli- ate conditions the iminium ion isomerized to an en-
zations,[15d,e] among others, often have drawbacks such amide (e.g., compound 4) which could undergo iodi-
as harsh reaction conditions, long reaction times, or nation.[21]
modest to poor yields. The introduction of new metal
In our previous work, an iodinated intermediate 5
catalysts has enabled several efficient, mild synthesis was trapped by external nucleophiles. In this work,
of oxazoles.[16,17] However, the toxicity, price or scarci- we report a new process in which the addition of ex-
ternal nucleophiles is replaced by a multistep domino
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Ivan Romero-Estudillo et al.
iodine (2 equiv.) proved unnecessary. The use of
a Lewis acid to favor conversion 6!2 (entry 4) result-
ed in decreased yields, but the addition of excess ben-
zoic acid clearly improved the one-pot process
(entry 5). This result could be due not only to Brønst-
ed acid catalysis of the two last steps, but also to the
initial in situ formation of (dibenzoyliodo)benzene.
This reagent would generate more stable reaction in-
termediates (such as scission promoter BzOI instead
of AcOI, and decarboxylation-resistant benzoate ions,
instead of acetate ions, for the next steps, particularly
the iodo substitution reaction. To ensure complete
formation of (dibenzoyliodo)benzene from DIB,
excess benzoic acid was needed (2 equiv. with respect
to DIB, and 4 equiv. with respect to substrate 1).
The influence of the reaction time was also studied,
observing that with shorter times the reaction was not
completed. In addition, heating was necessary for rea-
sonable reaction times and yields.
Remarkably, a similar result was obtained when
light irradiation was replaced by heating at 808C
(entry 6). The best conditions provided the oxazole 2
in 74% global yield. Since many steps are involved,
each must proceed in excellent yields to account for
the final result.
Scheme 1. One-pot decarboxylation–cyclization.
Table 1. One-pot decarboxylation–cyclization.
The optimized conditions were then tried with
other N-acylphenylalanines 8–14, in order to deter-
mine the role of the acyl substituent (Table 2).
Thus, differently substituted benzamides 8 and 9
(entries 1 and 2), and the furan carboxamide 10
Entry 1/DIB/I2
Additive
(equiv.)[b]
Solvent Yield
[%]
(equiv.)
1
2
3
4
5
1/2/1
1/2/1
1/2/1
1/2/2
1/2/1
–
–
–
–
DCE
55
CH3CN 56
Tol
DCE
DCE
12
54
43
BF3·OEt2
(1 equiv.)
PhCO2H
(4 equiv.)
PhCO2H
(4 equiv)
PhCO2H
(4 equiv.)
Table 2. One-pot decarboxylation–cyclization.
6
7
8
1/2/1
DCE
DCE
71
74
1/2/1[a]
1/2/1
CH3CN 59
[a]
[b]
No irradiation with visible light; only heating at 808C.
Yields obtained after purification by chromatography.
Entry
1
Substrate
R
Product [%][a]
8
15 (59)
sequence where the intermediate 5 is trapped intra-
molecularly by the amido carbonyl group. A 4-substi-
tuted oxazoline 6 is formed,[22] which is converted into
an oxycarbenium ion 7, precursor of the desired oxa-
zoles (such as product 2).
2
3
9
16 (64)
17 (52)
10
The feasibility of this approach was studied using
N-benzoylphenylalanine 1 as the substrate (Table 1).
Different solvents (entries 1 and 2), amounts of
iodine (entries 1 and 3) and additives (entries 4-6)
were tried under irradiation with visible light and/or
heating, affording 2,5-diphenyloxazole 2.[18a] In the ab-
sence of iodine or DIB, oxazoles were not produced.
Interestingly, non-polar DCE and polar acetonitrile
gave similar results, while the addition of excess
4
5
11
12
18 (55)
19 (51)
6
13
14
20 (14)[b]
7
Me
–
[a]
Yields obtained after purification by column chromatog-
raphy.
22% without the additive PhCO2H.
[b]
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One-Pot Conversion of Amino Acids into 2,5-Disubstituted Oxazoles
Scheme 2. Role of the lateral chain in the one-pot process.
Scheme 3. Derivatization of the oxazole rings.
(entry 3) were studied. With these aromatic rings, the the 2,5-disubstituted compounds 25[20b,26] and 26 were
process took place in satisfactory yields, affording obtained in good yields. Compound 26 presents an
compounds 15–20. The formation of bromophenyl de- ester functionality which allows introduction of new
rivative 16[18a] is interesting, since the bromo group chains.
allows the introduction of new chains by radical or
In a similar way, the glutamic acid derivatives 27
sp2–sp2 couplings.[23] The furan ring in compound and 28 (Scheme 3) underwent the decarboxylation–
17[17a] can also be readily derivatized (e.g., reduction, cyclization reaction to give the oxazoles 29 and 30, re-
Diels–Alder) into a variety of other chains.[24]
spectively. Oxazole 29 could be functionalized at both
The aromatic rings were then replaced by vinyl and ends, for instance, using the iodophenyl ring for sp2–
alkyl groups (entries 4–7). The use of vinyl (entry 4) sp2 couplings, and by attachment of the carboxyl
and tertiary alkyl (tert-butyl, entry 5) groups afforded group to other chains. Besides, the acid can be manip-
compounds 18 and 19,[17a] respectively, in yields simi- ulated to introduce other functions. For instance,
lar to those of the previous entries. The results sug- saponification of the ester 30[27] afforded the acid 31.
gest that these groups provide enough stabilization of Its oxidative radical scission generated an intermedi-
the cationic intermediates. However, the use of secon- ate cation which was trapped by acetate to give prod-
dary and primary alkyl groups gave inferior results. uct 32.[28] The introduction of other nucleophiles is
Thus, with the sec-butyl group (entry 6) the oxazole currently under study.
derivative 20 was formed in low yields (14% and 22%
An interesting application of the decarboxylation–
with and without the additive, respectively). The use cyclization process would be the selective modifica-
of the methyl group (entry 7) resulted in complex re- tion of peptides, so that an oxazole ring could be in-
action mixtures, probably by failure of the cyclization troduced into a certain position of the peptide with-
step after decarboxylation and decomposition of the out affecting the others. Since many bioactive pep-
enamide intermediate.
tides contain oxazole rings in their structure, the pos-
Fortunately, the reduction or functionalization of sibility of increasing the diversity of a peptide library
vinyl derivatives such as compound 18 can provide by introduction of oxazole rings was attractive. This
a variety of primary and secondary alkyl chains. The approach was studied with the dipeptide 33[21c]
vinyl derivatives are interesting not only as synthetic (Scheme 4), which underwent the one-pot decarboxy-
intermediates but as components of many natural pro- lation–cyclization process, to give the oxazole deriva-
ducts[1,18a] and dyes.[6a]
tive 34 in 48% yield.
The role of the amino acid chain substituents was
To check that the leucine residue did not undergo
explored next. Thus, alanine 21 (Scheme 2), leucine epimerization during the process, compound 34 was
22 and aspartic 23 benzamides underwent the scis- prepared from the acid 31 and leucine methyl ester
sion–cyclization process to give the 2-phenyloxazoles using conventional peptide coupling conditions. Both
24–26. Both the monosubstituted derivative 24[25] and compounds displayed similar optical activities ([a]D ꢀ
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Ivan Romero-Estudillo et al.
Scheme 4. Derivatization of dipeptide 33.
ꢁ27 in MeOH at c=0.35), proving that no epimeriza-
tion had taken place.
In another example, the Lys-Aib derivative 35
(Scheme 5) was converted into the acid 36, which was
transformed into the lysine-derived oxazole derivative
37 in good yield under two different sets of condi-
tions, the standard decarboxylation–cyclization (70%)
and the process without additive (64%).
The process was also studied with the Aib-Leu de-
rivative 38 (Scheme 6). Interestingly, the acyl group
involved in the cyclization step is an amino acid, and
the resulting oxazole derivative 39 presents a chain
with an amino group which allows extension of the
peptidyl chain.
Scheme 5. Derivatization of dipeptide 36.
The optimization of this process for peptides, the
use of non-proteinogenic units such as dehydroamino
acids in the cyclization process, and its application to
the generation of peptide libraries will be reported in
due course.
In summary, N-acylamino acids can be converted
into 2,5-disubstituted oxazoles using a one-pot process
in which a radical decarboxylation–oxidation–isomeri-
Scheme 6. Derivatization of dipeptide 33.
zation reaction generates an enamide intermediate, Experimental Section
which then undergoes an iodine-promoted cyclization.
Remarkably, no metals are needed to promote this General Procedure for the Scission–Cyclization
cyclization. The reaction proceeds with a variety of Process
amino acids and acyl chains and, although many steps
A mixture of (diacetoxyiodo)benzene (258 mg, 0.8 mmol)
take place in this sequential process, the products are
and benzoic acid (195 mg, 1.6 mmol) in dry dichloroethane
obtained in good global yields.
The one-pot process generates oxazoles in which
both substituents can be manipulated independently.
The reaction mixture was heated under reflux for 18 h. Then
(4 mL) was heated at 508C for 2 h. Then the N-acylamino
acid (0.4 mmol) and iodine (102 mg, 0.4 mmol) were added.
Besides, the mild conditions are suitable for the selec-
tive modification of peptides. The applications of this
method to generate libraries of potentially antimicro-
bial and antitumoral oxazoles, including oxazole ana-
the mixture was allowed to cool to room temperature
(268C) and was poured into a 1:1 mixture of 10% aqueous
Na2S2O3 and saturated aqueous NaHCO3, and extracted
with CH2Cl2. The organic layer was dried over sodium sul-
logues of bioactive peptides, is currently underway fate and filtered, then the solvent was removed under
and will be reported in due course.
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One-Pot Conversion of Amino Acids into 2,5-Disubstituted Oxazoles
vacuum and the residue was purified by column chromatog-
raphy (hexane/EtOAc), yielding the oxazole derivatives.
Ethyl 2-(2-phenyloxazol-5-yl)acetate (30): Obtained from
d-ethyl N-benzoylglutamate (28) (111 mg, 0.4 mmol) accord-
ing to the general procedure above. The reaction mixture
was purified by column chromatography on silica gel
(hexane/EtOAc 90:10), affording compound (30) as a yellow-
ish solid; yield: 63 mg (68%). Compound (30) has been pre-
viously reported.{27] 1H NMR (400 MHz, CDCl3): d=1.29
(dd, J=7.1 Hz, 3H), 3.79 (s, 2H), 4.22 (ddd, J=7.1, 7.2,
7.2 Hz, 2H), 7.08 (s, 1H), 7.43–7.47 (m, 3H), 8.00–8.04 (m,
2H); 13C NMR (125.7 MHz, CDCl3, 268C): d=14.1 (CH3),
31.9 (CH2), 61.5 (CH2), 126.3 (2ꢃCH), 127.4 (C), 128.7 (3ꢃ
CH), 130.3 (CH), 145.0 (C), 161.5 (C), 168.3 (C).
173.1 (C); IR (CHCl3): n=3426, 1741, 1684 cmꢁ1; HR-MS
(EI): m/z=330.1591, calcd. for C18H22N2O4 [M+]: 330.1580;
anal. calcd. for C18H22N2O4: C 65.44, H 6.71, N 8.48; found:
C 65.58, H 6.86, N 8.36.
N-[2-(2-Phenyloxazol-5-yl)acetyl]leucine methyl ester
(34): To a solution of acid 31 (12 mg, 0.60 mmol) in CH2Cl2
(3 mL) was added H-Leu-OMe HCl (142 mg, 0.78 mmol),
DIPEA (0.20 mL, 1.2 mmol) and HBTU (250 mg,
0.66 mmol). The reaction mixture was allowed to reach
268C and stirred for 3 h, then was poured into saturated
aqueous NaHCO3·and extracted with EtOAc. The organic
layer was washed with 10% aqueous HCl, and then was
dried and evaporated as usual. The residue was purified by
column chromatography on silica gel (hexane/EtOAc 60:40)
affording the compound 32 as a yellowish syrup; yield:
163 mg (82%); [a]D: ꢁ28 (c 0.35, MeOH).
2-(2-Phenyloxazol-5-yl)acetic acid (31): To a solution of
the ester 30 (56 mg, 0.24 mmol) in methanol (9 mL) at 08C
was added 2N aqueous NaOH (1 mL). The mixture was al-
lowed to reach 268C and was stirred for 2 h; then was
poured into 10% aqueous HCl and extracted with EtOAc.
The organic layer was dried and evaporated in the usual
way, affording acid 31 as a white amorphous solid; yield:
Supporting Information
1
Experimental details, H and 13C NMR for all new
1
products, and 2D-NMR spectra for compounds 15, 34
and 37 are available in the Supporting Information
45 mg (92%). H NMR (500 MHz, CD3OD: d=3.86 (s, 2H),
7.11 (s, 1H), 7.45–7.48 (m, 3H), 7.96–8.00 (m, 2H).
13C NMR (125.7 MHz, CD3OD): d=32.0 (CH2), 126.8 (CH),
127.2 (2ꢃCH), 128.3 (C), 130.0 (2ꢃCH), 131.7 (CH), 148.1
(C), 163.0 (C), 172.0 (C); HR-MS (EI): m/z=203.0579,
calcd. for C11H9NO3 [M+]: 203.0582; anal. calcd. for
C11H9NO3: C 65.02, H 4.46, N 6.89; found: C 64.87, H 4.80,
N 6.89.
Acknowledgements
This work was supported by Plan Nacional de I+D
(CTQ2009-07109 and SAF-2013-48399-R), MICINN/
MINECO, Spain, and European Regional Development
(FEDER) Funds. I.R.E. thanks CSIC for a JAE predoctoral
contract.
(2-Phenyloxazol-5-yl)methyl acetate (32): A solution of
acid 31 (21 mg, 0.1 mmol) in dry dichloroethane (1.5 mL)
was
treated
with
(diacetoxyiodo)benzene
(48 mg,
0.15 mmol) and iodine (13 mg, 0.05 mmol). The mixture was
heated under reflux for 30 min, then was allowed to reach
268C and poured into saturated aqueous Na2S2O3, and ex-
tracted with dichloromethane. The organic layer was dried
and evaporated as usual, and the residue was purified by
column chromatography (hexanes:EtOAc 90:10) affording
compound 32 as a yellow syrup; yield: 16 mg (73%). The
spectroscopic data of compound 32 have been previously re-
ported.[28] 1H NMR (500 MHz, CDCl3): d=2.11 (s, 3H), 5.18
(s, 2H), 7.28 (br s, 1H), 7.45–7.50 (m, 3H), 8.05–8.10 (m,
2H); 13C NMR (125.7 MHz, CDCl3, 268C): d=20.8 (CH3),
55.6 (CH2), 126.7 (2ꢃCH), 128.1 (CH), 128.9 (2ꢃCH+C),
131.0 (CH), 146.8 (C), 162.5 (C), 170.4 (C); HR-MS (EI):
m/z=218.0821, calcd. for C12H12NO3 [M+ +H]; 218.0817;
anal. calcd. for C12H11NO3: C 66.35, H 5.10, N 6.45; found:
C 62.60, H 5.34, N 6.13.
N-[2-(2-Phenyloxazol-5-yl)acetyl]leucine methyl ester
(34): Obtained from the dipeptide 33 (151 mg, 0.4 mmol) ac-
cording to the general procedure. The reaction mixture was
purified by column chromatography on silica gel (hexane/
EtOAc 50:50), affording compound (34) as a as a yellowish
syrup; yield: 63 mg (48%); [a]D: ꢁ27 (c 0.35, MeOH);
1H NMR (500 MHz, CDCl3): d=0.89 (d, J=6.4 Hz, 3H),
0.92 (d, J=6.3 Hz, 3H), 1.53 (m, 1H), 1.60–1.68 (m, 2H),
3.71 (s, 3H), 3.74 (s, 2H), 4.66 (ddd, J=5.0, 8.4, 8.8 Hz,
1H), 6.25 (br d, J=8.0 Hz, 1H), 7.12 (brs, 1H), 7.44–7.47
(m, 3H), 8.01–8.05 (m, 2H); 13C NMR (125.7 MHz, CDCl3,
268C): d=21.9 (CH3), 22.7 (CH3), 24.8 (CH), 33.8 (CH2),
41.4 (CH2), 51.0 (CH), 52.4 (CH3), 126.3 (3ꢃCH), 126.8 (C),
128.8 (2ꢃCH), 130.6 (CH), 145.7 (C), 161.9 (C), 166.9 (C),
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suggesting the formation of an iodonium intermediate
5a (X=I). However, this iodo group could also be
result of iodide opening of an initial (acetoxy)phenylio-
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Adv. Synth. Catal. 0000, 000, 0 – 0
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asc.wiley-vch.de
7
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These are not the final page numbers!

COMMUNICATIONS
8 One-Pot Conversion of Amino Acids into 2,5-Disubstituted
Oxazoles: No Metals Needed
Adv. Synth. Catal. 2014, 356, 1 – 8
Ivan Romero-Estudillo, Venkateswara Rao Batchu,
Alicia Boto*
8
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Adv. Synth. Catal. 0000, 000, 0 – 0
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These are not the final page numbers!