Synthesis of α-(4-Oxazolyl)amino Esters via Br?nsted Acid Catalyzed Tandem Reaction

Article abstract of DOI:10.1021/acs.orglett.8b01212

A one-step, Br?nsted acid catalyzed tandem reaction for the synthesis of α-(4-oxazolyl)amino esters was developed. 4-Nitrobenzenesulfonic acid was found to be an efficient catalyst for the coupling of ethyl 2-oxobut-3-ynoates with amides to provide variou

Full text of DOI:10.1021/acs.orglett.8b01212

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of α‑(4-Oxazolyl)amino Esters via Brønsted Acid Catalyzed
Tandem Reaction
Ansoo Lee, Seohee Oh, and Hyunwoo Kim*
Department of Chemistry, KAIST, Daejeon 34141, Korea
S
* Supporting Information
ABSTRACT: A one-step, Brønsted acid catalyzed tandem
reaction for the synthesis of α-(4-oxazolyl)amino esters was
developed. 4-Nitrobenzenesulfonic acid was found to be an
efficient catalyst for the coupling of ethyl 2-oxobut-3-ynoates with
amides to provide various α-(4-oxazolyl)amino esters. The
experimental and X-ray crystallographic data suggest that a series
of bond-forming reactions including imine formation, intermo-
lecular Michael addition, and intramolecular Michael addition are involved to generate both the oxazole and amino acid
functionalities.
nnatural α-amino acids are an important class of building
blocks continuously used in the synthesis of modified
Scheme 1. Bioactive Molecules and Their Synthesis
U
peptides to improve their bioactivity and metabolic stability.1
Various α-amino acids with modified side chains are not
recognized by enzymes, resulting in enhanced resistance toward
enzyme-mediated biodegradation.2 In addition, they have been
widely used in bioconjugation chemistry, including in click or
cross-coupling reactions for engineering proteins.3 Given the
biological importance of unnatural α-amino acids, there is
strong interest in developing efficient synthetic methods for
preparing them. The reported general synthesis of α-amino
acids includes amination of carboxylic acids,4 alkylation of
glycine derivatives or oxazolones,5 alkene hydrogenation,6 and
Strecker synthesis.7
In recent years, synthesis of unnatural α-amino acids with
heteroaromatic groups has been developed to achieve various
pharmacological and biological properties.8 In particular, α-
amino acids with oxazole side chains are found in drug
molecules such as a nonpeptide galanin receptor agonist,
galmic,9 as well as an oxytocin receptor antagonist, GSK-
221,149-A10 (Scheme 1a). Because of the potent bioactivity of
these structures, several strategies have been developed for their
synthesis including Ugi reaction,10,11 Chan rearrangement,12
oxidative cyclodehydration,13 and amination of α-oxazolyl
esters14 (Scheme 1b). However, the reported methods require
a multistep procedure including preintroduction of the oxazole
or the amino acid functionality. The structural variation of α-
(oxazolyl)amino acids is thus quite limited. To address this
challenge, the generation of oxazole and amino acid functional
groups in a single step using commercially available or readily
accessible starting materials is necessary to construct α-
(oxazolyl)amino acid scaffolds with structural variation. Herein,
we report a Brønsted acid catalyzed tandem reaction of ethyl 2-
oxobut-3-ynoates 1, synthesized through a one-step process
from arylacetylene,15 with commercially available amides 2 to
access α-(4-oxazolyl)amino acid derivatives 3 (Scheme 1c). We
believe that the development of a straightforward method to
Received: April 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01212
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
access α-(oxazolyl)amino acid derivatives will provide new
opportunities for the discovery and development of biologically
active compounds.
Scheme 3. Substrate Scope of Various Amides 2 with Ethyl
2-Oxo-4-phenylbut-3-ynoate 1a
a
In our research on Rh-catalyzed conjugate additions of
boronic acids,16 we sought to prepare an unsaturated imino
compound by the reaction of ethyl 2-oxo-4-phenylbut-3-ynoate
1a and acetamide 2a. In principle, the unsaturated carbonyl
compound 1a with two electrophilic sites could potentially
undergo both 1,2- and 1,4-additions. According to previous
studies using 1a as an electrophile, we found that 1a showed
mostly 1,2-selectivity with a variety of nucleophiles.17 There-
fore, a reaction of 1a with 2a may provide a 1,2-adduct, leading
to an imino ester. In our experiments, the reaction of 1a with
acetamide 2a in the presence of catalytic p-toluenesulfonic acid
BA1 provided an unexpected product 3aa in 42% yield
(Scheme 2a). Because the product 3aa contains two acetamide
a
Scheme 2. Catalyst Screening
a
Conditions: 1a (0.5 mmol), 2 (2.0 mmol), BA4 (20 mol %), and
toluene (5.0 mL) were refluxed for 22 h with a Dean−Stark trap.
b
c
Yield of isolated product. Reaction was carried out with BA4 (100
mol %).
a
Conditions: 1a (0.5 mmol), 2a (1.05 or 2.0 mmol), catalyst (20 mol
3ab−ae in good yields (73−86%). Although the reaction with
2-chloroacetamide 2f provided the product 3af in low yield
(26%), the use of a stoichiometric amount of BA4 increased the
product yield to 58%. When 3-chloropropionamide 2g was
reacted with 1a in the presence of 20 mol % of BA4, the
desirable product 3ag was obtained in 51% yield together with
the dehalogenated product 3ag′ in 25% yield (see the
Supporting Information).
The scope of aromatic amides was then explored. When
aromatic amides with electronic and steric functional groups
were reacted with 1a, desirable α-amino esters 3ah−ap were
obtained in good yields (60−82%), but the reaction with 4-
bromobenzamide 2m gave the corresponding product 3am
with a somewhat decreased yield of 45%. In addition, the
reactions with 2-thiophenecarboxamide 2q, crotonamide 2r,
and cinnamamide 2s gave the desired products 3aq−as in good
yields (62−76%).
The exact structure of the products was confirmed by the X-
ray crystal structure analysis of 3aa and 3ah (Figure 1).19 We
demonstrated that this method is amenable to a gram-scale
synthesis of amino ester 3ah (2.28 g, 67% yield). Amino esters
3 were concisely deprotected to access unprotected amino acid
derivatives with various oxazolyl side groups. Compound 3aa
was hydrolyzed to provide the N-acylamino acid and 3ah was
%), and toluene (5.0 mL) were refluxed for 22 h with a Dean−Stark
b
trap. Yield of isolated product. Reaction was carried out without a
c
Dean−Stark trap. Reaction was carried out with BA4 (10 mol %).
units, it appears that an additional addition reaction with 2a
takes place after the reaction between 1a and 2a. It is quite
interesting that acetamide 2a was selectively added to the β-
position of the possible imino ester intermediate. Given the
structural interest and potential of α-(4-oxazolyl)amino acids,
we further explored this tandem reaction.
We optimized the reaction conditions by using various
Brønsted acids. A phosphoric acid PA or HNTf2 showed poor
yields, indicating that significantly weaker or stronger Brønsted
acids than BA1 were inefficient (Scheme 2a).18 As shown in
Scheme 2b, the use of excess amount of 2a and a Dean−Stark
trap enhanced product yields. Based on these findings, we
screened a variety of aryl sulfonic acids BA2−BA6. Notably,
substituted sulfonic acids can be used in this process to increase
the yields of 3aa, where 4-nitrobenzenesulfonic acid BA4
proved optimal, resulting in 72% yield. In addition, the reaction
with low loading of BA4 decreased the product yield.
Then we investigated the reaction scope of 1a with a variety
of amides 2 (Scheme 3). Aliphatic amides such as 1°, 2°, or 3°
aliphatic amides 2b−d and 2-phenylacetamide 2e afforded
B
DOI: 10.1021/acs.orglett.8b01212
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Organic Letters
Letter
To gain insight into the reaction mechanism, we conducted
several control experiments (Scheme 5). First, the ynone 4 did
Scheme 5. Control Experiments
Figure 1. Crystal structures of (a) 3aa and (b) 3ah.
converted to the N-unprotected amino ester in 90 and 85%
yields, respectively. In addition, DIBAL reduction of 3aa
provided the corresponding amino alcohols (see the SI).
Next, we evaluated the scope of ethyl 2-oxo-4-arylbut-3-
ynoates 1, as shown in Scheme 4. To examine the generality of
Scheme 4. Substrate Scope of Various Amides 2 with Ethyl
a
2-Oxo-4-arylbut-3-ynoate 1
not react with acetamide 2a, indicating the crucial role of the
ester group for the desired reactivity (Scheme 5a). From the
reaction of 1a in the presence of both acetamide 2a and
benzamide 2h, four compounds were obtained with 82% yield
overall (Scheme 5b). The reactivity difference of the two
amides 2a and 2h for 1,2-addition (3aa + 5a/3ah + 5b =
56%:26%) was more significant than that for 1,4-addition (3aa
+ 5b/3ah + 5a = 38%:44%). Therefore, the properties of the
amides have more influence on the reactivity of 1,2-addition
than 1,4-addition. In addition, reaction of 6 containing a bulky
silyl group provided aminal product 7, and thus, the 1,2 or 1,4-
selectivity of the second amide addition can be controlled by
the size of the keto ester substrates (Scheme 5c).
On the basis of the above observations, a proposed reaction
mechanism is described in Scheme 6. On the basis of the
previous reports17 and our observations for the formation of
aminal product 7 using 6 as an electrophile, substrate 1a
initially reacts with an amide to form the iminium ion A in the
a
Conditions: 1 (0.5 mmol), 2 (2.0 mmol), BA4 (20 mol %), and
toluene (5.0 mL) were refluxed for 22 h with a Dean−Stark trap.
b
Scheme 6. Proposed Mechanism
Reaction was carried out with 1 (0.27 mmol), 2 (1.08 mmol), BA4
(20 mol %), and toluene (2.7 mL).
the method, benzamide 2h and butyramide 2b were used for
the reactions. First, reactions of 2h with 1 substituted with
electron-donating group such as Me, MeO, and tBu groups as
well as electron-withdrawing group such as F, Cl, Br, and CF3
groups at the para, meta, and ortho positions provided desirable
amino esters 3bh−jh in moderate to good yields (51−89%).
Good yields (79 and 63%) were observed for 1 containing
either a 1-naphthyl (1k) or 2-thienyl group (1l). To our
satisfaction, reaction of 1m provided the desired amino ester
3mh in 57% yield. Moreover, in reactions with butyramide 2b,
a variety of 1 afforded 3bb−3lb in good to high yields (65−
85%).
C
DOI: 10.1021/acs.orglett.8b01212
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Organic Letters
Letter
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* Supporting Information
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Experimental procedures, spectroscopic, and crystallo-
graphic details (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hwkim@kaist.edu.
ORCID
Hyunwoo Kim: 0000-0001-5030-9610
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The authors are grateful for the financial support provided by
t h e C 1 G a s R e fi n e r y P r o g r a m ( N R F -
2016M3D3A1A01913256) and the National Research Founda-
tion of Korea (NRF-2017R1A2B4002650).
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DOI: 10.1021/acs.orglett.8b01212
Org. Lett. XXXX, XXX, XXX−XXX