Development of a method for the synthesis of 2,4,5-trisubstituted oxazoles composed of carboxylic acid, amino acid, and boronic acid

Article abstract of DOI:10.3762/bjoc.13.146

A novel method for the synthesis of trisubstituted oxazoles via a one-pot oxazole synthesis/Suzuki–Miyaura coupling sequence has been developed. One-pot formation of 5-(triazinyloxy)oxazoles using carboxylic acids, amino acids and a dehydrative condensing reagent, DMT-MM, followed by Ni-catalyzed Suzuki–Miyaura coupling with boronic acids provided the corresponding 2,4,5-trisubstituted oxazoles in good yields.

Full text of DOI:10.3762/bjoc.13.146

Development of a method for the synthesis of 2,4,5-
trisubstituted oxazoles composed of carboxylic
acid, amino acid, and boronic acid
Kohei Yamada, Naoto Kamimura and Munetaka Kunishima*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1478–1485.
Faculty of Pharmaceutical Sciences, Institute of Medical,
Pharmaceutical, and Health Sciences, Kanazawa University,
Kakuma-machi, Kanazawa 920-1192, Japan
doi:10.3762/bjoc.13.146
Received: 07 April 2017
Accepted: 10 July 2017
Published: 27 July 2017
Email:
Munetaka Kunishima* - kunisima@p.kanazawa-u.ac.jp
Associate Editor: T. J. J. Müller
* Corresponding author
© 2017 Yamada et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
one-pot oxazole synthesis; Suzuki–Miyaura coupling; triazine;
5-(triazinyloxy)oxazole; trisubstituted oxazole
Abstract
A novel method for the synthesis of trisubstituted oxazoles via a one-pot oxazole synthesis/Suzuki–Miyaura coupling sequence has
been developed. One-pot formation of 5-(triazinyloxy)oxazoles using carboxylic acids, amino acids and a dehydrative condensing
reagent, DMT-MM, followed by Ni-catalyzed Suzuki–Miyaura coupling with boronic acids provided the corresponding 2,4,5-
trisubstituted oxazoles in good yields.
Introduction
Oxazoles are found in numerous natural products and are used and modifications of these [6,7], have been developed. More-
as a broad range of artificial compounds [1,2]. In particular, over, cycloaddition of two starting materials, such as α-haloke-
2,4,5-trisubstituted oxazoles attract attention as pharmacologi- tones and primary amides [8], alkynes and nitriles [9], amines
cally potent scaffolds because structural diversity can be effi- and α,β-unsaturated carbonyl compounds [10], etc. [11] have
ciently generated by the introduction of a variety of substitu- been reported. However, these reactions are often conducted
ents. Accordingly, numerous synthetic methods have been de- under harsh reaction conditions and multistep syntheses of the
veloped and can be roughly classified into three synthetic strate- starting materials are needed. ii) The functionalization method:
gies (Scheme 1a).
various regioselective metalations and subsequent functional-
izations of the oxazole core skeleton using Cu [12], Pd [13], Mg
i) The cyclization method: many methods, such as the [14], Zn [14], etc. [15] have been developed. This linear synthe-
Robinson–Gabriel oxazole synthesis using α-acylaminoketone tic approach inevitably requires multistep processes and often
[3,4], the Davidson oxazole synthesis with α-acyloxyketone [5], needs prehalogenation [16]. iii) The multicomponent method:
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Beilstein J. Org. Chem. 2017, 13, 1478–1485.
Scheme 1: Our strategy for the concise synthesis of 2,4,5-trisubstituted oxazoles.
only two strategies have been reported to the best of our know- Results and Discussion
ledge. One is a combination of the Ugi reaction, which uses 2,4- The study was initiated with the preparation of the key interme-
dimethoxybenzylamine, arylglyoxal, carboxylic acid, and isoni- diate, 5-(triazinyloxy)oxazole 3, from carboxylic acid 1 and
trile as components, and a subsequent Robinson–Gabriel reac- amino acid 2 under conditions improved from [23] (Table 1). A
tion [17]. The other is an Au-catalyzed tandem oxazole synthe- one-pot sequence involving formation of an activated ester from
sis using a primary amide, aldehyde, and alkyne [18]. These benzoic acid (1a) with DMT-MM, N-benzoylation of alanine
methods are reasonable for the synthesis of diverse libraries of (2a), cyclodehydration, and introduction of the triazinyl group
trisubstituted oxazoles because the combination of three starting was conducted in 1,4-dioxane/H2O to give the desired
materials that are corresponding to the substituents can be 5-(triazinyloxy)oxazole 3aa in 78% yield (Table 1, entry 1). A
readily altered. However, these reactions require strongly acidic series of carboxylic acids were subjected to the reaction condi-
conditions or high temperatures. Therefore, a mild method for tions. Aromatic carboxylic acids with both electron-with-
the synthesis of diverse trisubstituted oxazoles using three com- drawing and electron-donating groups gave good yields
mercially available compounds with a wide variety of struc- (Table 1, entries 2 and 3). In the case of aliphatic carboxylic
tures is still desired.
acids, 3-phenylpropionic acid (1d) gave a slightly decreased
amount of 3da in 54% yield (Table 1, entry 4), whereas the
Previously, we reported a one-pot synthesis of oxazolone from more sterically demanding 1e gave the desired product 3ea in a
carboxylic acids and amino acids using a dehydrative good yield (Table 1, entry 5). The reaction was carried out with
condensing reagent, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4- different amino acids, resulting in a varied substitution pattern
methylmorpholinium chloride (DMT-MM [19-22])[23]. Forma- at the 4-position of the oxazole. The one-pot oxazole synthesis
tion of 5-(triazinyloxy)oxazole is also reported to occur when with phenylalanine (2b), valine (2c), leucine (2d), methionine
an excess of DMT-MM was used. Recently, Jin and co-workers (2e), and phenylglycine (2f) proceeded to give the correspond-
reported that Ni-catalyzed Suzuki–Miyaura coupling between ing intermediates in good yields (Table 1, entries 6–10).
triazinyloxybenzene and arylboronic acids affords the corre- Despite the existence of highly polar starting materials and
sponding biaryl compounds [24-33]. In this context, we envi- relatively more lipophilic activated esters and oxazolone
sioned application of this Suzuki–Miyaura coupling to a intermediates during the course of the reaction, various
5-(triazinyloxy)oxazole would provide trisubstituted oxazoles 5-(triazinyloxy)oxazoles were uneventfully synthesized under
(Scheme 1b). Since many kinds of carboxylic acids, amino these improved conditions.
acids and boronic acids, which are corresponding to 2-, 4-, and
5-substituents of the oxazole, respectively, are commercially According to the procedure previously reported [24], we exam-
available, this method is suitable for the synthesis of a diverse ined Ni-catalyzed Suzuki–Miyaura coupling between
variety of trisubstituted oxazoles. Herein, we described an effi- 5-(triazinyloxy)oxazole 3aa and phenylboronic acid (4a,
cient method for the synthesis of trisubstituted oxazoles through Table 2). As expected, the desired trisubstituted oxazole 5aaa
a one-pot oxazole synthesis and subsequent Suzuki–Miyaura was obtained in 21% yield (Table 2, entry 1). The use of differ-
coupling.
ent bidentate (dppp) or monodentate (PCy3) phosphines as
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Beilstein J. Org. Chem. 2017, 13, 1478–1485.
Table 1: One-pot synthesis of 5-(triazinyloxy)oxazole under improved conditions.
entry
1
carboxylic acid 1
amino acid 2
alanine (2a)
yield of 3 (%)a
3aa, 78
1a
2
3
2a
2a
3ba, 69
3ca, 60
1b
1c
1d
4
5
2a
2a
3da, 54
3ea, 71
1e
1a
1a
1a
1a
1a
6
7
phenylalanine (2b)
valine (2c)
3ab, 78
3ac, 83
3ad, 70
3ae, 70
3af, 78
8
leucine (2d)
9
methionine (2e)
phenylglycine (2f)
10
aIsolated yield.
ligands for the Ni catalyst resulted in poor yields (Table 2, the additive provided inferior results (Table 2, entries 8 and 9).
entries 2 and 3). Notably, we found that 3 equiv of LiCl was an Interestingly, switching the counter cation of the base to Li+ did
effective additive for shortening the reaction time (3 h) and im- not afford any product (Table 2, entry 10). The reaction with
proving the yield (73%, Table 2, entry 4) [34]. Other lithium PdCl2(dppf) instead of NiCl2(dppf) reduced the outcome of the
halides, except for LiF, were also effective (Table 2, entries reaction (Table 2, entry 11). No product was obtained when
5–7). However, utilization of Na+ and K+ as counter cations for boronic acid pinacol ester 6 and borate salt 7 were used as a
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Table 2: Screening of reaction conditions of Suzuki–Miyaura coupling with 3aa.
entry
metal cat.
base
additive (3 equiv)
solvent
time (h)
yield of 5aaa (%)a
1
2
NiCl2(dppf)
NiCl2(dppp)
NiCl2(PCy3)2
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
PdCl2(dppf) ·CH2Cl2
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
NiCl2(dppf)
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Li3PO4
K3PO4
K3PO4
–
–
toluene
toluene
19
12
20
3
21
–
9
3
–
toluene
12
4
LiCl
LiF
LiBr
LiI
toluene
73 (68%)b
5
toluene
21
3
35
64
70
0
6
toluene
7
toluene
3
8
NaI
KI
toluene
24
17
26
22
20
12
10
21
23
20 min
9
toluene
51
0
10
11
12c
13d
14
15
16
17
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
toluene
toluene
0
toluene
0
toluene
0
K3PO4
K3PO4
K3PO4
K3PO4
DME
0
1,4-dioxane
toluene 80 °C
toluene 160 °C (MW)
0
36
30
aNMR yield. bIsolated yield. cBoronic acid pinacol ester 6 was used instead of boronic acid 4a. dBorate 7 was used instead of boronic acid 4a.
coupling partner (Table 2, entries 12 and 13) [35]. Dimethoxy- acid with an electron-donating group 4c also provided a better
ethane (DME) and 1,4-dioxane as ethereal solvents did not yield under conditions B rather than conditions A (Table 3,
improve the yields (Table 2, entries 14 and 15). Decreasing the entries 3 and 4). The desired naphthyloxazole 5aad was ob-
temperature to 80 °C or increasing to 160 °C by microwave ir- tained in a high yield (77%, Table 3, entry 5). Introduction of a
radiation were not effective for improving the reaction (Table 2, p-tolyl group afforded a good yield of 71% (Table 3, entry 6),
entries 16 and 17). Consequently, we found that the reaction whereas reactions of the o-tolyl group resulted in moderate
shown in entry 4 afforded the optimal result (see Table S1 in yields under both conditions owing to the steric effect (Table 3,
Supporting Information File 1 for further manipulation of the entries 7 and 8). The reaction with 3-thienylboronic acid (4g)
reaction conditions).
under conditions B proceeded to give 5aag in 68% yield
(Table 3, entries 9 and 10). No product was obtained when
A number of trisubstituted oxazoles were synthesized using n-butylboronic acid (4h) was used as an aliphatic boronic acid
5-(triazinyloxy)oxazoles 3 and various boronic acids 4 (Table 3, entry 11). Subsequently, the effect of substituents at
(Table 3). To our disappointment, the reaction of 3aa with the the 2-position, which was derived from the carboxylic acids,
arylboronic acid possessing an electron-withdrawing group 4b was tested. Aryl substituents possessing both electron-with-
decreased the yield of 5aab (25%, Table 3, entry 1). Further in- drawing and electron-donating groups proceeded to give the
vestigation of the reaction conditions revealed that the reaction corresponding oxazoles in good yields (Table 3, entries 12 and
with additional dppf (5 mol %) in a sealed tube increased the 13). Aliphatic substituents are innocent in the reaction outcome
yield to 64% (Table 3, entry 2) [36,37]. These reaction condi- (Table 3, entries 14 and 15). Suzuki–Miyaura coupling of
tions were defined as conditions B, whereas the conditions in several intermediates 3ab–3af, which have different substitu-
Table 2, entry 4 are defined as conditions A. The arylboronic ents at the 4-position, were examined (Table 3, entries 16–20).
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Table 3: Synthesis of various trisubstituted oxazoles.
entry
3
4
product 5
conditions
yield of 5 (%)a
1
3aa
4b
A
25
5aab
5aab
2
3
3aa
3aa
4b
4c
B
A
64
54
5aac
5aac
4
5
3aa
3aa
4c
4d
B
A
67
77
5aad
5aae
6
7
3aa
3aa
4e
4f
A
A
71
42
5aaf
5aaf
8
9
3aa
3aa
3aa
4f
4g
4g
B
A
B
46
30
68
5aag
5aag
10
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Table 3: Synthesis of various trisubstituted oxazoles. (continued)
11
12
3aa
3ba
4h
4a
B
A
0
5aah
5baa
69
13
3ca
4a
A
64
5caa
5daa
14
15
16
3da
3ea
3ab
4a
4a
4a
A
A
A
68
73
60
5eaa
5aba
17
3ac
4a
B
54
5aca
18
19
3ad
3ae
4a
4a
B
A
62
62
5ada
5aea
20
3af
4a
B
47
5afa
aIsolated yield.
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Beilstein J. Org. Chem. 2017, 13, 1478–1485.
Compared with 3aa, the yields using these compounds were Acknowledgements
slightly lower, especially in the case of sterically more hindered This work is financially supported by JSPS KAKENHI Grant
3ac and 3af (Table 3, entries 17 and 20). Thus, Suzuki–Miyaura Numbers 26293003, 25460012 and Teijin Pharma Award in
coupling is affected by steric hindrance from the 4-substituent Synthetic Organic Chemistry, Japan.
of oxazoles.
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Scheme 2: Synthesis of DMPOPOP.
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License and Terms
19.Kunishima, M.; Kawachi, C.; Iwasaki, F.; Terao, K.; Tani, S.
Tetrahedron Lett. 1999, 40, 5327–5330.
This is an Open Access article under the terms of the
Creative Commons Attribution License
doi:10.1016/S0040-4039(99)00968-5
20.Kunishima, M.; Kawachi, C.; Monta, J.; Terao, K.; Iwasaki, F.; Tani, S.
Tetrahedron 1999, 55, 13159–13170.
(http://creativecommons.org/licenses/by/4.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
doi:10.1016/S0040-4020(99)00809-1
21.Kunishima, M.; Kawachi, C.; Hioki, K.; Terao, K.; Tani, S. Tetrahedron
2001, 57, 1551–1558. doi:10.1016/S0040-4020(00)01137-6
22.Kitamura, M.; Kunishima, M.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride. In
e-EROS (Encyclopedia of Reagents for Organic Synthesis) [Online];
Crich, D.; Charette, A. B.; Fuchs, P. L., Eds.; John Wiley & Sons, Ltd:
West Sussex, 2013.
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
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