A novel synthetic method of 2,4-disubstituted oxazoles using carboxylic acid-derived Bu2Sn[OC(O)R]2

Article abstract of DOI:10.1016/j.tetlet.2020.151983

A novel synthetic method for the preparation of 2,4-disubstituted oxazoles was developed, entailing the reaction of dibutyltin diacylates Bu₂Sn[OC(O)R]₂ with 1-substituted acetylenes and TMSN₃ to afford a range of 2,4-disu

Full text of DOI:10.1016/j.tetlet.2020.151983

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A Novel Synthetic Method of 2,4-Disubstituted Oxazoles Using Carboxylic
Acid-derived Bu2Sn[OC(O)R]2
Hiroki Yoneyama, Naoki Oka, Yoshihide Usami, Shinya Harusawa
PII:
S0040-4039(20)30426-3
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151983
TETL 151983
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
19 March 2020
24 April 2020
27 April 2020
Please cite this article as: Yoneyama, H., Oka, N., Usami, Y., Harusawa, S., A Novel Synthetic Method of 2,4-
Disubstituted Oxazoles Using Carboxylic Acid-derived Bu2Sn[OC(O)R]2, Tetrahedron Letters (2020), doi:
https://doi.org/10.1016/j.tetlet.2020.151983
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A Novel Synthetic Method of 2,4-Disubstituted
Oxazoles Using Carboxylic Acid-
derived Bu2Sn[OC(O)R]2
Leave this area blank for abstract info.
Hiroki Yoneyama, Naoki Oka, Yoshihide Usami, Shinya Harusawa*
R2
O
Bu2SnO
TMSN3
O
R1
R1
4
2
Bu2Sn OC
COOH
2
toluene
reflux
R2
R1
toluene
reflux
N

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A Novel Synthetic Method of 2,4-Disubstituted Oxazoles Using Carboxylic Acid-
derived Bu2Sn[OC(O)R]2
Hiroki Yoneyama, Naoki Oka, Yoshihide Usami, and Shinya Harusawa*
Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A novel synthetic method for the preparation of 2,4-disubstituted oxazoles was developed,
entailing the reaction of dibutyltin diacylates Bu2Sn[OC(O)R]2 with 1-substituted acetylenes and
TMSN3 to afford a range of 2,4-disubstituted oxazoles in good yields.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
2,4-Disubstituted oxazoles
TMSN3
Bu2Sn[OC(O)R]2
Carboxylic acids
1. Introduction
Considerable efforts have been directed towards the development of regioselective syntheses of substituted oxazoles over the years,
as various substituted oxazoles were found in natural products and synthetic pharmaceutical molecules.1 2,4-disubstituted oxazoles, in
particular are common structural elements in a wide variety of biologically relevant natural products, including neopeltolide A
(antiproliferative), hennoxazole A (antiviral) and leucascandrolide A (cytoxic and antifungal).2
The biosynthesis of 2,4-disubstituted oxazoles entails the cyclodehydration and oxidation of serine or threonine moieties in peptide
derivatives.3 In this context, the oxidation of unsaturated oxazolines from N-acylserines and cyclodehydration of -acylamino
aldehydes derived from amino acids have been reported.4,5 Another efficient strategy is the preparation of various pre-formed 2,4-
difunctionalized oxazole units, which could be sequentially elaborated under metal-catalyzed cross coupling conditions to provide a
range of 2,4-disubstituted oxazoles.6 Additionally, metal catalyzed conversion of -diazocarbonyl compounds7 or multi-component
coupling8 from ketones have been devised for the synthesis of 2,4-disubstituted oxazoles. Although numerous procedures have been
reported for the synthesis of oxazoles, straightforward and expedient approaches to 2,4-disubstituted oxazoles remain scarce. In this
paper, we report a novel synthetic method of 2,4-disubstituted oxazoles 4 using dibutyltin diacylates {Bu2Sn[OC(O)R]2, 2}, which are
directly prepared from carboxylic acids 1 (Scheme 1). To the best of our knowledge, synthetic methodology for the assembly of 2,4-
disubstituted oxazoles starting from carboxylic acids has not been reported thus far.
Scheme 1. Transformation of carboxylic acids 1 into 2,4-disubstituted oxazoles 4 via dibutyltin diacylates 2.
2. Results and discussion
The treatment of a range of carbonyl compounds 5 with diethyl phosphorocyanidate (DEPC)9 in the presence of a catalyst readily
afforded cyanophosphates (6, CPs) under non-aqueous conditions.9 CPs have been extensively utilized as useful synthetic intermediates
in organic synthesis.9 As part of our ongoing studies on the synthetic applications of CPs, we recently demonstrated the efficient
transformation of carbonyl compounds 5 into homologous alkynes 1010 or five-membered unsaturated cyclic compounds 11 under
neutral conditions,11 in which the fragmentation of tetrazolylphosphates 7 derived from CPs 6 generated alkylidene carbenes 9, as
illustrated in Scheme 2.12
R2
TMS
3
O
O
Bu2SnO
N
3
R1
R1
R2
COOH
R1
Bu2Sn O C
2
N
4
toluene
reflux, 24 h
toluene
reflux, 24 h
1
2

2
Tetrahedron
Furthermore, we recently reported a mild and efficient alternative reagent system for tetrazole-synthesis, in which the treatment of
o
various nitriles with TMSN3 and Bu2Sn(OAc)2 at 30 C in benzene for 60 h yielded the corresponding 5-substituted 1H-tetrazoles in
excellent yields (Scheme 3).13 Therefore, we focused our attention on the reaction of this reagent system with CPs.
O
TMS
O
(EtO)2PO
N
TMSN3
cat. Bu2SnO
(EtO)2P CN
(DEPC)
N
N
N
O
O
R1 R2
5
(EtO) P
O
CN
2
R1 R2
cat. LiCN
R2
R1
toluene, reflux
7
6
[1,2]
N
N
N
N
R2
R1
10
11
- 2 N2
- (EtO)2P(O)OTMS
C
R4
R3
R2
R1 R2
R1
[1,5] C＿
H
X
8
9
R1
(R2 = -CH2XCHR3R4)
Scheme 2. Synthesis of homologous alkynes 10 or five-membered unsaturated cyclic compounds 11 from ketones 5 via CPs 6
TMSN3 (2 eq)
N
HN
Bu2Sn(OAc)2 (1 eq)
benzene, 30 oC, 60 h
N
N
C
R
N
R
Scheme 3. Formation of 5-substituted tetrazoles from nitriles using TMSN3/Bu2Sn(OAc)2
Initially, when the reaction of CP 6a with TMSN3 (2 eq) and commercially available Bu2Sn(OAc)2 (2 eq) was performed in refluxing
toluene for 2 h, 4-(4-isobutylphenyl)-2-methyl oxazole (4a) was unexpectedly produced in 27% yield, together with alkyne 3a in trace
amounts (Scheme 4). We consideded that the production of oxazole 4a might be caused by the overreaction of alkyne 3a with
TMSN3/Bu2Sn(OAc)2. Indeed, the reaction of alkyne 3a with TMSN3 (1 eq)/Bu2Sn(OAc)2 (1 eq) in refluxing toluene for 2 h afforded
the oxazole 4a (35%), as shown in Scheme 4. Based on this experiment, we envisaged that alkynes 3 could be transformed directly into
2,4-disubstituted oxazoles 4 employing TMSN3 and dibutyltin diacylate Bu2Sn[OC(O)R)]2.
TMSN3 (1 eq)
Bu2Sn(OAc)2 (1 eq)
TMSN3 (2 eq)
toluene, 2 h reflux, (35%)
CH3
N
O
O
P
O
Bu2Sn(OCCH3)2
(2 eq)
EtO
EtO
O
CN
+
iBu
iBu
toluene
iBu
reflux, 2 h
6a
4a
3a
(trace)
(27%)
Scheme 4. Reaction of CP 6a with TMSN3/Bu2Sn(OAc)2
We therefore investigated the reaction of ethynylbenzene (3b) with TMSN3 (1 eq) in the presence of a catalytic amount of
Bu2Sn(OAc)2 in refluxing toluene for 2 h, which yielded 2-methyl-4-phenyloxazole (4b) in low yields (Table 1, entries 1_2). Increasing
the amount of Bu2Sn(OAc)2 and extending the reaction time led to an improved yield of 4b (60 %) (entry 4). Furthermore, the use of 2
eq of TMSN3 afforded the oxazole 4b in 66% yield (entry 6).
Table 1. Reaction of ethynylbenzene 3b with TMSN3/ Bu2Sn[OC(O)R)]2
TMSN3
Bu2Sn(OAc)2
O
(2)
(4)
Ph
Ph
N
Me
toluene, reflux
3b
4b

3
entry
TMSN3 (eq)
Bu2Sn(OAc)2 (eq)
RTa (h)
yield (%)
trace
14
1
2
3
4
5
1
1
1
1
2
0.1
0.5
1
2
2
2
4
4
35
1
60
1
66
aRT: reaction time
Next, the synthesis of 2,4-diphenyloxazole (4c) was attempted using Bu2Sn[OC(O)Ph]2,14 which was prepared in situ from an
azeotrope of benzoic acid (2 eq) and Bu2SnO (1 eq) in refluxing toluene, implementing a Dean_Stark water separator for 12 h (Table 2).
Subsequently, 3b (1 eq) and TMSN3 (2 eq) were added to the resulting Bu2Sn[OC(O)Ph]2 solution in toluene. The resulting mixture was
further refluxed for 4 h to yield 4c (36%) (entry 1). Furthermore, the extension of both reaction times (RTs) to 24 h significantly
improved the yield of 4c to 97% (entry 4).
Table 2. Reaction of ethynylbenzene 3b with TMSN3/ Bu2Sn[OC(O)Ph]2
3b
Ph
(1 eq)
Bu2SnO
(1 eq.)
TMSN3
(2 eq)
O
O
(4)
(2)
Ph
Ph
2
COOH
Bu2Sn O C
Ph
Ph
N
toluene
reflux
Dean-Stark
toluene
reflux
1c
(2 eq)
4c
2c
entry
RT (h)
12
RT (h)
yield (%)a
1
2
3
4
4
24
2
36
64
24
97
12
20
24
24
aThe yield was based on ethynylbenzene.
Applying the synthetic procedure from above (Table 2, entry 4), various carboxylic acids 1 were transformed into 2,4-disubstituted
oxazoles 4 via reaction of 2 with mono-substituted acetylenes 3 and TMSN3 (Table 3).15 In cases of benzoic acids 1d_h containing para
(p)-functional groups (Me, OMe, Cl, CF3, and NO2) and 2-thiophene-2-carboxylic acid 1i, the corresponding oxazoles 4d_i were readily
obtained in yields of 60_96%. Subsequently, the effect of functional groups at the p-position of ethynyl benzenes 3 was examined. p-
Substituted Me, MeO, and Cl derivatives afforded the respective 2-phenyl-4-(p-substituted phenyl) oxazoles 4j (98%), 4k (81%), and 4l
(76%) in high yields, while p-substituted with electron-withdrawing groups, such as 1-ethynyl-4-nitrobenzene 3m afforded the
corresponding oxazole 4m in only 30% yield. Meanwhile, the present method proved suitable for the the formation of dimethylamino-
containing 2,4-biphenyloxazoles 4n (28%) and 4o (55%). 2-Phenylpropyl-, 2-cyclohexyl-, and 2-adamantyl-4-phenyl oxazoles 4p
(72%), 4q (56%) and 4r (39%), respectively, as well as 4-phenethyl- and 4-cyclohexyl-2-phenyl oxazoles 4s (64%) and 4t (41%) could
be prepared in moderate to high yields. The oxazole 4u (78%) bearing a vinyl function could be also prepared. Furthermore, N-Boc-L-
protected proline (1v) was also converted to the corresponding oxazole 4v (73%, 99% ee)16 with retention of the enantiomeric purity at
the -chiral carbon, as determined by the Mosher method.17 Interestingly, the present method was applicable to the formation of 2,4-
dialkyloxazoles 4w (48%) and 4x (27%), while other currently available synthetic methods3-8 have not been successful in the direct
formation of 2,4-dialkyloxazoles when both R1 and R2 are aliphatic.7b
A plausible mechanism of this reaction is proposed in Scheme 5. The mechanism of the Bu2SnO-catalyzed TMSN3-nitrile
cycloaddition for tetrazole synthesis has been studied in detail.18 By analogy with the reaction, TMSN3 and dibuthyltin diacylate 2 form
a tetracoordinate organotin (IV) intermediate 12, and the subsequent [2+3] cycloaddition with acetylene 3 leads to an intermediate N-
[dibutyl(O-acyl)stannyl]triazole 13. This intermediate undergoes expulsion of stable dibutyltin oxide through an intramolecular retro-
ene process to give N-(acyl)triazole 14. Loss of N2 forms the carbocation complex intermediate 15a or diradical species 15b and
spontaneous cyclization produces the desired 2,4-disubstituted oxazole 4.19
O
TMSN3
R1
OC
N3
Bu
Bu
+
Sn
O
O
R1
Bu2Sn(OC-
)
2
O
N
Bu
12
R1
2
Sn
R2
N
Bu
N
- Bu2SnO
3
R2
retro-ene
13
SnIV
N
R1
R1
O
R1
R1
SnIV
- N

4
Tetrahedron
Scheme 5. A plausible mechanism for the conversion of dibutyltin diacylates 2 to 2,4-disubstituted oxazoles 4.
Conclusions
In this study, we demonstrated that reaction of Bu2Sn[OC(O)R]2 with mono-substituted acetylenes/TMSN3 furnishes a range of 2,4-
disubstituted oxazoles in moderate to excellent yields.15 Bu2Sn[OC(O)R]2 can be readily prepared from various carboxylic acids, which
have not been used as substrates in the synthesis of 2,4-disubstituted oxazoles thus far. Dimethyl amino groups as well as N-Boc-L-
protected proline remain intact. In addition, the present method was successfully applied for the assembly of 2,4-dialkyloxazoles.
Therefore, this methodology is general and applicable to the synthesis of a broad range of 2,4-disubstituted oxazole derivatives, which
can be assessed for biological activity, and used as starting points for the development of biologically active molecules. The further
investigation for the mechanism and applications are in progress in our laboratory.
Acknowledgments
We would like to thank Professor Emeritus T. Shioiri at Nagoya City University for providing encouragement. We thank Ms. M.
Yoshii, Ms. H. Kusuki, and Ms. M. Satake at our lab for their technical supports.
Supplementary Material
Supplementary data to this article can be found online at ----------------------.
References and notes
1.
For recent reviews on oxazoles, see: (a) A. Khartulyari; M.E. Maier, ‘Science of Synthesis Knowledge Updates; K. Ishihara; D.J. Procter; E.
Schaumann, Ed; Thieme:Stuttgart, 2010, Vol. 3, pp. 57_120.
(b) A.M. Azman, R.J. Mullins 'Oxazoles, Benzoxazoles, and Isoxazoles, In Heterocyclic Chemistry in Drug Discovery;' J.J. Li, Ed; Wiely; Hoboken,
2013, pp. 231_281
(c) J. Revuelta, F. Machetti, and S. Cicchi 'Five-Membered Heterocycles: 1, 3-Azoles, In Modern Heterocyclic Chemistry' J. Alvarez-Builla, J. J.
Vaquero, J. Barluenga, Ed. Wiley-VCH; Weinheim, 2011; Vol. 2. pp. 809_923.
2.
For recent reviews on biological activities of oxazoles, see: (a) S. Kakkar, B. Narasimhan, BMC Chemistry 13 (2019) 16.
(b) H.-Z. Zhang, Z.-L. Zhao, C.-H. Zhou, Eur. J. Med. Chem. 144 (2018) 444_492.
3.
4.
R.S. Roy, A.M. Gehring, J.C. Milne, P.J. Belshaw, C.T. Walsh, Nat. Prod. Rep. 16 (1999) 249_263
(a) F. Yokokawa, Y. Hamada, T. Shioiri, Synlett (1992) 153_155.
(b) D. Hernández, G. Vilar, E. Riego, L.M. Cañedo, C. Cuevas, F. Alberico, M. Álvarez, Org. Lett. 9 (2007) 809_811.
T. Morwick, M. Hrapchak, M. DeTuri, S. Campbell, Org. Lett. 4 (2002) 2665_2668.
5.
6.
(a) G.L. Young, S.A. Smith, R.J. K. Taylor, Tetrahedron Lett. 45 (2004) 3797_3801.
(b) A.B. Smith III, K. P. Minbiole, S. Freeze, Synlett (2001) 1739_1742.
(c) S. A. Hermitage, K.S. Cardwell, T. Chapman, J. W. B. Cooke, R. Newton, Org. Process Res. Dev. 5 (2001) 37_44.
(d) Z. Zhao, G. R. Scarlato, R. W. Armstrong, Tetrahedron Lett. 32 (1991) 1609_1612.
(e) N.A. Strotman, H.R. Chobanian, J. He, Y. Guo, P.G. Dormer, C.M. Jones, J.E. Steves, J. Org. Chem. 75 (2010) 1733_1739.
(a) R.D. Connell, M. Tebbe, P. Helquist, Tetrahedron Lett. 32 (1991) 17_20.
7.
(b) M.R. Reddy, G.N. Reddy, U. Mehmood, I.A. Hussein, S.U. Rahman, K. Harrabi, B.V.S. Reddy, Synthesis 47 (2015) 3315_3320.
Z. Cao, H. Lv, Y. Liu, Z. Nie, H. Liu, T. Yang, W. Luo, Q. Liu, C. Guo, Adv. Synth. Catal. 361 (2019) 1632_1640.
For a recent review of DEPC, see: (a) S. Harusawa, T. Shioiri, Tetrahedron 72 (2016) 8125_8200.
(b) S. Harusawa, Chem. Pharm. Bull. 68 (2020) 1_33.
8.
9.
10. H. Yoneyama, M. Numata, K. Uemura, Y. Usami, S. Harusawa, J. Org. Chem. 82 (2017) 5538_5556.
11. (a) H. Yoneyama, K. Uemura, Y. Usami, S. Harusawa, Tetrahedron 73 (2017) 6109_6117.
(b) H. Yoneyama, K. Uemura, Y. Usami, S. Harusawa, Tetrahedron 74 (2018) 2143_2150.
12. For a recent review of generation of alkylidene carbenes from CPs, see: H, Yoneyama, S. Harusawa, Heterocycles 96 (2018) 2037_2078.
13. H. Yoneyama, N. Oka, Y. Usami, S. Harusawa, Tetrahedron Lett. 61 (2020) 151517.
14. S. Abbas, M. Hussain, S. Ali, M. Parvez, A. Raza, A. Haider, J. Iqbal, J. Organomet. Chem. 724 (2013) 255_261.
15. The present method did not give 2,4,5-trisubstituted oxazoles from 1,2-disubstituted acetylenes.
16. (a) S. Nordhoff, S. Bulat, S. Cerezo-Gálvez, O. Hill, B. Hoffmann-Enger, M. López-Canet, C. Rosenbaum, C. Rummey, M. Thiemann, V. G.
Matassa, P. J. Edwards, A. Feurer, Bioorg. Med. Chem. Lett. 19 (2009) 6340_6345.
(b) P.F. Carneiro, B. Gutmann, R.O.M.A. de Souza, C.O. Kappe, ACS Sustainable Chem. Eng. 3 (2015) 3445_3453.
17. G.R. Sullivan, J.A. Dale, H. S. Mosher, J. Org. Chem. 38 (1973) 2143_2147.
18. (a) S. J. Wittenberger, B. G. Donner, J. Org. Chem. 58 (1993) 4139_4141.
(b) D. Cantillo, B. Gutmann, and C. O. Kappe, J. Am. Chem. Soc. 133 (2011) 4465_4475.
19. (a) Addition of radical inhibitors TEMPO or HQ remarkedly decreased the formation of oxazole 4, suggesting the generation of radical species in the
reaction mechanism [See Supplementary Data]. Meanwhile, in case of 4-pentenoic acid 1u, which was likely to undergo radical cyclization, the
regular oxazole 4u (78%) bearing a vinyl group was obtained, as shown in Table 3..

5
(b) A.S. Singh, N. Mishra, D. Kumar, V. K. Tiwari, ACS Omega 2 (2017) 5044-5051.
Table 3. Transformation of carboxylic acids 1 into 2,4-disubstituted oxazoles 4 by the present method.
R2
3
(1 eq)
O
(1 eq)
O
Bu2SnO
TMSN3 (2 eq)
R1
R1
COOH
R2
Bu2Sn OC
R1
2
N
toluene
reflux, 24 h
Dean-Stark
toluene
reflux, 24 h
1
(2 eq)
4a
2
O
O
N
O
Me
OMe
Cl
N
N
4d
(96%)
4e
(82%)
(94%)
4f
(60%)
O
O
N
S
O
N
NO2
CF3
N
4i
(90%)
O
4h
4g
(94%)
O
N
O
N
N
Cl
N
MeO
Me
4l
4j
4k
(76 %)
(98 %)
(81 %)
O
O
N
O
N
N
N
O2N
4m
(30 %)
4n
(28%)
O
4o
4r
(55 %)
O
N
O
N
N
4p
4q
(56 %)
(72 %)
O
(39 %)
O
N
4t
(41 %)
N
4s
(64 %)
(78 %)
O
O
N
Boc
N
4u
4v
(73 %, 99% ee)
N
(S)
O
O
N
N
N
b
4w
(48 %)
4x
Cl
(27 %)
aThe isolated yield was based on alkyne 3. b1 (4 eq), Bu2SnO (2 eq), and TMSN3 (1 eq) were used.
Highlights
1. This article describes a new synthetic method of 2,4-disubstituted oxazoles.

6
Tetrahedron
2. This method uses Bu2Sn[OC(O)R]2, 1-substituted acetylenes, and TMSN3.
3. Bu2Sn[OC(O)R]2 are prepared readily from carboxylic acids.
4. The present method affords a range of 2,4-disubstituted oxazoles in good yields.
Graphical Abstract
A Novel Synthetic Method of 2,4-Disubstituted
Oxazoles Using Carboxylic Acid-
derived Bu2Sn[OC(O)R]2
Hiroki Yoneyama, Naoki Oka, Yoshihide Usami, Shinya Harusawa*
R2
O
Bu2SnO
TMSN3
O
R1
R1
4
2
Bu2Sn OC
COOH
2
toluene
reflux
R2
R1
toluene
reflux
N
The authors declare no conflict of interest/