Synthesis of 2,5-diaryloxazoles through rhodium-catalyzed annulation of triazoles and aldehydes

Article abstract of DOI:10.1039/d0ra03966g

An efficient synthesis of a variety of 2,5-diaryloxazole derivatives via a rhodium-catalyzed annulation of triazoles and aldehydes is achieved. Various oxazole derivatives could be obtained in good to excellent yields. A concise synthesis of antimycobaterial natural products balsoxin and texamine has been achieved using this method. This journal is

Full text of DOI:10.1039/d0ra03966g

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Synthesis of 2,5-diaryloxazoles through rhodium-
catalyzed annulation of triazoles and aldehydes†
Cite this: RSC Adv., 2020, 10, 24795
*
Jian Li,
Shang-Rong Zhu, Yue Xu, Xue-Chen Lu, Zheng-Bing Wang, Li Liu
*
and De-feng Xu
Received 2nd May 2020
Accepted 11th June 2020
An efficient synthesis of a variety of 2,5-diaryloxazole derivatives via a rhodium-catalyzed annulation of
triazoles and aldehydes is achieved. Various oxazole derivatives could be obtained in good to excellent
yields. A concise synthesis of antimycobaterial natural products balsoxin and texamine has been
achieved using this method.
DOI: 10.1039/d0ra03966g
rsc.li/rsc-advances
Oxazoles, an important class of heterocycles, are present in
N-Sulfonyl-1,2,3-triazoles have recently emerged as structural
a wide range of natural products and biologically active mole- motifs that are studied for synthesizing a variety of biologically
cules,1 as exemplied by salinazinone A,2 peptide alkaloid active heterocycles,15 including pyrrole,16 imidazole,17 oxazoline,18
(ꢀ)-muscoride A,3 and antidiabetic agent AD-5061.4 In partic- pyrroloindoline19 and others.20 In these transformations, Rh(II)-
ular, 2,5-diaryl substituted oxazoles are found in pharmaco- azavinylcarbene (Rh-AVC) was considered as the key intermediate,
logically active molecules such as antipancreatic cancer agent which derived from N-sulfonyl-1,2,3-triazoles under the treatment
PC-046,5 antimycobaterial natural product texamine6 and bal- with rhodium(II) catalysts through denitrogenative reaction.21 Due
soxin.7 Given this signicant importance, several methodolo- to its dipolar nature, Rh-AVC could serve as an aza-[3C]-synthons
gies have been developed to access functionalized oxazole in various [3 + 2] cycloaddition reactions. So far, a wide range of
skeletons.8 Some groups reported a metal-catalyzed synthetic unsaturated chemical bonds, including aldehyde, nitrile, have
method for 2,5-diaryl substituted oxazoles through the reaction been well explored in the [3 + 2] cycloadditions.22 2008, Fokin and
of alkynes and arylnitrile or aryl carbonyl azides or N-piv- co-workers exploited the reactivity of Rh-AVC to achieve imidaz-
aloyloxyamides (Scheme 1(a)).9 In 2012, a copper-catalyzed oles in good to excellent yields with N-sulfonyl 1,2,3-triazoles and
oxidative dehydrogenative annulation method of alkynes and nitriles.17 2013, they reported that Rh-AVC react with aldehydes to
amines was developed by Jiao's group (Scheme 1(b)).10 Wang's give 3-sulfonyl-4-oxazolines through an intramolecular cyclization
group demonstrated a TBHP/I2-mediated tandem oxidative (Scheme 2(a)).18 We were curious what would happen if o-cyano-
cyclization with 2-amino-1-arylethan-1-one and arylaldehyde to benzaldehyde, containing aldehyde group and cyano group
prepare 2,5-diaryl substituted oxazoles (Scheme 1(c)).11 In together, react with 1,2,3-triazoles?
A variety of nitrogen-
addition, a-bromoketones and arylamine or arlyamides deriv- containing heterocycles,23 such as 3-amino-substituted iso-
atives were utilized by Moses,12 Zhang13 and Cho14 group for the indolinones (Scheme 2(b1)),23a 3-(2-oxopropyl)-2-arylisoindolinone
synthesis of substituted oxazoles (Scheme 1(d)). Despite (Scheme 2(b2)),23b 3-aryl isoindolinones (Scheme 2(b3))23c and
signicant progress in this eld, several limitation including benzo[4,5]imidazo[2,1-a]isoquinolines (Scheme 2(b4)),23d could be
low efficiency of activation, tedious side reactions and the lack constructed with o-cyanobenzaldehyde. As a continuation of our
of easy access to structurally diversity, have hampered their
further application. Thus, the development of efficient and
economy strategy for the synthesis of 2,5-diaryl substituted
oxazoles has been both a challenge and a focus of synthetic
chemistry. Herein, we report an approach that N-sulfonyl 1,2,3-
triazoles react with aldehydes to give 2,5-diaryloxazoles via
a cyclization.
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, School of
Pharmaceutical Engineering & Life Sciences, Changzhou University, Changzhou,
213164, China. E-mail: lijianchem@cczu.edu.cn; markxu@cczu.edu.cn
† Electronic supplementary information (ESI) available: Synthetic details,
additional spectroscopic data, and characterization of the new compounds.
CCDC 1960749. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/d0ra03966g
Scheme
oxazoles.
1
Selected synthetic strategies for 2,5-disubstituted
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 24795–24799 | 24795

View Article Online
RSC Advances
Paper
Table 1 Optimization of the reaction conditionsa
Entry Catalyst
Solvent
Temperature (ꢁC) Time (h) Yieldb (%)
1
2
3
4
5
6
7
8
Rh2(OAc)4 CHCl3
Rh2(OAc)4 CHCl3
Rh2(OAc)4 CHCl3
Rh2(OAc)4 CHCl3
rt
80
12
12
12
12
12
12
12
12
12
12
12
12
12
12
14
24
79
47
21
28
—
52
11
—
120
150
120
120
120
120
120
120
120
120
120
Rh2(esp)2
Rh2(otc)4
CHCl3
CHCl3
Rh(Ph3P)3Cl CHCl3
Rh2(OAc)4 DCE
Rh2(OAc)4 Toluene
Rh2(OAc)4 EtOH
Rh2(OAc)4 CH3CN
Rh2(OAc)4 DMF
Rh2(OAc)4 THF
9
10
11
12
13
14
Scheme 2 Reactions between N-sulfonyl 1,2,3-triazoles and nitriles/
aldehydes.
7
—
—
Trace
Rh2(OAc)4 1,4-Dioxane 120
a
research on cyano activation for the synthesis of nitrogen-
containing heterocycles,24 we envisioned that the [3 + 2] cycload-
ditions between N-sulfonyl 1,2,3-triazoles and o-cyanobenzalde-
hyde would afford a novel approach to the synthesis of nitrogen-
containing heterocyclic compounds (Scheme 2(c)).
Reaction condition: 1a (0.6 mmol), 2a (0.3 mmol) in solvent (2.0 mL),
b
1 mol% of catalyst, 12 h. Isolated yield.
nature of the substituents on the aryl ring as shown by the
reactions of o-cyanobenzaldehyde 2a with triazoles bearing
electron-donating substituents, which gave higher yields (3e
To test the hypothesis, we started the investigation by using
4-phenyl-1-tosyl-1H-1,2,3-triazole 1a and o-cyanobenzaldehyde
2a as model substrates in the presence of 1 mol% of Rh2(OAc)4
in CHCl3 at room temperature. Interestingly, we did not nd the
corresponding oxazoline product reported by Fokin's group.
Instead, the oxazole 3a, which is the product of the sulnic acid
elimination was isolated in 14% yield aer 12 hours, and the
starting materials 2a was recovered in 68% yield. Due to the
importance of oxazoles, we decided to optimize the reaction
conditions with oxazoles as the target product. Increasing the
temperature is benecial to improve the yields of the products,
the reactions afforded the desired product 3a in 24% yield at
Table 2 1,2,3-Triazole and o-cyanobenzaldehyde scopea,b
ꢁ
ꢁ
80 C and 79% yield at 120 C (Table 1, entries 2, 3). From the
experiment we could conclude that the product was easier to
obtain at higher temperature, it seems that high temperatures
help to the elimination of sulnic acid. Other rhodium catalysts
were tested, but no better results were obtained for this trans-
formation (Table 1, entries 5–7). For Rh2(OAc)4 (1 mol%), the
yields of the desired product 3a in various solvents were as
follows: DCE (52%), toluene (11%) and CH3CN (7%), none or
trace of product was found in other solvents (entries 8–14).
With an optimized set of reaction conditions in hand, we
assessed the scope of these new reactions with various 4-phenyl-
1-tosyl-1H-1,2,3-triazole 1 and o-cyanobenzaldehyde 2; the
results are summarized in Table 2. As shown in Table 2, our
cycloaddition reaction turned out to be widely applicable
regardless of the electronic and steric properties of the aryl ring
of the substrates 1. For 1,2,3-triazole substrates bearing 4-
substituted 4-phenyl-1-tosyl-1H-1,2,3-triazoles (1a–1h; R1 ¼ 4-
XC6H4; X ¼ F, Cl, Br, OMe, n-Bu, CO2Me, and Ph), rhodium-
catalyzed reactions gave desired 3a–3h in 79–88% yields. The
reaction was found to be marginally affected by the electronic
a
Reaction condition: 1 (0.6 mmol), 2 (0.3 mmol) in CHCl3 (2.0 mL),
b
120 ꢁC, 12 h. Isolated yield.
24796 | RSC Adv., 2020, 10, 24795–24799
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
Table 3 Aldehyde scopea,b
Scheme 3 One-step synthesis of natural products.
a
Reaction condition: 1a (0.6 mmol), 2 (0.3 mmol) in CHCl3 (2.0 mL),
b
120 ꢁC, 12 h. Isolated yield.
and 3f). We tested the reaction with 2-substituted and 3-
substituted 4-phenyl-1-tosyl-1H-1,2,3-triazoles, and the corre-
sponding products 3i–3l were obtained in 79–85% yields. For
disubstituted analogue 1m, the corresponding product 3m was
produced in 52% yield. We also performed the reactions with
reactants with 4-(phenylethynyl)-1-tosyl-1H-1,2,3-triazole 1n,
which afforded alkynyl-containing compound 3n in 72% yield,
this indicated that alkynyl group could be tolerated in the
reaction conditions. The reaction was further compatible with
heterocyclic substituted triazole (1o), yielding the desired thio-
phen product 3o in 86% yield.
We next assessed the scope of o-cyanobenzaldehyde 2. To our
delight, with a series of substituents at different position of the
o-cyanobenzaldehyde, including 4-F, 5-F, 5-Cl, 5-Br, 5-Ph and 5-
OPh, the corresponding products 3p–3x were formed in 75–91%
yields (Table 2). The molecular structure of compound 3x was
conrmed by X-ray diffraction.
Scheme 4 Possible mechanistic pathways.
butyl group (4c), methoxy group (4d), methyl group (4i, 4k), and
cyano group (3, 4f). Singly ortho-substitued (2ah, 2al) or doubly
ortho-substitued (2ai, 2ak, 2am) aldehydes lead to the corre-
sponding products smoothly. Complex substrate 3,30-diuoro-
20-formyl-[1,10-biphenyl]-2-carbonitrile 2am was prepared for
this annulation, which proved to be applicable substrate and
afforded compound 4m in 55% yield. The reaction was further
compatible with 2-oxo-2-phenylacetaldehyde 2an, yielding the
desired product 4n in 86%. Several cases of aliphatic aldehydes,
such as butyraldehyde, isopropanal, phenylacetaldehyde were
also investigated, but none of the corresponding products were
found under the standard conditions.
As cyano group was oen employed as a ligand in transition
metal-catalyzed reactions, we wondered whether the cyano
group in o-cyanobenzaldehyde participated in the coordination
with the rhodium metal in this reaction to promote the reac-
tion. We chose unsubstituted benzaldehyde 2aa as a substrate
to react with 4-phenyl-1-tosyl-1H-1,2,3-triazole 1a under the
same conditions. It was surprising that the product 2,5-diphe-
nyloxazole 4a was collected in 76% yield. To demonstrate the
generality of the present rhodium-catalyzed reactions of benz-
aldehydes, a series of aromatic aldehydes were investigated
under the optimized reaction conditions, the results are
summarized in Table 3.
For the scope with respect to the aromatic aldehyde
substrate, the corresponding 2,5-disubstituted oxazole products
were obtained in good yields in all cases. In terms of electronic
effect, both electron-rich substrates (2ab–2ad, 2ag, and 2ai–2ak)
and electron-decient substrate (2af) could be tolerated (yield
from 62% to 88%, Table 3), including isopropyl group (4b), t-
To demonstrate the synthetic utility of this protocol devel-
oped herein, we carried out the reaction with 4-(3,4-dimethox-
yphenyl)-1-tosyl-1H-1,2,3-triazole 1aa and benzaldehyde 2aa in
CHCl3 for the preparation of natural product balsoxin
(Scheme 3). Gratifyingly, the desired product balsoxin could be
obtained in 85% yield in one step. With the same strategy,
natural product texamine, could be produced in 79% yield in 12
hours.
With literature precedents in hand, a reaction pathway is
proposed in Scheme 4. 1,2,3-Triazole 1, upon reaction with
Rh2(OAc)4, extrudes dinitrogen and forms Rh(II)-azavinyl car-
bene species A. Interaction of the carbonyl group with the car-
bene center leads to the formation of ylide B, which undergoes
cyclization, leading to the formation of oxazoline C. Finally,
removal of the p-toluenesulfonic acid followed afforded the
desired oxazole 3.
In conclusion, a rhodium-catalyzed annulation of 1,2,3-tri-
azoles and aldehydes has been developed. The developed
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 24795–24799 | 24797

View Article Online
RSC Advances
Paper
methodology provides straightforward access to valuable 2,5-
diaryl substituted oxazole derivatives. Applying this strategy,
a concise synthesis of natural products balsoxin and texamine
have been accomplished in good yields in one step. Further
studies to explore the possibility for synthesis of various oxa-
zoles are currently underway in our laboratory.
R. R. Donthiri, M. Dinda and S. Adimurthy, RSC Adv., 2015,
5, 66718; (e) H. Peng, N. G. Akhmedov, Y.-F. Liang, N. Jiao
and X. Shi, J. Am. Chem. Soc., 2015, 137, 8912; (f) L. Chen,
H. Li, P. Li and L. Wang, Org. Lett., 2016, 18, 3646; (g)
T. Soeta, A. Matsumoto, Y. Sakata and Y. Ukaji, J. Org.
Chem., 2017, 82, 4930; (h) X. Duan, K. Yang, J. Lu, X. Kong,
N. Liu and J. Ma, Org. Lett., 2017, 19, 3370; (i) R. J. Reddy,
M. P. Ball-Jones and P. W. Davies, Angew. Chem., Int. Ed.,
2017, 56, 13310; (j) M. Mei, D. Anand and L. Zhou, Org.
Lett., 2019, 21, 3548.
Conflicts of interest
There are no conicts to declare.
9 (a) W. He, C. Li and L. Zhang, J. Am. Chem. Soc., 2011, 133,
´
´
8482; (b) . Cano, E. Alvarez, M. C. Nicasio and P. J. Perez, J.
Acknowledgements
´
Am. Chem. Soc., 2011, 133, 191; (c) E. Haldon, M. Besora,
`
I. Cano, X. C. Cambeiro, M. A. Pericas, F. Maseras,
We thank Jiangsu Key Laboratory of Advanced Catalytic Mate-
rials and Technology (BM2012110), Advanced Catalysis and
Green Manufacturing Collaborative Innovation Center in
Changzhou University.
´
M. C. Nicasio and P. J. Perez, Chem.–Eur. J., 2014, 20, 3463;
(d) X. Yu, K. Chen, Q. Wang, W. Zhang and J. Zhu, Chem.
Commun., 2018, 54, 1197.
10 Z. Xu, C. Zhang and N. Jiao, Angew. Chem., Int. Ed., 2012, 51,
11367.
11 C. Wan, L. Gao, Q. Wang, J. Zhang and Z. Wang, Org. Lett.,
2010, 12, 3902.
Notes and references
1 (a) P. Wipf, Chem. Rev., 1995, 95, 2115–2134; (b) Oxazoles:
Synthesis, Reactions and Spectroscopy, Part B, ed. D. C. 12 D. J. Ritson, C. Spiteri and J. E. Moses, J. Org. Chem., 2011, 76,
Palmer, John Wiley Sons, Hoboken, NJ, 2004; (c) 3519.
K. C. Nicolaou, J. Hao, M. V. Reddy, P. B. Rao, G. Rassias, 13 W.-C. Gao, R.-L. Wang and C. Zhang, Org. Biomol. Chem.,
S. A. Snyder, X. Huang, D. Y. K. Chen, W. E. Brenzovich, 2013, 11, 7123.
N. Giuseppone, P. Giannakakou and A. O'Brate, J. Am. 14 T. Chatterjee, J. Y. Cho and E. J. Cho, J. Org. Chem., 2016, 81,
Chem. Soc., 2004, 126, 12897; (d) Z. Jin, Nat. Prod. Rep.,
6995.
2011, 28, 1143; (e) J. Zhang and M. A. Ciufolini, Org. Lett., 15 For leading reviews, see: (a) H. C. Kolb, M. G. Finn and
&
2011, 13, 390; (f) S. Imai, H. Kikui, K. Moriyama and
H. Togo, Tetrahedron, 2015, 71, 5267; (g) M. A. Chiacchio,
G. Lanza, U. Chiacchio, S. V. Giofre, R. Romeo, D. Iannazzo
and L. Legnani, Curr. Med. Chem., 2019, 41, 7337.
2 (a) M. C. Kim, J. H. Lee, B. Shin, L. Subedi, J. W. Cha,
J.-S. Park, D.-C. Oh, S. Y. Kim and H. C. Kwon, Org. Lett.,
2015, 17, 5024; (b) P. Fu, S. La and J. B. MacMillan, J. Nat.
Prod., 2016, 79, 455.
3 (a) A. Nagatsu, H. Kajitani and J. Sakakibara, Tetrahedron
Lett., 1995, 36, 4097; (b) A. Mattila, R. M. Andsten,
M. Jumppanen, M. Assante, J. Jokela, M. Wahlsten,
K. M. Mikula, C. Sigindere, D. H. Kwak, M. Gugger,
H. Koskela, K. Sivonen, X. Y. Liu, J. Yli-Kauhaluoma,
H. Iwai and D. P. Fewer, ACS Chem. Biol., 2019, 12, 2683.
K. B. Sharpless, Angew. Chem., Int. Ed., 2001, 40, 2004; (b)
F. Amblard, J. H. Cho and R. F. Schinazi, Chem. Rev., 2009,
109, 4207; (c) B. Chattopadhyay and V. Gevorgyan, Angew.
Chem., 2012, 124, 886; Angew. Chem., Int. Ed., 2012, 51,
862; (d) A. V. Gulevich and V. Gevorgyan, Angew. Chem.,
Int. Ed., 2013, 52, 1371; (e) P. Thirumurugan, D. Matosiuk
and K. Jozwiak, Chem. Rev., 2013, 113, 4905.
16 (a) T. Miura, M. Yamauchi and M. Murakami, Chem.
Commun., 2009, 45, 1470; (b) B. Chattopadhyay and
V. Gevorgyan, Org. Lett., 2011, 13, 3746; (c) Y. Shi and
V. Gevorgyan, Org. Lett., 2013, 15, 5394; (d) T. Miura,
K. Hiraga, T. Biyajima, T. Nakamuro and M. Murakami,
Org. Lett., 2013, 15, 3298; (e) J. S. Alford, J. E. Spangler and
H. M. L. Davies, J. Am. Chem. Soc., 2013, 135, 11712.
4 Y. Momose, T. Maekawa, T. Yamano, M. Kawada, H. Odaka, 17 T. Horneff, S. Chuprakov, N. Chernyak, V. Gevorgyan and
H. Ikeda and T. Sohda, J. Med. Chem., 2002, 45, 1518.
V. V. Fokin, J. Am. Chem. Soc., 2008, 130, 14972.
5 A. Y. Shaw, M. C. Henderson, G. Flynn, B. Samulitis, H. Han, 18 M. Zibinsky and V. V. Fokin, Angew. Chem., 2013, 125, 1547;
S. P. Stratton, H.-H. S. Chow, L. H. Hurley and R. T. Dorr, J.
Pharmacol. Exp. Ther., 2009, 331, 636.
Angew. Chem., Int. Ed., 2013, 52, 1507.
19 J. E. Spangler and H. M. L. Davies, J. Am. Chem. Soc., 2013,
135, 6802.
´
´
6 X. A. Domınguez, G. D. L. Fuente, A. G. Gonzalez, M. Reina
´
and I. Timyan, Heterocycles, 1988, 27, 35.
20 (a) T. Miura, T. Tanaka, K. Hiraga, S. G. Stewart and
M. Murakami, J. Am. Chem. Soc., 2013, 135, 13652; (b)
S. Chuprakov, S. W. Kwok and V. V. Fokin, J. Am. Chem.
Soc., 2013, 135, 4652; (c) T. Miura, Y. Funakoshi and
M. Murakami, J. Am. Chem. Soc., 2014, 136, 2272.
7 B. Burke, H. Parkins and A. M. Talbot, Heterocycles, 1979, 12,
349.
8 For reviews on the synthesis of oxazoles, see: (a) I. J. Turchi
and M. J. S. Dewar, Chem. Rev., 1975, 75, 389; (b)
S. Bresciani and N. C. O. Tomkinson, Heterocycles, 2014, 21 (a) H. M. L. Davies and J. S. Alford, Chem. Soc. Rev., 2014, 43,
89, 2479; (c) A. Ibrar, I. Khan, N. Abbas, U. Farooq and
A. Khan, RSC Adv., 2016, 6, 93016For recently selected
examples on the synthesis of oxazoles, see: (d) S. Samanta,
5151; (b) P. Anbarasan, D. Yadagiri and S. Rajasekar,
Synthesis, 2014, 46, 3004; (c) Y. Jiang, R. Sun, X.-Y. Tang
and M. Shi, Chem.–Eur. J., 2016, 22, 17910.
24798 | RSC Adv., 2020, 10, 24795–24799
This journal is © The Royal Society of Chemistry 2020

View Article Online
Paper
RSC Advances
22 (a) E. E. Schultz and R. Sarpong, J. Am. Chem. Soc., 2013, 135,
4696; (b) C. Kim, S. Park, D. Eom, B. Seo and P. H. Lee, Org.
Lett., 2014, 16, 1900; (c) R.-Q. Ran, J. He, S.-D. Xiu,
K.-B. Wang and C.-Y. Li, Org. Lett., 2014, 16, 3704.
23 (a) A. Capobianco, A. D. Mola, V. Intintoli, A. Massa,
V. Capaccio, L. Roiser, M. Waser and L. Palombi, RSC Adv.,
2016, 6, 31861; (b) L. Liu, S.-H. Bai, Y. Li, X.-D. Ding,
Q. Liu and J. Li, Adv. Synth. Catal., 2018, 360, 1617; (c)
J. Hu, H.-L. Qin, W. Xu, J. Li, F. Zhang and H. Zheng,
Chem. Commun., 2014, 50, 15780; (d) A. L. Bagdasarian,
H. H. Nguyen, T. A. Palazzo, J. C. Fettinger, M. J. Haddadin
and M. J. Kurth, J. Org. Chem., 2016, 81, 3924.
24 (a) L. Liu, S.-H. Bai, Y. Li, L.-X. Wang, Y. Hu, H.-L. Sung and
J. Li, J. Org. Chem., 2017, 82, 11084; (b) L. Liu, J. Qiang,
S.-H. Bai, H.-L. Sung, C.-B. Miao and J. Li, Adv. Synth.
Catal., 2017, 359, 1283; (c) J. Li, S.-H. Bai, Y. Li, Z.-B. Wang,
X. Huo and L. Liu, J. Org. Chem., 2018, 83, 8780.
This journal is © The Royal Society of Chemistry 2020
RSC Adv., 2020, 10, 24795–24799 | 24799