Zn(OTf)2-catalyzed, microwave-promoted synthesis of 2-substituted 5-methyloxazoles from propargylic amides

Article abstract of DOI:10.1016/j.tetlet.2019.02.011

The versatile conversion of propargylic amides to the respective 2-substituted 5-methyloxazoles was efficiently catalyzed by Zn(OTf)₂ (5 mol%) under microwave irradiation in toluene. The method was applicable to a wide range of aliphatic, aroma

Full text of DOI:10.1016/j.tetlet.2019.02.011

Accepted Manuscript
Zn(OTf)2-catalyzed, microwave-promoted synthesis of 2-substituted 5-methyl-
oxazoles from propargylic amides
Alexander Safrygin, Dmitry Dar'in, Alexei Lukin, Anna Bakholdina, Alexander
Sapegin, Mikhail Krasavin
PII:
S0040-4039(19)30118-2
https://doi.org/10.1016/j.tetlet.2019.02.011
TETL 50605
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 January 2019
30 January 2019
4 February 2019
Please cite this article as: Safrygin, A., Dar'in, D., Lukin, A., Bakholdina, A., Sapegin, A., Krasavin, M.,
Zn(OTf)2-catalyzed, microwave-promoted synthesis of 2-substituted 5-methyloxazoles from propargylic amides,
Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.02.011
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Zn(OTf)2-catalyzed, microwave-promoted synthesis of 2-substituted
5-methyloxazoles from propargylic amides
Alexander Safrygin, Dmitry Dar’in, Alexei Lukin, Anna Bakholdina, Alexander Sapegin and
Mikhail Krasavin*

Zn(OTf)2-catalyzed, microwave-promoted synthesis of 2-substituted
5-methyloxazoles from propargylic amides
Alexander Safrygin,a Dmitry Dar’in,a Alexei Lukin,b Anna Bakholdina,b Alexander Sapegina and
Mikhail Krasavin*,a
aSaint Petersburg State University, Saint Petersburg, 199034 Russian Federation
bLomonosov Institute of Fine Chemical Technologies, MIREA Russian Technological
University, Moscow 119571 Russian Federation
* Corresponding author: Laboratory of Chemical Pharmacology, Institute of Chemistry, Saint
Petersburg State University, 26 Universitetskyi prospekt, Peterhof 198504 Russian Federation
e-mail: m.krasavin@spbu.ru (M. Krasavin)
Abstract: The versatile conversion of propargylic amides to the respective 2-substituted 5-
methyloxazoles was efficiently catalyzed by Zn(OTf)2 (5 mol%) under microwave irradiation in
toluene. The method was applicable to a wide range of aliphatic, aromatic and heteroaromatic
propargylic amides and thus represents a useful method which is complementary to the existing
metal-catalyzed protocols, considering the ready availability of Zn(OTf)2.
Keywords: propargylic amides; cyclization; Zn(II) triflate; oxazoles.
Recently, we developed a novel approach to 1,2,4-trisubstituted imidazoles 2 via a
Zn(OTf)2-catalyzed hydroamination-cyclization strategy employing tertiary propargylic amides 1
as well as ammonium chloride as a convenient source of ammonia.1 This method was realized
under conventional heating in anisole and provided a convenient entry into medicinally
important imidazoles which was complementary to the related approach (also involving
Zn(OTf)2 catalysis) based on secondary propargylic amides and primary amines reported earlier
by Beller and co-workers.2 While investigating the scope of our procedure, we attempted to
cyclize secondary amide 1a with ammonium chloride in anticipation of forming product 2a.
Contrary to our expectations, no incorporation of ammonia took place and oxazole compound 3a
was isolated in a respectable 52% yield (Scheme 1). The facility with which the latter
tranformation ocurred was rather notable. Secondary propargylic amides3 have been reported to
cyclize into oxazoles under the influence of Ce(III),4 Fe(III),5 Cu(I),6 Au(III),7 Hg(II)8 salts,
silica9 or sodium hydride.10 Also, two relevant cases of using Zn(OTf)2 as part of a dual
Zn(II)/Sc(III) catalyst system11 or in reactions with allylic alcohols, also involving the formation

of an oxazole ring,12 have been reported. Considering this, we were surprised to find that such
cyclizations have not been investigated under catalysis by the readily available Zn(OTf)2 alone,
which is normally part of the standard Lewis acid catalyst toolkit in most synthetic organic
chemistry laboratories. Therefore, we sought to find optimal conditions for the tranformation
13 and investigate its scope for a wider range of secondary propargylic amides.
Scheme 1. Results of the investigated (a) and failed (b) Zn(OTf)2-catalyzed imidazole synthesis.
The similarity of the reaction conditions which led to the formation of 3a (vide supra) to
those reported by Beller and co-workers2 and the convenience of using lower-boiling toluene
instead of anisole prompted us to investigate this reaction under microwave irradiation. To our
delight, simply by varying the reaction temperature and time, we were able to increase the yield
of 3a to 84% (Table 1).
Table 1. Optimization of 1a3a conversion with respect to temperature and reaction time under
microwave irradiation.
Isolated
Time
Entry T (ºC)
yield 3a
(min)
(%)
1
2
110
130
60
60
40
64

3
4
5
6
7
8
150
170
150
150
150
150
60
60
15
30
45
90
70
70
77
84
73
64
These optimized conditions (MW, toluene, 150 ºC, 30 min) were subsequently used to
investigate the scope of the Zn(OTf)2-catalyzed preparation of oxazoles 3. As can be seen from
Table 2, the transformation could be realized for a wide range of aromatic, heteroaromatic, and
aliphatic acyl substituents of the propargylamino portion of substrates 1. The yields were
generally higher for aromatic substituents than for aliphatic groups (cf. entries 3, 7-8) as well as
the pyridine derivative (Entry 26).
Table 2. Scope of microwave-promoted, Zn(OTf)2-catalyzed preparation of oxazoles 3a-z.
Yield
3(%)
84
Yield
3(%)
89
Entry Product 3
R
Entry Product 3
R
1
2
3
Ph(CH2)2
14
15
16
4-MeOC6H4
3-ClC6H4
3a
3b
3c
3n
3o
3p
81
56
91
86
i-Bu
3-MeOC6H4
4
5
6
7
8
67
77
74
57a
58
17
18
19
20
21
2,4-diClC6H3 94
3d
3e
3f
3q
3r
3s
3t
Bn
2-MeOC6H4
1-Naphthyl
4-PhC6H4
77
93
91
67
75
PhOCH2
3g
3h
c-Hexyl
3u
9
Ph
78
83
22
23
3i
3j
3v
10
4-FC6H4
83
3w

11
12
13
4-ClC6H4
88
95
86
24
25
26
87
91
57
3k
3l
3x
3y
3z
4-O2NC6H4
3-pyridyl
3m
a Reaction time – 2 hours.
The mechanism for the formation of 3 is presumably similar to that investigated by
Hashmi and co-workers for a similar, Au(III)-catalyzed reaction.7a The propargylic triple bond
becomes activated by Zn(II) toward 5-exo-dig cyclization with the formation of olefinic zinc
species 4 from which the catalyst is regenerated to give 5. The latter, described in numerous
literature reports as the end-product of propargylic amide cyclization13 or a reactive intermediate
capable of being intercepted by olefinic substrates,12 is likely to undergo double bond
isomerization to give the observed oxazole 3 (Scheme 2).
Scheme 2. Proposed mechanism for the transformation 13.
Aiming to test for the possible participation of an internally placed primary amino
functionality in the formation of imidazoles 2, we synthesized substrate 7 via the Mitsunobu
coupling of methyl salicylate with Boc-protected 2-aminoethanol followed by subsequent ester
hydrolysis and CDI-promoted amidation of resulting carboxylic acid 6. While secondary
propargylic amide 7 itself can be transformed, in moderate yield, to the respective oxazole 8, its
deprotected version (9) underwent essentially the same transformation into oxazole 10 and no

tricyclic product 11 (which can be anticipated if the internal aminoalkyl side chain participated
in the formation of the imidazole nucleus) was formed (Scheme 3).
Scheme 3. Zn(OTf)2-catalyzed transformations of substrates containing Boc-protected and
unprotected aminoalkyl side chains.
In conclusion, we have described a general and high-yielding protocol for the Zn(OTf)2-
catalyzed transformation of secondary propargylic amides into oxazoles under microwave
irradiation. This method is complementary to the existing protocols involving other, often much
less available and more expensive catalysts and employs a common Lewis acid which is
normally a part of standard organic chemist’s toolbox of reagents.
Acknowledgements
This research was supported by the Russian Science Foundation (grant no. 17-73-20185).
Alexander Safrygin is grateful to Saint Petersburg State University for providing his postdoctoral
fellowship. We thank the Cryogenic Department and the Research Centre for Magnetic
Resonance, the Center for Chemical Analysis and Materials Research of Saint Petersburg State
University Research Park for obtaining the analytical data.
References and notes
1. Safrygin, A.; Krivosheyeva, E.; Dar'in, D.; Krasavin, M. Synthesis 2018, 50, 3048.
2. (a) Pews-Davtyan, A.; Beller, M. Chem. Commun. 2011, 47, 2152; (b) Pews-Davtyan, A.;
Tillack, A.; Schmole, A.-C.; Ortinau, S.; Frech, M. J.; Rolfs, A.; Beller, M. Org. Biomol. Chem.
2010, 8, 1149.
3. Hu, Y.; Xin, X.; Wan, B. Tetrahedron Lett. 2015, 56, 32.

4. Bartoli, G.; Cimarelli, C.; Cipolletti, R.; Diomedi, S.; Giovannini, R.; Mari, M.; Marsili, L.;
Marcantoni, E. Eur. J. Org. Chem. 2012, 3, 630.
5. Senadi, G. C.; Hu, W-P.; Hsiao, J-S.; Kishore, J.; Chen, C-Y.; Wang, J-J. Org. Lett. 2012,
14, 4478.
6. Hashmi, S.; Schuster, A.; Litters, S.; Rominger, F.; Pernpointner, M. Chem. Eur. J. 2011,
17, 5661.
7. (a) A. S. K. Hashmi, J.P. Weyrauch, W. Frey, J.W. Bats. Org. Lett. 2004, 6, 4391–4394; (b)
D. Aguilar, M. Contel, R. Navarro, T. Soler, E.P. Urriolabeitia. J. Organometal. Chem. 2009,
694, 486; (c) C.L. Paradise, P.R. Sarkar, M. Razzaka, J.K. De Brabander. Org. Biomol. Chem.
2011, 9, 4017; (d) M. Üçüncü, E. Karakuşa, M. Emrullahoğlu. New J. Chem. 2015, 39, 8337.
8. H. Lee, H.-J. Kim. Tetrahedron Lett. 2011, 52, 4775.
9. P. Wipf, Y. Aoyama, T. E. Benedum. Org. Lett. 2004, 6, 3593.
10. (a) H. Araki, T. Katoh, M. Inoue. Synlett 2006, 555; (b) B. M. Nilsson, U. Hacksell. J.
Heterocycl. Chem. 1989, 26, 269-275.
11. B. Wang, Y. Chen, L. Zhou, J. Wang, Z. Xu. Org. Biomol. Chem. 2016, 14, 826.
12. Wang, B.; Chen. Y.; Zhou, L.; Wang, J.; Tung, C.-H.; Xu, Z. J. Org. Chem. 2015, 80,
12718.
13. (a) X.-Z. Shu, S. C. Nguyen, Y. He, F. Oba, Q. Zhang, C. Canlas, G. A. Somorjai, A. P.
Alivisatos, F. D. Toste. J. Am. Chem. Soc. 2015, 137, 7083; (b) M. Harmata, C. Huang. Synlett
2008, 1399; (c) X. Meng, S. Kim. Org. Biomol. Chem. 2011, 9, 4429-4431; (d) M. R. Bhandari,
M. Yousufuddin, C. J. Lovely. Org. Lett. 2011, 13, 1382; (e) A. S. K. Hashmi, Y. Yu, F.
Rominger. Organometallics 2012, 31, 895; (f) A. S. K. Hashmi, A. M. Schuster, F. Rominger.
Angew. Chem. Ind. Ed. 2009, 48, 8247; (g) X. Zeng, S. Liu, B. Xu. RSC Adv. 2016, 6, 77830.

Highlights
Cyclization of secondary propargylic amides is a popular way of making 1,3-oxazoles
Zn(II) triflate has been found to efficiently catalyze this reaction
This Zn(II) salt is commonly available in synthetic organic chemistry labs
The reaction displayed a wide scope with regard to the acyl component