A Mild Synthesis of Bicyclic Alkoxyoxazolium Salts from Proline and Pipecolic Acid Derivatives

Article abstract of DOI:10.1002/ejoc.201900985

A regio- and chemoselective preparation of bicyclic alkoxyoxazolium salts from amide derivatives of proline and pipecolic acid by electrophilic amide activation is reported. Mechanistic NMR experiments suggest an unusual role for the base and highlight the effect of substitution pattern of the substrates.

Full text of DOI:10.1002/ejoc.201900985

DOI: 10.1002/ejoc.201900985
Communication
Heterocycle Synthesis
A Mild Synthesis of Bicyclic Alkoxyoxazolium Salts from Proline
and Pipecolic Acid Derivatives
Eleonora Spinozzi,[a][‡] Adriano Bauer,[a][‡] and Nuno Maulide*[a]
Abstract: A regio- and chemoselective preparation of bicyclic Mechanistic NMR experiments suggest an unusual role for the
alkoxyoxazolium salts from amide derivatives of proline and base and highlight the effect of substitution pattern of the sub-
pipecolic acid by electrophilic amide activation is reported. strates.
Introduction
recognition that the poor electrophilicity of the carbonyl-
carbon of carboxamides can be readily enhanced by electro-
philic activation.[2] Robinson[4a] and Gabriel[4b] discovered inde-
pendently that acylated α-amino ketones form oxazoles upon
treatment with similar dehydrating agents (Scheme 1a).[5,6] The
resulting oxazole products can be alkylated, although this re-
quires highly reactive alkylating agents (Scheme 1b).[7] Recently,
the electrophilic activation of tertiary amides has been used for
the synthesis of certain N-aryloxazolium salts (Scheme 1c).[8]
However, that report restricted itself to the formation of oxazo-
lium salts derived from aromatic amides.
The high abundance of carboxamides[1] in combination with
their distinct, mild nucleophilic properties[2] makes them an in-
teresting target for the investigation of organic reactions. Al-
ready in the 19th century it was observed that primary amides
react readily with dehydrating agents such as PCl5 or concen-
trated sulfuric acid to give nitriles.[3] This resulted in an early
Herein we would like to report the synthesis of bicyclic
oxazolium salts based on proline- and pipecolic acid-derived
amides (Scheme 1d). The products display interesting reactivity
and can be converted to complex structures by formal cyclo-
addition.[7a,9]
Results and Discussion
As part of our interest in electrophilic amide activation,[2,10] we
recently investigated the suitability of proline as a chiral auxil-
iary for certain α-functionalization reactions. However, when 1a
(Scheme 2) was subjected to electrophilic activation using tri-
fluoromethanesulfonic anhydride (triflic anhydride) and 2-iodo-
pyridine, quantitative and fast formation of the oxazolium salt
2a was observed.[11] Surprisingly, slight modification of the ali-
phatic backbone of the amide lead to a dramatic change in
reactivity: when the linear propionamide 1b (Scheme 2) was
employed instead of 2-methylpropionamide 1a, mostly recov-
ered starting material was observed. Conversion of 1b did not
improve with other bases or with elevated temperature.
It is noteworthy that not only do the reaction mixtures of 1a
and 1b differ considerably in appearance,[12] but in situ 1H-NMR
spectra of those two mixtures in deuterated DCM are also strik-
ingly different (Figure 1). As shown, while the reaction mixture
of 1a shows almost exclusively the product and the base after
5 minutes of reaction time, the spectrum of 1b under the same
reaction conditions is much more complicated.
Scheme 1. (a–c) Prior art for the synthesis of oxazolium salts and (d) this
work.
[a] Institute of Organic Chemistry, University of Vienna,
Währinger Straße 38, 1090 Vienna, Austria
E-mail: nuno.maulide@univie.ac.at
http://maulide.univie.ac.at
[‡] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201900985.
The successful reaction of 1a most likely proceeds via inter-
ception of the activated amide 3a (Figure 1) by the pendant
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reaction conditions. These findings suggest that, in the case of
1a, limited accessibility of the α-proton (by virtue of the α-
substituent) slows deprotonation and formation of enamine-
type adducts; this in turn is likely to greatly favor oxazolium
formation in these systems.
These observations would suggest that omitting the base
might allow oxazolium formation even in “unbranched” sub-
strates such as 1b. In the event, such a simple modification
(Scheme 3) indeed led to the expected oxazolium 2b in 82 %
yield.[13] The 1H NMR spectrum of 1b in d2-DCM after 5 minutes
reaction time (Figure 2) now shows clean product formation,
with a species assigned as intermediate 3b as the major com-
pound in the mixture. The conspicuous absence of vinylic
C-H resonances, indicative of a slower deprotonation, should be
noted.
Scheme 2. Preliminary results: oxazolium synthesis from 2-methylpropion-
amide 1a and failed reaction for propionamide 1b.
Figure 1. Upper NMR trace: reaction of 1b with 2-I Py (2.2 eq.) and Tf2O (1.1
eq.) in d2-DCM after 5 minutes reaction time. The multiplet at 4.9 ppm is
assigned to 2-I-pyridine adduct 4b. Lower NMR trace: reaction of 1a with 2-I
Py (2.2 eq.) and Tf2O (1.1 eq.) in d2-DCM after 5 minutes reaction time. The
spectrum shows a very clean formation of the desired product.
ester moiety, with a subsequent (formal) elimination of tri-
fluoromethanesulfonic acid (triflic acid).
Scheme 3. See Supporting Information for detailed reaction conditions. Yield
refers to the pure isolated product.[a] 2.5 equiv. of Tf2O used.
In the case of 1b, although trace amounts of the product can
be detected, other species dominate the spectrum. The species
characterized by a signal at ca. 5.0 ppm, labelled as 4b (Fig-
ure 1), appears to be the main compound. The structure of 4b
has been assigned as a 2-iodopyridine adduct by 2D-NMR anal-
ysis (see Supporting Information for details) and is a common
intermediate in the electrophilic amide activation regime.[10d]
Several other bicyclic, alkoxyoxazolium salts could be synthe-
sized through this procedure in good to excellent yields
(Scheme 3). Halogens such as chloride (2d) or bromide (2i) were
tolerated. Pleasingly, an additional ester on the aliphatic chain
does not interfere in the process.[2e] It is also noteworthy that
a phenyl ring in proximity to the activated amide (2c) does not
Interestingly, not even traces of an analogous species de- trigger Friedel-Crafts reactivity. The reaction was also found to
rived from 1a can be detected by 1H NMR under the same be amenable to pipecolic acid derivatives (2f–2j).
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Figure 2. Upper NMR trace: reaction of 1b with Tf2O (1.1 eq.) in d2-DCM after 5 minutes reaction time. The multiplet at 4.8 ppm is assigned to the cation 3b
(the only other species present in considerable amounts is the desired oxazolium product). Lower NMR trace: reaction of 1a with Tf2O (1.1 eq.) in d2-DCM
after 5 minutes reaction time.
We noted that the products structurally resemble münch-
Keywords: Amide activation · Oxazolium ·
nones[14] to some extent. The latter are well-known for their
Chemoselectivity · Cycloaddition · Synthesis design
ready participation in interesting (3+2) cycloadditions.[14] In the
event, we achieved a reductive formal [2+2]-cycloaddition of
oxazolium salt 2b with dimethyl acetylenedicarboxylate
(DMDA) leading to product 6b in good yield and as a single
diastereoisomer (Scheme 4).[9] The NOESY NMR spectrum of
compound 6 is consistent with the stereochemistry shown in
Scheme 4.
[1] A. Greenberg, C. M. Breneman, J. F. Liebman, The Amide Linkage: Struc-
tural Significance in Chemistry, Biochemistry and Materials Science, Wiley,
New York, 2003.
[2] For reviews on amide activation see: a) D. Kaiser, A. Bauer, M. Lemmerer,
N. Maulide, Chem. Soc. Rev. 2018, 47, 7899–7925; b) D. Kaiser, N. Maulide,
J. Org. Chem. 2016, 81, 4421–4428; c) V. Pace, W. Holzer, B. Olofsson, Adv.
Synth. Catal. 2014, 356, 3697–3736; d) P.-Q. Huang, Acta Chim. Sinica
2018, 76, 357–365; e) T. Sato, M. Yoritate, H. Tajima, N. Chida, Org. Biomol.
Chem. 2018, 16, 3864–3875.
[3] O. Wallach, Justus Liebigs Ann. Chem. 1877, 184, 1–127.
[4] a) R. Robinson, J. Chem. Soc. Trans. 1909, 95, 2167–2174; b) S. Gabriel,
Ber. Dtsch. Chem. Ges. 1910, 43, 134–138; c) H. H. Wasserman, F. J. Vinick,
J. Org. Chem. 1973, 38, 3407–2408. For a variation of the Robinson-Ga-
briel synthesis with Tf2O:; d) A. Thalhammer, J. Mecinović, C. J. Schofield,
Tetrahedron Lett. 2009, 50, 1045–1047.
[5] The Robinson-Gabriel reaction in total synthesis: a) M. C. Bagley, K. E.
Bashford, C. L. Hesketh, C. J. Moody, J. Am. Chem. Soc. 2000, 122, 3301–
3313; b) K. C. Nicolaou, J. Hao, M. V. Reddy, P. B. Rao, G. Rassias, S. A.
Snyder, X. Huang, D. Y.-K. Chen, W. E. Brenzovich, N. Giuseppone, A.
O'Brate, P. Giannakakou, J. Am. Chem. Soc. 2004, 126, 12897–12906; c)
K. C. Nicolaou, S. A. Snyder, X. Huang, K. B. Simonsen, A. E. Koumbis, A.
Bigot, J. Am. Chem. Soc. 2004, 126, 10162–10173; d) P. Wipf, S. Venkatra-
man, J. Org. Chem. 1996, 61, 6517–6522.
[6] For a summary of variations of the Robinson-Gabriel reaction see: I. Tur-
chi, The Chemistry of Heterocyclic Compounds, Oxazoles. Wiley, New York,
2009.
[7] a) E. Vedejs, J. W. Grissom, J. Org. Chem. 1988, 539, 1876–1882; b) S.
Swaleh, J. Liebscher, J. Org. Chem. 2002, 67, 3184–3193.
[8] a) J. Zhang, J. Fu, X. Su, X. Qin, M. Zhao, M. Shi, Chem. Commun. 2012,
48, 9625–9627; b) J. Zhang, J. Fu, X. Su, X. Wang, S. Song, M. Shi, Chem.
Asian J. 2013, 558–555.
[9] E. Vedejs, J. Wisniewski Grissom, J. Am. Chem. Soc. 1986, 108, 6433–6434.
[10] a) P. Adler, C. J. Teskey, D. Kaiser, M. Holy, H. H. Sitte, N. Maulide, Nat.
Chem. 2019, 11, 329–334; b) T. Stopka, P. Adler, G. Hagn, H. Zhang, V.
Tona, N. Maulide, Synthesis 2019, 51, 194–202; c) C. J. Teskey, P. Adler,
C. R. Gonçalves, N. Maulide, Angew. Chem. Int. Ed. 2019, 58, 447–451;
Angew. Chem. 2019, 131, 456; d) B. Peng, D. Geerdink, C. Farès, N. Maul-
Scheme 4. Possible further transformation of one oxazolium salt.
Conclusion
Herein we reported that bicyclic, alkoxyoxazolium salts can be
readily prepared from simple proline- and pipecolic acid deriva-
tives. Mechanistic experiments highlighted a deleterious role
for the base. The products lend themselves to synthetic elabo-
ration by cycloaddition reactions.
Acknowledgments
Support of this research by the Erasmus + Program (fellowship
to E.S.) and the Austrian Science Fund (FWF, Grant P30226) is
gratefully acknowledged. We thank the University of Vienna for
continued support of our research programs.
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ide, Angew. Chem. Int. Ed. 2014, 53, 5462–5466; Angew. Chem. 2014, 126,
5566.
when the base was added after stirring the mixture of substrate and
triflic anhydride for 14 h.
[14] a) R. Huisgen, H. Gotthardt, H. O. Bayer, Angew. Chem. Int. Ed. Engl. 1964,
3, 135–136; Angew. Chem. 1964, 76, 185; b) R. Huisgen, H. Gotthardt,
H. O. Bayer, F. C. Schaefer, Angew. Chem. Int. Ed. Engl. 1964, 3, 136–137;
Angew. Chem. 1964, 76, 185; c) T. K. K. Kakaawla, W. C. Hartley, J. P. A.
Harrity, Eur. J. Org. Chem. 2016, 2789–2792; d) H.-U. Reißig, R. Zimmer,
Angew. Chem. 2014, 126, 9864–9866.
[11]
For selected methods for the synthesis of polysubstituted amidines,
benzimidazoles and pyrimidines see: J. Wang, Z. He, X. Chen, W. Song, P.
Lu, Y. Wang, Tetrahedron 2010, 66, 1208–1214.
[12] The reaction mixture of 1b is a deep red clear solution, while the reac-
tion mixture of 1a is slightly yellowish.
[13] The formal elimination of triflic acid was accomplished by quenching
the reaction with water saturated-DCM. Similar results were achieved
Received: July 9, 2019
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Heterocycle Synthesis
All about no base: A regio- and
chemoselective preparation of bicyclic
alkoxyoxazolium salts from amide de-
rivatives of proline and pipecolic acid
by electrophilic amide activation is re-
ported. Mechanistic NMR experiments
suggest an unusual role for the base
and highlight the effect of substitution
pattern of the substrates.
E. Spinozzi, A. Bauer,
N. Maulide* .......................................... 1–5
A Mild Synthesis of Bicyclic Alkoxy-
oxazolium Salts from Proline and
Pipecolic Acid Derivatives
DOI: 10.1002/ejoc.201900985
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim