A Strategy for Amide to β-Oxo Ester Transformation via N-Alkenoxypyridinium Salts as the Activator and H2O as the Nucleophile

Article abstract of DOI:10.1021/acs.orglett.0c02457

N-Alkenoxypyridinium salts were found to be highly active electrophilic reagents that could be used to activate the C-N bond of amides. Both aromatic amides and aliphatic amides could be transformed into the corresponding β-oxo esters with good yields via the combined use of N-alkenoxypyridinium salts and water. The methodology proceeds under mild reaction conditions and is tolerant of various functional groups in both reaction partners.

Full text of DOI:10.1021/acs.orglett.0c02457

pubs.acs.org/OrgLett
Letter
A Strategy for Amide to β‑Oxo Ester Transformation via
N‑Alkenoxypyridinium Salts as the Activator and H2O as the
Nucleophile
Nan Wu,† Chuang Li,† Jiajia Mi,† Yan Zheng, and Zhou Xu*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02457
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: N-Alkenoxypyridinium salts were found to be highly active electrophilic
reagents that could be used to activate the C−N bond of amides. Both aromatic amides
and aliphatic amides could be transformed into the corresponding β-oxo esters with
good yields via the combined use of N-alkenoxypyridinium salts and water. The
methodology proceeds under mild reaction conditions and is tolerant of various
functional groups in both reaction partners.
mides are important structural moieties in the preparation
Aof a wide variety of pharmaceutical compounds and
natural products.1,2 In living organisms, the cleavage of amide
bonds in proteins or amino acids is a common phenomenon,
but it can occur only during the catalysis of enzymes.3 The
amide group is also an important guiding group for
functionalization of the C−H bond, which needs to be
converted into target compounds by subsequent reactions.4
There are also many requirements for the conversion of amides
in drug synthesis. However, the direct conversion of amides
often requires drastic reaction conditions, multistep processes,
etc., which makes it difficult to meet the requirements of
modern organic synthesis for chemical conversion.5
Amides are the lowest electrophilic carbonyl compounds in
carboxylic acid derivatives, and they are known to be poor
electrophiles and have high stability, which is typically
attributed to the resonance running through the O−C−N
unit of amides. Activation of heterocyclic amides has been well
developed.6 Some remarkable advances in transition-metal-free
activation of amides by C−N bond cleavage have also been
reported.7 However, as for the transformation of amides into
esters, it is still difficult for stable amides to undergo
esterification. The activity of esters is higher than that of
amides. Under the strong acidic or basic harsh reaction
conditions, a large number of esterification reagents (alcohols)
were required to realize the esterification of amides. In 1998,
the first example of the transformation of amides into esters
was reported by Charette and Dossena independently with a
stoichiometric amount of triflic anhydride.8 The group of Garg
and Houk achieved an important breakthrough in conversion
of amides to esters under nickel catalysis (Scheme 1a).9
However, the limitation is that amides were restricted to N-
arylbenzamides. Recently, Huang reported the Ni-catalyzed
direct alcoholysis of tertiary heterocyclic amides into esters
(Scheme 1b).10 A series of activated twisted amides could be
esterified under transition-metal-free conditions (Scheme
1c).11,12 Despite these important advances, the efforts to
extend the substrate scope to aliphatic amides, such as N,N-
dimethylformamide (DMF), remained unsuccessful.13 In
addition, only alcohol was used as the nucleophile in reactions
and only common esters were prepared. Developing a general
and efficient common amide esterification method, especially
β-oxo esters, is still in great demand.
Due to the resonance effect, the electronegativity of the
amidocarbonyl carbon is dispersed and its electrophilicity is
poor. We assume that the highly active electrophile (E+) might
be used to capture the oxygen negative ionomer, and thus, the
equilibrium between I and II could be pushed to the right
(Scheme 1d).14 Resonance III is induced by the electron
absorption of OE and N+ groups, which could improve the
electrophilicity of iminocarbon, and resonance III is conducive
to the attack of a nucleophile (H2O). Thus, our strategy is to
Received: July 23, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02457
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 1. (a−c) Amide to Ester Transformation via
Alcoholysis Reactions and (d) Our Strategy (amide
hydrolysis)
Table 1. Optimization of Reaction Conditions
a
Reaction conditions: 1a−1f (2−10 equiv), 2a (0.2 mmol, 104 mg),
DCM (1 mL), 4.5−24 h at the specified temperatures (oil bath).
b
c
Isolated yields. Amide was used as both the substrate and the
solvent without the use of DCM.
the reaction yield (entry 3). A significant decrease in yield was
observed when the dose of DMF was decreased to 2 or 5 equiv
of substrate 2a (entry 4 or 5, respectively).
Different N-substituents were also surveyed; in addition to
the DMF (1a) used for the model reaction, amides containing
N,N-diethyl (1b), N-methoxy-N-methyl (1c), and N-methyl-
N-phenyl (1d) were also successfully transformed into the
corresponding ester with excellent yields (entries 6−8). When
DMF was used as both the substrate and the solvent, the
reaction could be finished within 4.5 h in 96% isolated yield
(entry 9). Moreover, the primary amide or secondary amides
can also be used as substrates directly for esterification, but
with less activity and lower yields (entries 10 and 11).
Having identified suitable reaction conditions, we examined
the scope of the transformation with regard to the tertiary
amide substrates (Scheme 2). All of these amides are
commercially available. When the reaction was conducted in
DMA instead of DMF, the corresponding ester 3b was
obtained with excellent yield. Unsaturated amide N,N-
dimethylmethacrylamide produced the corresponding ester
3c in 82% yield, and the CC bond did not affect the
reaction. The length of the aliphatic chain did not affect the
reaction. All of them could give satisfactory yields (3d and 3e).
In addition to the parent benzamide, substrates containing
electron-withdrawing groups such as an ester substituent
(-CO2Me), halogen substituents (F, Cl, and Br), and
trifluoromethyl (CF3) were well tolerated (3f−3k). The
transformation also proceeded smoothly using electron-
donating substituents at the para, meta, and ortho position of
the benzene ring, affording the desired esters 3l−3n,
respectively, in good yields. It is noteworthy that the sensitive
phenol group (Ar-OH), at the ortho position of the benzene
ring, was not affected under the reaction conditions, suggesting
that the methodology has good group tolerance. The extended
find a suitable electrophilic reagent E+, not only to destroy the
equilibrium of two limit resonators of amides but also to
participate in the reaction as a substrate that is the source of
carbonyl groups in β-oxo esters. In recent years, our group and
other groups have reported the preparation and application of
N-alkenoxypyridinium salts that could react well with alcohol,
mercaptan, and other relatively “soft” reagents.15−17 These
enolate salts are stable at room temperature (for ≥7 days) and
showed high electrophilic activity in many reactions. They
could be used as a type of electrophilic reagent and render
useful synthetic building blocks. Inspired by this, we speculated
that N-alkenoxypyridinium salts might react with the oxygen of
the amides’ carbonyl group, to consume the amides through
the equilibrium between two limit resonators of amides.
Herein, we demonstrated the conversion of common amides to
β-oxo ethers18 via the concept described above, which
proceeded under mild reaction conditions with good to
excellent yields.
DMF is a large supply of chemical raw material in industry,
which has been used as an excellent polar solvent for various
reactions.19 Thus, the conversion of DMF (1a) with enolate
salt (2a) to formate (3a) was chosen and investigated as a
model reaction. The reaction temperature was first tested. At
25 °C, the reaction could hardly proceed and only a trace of
the product was observed (Table 1, entry 1). Increasing the
reaction temperature to 60 °C could improve the reaction
efficiency in 95% isolated yield within 18 h (entry 2). A further
increase in temperature to 80 °C obviously could not enhance
B
https://dx.doi.org/10.1021/acs.orglett.0c02457
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 2. Scope of Amide to Ester Transformation
Evaluated with Respect to the Tertiary Amide Substrate
Scheme 3. Reaction Scope of the DMF to Ester
a
Transformation with Respect to N-Alkenoxypyridinium
a
Salts
a
Reaction conditions: 1 (10 equiv), 2a (0.4 mmol, 208 mg), DCM
b
(wet, 2 mL), 18 h at 60 °C (oil bath). DMA (0.5 mL) was used as
both a substrate and a solvent; reaction time of 4 h. Isolated yields
c
obtained by using 5 equiv of amides for 48 h.
aromatic furan unit could also be employed to give 3o in 84%
isolated yield.
a
Reaction conditions: DMF (1 mL), 2a (0.4 mmol), 4−5 h at 60 °C
(oil bath).
We subsequently turned to evaluating the reaction scope of
the N-alkenoxypyridinium salts with regard to DMF.
Pleasingly, as revealed in Scheme 3, we found a broad range
of enolates possessing various functional groups that readily
participate in this reaction in moderate to excellent yields. For
the N-alkenoxypyridinium salts containing benzene rings,
although we reported in our previous study12a that the
corresponding N-alkenoxypyridinium intermediates would
undergo the intramolecular Friedel−Crafts reaction, to our
delight, under the current reaction conditions no cyclization
product was observed and the corresponding esters were
obtained in high yields. The N-alkenoxypyridinium salts
bearing alkyl, ester, acetyl, chlorine, and alkyne functional
groups are compatible with the transformation, and the
corresponding products were obtained in good yields (3p−
3v). N-Alkenoxypyridinium salts, with different lengths of
straight alkyl, α-branched alkyl, or cyclic carbon chains, could
react with DMF smoothly and produced the corresponding
ethers in good to excellent yields (3w−3ac). Furthermore,
other examples for the scope of N-alkenoxypyridinium salts
and amides were tested, and satisfying results were obtained as
expected (Scheme 4).
Scheme 4. More Examples for Tertiary Amide to β-Oxo
Ester Transformation
a
a
Reaction conditions: amide (10 equiv), N-alkenoxypyridinium salts
(0.4 mmol), DCM (2 mL), 60 °C (oil bath).
a
Scheme 5. Control Experiments
To gain insight into the mechanism, an isotope labeling
experiment and a control experiment were performed (Scheme
5). Air and moisture had shown an important effect on
reaction efficiency. No observed 3a was detected with
anhydrous DMF (4 Å molecular sieves or MgSO4), which
indicated that the water was necessary for this transformation.
Further investigation of the presence of H2O18 (20 μL)
indicates that the carbonyl oxygen of ethers comes from water.
Too much water (for example, 0.5 mL) could cause partial
hydrolysis of N-alkenoxypyridinium salts.
a
Reaction conditions: (1) DMF (0.5 mL), 2a (0.2 mmol), 4 Å
molecular sieves or MgSO4 (0.2 g), Ar, 60 °C (oil bath) for 5 h; (2)
DMF (0.5 mL), 2a (0.2 mmol), H2O18 (20 μL), Ar, 60 °C (oil bath),
5 h.
C
https://dx.doi.org/10.1021/acs.orglett.0c02457
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Author Contributions
†N.W., C.L., and J.M. contributed equally to this work.
On the basis of the results presented above, a plausible
mechanism of this reaction could be described as follows using
DMF (1a) as an example (Figure 1). First, intermediate A
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (Grant 21602191) and the Natural Science Foundation
of Jiangsu Province (Grant BK 20171175). The work is also
sponsored by the Qing Lan Project of Jiangsu Province,
Jiangsu Six Talent Peaks Program (YY-042), and 333 Project
of Jiangsu Province. The authors also thank the Public
Experimental Research Center, Xuzhou Medical University,
for NMR determination. The authors thank Professor Zhang
Liming (University of California, Santa Barbara, Santa Barbara,
CA) for insightful discussions.
Figure 1. Proposed reaction mechanism.
REFERENCES
■
(1) (a) Greenberg, A., Breneman, C. M., Liebman, J. F., Eds. The
Amide Linkage: Structural Significance in Chemistry, Biochemistry, and
Materials Science; Wiley, 2003. (b) Huang, P. Q. Asymmetric
Synthesis of Five-Membered Ring Heterocycles. In Asymmetric
Synthesis of Nitrogen Heterocycles; Royer, J., Ed.; Wiley-VCH:
Weinheim, Germany, 2009; pp 51−94.
(2) (a) Radzicka, A.; Wolfenden, R. J. Am. Chem. Soc. 1996, 118,
6105−6109. (b) Smith, R. M.; Hansen, D. E. J. Am. Chem. Soc. 1998,
120, 8910−8913.
(3) Brix, K., Stocker, W., Eds. Proteases: Structure and Function;
Springer, 2013.
(4) (a) Wu, Q. F.; Shen, P. X.; He, J.; Wang, X. B.; Zhang, F.; Shao,
Q.; Zhu, R. Y.; Mapelli, C.; Qiao, J. X.; Poss, M. A.; Yu, J. Q. Science
2017, 355, 499. (b) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.;
Zultanski, S. L.; Peters, J. C.; Fu, G. C. Science 2016, 351, 681.
(c) Luo, F. H.; Long, Y.; Li, Z. K.; Zhou, X. G. Huaxue Xuebao 2016,
74, 805.
underwent an addition reaction to give intermediate B in the
presence of water. Finally, B underwent oxidation and proton
transfer to furnish the desired product.
In summary, we have presented a highly efficient way to
convert amides to esters without catalysts. The method is
amenable to both aromatic amides and aliphatic amides
(common amides) with a broad scope of functional groups.
The mild conditions allow for excellent compatibility of
functional groups, and the broad substrate scope in the N-
alkenoxypyridinium salts enabled a new and complementary
synthetic method for densely β-oxo ethers.
ASSOCIATED CONTENT
* Supporting Information
■
sı
(5) (a) White, E. H. J. Am. Chem. Soc. 1955, 77, 6011−6014.
(b) Nishimoto, S.−i.; Izukawa, T.; Kagiya, T. Bull. Chem. Soc. Jpn.
1982, 55, 1484−1488. (c) Keck, G. E.; McLaws, M. D.; Wager, T. T.
Tetrahedron 2000, 56, 9875−9883. (d) Glatzhofer, D. T.; Roy, R. R.;
Cossey, K. N. Org. Lett. 2002, 4, 2349−2352. (e) Toyao, T.; Nurnobi
Rashed, M.; Morita, Y.; Kamachi, T.; Hakim Siddiki, S. M. A.; Ali, M.
A.; Touchy, A. S.; Kon, K.; Maeno, Z.; Yoshizawa, K.; Shimizu, K. i.
ChemCatChem 2019, 11, 449−456.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02457.
Experimental procedures along with characterization
data and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(6) (a) Buchspies, J.; Rahman, Md. M.; Szostak, R.; Szostak, M. Org.
Lett. 2020, 22, 4703−4709. (b) Meng, G. R.; Szostak, R.; Szostak, M.
Org. Lett. 2017, 19, 3596−3599.
Zhou Xu − Jiangsu Key Laboratory of New Drug Research and
Clinical Pharmacy, School of Pharmacy, Xuzhou Medical
University, Xuzhou 221004, China; orcid.org/0000-0002-
9703-8245; Email: xuzhou@xzhmu.edu.cn
(7) Li, G. C.; Szostak, M. Nat. Commun. 2018, 9, 4165. (b) Li, G. C.;
Ji, C. L.; Hong, X.; Szostak, M. J. Am. Chem. Soc. 2019, 141, 11161−
11172. (c) Rahman, Md. M.; Li, G. C.; Szostak, M. Synthesis 2020, 52,
1060−1066.
(8) (a) Charette, A. B.; Chua, P. Synlett 1998, 1998, 163−165.
(b) Sforza, S.; Dossena, A.; Corradini, R.; Virgili, E.; Marchelli, R.
Tetrahedron Lett. 1998, 39, 711−714.
(9) (a) Hie, L.; Fine Nathel, N. F.; Shah, T. K.; Baker, E. L.; Hong,
X.; Yang, Y. F.; Liu, P.; Houk, K. N.; Garg, N. K. Nature 2015, 524,
79−83. (b) Dander, J. E.; Weires, N. A.; Garg, N. K. Org. Lett. 2016,
18, 3934−3936. (c) Weires, N. A.; Caspi, D. D.; Garg, N. K. ACS
Catal. 2017, 7, 4381−4385.
(10) Chen, H.; Chen, D. H.; Huang, P. Q. Sci. China: Chem. 2020,
63, 370−376.
Authors
Nan Wu − Jiangsu Key Laboratory of New Drug Research and
Clinical Pharmacy, School of Pharmacy, Xuzhou Medical
University, Xuzhou 221004, China
Chuang Li − Jiangsu Key Laboratory of New Drug Research and
Clinical Pharmacy, School of Pharmacy, Xuzhou Medical
University, Xuzhou 221004, China
Jiajia Mi − Jiangsu Key Laboratory of New Drug Research and
Clinical Pharmacy, School of Pharmacy, Xuzhou Medical
University, Xuzhou 221004, China
(11) Some reviews of twisted amides: (a) Li, G. C.; Szostak, M.
Chem. Rec. 2020, 20, 649−659. (b) Szostak, R.; Szostak, M. Molecules
2019, 24, 274. (c) Liu, C. W.; Szostak, M. Chem. - Eur. J. 2017, 23,
7157−7173.
(12) Some selective catalytic transformation of special amides:
(a) Adachi, S.; Kumagai, N.; Shibasaki, M. Synlett 2018, 29, 301−305.
Yan Zheng − Jiangsu Key Laboratory of New Drug Research
and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical
University, Xuzhou 221004, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02457
D
https://dx.doi.org/10.1021/acs.orglett.0c02457
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(b) Deguchi, T.; Xin, H. L.; Morimoto, H.; Ohshima, T. ACS Catal.
̈
̈
2017, 7, 3157−3161. (c) Brohmer, M. C.; Mundinger, S.; Brase, S.;
Bannwarth, W. Angew. Chem., Int. Ed. 2011, 50, 6175−6177. (d) Li,
G.; Lei, P.; Szostak, M. Org. Lett. 2018, 20, 5622−5625.
(13) Hie, L.; Baker, E. L.; Anthony, S. M.; Desrosiers, J. N.;
Senanayake, C.; Garg, N. K. Angew. Chem., Int. Ed. 2016, 55, 15129−
15132.
(14) Ruider, S. A.; Maulide, N. Angew. Chem., Int. Ed. 2015, 54,
13856−13858.
(15) (a) Xu, Z.; Chen, H. Y.; Wang, Z. X.; Ying, A. G.; Zhang, L. J.
Am. Chem. Soc. 2016, 138, 5515−5518. (b) Xu, Z.; Zhai, R. L.; Liang,
T.; Zhang, L. Chem. - Eur. J. 2017, 23, 14133−14137. (c) Zhai, R. L.;
Xue, Y. S.; Liang, T.; Mi, J. J.; Xu, Z. J. Org. Chem. 2018, 83, 10051−
10059.
(16) (a) Xia, X.; Chen, B.; Zeng, X.; Xu, B. Adv. Synth. Catal. 2018,
360, 4429−4434. (b) Xia, X.; Chen, B.; Zeng, X.; Xu, B. Org. Biomol.
Chem. 2018, 16, 6918−6922.
(17) (a) Rong, Z. T.; Hu, W. C.; Dai, N.; Qian, G. Y. Org. Lett.
2020, 22, 3286−3290. (b) Mathi, G. R.; Jeong, Y.; Moon, Y.; Hong,
S. Angew. Chem., Int. Ed. 2020, 59, 2049−2054.
(18) (a) Santhosh Kumar, P.; Ravikumar, B.; Chinna Ashalu, K.;
Rajender Reddy, K. Tetrahedron Lett. 2018, 59, 33−37. (b) Cutulic, S.
P. Y.; Findlay, N. J.; Zhou, S. Z.; Chrystal, E. J. T.; Murphy, J. A. J. J.
Org. Chem. 2009, 74, 8713−8718.
(19) (a) Muzart, J. Tetrahedron 2009, 65, 8313−8323. (b) Ding, S.
T.; Jiao, N. Angew. Chem., Int. Ed. 2012, 51, 9226−9237.
E
https://dx.doi.org/10.1021/acs.orglett.0c02457
Org. Lett. XXXX, XXX, XXX−XXX