Accessing N-Acyl Azoles via Oxoammonium Salt-Mediated Oxidative Amidation

Article abstract of DOI:10.1021/acs.orglett.7b00060

An operationally simple, robust, metal-free approach to the synthesis of N-acyl azoles from both alcohols and aldehydes is described. Oxidative amidation is facilitated by a commercially available organic oxidant (4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate) and proceeds under very mild conditions for an array of structurally diverse substrates. Tandem reactions of these activated amides, such as transamidation and esterification, enable further elaboration. Also, the spent oxidant can be recovered and used to regenerate the oxoammonium salt.

Full text of DOI:10.1021/acs.orglett.7b00060

Letter
pubs.acs.org/OrgLett
Accessing N‑Acyl Azoles via Oxoammonium Salt-Mediated Oxidative
Amidation
John M. Ovian, Christopher B. Kelly, Vincent A. Pistritto, and Nicholas E. Leadbeater*
Department of Chemistry, University of Connecticut, 55 North Eagleville Road, Storrs, Connecticut 06268, United States
S
* Supporting Information
ABSTRACT: An operationally simple, robust, metal-free
approach to the synthesis of N-acyl azoles from both alcohols
and aldehydes is described. Oxidative amidation is facilitated
by a commercially available organic oxidant (4-acetamido-
2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoro-
borate) and proceeds under very mild conditions for an
array of structurally diverse substrates. Tandem reactions of
these activated amides, such as transamidation and ester-
ification, enable further elaboration. Also, the spent oxidant can be recovered and used to regenerate the oxoammonium salt.
he unrivaled ubiquity of the amide bond throughout a
Scheme 1. Potential Outcomes of Oxidative Amidation
T
variety of fields is a testament to its utility.1 This linkage
comprises the backbone of enzymes and the core of some of the
most common polymers, in addition to routinely serving as the
critical synthetic link between fragments of pharmacons.1 Indeed,
in the context of synthetic chemistry, amide coupling is one of the
most important reactions1b and, as in nature, the C−N bond is
most commonly forged via the condensation of an activated
carboxylicacidandanamine. Anarrayofcarboxylicacidactivators
are available, thus enabling practitioners to tailor their synthetic
strategy to the appropriate reagent.2 Divergent from the typical
approach is the paradigm of oxidative amidation.3 Using this
model, aldehydes (and alcohols via a separate oxidation event)
become the carbonyl-containing progenitor of the amide and are
oxidatively functionalized with an amine (Scheme 1, eq 1).
Although highly attractive, optimization of such a process is not
without its unique challenges. The rapidity with which amines
condensewithaldehydesaswellasthepropensityforaminestobe
oxidized can ultimately render the oxidative amidation pathway
inaccessible (Scheme 1, eq 2).4,5 In spite of these challenges, this
approach has been executed elegantly in several reports such as
the Ru-catalyzed process described by Milstein and a recent
report by Stahl.6
N-Acyl azoles are one class of amides whose utility has recently
beenrealizedbyanumberofgroupsbecausetheseamidesbalance
reactivity with stability. In addition to serving as viable amide
coupling partners (i.e., N-acyl imidazoles), certain N-acyl azoles
(i.e., N-acyl pyrazoles) have been used to great effect for
asymmetric transformations.2,7 The latter capitalizes on the
unique ability of N-acyl pyrazoles to undergo enolization when
coordinated to transition metal catalysts. The resulting function-
alized N-acyl pyrazole can then be further elaborated through
displacement processes. In addition to being a powerful directing
group, azolesubunitsarecommonstructuralmotifsinmedicinally
relevant compounds.8 Current methods to access N-acyl azoles
via oxidative amidation are restricted to harsh conditions relying
on superstoichiometric loadings of peroxides at temperatures
exceeding100°C.9 Suchmethodsdonottoleratemanyfunctional
groups (e.g., electron-rich arenes, olefins, alcohols, etc.) and are
not amenable to scale up.
Recently, acyl pyridinium species were identified as the key
intermediates formed when performing oxidative functionaliza-
tionusing1a.10 Sincethesearethesameintermediateswhenusing
acid chlorides and pyridine, we envisioned that N-acyl azoles
could be accessed via a similar approach (Figure 1). Alternatively,
the azole itself could serve as an activator in the same manner as
pyridine. Regardless of the mode of activation, both pathways
furnish the desired N-acyl azole. Given the numerous advantages
of this approach such as it being the first instance of direct
oxidative amidation using benign, recyclable, metal-free oxidant
1a,11 the ability to access N-acyl azoles directly from aldehydes at
room temperature under mild conditions, and the excellent
nucleophilicity of azoles, we explored the viability of this
transformation.
Assessment of the feasibility of oxidative amidation began with
the examination of the coupling of p-tolualdehyde (2a) with
pyrazole using 4-acetamido-2,2,6,6-tetramethylpiperidine-1-ox-
oammonium tetrafluoroborate (Bobbitt’s salt, 1a) (Table 1), as
the oxidant of choice. Pyrazole, 3a, was chosen as a representative
azole given its low basicity relative to pyridine and that the
Received: January 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00060
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Organic Letters
Letter
that reaction efficiency was independent of the reaction medium,
given a variety of polar solvents could be used with minimal effect
on conversion. Ultimately, we elected to utilize dichloromethane
as the solvent for two reasons: (1) the low water content of this
solvent would deter any possible carboxylic acid formation when
screening electronically disparate aldehydes,14 and (2) this
solvent has been used previously with other oxidative
functionalization processes facilitated by 1a. To complete
optimization, we varied the loading of pyridine and pyrazole,
ultimately finding 1.2 equiv of pyrazole and 2.25 equiv of pyridine
to be best.
After establishing optimal conditions, the scope of the
transformation was assessed in the context of various aldehydes
(Scheme 2). We were very pleased to find that the developed
a
Scheme 2. Oxidative Amidation of Aldehydes with 3a
Figure 1. Envisioned mechanistic pathway for oxidative amidation.
a
Table 1. Optimization of Oxidative Amidation of 2a with 3a
b
entry
3a (equiv)
pyridine (equiv)
solvent
conv (%)
c
1
3
12.75
12.75
3
neat
90
2
3
neat
99
3
3
MeCN
MeCN
DMF
100
66
4
3
0
5
3
3
99
6
3
3
EtOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
100
100
90
7
3
3
8
2.5
1.5
1.2
1.1
2.25
2.25
9
100
d
10
100 (95)
a
Unless otherwise noted, reactions run at 1 M in substrate, using 2.5
b
c
1
equiv of 1a for 12 h at rt. Conversion determined by H NMR. 0.1
equiv of HFIP added. Isolated yield in parentheses.
d
a
Unless otherwise noted, reactions run on 5 mmol at 25 °C; isolated
b
yields after purification. 1.5 equiv of pyrazole, 2.5 equiv of pyridine
resulting N-acyl pyrazole can be readily functionalized. Initially,
we elected to employ hexafluoroisopropanol (HFIP) as an
additive, thus forming substoichiometric amounts of reactive
HFIP estersintheevent thatpyrazole wastoo poorlynucleophilic
to undergo direct oxidative amidation (Table 1, entry 1).12 We
quickly determined that HFIP was not a necessary additive.
Although the reaction could be performed neat, it was somewhat
exothermic, and thus we decided to conduct the reaction in a
solvent to serve as a thermal sink (Table 1, entries 3−10).
Acetonitrile was initially used and served adequately for heat
dispersal.13 We simultaneously reduced the loading of pyridine as
well, given that it was no longer serving as the solvent. While the
reaction could proceed without pyridine, it was rather sluggish.
This indicates that a pyrazole-derived hemiaminal intermediate
may form (Table 1, entry 4). This is likely because pyrazole has to
serve two roles: as a base in the concomitant comproportionation
of 1a with 1b, and also as a reactant. Thus, pyridine was necessary
forrapidandreliablereactivity. Abriefsurveyofsolventsindicated
and 3.0 equiv of 1a were used.
process displayed a broad tolerance across various sterically and
electronically distinct aldehydes. Aryl aldehydes were amidated in
consistentlyhighyieldregardless ofsubstitutionpattern ordegree
of ring electron density. In addition, a number of different
heteroaryl aldehydes, such as pyridyl, indolyl, and furyl, could
successfully be converted to their corresponding N-acyl pyrazoles
in good to excellent yields. Conjugated and aliphatic aldehydes
(even those with branching at the α-position) underwent
amidation without issue and gave similarly good yields. Of note
is that, in all cases, no chromatography was required; acyl
pyrazoles obtained in this manner were pure upon workup, and
the spent oxidant could be recovered following each oxidation
(see SI for details).
Not satisfied with using aldehydes as forebears to N-acyl
pyrazoles, we next investigated whether alcohols were viable
B
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a
of azoles, reaction success can be dramatically influenced by the
electronic nature of the azole (e.g., 4ah vs 4ai). While some
acylation was observed when using imidazole (not shown), the
low conversion and instability of N-acyl imidazoles complicated
isolation. Thus, inour view, N-acyl imidazoles cannot beprepared
using the protocol outlined here, although they could be
generated in situ.
Scheme 3. Oxidative Amidation of Alcohols with 3a
In addition to the new chemical space accessible using this
method, N-acyl azoles are ideal partners for further derivatization.
N-acyl azoles represent a fine balance between long-term stability
(mostN-acylazolesarebenchstablepowdersthatcanbestoredat
room temperature for several months) and reactive acylating
agents. N-acyl pyrazoles are particularly ideal as compared to the
HFIP esters studied previously by our group from both a cost
standpoint and lower loading of nucleophile (1.2 equiv vs 3−3.5
equiv), while retaining the same type of reactivity. To
demonstrate the utility of these species, a series of tandem
reactionswereperformed. Inadditiontodemonstratingthatthese
systems readily participated in nucleophilic acyl substitution
processes in excellent yield (Scheme 5), we also had impetus to
a
Unless otherwise noted, reactions run on 5 mmol scale at 25 °C;
b
isolated yields after purification. 1.5 equiv of pyrazole used.
starting materials for oxidative amidation (Scheme 3). By simply
switching to 2,6-lutidine as the base, hence avoiding concomitant
oxidative esterification,10,12 and doubling the loading of the
oxidant (adding an additional 2.5 equivalents), we were able to
effect this transformation in comparable yield to those obtained
when using aldehydes. This is especially noteworthy given these
yieldsrepresenttwodistinctchemicalsteps:alcoholoxidationand
oxidative functionalization. A variety of functionally dense
alcohols were well-tolerated in this two-step, one-pot process.
One exception to this was the allylic substrate 4w which required
more extensive purification resulting in a diminished yield. The
greater impurity profile in this case is likely a consequence of
various alternate reaction pathways including a Michael-like
reaction facilitated by pyrazole.
Scheme 5. Functionalization Reactions of 4i
Finally, the scope of the oxidative amidation process was
assessed by varying the azole component (Scheme 4). Both the
substitution pattern of pyrazole and other structurally distinct
azoles were explored. We were again pleased to find that both
electronically and sterically distinct pyrazoles could be coupled in
good to excellent yield. Although this reaction tolerates a number
probe the scalability of our process because of the amount of
requisite N-acyl pyrazole, 4i, required for these functionalization
studies. Pleasingly, the reaction could be scaled easily to 20 mmol,
and likely even larger, without significantly compromising the
yield. Transamidation was next attempted by forming 4a and
treating the crude N-acyl pyrazole (after removal of nitroxide 1c
by precipitation) with several representative amines (Scheme 6).
Not only was this highly successful, but this two-step approach
effects oxidative amidation without concomitant amine oxidation
or imine formation. To further add modularity, we assessed
whether alcohols were also compatible with this amidation
method. Gratifyingly, 5t could be converted into amide 6t in
excellent yield, equating to >95% yield per chemical step. To
demonstrate further the utility of this net two-step amidation
process, we probed whether any loss in stereochemical
information occurred over the three chemical steps involved.
Starting from (S)-(+)-1,2-isopropylideneglycerol, 5v′, we
executed the two-step amidation sequence to prepare the
known chiral benzamide 6v′ (Scheme 6).15 We were pleased to
find that no appreciable epimerization occurred thus enabling
substrates with chirality at the α-position to be amenable to the
both the oxidative amidation process and subsequent function-
alization.
a
Scheme 4. Oxidative Amidation of 2a with Azoles
a
In summary, a mild, user-friendly, metal-free oxidative
amidation approach to the synthesis of N-acyl azoles utilizing
Reactions run on 5 mmol scale at 25 °C; isolated yields after
purification.
C
DOI: 10.1021/acs.orglett.7b00060
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Organic Letters
Letter
Lang, andMs. RebeccaWilesoftheUniversityofPennsylvaniafor
useful discussions. We thank Mr. Kyle Lambert (UConn) for
helpful discussions and assistance in obtaining optical rotations.
We thank Dr. You-Jun Fu (UConn)for obtaining HRMS of novel
compounds.
Scheme 6. N-Acyl Pyrazoles As Intermediates to Amides
REFERENCES
■
(1) (a) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
(b) Schneider, N.; Lowe, D. M.; Sayle, R. A.; Tarselli, M. A.; Landrum, G.
A. J. Med. Chem. 2016, 59, 4385.
(2) Montalbetti, C. A. N. G.; Falque, V. Tetrahedron 2005, 61, 10827.
(3) Ekoue-Kovi, K.; Wolf, C. Chem. - Eur. J. 2008, 14, 6302.
(4) Amines are notorious for undergoing side reactions when
attempting oxidative amidation; see: Bartelson, A. L.; Lambert, K. M.;
Bobbitt, J. M.; Bailey, W. F. ChemCatChem 2016, 8, 3421.
(5) Lambert, K. M.; Bobbitt, J. M.; Eldirany, S. A.; Wiberg, K. B.; Bailey,
W. F. Org. Lett. 2014, 16, 6484.
(6) For some recent examples, see: (a) Krabbe, S. W.; Chan, V. S.;
Franczyk, T. S.; Shekhar, S.; Napolitano, J. G.; Presto, C. A.; Simanis, J. A.
J. Org. Chem. 2016, 81, 10688. (b) Gunanathan, C.; Ben-David, Y.;
Milstein, D. Science 2007, 317, 790. (c) Zultanski, S. L.; Zhao, J.; Stahl, S.
S. J. Am. Chem. Soc. 2016, 138, 6416. (d) Nordstrøm, L. U.; Vogt, H.;
Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672. (e)Ekoue-Kovi, K.;Wolf,
C. Org. Lett. 2007, 9, 3429. (f) Vora, H. U.; Rovis, T. J. Am. Chem. Soc.
2007, 129, 13796. (g) Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128,
13064. (h)Whittaker, A. M.;Dong, V. M. Angew. Chem., Int. Ed. 2015, 54,
1312.
(7) For recent applications of N-acyl pyrazoles, see: (a) Tokumasu, K.;
Yazaki, R.; Ohshima, T. J. Am. Chem. Soc. 2016, 138, 2664. (b) Huo, H.;
Harms, K.; Meggers, E. J. Am. Chem. Soc. 2016, 138, 6936. (c) Ma, J.;
Ding, X.; Hu, Y.;Huang, Y.;Gong, L.;Meggers, E. Nat. Commun. 2014, 5,
4531. (d) Uraguchi, D.; Yamada, K.; Ooi, T. Angew. Chem., Int. Ed. 2015,
54, 9954.
(8) (a) Giovannoni, M. P.; Schepetkin, I. A.; Crocetti, L.; Ciciani, G.;
Cilibrizzi, A.; Guerrini, G.; Khlebnikov, A.; Quinn, M. T.; Vergelli, C. J.
Enzyme Inhib. Med. Chem. 2016, 31, 628. (b) Crocetti, L.; Schepetkin, I.
A.; Cilibrizzi, A.; Graziano, A.; Vergelli, C.; Giomi, D.; Khlebnikov, A. I.;
Quinn, M. T.; Giovannoni, M. P. J. Med. Chem. 2013, 56, 6259.
(9) (a) Zhao, J.; Li, P.; Xia, C.; Li, F. Chem. Commun. 2014, 50, 4751.
(b) Yu, L.; Wang, M.; Wang, L. Tetrahedron 2014, 70, 5391. (c) For a
useful tutorial on azoles and the synthesis of N-acyl azoles, see: Begtrup,
M.; Larsen, P. Acta Chem. Scand. 1990, 44, 1050.
the oxoammonium salt 1a has been developed. The reaction
tolerates an array of aldehydes and alcohols as precursors to the
amide carbonyl as well as numerous azoles. The resulting
“activated amides”, more specifically N-acyl pyrazoles, proved
suitable for further functionalization. Reduction, esterification,
and hydrolysis could be carried out with ease. Using the oxidative
amidation strategy outlined here, non-azole amides could be
prepared from both alcohols and aldehydes via a multistep, one-
pot approach.
ASSOCIATED CONTENT
* Supporting Information
(10) Bobbitt, J. M.; Bartelson, A. L.; Bailey, W. F.; Hamlin, T. A.; Kelly,
C. B. J. Org. Chem. 2014, 79, 1055.
(11) Relevant reviews: (a) Mercadante, M. A.; Kelly, C. B.; Bobbitt, J.
M.; Tilley, L. J.; Leadbeater, N. E. Nat. Protoc. 2013, 8, 666. (b) Stockerl,
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b00060.
S.; García Mancheno, O. Org. Chem. Front. 2016, 3, 277. (c) García
̃
Experimental procedures and characterization data (PDF)
Mancheno, O.; Stopka, T. Synthesis 2013, 45, 1602. For recent examples,
̃
see: (d) Rohlmann, R.; Stopka, T.; Richter, H.; García Mancheno, O. J.
Org. Chem. 2013, 78, 6050. (e) Richter, H.; Frohlich, R.; Daniliuc, C.-G.;
García Mancheno, O. Angew. Chem., Int. Ed. 2012, 51, 8656. (f) Hayashi,
M.; Shibuya, M.; Iwabuchi, Y. Org. Lett. 2012, 14, 154. (g) Shibuya, M.;
Osada, Y.;Sasano, Y.;Tomizawa, M.;Iwabuchi, Y. J. Am. Chem. Soc. 2011,
133, 6497.
̃
̈
AUTHOR INFORMATION
■
̃
Corresponding Author
*E-mail: nicholas.leadbeater@uconn.edu.
ORCID
(12) Kelly, C. B.; Mercadante, M. A.; Wiles, R. J.; Leadbeater, N. E. Org.
Christopher B. Kelly: 0000-0002-5530-8606
Nicholas E. Leadbeater: 0000-0003-1823-5417
Notes
Lett. 2013, 15, 2222.
(13) Such a strategy was used successfully in our previous report to
mediate the exothermic nature of oxidative functionalization; see: Kelly,
C. B.; Lambert, K. M.; Mercadante, M. A.; Ovian, J. M.; Bailey, W. F.;
Leadbeater, N. E. Angew. Chem., Int. Ed. 2015, 54, 4241.
(14) We found later that this reaction was highly water tolerant. The
reaction could be conducted in 5−75% by volume H2O to CH2Cl2 or
MeCN and even in 100% water (albeit at longer reaction times).
(15) Andurkar, S. V.; Stables, J. P.;Kohn, H. Bioorg. Med. Chem. 1999, 7,
2381.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CAREER Award CHE-0847262 C.B.K., N.E.L.), the University
of Connecticut (UConn) Office of Undergraduate Research
(J.M.O., V.A.P.), and the National Collegiate Honors Council
Portz Fellowship (J.M.O.). We thank Dr. Leon Tilley of Stonehill
College and Mr. David Primer, Mr. Geraint Davies, Dr. Simon
D
DOI: 10.1021/acs.orglett.7b00060
Org. Lett. XXXX, XXX, XXX−XXX