A metal-free approach for the synthesis of amides/esters with pyridinium salts of phenacyl bromides via oxidative C–C bond cleavage

Article abstract of DOI:10.3762/bjoc.15.182

An efficient, simple, and metal-free synthetic approach for the N- and O-benzoylation of various amines/benzyl alcohols with pyridinium salts of phenacyl bromides is demonstrated to generate the corresponding amides and esters. This protocol facilitates the oxidative cleavage of a C–C bond followed by formation of a new C–N/C–O bond in the presence of K₂CO₃. Various pyridinium salts of phenacyl bromides can be readily transformed into a variety of amides and esters which is an alternative method for the conventional amidation and esterification in organic synthesis. High functional group tolerance, broad substrate scope and operational simplicity are the prominent advantages of the current protocol.

Full text of DOI:10.3762/bjoc.15.182

A metal-free approach for the synthesis of amides/esters
with pyridinium salts of phenacyl bromides via
oxidative C–C bond cleavage
Kesari Lakshmi Manasa1, Yellaiah Tangella2, Namballa Hari Krishna1
and Mallika Alvala*1,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 1864–1871.
1Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER), Hyderabad-500
037, India and 2Fluoro-Agrochemicals, CSIR-Indian Institute of
Chemical Technology, Hyderabad-500 007, India
doi:10.3762/bjoc.15.182
Received: 16 April 2019
Accepted: 26 July 2019
Published: 05 August 2019
Email:
Mallika Alvala* - mallikaalvala@yahoo.in
Associate Editor: B. Stoltz
* Corresponding author
§ Phone +91-9441117803
© 2019 Manasa et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
amidation; benzoylation; benzylamines; pyridinium salt of phenacyl
bromides
Abstract
An efficient, simple, and metal-free synthetic approach for the N- and O-benzoylation of various amines/benzyl alcohols with pyri-
dinium salts of phenacyl bromides is demonstrated to generate the corresponding amides and esters. This protocol facilitates the ox-
idative cleavage of a C–C bond followed by formation of a new C–N/C–O bond in the presence of K2CO3. Various pyridinium
salts of phenacyl bromides can be readily transformed into a variety of amides and esters which is an alternative method for the
conventional amidation and esterification in organic synthesis. High functional group tolerance, broad substrate scope and opera-
tional simplicity are the prominent advantages of the current protocol.
Introduction
Amidation and esterification are fundamental transformations in anhydrides [8], esters [9], and acyl azides [10] with amines by
synthetic chemistry. The occurrence of an amide and/or ester employing coupling reagents [11]. Alternative protocols include
bond is widely realized in organic molecules, proteins, natural the Staudinger–Vilarrasa reaction [12], Schmidt reaction
products, pharmaceuticals, polymers and agrochemicals [1-5]. [13,14], Beckmann rearrangement [15], aminocarbonylation of
The conventional synthesis of amides involves the reaction of aryl halides [16], Staudinger ligation [17], rearrangement of
carboxylic acids or their derivatives such as acyl halides [6,7], aldoximes [18], hydration of nitriles [19], dehydrogenative cou-
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pling of primary alcohols with amines [20,21] and hydration of synthesis of amides and esters in the presence of a suitable
organonitriles to amides [22-24]. However, these traditional amine or alcohol under basic conditions (Scheme 1). To the best
methods have certain disadvantages such as generation of toxic of our knowledge, this is the first report for the synthesis of
chemical waste, involvement of tedious work-up procedures amides and esters from the pyridinium salts of phenacyl bro-
and the requirement of stoichiometric amounts of coupling mides and benzylamines/alcohols via C(CO)–C(α) bond
reagents. On the other hand, benzoylation reactions are usually cleavage.
performed with benzoyl chloride or benzoic anhydride which
results in the formation of a substantial amount of undesired Results and Discussion
chemical waste. Moreover, these benzoic acid derivatives are To optimize the reaction conditions for N- and O-benzoylation,
commonly lachrymatory and are inconvenient to handle and a model reaction was performed between 1-(2-oxo-2-phenyl-
store.
ethyl)pyridin-1-ium bromide and benzylamine. Initially, the
reaction was carried out in acetonitrile at reflux temperature for
Over the past decades, the thermodynamic stability of C–C 8 h in the presence of K2CO3 (2 equiv), which resulted in the
bonds has attracted considerable attention of the synthesis formation of 3a in 78% yield (Table 1, entry 2). This inspiring
community for the reorganization of organic compound by a result led us to scrutinize the reaction conditions in detail. In-
sequential C–C cleavage and formation of new C–N bonds in creasing the amount of K2CO3 to 2.5 equiv resulted in a higher
the presence of transition metal catalysts [25-34]. Tang and Jiao yield of 81% (Table 1, entry 3). It was observed that further
reported copper catalyzed C–C single bond cleavage and C–N increase the number of equivalents of K2CO3 had no signifi-
bond formation [35]. However, the transition metal catalysts cant effect on the improvement of the yields (Table 1, entry 4).
and additives employed in these transformations are toxic and A decrease in the yields of the product was observed when the
restrict the substrate scope. Qandil et al. reported a transition number of equivalents of K2CO3 (1 equiv) were reduced
metal-free approach for the formation of amides and esters from (Table 1, entry 5), which suggests that 1 equiv of K2CO3 was
phenacyl bromides or chlorides [36]. Zhang et al. developed a insufficient to complete the reaction (Table 1, entry 5). Next,
milder and metal-free approach for the selective cleavage of we focused our attention on screening of other bases such as
C(CO)–C(α) bonds [37-40]. Kamal and co-workers also demon- KOH, NaOH, t-BUOK, Na2CO3, Et3N and DBU. It was ob-
strated a transition metal-free aerobic oxidative cleavage of served that K2CO3 is superior to other organic and inorganic
C–C bonds of phenacyl azides employed in the construction of bases employed (Table 1, entries 6–11). To further understand
amides utilizing benzylamines [41].
the effect of solvent a series of polar and non-polar solvents
such as toluene, THF, DMF and DMSO was employed in the
Herein we wish to report a metal-free C(CO)–C(α) bond reaction (Table 1, entries 12–15). However, there was no
cleavage of pyridinium salts of phenacyl bromides for the facile noticeable improvement in the yields of the desired product.
Scheme 1: Comparison of our work with previous studies.
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Table 1: Optimization of reaction conditions.a
Entry
Base (equiv)
Solvent
T [°C]
Time [h]
Yieldb [%]
1
2
3
4
5
6
7
8
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
THF
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
–
K2CO3 (2)
K2CO3 (2.5)
K2CO3 (3)
K2CO3 (1.0)
KOH (2.5)
NaOH (2.5)
t-BUOK (2.5)
Na2CO3 (2.5)
Et3N (2.5)
DBU (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
K2CO3 (2.5)
78
81
62
35
43
36
48
46
39
46
61
63
69
67
9
10
11
12
13
14
15
DMF
DMSO
aReaction conditions: 1a (1 mmol), 2a (1 mmol), base (2.5 mmol), solvent (5 mL), 8 h. bIsolated yields.
Hence, the optimal conditions for the required transformation like 1-phenylethanamine and a secondary amine like
were found to be 2.5 equiv of K2CO3 in CH3CN at 80 ºC for dibenzylamine were also found to be amenable for this transfor-
8 h.
mation and delivered the corresponding amides 3t and 3u in
good yields.
To understand the synthetic feasibility of the optimized reac-
tion conditions, we extended our studies to various substituted Inspired by the above results, we thought to study the feasi-
1-(2-oxo-2-phenylethyl)pyridin-1-ium bromides reacted with bility of O-benzoylation by utilizing benzyl alcohols under sim-
diverse benzylamines, and the results are illustrated in ilar reaction conditions. To our pleasure, various benzyl alco-
Scheme 2. Both electron-withdrawing and electron-donating hols bearing electron-withdrawing and electron-donating sub-
groups on both the aryl moieties of the pyridinium salt of stituents smoothly underwent O-benzoylation and delivered the
phenacyl bromides and benzylamines were well tolerated corresponding benzoate esters 5a–i in good yields (Scheme 3).
and delivered the corresponding products in good yields. The Similar results as for the of N-benzoylation were obtained with
electron-rich pyridinium salts of phenacyl bromides reacted respect to the electronic nature of the substituents on 1-(2-oxo-
smoothly with the amines and furnished the corresponding 2-phenylethyl)pyridin-1-ium bromides, where the presence of
products in excellent yields (3g–l and 3n, Scheme 2); however, electron-withdrawing groups on the pyridinium salts of
comparably lower yields were obtained with electron-with- phenacyl bromides resulted in lower yields compared to elec-
drawing pyridinium salts of phenacyl bromides (3m and 3o–s, tron-donating substituents.
Scheme 2). Similar results were observed with respect to the
electronic nature of substituents on the benzene ring of benzyl- To further investigate the synthetic applicability of the present
amines, where electron-donating substituents resulted in protocol, various anilines were also utilized which yielded the
comparably higher yields than the electron-withdrawing corresponding amides in moderate to good yields (Scheme 4,
substituents. An alkaloid amine like tryptamine was well 7a–g). Variously substituted anilines with electron-donating and
reacted and produced the corresponding amide 3f in a good electron-withdrawing groups such as –OCH3, –Cl, and –NO2
yield. It is worth mentioning that a sterically bulkier amine were well tolerated under the optimized reaction conditions
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Scheme 2: Scope of pyridinium salts and benzylamine substrates. Reaction conditions: 1 (1 mmol), 2 (1 mmol), base (2.5 mmol), solvent (5 mL),
80 °C, 8 h. Isolated yields are given in parentheses.
and delivered the corresponding products in good yields Control experiments
(7b–d). Even a heterocyclic amine such as benzo[d]thiazol-2- In order to elucidate the reaction mechanism for the formation
amine and a cyclic amine like pyrrolidine also reacted well of amides, a few control experiments were performed
and produced the corresponding amides in decent yields (7e and (Scheme 5). In this context we carried out the reaction under
7f).
oxygen (Scheme 5a) and nitrogen atmosphere by using stan-
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Scheme 3: Scope of pyridinium salts and benzyl alcohol substrates. Reaction conditions: 1 (1 mmol), 4 (1 mmol), base (2.5 mmol), solvent (5 mL),
80 °C, 8 h. Isolated yields are given in parentheses.
Scheme 4: Scope of pyridinium salts, primary and secondary amine substrates. Reaction conditions: 1 (1 mmol), 6 (1 mmol), base (2.5 mmol), sol-
vent (5 mL), 80 °C, 8 h. Isolated yields are given in parentheses.
dard optimized conditions to afford 3a. In the case of the reac- Plausible mechanism
tion under a nitrogen atmosphere (Scheme 5b) the yield of the A plausible reaction mechanism for the formation of amides is
product was decreased. The product was not detected in the depicted in Scheme 6. It is assumed that initially the nucleo-
reaction with water as solvent (Scheme 5c). And finally, the philic nitrogen/oxygen attacks the carbonyl carbon of the pyri-
pyridinium salt was replaced with phenacyl bromide (I) as a dinium salt of the phenacyl bromide to generate intermediate A.
starting material and the reaction was performed under stan- The attack of the ortho-position of the pyridinium moiety by the
dard optimized conditions, but the expected product could not nucleophilic oxygen of intermediate A is then proposed to
be detected (Scheme 5d).
generate cyclic oxazolopyridine intermediate B [42,43]. The
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Scheme 5: Control experiments for the oxidative cleavage of C–C bonds.
Scheme 6: Plausible reaction mechanism for the synthesis of N-alkylated benzamides 3.
intermediate B then undergoes a rearrangement to afford methodology include the absence of a metal catalyst, employ-
N-alkylated benzamide 3 via a C–C bond cleavage with ing a simple inorganic base and operational simplicity for appli-
the subsequent release of pyridin-1-ium-1-ylmethanide, cation in organic synthesis.
which further reacts with hydrogen bromide to form the
1-methylpyridin-1-ium bromide salt.
Supporting Information
Conclusion
Supporting Information File 1
In conclusion, we have developed an efficient, metal-free
protocol for the N- and O-benzoylation of various amines/
benzyl alcohols with pyridinium salts of phenacyl bromides for
the construction of amides and esters in the presence of base via
oxidative C–C bond cleavage. The promising features of this
Experimental procedures, characterization data and copies
of 1H and 13C NMR spectra of the compounds.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-182-S1.pdf]
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Acknowledgements
The authors thank the Department of Pharmaceuticals, Ministry
of Chemicals and Fertilizers Govt. of India, New Delhi for the
award of NIPER fellowship.
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