Triethyl Phosphite/Benzoyl Peroxide Mediated Reductive Dealkylation of O-Benzoylhydroxylamines: A Cascade Synthesis of Secondary Amides

Article abstract of DOI:10.1002/ejoc.202000611

A new triethyl phosphite/benzoyl peroxide (BPO) mediated system has been developed for the synthesis of secondary amides with good to excellent yields in a single step. This unprecedented cascade process involves sequential reduction of N–O bond and benzoylation followed by dealkylation of N–C bond of O-benzoylhydroxylamines (O-BHA). The methodology is versatile as it tolerates a variety of aromatic and aliphatic O-BHA as substrates to access secondary amides.

Full text of DOI:10.1002/ejoc.202000611

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Triethyl Phosphite/Benzoyl Peroxide Mediated Reductive
Dealkylation of O-Benzoylhydroxylamines: A Cascade Synthesis
of Secondary Amides
Authors: Balakrishna Aegurla, Ram D. Mandle, Prasad G. Shinde,
Ratan S. Parit, P. Kamble, A. Sudalai, and Senthilkumar
Beeran
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000611
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01/2020

10.1002/ejoc.202000611
European Journal of Organic Chemistry
COMMUNICATION
Triethyl Phosphite/Benzoyl Peroxide Mediated Reductive
Dealkylation of O-Benzoylhydroxylamines: A Cascade Synthesis
of Secondary Amides
Balakrishna Aegurla,§ Ram D. Mandle,§ Prasad G. Shinde,‡ Ratan S. Parit,‡ Sanjay, P. Kamble,§
Arumugam Sudalai,*,§ [a] and Beeran Senthilkumar*,‡ [b]
[a]
Dr. Arumugam Sudalai
Chemical Engineering & Process Development Division
CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune - 411008, Maharashtra, India
E-mail: a.sudalai@ncl.res.in; URL: https://www.ncl-india.org/files/Research/ScientistProfile/Default.aspx?menuid=ql8&Id=35&NCLEmpId=1317&UserId=71
Dr. Beeran Senthilkumar
[b]
Organic Chemistry Division
CSIR-National Chemical Laboratory
Dr. Homi Bhabha Road, Pune - 411008, Maharashtra, India
E-mail: b.senthilkumar@ncl.res.in; URL: http://academic.ncl.res.in/b.senthilkumar
Supporting information for this article is given via a link at the end of the document.
Abstract:
A
new triethyl phosphite/benzoyl peroxide (BPO)
mediated system has been developed for the synthesis of secondary
amides with good to excellent yields in a single step. This
unprecedented cascade process involves sequential reduction of
N−O bond and benzoylation followed by dealkylation of N−C bond of
O-benzoylhydroxylamines (O-BHA). The methodology is versatile as
it tolerates a variety of aromatic and aliphatic O-BHA as substrates
to access secondary amides.
The amide bond (−CO−NH−) is an essential functional group in
chemical synthesis, biology, and drug discovery.[1] Due to the
prevalence of amides in both natural and unnatural materials,
many synthetic protocols have been developed.[2,3] The classical
methods of preparation of secondary (2o) amides include the
reaction of amines with carbonyl derivatives,[4] and
hydroamination of alkynes.[5] Despite these developments,[3−5]
current trends on 2o amide syntheses are being focused on
direct transamidation of unactivated amides & amidation of alkyl
esters (entry A, Figure 1),[6] reaction between readily accessible
phenyl thiocarbamates and Grignard reactants (entry B, Figure
1),[7] aerobic oxidative couplings of alcohols and amines,[8] and
oxidation of benzylamines to benzamides under metal[9] and
metal-free conditions.[10] Recently, Lei et. al., reported an
efficient Bu4NI-catalyzed oxygen-centered radical addition
between acyl peroxides and isocyanides for the synthesis of 2o
amides (entry C, Figure 1).[11]
The development of efficient protection/deprotection routes
is crucial in organic synthesis. Mainly the reactivity of amines
can be a challenge when synthesizing the essential building
blocks, thus requiring protection/deprotection during a chemical
conversion.[12−15] O-Benzoylhydroxylamine 1 (O-BHA), readily
available electrophilic aminating reagents and an umpolung of a
nitrogen atom, has attracted much attention among the research
communities.[16−18] The nitrogen umpolung properties can be
fine-tuned through structural modifications.[16] Some of the
strategies developed to date rely upon electrophilic amination of
alkenes and alkynes using O-BHA as electrophilic aminating
reagents.[18] Recently, Bode et. al., have documented few
protocols for the amide bond formation using O-hydroxylamines
Figure 1. Recent progress in secondary amide formation and our approach.
and monofluoro acylboronates under mild conditions.[19]
However, in some of the cases, the synthesis of amides and
protection/deprotection
of
amines
requires
different
stoichiometric amounts of poisoning reagents and harsh reaction
conditions.[7,12−15,19] Due to current interest in the electrophilic
amination leading to amide synthesis,[16−19] we herein report an
1
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10.1002/ejoc.202000611
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Optimization of the reaction conditionsa.
efficient, straightforward, and operationally simple protocol for
the synthesis of secondary amides via sequential reduction,
benzoylation
followed
by
dealkylation
of
O-
benzoylhydroxylamines (entry D, Figure 1).
Initially, we were interested in the electrophilic amination of
styrene using acetone cyanohydrin as CN source and O-BHA 1
as a nitrogen electrophile.[20] Thus, when the reaction was
carried out using triethyl phosphite as promoter and benzoyl
peroxide (BPO) 2 as an oxidant in dichloroethane (DCE) as
solvent at 85 °C, unexpectedly, 2o amide 3 was obtained in 90%
yield (Scheme 1).
Temp
(°C)
Yield of 3
Entry
Oxidant
Base
(%)b
1
2
BPO
BPO
BPO
BPO
BPOd
TBHP
DMSO
BPO
BPO
-
P(OEt)3 1.5 equiv
P(OEt)3 1.5 equiv
P(OEt)3 1.5 equiv
P(OEt)3 1.0 equiv
P(OEt)3 1.5 equiv
P(OEt)3 1.5 equiv
P(OEt)3 1.5 equiv
P(OiPr)3 1.5 equiv
P(OPh)3 0.5 equiv
P(OPh)3 1.5 equiv
-
60
85
95
85
85
85
85
85
85
85
85
85
85
62 (30)c
94
90
80
65
nr
3
4
5
Scheme 1. Electrophilic amination and cyanation of styrene.
6
Encouraged by this result, O-BHA 1[22] and BPO 2 were
chosen as representative reactants for further optimization of the
reaction. In the presence of triethyl phosphite in DCE at 60 °C,
reductively dealkylated 2o amide 3 was indeed obtained in 62%
yield, along with benzaldehyde (44%) and benzoic acid (90%) as
side products (Table 1, entry 1). A significant increase in yield of
3 (94%) could be realized when the temperature was increased
to 85 °C (entry 2). However, a slight decrease in yield was
observed when the temperature was further increased to 95 °C
(entry 3). Reducing the amounts of P(OEt)3 and BPO to 1 and
1.5 equiv, respectively, resulted in a lower yield of 3 (80% &
65%; entries 4 & 5). Surprisingly, the reaction failed with other
oxidants like TBHP and DMSO (entries 6 & 7). The effect of
other phosphorus sources like P(OiPr)3, and P(OPh)3 was also
examined, which gave a moderate yield (50 & 66%) of 2o amide
3 (entries 8 & 9), while no reaction occurred with other bases
such as Et3N, Cs2CO3, Na2CO3 or KOtBu. The reaction also
failed with other organic solvents (CH3CN, and 1,4-dioxane).
Finally, to establish the role of BPO and P(OEt)3, we carried out
some control experiments in the absence of BPO, P(OEt)3 or
with other phosphorus sources (entries 12 & 13). The reaction,
however, failed to give 2o amide 3 in these cases.
7
nr
8
50
66
nr
9
10
11
12
13
BPO
BPO
BPO
nr
O=P(OEt)3
1.5 equiv
nr
O=P(Ph)3
1.5 equiv
nr
[a]
Reaction conditions: 1 (1 equiv), BPO (2 equiv), P(OEt)3 (1.5 equiv), DCE,
85 °C, 24 h. [b] isolated yield. [c] RT, [d] BPO (1 equiv), nr = no reaction.
In the case of cyclic protected hydroxylamines such as
pyrrolidin-1-yl benzoate 30 and morpholinobenzoate 31, it was
strangely found that the reaction provided 3o amides 32 & 33 in
91 and 87% yields, respectively,) via the simple reductive
process only (Scheme 4).
In order to determine its substrates scope, various
symmetrically substituted O-BHAs 1, 4–13 having alkyl, benzyl,
allyl, and aryl groups were subjected to reactions under
optimized conditions (Scheme 2). Evidently, good to excellent
yields (71–94%), of 2o amides 3, 14–22, were obtained in most
cases, indicating that the reaction is not sensitive to electronic
effects. However, the present dealkylation strategy afforded the
lower yield (56%) in the case of aromatic hydroxylamine 13.
Finally, we decided to test the behavior of mono protected
O-BHA such as N-(1-phenylethyl)-O-benzoylhydroxylamine 34.
In this case, the reaction afforded the benzoylated product 28 in
66% yield exclusively via simple reduction, without undergoing
the dealkylation process (Scheme 5). This result suggests that
the reductive benzoylation is facile and precedes dealkylation
step, leading to the formation of 2o amides (Schemes 4 & 5).
To demonstrate its scalability and practicality, we
performed the reaction of O-BHA 1 at the 2.0 g scale, for 24 h
under standard conditions, which afforded 3 in 91% yield, with
no significant decrease in reaction efficiency. To extend its
scope further, a “one-pot” experiment was carried out directly
from dibenzylamine instead of 1 that gave the amide 3 in
moderate yield (63%) along with some complex mixture.
Next, unsymmetrically substituted O-BHAs 24–27 were
subjected to reaction under the optimized condition. Interestingly,
the reaction proceeded smoothly to afford the corresponding 2o
amides 3, 15, 28 & 29 in 91, 83, 80 and 76% yields, respectively.
This result has shown that the reaction proceeds via preferential
defurfurylation and deethylation over debenzylation reductive
processes (Schemes 3).
2
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10.1002/ejoc.202000611
European Journal of Organic Chemistry
COMMUNICATION
Scheme 5. Reductive benzoylation for the synthesis of secondary amide.
In order to get an insight into the reaction mechanism, we
performed the following control experiments: (i) Firstly, when
TEMPO and BHT was employed in varying amounts (1 & 2
equiv) and (1.2 equiv), respectively, in the reaction,
a
significantly decreased yield of 3 was obtained in both cases,
thereby indicating that the reaction probably proceeds by a
radical pathway; (ii) Further, when O-4-methoxy-BHAs 35 & 36
were employed as substrates under optimal conditions, 2o
amides 3 and 14 were produced in 76% and 69% yield,
respectively; (iii) Finally, the reaction of O-BHA 1 & 8 with 4-
methoxybenzoic peroxyanhydride 37 was conducted under the
optimized conditions, that afforded the corresponding 2o amides
38 & 39 in 76%, and 69% yields, respectively. These results
clearly establish that benzoyl groups in 2o amides 3, 14, 38 & 39
have come from the corresponding BPO 2 & 37 respectively
(Scheme 6).
Scheme 2. Substrates scope for the reductive benzoylation followed by
dealkylation of O-BHA.
Scheme 6. Control experiments for mechanistic studies.
Based on our experimental results and literature
precedence,[18,20,21] a plausible mechanism for the cascade
reductive
benzoylation
and
dealkylation
of
O-
benzoylhydroxylamine 1 is outlined in Scheme 7, although a
detailed mechanism remains unclear. We believe that, first of all,
a redox process sets in when O-benzoylhydroxylamine 1
undergoes reaction with equimolar amount of P(OEt)3 and BPO
producing a phosphorus cation radical species A. Subsequently,
species A can possibly undergo intramolecular migration to
provide nitrogen cation radical B with the concomitant removal
of O=P(OEt)3. This is then followed by abstraction of hydrogen
radical by benzoate radical from another equivalent of BPO
leading to the formation of an iminium ion C. This upon
Scheme 3. Substrates scope for the unsymmetrical O-BHAs.
Scheme 4. Substrates scope for the synthesis of 3o amides.
3
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10.1002/ejoc.202000611
European Journal of Organic Chemistry
COMMUNICATION
hydrolysis furnishes the 2o amide 3 along with PhCO2H and
PhCHO as by-products (Scheme 7).
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Scheme 7. Plausible reaction mechanism.
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In summary, we have developed, for the first time, a simple
protocol involving triethyl phosphite/benzoyl peroxide (BPO)
mediated C−N bond formation that provides for the synthesis of
a variety of 2o amides. This novel cascade reaction proceeds via
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reductive
benzolylation
and
dealkylation
of
O-
benzoylhydroxylamines. The salient features of the methodology
are: (1) metal-free synthesis; (2) easily accessible starting
materials and inexpensive reagents; (3) good functional group
tolerance and (4) high yields of secondary amides. We believe
that this operationally simple and mild process would serve as a
useful method that will find tremendous applications in the
chemical synthesis of widely occurring natural products and
medicinal chemistry.
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Acknowledgements
The authors would like to thank CSIR, New Delhi (No.
CSIR/21(1003)/16/EMR-II) partially by the Science and
Engineering Research Board (SERB) (EEQ/2016/000223) and
(EMR/2016/007030) New Delhi, India for financial support.
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Wang, J. Org. Chem. 2019, 84, 1468–1488; b) A. M. Berman, J. S.
Johnson, J. Am. Chem. Soc. 2004, 126, 5680–5681, refer the scheme
below.
Keywords: O-Benzoylhydroxylamines 1 • 2o Amides 2 •
Cascade 3 • Reductive 4 • Dealkylation 5
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4
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10.1002/ejoc.202000611
European Journal of Organic Chemistry
COMMUNICATION
Entry for the Table of Contents
Key Topic: Secondary amides synthesis
Triethyl Phosphite/Benzoyl Peroxide Mediated Reductive Dealkylation of O-
Benzoylhydroxylamines: A Cascade Synthesis of Secondary Amides
Balakrishna Aegurla,§ Ram D. Mandle,§ Prasad G. Shinde,‡ Ratan S. Parit,‡ Sanjay, P. Kamble,§ Arumugam Sudalai,*,§ and Beeran
Senthilkumar*,‡
An efficient and operationally simple protocol for the synthesis of 2o amides via reductive benzoylation dealkylation of O-
benzoylhydroxylamines (O-BHA), by using triethyl phosphite as a reducing agent and benzoyl peroxide as an oxidizing agent is
described.
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