Base-Mediated Anti-Markovnikov Hydroamidation of Vinyl Arenes with Arylamides

Article abstract of DOI:10.1021/acs.orglett.0c04084

We investigated a base-promoted protocol for the intermolecular anti-Markovnikov hydroamidation of vinyl arenes with arylamides to furnish the arylethylbenzamides with excellent chemo- and regioselectivity. The reaction tolerates an extensive variety of functional groups and has been successfully extended with electronically varied handles, aminobenzamides, electron-rich/electron-deficient heterocyclic amides, and vinyl arenes to afford the hydroamidated products. Excellent chemoselectivity was observed for the amide group over amine. The proposed mechanism and vital role of the solvent was well supported by deuterium labeling studies and control experiments.

Full text of DOI:10.1021/acs.orglett.0c04084

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Letter
Base-Mediated Anti-Markovnikov Hydroamidation of Vinyl Arenes
with Arylamides
Ayushee, Monika Patel,# Priyanka Meena,# Kousar Jahan, Prasad V. Bharatam, and Akhilesh K. Verma*
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ABSTRACT: We investigated a base-promoted protocol for the intermolecular anti-Markovnikov hydroamidation of vinyl arenes
with arylamides to furnish the arylethylbenzamides with excellent chemo- and regioselectivity. The reaction tolerates an extensive
variety of functional groups and has been successfully extended with electronically varied handles, aminobenzamides, electron-rich/
electron-deficient heterocyclic amides, and vinyl arenes to afford the hydroamidated products. Excellent chemoselectivity was
observed for the amide group over amine. The proposed mechanism and vital role of the solvent was well supported by deuterium
labeling studies and control experiments.
Scheme 1. Strategies for the Hydroamidation of Vinyl
Arenes
he amide pharmacophore is ubiquitous in diverse
pharmaceutical and biologically active molecules.1a,b
T
Recently, the amide linkages have shown a potent activity
against COVID-19 respiratory syndrome.1c−e Amides are the
common templates for amino acids, which are considered as
building blocks of peptides and proteins.2 The construction of
suitably functionalized amide frameworks is useful in many
industrial and natural product syntheses.3 In the past few
decades, many traditional approaches for transition-metal-
catalyzed hydroamination of N-heterocycles and primary/
secondary amines with alkynes and alkenes have been well
explored.4−6 Base-mediated nucleophilic addition of hetero-
cycles as well as amine moieties has also been known from
many renowned reactions reported in the literature.7,8
However, due to the formation of highly stable resonating
structures and poor nucleophilicity hydroamination of amides
is still challenging.9−11
An elegant approach to Markovnikov’s addition12a,b of
amides on to vinyl arenes using Pt complex was depicted by
Widenhoefer and co-workers12c in 2005 (Scheme 1a). A
similar type of chemistry has been demonstrated by the
Limbach13 group using cationic platinum(II) complexes with
bi- or tridentate NHC ligands for the hydroamidation of
unactivated alkenes (Scheme 1b). Asymmetric hydroamination
permits the straightforward and selective formation of a new
C−N bond as a convenient methodology toward valuable
synthons.14a,b In 2012, Hartwig et al. described the addition of
4-tert-butylbenzamide to 1-octene in the presence of iridium
cataylst.14c In recent years, transition-metal-free reactions have
Received: December 10, 2020
Published: January 4, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04084
© 2021 American Chemical Society
Org. Lett. 2021, 23, 565−570
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extended its relevance due to its low toxicity, cost-effectiveness,
and no requirement for noncommercial ligands in chemical
reactions.15 In continuation of our ongoing research on base-
promoted reactions16 and hydroamination chemistry,17 we
anticipated that the direct hydroamidation of alkene could
occur via KOH-DMSO assisted nucleophilic addition (Scheme
1c).
To explore the base-assisted nucleophilic addition we began
with the examination of a several bases and solvent reported in
the literature using benzamide 1a and styrene 2a as a model
substrate (Table 1). Inspired by our previous conditions,17 we
reactants and product 3a is negligible (0.028 kcal/mol); i.e.,
the reactant and product exist in equilibrium. Alternatively, the
product 3a′ (Markovnikov’s) formation is an endergonic
process by 4.18 kcal/mol and hence is not a preferred path (as
supported by experimental observation).
With the optimized reaction conditions in hand, we
extended the scope of the developed protocol with various
arylalkyl alkenes (Scheme 2). The reaction of benzamide 1a
a b
,
Scheme 2. Scope of Vinyl Arenes
a
Table 1. Optimization Table
b
entry
base
solvent
time (h) temp (°C) yield (%) 3a
117
2
3
4
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
K2CO3
K3PO4
Et3N
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
EtOH
EG
NMP
THF
toluene
DMSO
DMSO
DMSO
0.5
6
12
120
120
120
120
80
120
70
120
120
60
c
30
48
80
30
c
trace
55
61
c
24
24
24
24
24
24
24
24
24
24
24
5
6
d
a
b
Optimized conditions (entry 4, Table 1). Isolated yield.
7
8
9
10
11
12
13
14
with styrene 2a, electron-releasing alkenes 2b (4-Me), and 2c
(4-OMe) furnished the products 3a−c in 70−80% yields.
Notably, the halogen-substituted styrene 2d effectively gave
the corresponding hydroamidated product 3d in 75% yield. It
is worth noting that reaction of 1a with a bulky and sterically
hindered alkene such as diphenyl(4-vinylphenyl)phosphine 2e
and (4-methylpent-1-ene-2,4-diyl) dibenzene 2f provided the
desired products 3e and 3f in 71 and 60% yield, respectively.
However, the 4-nitrostyrene 2g, aliphatic alkene 2h, and
acrylate 2i were incapable of producing the hydroamidated
product (Scheme 2).
100
120
120
120
c
40
50
c
a
Reactions were carried out using 0.5 mmol of 1a, 2a (0.8 mmol), and
b
c
base (0.5 equiv) in 2.0 mL of solvent. Isolated yield. No reaction.
d
Base (0.2 equiv). 3a′ product was not obtained. EG = ethylene
glycol, NMP = N-methylpyrrolidone, THF = tetrahydrofuran.
Encouraged by the above results, the reaction of alkene 2
with electronically bias ring/substituents on the amide partner
was performed (Scheme 3). The reaction of amide 1b bearing
an electron-releasing methyl group provided the desired
hydroamidated products 4a−f in 60−79% yields. The reaction
of 4-methoxybenzamide 1c with styrene 2a was fruitful in
providing the product 4g in 78% yield. It was interesting to
note that the 4-hydroxybenzamide 1d selectively gave the
hydroamidated product 4h in 65% yield. However, strong
electron-withdrawing nitro-substituted benzamide 1e did not
undergo the addition reaction smoothly. The addition of 3-
(trifluoromethyl) benzamide 1f on to alkene 2a furnished the
product 4j in 81% yield. The halogen and electron-with-
drawing group containing alkenes 2j (4-Cl) and 2k (4-CF3)
were successful in delivering the nucleophilic addition product
4k−l in good yield. When benzamide 1g containing a bromo
substituent at the ortho position of aryl ring was used for the
reaction, the desired addition products 4m−o were obtained in
69−78% yields. In contrast to o-bromobenzamide, the para-
substituent 1h gave 4-bromo-N-phenethylbenzamide 4p in
80% yield. A sluggish reaction of 4-fluoro-3-formylbenzamide
1i with 2a was observed (Scheme 3).
carried out the reaction of 1a with alkene 2a using KOH in
DMSO at 120 °C for 0.5 h, but the conversion did not initiate
(entry 1). The promotional effect of time elevates the yield of
the product 3a (entries 2−4). On lowering the reaction
temperature, a 30% yield of the hydroamidated product was
observed (entry 5). When 0.2 equiv of KOH was loaded in the
system, the nucleophilic addition reaction did not occur (entry
6). Exchanging the solvents EtOH, ethylene glycol, NMP,
THF, and toluene with KOH proved to be inferior for the
reaction (entries 7−11). Different bases such as K2CO3, and
K3PO4 were studied, and it was found that the nature of bases,
as well as their counterions, influenced the reactivity of the
hydroamidation reaction and provided compound 3a in
moderate yields (entries 12 and 13), while no product was
observed with Et3N (entry 14).
To understand the possible reason for the selective
formation of anti-Markovnikov product, quantum chemical
calculations were accomplished using the B3LYP/6-311+G(d)
method. Complete optimization of the 3D structures of 1a, 2a,
3a, and 3a′ (Table 1) were performed using the Berny
optimization procedure. The enthalpy of the reactions was
carried out by estimating the relative energies. The formation
of 3a (anti-Markovnikov product) is a thermodynamically
favorable process because the energy difference between the
Subsequently, we explored the chemoselectivity of the
reaction using aminobenzamides (Scheme 4). To study the
chemoselective hydroamidation, we carried out reaction
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a b
,
a b
,
Scheme 3. Scope of Aryl Amides
Scheme 5. Scope of Heterocyclic Amides
a
b
Optimized conditions (entry 4, Table 1). Isolated yield.
Scheme 6. Late-Stage Modification of Probenecid Derivative
a
b
c
Optimized conditions (Table 1, entry 4). Isolated yield. Using 2.0
equiv of KOH
Scheme 7. Comparative and Selectivity Hydroamidation
Studies
a b
,
Scheme 4. Scope of Chemoselective Hydroamidation
a
b
Optimized conditions (Table 1, entry 4). Isolated yield.
between 2-aminobenzamide (1j) and 4-aminobenzamide (1k)
with vinyl arenes 2a,b, 2j, and 2d; the hydroamidated products
5a,b, and 5c−f were obtained chemoselectively in 65−80%
yields without effecting the 1° amino group (Scheme 4).
The scope of this base-assisted hydroamidation was further
explored by using electron-deficient and electron-rich hetero-
cyclic amides 6a and 6b (Scheme 5). Reaction of both the
amides 6a and 6b with vinyl arenes 2a,b, 2j, and 2l provided
the respective hydroamidated products 7a−g in 69−88% yields
(Scheme 5).
Probenecid has shown curative activity toward gout and
hyperuricemia diseases. To our delight, the conversion of 4-
(N,N-dipropylsulfamoyl)benzamide 8 produced the pharma-
ceutically promising 4-(N,N-dipropylsulfamoyl)-N-phenethyl
benzamide 9 in 78% yield (Scheme 6). In order to observe the
comparative hydroamidation studies between styrene (2a) and
phenylethyne 10a and 10b with benzamide (1a), we carried
out a control experiment (Scheme 7a) using 0.5 equiv of KOH
at 120 °C. We observed that alkyne hydroamidated product
11a,b was obtained in 77−72% yield within 15 min; however,
the formation of product 3a was not observed (Scheme 7a).18
In another set of control experiments, o-arylalkyne benzamide
12 was reacted with styrene (2a); an intramolecular cyclized
isoquinoline 13 was obtained in 92% yield, and no hydro-
amidated product 13′ was observed (Scheme 7b).
Further, to study the selective hydroamidation of bis-amide
6c and 1,3-divinylbenzene 2m we performed four sets of
control experiments (Scheme 7c, i−iv) and monitored the
formation of products. In the first set of reactions, we reacted
2m with 6a (0.5 mmol) using 0.5 equiv of KOH at 120 °C for
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24 h; mono-hydroamidated product 14 was observed in 63%
yield (Scheme 7c, i). However, the reaction of 1,3-
divinylbenzene 2m with benzamide (1a) using 1.5 equiv of
KOH provided bis-hydroamidated product 15 in 67% yield
(Scheme 7c, ii). Another control experiment was carried out
between a bis-amide 6c and styrene 2a. It was observed that
the use of 0.5 equiv of KOH provided the mono-hydro-
amidated product 16 in 66% yield; however, bis-hydro-
amidated product 16′ was obtained in 65% yield using 1.5
equiv of KOH (Scheme 7, iii, iv).
Scheme 9. Proposed Mechanism
In addition, to support the proposed mechanistic pathway,
assorted preliminary experiments were performed (Scheme 8).
Scheme 8. Mechanistic Control Experiments
B in the presence of base to form amidoyl radical species C.22
The radical species C reacts with vinyl arene 2 in anti-
Markovnikov fashion to form species D (a stable benzyl
radical). After the abstraction of a deuterium atom from
DMSO-d6, monodeuterated product 3 is formed and the
dimesyl radical is regenerated.
In conclusion, this study disclosed the first example of anti-
Markovnikov addition of aryl amides on vinyl styrenes under
metal-free conditions with excellent chemo- and regioselectiv-
ity. The generality of the reaction was manifested by the broad
scope of electron-donating and electron-withdrawing aryl
amides and vinyl arenes. The versatility of the reaction has
been demonstrated by performing controlled mono- and bis-
hydroamidation reactions of 1,3-divinylbenzene and pyridine-
2,6-dicarboxamide. The methodology was further extended for
the late-stage modification of pharmaceutically important
probenecid. A proposed possible mechanism was established
by the control experiments, isotopic labeling studies, and
capturing of K+ ion using 18-crown-6.
The reaction of 1a with styrene 2a was conducted under N2
atmosphere, and the hydroamidation reaction occurred
smoothly to provide product 3a in good yield (see the
Supporting Information). We performed gram-scale experi-
ments for the hydroamidation reaction using benzamide 1a
and styrene 2a as the starting substrate. The gram-scale
reaction was successful in providing the desired product in
78% yield (eq i). Initially, we thought that the source of −CH2
protons in the addition linkage between amide and alkene
came from the DMSO solvent. In order to determine the
source of protons, the reaction of benzamide 1a with styrene
2a was conducted in DMSO-d6. The deuterated product 3a′′
was isolated in 74% yield with a single H−D exchange,
indicating the proton comes from solvent the (eq ii).
ASSOCIATED CONTENT
■
sı
* Supporting Information
For further validation, we planned the reaction of benzamide
1a and deuterated styrene-d3 17 in KOH/DMSO; we fruitfully
obtained the deuterated product 18 in 72% yield, confirming
the anti-Markovnikov mechanism of hydroamidation (eq iii).
We further examined the reaction of 1a with 2a in TEMPO/
AIBN at 120 °C, where no formation of hydroamidated
product 3a infers that the reaction follows the radical pathway
(eq iv). The hydroamidation reaction failed in the presence of
18-crown ether (1.0 equiv), which further validates the
mechanism and deduces that the K+ ion polarizes the alkene
(eq v). Hydroamidated product was not observed when the
reaction of benzamide 1a with styrene 2a was performed in the
presence of heavy water. This illustrate that KOH/DMSO is
essential for the protonation during nucleophilic addition
linkage (Scheme 8, vi).
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04084.
1
Data and spectral copies of H, 13C NMR, and HRMS
for target compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Akhilesh K. Verma − Department of Chemistry and Ramjas
College, Department of Chemistry, University of Delhi, Delhi
110007, India; Ramjas College, Department of Chemistry
and Department of Chemistry, University of Delhi, Delhi
110007, India; Department of Medicinal Chemistry,
National Institute of Pharmaceutical Education and Research
(NIPER), Mohali 160062, Punjab, India; orcid.org/
0000-0001-7626-5003; Email: averma@acbr.du.ac.in
On the basis of the preceding mechanistic studies,19,20 we
put forth a reasonable mechanistic hypothesis as described in
Scheme 9. The mechanism is initiated by the generation of
dimesyl radical B21 via a single electron transfer (SET) from
dimesyl anion A. Then amide 1 is induced by a dimesyl radical
Authors
Ayushee − Department of Chemistry, University of Delhi,
Delhi 110007, India
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Monika Patel − Ramjas College, Department of Chemistry,
University of Delhi, Delhi 110007, India
Priyanka Meena − Department of Chemistry, University of
Delhi, Delhi 110007, India
Kousar Jahan − Department of Medicinal Chemistry, National
Institute of Pharmaceutical Education and Research
(NIPER), Mohali 160062, Punjab, India
Prasad V. Bharatam − Department of Medicinal Chemistry,
National Institute of Pharmaceutical Education and Research
(NIPER), Mohali 160062, Punjab, India
Complete contact information is available at:
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Author Contributions
#M.P. and P.M. contributed equally
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was supported by IoE/FRP/PCMS/2020/27 and
USIC for instrumentation facilities. A.Y.U. and P.M. are
thankful for the UGC for fellowships.
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