Keteniminium-Driven Umpolung Difunctionalization of Ynamides

Article abstract of DOI:10.1002/anie.201915522

A three-component Pd-catalyzed coupling of ynamides, aryl diazonium salts, and aryl boronic acids for the synthesis of novel triaryl-substituted enamides is described. This transformation represents the first example of an umpolung regioselective unsymmetrical syn-1,2-diarylation/aryl-olefination of ynamides. The aryl moieties of the diazonium salt (electrophile) and boronic acid (nucleophile) are explicitly incorporated in the electrophilic α- and nucleophilic β-position, respectively, of the ynamide, resulting in a single isomer of the N-bearing tetrasubstituted olefin. The scope is broad (68 examples), showing excellent functional-group tolerance. DFT calculations substantiate the rationale of the mechanistic cycle and the regioselectivity. The chemoselectivity and synthetic potential of the enamide products were also studied.

Full text of DOI:10.1002/anie.201915522

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Accepted Article
Title: Keteniminium Driven Umpolung Difunctionalization of Ynamides
Authors: Akhila Kumar Sahoo, Shubham Dutta, shengwen yang,
Rajeshwer Vanjari, Rajendra kumar Mallick, and vincent
gandon
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201915522
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Keteniminium Driven Umpolung Difunctionalization of Ynamides
Shubham Dutta,† Shengwen Yang,‡¥# Rajeshwer Vanjari,†# Rajendra K. Mallick,† Vincent Gandon,‡¥*
and Akhila K. Sahoo†*
[†]
[‡]
Shubham Dutta, Rajeshwer Vanjari, Rajendra. K. Mallick, and Prof. Dr. Akhila K. Sahoo, School of Chemistry, University of Hyderabad, Hyderabad (India)
E-mail: akhilchemistry12@gmail.com
Shengwen Yang and Vi -
91405 Orsay cedex (France)
E-mail: vincent.gandon@u-psud.fr
[¥]
[#]
Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Université Paris-Saclay, route de Saclay, 91128 Palaiseau cedex
(France)
These authors contributed equally.
Abstract: A three component Pd-catalyzed coupling of ynamides,
aryl diazonium salts, and aryl boronic acids for the synthesis of novel
triaryl-substituted enamides is described. This transformation
represents the first example of an umpolung regioselective
unsymmetrical syn-1,2-diarylation/aryl-vinylation of ynamides. The
aryl moieties of diazonium salt (electrophile) and boronic acid
(nucleophile) are explicitly incorporated in the electrophilic - and
nucleophilic -position of the ynamide, respectively, resulting in a
single isomer of N-bearing tetrasubstituted olefin. The scope is
broad (67 examples) showing excellent functional group tolerance.
DFT calculations substantiate the rationale of the mechanistic cycle
and the regioselectivity. Chemoselectivity and synthetic potential of
the enamide products are also studied.
Ynamide, a versatile N-containing alkyne synthon, has had a
profound impact in uncovering novel synthetic methods. It has
also been used for the synthesis of complex molecular
frameworks.[1] In this regard, functionalization of the electron-rich
polarizable N-bearing alkyne (i.e. ynamide; I) via trapping of a
nucleophile and an electrophile at the  and  positions of the
keteniminium species (II), respectively, provides substituted
olefins III (Fig. 1a, path-I)].[2] However, on a conceptual note,
umpolung difunctionalization of ynamides with electrophiles and
nucleophiles at the - and -positions, respectively, is
significantly challenging although exceedingly valuable (Fig. 1a,
path-II). However, such umpolung difunctionalization of
ynamides is so far confined to: i)
a strain controlled
intramolecular trapping of a nucleophile (Fig. 1b, path-I),[3] or ii) a
chelation driven carbometalation and functionalization sequence
that primarily requires a bimetallic system (Fig. 1b, path-II).[4] In
these approaches, the attack of the nucleophile is pivotal in
making such strategies synthetically viable. On the other hand,
the development of a non-directed multicomponent umpolung
difunctionalization of ynamides that is initiated by the attack of
the electrophile is undoubtedly a worthwhile endeavor.
Figure 1. a) Background, b) Umpolung reactivity of ynamide c) Hypothesis, d)
This work: regioselective diarylation of ynamides.
Thus, an electrophilic activation of ynamide I with aryl metal-
complex {generated in-situ from an electrophile Ar1N2BF4 (E)[5]
with a low-valent transition metal species [i.e. Pd(0)]} to a
keteniminium species XI, regioselective 1,3-aryl (E′) migration to
the -position of XI to give the vinylic metal-complex XII, and
then the trapping of the nucleophile Ar2B(OH)2 with XII for the
synthesis of tetra substituted N-bearing olefin XIII is precisely
envisaged (Fig. 1c). Inspired by the challenges and
shortcomings related to regioselectivity and harsh conditions in
the unsymmetrical difunctionalization of unsaturated systems for
the construction of tetra substituted olefins and tamoxifen
analogues,[6] an unsymmetrical diarylation of ynamides with aryl
diazonium salts and aryl/vinyl boronic acids in the presence of
a Pd(0)-catalyst and a base at room temperature (rt) has been
developed. The transformation reported below is exclusively
regio- and stereoselective and is synthetically practical (Fig. 1d).
The investigation was initiated by examining the reaction of N-
benzyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (1a) with
p-methoxybenzene diazonium tetrafluoroborate (2a) and p-
methylbenzene boronic acid (3a) using Pd2(dba)3·CHCl3 as
catalyst and a base (Scheme 1). An extensive screening led to
these optimized reaction conditions: [1a (1.0 equiv), 2a (1.5
equiv), 3a (1.2 equiv), Pd2(dba)3·CHCl3 (5.0 mol%), NaHCO3

(1.2 equiv), DMSO as solvent, at 25 C, overnight]. With these,
the desired diarylation product 4a was isolated in 92% yield (I).
1
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butadienes [4aa (59%), 4ab (58%), 4ac (62%), and 4ad (61%)].
The structures of 4p, 4v, and 4ab were confirmed by single
crystal X-ray analysis; thus, the electronic factor does not affect
the product regioselectivity.[1214]
Having demonstrated the synthetic potential of this
regioselective double arylation of ynamides with respect to
boronic acids and diazonium salts, we next investigated the
ynamide scope towards 2a and 3d under the optimized
conditions (Scheme 3). The reaction of respective ynamides
100
92%
90
80
72%
70%
70
61%
61%
58%
55%
60
50
40
30
20
10
0
51%
22%
III
I
II
IV
V
VI
VII
VIII
IX
Scheme 1. Optimization Graph[a,b] [a]Reaction condition: ynamide 1a (0.15
.
mmol), diazonium salt 2a (0.225 mmol), boronic acid 3a (0.18 mmol) for
overnight. [b]Isolated yield.
K2CO3 and LiOtBu proved to be far less efficient bases (II and III).
Comparable results were observed when other Pd(0) catalysts
[Pd2(dba)3, Pd(dba)2, and Pd(PPh3)4] were used (IVVI). The
use of THF, toluene, and 1,4-dioxane as solvent led to moderate
yields (VIIIX).
The optimized catalytic conditions were next probed while
examining the scope of this regioselective double arylation of
ynamides with distinct coupling partners (Schemes 2 and 3).
The reactivity of aryl boronic acid coupling partners (3) with
ynamides 1a and 2a was at first surveyed (Scheme 1a). The
reaction of electron-rich p-substituted aryl boronic acids [p-Me
(3a), p-OMe (3b), p-OCF3 (3c)] with 1a and 2a provided the
respective products 4ac in good to excellent yields. Likewise,
tetra-substituted enamides 4di (7895%) were constructed
from the electron-neutral phenyl boronic acid (3d) and electron-
poor [p-CN (3e), p-CF3 (3f), p-CHO (3g), p-CO2Me (3h), p-
COMe (3i)] substituted aryl boronic acids when exposed
independently to 1a and 2a. Gratifyingly, the aryl boronic acids
having labile halo groups [p-F (3j), p-Cl (3k), p-Br (3l), even the
oxidizable p-I (3m), m,p-dibromo (3n), and p-Cl-m-F (3o)] were
tolerated under the Pd-catalysis and the desired products 4jo
were isolated in excellent yields. The desired thienyl substituted
enamides 4p (65%) and 4q (78%) were accessed from the
coupling of 2/3thienyl boronic acids (3p and 3q) with 1a and 2a,
p . T π-extended 1-naphthyl-(3r) and 2-naphthyl
boronic acids (3s) could also participate in this transformation,
delivering 4r (81%) and 4s (58%), respectively.
Next, the scope of aryl diazonium tetrafluoroborates in the
coupling of 1a with 3a/3d was surveyed (Scheme 1b). The
electron-rich [3,4-methylenedioxy (2b), p-Me (2c)] substituted
aryl diazonium salts provided a better outcome over the
electron-deficient substrates [m-CN (2d), m-CF3 (2e)], furnishing
4t (81%), 4u (94%), 4v (71%), and 4w (75%), respectively. This
might be explained by the poor stability of electron-deficient
diazonium salts. Once again, the halo groups were well-
tolerated under the Pd-catalytic conditions, as the halo-
substituted aryl diazonium salts were fruitfully employed in this
double arylation of 1a in the presence of 3a [p-I (2f) 4x, p-Br
(2g) 4y, and p-Cl (2h) 4z]. Unlike aryl boronic acids, the
alkenyl boronic acids (generally susceptible to the Heck
reaction) were also relevant partnersin this three-component
coupling transformation, yielding highly substituted 1,3-trans-
Scheme 2. Scope of aryl diazonium salts and aryl boronic acids. Ynamide 1a
(0.3 mmol), diazonium salt 2 (0.45 mmol), boronic acid 3 (0.36 mmol) for
overnight. [a]1,4-dioxane was used instead of DMSO at 10 C.
2
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{having aryl motifs [electron-rich (p-Me), electron-poor (m-NO2,
p-CHO), labile (p-F, m-F, p-Cl, m,p-diCl, m,p-methylenedioxy) at
the ynamide terminus} with 2a and 3d independently furnished
the desired diarylation products 5a–h in good yields. The
tetrasubstituted enamide 5i (with a cyclohexyl group on -atom)
was prepared in 66% yield. The N-Me protected ynamides with
various aryl substituents at the ynamide terminus effectively
participated, affording 5j (92%), 5k (91%), and 5l (84%). Next,
N- sulfonyl protected diarylated enamides 5m5p {having N-Me-
[SO2C6H4-p- I/ SO2C6H4-p-Br/ SO2C6H4-p-F/ SO2C6H4-p-NO2]}
were synthesized in good yields. Likewise, several enamides
{having N-Bn -[SO2C6H5 (5q) / SO2C6H3-m,p-diOMe (5r) / SO2-
C6H4-p-Ph (5s) /SO2-2-thienyl (5t) / SO2-2-naphthyl (5u) /
SO2C6H4-p-COMe (5v) / SO2C6H4-p-CN (5w) / SO2C6H4-p-CF3
(5x) / SO2C6H4-m-CF3 (5y) / SO2C6H4-p-Cl (5z) / SO2C6H4-p-Br
(5aa) / SO2Me (5ab) / SO2Et (5ac and 5af) / SO2 Bu (5ad) /
n
SO2Bn (5ae)} were accessed. Compound 5ag (81%) was
obtained from 1ag and its structure was further confirmed by
single crystal X-ray analysis.[15] The N,N-dimethyl group (which
easily binds transition metal catalysts) did not prevent the
reaction, yielding 5ah (71%). The steric demand at the sulfonyl
side in the chiral camphor sulfonyl protected ynamide 1ai did not
prevent the delivery of 5ai (exo/endo = 58/42) in 75% yield. To
our delight, alkyl-substituted ynamide provided the desired
product 5aj albeit in moderate yield. However, the terminal
ynamide led to a complex mixture instead of providing the
respective diarylation product.
To understand the reactivity of the functionalized arene motifs, a
crossover
experiment
mixing
electron-rich
p-OMe
benzenediazonium tetrafluoroborate (2a), electron-poor m-CF3
benzenediazonium tetrafluoroborate (2e), 1a, and 3a under the
optimized conditions delivered 4w (41%) and 4a (trace); thus,
oxidative addition of Pd(0) is faster with 2e than with 2a (eq 1,
Scheme 4). Probing the reaction of 1a and 2a along with p-Me-
aryl-boronic acid (3a) and p-CHO-aryl-boronic acid (3g) gave 4a
(35%) and 4g (55%), respectively; thus, the reaction of 3g is fast
(eq 2, Scheme 4).[7] Among the alkyne derivatives, the reaction
with ynamide 1a is preferred over 1,2-diphenylacetylene (6)
Scheme 4. a) Cross-over Experiments, b) Chemoselectivity All reactions are
carried out in 0.3 mmol scale for overnight. [a]1,4-dioxane was used instead
DMSO at 10 C.
Scheme 3. Scope of Ynamides.Ynamide 1 (0.3 mmol), diazonium salt 2a
(0.45 mmol), boronic acid 3d (0.36 mmol) for overnight. [a]unreacted ynamide
recovered.
3
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Figure 2. M06L/def2-TZVPP calculations (PCM-corrected, G298, kcal/mol)
carbon to Pd). Transmetalation through TSEF (4.8 kcal/mol)
delivers F (63.0 kcal/mol); the boric acid serves as L-type
ligand. The exchange of boric acid ligand by DMSO then
dispenses G (67.4 kcal/mol). The reductive elimination of G
passes through transition state TSGH (52.1 kcal/mol, requiring
15.3 kcal/mol from G) to provide H (77.4 kcal/mol). Ligation of
ortho-carbon of p-MeOPh and the ipso-carbon of p-tolyl moieties
makes the (DMSO)Pd(0) intermediate H stable. Finally, the
desired product I is liberated from H, which requires 9.5 kcal/mol
of free energy, along with the regeneration of the active catalyst
species A for further use. The DFT studies thus rationalize the
reactivity preference of aryl diazonium salts over aryl boronic
acid species, as well as the chemo- and regio-selectivity of the
reaction (see the Supporting Information for the full study).
The reaction scalability was validated through the gram-scale
preparation 4a (1.2 g, 90%) and 4m (0.58 g, 63%), respectively,
from 1a (1.0 g, 2.67 mmol) and 2a (1.5 equiv) independently
with 3a (1.2 equiv) or 3m (1.2 equiv) in Pd2(dba)3·CHCl3 (5.0
mol%) (Scheme 5). The synthetic versatility of these newly
constructed tetrasubstituted enamides was next probed
(Scheme 5). The selectfluor assisted oxy-fluorination of 4a
provided 9 in 40% yield.[8] An unusual epoxidation product 10
was accessed from 4a when exposed to m-CBPA at 100 C for 3
producing 4g (71%) while leaving 6 intact (eq 3, Scheme 4).
Interestingly, the reaction explicitly occurred with ynamide motifs
leaving the yne/ene species completely untouched and finally,
provided the respective products 7 and 8 in appreciable yields
(eq 4 and 5, Scheme 4). Structure of 8 was elucidated by single
crystal X-ray analysis.[16]
To gain insight into the reaction mechanism and the
stereo/regioselective1,2-diarylation of the ynamide scaffold, DFT
calculations were performed (Figure 2, see the Supporting
Information for details). The transformation begins with the
barrierless oxidative insertion of Pd(DMSO)2 (A) to the CN
bond of p-methoxy phenyl diazonium cation 2a to provide
cationic Pd-complex B; this process is highly exergonic by 58.4
kcal/mol. Next, coordination of B to the ynamide 1r through
ligand exchange with N2 delivers keteniminium complex C with a
release of 12.8 kcal/mol. A suprafacial 1,3-aryl migration from
Pd to the C=N bond of C proceeds through transition state TSCD
(found at 0.1 kcal/mol on the free energy surface) and results in
Pd-enamide Complex D (24.5 kcal/mol; with trans orientation of
phenyl and p-methoxyphenyl groups). The ligand exchange
between D and 3a' is exergonic, leading to complex E (42.7
kcal/mol; with the chelation of borate oxygen and ipso aryl
4
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days.[9] The cross-dehydrogenative coupling of 4a led to 9-amino
phenanthrene 11 in 51% yield. The TBHP and CuCl mediated
oxidation of 4g (R= CHO) delivered 12 (R = COOH), the
enamide motif did not affect this oxidation.[10] Independent
coupling of I-moiety in 4m with NaN3 and p-TolB(OH)2 furnished
13 (47%) and 14 (87%), respectively.[11]
In summary, a base-mediated Pd(0)-catalyzed keteniminium
driven umpolung regioselective unsymmetrical diarylation of
ynamides with distinct reactive partners aryl-diazonium salts and
boronic acids has been revealed for the first time. The
transformation proceeds at room temperature and exhibits a
broad scope [67 examples; the catalytic system tolerates
Council (CSC) for PhD grant. We thank Dr. Nagarjuna and Dr.
Junaid Ali for the help in solving the X-ray crystal data. SD
thanks Mr. Shashank for his support during the project.
Keywords: • • umpolung reactivity • regio- and
stereoselective difunctionalization • triaryl substituted enamides •
DFT studies
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oxidizable
halo-species
(I/Br),
easily
transformable
functionalities (CHO, COMe, CO2Me, CN), and sulfonyl-
protecting groups]. This process is thus practical and even
successful on a gram-scale. DFT studies support the viability of
intramolecular 1,3-aryl migration and the possibility of
transmetalation of boronic acid to vinylic Pd-species and makes
the transformation explicitly chemo-, regio- and stereoselective.
This finding paves the way for a diverse range of unknown
difunctionalization of ynamides; the results will be reported in
due course.
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Scheme 5. Gram Scale Synthesis and Applications Cond. A: AlCl3 (2.0 equiv),
toluene, 120 C. Cond. B: ptolB(OH)2 (1.2 equiv), Pd(PPh3)4 (5.0 mol%),
K3PO4 (3.0 equiv), EtOH, 90 C.
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Acknowledgements
This research was supported by the SERB-India (grant no.:
CRG-2019-1802). We thank University of Hyderabad (UoH;
UPE-CAS and PURSE-FIST) for overall facility. SD, RV, and
RKM thank CSIR, N-PDF-SERB, and UGC India, respectively,
for fellowship. VG thank CNRS, UPS, Ecole Polytechnique and
IUF for financial support. SY thanks the China Scholarship
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[12] CCDC 1977850 contains the supplementary crystallographic data for
compound 4p.
[13] CCDC 1977848 contains the supplementary crystallographic data for
compound 4v.
[14] CCDC 1977849 contains the supplementary crystallographic data for
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[15] CCDC 1968461 contains the supplementary crystallographic data for
compound 5ag.
[16] CCDC 1977851 contains the supplementary crystallographic data for
compound 8.
6
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10.1002/anie.201915522
Angewandte Chemie International Edition
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Entry for the Table of Contents
A non-directed keteniminium driven multicomponent 1,2-umpolung difunctionalization of ynamides with aryl diazonium salts and aryl
boronic acids under pd-catalysis for the synthesis of novel triaryl-substituted enamides is showcased for the first time. This
transformation proceeds via 1,3-migration of electrophile from in-situ generated keteniminium species to the electrophilic -position of
ynamide, followed by trapping of nucleophilic -vinylic metal species with nucleophile. DFT studies support the chemo-, regio- and
stereoselectivity of this current transformation.
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