Palladium-catalyzed denitrogenative functionalizations of benzotriazoles with alkenes and 1,3-dienes

Article abstract of DOI:10.1039/c7cc07543j

Pd-Catalyzed denitrogenative functionalizations of benzotriazoles with alkenes and 1,3-dienes have been developed, which enable the rapid access of diverse ortho-amino styrenes and 2-vinylindolines, respectively. This study shows the great potential of benzotriazoles as a [1C]-synthon in cross-coupling reactions and an aza-[3C]-synthon in cycloaddition reactions.

Full text of DOI:10.1039/c7cc07543j

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Palladium-Catalyzed Denitrogenative Functionalizations of
Benzotriazoles with Alkenes and 1,3-Dienes
Yuanhao Wang,a Yuanhe Li, b Yijun Fan,a Zhiguo Wanga and Yefeng Tang*abc
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Pd-catalyzed denitrogenative functionalizations of benzotriazoles withdrawing group on
with alkenes and 1,3-dienes are developed, which enable the
A) Denitrogenative [3+2] cycloaddition of benzotriazoles with alkynes (Nakamura's work)
rapid access of diverse ortho-amino styrenes and 2-vinylindolines,
respectively. This study shows the great potential of
benzotriazoles as a [1C]-synthon in cross-coupling reaction and an
aza-[3C] synthon in cycloaddition reaction.
R2
Dimroth
equilibrium
Pd
N
N
N
N
R1
R2
Pd(0)
-N2
N
1
R1
2
130 oC, neat
NBz
N
Bz
Bz
NBz
B) Denitrogenative Suzuki coupling of benzotriazoles with boronic acids (our previous work)
NHTf
Pd(II)/PPh3
Since their discovery in the 1860s,1 arenediazonium salts have
Ar
Suzuki coupling
Pd(II)/PPh3, CO
B(OH)2
N2BF4
N
AgBF4
evolved into
a class of reactive electrophiles displaying
Ar
N
+
NHTf
O
N
Tf
NTfAg
versatile reactivity from free-radical chemistry to
organometallic synthesis.2 Generally, arenediazonium salts are
prepared from the corresponding anilines through
diazotization. However, the high nucleofugic property of
diazonium function makes these compounds unstable and
potentially explosive, and thus have to be used immediately
after preparation. To address this issue, considerable effort
has been devoted to developing new methods to access
stabilized arenediazonium salts.3 In addition, some
operationally simple protocols to effect the generation of
arenediazonium salts and following transformations in one pot
have also been developed.4 Despite such advances, these
methods usually necessitate the usage of expensive reagents
or/and take additional synthetic operations, which to some
extent compromises their applicability. Thus, the development
of conceptually novel and synthetically useful method to
access arenediazonium salts is highly desirable.
Ar
arenediazonium salts
carbonylative
Suzuki coupling
C) Denitrogenative alkenylation benzotriazoles with alkenes and 1,3-dienes (this work)
R2
R2
Pd(0)/PPh3
Ar
denitrogenative
alkenylation
NHTf
N
N2BF4
AgBF4
ortho-amino styrene
Ar
N
N
Tf
R2
NTfAg
R2
Pd(0)/PPh3
Ar
arenediazonium salts
N
Tf
formal [3+2]
cycloaddition
2-vinylindoline
Scheme 1 Application of benzotriazoles as synthetic equivalent of ortho-
amino arenediazoniums.
N1 position could undergo ring opening to form its isomeric
ortho-amino-arenediazonium species via
a Dimroth-type
equilibrium.6 In this context, benzotriazoles could be viewed as
a masked ortho-amino-arenediazonium. While such potential
seems to be attractive, it has been rarely explored by synthetic
community during the past decades. In 2009, Nakamura and
Benzotriazoles represent an important class of heterocycles
that are recognized for their versatile reactivities.5 In
co-workers
reported
a
novel
palladium-catalyzed
particular, benzotriazoles bearing
a
strong electron-
denitrogenative formal [3+2] cycloaddition of N-
aroylbenzotriazoles with internal alkynes (Scheme 1A).7
Mechanistically, the reaction was assumed to proceed via an
ortho-amino-arenediazonium intermediate in situ generated
from the benzotriazole precursor. This discovery open a new
avenue to utilize benzotriazole as a synthetic equivalent of
ortho-amino-arenediazonium in transition-metal-catalyzed
reactions. However, the harsh conditions and moderate
efficiency of the transformation restrict its widespread
application in organic synthesis. Thus, the development of a
general, efficient and robust method to effect the ring open of
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reaction may provide a new method to access this type of of are rationalized in Scheme 2. Thus, benzotriazoles (
scaffold.12 To test the viability of this method, we evaluated a
1
) could
advance to the arenediazonium tetrafluoroborates A through
a Dimroth-type equilibrium with the action of a synergistic
activating-stabilizing effect. The resulting arenediazonium
species would then undergo oxidative addition with Pd(0)-
Table 3 Scope of Denitrogenative [3+2] Cycloadditiona,b
Pd(PPh3)4 (5%)
PPh3 (30%)
R3
N
R1
N
R1
R3
+
AgBF4 (250%)
N
N
catalyst to generate the Pd(II)-complex
pathways, namely -hydride elimination and nucleophilic
attack, are possible. The former one leads to Heck-type
reaction product via intermediate , while the latter one
provides formal [3+2] cycloaddition product
B, from which, two
MeCN, 90 o
C
Tf
4
Tf
1
5
β
Me
MeO
Ph
Ph
Ph
Ph
Ph
N
N
N
N
3
C
Tf
Tf
5b: 87%
Tf
5c: 92%
Tf
5.
5a: 92%
5d: 78%
Me
To investigate the origin of distinct chemoselectivity
between 1,3-dienes and simple alkenes, DFT calculation was
carried out.14 Shown in Fig. 1a, the computation confirms that,
after alkene insertion, the activation energy of β-hydride
elimination is significantly lower than that of formal [3+2]
cyclization for the simple alkene substrates; and vice versa for
1,3-dienes. This difference could be attributed to two factors.
Firstly, the highly electrophilic nature of π-allyl-palladium
Ph
Ph
Ph
Ph
N
N
N
MeO2C
F
Ph
N
Tf
Tf
5f: 85%
Tf
Tf
5e: 76%
5g: 95%
5h: 90%
Ph
Me
OMe
N
N
N
Tf
Tf
Tf
5i: 75%
5j: 94%
5k: 83%
OMe
OMe
O
O
N
OMe
N
species in the 1,3-diene version of intermediate
to that of simple alkenes, makes it much less facile to undergo
H elimination.13c Instead, it would ultimately undergo an
intramolecular N-allylation to give formal [3+2] cycloadducts
5 13d-f
Secondly, there exists a significant agnostic effect for the
intermediate generated using substrate . The C-H bond cis-
B, comparing
N
Tf
Tf
Tf
5l: 81%
5m: 81%
5n: 80%
F
CF3
CN
β
−
N
N
N
Tf
Tf
5o: 80%
Tf
5p: 82%
.
5q: 62%
Cl
NTs
B
2
coplanar with the C-Pd bond is significantly lengthened
comparing to the other benzylic C-H bond (Fig. 1b). The
Laplacian bond order of the cis-coplanar C-H bond is only 0.64,
which also shows the agnostic effect, comparing to a value of
0.8~0.9 for average C-H bonds.15 This effect, which is almost
absent in the cases using 1,3-diene substrates, significantly
lowers the energy required for β-hydride elimination pathway.
N
N
N
O2
N
Tf
Tf
Tf
5s: 88%
5r: 45%
5t: 84%
a Reaction conditions: 1 (0.30 mmol), 4 (0.60 mmol), Pd(PPh3)4 (0.015 mmol),
PPh3 (0.09 mmol) and AgBF4 (0.75 mmol) in MeCN (3.0 mL). b Isolated yield.
range of benzotriazoles using 4a as reaction partner (Table 3).
Pleasingly, all of the substrates bearing electron-withdrawing, -
neutral, and -donating substituents on the aromatic ring
tolerated well in the reactions, and thus the corresponding
(a)
monoene substrates
diene substrates
PPh3
Pd
PPh3
products (5a-i) were obtained in good to excellent yields.
H
Pd
PPh3
Furthermore, an array of 1-aryl 1,3-dienes bearing different
substituents were also evaluated with 1a as reaction partner.
Gratifyingly, all of the reactions proceeded smoothly to yield
H
Denitrogenative
Alkenylation
Ph
Ph
Ag
H
N
N
Tf
Tf Ag
G
= 44.8 kJ/mol
G
= 90.0 kJ/mol
Disfavored
the corresponding products (5j-t), which further illustrates the
Favored
generality of our method.
Ph3
P
Ph3P
Denitrogenative
Formal [3+2]
Cyclization
Pd PPh3
Ph
Pd
Ph
PPh3
H
[Pd]
R
H
[Pd]
R
R
N
N
Ar
Ag
Ag
Ar
Tf
Tf
NHTf
Ar
H
NTfAg
G
= 56.9 kJ/mol
G
= 127.1 kJ/mol
Disfavored
3
Pd(0), Ag+
AgBF4
C
NTfAg
Favored
(b)
denitrogenative
alkenylation
Pd(0)
-H elimination
R
H
[Pd]
N2
[Pd]
R
N
N
N
N2BF4
AgBF4
Ar
Ar
Ar
H
NTfAg
Tf
1
R
NTfAg
B
A
denitrogenative
formal [3+2]
Pd(0) AgBF4
nucleophilic
R
attack
[Pd]
R
Ag+
Pd(0)
Ar
R
R
Ar
Ar
N
N
N
Tf
Ag
Tf
Ag
Tf
5
C'
Fig. 1 (a) Calculated activation Gibbs free energy of ꢀ-hydride elimination
and formal [3+2] cyclization after the formation of intermediate B. (b)
Optimized structure and geometry parameters of intermediate B for
Scheme 2 Mechanistic rationalization.
substrate 2a.14
.
Based on our previous studies as well as some inspiring
cases,9,13 the plausible mechanisms of above transformations
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5805; (f) M. Uhde, M. U. Anwar and T. Ziegler, Synth.
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In summary, the palladium-catalyzed denitrogenative
functionalizations of benzotriazoles with alkenes and 1,3-
dienes are reported. Mechanistically, both transformations
proceed through an ortho-amino arenediazonium salt in situ
generated from the ring opening of benzotriazole. Differently,
the reactions with simple alkenes follows a mechanism of
Heck-type coupling and the reactions with 1,3-dienes adopts a
formal [3+2] mechanism. DFT calculation was conducted to
explain the distinct behavior of simple alkenes and 1,3-dienes
in these transformations. The present study not only further
showcases the appealing synthetic utility of benzotriazoles as a
[1C] synthon in cross-coupling reactions, but also extends its
application as an aza-[3C] synthon in cycloaddition reactions.
We anticipate that more synthetically useful transformations
will be developed under the guidance of this concept, and
relevant work is currently underway in our laboratory.
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(3f) contains the supplementary
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National Natural Science Foundation of China (21572112,
21772109) and Beijing Natural Science Foundation (2172026).
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There are no conflicts to declare.
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Graphic Abstract
Pd-catalyzed denitrogenative functionalizations of benzotriazoles with alkenes and 1,3-dienes are
developed, which enable the rapid access of diverse ortho-amino styrenes and 2-vinylindolines,
respectively.