N-Heterocyclic Carbene Catalyzed Concerted Nucleophilic Aromatic Substitution of Aryl Fluorides Bearing α,β-Unsaturated Amides

Article abstract of DOI:10.1002/anie.201907837

Concerted nucleophilic aromatic substitution (CS_NAr) has emerged as a powerful mechanistic manifold, in which nucleophilic aromatic substitution can proceed in one step without the need to form a Meisenheimer intermediate. However, all of the CS_NAr reactions reported thus far require a stoichiometric strong base or activating reagent, and no catalytic variants have yet been reported. Herein, we report an N-heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of acrylamides that contain a 2-fluorophenyl group on the nitrogen through a CS_NAr reaction. By using this catalytic method, it is possible to synthesize an array of quinolin-2-one derivatives, which are common structural motifs in pharmaceuticals and organic materials. DFT calculations unambiguously revealed that this reaction proceeds through the concerted nucleophilic aromatic substitution of aryl fluorides, in which a stereoelectronic σ (C_ipso-C_β)→ σ*(C_ipso-F) interaction critically contributes to the stabilization of the transition state for the cyclization.

Full text of DOI:10.1002/anie.201907837

A Journal of the Gesellschaft Deutscher Chemiker
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Accepted Article
Title: N-Heterocyclic Carbene-Catalyzed Concerted Nucleophilic
Aromatic Substitution of Aryl Fluorides Bearing α,β-Unsaturated
Amides
Authors: Mamoru Tobisu, Kosuke Yasui, and Miharu Kamitani
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907837
Angew. Chem. 10.1002/ange.201907837
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10.1002/anie.201907837
Angewandte Chemie International Edition
COMMUNICATION
N-Heterocyclic Carbene-Catalyzed Concerted Nucleophilic
Aromatic Substitution of Aryl Fluorides Bearing α,β-Unsaturated
Amides
Kosuke Yasui, Miharu Kamitani and Mamoru Tobisu*
Abstract: Concerted nucleophilic aromatic substitution (CSNAr) has
emerged as a powerful mechanistic manifold, in which nucleophilic
aromatic substitution can proceed in one-step without the need to
form a Meisenheimer intermediate. However, all of the CSNAr
reactions reported thus far require a stoichiometric strong base or
activating reagent and no catalytic variants have yet been reported.
Herein, we report on the N-heterocyclic carbene (NHC)-catalyzed
intramolecular cyclization of acrylamides that contain a 2-fluorophenyl
group on the nitrogen via a CSNAr reaction. Using this catalytic
protocol, it is possible to synthesize an array of quinolin-2-one
derivatives, which are common structural motifs found in
pharmaceuticals and organic materials. DFT calculations
unambiguously revealed that this reaction proceeds through the
concerted nucleophilic aromatic substitution of aryl fluorides, in which
a stereoelectronic (Cipso-Cβ) → (Cipso-F) interaction critically
contributes to the stabilization of the transition state for this cyclization.
the CSNAr reaction less sensitive to the electronic nature of the
substrate. In fact, several reports dealing with nucleophilic
aromatic substitution reactions of electron-neutral and electron-
rich substrates have now been documented, including
iodination,[8] hydride reduction,[9,10] fluorination,[11-15] amination,[16]
silylation,[17] thionylation,[18] and aryl migration[19,20] reactions.
Although these examples significantly advanced the scope of
CSNAr reactions, all of these reactions require stoichiometric
amounts of activating reagents and/or strong bases, such as NaH
or MHMDS (M = Li, K) to generate the key reactive species.
a SNAr vs. CSNAr ( (EWG = electron withdrawing group, LG = leaving group, Nu = nucleophile)
S
NAr:
LG
Nu
LG
LG
Nu
Nu
Nu
EWG
EWG
EWG
Meisenheimer Intermediate
CSNAr:
R

LG
Nu
Nu
R
R

Nucleophilic aromatic substitution (SNAr) is a classical type of
reaction, and has been used to elaborate
a number of
Transition State
Awaiting solutions: Stoichiometric reagents or strong bases are required
functionalized aromatic compounds related to pharmaceutical
and organic materials.[1] In fact, analysis in 2016 revealed that
SNAr is the second most frequently used reaction in medicinal
chemistry research.[2] In SNAr reactions, a nucleophile attacks the
aromatic ring at the ipso position of a leaving group to form a so-
called Meisenheimer intermediate (Scheme 1a, top).[3,4] This
intermediate is formed via the complete loss of aromaticity, which
requires a high activation energy of around 30 kcal/mol.[5] To
make the process energetically feasible, a strong electron-
withdrawing group is essential to stabilize a discrete negative
charge that develops in the Meisenheimer intermediate, thereby
decreasing the activation barrier. This mechanistic feature limits
the scope of aromatic substrates to highly electron-deficient
(hetero)arenes, which is an obvious disadvantage of classical
SNAr reactions when applied to organic synthesis.
b
This work: Catalytic CSNAr (EDG = electron donating group)
F
F
O
cat. NHC
O
EDG
N
EDG
N
O
EDG
N
NHC
Key intermediate
c Energy diagrams for SNAr and CSNAr
SNAr with EWG:
SNAr without EWG:
Our strategy for catalytic CSNAr:
Meisenheimer
Products
G
G
Reactants
Reaction coordinate
Reaction coordinate
Reaction coordinate
Scheme 1. SNAr and CSNAr reactions.
Several reports recently revealed that the SNAr reaction can
proceed, not in a stepwise, but, rather, in a concerted manner
(CSNAr, Scheme 1a, bottom).[6] The CSNAr pathway generally has
a lower activation energy (13~25 kcal/mol)[6] than what is required
for the formation of the Meisenheimer intermediate since part of
the aromaticity of the substrate can be retained.[7] In addition, the
negative charge in the transition state can be dispersed not only
on an aromatic ring but also on a leaving group, thereby making
To further expand the synthetic utility of CSNAr reactions, we
hypothesized that a catalytic variant that would permit the use of
stoichiometric strong bases or reagents to be avoided would be
highly desirable. Moreover, the scope of CSNAr reactions is
currently limited to the formation of carbon-heteroatom bonds,
except for aryl migration,[19,20] and applications to carbon-carbon
bond-forming processes remain underdeveloped. The use of
carbon nucleophiles in aromatic substitution reactions has been
considered to be intrinsically more difficult than heteroatom-based
nucleophiles, since the latter can provide extra stabilization for the
transition state through the interaction between the lone pair of
electrons and a  orbital and assist in the bond-breaking
[*]
Kosuke Yasui, Miharu Kamitani and Mamoru Tobisu
Department of Applied Chemistry, Graduate School of Engineering
Osaka University, Suita, Osaka 565-0871, Japan
Fax: (+) 81-6-6879-7396
E-mail: tobisu@chem.eng.osaka-u.ac.jp
process.[21]
reactions, we envisioned the use of N-heterocyclic carbene
To realize catalytic C–C bond-forming CSNAr
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201907837
Angewandte Chemie International Edition
COMMUNICATION
(NHC) catalysts, which can be used to generate a nucleophile
from a carbonyl compound or an alkyl halide in a catalytic
manner.[22-24] Among the several precursors that can be activated
by an NHC catalyst, we opted to use α,β-unsaturated carbonyl
compounds, which are known to serve as a latent β-carbanion via
umpolung. Although the generation of this type of nucleophile has
been utilized in several NHC-catalyzed reactions[25] since the first
report by Fu,[26] its use in catalytic aromatic substitution reactions
has not been accomplished.[27,28] We used an aromatic fluoride
bearing an α,β-unsaturated amide, which would undergo an
aromatic substitution reaction by a catalytically generated β-
carbanion (Scheme 1b). This reaction allows readily available
anilides to be converted into quinolin-2-one derivatives, which are
structures contained in a number of natural products and
pharmaceuticals.[29,30] According to Jacobsen’s analysis of SNAr
reactions based on the Marcus theory,[31] the Meisenheimer
intermediate is highly stabilized by a strong electron-withdrawing
group, leading to a minimum along the reaction coordinate
(Scheme 1c, left). In contrast, the energy surface of the
Meisenheimer intermediate does not have intersections between
those of a reactant and a product when the substrate does not
contain a strong electron-withdrawing group, which results in a
transition state with an insurmountable barrier (Scheme 1c,
middle). We envisioned that increasing the nucleophilicity of the
carbanion intermediate should destabilize the reactant, thereby
decreasing the activation energy required for a CSNAr reaction
(Scheme 1c, right). Here we report the realization of the NHC-
catalyzed cyclization of aryl fluorides via a CSNAr pathway
(Scheme 1b).
A close look at the structure of the key intermediate shown in
Scheme 1b led us to hypothesize that the nucleophilicity of this
carbanion intermediate should depend on the electron-donating
ability of an NHC catalyst, which is adjacent to the β anion in the
transition state. Based on these hypotheses, we examined the
catalytic activity of an array of NHCs for the cyclization of 1a,
which does not normally undergo aromatic substitution reactions,
since no electron-withdrawing group is present. Intensive
optimization studies (see SI for details) led us to determine that
L6 as an optimal NHC catalyst and CsF as an optimal base in the
cyclization of 1a. Thus, the reaction of 1a in the presence of
L6ꞏHCl (20 mol%) and CsF (2.0 equiv) in toluene at 160 °C for 5
h gave the cyclized product 2a in quantitative isolated yield
(Scheme 2a). It should be noted that this cyclization can proceed
at a lower temperature of 120 °C (96%).
a
Typical conditions
F
L6
10 mol %
ꞏHCl
O
N
N
2.0 equiv CsF
toluene, 5 h, 160 °C
N
N
O
MeO
OMe
1a
2a quantitative
L6
(96% yield at 120 °C for 24 h)
b
Scope of aryl groups
f Electron-rich substrates
NC
30 mol% L6ꞏHCl
F
O
2.0 eq. CsF
O
N
O
F3C
N
O
N
O
N
N
toluene
N
N
O
O
72 h, 160 °C
2d 95%
2b 88%
2c 92%
1r
2r 76% (19% recovery of 1r)
F
Br
I
O
O
N
N
N
N
O
as above
as above
Cl
N
O
N
O
N
O
2g 92%
2e 96%
2f 95%
1s
2s
1s
71% (28% recovery of )
F
MeO
O
N
O
N
O
N
N
O
N
N
O
N
O
1t
2t 78% (19% recovery of 1t)
O
OMe
g
Late-Stage derivatization of bioactive molecules
a
2h
2i
2j
2k
90%
97%
92%
83%
F
F
F
F
F
O
c
NH
N
Scope of alkenyl moieties
N
O
1. BH3ꞏTHF
then HCl aq
L6
ꞏHCl
10 mol%
2.0 eq. CsF
O
toluene
O
2.
N
O
N
O
N
O
24 h, 160 °C
Me
N
O
N
O
N
O
N
O
Cl
CF3
CF3
62% (over 2 steps)
CF3
K2CO3, MeCN
reflux
a
a
a
a
2l
97%
2m
2n
2o
84%
81%
98%
1u
2u
94%
Diflufenican
Scalability
d
N-Protecting group
h
e
Substrate for double cyclization
L6
10 mol% ꞏHCl
F
O
2.0 eq. CsF
N
O
N
N
O
toluene
reflux
24 h,
O
N
N
O
1a (1.5 g)
2a 92% (1.25 g)
Bu
Bu
2p 94%a
TLC after this cyclization
a
2q
69%
Scheme 2. Reaction scope. Conditions: Conditions: 1 (0.20 mmol), L6ꞏHCl (0.030 mmol), CsF (0.60 mmol), in toluene (1.0 mL) at 160 °C for 5 h using a sealed
vial. The reaction temperature refers to the preset temperature of the heater of the reactor. Isolated yields of the cyclized products are shown. a Reacted for 24 h.
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With the optimized reaction conditions in hand, we next
examined the scope of substrates (Scheme 2b). Not surprisingly,
electron-deficient substrates bearing CF3 (2b), methyl ester (2c),
or cyano (2d) groups smoothly participated in this catalytic
cyclization to produce the corresponding functionalized quinolin-
2-one derivatives. Our NHC-catalyzed protocol can be used for
the synthesis of quinoline-2-one derivatives bearing chloro (2e),
bromo (2f) and even iodo (2g) groups without their loss, which
can serve as handles for further structural elaboration. It was also
revealed that the use of the corresponding chloride, bromide and
iodide, instead of fluoride, as the leaving group failed to undergo
this catalytic cyclization. Whereas pyridines bearing a leaving
group at the C2 or C4 position are suitable substrates for
nucleophilic aromatic substitution, pyridines bearing a leaving
group at the C3 position are known to be much less reactive.[32]
Nevertheless, this catalytic cyclization could be applied
successfully to a 3-fluoropyridine derivative 1j to form the aza-
quinoine-2-one skeleton 2j. The tricyclic skeleton 2k, a common
structural motif of drugs for Cushing’s syndrome and the
metabolic syndrome,[33] are also accessible.
This method is applicable to substrates with a cyclic alkene
moiety, which allows for the rapid access to an array of fused ring
systems containing a quinolin-2-one core, such as 2m, 2n, and
2o (Scheme 2c). One might expect that these ring systems can
be accessed by the Mizoroki-Heck reaction of the bromide
analogue of 1. However, such an approach was reported to favor
the formation of a five-membered ring via a 5-exo cyclization
mode, which is complementary to our 6-membered ring
formation.[34]
Figure 2e. Although more forcing conditions were needed (30
mol% of L6, 72 h), substrates bearing indoline 2r, NMe2 2s, or
OMe 2t groups, the most challenging class of substrates for
nucleophilic aromatic substitution, participated in the catalytic
cyclization to deliver the corresponding products (Scheme 2f).
Because stoichiometric strong bases are not required in this
reaction, this nucleophilic aromatic substitution method can be
used for the late-stage functionalization of intricate molecules. For
example, Diflufenican, a herbicide bearing an ortho-fluoroaniline
moiety, can be readily elaborated into quinolin-2-one analogue 2u
in three steps (Scheme 2g).
To demonstrate the scalability of this reaction, the cyclization of
1a was conducted on a 1.5 g scale, resulting in the complete
consumption of starting materials and the formation of the desired
product in 92% (1.25 g) isolated yield without any difficulty
(Scheme 2h).
To elucidate whether this reaction proceeds through the
classical SNAr or CSNAr reactions, we investigated the reaction
pathway using DFT calculations. The energy changes at the M06-
2X/def2-TZVPP level of theory [SCRF (pcm, solvent = toluene)]
are shown in kcal/mol (Scheme 3a). Because the reaction route
from an α,β-unsaturated ester and an NHC catalyst to the ylide
intermediate similar to Int 1 was previously calculated,[35] our
calculations were focused on the key intramolecular nucleophilic
substitution process. This catalytic cyclization was found to
proceed through a single transition state, in which both a
nucleophilic attack of the β carbon and the dissociation of the
fluorine leaving group proceeded in a synchronized fashion.
Approaching the TS requires a barrier of 26.2 kcal/mol, which lies
within the range of that reported for other CSNAr reactions,[6]
following the formation of thermodynamically stable Int 2. It
should be noted that the intrinsic reaction coordinate (IRC)
analysis for TS led us to identify no additional intermediates along
the pathway from Int1 to Int2, excluding the intermediacy of a
Meisenheimer type intermediate in this catalytic cyclization
reaction. In addition, all of our attempts to locate the
Meisenheimer type complex did not provide any stable
intermediates, which suggests that the intermediate lies in a much
higher energy as previously reported.[5]
Although our protocol failed to cyclize a secondary amide
substrate, an N-benzyl group 2p was well-tolerated, allowing for
the modification of the N-substituent of quinolin-2-one products
after debenzylation (Scheme 2d). The substrate derived from 9,9-
bis(4-amino-3-fluorophenyl)fluorene 1q, a promising scaffold for
the synthesis of organic electroluminescence materials, could
also deliver the corresponding double cyclized product 2q
(Scheme 2e).
The unambiguous advantage of this catalytic cyclization is that
electron-rich substrates can participate in the reaction, as shown
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10.1002/anie.201907837
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COMMUNICATION
a
b
c
Ar
GM06-2X/def2-TZVPP (kcal/mol)
N
F
Ar
N
N
N
F
N

O
Ar
Ar
O
F
N
NHC
N
-0.239
Int 1
O
NICS(0) = -12.3357
-0.377
Transition state
-0.366
-0.232
TS (26.2)
Ar
0.381
N
F
Ar
N
N
N
N
-0.439

Ar
Ar
Int 1 (0.0)
0.034
O
-0.408
F
F
N
NHC
O
O
N
TS
Ar = p-(OMe) C6H4
Int 2 (-17.4)
NICS(0) = -8.2813
CSNAr
d
e
f
MeO
MeO
O
R
N
R
R
R
R
Ar
N
N
N
N
N
Me
Me
N
N
N
N
N
Ar
Int 3
Me
Me
OMe
OMe
HOMO: -0.14781
L6
HOMO: -0.16487
L9
HOMO: -0.15691
L5
HOMO: -0.15614
L8
with
with
with
with
Increased nucleophilicity (B3LYP/6-31+G*)
(Cipso-C)(C-F)= 2.96 kcal/mol
Scheme 3. DFT calculations. a: Energy diagram for the cyclization reaction of 1a with L6. b. HOMO orbitals in TS b: The NICS(0) values of Int 1 and TS. c:
Charge distribution in TS based on NBO analysis. d: (Cipso-Cβ) Bond orbital from NBO analysis. e: (Cipso-F) Bond orbital from NBO analysis. f. Comparison of
nucleophilicity of the simplified ylide intermediate Int3 depending on the NHC catalysts based on the HOMO energy levels.
The Meisenheimer intermediate involved in SNAr reactions is
known to possess no aromaticity.[3-5] In contrast, the transition
state in CSNAr was reported to retain partial aromaticity,[7] which
is likely to be critical to lowering the activation energy for CSNAr.
To investigate the aromaticity of the TS in our reaction, the NICS
values[36] of the TS and Int1 were calculated (HF/6-31+G*).
Although the NICS value of TS (-8.28) increased compared with
that for Int1 (-12.3), it is still largely negative, which indicates that
the TS possesses an aromatic character (Scheme 3b). These
results suggest that this NHC-catalyzed CSNAr reaction can
significant stereoelectronic interaction explains the concerted
nature of this substitution reaction well. Although the π* orbital at
the ipso carbon of the leaving group is reported to be involved in
CSNAr reactions [4,12], our calculations revealed that the (Cipso
-
F) orbital lying on the C-F bond (Scheme 3f) serves as an
acceptor orbital for (Cipso-Cβ) bond in the transition state during
the CSNAr process.
We next investigated the energy levels of the highest occupied
molecular orbital (HOMO) of the ylide intermediates Int3
generated using different NHC catalysts (L5, L6, L8, L9) to gain
insights into the nucleophilicity of the β carbon (B3LYP/6-31+G*)
(Scheme 3g). The HOMO energies were found to increase when
p-MeO groups were introduced to the pendant N-aromatic rings
(L5 vs L9) and methyl groups at the 4 and 5 positions of the
imidazole ring (L8 vs L9). By combining both substituent effects,
the highest HOMO level was observed with L6, which is in
agreement with the experimental results (see SI for details).
These results indicate that the excellent catalytic activity of L6 can
be attributed, not to the stabilization of the TS or Int2 but largely
to the destabilization of Int1, as we initially envisioned (Scheme
1d, right).
proceed with
a lower energy barrier because complete
dearomatization is not required in the TS, unlike classical SNAr
reactions involving the Meisenheimer intermediate.
We next conducted a natural bond orbital (NBO) analysis to
obtain insights into the charge distribution in the transition state
(M062X/6-31+G*) (Scheme 3c). The negative charges were
found to be distributed, not only on an aromatic ring (C3: -0.377,
C4:-0.239, C5: -0.366, C6: -0.232), but also on the fluorine leaving
group (F: -0.408) and the nucleophilic β carbon (-0.439), which is
a characteristic charge distribution for CSNAr.[13] These results are
in agreement with the experimental observation that electron-rich
aryl fluorides were compatible with this catalytic cyclization
(Scheme 2f).
In summary, we report on the first catalytic concerted
nucleophilic aromatic substitution, in which
a catalytically
An NBO analysis also revealed the essential orbital interactions
in the TS.[37] A noncovalent stereoelectronic interaction between
the (Cipso-Cβ) bond orbital (Scheme 3d) and the (Cipso-F)
antibonding orbital (Scheme 3e) was observed with an NBO
interaction energy of 2.96 kcal/mol, which contributes to
stabilizing the TS. It must also be noted that this weak but
generated carbanion displaces the fluorine group on the aromatic
ring. The concerted nature of the transition state allows electron-
rich aryl fluorides to be cyclized in a catalytic manner. Since this
method does not rely on the use of strong bases or transition
metals, it is possible to synthesize quinolin-2-one derivatives
bearing a diverse range of functional groups including iodides and
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10.1002/anie.201907837
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COMMUNICATION
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Acknowledgements
This work was supported by Scientific Research on Innovative
Area "Hybrid Catalysis" (18H04649) from MEXT, Japan. MT
thanks the Hoansha Foundation for their financial support. KY
thanks JSPS Research Fellowship for Young Scientists. We also
thank the Instrumental Analysis Center, Faculty of Engineering,
Osaka University, for their assistance with HRMS and Dr.
Yoshihiro Masuya and Dr. Takuya Kodama for suggestions
regarding DFT calculations.
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Keywords: catalytic concerted nucleophilic aromatic substitution
• N-heterocyclic carbene • aryl fluoride • DFT calculations •
umpolung
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10.1002/anie.201907837
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COMMUNICATION
Kosuke Yasui, Miharu Kamitani and
Mamoru Tobisu*
Page No. – Page No.
N-Heterocyclic Carbene-Catalyzed
Concerted Nucleophilic Aromatic
Substitution of Aryl Fluorides Bearing
α,β-Unsaturated Amides
We
report on the N-heterocyclic carbene (NHC)-catalyzed intramolecular cyclization of
acrylamides that contain a 2-fluorophenyl group on the nitrogen via a Concerted
Nucleophilic Aromatic Substitution (CSNAr) reaction. DFT calculations
unambiguously revealed that this reaction proceeds through CSNAr.
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