Selective C?N Bond Cleavage of N-Acylisatins: Towards High Performance Acylation/Arylation/Transamination Reagents

Article abstract of DOI:10.1002/adsc.201900819

New multipurpose arylation/acylation/transamination reagents, N-acylisatins, have been developed by selective ‘inside-outside’ C?N bond cleavage under different catalytic conditions. As activated amides, N-acylisatins undergo Rh-catalyzed C?H arylation and Pd-catalyzed acylation by cleavage outside the C?N bond, and the desired biaryls and diaryl ketones were obtained in good to excellent yields. Generally, the combination of N-acylisatins with amines leads to a ring-opening reaction and formation of transamination products in a predictable manner through inside C?N bond cleavage. Interestingly, treatment of N-acylisatins with amines lead to unexpected outer-ring transamination products when CsF is added, which shows that CsF can favor the outside C?N bond cleavage path. Notably, this work presents a new strategy for multiple chemical transformations of a single amide to achieve various products by selective C?N bond cleavage. (Figure presented.).

Full text of DOI:10.1002/adsc.201900819

FULL PAPER
DOI: 10.1002/adsc.201900819
Selective CÀ N Bond Cleavage of N-Acylisatins: Towards High
Performance Acylation/Arylation/Transamination Reagents
Li Xiong,+a Rong Deng,+b Tingting Liu,a Zhongfeng Luo,a Zijia Wang,a
Xiao-Feng Zhu,b,* Hui Wang,a and Zhuo Zenga, c,*
a
College of Chemistry and Environment, South China Normal University, Guangzhou 510006, People’s Republic of China
Fax: (+86)-20-3931-0187
E-mail: zhuoz@scnu.edu.cn
b
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key
Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060,
People’s Republic of China
Fax: (+86)-20-8734-3170
E-mail: zhuxfeng@email.sysu.edu.cn
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
c
Shanghai, People’s Republic of China, 200032
+
These authors contributed equally to this work.
Manuscript received: July 5, 2019; Revised manuscript received: September 27, 2019;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.201900819
Abstract: New multipurpose arylation/acylation/transamination reagents, N-acylisatins, have been developed
by selective ‘inside-outside’ CÀ N bond cleavage under different catalytic conditions. As activated amides, N-
acylisatins undergo Rh-catalyzed CÀ H arylation and Pd-catalyzed acylation by cleavage outside the CÀ N
bond, and the desired biaryls and diaryl ketones were obtained in good to excellent yields. Generally, the
combination of N-acylisatins with amines leads to a ring-opening reaction and formation of transamination
products in a predictable manner through inside CÀ N bond cleavage. Interestingly, treatment of N-acylisatins
with amines lead to unexpected outer-ring transamination products when CsF is added, which shows that CsF
can favor the outside CÀ N bond cleavage path. Notably, this work presents a new strategy for multiple
chemical transformations of a single amide to achieve various products by selective CÀ N bond cleavage.
Keywords: Selective inside-outside CÀ N bond cleavage; N-acylisatins; coupling; transamination; multipurpose
reagents.
Introduction
resources superior to conventional acylation reagents,
such as acyl chloride and acid anhydride.
The carbon-nitrogen bond is a crucial and ubiquitous
Although the reactivity of the CÀ N bond has made
structural motif in thousands of natural products and great advances, the high CÀ N bond activation energy
decisively affect the biological properties of pharma- hinders the development of amide transformations.
ceutical molecules.[1] The selective CÀ N bond cleavage Remarkably, in 2016, the Garg group reported a two-
of activated amides has been a necessary and powerful step approach to obtain transamination products from
route to obtain diverse molecules in organic secondary amides in the presence of a nickel catalyst
synthesis.[2] In recent decades, tremendous develop- (Scheme 1).[7g] The Szostak group developed the first
ments have been made in this field.[3-6] The Garg,[7] Pd-catalyzed acyl and Ni-catalyzed decarboxylative
Szostak,[8-12] Yamaguchi,[13] Shi,[14] Zou,[15] and Suzuki-Miyaura cross-coupling of N-acetylamides with
Huang[16–17] groups reported many strategies for amide aryl boronic acids in 2018 (Scheme 1).[27] According to
activation and CÀ N bond cleavage, which makes this report, the multifunctional features of activated
amides promising synthons in organic synthesis. These amide make these species attractive candidates for
activated amides are developed as new acyl or aryl further investigation.
Adv. Synth. Catal. 2019, 361, 1–10
1
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
‘inside-outside’ CÀ N bond of N-acylisatins was selec-
tively cleaved to obtain diaryl ketones, biaryls and
transamination products in high yields. The significant
characteristics of our study include the following
(Scheme 1d): a) Rh-catalyzed CÀ H arylation was
achieved via outside CÀ N bond cleavage; b) cleavage
of the outside CÀ N bond of N-acylisatins in the
presence of a Pd-catalyst yielded acylation Suzuki-
Miyaura coupling products; c) inside CÀ N bond
cleavage of N-acylisatins resulted in ring-opening
transamination, which has a higher tolerance of steric
hindrance; d) remarkably, selective cleavage of ‘inside-
outside’ CÀ N bonds can be modified, and the addition
of CsF yields outside CÀ N bond cleavage trans-
amination products.
Results and Discussion
Initially, 1-benzoylindoline-2,3-dione 1a was selected
as an electrophile to couple with benzo[h]quinoline 2
to form 10-phenylbenzo[h]quinoline 3a in the pres-
ence of a rhodium catalyst. After several experiments,
Scheme 1. Previous work on acylation/ arylation/ transamina-
tion.
In this context, interest in the development of we found that [Rh(COD)Cl]2 gave the best results
activated amide multipurpose conversion continues at (Table 1, entries 1–3). For example, in contrast, target
a very high level. The Szostak group has made great compound 3a was obtained in low yield (20%) in the
contributions in decarboxylative cross-couplings and presence of a 5 mol% RhCl(PPh3)3 catalyst with
the direct CÀ H arylation of amides.[18] The series of Na2CO3 as the base in o-xylene. Bases were screened,
amides and amide-based reagents, including the most and Li2CO3 was determined to be the best choice;
reactive N-acylphthalimides,[19] N-acyl-glutarimides,[20] using Na2CO3, K2CO3 and NaOH delivered the product
anilides,[21]
N-Boc-carbamates,[22]
N,N-di-Boc-amides,[24]
N-Ts- in low yields (Table 1, entries 4–6). Some common
N-acyl- solvents, such as DMSO, DMF and toluene, were
sulfonamides,[23]
saccharins,[25] N-acyl-pyrroles,[26] N-Ac-amides,[27] N- employed to replace the o-xylene, but none of them
Ms-sulfonamides,[28] and N-acyl-succinimides,[29] have resulted in high yields (Table 1, entries 7–9).
successfully undergone outside CÀ N bond cleavage to
To our delight, the desired product could be
°
form new acylation resources so far.
obtained in 93% yield at 130 C. When the temperature
°
Selective cleavage of the inside CÀ N bond of these was decreased to 120 C, the yield of 3a yield dropped
amides has been preliminary achieved,[30] but it still significantly (Table 1, entries 10). In addition, the
remains a considerable challenge for amide trans- loading of the [Rh(COD)Cl]2 catalyst also caused a
formations. Notably, N-acylisatins differ from the decrease in the yield (Table 1, entries 11–12). Thus,
previous amides and contain two adjacent carbonyl the optimal conditions for this CÀ H functionalization
groups on the same side; this unique characteristic may with N-acylisatins were set as 5 mol% [Rh(COD)Cl]2
lead to the use of these molecules as new amide in the presence of Li2CO3 (3 equiv.) in o-xylene at
°
substrates to explore selective cleavage of ‘inside- 130 C for 15 h.
outside’ CÀ N bonds.
With the optimized reaction conditions in hand, a
As previously reported,[31] the carbonyl group at series of N-acylisatins were studied to explore the
position 2 of N-acylisatins behaves as amides that are scope and limitations of this approach (Scheme 2). To
more susceptible to nucleophilic attack via ring open- investigate the influence of electronic effects, a variety
ing in the presence of nucleophiles, affording a series of N-acylisatins with neutral and electron-donating
of α-ketoamide derivatives as pharmaceutical mole- groups were coupled to benzo[h]quinoline 2a. The
cules (Scheme 1c).[33a]
corresponding CÀ H functionalized compounds (3a–
Interest in selective CÀ N bond cleavage of amides 3e) were obtained in good to excellent yields. p-
continues to grow, and two different reactive CÀ N Chloro- and p-fluoro-substituted substrates generated
bonds (inside and outside) promote the use of N- 3f and 3g in 82% and 83% yields, respectively. A
acylisatins as new promising multifunctional trans- slightly increased yield (3h) was obtained for the
formation reagents. In this paper, we have demon- reaction with the trifluoromethyl-substituted substrate
strated that the reaction characteristics of N-acylisatins (1h). Heterocyclic groups, such as 2-furanyl and 2-
can be adjusted by using different catalysts. The thiopheneyl, were obtained in good yield (3j and 3k).
Adv. Synth. Catal. 2019, 361, 1–10
2
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
Table 1. Effect of catalyst, solvent and base.
Entry
Catalyst
Base
Solvent
Temp.
Yield[b] (%)
°
1
2
3
4
5
6
7
8
[Rh(CO)4Cl]
RhCl(PPh3)3
Na2CO3
Na2CO3
Na2CO3
K2CO3
Li2CO3
NaOH
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
Li2CO3
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
DMSO
DMF
toluene
o-xylene
o-xylene
o-xylene
130 C
18
20
35
52
93
36
0
10
82
62
78
53
°
130 C
°
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
130 C
°
130 C
°
130 C
°
130 C
°
130 C
°
130 C
°
9
130 C
°
10
11[c]
12[d]
120 C
°
130 C
°
130 C
[a] Conditions: 1a (0.5 mmol, 1.0 equiv.), 2a (2.0 equiv.), catalyst (5 mol%), base (3.0 equiv.), solvent (1.0 M) were stirred in a
°
sealed tube at 130 C for 15 h.
[b] Isolated yield.
[c] Catalyst (3 mol%).
[d] Catalyst (1 mol%).
Notably, fused naphthyl (1i) and cyclohexyl substrates
(1l) were compatible and showed good reactivity in
this transformation (3i and 3l). Substrates containing
aliphatic substituents (1m and 1n) resulted in moder-
ate yields (3m/58% and 3n/62%).
Indoles are the most explored heterocyclic com-
pounds and are common in natural products and
pharmaceuticals.[32] Hence, a range of N-(2-pyrimidyl)
indole derivatives were reacted with N-acylisatin 1a
under standard conditions (Scheme 3). Both electron-
donating (2b–2f) and electron-withdrawing (2g–2l)
substituents exhibited high reactivity and afforded the
desired products (3o–3y) in good to excellent yields.
These results indicate that direct access to C-2 arylated
indoles/arylated quinoline via activated amide decar-
boxylation coupling is a feasible method in synthetic
chemistry.
Having confirmed the high reactivity of N-acylisa-
tin, we next explored acylation via Suzuki cross-
coupling of this activated amide. After extensive
optimization (see SI for optimization details), we
identified conditions to achieve this cross coupling of
N-acylisatin (Scheme 4). The diaryl ketone products
were obtained in the highest yield with 5 mol% Pd
(OAc)2 catalyst, 20 mol% PCyHBF4, KF (4 equiv.) in
°
o-xylene/water (4/1) at 80 C for 15 h. Other Pd(II)/ Rh
(II) precatalysts, bases, ligands and solvents were
screened (see SI) and provided diaryl ketones in lower
Scheme 2. Amide scope in CÀ H functionalization. Conditions:
1a (0.5 mmol, 1.0 equiv.), 2a (2.0 equiv.), [Rh(COD)Cl]2
(5 mol%), Li2CO3 (3.0 equiv.), solvent (2 M) were stirred in a
yields. As shown in the SI, KF obtained a better yield
compared with other bases, such as Cs2CO3, Li2CO3,
°
sealed tube at 130 C for 15 h under nitrogen atmosphere.
Adv. Synth. Catal. 2019, 361, 1–10
3
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
Scheme 4. Scope of boronic acids in the cross-coupling of
amides. Conditions: 1a (0.5 mmol, 1.0 equiv.), 4 (2.0 equiv.),
Pd(OAc)2 (8 mmol), PCy3HBF4 (20 mol%), KF (4.0 equiv.),
°
solvent (2 M), were stirred in a sealed tube at 80 C for 15 h
under nitrogen atmosphere.
K2CO3 and K3PO4. Additionally, the reactions using o-
xylene/H2O as a solvent had a higher yield than those
of the corresponding reaction that used DMF, 1,4-
dioxane, toluene, THF or o-xylene. The high reactivity
of the developed reaction system was emphasized in
this transformation, as electron-neutral (5a, 5b, 5d,
5e), electron-rich (5c and 5f) and electron-deficient
(5g and 5h) substrates were well tolerated (Scheme 4).
In an effort to synthesize alkylaryl ketones, alkyl-
substituted substrates (1m and 1n) were coupled with
arylboronic acid, but the desired alkylaryl ketone
products were not observed. N-Acylisatins will be
developed as new acylation reagents in lieu of aryl
halides and pseudohalides to generate a variety of
ketones.
Scheme 5. Inside-outside transamination of N-acylisatin. Con-
ditions for (a) and (c): 1a (0.5 mmol, 1.0 equiv.), amines
(1.0 equiv.) and solvent (2 M) were stirred in a sealed tube at
°
100 C for 12 h. Conditions for (b): 1a (0.5 mmol, 1.0 equiv.),
amines (1.0 equiv.), CSF (4 equiv.) and solvent (2 M) were
°
stirred in a sealed tube at 120 C for 6 h.
The carbonyl group at position 2 of N-acylisatins
was easily attacked by amines to induce the ring-
opening reaction, yielding various α-ketoamides,
which are of interest in organic and medicinal
chemistry.[33] The previous results obtained with simple
amines encouraged us to extend this approach to
employ sterically bulky amines. Synthesis of α-
ketoamides from sterically bulky amines (N-methyl-N-
phenylbenzamide or N-(tert-butyl)benzamide) and N-
acylisatin was unsuccessful under the reported
conditions.[31d—e] When sterically bulky amines were
employed as nucleophiles with N-acylisatin, a higher
°
reaction temperature (120 C) and milder solvent were
required to drive the reaction to completion. (Sche-
me 5a) To provide a fuller picture of the N-acylisatins,
we employed typical nucleophiles (aniline and butanol)
to attempt the ring-opening reaction and the result
showed good yields. (Scheme 5c) The corresponding
optimization can be seen in Table 2.
We anticipate that the use of this simple synthetic
pathway will allow the preparation of α-ketoamides
with various amines to develop new biologically active
molecules.
Scheme 3. Indole Scope in C2 Arylation of N-(2-Pyrimidyl)
indoles. Conditions: 1a (0.5 mmol, 1.0 equiv.), 2d–n
(2.0 equiv.), [Rh(COD)Cl]2 (5 mol%), Li2CO3 (3.0 equiv.),
°
solvent (2 M) were stirred in a sealed tube at 130 C for 15 h
under nitrogen atmosphere.
Adv. Synth. Catal. 2019, 361, 1–10
4
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
Table 2. Optimization studies in the ring-opening reaction of
N-acylisatin.
Figure 1. Crystal structure of 1a.
entry product conditions
Yield (%)
fluoride and allowed the outside CÀ N bond cleavage to
produce new amides.[35b] To verify this discovery, N-
acylisatin 1a was stirred with CsF for 4 h under
standard conditions, and the presence of an acyl
fluoride in the reaction mixture was confirmed by the
19F NMR spectrum (À 14.307 ppm). Additionally, the
reaction mixture was analyzed by gas chromatography-
flame ionization detector (GC-FID), and the result
shows that the mixture contained an acyl fluoride (see
SI).
1
2
3
4
5
6
6a
6a
6a
6a
6a
6a
CH3CN, 12 h, rt.
CH3CN, 12 h, 80 C
CH3CN, 12 h, 100 C
CH3CN, 12 h, 110 C
CH3CN/H2O (2/1), 12 h, 100 C 55
CH3CN/H2O (4/1), 12 h, 100 C 50
trace
trace
36
°
°
°
30
°
°
Conditions: 1a (0.5 mmol, 1.0 equiv.), 6a (1.0 equiv.), solvent
(2 M) were stirred in a sealed tube at 100 C for 12 h.
°
To investigate the structural factors controlling the
Although ring-opening products have been high reactivity of N-acylisatin, the X-ray structure was
achieved, it is still a major challenge to activate the generated (Figure 1, CCDC reference number
outside CÀ N bond due to the high CÀ N bond 1815157). The X-ray structure indicates that 1a
°
dissociation energy. Transamination by Szostak’s team contains a highly distorted amide bond (τ=21.95 ,
°
°
provided a certain basis for the study of activated ring χN =13.87 , χC =4.7 ). The NÀ C(O) and C=O bond
CÀ N bonds.[34] Our group has already reported that lengths are 1.412 A and 1.199 A.
CsF can react with amide bonds to form the
Furthermore, comparative experiments under the
corresponding acyl fluoride by site-selective CÀ N optimized reaction conditions of Rh-catalyzed CÀ H
bond cleavage, as mentioned above.[35] Thus, we arylation and the Pd-catalyzed acyl Suzuki-Miyaura
hypothesized that this in situ-generated acyl fluoride cross-coupling reaction were carried out (Scheme 6).
could be utilized in activated outside CÀ N bonds of N- The experimental data show that the coupling/decar-
acylisatin.
bonation yields of N-acylsuccinimides (1p) and N-
To investigate our proposed transformation, we acyl-glutarimides (1q) reached 88/56% and 80/50%,
conducted a series of conditional screenings with 1a respectively. However, the yield of N-acylphthalimide
and N-methyl-N-phenylbenzamide as substrates (Ta- (1o) was only 28/17%. N-Ts amide (1s) and N-Boc
ble 3). The benzamide products were observed under amide (1r) afford low coupling/decarbonation yields
°
CsF (4 equiv.) in CH3CN at 120 C for 6 h. (Sche- (32/26%, 50/48%), while the yield of N-acylisatin (1a)
me 5b) To be more precise, sterically bulky amides gave the highest yield (93/78%) under the same
performed smoothly under these reaction conditions. conditions. It is currently well established that N-acyl-
As the result showed, 1a underwent activation by glutarimides are the most reactive amide reagents in
Table 3. Optimization studies in transamination of N-acylisatin.
entry
product
conditions
Yield (%)
°
1
2
3
4
5
6
7a
7a
7a
7a
7a
7a
CsF (1 equiv.), CH3CN/H2O (2/1), 12 h, 100 C
trace
27
45
50
64
°
CsF (1 equiv.), CH3CN, 12 h, 100 C
°
CsF (1 equiv.), CH3CN, 12 h, 120 C
°
CsF (2 equiv.), CH3CN, 12 h, 120 C
°
CsF (4 equiv.), CH3CN, 12 h, 120 C
°
CsF (4 equiv.), CH3CN, 6 h, 120 C
67
°
Conditions: 1a (0.5 mmol, 1.0 equiv.), 7a (1.0 equiv.), CsF (4 equiv.), solvent (2 M) were stirred in a sealed tube at 120 C for 6 h.
Adv. Synth. Catal. 2019, 361, 1–10
5
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
rhodium catalytic condition: oxidative addition of N-
acylisatins to Rh catalyst I forms an acyl rhodium
complex, a molecule of carbon monoxide is extracted
to produce complex II, the CÀ H bond is then activated
through ortho chelation in the presence of Li2CO3 to
provide complex III, and finally, a new CÀ C bond and
the Rh(I)-species are formed by reductive elimination;
b) Pd-catalyzed Suzuki-Miyaura acylation coupling:
oxidative addition takes place at the CÀ N bond of N-
acylisatins to generate an acylpalladium(II) complex V,
complex VI is obtained by transmetalation, and then,
the new CÀ C bond is formed via reductive elimination;
c) the ring-opening reaction: the carbonyl group at
position 2 of N-acylisatins is attacked by nucleophiles
to produce a transient intermediate VIII, which then
undergoes a ring-opening reaction to yield the trans-
amination products; d) transamination catalyzed by
CsF: fluoride attacks the carbonyl group of N-
acylisatins to form acyl fluoride VII, which serves as a
strong nucleophile, and then intermediate species VII
is captured by sterically bulky amines to generate the
transamination products.
Scheme 6. Control reactions.
Conclusion
cross-coupling.[36] We tried to compare the best In summary, we have designed N-acylisatins for the
conditions in the literature for cross-coupling of N- first time as novel multipurpose reagents by selectively
acylglutarimides[37] to the present ideal conditions for cleaving the ‘inside-outside’ CÀ N bonds under differ-
optimal reactivity. The results demonstrate that the ent conditions, thus leading to acylation/arylation/
reactivity of N-acylisatin is only slightly lower than transamination of N-acylisatins. N-acylisatins contain
that of N-acylglutarimides. Therefore, these parameters two adjacent carbonyl groups on the same side of the
and control experiments of amide bonds in N-acylisatin five-membered ring, which differs from the reactivity
support ground-state destabilization, accounting for the of other activated amides. The high functional group
high reactivity.[38]
tolerance of this approach allows the production of a
Based on our observations and typical Suzuki variety of diaryl ketones/biaryls/amides in good yields.
cross-coupling, we propose a mechanism for the whole Notably, we have also demonstrated an efficient way
catalytic cycle (Scheme 7): a) CÀ H arylation under to convert amides using CsF via selective cleavage of
the outside CÀ N bond of N-acylisatins. Furthermore,
this approach introduces a class of high-performance
reagents, N-acylisatins, and demonstrates a new strat-
egy for multiple chemical transformations based on a
single amide.
Experimental Section
General Procedure for Amide Synthesis
Benzoyl chloride (1.16 mL, 10 mmol) was added dropwise via
a syringe to a stirring mixture of saccharin (1.84 g, 10 mmol)
°
and NEt3 (1.4 mL, 10 mol) in DMAc (8 mL) at 0 C. The
mixture was stirred for 1 h and slowly poured into H2O
°
(100 mL) at 0 C. The pale-yellow precipitate was filtered,
°
washed with H2O (0–5 C, 10 mL), and dried in vacuo to afford
the crude residue. The resulting crude residue was purified by
flash chromatography (40:1 petroleum ether: EtOAc) to afford a
yellow solid in 96% yield (2.76 g).
Scheme 7. Proposed mechanism for multitransformations of N-
acylisatins.
Adv. Synth. Catal. 2019, 361, 1–10
6
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
General Procedure for the CÀ H Functionalization
Acknowledgements
Reaction
The authors gratefully acknowledge the support of Science and
Technology Planning Project of Guangdong Province
(2017 A010103017), National Natural Science Foundation of
China (51703069, 21272080), Special Innovation Projects of
Common Universities in Guangdong Province (20178 S0182).
In an oven-dried Teflon septum screw-capped tube (15 mL),
benzo[h]quinoline (35.8 mg, 0.2 mmol, 1.0 equiv.) 2a or 1-
(pyridin-2-yl)-1H-indole (38.8 mg, 0.2 mmol, 1.0 equiv.) 2b, N-
acylisatins 1a–1l (1.0 equiv.), [Rh(COD)Cl]2 (5 mol%), and
Li2CO3 (3.0 equiv.) were added. The dry o-xylene (2 mL) was
injected into the tube, and then the reaction was removed to a
°
References
130 C preheated oil bath and stirred for 15 h. After cooling to
room temperature, the solvents were removed, and the crude
product was purified by silica gel column chromatography
using petroleum ether/ethyl acetate (40/1) as an eluent to afford
biaryls.
[1] a) S. A. Ruider, N. Maulide, Angew. Chem. Int. Ed.
2015, 54, 13856–13858. b) S. Shi, G. Meng, M. Szostak,
Angew. Chem. Int. Ed. 2016, 55, 6959–6963.
[2] a) Z. Mucsi, G. A. Chass, I. G. Csizmadia, J. Phys.
Chem. B. 2008, 112, 7885–7893. b) S. A. Ruider, N.
Maulide, Angew. Chem. Int. Ed. 2015, 54, 13856–13858.
[3] a) D. Y. Wang, M. Kawahata, Z. K. Yang, K. Miyamoto,
Nat. Commun. 2016, 7, 12937. b) M. Cui, H. Wu, J. Jian,
H. Wang, C. Liu, S. Daniel, Z. Zeng, Chem. Commun.
2016, 52, 12076–12079. c) M. Guisán-Ceinos, V. Mar-
tín-Heras, M. Tortosa, J. Am. Chem. Soc. 2017, 139,
8448–8451. d) J. Amani, R. Alam, S. Badir, G. A.
Molander, Org. Lett. 2017, 19, 2426–2429. e) T.-T.
Zhao, W.-H. Xu, Z.-J. Zheng, P.-F. Xu, H. Wei, J. Am.
Chem. Soc. 2018, 140, 586–589.
[4] a) Y. Li, Z. Wang, X.-F. Wu, ACS Catal. 2018, 8, 738–
741. b) X. Liu, C.-C. Hsiao, L. Guo, M. Rueping, Org.
Lett. 2018, 20, 2976–2979. c) Y. Bourne-Branchu, C.
Gosmini, G. Danoun, Chem. Eur. J. 2017, 23, 10043–
10047. d) Z. Luo, T. Liu, W. Guo, Z. Wang, J. Huang, Y.
Zhu, Z. Zeng, Org. Process Res. Dev. 2018, 22, 1188–
1199.
[5] a) X. Cong, F. Fan, P. Ma, M. Luo, H. Chen, X. Zeng, J.
Am. Chem. Soc. 2017, 139, 15182–15190. b) C. Liu, M.
Szostak, Angew. Chem. Int. Ed. 2017, 56, 12718–12722.
c) Z. Zhang, D. Zheng, Y. Wan, G. Zhang, J. Bi, Q. Liu,
T. Liu, L. Shi, J. Org. Chem. 2018, 83, 1369–1376.
[6] a) S. Shojaei, Z. Ghasemi, A. Shahrisa, Tetrahedron Lett.
2017, 58, 3957–3965. b) Y. Li, Z. Wang, X.-F. Wu, ACS
Catal. 2017, 8, 738–741. c) H. Wu, T. Liu, M. Cui, Y. Li,
J. Jian, H. Wang, Z. Zeng, Org. Biomol. Chem. 2017, 15,
536–540.
[7] a) E. L. Baker, M. M. Yamano, Y. Zhou, S. M. Anthony,
Nat. Commun. 2016, 7, 11554. b) L. Hie, N. F. Fine Na-
thel, T. K. Shah, E. L. Baker, X. Hong, Y.-F. Yang, P.
Liu, K. N. Houk, N. K. Garg, Nature. 2015, 524, 79–83.
c) N. A. Weires, E. L. Baker, N. K. Garg, Nat. Chem.
2016, 8, 75–79. d) L. Hie, E. L. Baker, S. M. Anthony,
J.-N. Desrosiers, C. Senanayake, N. K. Garg, Angew.
Chem. Int. Ed. 2016, 55, 15129–15132. e) J. E. Dander,
N. T. B. Boit, N. A. Weires, J. Kim, N. K. Garg, ACS
Catal. 2018, 8, 1003–1008. f) J. E. Dander, Emma L.
Baker, N. K. Garg, Chem. Sci. 2017, 8, 6433–6438.
g) E. L. Baker, M. M. Yamano, Y. Zhou, S. M. Anthony,
N. K. Garg, Nat. Commun. 2016, 7, 11554.
Representative Procedure for Acyl Suzuki-Miyaura
Cross-Coupling
An oven-dried vial equipped with a stir bar was charged with
N-acylisatins (0.2 mmol, 1.0 equiv.), phenylboronic acid
(0.4 mmol, 3.0 equiv.), Pd(OAc)2 (8 mol%), PCy3HBF4
(20 mol%), and KF (3 mmol, 3.0 equiv.) in o-xylene/water (4/1)
under a positive pressure of nitrogen. The reaction mixture was
°
placed in a preheated oil bath at 80 C and stirred for 15 h. After
the indicated time, the reaction mixture was cooled to room
temperature, diluted with CH2Cl2 (20 mL), filtered, and
concentrated. Purification by chromatography on silica gel
(hexanes/ethyl acetate) afforded the title product.
Representative Procedure for Ring-Opening Reac-
tion
In an oven-dried Teflon septum screw-capped tube, 1a
(0.2 mmol, 1.0 equiv.) and sterically bulky amines (N-Methyl-
N-phenylbenzamide or N-(Tert-butyl)benzamide) (0.24 mmol,
1.2 equiv.) was dissolved in CH3CN/H2O (2/1, 3 mL) stirring at
°
100 C for 12 h. After cooling to room temperature, the solvents
was removed, the resulting crude residue was purified by flash
chromatography (15:1 Petroleum ether : EtOAc) to obtained the
desired product.
Representative Procedure for Transamination
1a (0.2 mmol, 1.0 equiv.) was dissolved in CH3CN (2 mL),
then sterically bulky amines (N-Methyl-N-phenylbenzamide or
N-(Tert-butyl)benzamide) (0.24 mmol, 1.2 equiv.) and CsF
(30 mg, 0.2 mmol, 0.2 equiv.) were added into the sealed vessel.
°
After stirring at 120 C for 6 h, the reaction mixture was
concentrated under reduced pressure. The resulting crude
residue was purified by flash chromatography (20:1 Petroleum
ether : EtOAc) to yield amide.
X-ray Crystal Structure of 1a
CCDC-1815157 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[8] a) C. Liu, M. Achtenhagen, M. Szostak, Org. Lett. 2016,
18, 2375–2378. b) G. Meng, M. Szostak, Angew. Chem.
Int. Ed. 2015, 54, 14518–14522. c) G. Meng, M.
Adv. Synth. Catal. 2019, 361, 1–10
7
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
Szostak, Org. Lett. 2015, 17, 4364–4367. d) C. Liu, G.
Meng, M. Szostak, J. Org. Chem. 2016, 81, 12023–
J.-M. Luo, K.-Y. Ye, Y. Wang, P.-Q. Huang, Angew.
Chem. Int. Ed. 2010, 49, 3037–3040.
12030. e) C. Liu, G. Meng, Y. Liu, R. Liu, R. Lalancette, [17] a) K.-J. Xiao, A.-E. Wang, P.-Q. Huang, Angew. Chem.
R. Szostak, M. Szostak, Org. Lett. 2016, 18, 4194–4197.
[9] a) G. Meng, S. Shi, M. Szostak, ACS Catal. 2016, 6,
7335–7339. b) Y. Liu, G. Meng, R. Liu, M. Szostak,
Chem. Commun. 2016, 52, 6841–6844. c) C. Liu, M.
Szostak, Chem. Eur. J. 2016, 23, 7157–7173. d) G.
Int. Ed. 2012, 51, 8314–8317. b) K.-J. Xiao, A.-E. Wang,
Y.-H. Huang, P.-Q. Huang, Asian J. Org. Chem. 2012, 1,
130–132. c) J.-L. Zhang, L.-A. Chen, R.-B. Xu, C.-F.
Wang, Y.-P. Ruan, A.-E. Wang, P.-Q. Huang, Tetrahe-
dron: Asymmetry 2013, 24, 492–498.
Meng, M. Szostak, Org. Biomol. Chem. 2016, 14, 5690– [18] a) C. Liu, M. Szostak, Org. Biomol. Chem. 2018, 16,
5707. e) S. Shi, G. Meng, M. Szostak, Angew. Chem. Int.
Ed. 2016, 55, 6959–6963. f) G. Meng, M. Szostak, Org.
Lett. 2016, 18, 796–799.
7998–8010. b) G. Meng, M. Szostak, ACS Catal. 2017,
7, 7251–7256. c) S. Shi, M. Szostak, Org. Lett. 2017, 19,
3095–3098.
[10] a) P. Lei, G. Meng, S. Shi, Y. Ling, J. An, R. Szostak, M. [19] M. Rahman, J. Buchspies, M. Szostak, Catalysts 2019, 9,
Szostak, Chem. Sci. 2017, 8, 6525–6530. b) P. Lei, G. 129.
Meng, M. Szostak, ACS Catal. 2017, 7, 1960–1965. [20] G. Meng, M. Szostak, Org. Lett. 2015, 17, 4364–4367.
c) C. Liu, Y. Liu, R. Liu, R. Lalancette, R. Szostak, M. [21] L. Hie, N. F. Fine Nathel, T. K. Shah, E. L. Baker, X.
Szostak, Org. Lett. 2017, 19, 1434–1437. d) S. Shi, M.
Szostak, Chem. Eur. J. 2016, 22, 10420–10424. e) S. Shi,
M. Szostak, Org. Lett. 2016, 18, 5872–5875.
Hong, Y.-F. Yang, P. Liu, K. N. Houk, N. K. Garg,
Nature. 2015, 524, 79–83.
[22] N.-A. Weires, E.-L. Baker, N.-K. Garg, Nat. Chem. 2016,
8, 76–80.
[11] a) G. Meng, R. Szostak, M. Szostak, Org. Lett. 2017, 19,
3596–3599. b) Y. Osumi, C. Liu, M. Szostak, Org. [23] X. Li, G. Zou, Chem. Commun. 2015, 51, 5089–5092.
Biomol. Chem. 2017, 15, 8867–8871. c) G. Meng, R. [24] M. Szostak, G. Meng, S. Shi, ACS Catal. 2016, 6, 7335–
Lalancette, R. Szostak, M. Szostak, Org. Lett. 2017, 19,
7339.
4656–4659. d) G. Meng, P. Lei, M. Szostak, Org. Lett. [25] a) C. Liu, G. Meng, Y. Liu, R. Liu, R. Lalancette, R.
2017, 19, 2158–2161. e) S. Shi, M. Szostak, Synthesis.
2017, 49, 3602–3608.
[12] a) R. Szostak, S. Shi, G. Meng, R. Lalancette, M.
Szostak, M. Szostak, Org. Lett. 2016, 18, 4194–4197.
b) H. Wu, Y. Li, M. Cui, J. Jian, Z. Zeng, Adv. Synth.
Catal. 2016, 358, 3876–3880.
Szostak, J. Org. Chem. 2016, 81, 8091–8094. b) P. Lei, [26] G. Meng, R. Szostak, M. Szostak, Org. Lett. 2017, 19,
G. Meng, Y. Ling, J. An, S. P. Nolan, M. Szostak, Org. 3596–3599.
Lett. 2017, 19, 6510–6513. c) P. Lei, G. Meng, Y. Ling, [27] C. Liu, G. Li, S. Shi, G. Meng, R. Lalancette, R. Szostak,
J. An, S. P. Nolan, M. Szostak, J. Org. Chem. 2017, 82, M. Szostak, ACS Catal. 2018, 8, 9131–9139
6638–6646. d) G. Meng, S. Shi, M. Szostak, Synlett. [28] M. Szostak, C. Liu, Y. Liu, R. Liu, R. Lalancette, R.
2016, 27, 2530–2540. Szostak, Org. Lett. 2017, 19, 1434–1437
[13] a) R. Takise, K. Muto, J. Yamaguchi, Chem. Soc. Rev. [29] a) Y. Osumi, C. Liu, M. Szostak, Org. Biomol. Chem.
2017, 46, 5864–5888. b) E. Koch, R. Takise, A. Studer,
J. Yamaguchi, K. Itami, Chem. Commun. 2015, 51, 855–
857. c) K. Muto, J. Yamaguchi, K. Itami, J. Am. Chem.
Soc. 2011, 134, 169–172. d) K. Amaike, K. Muto, J.
2017, 15, 8867–8871. b) M. Cui, Z. Chen, T. Liu, H.
Wang, Z. Zeng, Tetrahedron Lett. 2017, 58, 3819–3822.
c) T. Wang, J. Guo, H. Wang, H. Guo, D. Jia, W. Zhang,
L. Liu, J. Organomet. Chem. 2018, 877, 80–84.
Yamaguchi, K. Itami, J. Am. Chem. Soc. 2012, 134, [30] Y. Liu, M. Achtenhagen, R. Liu, M. Szostak, Org.
13573–13576. Biomol. Chem. 2018, 16, 1322–1329.
[14] a) J. Hu, M. Wang, X. Pu, Z. Shi, Nat. Commun. 2017, 8, [31] a) G.-A. Shirokii, K.-N. Zelenin, Russ. J. Gen. Chem.
14993. b) J. Hu, Y. Zhao, J. Liu, Y. Zhang, Z. Shi,
Angew. Chem. Int. Ed. 2016, 55, 8718–8722. c) Y. Yang,
X. Qiu, Y. Zhao, Y. Mu, Z. Shi, J. Am. Chem. Soc. 2016,
138, 495–498. d) P. Gao, W. Guo, J. Xue, Y. Zhao, Y.
Yuan, Y. Xia, Z. Shi, J. Am. Chem. Soc. 2015, 137,
12231–12240.
2002, 72, 244–250. b) J.-F. Da Silva, S.-J. Garden, A.-C.
Pinto, J. Braz. Chem. Soc. 2001, 12, 273–324. c) K.
Bharathimohan, T. Ponpandian, A. A. Jafar, Eur. J. Org.
Chem. 2017, 2806–2813. d) V. Suryanti, M. Bhadbhade,
R. Bishop, D. S. Black, N. Kumar, Tetrahedron. 2013,
69, 8446–8455. e) S. Nizalapur, K. K. K. Ho, Ö.
Kimyon, E. Yee, T. Berry, M. Manefield, C. G. Cranfield,
M. Willcox, D. S. Black, N. Kumar, Org. Biomol. Chem.
2016, 14, 3623–3637.
[15] a) C. Wang, L. Huang, F. Wang, G. Zou, Tetrahedron
Lett. 2018, 59, 2299–2301. b) X. Li, G. Zou, J. Organo-
met. Chem. 2015, 794, 136–145. c) X. Li, G. Zou, Chem.
Commun. 2015, 51, 5089–92. d) G. Zou, Y. K. Reddy, [32] a) S. Cacchi, G. Fabrizi, Chem. Rev. 2005, 105, 2873–
J. R. Falck, Tetrahedron Lett. 2001, 42 7213–7215. e) W.
Huang, J. Guo, Y. Xiao, M. Zhu, G. Zou, Tetrahedron
Lett. 2005, 61, 9783–9790.
2920. b) M. Platon, R. Amardeil, L. Djakovitch, J.-C.
Hierso, Chem. Soc. Rev. 2012, 41, 3929–3968. c) M.
Inman, C.-J Moody, Chem. Sci. 2013, 4, 29–41.
[16] a) P.-Q. Huang, H. Chen, Chem. Commun. 2017, 53, [33] a) A. El-Faham, W. N. Hozzein, M. A. M. Wadaan, S. N.
12584–12587. b) P.-Q. Huang, H. Chen, Green Chem.
2018, 20, 593–599.) P.-Q. Huang, Y.-H. Huang, K.-J.
Xiao, J. Org. Chem. 2016, 81, 9020–9027. c) K.-J. Xiao,
Khattab, H. A. Ghabbour, H.-K. Fun, M. R. Siddiqui, J.
Chem. 2015, 8, 27. b) M. M. H. Arief, M. H. M. Ahmed,
Adv. Synth. Catal. 2019, 361, 1–10
8
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

FULL PAPER
asc.wiley-vch.de
A. A. Said, N. M. M. Selim, Int. J. Basic Appl. Sci. 2013,
2, 153.
[34] a) G. Li, C.-L. Ji, X. Hong, M. Szostak, Y. Liu, J. Am.
Chem. Soc. 2019, 141, 11161–11172. b) G. Li, M.
Lalancette, R. Szostak, M. Szostak, Chem. Eur. J. 2016,
22, 14494–14498. c) G. Meng, S. Shi, R. Lalancette, R.
Szostak, M. Szostak, J. Am. Chem. Soc. 2018, 140, 727–
734.
Szostak, Nat. Commun. 2018, 9, 4165. c) Y. Liu, S. Shi, [38] a) S. Shi, S. P. Nolan, M. Szostak, Acc. Chem. Res. 2018,
M. Achtenhagen, R. Liu, M. Szostak, Org. Lett. 2017,
19, 1614–1617.
[35] a) W. Guo, J. Huang, H. Wu, T. Liu, Z. Luo, J. Jian, Z.
Zeng, Org. Chem. Front. 2008, 5, 2950–2954. b) H. Wu,
W. Guo, S. Daniel, Y. Li, C. Liu, Z. Zeng, Chem. Eur. J.
2018, 24, 3444–3447.
51, 2589–2599. b) J. Buchspies, M. Szostak, Catalysts
2019, 9, 53. c) J. Buchspies, M. Szostak, Molecules
2019, 24, 274. d) G. Meng, M. Szostak, Eur. J. Org.
Chem. 2018, 20–21, 2352–2365. e) R. Szostak, M.
Szostak, Org. Lett. 2018, 20, 1342–1345. f) C. Liu, S.
Shi, Y. Liu, R. Liu, R. Lalancette, R. Szostak, M.
Szostak, Org. Lett. 2018, 20, 7771–7774.
[36] a) G. Meng, M. Szostak, Org. Lett. 2015, 17, 4364. b) G.
Meng, M. Szostak, Org. Lett. 2016, 18, 796.
[37] a) M. Szostak, J. Aubé, Chem. Rev. 2013, 113, 5701–
5765. b) V. Pace, W. Holzer, G. Meng, S. Shi, R.
Adv. Synth. Catal. 2019, 361, 1–10
9
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
��
These are not the final page numbers!

FULL PAPER
Selective CÀ N Bond Cleavage of N-Acylisatins: Towards
High Performance Acylation/Arylation/Transamination
Reagents
Adv. Synth. Catal. 2019, 361, 1–10
L. Xiong, R. Deng, T. Liu, Z. Luo, Z. Wang, X.-F. Zhu*, H.
Wang, Z. Zeng*