Palladium-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of amides by carbon-nitrogen bond activation

Article abstract of DOI:10.1039/c9sc03169c

Palladium-catalyzed Suzuki-Miyaura cross-coupling or aryl halides is widely employed in the synthesis of many important molecules in synthetic chemistry, including pharmaceuticals, polymers and functional materials. Herein, we disclose the first palladium-catalyzed decarbonylative Suzuki-Miyaura cross-coupling of amides for the synthesis of biaryls through the selective activation of the N-C(O) bond of amides. This new method relies on the precise sequence engineering of the catalytic cycle, wherein decarbonylation occurs prior to the transmetallation step. The reaction is compatible with a wide range of boronic acids and amides, providing valuable biaryls in high yields (>60 examples). DFT studies support a mechanism involving oxidative addition, decarbonylation and transmetallation and provide insight into high N-C(O) bond activation selectivity. Most crucially, the reaction establishes the use of palladium catalysis in the biaryl Suzuki-Miyaura cross-coupling of the amide bond and should enable the design of a wide variety of cross-coupling methods in which palladium rivals the traditional biaryl synthesis from aryl halides and pseudohalides.

Full text of DOI:10.1039/c9sc03169c

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DOI: 10.1039/C9SC03169C
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EDGE ARTICLE
Palladium-Catalyzed Decarbonylative Suzuki–Miyaura Cross-
Coupling of Amides by Carbon–Nitrogen Bond Activation
Tongliang Zhou,a Chong-Lei Ji,b Xin Hong*,b and Michal Szostak*,a
Received 00th January 20xx,
Accepted 00th January 20xx
Palladium-catalyzed Suzuki–Miyaura cross-coupling or aryl halides is widely employed in the synthesis of many important
molecules in synthetic chemistry, including pharmaceuticals, polymers and functional materials. Herein, we disclose the
first palladium-catalyzed decarbonylative Suzuki–Miyaura cross-coupling of amides for the synthesis of biaryls through the
selective activation of the N–C(O) bond of amides. This new method relies on the precise sequence engineering of the
catalytic cycle, wherein decarbonylation occurs prior to the transmetallation step. The reaction is compatible with a wide
range of boronic acids and amides, providing valuable biaryls in high yields (>60 examples). DFT studies support a
mechanism involving oxidative addition, decarbonylation and transmetallation and provide insight into high N–C(O) bond
activation selectivity. Most crucially, the reaction establishes the use of palladium catalysis in the biaryl Suzuki–Miyaura
cross-coupling of the amide bond and should enable the design of a wide variety of cross-coupling methods in which
palladium rivals the traditional biaryl synthesis from aryl halides and pseudohalides.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Palladium-catalyzed cross-coupling reactions are fundamental
methods for the construction of many important molecules in
chemical synthesis and these reactions are widely used to
expediate the synthesis of target motifs.1–3 In particular, due to
broad generality, predictable functional group tolerance, high
reaction selectivity and operational-simplicity, palladium-
catalyzed cross-couplings have enabled the rapid progress in
the development of improved medicines, precise electronic
devices, and multifunctional dyes that broadly benefit
society.4–6
While typical Suzuki-Miyaura cross-couplings employ aryl
halides as electrophiles, unconventional C–X (X = O, N, S) cross-
coupling partners have attracted significant attention because
they enable orthogonal selectivity paradigm.4–6 In this context,
amides (X = CONR2) are particularly attractive as aryl
electrophiles in the Suzuki–Miyaura cross-coupling because
amides are among the most widespread functional groups in
chemical science,7 including in the synthesis of
pharmaceuticals, and play an essential role as linkages in
peptides and proteins.8,9 While significant progress has been
achieved in cross-coupling of amides enabled by selective
Fig. 1 (a) Acyl- and decarbonylative cross-coupling of amides. (b) Pd-
catalyzed decarbonylative biaryl cross-coupling of amides enabled
by sequence engineering (this study).
Herein, we disclose the first palladium-catalyzed
decarbonylative Suzuki–Miyaura cross-coupling of amides for
the synthesis of biaryls (Fig. 1B). This new method relies on the
precise sequence engineering of the catalytic cycle, wherein
decarbonylation occurs prior to the transmetallation step. The
reaction proceeds through the selective activation of the N–
C(O) bond of both cyclic and acyclic amides. DFT studies were
conducted and support a mechanism involving oxidative
addition, decarbonylation and transmetallation, and provide
insight into the origin of the high N–C(O) bond activation
selectivity. The reaction shows unprecedented generality and
metal insertion into the N–C(O) amide bond (nN → *
C=O
conjugation, 15-20 kcal/mol in planar amides),10–14 the
palladium-catalyzed Suzuki-Miyaura biaryl cross-coupling of
amides has been a major challenge (Fig. 1A).
aDepartment of Chemistry,Rutgers University, 73 Warren Street, Newark, NJ 07102,
USA. E-mail: michal.szostak@rutgers.edu.
bDepartment of Chemistry, Zhejiang University, Hangzhou 310027, China. E-mail:
hxchem@zju.edu.cn.
†Electronic Supplementary Information (ESI) available: Experimental details and
characterization data. See DOI: 10.1039/x0xx00000x
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Table
1 Reaction Optimization: Pd-Catalyzed Decarbonylative
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functional group tolerance in decarbonylative amide bond
cross-coupling, providing valuable biaryls in high yields (>60
examples). Most crucially, the reaction establishes versatile
palladium catalysis for the synthesis of high-value biaryls from
amides, rivaling the substrate scope achieved with the
traditional Suzuki cross-coupling of aryl halides.
Suzuki–Miyaura Cross-Couplinga
DOI: 10.1039/C9SC03169C
2
Yield
Entry
Catalyst
Base
Selectivityc
(equiv) 3 (%)b
Results and discussion
The decarbonylative biaryl Suzuki-Miyaura cross-coupling of
amides is a challenging reaction, in which several elementary
1
2
3
4
5
6
7
Pd(dppf)Cl2
Pd(dppb)Cl2
Pd(PCy3)2Cl2
Pd(dppf)Cl2
Pd(PCy3)2Cl2
Pd(PPh3)2Cl2
Pd(dcypf)Cl2
Pd(PCy3)2Cl2
Pd(PCy3)2Cl2
Pd(PCy3)2Cl2
Pd(PCy3)2Cl2
Pd(PCy3)2Cl2
Pd(PCy3)2Cl2
Pd(PCy3)2Cl2
Pd(PCy3)2Cl2
Pd(PCy3)2Cl2
Pd(PCy3)2Cl2
Pd(PCy3)2Cl2
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K2CO3
1.2
1.2
1.2
2.0
2.0
2.0
2.0
1.05
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.2
1.2
1.2
1.2
90
88
83
82
70
67
65
83
<10
<2
50
15
<2
<2
<2
<2
16
31
<2
63
78
47
>10:1
90:10
84:16
86:14
72:26
69:31
66:34
85:15
6:94
<5:>95
53:47
56:44
<5:>95
<5:>95
nd
<5:>95
55:45
51:49
<5:>95
79:21
80:20
53:47
organometallic steps must occur in
a well-engineered
sequence.15–18 To date, very few examples of the biaryl Suzuki-
Miyaura cross-coupling of amides have been reported; all of
them limited to nickel-catalysis.15 The high reactivity of Ni has
been ascribed to a facile CO migration, which permitted for
transmetallation preceding decarbonylation.18 However, Ni-
catalyzed biaryl Suzuki coupling of amides has been severely
limited to specific substrate combinations and showed narrow
functional group tolerance.
8
9d
10d
11d
12d
13d
14d
15d
16d,e
17d,f
18d,g
19h
20h
21i
22j
K3PO4
KHCO3
Na2CO3
KF
KOAc
-
NaHCO3
NaHCO3
NaHCO3
In consideration of the tremendous utility of Pd-catalyzed
cross-couplings in organic synthesis,19,20 we questioned
whether general palladium catalysis might be applied for the
decarbonylative biaryl Suzuki–Miyaura cross-coupling of
amides by N–C(O) bond activation. Our investigation started
with evaluation of the coupling of a challenging, electronically-
Pd(OAc)2/PCy3 NaHCO3
PdCl2/PCy3
Pd(dppb)Cl2
Pd(dppb)Cl2
NaHCO3
NaHCO3
NaHCO3
neutral N-benzoyl glutarimide
(1) with 4-methoxyphenyl
boronic acid ( ) in the presence of various Pd catalysts (Table
2
aConditions: amide (1.0 equiv), Ar-B(OH)2, [Pd] (5 mol%), base
1); note that this combination is unsuccessful using Ni
catalysis. After very extensive optimization (Table 1 and ESI),
(3 equiv), dioxane (0.125 M), 160 °C, 12 h. bGC/1H NMR yields.
we found that a catalytic system using Pd(dppf)Cl2 (5 mol%) in cRefers to biaryl:ketone selectivity. d[Pd] (3 mol%). Note that in
entries 9, 10, 13 and 14, the ketone is formed in 92-98% yields.
the presence of close to a stoichiometric amount of boronic
acid (1.2 equiv) and NaHCO3 (3.0 equiv) in dioxane at 160 °C,
delivered the desired biaryl product in 90% yield and >10:1
biaryl:ketone selectivity (entry 1). Interestingly, a comparable
efficiency was observed using Pd(dppb)Cl2 (5 mol%) as the
precatalyst (entry 2). The use of a weak base is crucial (entries
8-15). From the outset, we hypothesized that the use of a
weak base would slow down transmetallation,21 permitting for
decarbonylation preceding aryl transfer. Furthermore, the
effect of boronic acid stoichiometry (entries 1-8) as well as the
counterion (entries 19-20) is the key in determining the
selectivity for the formation of biaryl, as expected from
decarbonylation vs. transmetallation selectivity. It is
worthwhile to note the impact of the reaction temperature on
the selectivity (entries 21-22). The use of precatalysts22
(entries 1-3 vs. 19-20) simplifies the reaction set-up and
facilitates CO de-insertion. It is further important to note that
both bidentate and monodentate phosphane ligands are
similarly effective (entries 1-7), consistent with the importance
of decarbonylation prior to generating the aryl–Pd
intermediate.17,18
f
eToluene. DME. gNMP. h[Pd] (10 mol%), L (20 mol%). Entry 19:
ketone formed in 71%. i140 °C. j120 °C. See ESI for full details.
withdrawing boronic acids is compatible (3a-3f), all using the
challenging electron-neutral, parent amide electrophile that is
not suitable using Ni. Substitution at the meta-position with
electronically-diverse boronic acids is well-tolerated (3g-3i).
Sterically-hindered, polyaromatic, heterocyclic, including
dioxolane, pyridine and thiophene boronic acids coupled with
high levels of selectivity (3j-3o). Strikingly, the reaction is
compatible with halides, including chlorides, as well as
phenols, aldehydes, esters and nitriles (3p-3s), providing
effective handles for further functionalization by established
methods. In addition, electronically-diverse amides bearing
representative electron-withdrawing, electron-donating and
important fluorine-containing substituents are transferred
with high selectivity across various boronic acids (3s-3ag),
including such groups as prone to O–N cleavage isoxazolyl,
aliphatic cyclopropyl, and sterically-hindered mesityl (3w-3y).
The synthetic potential is highlighted in the cross-coupling of
carboxyphenylboronic acid
(3ag). Since amides can be
With optimized conditions in hand, the scope of this novel
Suzuki–Miyaura biaryl cross-coupling of amides was next
investigated (Table 2). The functional group tolerance and
generality of this Pd-catalyzed method is remarkable. A broad
range of electron neutral, electron-donating and electron-
ultimately derived from carboxylic acids, this preliminary result
suggests the viability of iterative cross-coupling and is
performed in the presence of an electrophilic nitrile handle,
which serves as another orthogonal amide precursor. These
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Table 2 Palladium-Catalyzed Decarbonylative Suzuki–Miyaura Biaryl Cross-Coupling of N-Acyl-Glutarimide Amides with BoronVicieAwcAirdtisclae,bOnline
DOI: 10.1039/C9SC03169C
b
aConditions: amide (1.0 equiv), Ar-B(OH)2 (1.2 equiv), NaHCO3 (3 equiv), Pd(dppb)Cl2 (5 mol%), dioxane (0.125 M), 160 °C, 12 h. Isolated
yields. cAr-B(OH)2 (3 equiv), base (4.5 equiv). dPd(dppf)Cl2 (5 mol%). See ESI for details.
results are for the first time comparable to the scope achieved cleavage of the N-activating group, the main hurdle in
using the classical Suzuki cross-coupling of halides and decarbonylative cross-coupling of acyclic amides, is not
pseudohalides,1–6 and are unprecedented for any cross- observed under these mild conditions. This very rare use of
coupling of amides to date.10–18
acyclic amides in decarbonylative cross-coupling significantly
Remarkably, the optimized conditions are suitable for the expands the scope of biaryl Suzuki synthesis of amides and
cross-coupling of acyclic N-acetyl (N-Ac) amides (Table 3). A suggests a broad generality of this reactivity platform.
broad range of boronic acids and amides, including neutral,
electron-rich and electron-withdrawing coupling partners, is N-phthalimide (1q), atom-economic N-Ms (1r) and acyclic N-Ts
compatible 3a-3ah). Notably, Pd-catalysis enables the sulfonamides (1s-1t) are suitable substrates for the coupling
coupling of an array of sensitive functional groups, such as (Table 4). Interestingly, even the highly challenging N-Boc2
halides, ethers, esters and nitriles (3c 3e 3s 3q 3p’) with high amide (1u) that is prepared directly from 1
amide14c and
Furthermore, other amides, including N-succinimide (1p),
(
,
,
,
,
°
selectivity. Furthermore, the reaction delivers fluorinated prone to deactivation by a facile N–Boc cleavage afforded a
biaryls of great importance in medicinal chemistry (3f’-3am) as promising yield in the coupling. These preliminary results bode
well as biaryls bearing multiple electrophilic handles (3aq) as well for the development of general biaryl syntheses from
well as steric hindrance (3ar). It is noteworthy that the various amides, which is beyond the scope of Ni catalysis.
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a,b
DOI: 10.1039/C9SC03169C
Table 3 Palladium-Catalyzed Decarbonylative Suzuki–Miyaura Biaryl Cross-Coupling of N-Acyl-Amides with Boronic Acids
b
aConditions: amide (1.0 equiv), Ar-B(OH)2 (1.5 equiv), NaHCO3 (3 equiv), Pd(dppb)Cl2 (5 mol%), dioxane (0.125 M), 160 °C, 12 h. Isolated
yields. cAr-B(OH)2 (1.2 equiv). See ESI for details.
Table 4 Palladium-Catalyzed Decarbonylative Suzuki–Miyaura Biaryl
and di-phenyl amides are recovered unchanged from the
reaction, as expected from the amidic resonance (PhCONMe2,
RE = 16.5 kcal/mol; PhCONPh2, 12.7 kcal/mol). (4) Ar–Bpin are
not suitable substrates under the reaction conditions (<20%
yield); pleasingly, MIDA boronates are competent nucleophiles
(4-chlorophenyl MIDA boronate, 72% yield). (5) Although at
this stage tetra-ortho-substituted biaryls are beyond the scope
of the reaction, the cross-coupling of unactivated 1-
benzoylpiperidine-2,6-dione with mesitylene-2-boronic acid
proceeds in promising 48% yield. Further studies are in
progress to develop improved conditions and new ligands for
decarbonylative cross-coupling reactions of amides.
Cross-Coupling of Various Amides with Boronic Acidsa,b
DFT studies were conducted to gain insight into the
reaction mechanism (Fig. 2), using the experimental amide
substrate
coordinated complex
cleavageoccurs via TS6
intermediate . Subsequent decarbonylation occurs through
TS8 to generate the arylpalladium species then undergoes
the CO dissociation, and subsequent transmetallation via TS12
generates the LPd(Ph)2 intermediate 14. In TS12, the base
complexes with the boronic acid, which promotes the
efficiency of the rate-determining transmetallation and lowers
1
and mode ligand dmpe.11a,18,23 The substrate-
4
undergoes
a facile C-N bond
,
leading to the acylpalladium
a,bSee Table 2.
7
Several additional points should be noted: (1) At this stage,
cross-coupling of alkenyl-amides proceeds in 30% unoptimized
yield (1-cinnamoylpiperidine-2,6-dione). (2) Full selectivity for
the cross-coupling of aryl bromides in the presence of amide
electrophiles is observed. This allows to establish the following
order of reactivity: Ar–Cl < Ar–C(O)–NR2 < Ar–Br. (3) Di-methyl
9. 9
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DOI: 10.1039/C9SC03169C
Fig. 2. DFT-calculated reaction energy profile of Pd-catalyzed decarbonylative biaryl Suzuki–Miyaura cross-coupling of amides. See ESI for
computational details.
the overall reaction barrier. This is consistent with previous Me = 47:53, N-Ac) or amide (4-Me:2-Me = 55:45, N-Ac),
mechanistic studies,24 and corroborated the importance of consistent with decarbonylation preceding transmetallation.21
weak base for the reaction success (Table 1).25 From 14, the
aryl-aryl reductive elimination is quite efficient through TS15
,
Conclusions
leading to the product-coordinated complex 16 16 eventually
.
undergoes the product extrusion and regenerates the
palladium(0) catalyst. Based on the DFT-computed free energy
profile, the on-cycle resting state is the acylpalladium
In conclusion, we have developed the first palladium-catalyzed
decarbonylative Suzuki–Miyaura cross-coupling of amides for
the synthesis of biaryls. A catalyst system derived from a Pd(II)
precatalyst and a mild base enabled the direct route to biaryls
from amides by selective carbon–nitrogen bond cleavage. This
Pd-catalyzed reaction shows high generality and is compatible
with a broad range of electronically-diverse cross-coupling
partners. Furthermore, we demonstrated that a wide range of
amides including both N-cyclic and N-acyclic are readily
amendable to the cross-coupling. The key finding enabling the
synthesis of biaryls was realization that decarbonylation must
occur prior to the transmetallation step in palladium catalytic
cycle. DFT studies demonstrated that mechanism involving
decarbonylation prior to transmetalation is likely operative.
Given the great importance of palladium-catalyzed Suzuki-
Miyaura cross-couplings in chemical science, we believe that
intermediate
transmetallation via TS12, which requires a overall barrier of
29.5 kcal/mol ( to TS12).
7
.
The rate-determining step is the
7
We conducted additional competition studies to shed light
on the mechanism (Fig. 3). (1) Intermolecular competition
experiments revealed that electron-deficient boronic acids
couple preferentially (4-Ac:4-MeO = 93:7, glutarimide; 4-Ac:4-
MeO = 92:8, N-Ac), consistent with coordination of the leaving
group to boron, while electron-poor amides are more reactive
(4-CN:4-H >95:5, glutarimide; 4-CF3:4-H, 82:18, N-Ac),
consistent with facility of metal insertion.11 (2) Furthermore,
the reaction is not significantly affected by steric hindrance on
either boronic acid (4-Me:2-Me = 54:46, glutarimide; 4-Me:2-
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9
Reactions involving amide bonds are among the most
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Nat. Commun., 2013, 4, 2627.
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and M. Szostak, Acc. Chem. Res., 2018, 51, 2589; (b) G. Meng
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Acknowledgements
We thank the NSF (CAREER CHE-1650766, M.S.), Rutgers
University (M.S.), NSFC (21702182 and 21873081, X.H.), the
Fundamental Research Funds for the Central Universities (2-
2050205-19-361, X.H.) and Zhejiang University (X.H.) for
generous financial support. The Bruker 500 MHz spectrometer
used in this study was supported by the NSF-MRI grant (CHE-
1229030). Calculations were performed on the high-
performance computing system at the Department of
Chemistry, Zhejiang University.
11 For representative acyl coupling, see: (a) L. Hie, N. F. F.
Nathel, T. K. Shah, E. L. Baker, X. Hong, Y. F. Yang, P. Liu, K. N.
Houk and N. K. Garg, Nature, 2015, 524, 79; (b) G. Meng and
M. Szostak, Org. Lett., 2015, 17, 4364; For a reductive
coupling, see: (c) S. Ni, W. Zhang, H. Mei, J. Han and Y. Pan,
Org. Lett., 2017, 19, 2536; For a review, see: (d) J. Buchspies
and M. Szostak, Catalysts, 2019, 9, 53, and references cited
therein.
12 For representative decarbonylative coupling, see: (a) G.
Notes and references
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6 | J. Name., 2018, 00, 1-3
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Chemical Science
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Chemical Science
Edge Article
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25 DFT-computed transmetallation barriers with and without
base are included in the Supporting Information (Figure S1).
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Palladium-Catalyzed Decarbonylative Suzuki Cross-Coupling of Amides
O
B(OH)2
View Article Online
M / L
R'
DOI: 10.1039/C9SC03169C
N
Ar1
Ar2
+
Ar1
Ar2
R''
M = Pd
-CO, -NR'R''
R1
R2
R1
R2
amides
valuable biaryls
 high functional group tolerance
 broad scope and generality
>60 examples
28-93% yield
 decarbonylation prior to transmetallation DFT studies
Palladium-catalyzed Suzuki–Miyaura cross-coupling or aryl halides is widely employed in the synthesis of many important
molecules in synthetic chemistry, including pharmaceuticals, polymers and functional materials. Herein, we disclose the first
palladium-catalyzed decarbonylative Suzuki–Miyaura cross-coupling of amides for the synthesis of biaryls through the
selective activation of the N–C(O) bond of amides. This new method relies on the precise sequence engineering of the
catalytic cycle, wherein decarbonylation occurs prior to the transmetallation step. The reaction is compatible with a wide
range of boronic acids and amides, providing valuable biaryls in high yields (>60 examples). DFT studies support a mechanism
involving oxidative addition, decarbonylation and transmetallation and provide insight into high N–C(O) bond activation
selectivity. Most crucially, the reaction establishes the use of palladium catalysis in the biaryl Suzuki–Miyaura cross-coupling
of the amide bond and should enable the design of a wide variety of cross-coupling methods in which palladium rivals the
traditional biaryl synthesis from aryl halides and pseudohalides.
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