Suzuki-Miyaura Cross-Coupling of Amides using Well-Defined, Air-Stable [(PR3)2Pd(II)X2] Precatalysts

Article abstract of DOI:10.1002/adsc.202000122

A versatile method for the Suzuki-Miyaura cross-coupling of amides using highly active, well-defined, and air-stable Pd?phosphine precatalysts is reported. Most notably, the method represents the first example of using practical and operationally-simple Pd(II)?phosphine precatalysts in the emerging amide bond cross-coupling manifold. The reactions are efficient at 0.10 mol% loading, furnishing biaryl ketones with high chemoselectivity for N?C(O) bond cleavage. This versatile method enables for the first time to achieve Pd?phosphine-catalyzed cross-coupling of amides at ppm loading. This C?N cross-coupling can be used to efficiently furnish pharmaceutical intermediates by orthogonal Pd-catalyzed cross-couplings. We fully expect that operationally-simple [(PR₃)₂Pd(II)X₂] precatalysts as effective triggers for N?C(O) cross-coupling will be of broad synthetic and catalytic interest. (Figure presented.).

Full text of DOI:10.1002/adsc.202000122

Title: Suzuki–Miyaura Cross-Coupling of Amides using Active, Well-
Defined, Air-Stable [(PR3)2Pd(II)X2] Precatalysts
Authors: Siyue Ma, Tongliang Zhou, Guangchen Li, and Michal
Szostak
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Advanced Synthesis & Catalysis
10.1002/adsc.202000122
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Suzuki–Miyaura Cross-Coupling of Amides using Well-Defined,
Air-Stable [(PR ) Pd(II)X ] Precatalysts
3
2
2
a
a
a
,a
Siyue Ma, Tongliang Zhou, Guangchen Li, and Michal Szostak*
a
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102, United States
Fax: (+1)-973-353-1264; phone: (+1)-973-353-5329; e-mail: michal.szostak@rutgers.edu
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. A versatile method for the Suzuki–Miyaura attractive catalyst platform to access acyl-metals by
cross-coupling of amides using highly active, well-defined, directly engaging amide bonds.
and air-stable Pd–phosphine precatalysts is reported. Most
notably, the method represents the first example of using phosphine precatalysts now represents one of the
practical and operationally-simple Pd(II)–phosphine most common approaches to generate the
Significantly, the use of well-defined Pd(II)–
[11]
precatalysts in the emerging amide bond cross-coupling
manifold. The reactions are efficient at 0.10 mol% loading,
furnishing biaryl ketones with high chemoselectivity for N–
C(O) bond cleavage. This versatile method enables for the
first time to achieve Pd–phosphine-catalyzed cross-
coupling of amides at ppm loading. This C–N cross-
coupling can be used to efficiently furnish pharmaceutical
intermediates by orthogonal Pd-catalyzed cross-couplings.
catalytically-active mono-ligated L–Pd(0) species,
avoiding the use of excess of ancillary ligand, issues
arising from in situ metal complexation and variable
[12]
purity of Pd precursors. While noteworthy results
have been obtained using NHC ligands, it should be
pointed out that very few NHCs are commercially
available, and at present phosphines offer a
significantly more cost-economic approach to the
3 2 2
We fully expect that operationally-simple [(PR ) Pd(II)X ]
precatalysts as effective triggers for N–C(O) cross-coupling
will be of broad synthetic and catalytic interest.
cross-coupling
process.
Well-defined
Pd(II)
complexes that contain an equivalent of ancillary
ligand and do not require the addition of extra ligands
[8a–c]
are vastly preferred over in situ formed catalysts.
Keywords: cross-coupling; palladium; precatalysts; C–N
activation; catalysis; Suzuki-Miyaura
Herein, we detail the successful development of
the Suzuki–Miyaura cross-coupling of amides using
well-defined Pd–phosphine precatalysts (Figure 1).
The reactions are efficient at 0.10 mol% loading and
provide strong support for using well-defined
Introduction
[
(PR
3
)
2
Pd(II)X ] complexes as effective triggers to
2
access acyl-metals by selective oxidative addition of
the N–C(O) amide bond. In the broad perspective, we
expect that this study will lead to the development of
catalyst toolbox for the cross-coupling of bench-
stable acyl electrophiles.
The amide bond cross-coupling has recently emerged
as a powerful platform to capture acyl–metal
intermediates by oxidative addition of the
traditionally inert N–C(O) amide bond (amidic
[1,2]
resonance, 15-20 kcal/mol).
This pathway allows
to invent new chemical reactions that enable broad
access to acyl[ and decarbonylative motifs from
3]
[4]
[5]
amides in a predictable and catalytic manner. In
particular, the ubiquity of the amide bond in
pharmaceuticals, medicine, polymers and structural
biochemistry as well as the orthogonal properties of
acyl-metals (cf. aryl halides) have spurred the efforts
to develop practical methods for the cross-coupling of
bench-stable acyl electrophiles.[6]
Figure 1. Cross-Coupling of Amides Catalyzed by Air-
Stable, Well-Defined Pd–Phosphine Precatalysts at Low
Catalyst Loading.
To date, significant progress in the N–C(O)
cross-coupling has been achieved using Pd(II)–NHC
[7]
(
NHC = N-heterocyclic carbene) precatalysts.
However, the use of phosphines as practical, cheap
and readily available ancillary ligands remains a
major challenge. In this vein, we recently questioned
Results and Discussion
whether highly-active, well-defined and air-stable
Our investigation started with examination of various
[
(PR
3
)
2
Pd(II)X
2
] precatalysts[
8–10]
might provide an
[
(PR
3
)
2
Pd(II)X ] precatalysts in the cross-coupling of
2
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000122
hypothesize that the use of [(PCy
3
)
2
PdCl ] is optimal
2
in the amide cross-coupling due to combining
electron-rich nature of trialkylphosphine with
[
14]
favorable steric properties of PCy
3
.
A brief solvent
screen indicated that the reaction is also effective in
2
2
-MeTHF, toluene and dioxane (Table 1, entries 22-
4). We believe that THF and 2-MeTHF are preferred
over toluene and dioxane due to better solubility of
the reaction components. The effect of bases was also
briefly examined and identified K
NaOH as the most effective bases (Table 1, entries
5-27). Interestingly, dialkylbiarylphosphines
developed by Buchwald and co-workers
ineffective in the cross-coupling (not shown).
2
CO
3
, Na
2
CO and
3
2
[16]
proved
Table 1. Optimization of the Reaction Conditions.[a,b]
Figure 2. Structures of Pd(II)–PR
3
Precatalysts for
Suzuki–Miyaura Cross-Coupling of Amides.
N-acyl-glutarimides as benchmark models for amide
bond cross-coupling.[ In total, 12 sterically- and
electronically-diverse, mono- and bidentate Pd(II)–
phosphine precatalysts have been selected for the
study (Figure 2).[ Experiments showed that the
cross-coupling is efficient at 1.0 mol% loading using
13]
Entry
[Pd–PR
3
]
[Pd–PR
3
]
Additive Yield
[%]
[
mol %]
14]
1[c]
[(PCy
[(PCy
[(PCy
[(PCy
[(PCy
[(PCy
[(PCy
[(PCy
[(PCy
[(PCy
3
3
3
3
3
3
3
3
3
3
)
)
)
)
)
)
)
)
)
)
2
2
2
2
2
2
2
2
2
2
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
2
2
2
2
2
]
]
]
]
]
]
]
]
]
]
]
3.0
3.0
1.0
1.0
-
-
89
95
2
electron-rich, sterically-hindered [(PCy
3
)
2
Pd(II)Cl
2
]
[c]
3
-
79
precatalyst (Table 1, entries 1-4). Screening at 80 °C
and 100 °C afforded the coupling product in 86% and
4
5
6
7
8
9
-
-
>98
77
0.50
0.50
0.25
0.25
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
0.10
9
2%, respectively (not shown). Significant
imporvement of the catalytic performance was
realized using H BO as an additive, allowing to
H
H
3
3
BO
-
BO
-
3
3
>98
66
>98
56
3
3
decrease the catalyst loading to 0.10 mol% in the
absence of any added ligands (Table 1, entries 5-10).
1
1
1
1
1
1
1
1
1
1
2
2
0
1
2
3
4
5
6
7
8
9
0
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
BO
BO
BO
BO
BO
BO
BO
BO
BO
BO
BO
BO
BO
BO
BO
BO
BO
BO
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
>98
<2
<2
12
19
84
<2
51
46
44
47
58
>98
90
91
95
We hypothesize that the role of H
3
BO
3
is to promote
3 2 2
[(PPh ) PdCl
oxidative addition of the N–C(O) bond by O-/O-
[(DPEPhos)PdCl
[(XantPhos)PdCl
[(dppf)PdCl
[(dcypf)PdCl
[(dppb)PdCl
[(dcypp)PdCl
2
]
[5a]
protonation to decrease amidic resonance as well
as to prevent protodeboronation. The use of 1.0 and
2
]
2
]
]
]
0
9
.50 equiv of H
3
BO
3
afforded the coupling product in
2
0% and 76%, respectively (not shown).
2
Subsequently, we evaluated the effect of various
(PR Pd(II)X ] precatalysts on the N–C(O) cross-
coupling (Table 1, entries 11-21). Interestingly, we
found that while mono- and bidentate
triarylphosphines, such as [(PPh
[(XantPhos)
2
]
]
[
3
)
2
2
[(dcype)PdCl
[(PtBu PdCl
[(PCyPh
[(PCy Ph)
2
3
)
2
2
]
2
)
2
2
PdCl
PdCl
2
]
]
3
)
2
PdCl
PdCl
2
],
],
1
2
2
[
[
(DPEPhos)PdCl
(dppf)PdCl
2
],
2
[d]
2
2
2
3
[(PCy
[(PCy
[(PCy
[(PCy
[(PCy
[(PCy
3
3
3
3
3
3
)
)
)
)
)
)
2
2
2
2
2
2
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
2
]
2
]
unfortunately resulted in low
] led to
[e]
[f]
]
]
]
]
]
conversions, the electron-rich [(dcypf)PdCl
2
2
4
N–C(O) cross-coupling in 84% yield (entry 15), and
[g]
[h]
2
2
5
thus was identified at a promising scaffold for future
6
29
93
ligand tuning studies. Furthermore, [(dppb)PdCl
2
]
7[i]
2
resulted in unsuccessful reaction (Table 1, entry 16).
[
a]
Conditions: amide (1.0 equiv), Ar-B(OH) (2.0 equiv),
3
] (x mol%), K CO (3.0 equiv), H BO (2.0 equiv),
2
It should be pointed out that since the classic studies
[
Pd–PR
3
2
3
3
by Kumada,[ [(dppb)PdCl
] is well-known as an
15]
2
[
b]
1
THF (0.25 M), 120 °C, 15 h. GC/ H NMR yields.
effective catalyst for cross-coupling of aryl halides,
this result indicates the complementarity of cross-
coupling of aryl halides in the presence of reactive
amide bonds. Moreover, testing of other electron-rich
[
[
c]
[d]
[e]
[f]
[g]
6
2 3
0 °C. 2-MeTHF. Toluene. Dioxane. Na CO .
h]
[i]
3 4
K PO . NaOH.
With the optimized conditions in hand, next we
examined the scope of the cross-coupling using air-
and moisture-stable [(PCy PdCl precatalyst
Scheme 1). We were pleased to find that a broad
bi- and monodentate ligands, such as [(dcypp)PdCl
(dcype)PdCl ], [(PtBu PdCl ], [(PCyPh PdCl
and [(PCy Ph) PdCl ] (Table 1, entries 16-21)
2
],
2
[
2
3
)
2
2
2
)
2
]
3
)
2
2
]
2
2
2
(
resulted in moderate conversions, thus providing a
promising entry point for future studies. We
range of boronic acids and amides is amenable to this
cross-coupling protocol at 0.10 mol% catalyst loading.
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000122
As such, neutral (3a-b), electron-rich (3c, 3g) and
electron-deficient boronic acids (3d-f), including
sensitive carbonyls (3f), cross-coupled in excellent
yields. Polyaromatic ketones such as napththyl (3h-i)
and heterocyclic such as thienyl (3j) are also readily
accessible. Furthermore, the scope of the amide
component allows for a wide range of amides to be
engaged in this cross-coupling, including electron-
rich (3b’-c’, 3g’), electron-deficient (3k-m, 3e’-f’),
and fluorinated amides (3n-p) that give access to
biorelevant fluorinated ketones. It is particularly
noteworthy that electrophilic functional groups such
as OTs (3k), ketone (3m) and ester (3f’) are readily
tolerated, thus providing a handle for conventional
cross-coupling strategies and nucleophilic addition to
the carbonyl group. At present, steric-hindrance is not
tolerated in this cross-coupling.
Scheme 2. Suzuki–Miyaura Cross-Coupling of Amides
using [(PCy ) PdCl ] at 50 ppm loading.
3 2 2
[
a]
[a]
2 3 2 2
Conditions: amide, Ar-B(OH) (2.0 equiv), [(PCy ) PdCl ] (50 ppm),
K
2
CO (3.0 equiv), H BO (2.0 equiv), THF (0.25 M), 120 °C, 15 h.
3
3
3
Scheme 1. Suzuki–Miyaura Cross-Coupling of Amides
using [(PCy ) PdCl ].
3 2 2
[a,b]
Scheme 3. Suzuki–Miyaura Cross-Coupling of N-Ts and
N-Ms Amides using [(PCy ) PdCl ].
3 2 2
[a,b]
[a],[b]See Scheme 1.
Scheme 4. Sequential Suzuki–Miyaura Cross-Coupling
under Orthogonal Conditions.
Furthermore, we were delighted to find that the
cross-coupling could proceed at 50 ppm loading
(
Scheme 2). These reactions afford TON of 12,600-
9,200 with a range of electronically-variable
substrates using commercially-available, bench-stable
and highly operationally-convenient [(PCy PdCl
1
3
)
2
2
]
[
a]
Conditions: amide (1.0 equiv), Ar-B(OH)
2
(2.0 equiv), [(PCy
(2.0 equiv), THF (0.25 M),
PdCl ] (0.50 mol%).
3 2 2
) PdCl ]
precatalyst as the sole source of Pd–L. These results
for the first time rival and outperform the
significantly more -donating Pd(II)–NHC catalysis
(
0.10 mol%), K
2
CO
3
3 3
(3.0 equiv), H BO
[b]
[c]
1
20 °C, 15 h. Isolated yields. [(PCy
3
)
2
2
[7,13]
in amide Suzuki–Miyaura cross-coupling.
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202000122
Moreover, we were pleased to find that the
using highly active, well-defined, and air-stable Pd–
developed conditions are also amenable to the cross-
coupling of model N-acyclic amides, such as N-Ts
and N-Ms (Scheme 3).[17] N-Sulfonyl-amides
represent another class of highly attractive acyl-metal
precursors due low amidic resonance (RE = 9.7-10.3
kcal/mol) and capacity to prepare from common
primary and secondary amides. Furthermore, N-
benzoyl-succinimide coupled in 79% yield under
these reaction conditions (not shown). N-Boc
amides[ are not well compatible with phosphine
systems due to N–Boc scission; however, preliminary
phosphine precatalysts. This protocol demonstrates
for the first time that highly-useful [(PR
3
)
2
Pd(II)X ]
2
complexes operate as extremely effective catalysts
for amide bond N–C(O) cross-coupling. The complex
catalyzes cross-coupling of various amides and
boronic acids at 0.10 mol% loading. The broad
applicability is demonstrated by the synthesis of
pharmaceutical intermediate via orthogonal Pd–
phosphine cross-couplings. Given the tremendous
utility of Pd–phosphine catalysis as emphasized by
5b]
[19]
the 2010 Nobel Prize in Chemistry, we expect that
that this class of catalysts will be of broad interest for
amide cross-coupling. Further studies on acyl-cross-
couplings are underway and will be reported shortly.
results indicate the cross-coupling of N,N-Boc
benzamide in 59% yield (not shown).
2
One of the most interesting features of the amide
bond cross-coupling is that this platform is amenable
for orthogonal cross-coupling. We demonstrated that
the present protocol can be readily employed to Experimental Section
access pharmaceutical intermediates by sequential
orthogonal aryl halide/amide N–C(O) cross-coupling
General [3Ian] formation. General methods have been
published.
(
Scheme 4). Thus, an intermediate in the synthesis
1
7-HSD2 inhibitors for the treatment of
General Procedure for the Suzuki-Miyaura Cross-
Coupling. An oven-dried vial equipped with a stir bar was
charged with an amide substrate (1.0 equiv), boronic acid
[18]
osteoporosis was prepared in 87% combined yield
without isolation of the intermediate amide.
Importantly, full selectivity in the biaryl cross-
(
typically, 2.0 equiv), potassium carbonate (typically, 3.0
3 3
equiv), H BO (typically, 2.0 equiv), placed under a
coupling using the conventional Pd(PPh
observed in the presence of sensitive amide bond,
which was then cross-coupled using [(PCy PdCl
without modification of the reaction conditions.
To gain preliminary insight into the reactivity of
(PCy PdCl ], we conducted kinetic studies at
3
)
4
was
positive pressure of argon, and subjected to three
evacuation/backfilling cycles under high vacuum.
[(PCy ) PdCl ] (typically, 0.10 mol%, added as a solution
3 2 2
3
)
2
2
]
in THF, 0.25 M) was added with vigorous stirring at room
temperature, the reaction mixture was placed in a
preheated oil bath at 120 °C, and stirred for the indicated
time at 120 °C. After the indicated time, the reaction
mixture was cooled down to room temperature, diluted
[
3
)
2
2
different Pd loading (Figure 3). Thus, the reaction
reached >80% conversion at 0.50 mol% loading after
with CH
2 2
Cl (10 mL), filtered, and concentrated. The
1
sample was analyzed by H NMR (CDCl
3
, 500 MHz) and
5
0
h, while 45% and 26% conversion was observed at
.10 mol% and 0.025 mol% loading, respectively.
GC-MS to obtain conversion, selectivity and yield using
internal standard and comparison with authentic samples.
Purification by chromatography on silica gel
Studies on the mechanism are ongling and will be
reported in due course.
(
hexanes/ethyl acetate) afforded the title product.
Representative Procedure for the Suzuki-Miyaura
Cross-Coupling. An oven-dried vial equipped with a stir
bar was charged with 1-benzoylpiperidine-2,6-dione (43.4
mg, 0.20 mmol, 1.0 equiv), 4-tolylboronic acid (54.4 mg,
0
.40 mmol, 2.0 equiv), potassium carbonate (82.9 mg, 0.60
3 3
mmol, 3.0 equiv), H BO (24.7 mg, 0.40 mmol, 2.0 equiv),
placed under a positive pressure of argon, and subjected to
three evacuation/backfilling cycles under high vacuum.
[
3 2 2
(PCy ) PdCl ] (0.15 mg, 0.10 mol%, added as a solution
in THF, 0.25 M) was added with vigorous stirring at room
temperature, the reaction mixture was placed in a
preheated oil bath at 120 °C, and stirred for the indicated
time at 120 °C. After the indicated time, the reaction
mixture was cooled down to room temperature, diluted
with CH
2 2
Cl (10 mL), filtered, and concentrated. The
1
sample was analyzed by H NMR (CDCl
3
, 500 MHz) and
GC-MS to obtain conversion, selectivity and yield using
internal standard and comparison with authentic samples.
Purification by chromatography on silica gel
(
hexanes/ethyl acetate) afforded the title product. White
solid. Yield 98% (38.4 mg).
Figure 3. Kinetic profile of 1a. Conditions: 1a, 4-Tol-
B(OH)
equiv), H
2
(2.0 equiv), [(PCy
3 2 2 2 3
) PdCl ] (x mol%), K CO (3.0
Acknowledgements
3
BO (2.0 equiv), THF (0.25 M), 120 °C.
3
Rutgers University and the NSF (CAREER CHE-1650766) are
gratefully acknowledged for support. The Bruker 500 MHz
spectrometer was supported by the NSF-MRI grant (CHE-
Conclusions
1
229030).
In conclusion, we have developed a versatile method
for the Suzuki–Miyaura cross-coupling of amides
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000122
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Advanced Synthesis & Catalysis
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FULL PAPER
Suzuki–Miyaura Cross-Coupling of Amides using
Active, Well-Defined, Air-Stable [(PR
Precatalysts
3
)
2
Pd(II)X ]
2
Adv. Synth. Catal. Year, Volume, Page – Page
Siyue Ma, Tongliang Zhou, Guangchen Li, Michal
Szostak*
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