A General Method for Two-Step Transamidation of Secondary Amides Using Commercially Available, Air- and Moisture-Stable Palladium/NHC (N-Heterocyclic Carbene) Complexes

Article abstract of DOI:10.1021/acs.orglett.7b00796

The first general method is reported for transamidation of secondary carboxamides catalyzed by Pd-NHC (NHC = N-heterocyclic carbene) complexes. Commercially available, air- and moisture-stable (NHC)Pd(R-allyl)Cl complexes can effect C-N cross-coupling of a wide range of N-Boc and N-Ts amides, obtained by selective amide N-functionalization, with non-nucleophilic anilines and sterically hindered amines in very good yields. The first use of versatile Pd-NHC complexes as catalysts is represented for transition-metal-catalyzed C(acyl)-N amination of amides by N-C activation.

Full text of DOI:10.1021/acs.orglett.7b00796

Letter
pubs.acs.org/OrgLett
A General Method for Two-Step Transamidation of Secondary
Amides Using Commercially Available, Air- and Moisture-Stable
Palladium/NHC (N‑Heterocyclic Carbene) Complexes
Guangrong Meng, Peng Lei,† and Michal Szostak*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
S
* Supporting Information
ABSTRACT: The first general method is reported for
transamidation of secondary carboxamides catalyzed by Pd-
NHC (NHC = N-heterocyclic carbene) complexes. Commer-
cially available, air- and moisture-stable (NHC)Pd(R-allyl)Cl
complexes can effect C−N cross-coupling of a wide range of
N-Boc and N-Ts amides, obtained by selective amide N-
functionalization, with non-nucleophilic anilines and sterically
hindered amines in very good yields. The first use of versatile
Pd-NHC complexes as catalysts is represented for transition-
metal-catalyzed C(acyl)−N amination of amides by N−C
activation.
ransamidation of the carbon−nitrogen bond of secondary
Tcarboxamides represents a long-standing challenge in
catalysis due to kinetic and thermodynamic barriers for the
amide N−C bond activation and thermoneutral exchange.1−4
Secondary carboxamides are essential structures in proteins5
and synthetic polyamides.6,7 Moreover, secondary carboxa-
mides represent a fundamental functional group in organic
synthesis.8
Very few examples of the selective transamidation of
secondary carboxamides have been reported.3 In 2016, Garg
and co-workers developed Ni-catalyzed transamidation of
secondary carboxamides (Figure 1A).9 This is the first catalytic
system that provides a general route to functionalized amides
by transamidation of the secondary carboxamide group by N−
Figure 2. (A) Proposed mechanism for two-step transamidation. (B)
Structures of carbene ligands and well-defined Pd-NHC catalysts. Dipp
= 2,6-diisopropylphenyl; Mes = mesityl; Cy = cyclohexyl.
C cross-coupling. Very recently, Newman and co-workers
reported amide bond formation from esters catalyzed by Pd-
NHC (Figure 1B).10 Herein, we report the first general method
for transamidation of secondary carboxamides catalyzed by Pd-
NHC complexes (Figure 1C). The reported reaction represents
Figure 1. Transition-metal-catalyzed cross-coupling reactions of
amides and esters with amines: previous (A−B) and (C) this work.
Received: March 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00796
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Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Conditions
Table 2. Pd-NHC-Catalyzed Transamidation
b
entry
catalyst
ligand
base
t (°C) yield (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOt-Bu
KOt-Bu
Cs2CO3
K2CO3
K2CO3
K2CO3
110
110
110
110
110
110
110
110
110
110
110
110
60
<2
<2
<2
42
32
<2
>98
67
96
<2
10
60
<2
96
<2
2
PCy3HBF4
P(o-Tol)3
IPrHCl
3
4
5
IMesHCl
ICyHBF4
6
7
(IPr)Pd(cinnamyl)Cl
(SIPr)Pd(cinnamyl)Cl
(IPr)Pd(allyl)Cl
8
9
10
11
12
13
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
(IPr)Pd(cinnamyl)Cl
−
c
14
110
110
15
a
1 (1.0 equiv), Ar-NH2 (2.0 equiv), catalyst (3 mol %), base (3.0
equiv), DME (0.25 M), 15 h. Entries 1−3: ligand (12 mol %). Entries
b
c
4−6: ligand (6 mol %). GC/1H NMR yields. K2CO3 (1.2 equiv), Ar-
NH2 (1.2 equiv).
a
Scheme 1. Pd-NHC-Catalyzed Transamidation: Reaction
Scope
1 (1.0 equiv), Ar-NH2 (2.0 equiv), [Pd] (3 mol %), K2CO3 (3.0
a b
,
b
c
equiv), 110 °C, 15 h. Isolated yields. Ar-NH2 (3.0 equiv), K2CO3
(4.5 equiv).
Table 3. Transamidation of N-Activated 2° Amides
a
b
c
d
Reference 9. Reference 18w. This study. Deactivated 2° amines
are not reactive under metal-free conditions (see Supporting
Information, SI). For these transamidations we recommend a Ni-
catalyzed system.9
Scheme 2. One-Pot N-Activation/Transamidation
Scheme 3. Transamidation of α-Alkyl Amides
a
1 (1.0 equiv), Ar-NH2 (2.0 equiv), [Pd] (3 mol %), K2CO3 (3.0
b
c
equiv), 110 °C, 15 h. Isolated yields. Ar-NH2 (3.0 equiv), K2CO3
(4.5 equiv).
Ni-catalyzed process, which is the only example of this reaction
reported to date.9
It is highly desirable to extend the amination approach to Pd
for several reasons: (1) Substrate scope and reactivity can be
(1) the first Pd-catalyzed amination by N−C cross-coupling of
amides, and (2) the catalytic system is more reactive than the
B
DOI: 10.1021/acs.orglett.7b00796
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
or KOH.11a Finally, preliminary results suggest that a near-
stoichiometric amount of base and amine suffice for efficient
coupling (entry 14), providing a strong entry point for future
reaction development. No reaction is observed in the absence
of the catalyst (entry 15, vide infra).
Scheme 4. Pd-NHC-Catalyzed Exchange Reactions
The synthetic scope of this Pd-NHC-catalyzed N−C amide
amination reaction was explored (Scheme 1). Sterically
hindered (3a), unsubstituted (3b), electron-rich nucleophilic
(3c), electron-poor (3d), di-ortho-i-Pr-substituted (3e), and
secondary anilines (3f) furnished the desired N−C amination
products in high yields. Furthermore, the challenging primary
α-branched (3g), ortho-biphenyl (3h) and medicinally relevant
carbazoyl (3i) amines were well tolerated. The scope of the
amide component is also very broad and includes sterically
hindered (3k), electron-deficient (3l), electron-rich (3m),
fluorine- (3n), ester-containing (3o), and heterocyclic amides
(3p). Furthermore, various amides could be used as precursors
for this N−C amination (Table 2), including N-alkyl and N-aryl
Ts-amides as well as N-alkyl Boc amides.24 The reaction
provides modular access to diverse carboxamides of broad
synthetic utility in high to excellent yields.
Control reactions have been carried out to evaluate the
facility of uncatalyzed (metal-free) transamidation18w (see SI).
Metal catalysis (Table 3) enables transamidation with aromatic
and α-branched amines that are particularly appealing from the
synthetic point of view.
Three applications of this cross-coupling are shown in
Schemes 2−4. (1) One-pot N-activation/N−C cross-coupling
is feasible (Scheme 2). (2) Our preliminary studies illustrate
that cross-coupling of aliphatic amides is also feasible (Scheme
3). (3) Amide exchange reactions between two challenging sets
of substrates with complementary electronic properties can be
readily achieved (Scheme 4).
complementary to Ni. (2) Ligands and reaction protocols can
be complementary to Ni and offer new possibilities in ligand
design. (3) Pd/NHC-catalysis allows a catalytically efficient Pd/
ligand (1:1) ratio to be maintained, avoiding an excess of
expensive ligands, while using air- and moisture-stable reagents.
Nucleophilic N-heterocyclic carbenes (NHC) have emerged
as powerful ligands for the transition-metal-catalyzed cross-
coupling.11−14 We have recently identified (NHC)Pd(R-allyl)
Cl complexes, developed by Nolan and co-workers, as highly
efficient precatalysts for the direct Suzuki−Miyaura cross-
coupling of amides.15,16 The advent of N−C bond cross-
coupling of amides enables typically inert amide bonds to be
readily activated by general transition-metal-catalyzed mani-
folds.17,18 We hypothesized that the well-defined, air-stable,
commercially available Pd-NHC precatalysts might be used in
conjunction with non-nucleophilic amine nucleophiles19 to
enable broadly useful transamidation of common amides, which
is a challenging process using Pd/PR3 catalysis.
We postulated that, after site-selective N-activation of the
amide bond (Z = Boc, Ts),20 a Pd-NHC catalyst will undergo
chemoselective oxidative addition into the amide bond to
generate an acylpalladium intermediate (Figure 2). The
reaction with an amine nucleophile will generate an
acylpalladium-amido complex, in which the leaving amine (Z
= Boc, Ts) is less nucleophilic than the amine participating in
transamidation. Finally, reductive elimination will regenerate
the Pd(0) species. The major challenge is the oxidative addition
of Pd into the amide bond21,22 (nN → π*CO, ca. 15−20 mol/
kcal in planar amides).23 We postulated that the improved
reactivity of (NHC)Pd(R-allyl)Cl complexes (Figure 2B)16
compared to alternative complexes11−13 will allow for the direct
N−C activation/C(acyl)-amination using highly active, func-
tional group tolerant, and operationally convenient Pd-NHC
precatalysts with non-nucleophilic amines.11,12,16
Key optimization results are shown in Table 1. It should be
noted that 2,6-dimethylaniline is a challenging substrate for N−
C amination due to di-ortho steric hindrance.19 Under our
optimized conditions, amide 1 and 2,6-dimethylaniline under-
went N−C cross-coupling in quantitative yield (entry 7). The
key optimization result involved identification of DME as a
reaction solvent. Other solvents examined, such as toluene,
THF, and dioxane, afforded the desired product in lower yield
(not shown). Pd-PR3 complexes were ineffective (entries 1−3).
In situ formed Pd-NHC complexes showed inferior reactivity
(entries 4−6).16a (SIPr)Pd(R-cinnamyl)Cl and (IPr)Pd(R-
allyl)Cl also showed high reactivity under the developed
conditions (entries 7−9).16a Importantly, the reaction is
promoted by K2CO3, a weak base (entries 10−12), which
could enable cross-coupling of base-sensitive substrates. Pd-
NHC catalysis typically requires strong bases such as KOt-Bu
The turnover number (TON) of 850 was determined for the
cross-coupling of amide 1a with 2,6-dimethylaniline ((IPr)Pd-
(cinnamyl)Cl, 0.10 mol %, 110 °C).
The following advantages of the present Pd-NHC system
should be noted:
1. Efficient cross-coupling of sterically hindered anilines,
which is in contrast to the Ni-catalyzed system.
2. Much higher TON than Ni-catalysis. It is well-established
that in cross-couplings the bulk of cost is associated with
the ligand.11−13
3. Efficient cross-coupling of all types of acyclic amides17,18
irrespective of N-substitution (Table 2).
4. Cross-coupling of aliphatic amides (Scheme 3). A recent
report highlights this difficulty in Ni-catalysis.18e
5. One-pot cross-coupling (Schemes 2 and 4) without
purification of the intermediates.
In summary, we have reported the first general method for
transamidation of secondary carboxamides catalyzed by Pd-
NHC complexes. The method shows a broad scope with
respect to both the amine and amide components. In a broader
context, the method significantly enhances the potential of
versatile Pd-NHC catalysts in amide N−C bond cross-coupling
manifolds. Studies directed at developing improved catalyst
systems are ongoing.
C
DOI: 10.1021/acs.orglett.7b00796
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3612. (d) N-Heterocyclic Carbenes in Transition Metal Catalysis; Cazin,
C. S. J., Ed.; Springer: New York, 2011.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00796.
■
S
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Procedures and analytical data (PDF)
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: michal.szostak@rutgers.edu.
ORCID
Guangrong Meng: 0000-0002-3023-0654
Michal Szostak: 0000-0002-9650-9690
Present Address
†Department of Applied Chemistry, College of Science, China
Agricultural University, Beijing 100193, China.
Notes
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(b) Weires, N. A.; Baker, E. L.; Garg, N. K. Nat. Chem. 2015, 8, 75.
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Lett. 2016, 18, 3934. (e) Hie, L.; Baker, E. L.; Anthony, S. M.;
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(g) Meng, G.; Szostak, M. Org. Lett. 2015, 17, 4364. (h) Meng, G.;
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Chem. - Eur. J. 2016, 22, 10420. (j) Meng, G.; Szostak, M. Angew.
Chem., Int. Ed. 2015, 54, 14518. (k) Shi, S.; Meng, G.; Szostak, M.
Angew. Chem., Int. Ed. 2016, 55, 6959. (l) Meng, G.; Szostak, M. Org.
Lett. 2016, 18, 796. (m) Meng, G.; Shi, S.; Szostak, M. ACS Catal.
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(o) Liu, C.; Meng, G.; Liu, Y.; Liu, R.; Lalancette, R.; Szostak, R.;
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M. J. Org. Chem. 2016, 81, 12023. (q) Hu, J.; Zhao, Y.; Liu, J.; Zhang,
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81, 8091. (b) Pace, V.; Holzer, W.; Meng, G.; Shi, S.; Lalancette, R.;
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(22) For leading references on amide bond destabilization, see:
(a) Tani, K.; Stoltz, B. M. Nature 2006, 441, 731. (b) Greenberg, A.;
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́
(23) Review on acyl-metal intermediates: Gooßen, L. J.; Rodriguez,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Rutgers University. The 500
MHz spectrometer used in this study was supported by the
NSF-MRI grant (CHE-1229030). P.L. thanks the China
Scholarship Council (No. 201606350069) for a fellowship.
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DOI: 10.1021/acs.orglett.7b00796
Org. Lett. XXXX, XXX, XXX−XXX