Pd-catalyzed intermolecular C-H amination with alkylamines

Article abstract of DOI:10.1021/ja202563w

C-H amination of N-aryl benzamides with O-benzoyl hydroxylamines has been achieved with either Pd(II) or Pd(0) catalysts. Furthermore, we demonstrate that secondary amines can be directly used with benzoyl peroxide in a one-pot procedure that proceeds via

Full text of DOI:10.1021/ja202563w

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pubs.acs.org/JACS
Pd-Catalyzed Intermolecular CꢀH Amination with Alkylamines
Eun Jeong Yoo, Sandy Ma, Tian-Sheng Mei, Kelvin S. L. Chan, and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S Supporting Information
b
ABSTRACT: CꢀH amination of N-aryl benzamides with
O-benzoyl hydroxylamines has been achieved with either
Pd(II) or Pd(0) catalysts. Furthermore, we demonstrate
that secondary amines can be directly used with benzoyl
peroxide in a one-pot procedure that proceeds via the in situ
generation of the appropriate O-benzoyl hydroxylamines.
This catalytic reaction provides a new disconnection for the
convergent synthesis of tertiary and secondary arylalkyl
amines starting from benzoic acids.
Figure 1. Biologically active amines.
chemistry. We are aware that CꢀN bond forming reactions
represent a distinct challenge in comparison to CꢀC coupling
processes. Although Buchwald’s pioneering report established
the viability of intramolecular CꢀH amidation/carbazole forma-
tion via Pd(II)/Pd(0) catalysis (eq 1),3a we have been largely
unsuccessful in our attempts to develop an intermolecular
version, even after exploring the wide range of CꢀH functiona-
lization substrates previously reported in our laboratory. Re-
cently, intramolecular CꢀH amidation via Pd(II)/Pd(IV)
catalysis using bystanding Fþ oxidants (eq 2)3f,10 and its inter-
molecular version have been developed with acetamide and
sulfonamide partners.4c,d However, to date this approach has
not been extended to either generally useful substrates or amine
coupling partners.
he development of Pd-catalyzed CꢀH activation reactions
T
toward synthetic applications continue to face three major
interwoven challenges: (1) discovering general modes of cata-
lysis for a diverse range of carbonꢀcarbon and carbonꢀheteroa-
tom bond-forming reactions, (2) improving the reactivity with
broadly useful substrates, and (3) controlling the stereoselectiv-
ity and positional selectivity.1 Recently, a number of catalytic
systems have been established for Pd-catalyzed CꢀH activation/
CꢀC bondꢀforming reactions that are compatible with synthe-
tically useful substrates.1a In contrast, achieving the Pd-catalyzed
CꢀH amination reaction represents a distinct challenge and has
been met with a number of difficulties, as can be anticipated from
the many tremendous hurdles encountered in the development
of the BuchwaldꢀHartwig amination reaction.2
To date, the four modes of Pd-catalysis represented in eq 1ꢀ4
are only in their infancy in terms of scope and practicality.3ꢀ7 At
the present time, for instance, Pd-catalyzed intermolecular CꢀH
activation/CꢀN bond formation is only possible with amide
coupling partners.4 Since BuchwaldꢀHartwig amination reac-
tions that employ alkylamines and anilines are the most powerful
tool for enabling the convergent synthesis of arylamines in both
industrial and academic laboratories, complementary methods
involving catalytic CꢀH amination with alkylamines and anilines
would be highly desirable.
Herein, we report an ortho-CꢀH amination reaction of N-aryl
benzamides electrophilic O-benzoyl hydroxylamines catalyzed
by either Pd(II) or Pd(0) catalysts (eq 5). We also demonstrate
that a one-pot procedure of using secondary amines directly in
the presence of benzoyl peroxide is also possible. This finding not
only represents a complementary disconnection for the synthesis
of an important class of biologically active arylamines (Figure 1),8
but it also provides insights for further work in intermolecular
CꢀH amination with alkylamines.
In our continuing effort to search for an Evans auxiliary-like
directing group for versatile CꢀH activation reactions, we have
recently identified CONHAr (Ar = (4-CF3)C6F4) as an ex-
ceptionally capable auxiliary for assisting a diverse range of
CꢀH activation reactions that are elusive otherwise.11 We
therefore decided to revisit CꢀH amination using N-aryl
Encouraged by previous success in coupling CꢀH bonds with
organometallic reagents via a Pd(II)/Pd(0) catalytic manifold,9
we began to investigate the possibility of achieving CꢀH
amination with amine nucleophiles through analogous Pd redox
Received: January 26, 2011
Published: April 26, 2011
r
2011 American Chemical Society
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Scheme 1. CꢀH Amination with an Alkylamine
Table 2. Pd-Catalyzed Amination Reaction of N-Aryl
Benzamidesa,b
Table 1. Discovery and Evaluation of Reaction Conditionsa
Entry
[Pd]
X
Yield (%)b
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dba)2
Cl
<2
90 (58c)
98 (74c)
96 (70c)
32
OAc
OBz
OBz
OBz
Pd(OAc)2/PtBuMe HBF4
3
a Reaction conditions: 1a (0.1 mmol), N-substituted morpholine (2, 0.2
mmol), Pd catalyst (10 mol %), AgOAc (0.1 mmol), CsF (0.2 mmol),
1
DCE (1 mL), 130 °C, 18 h. b The yield was determined by H NMR
analysis of the crude product using dibromomethane as an internal
c
standard. The yields in the parentheses are obtained without AgOAc
(0.1 mmol).
benzamide substrate 1a by performing extensive screening of
amine partners, oxidants, solvents, and other reaction para-
meters (see Supporting Information). We found CꢀH amina-
tion of 1a with morpholine occurred in the presence of 10 mol %
Pd(OAc)2, 1.5 equiv of benzoyl peroxide, and 2 equiv of CsF in
DCE to give the desired amination product 3a in 53% yield.
Addition of 2 equiv of AgOAc to the reaction increased the yield
to 64% (Scheme 1).
a Reaction conditions: benzamide substrate 1 (0.2 mmol), O-benzoyl
hydroxylmorpholine (0.4 mmol), Pd(OAc)2 (10 mol %), AgOAc
(0.2 mmol), CsF (0.4 mmol), DCE (1 mL), 130 °C, 18 h. b Isolated yield.
c R,R,R-Trifluorotoluene was used as a solvent. d The yields in the
parentheses are obtained under the following conditions: Pd(OAc)2
(20 mol %) and 48 h.
1
Monitoring this new reaction by H NMR, we found that
Ag2CO3 was found to be equally effective (see Supporting In-
formation). The observed improvement by Ag oxidants remains
unclear at this stage. Interestingly, Pd(dba)2 was equally effective
(entry 4), which points to the possibility of CꢀH amination via
Pd(0)/Pd(II) catalysis, as demonstrated by an early intramolecular
example.3h The presence of phosphine ligands, however, was found
to be detrimental to this reaction (entry 5).
With this newly developed intermolecular CꢀH amination
reaction in hand, we examined the reactivity of representative
substrates containing synthetically useful functional groups.
Amination of electron-neutral or -rich substrates in DCE af-
forded the desired products in 79ꢀ89% isolated yields (Table 2,
3bꢀ3f). The use of R,R,R-trifluorotoluene as the solvent was
necessary to obtain acceptable yields with electron-deficient
substrates (3gꢀ3m). Although the yields decreased noticeably
with electron-deficient substrates (3gꢀ3m), the substrate scope
of this reaction is significantly broader than that of previous
intermolecular amidation reactions in terms of tolerance to
strongly electron-withdrawing substituents on the aryl ring.4c,d
Importantly, exclusive monoselectivity was observed in all
cases. The tolerance of bromo groups (3i and 3k) is espec-
ially useful, as subsequent Pd(0)-catalyzed cross-coupling and
morpholine reacted with benzoyl peroxide to form O-benzoyl
hydroxylmorpholine within the first 30 min before amination
products were observed. This observation suggests that the
CꢀH activation intermediate ArPd(II)Ln reacts with the in situ
generated electrophilic amine partner (O-benzoyl hydroxyla-
mine, a reagent initially developed by Johnson)12,13 to give the
desired amination product. In terms of catalysis, O-benzoyl
hydroxylamine could react with the ArPd(II)Ln intermediate
through electrophilic cleavage or could oxidize Pd(II) to Pd(IV)
to promote CꢀN reductive elimination.3e,f
With this insight in hand, we used substrate 1a to test a few
common electrophilic amine sources (2), which were prepared
beforehand (Table 1). While N-chloroamine was unsuitable for
this reaction (entry 1), both O-acetyl and O-benzoyl hydroxyla-
mines were found to be effective aminating reagents (entries 2
and 3). O-Benzoyl hydroxylamines were used for further opti-
mization due to their ease of preparation.12c CsF and KF were
observed to be the best bases while other bases gave significantly
lower yields (see Supporting Information). Although both of these
reaction pathways do not require external oxidants, the addition of
1 equiv of AgOAc increased the yield from 74% to 98% (entry 3).
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Table 3. Scope of O-Benzoyl Hydroxylamine Substratesa,b
Figure 2. Possible reaction pathways with Pd(II) catalyst.
generates an active Pd(II) species that can then cleave a CꢀH
bond.3h
In summary, we have developed a novel protocol to effect
CꢀH amination on a broad range of synthetically useful benza-
mide substrates with electrophilic O-benzoyl hydroxylamines
using either Pd(II) or Pd(0) catalysts. Additionally, a one-pot
procedure of using secondary amines directly in the presence of
benzoyl peroxide is also possible. The compatibility of this
amination reaction with several different O-benzoyl hydroxyla-
mine reagents derived from simple dialkylamines allows for the
convergent synthesis of an important class of tertiary and
secondary arylalkyl amines starting from benzoic acids.
a Reaction conditions: 1a (0.2 mmol), O-benzoyl hydroxylamine
(0.4 mmol), Pd(OAc)2 (10 mol %), AgOAc (0.2 mmol), CsF (0.4 mmol),
c
DCE (1 mL), 130 °C, 18 h. b Isolated yield. R,R,R-Trifluorotoluene
was used as a solvent.
BuchwaldꢀHartwig amination are possible. For instance, Pd(0)-
catalyzed amination of product 3i is an attractive route for the
preparation of drug candidate I (Figure 1).
’ ASSOCIATED CONTENT
The ability to incorporate alkylamine moieties other than just
morpholine into the O-benzoyl hydroxylamine scaffold is crucial
for broad utility. We were thus pleased to find that 1a reacted
with several O-benzoyl hydroxylamines derived from simple
dialkylamines in good to excellent yields (73ꢀ97%), thus allow-
ing for the introduction of a variety of alkylamino groups
(Table 3).14 Notably, the benzyl group in 3q can be cleaved to
afford a secondary amine. These results demonstrate that a wide
range of arylamines can be accessed from readily available
benzoic acids using this method. To showcase the potential
synthetic applications, we also performed the amination of 1a
with O-benzoyl hydroxylpiperazine, of which the product (3r) is
an analogue of drug molecule II (Figure 1).7 Finally, we demon-
strated that this directing group can be readily removed from the
amination products by treatment with TFA/H2O to afford the
corresponding carboxylic acids (eq 6).
S
Supporting Information. Complete ref 8b. Experimental
b
procedures and spectral data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
yu200@scripps.edu
’ ACKNOWLEDGMENT
We gratefully acknowledge The Scripps Research Institute for
financial support. This work was supported by a National Research
Foundation of Korea Grant funded by the Korean Government
(NRF-2009-352-C00077). We also thank the Agency for Science,
Technology and Research (A*STAR) Singapore for a predoctoral
fellowship (K.C.).
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