Palladium-Catalyzed Highly Chemoselective Intramolecular C-H Aminocarbonylation of Phenethylamines to Six-Membered Benzolactams

Article abstract of DOI:10.1021/acs.orglett.6b01171

A palladium-catalyzed highly selective intramolecular C-H aminocarbonylation of Br-functionalized phenethylamines in the presence of CO was achieved while leaving the C-Br bond unreacted to afford six-membered benzolactams with good to high yields. The re

Full text of DOI:10.1021/acs.orglett.6b01171

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Highly Chemoselective Intramolecular C−H
Aminocarbonylation of Phenethylamines to Six-Membered
Benzolactams
Hiroshi Taneda,† Kiyofumi Inamoto,*,‡ and Yoshinori Kondo*,†
†Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
‡School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women’s University, 11-68, 9-Bancho, Koshien, Nishinomiya, Hyogo
663-8179, Japan
S
* Supporting Information
ABSTRACT: A palladium-catalyzed highly selective intra-
molecular C−H aminocarbonylation of Br-functionalized
phenethylamines in the presence of CO was achieved while
leaving the C−Br bond unreacted to afford six-membered
benzolactams with good to high yields. The remaining C−Br
group in the cyclized product was successfully used as a reactive center for further functionalization through various palladium-
catalyzed coupling reactions.
Scheme 1. Chemoselectivity (C−H vs C−Br) in Pd-
Catalyzed C−H Functionalization
mides have received considerable attention in organic and
Amedicinal chemistry because of their ubiquity in natural
products, pharmaceuticals, and functional materials. Among the
amide synthesis methods reported so far, the palladium-
catalyzed aminocarbonylation of aryl halides (Ar−X, X =
halogen atom) with amines in the presence of carbon monoxide
(CO), first reported by Heck in 1974,1 has demonstrated high
versatility and efficiency.2 A variety of palladium-based catalytic
systems that successfully effect aryl C(sp2)−X bonds for
aminocarbonylation have been developed to date.3 However,
direct aminocarbonylation of aryl C(sp2)−H bonds with the aid
of palladium catalysts provides a more straightforward and
atom-economic route to the amide scaffold; several examples
have been reported to date.4−6 In some cases, the intra-
molecular aminocarbonylation process allows for the facile
synthesis of lactam compounds.5b−k
The transition-metal-catalyzed C−H functionalization is a
rapidly growing and intensive research area.7 Although the
development of chemoselective processes is critical in modern
organic synthesis, the control of chemoselectivity in transition-
metal-catalyzed C−H functionalization processes is relatively
unexplored. In particular, intramolecular selective C−H
functionalization of substrates containing both C−H and C−
X bonds still remains elusive. Thus, as previously reported by
our group, the indazole synthesis via palladium-catalyzed
intramolecular C−H amination of a substrate containing both
C−H and C−Br bonds exclusively proceeded via C−Br
functionalization, leading to a dehalogenated indazole com-
pound [Scheme 1a].8 The Orito’s palladium-catalyzed synthesis
of benzolactam by intramolecular C−H aminocarbonylation
utilizing CO yielded a mixture of products resulting from both
C−H and C−Br functionalization (ca. 3:2) [Scheme 1b].5b,c
There have only been a few examples of palladium-catalyzed
“C−H selective” cyclization while maintaining the reactive C−X
bond intact, which involve intramolecular C−N and C−O
bond formation [Scheme 1c].9
Herein, we describe a highly chemoselective palladium-
catalyzed intramolecular C−H aminocarbonylation. Thus,
under the reaction conditions herein developed, cyclization of
1 (containing both C−H and C−Br reactive bonds) exclusively
proceeded via C−H functionalization, thereby affording six-
Received: April 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01171
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
membered benzolactam 2 with good to high yields [Scheme
1d].10 Further functionalization of 2 was conducted through
various palladium-catalyzed coupling reactions involving the
remaining C−Br bond.
In our continuous research on the transition-metal-catalyzed
carbonylation reaction,11 the carbonylative cyclization of
substrate 1a was investigated (Scheme 2). A twofold C−Br
sources tested (Table 1, entries 1−4), Pd(TFA)2 was found to
be a suitable catalyst as it achieved C−H functionalization to
Scheme 3. Further Functionalization of 2b via Pd-Catalyzed
Coupling Reactions
Scheme 2. Pd-Catalyzed Cyclization of Substrate 1a
the desired cyclized product 2b in quantitative yields (Table 1,
entry 4). In contrast, the use of ligands other than BINOL led
to a considerable decrease in yields (Table 1, entries 5−7).
Ag3PO4 was found to be crucial for efficient C−H cyclization.
Thus, the utilization of other oxidants such as AgOAc, Ag2CO3,
and Cu(OAc)2 resulted in lower yields (Table 1, entries 8−10).
Essentially, in the absence of Pd(TFA)2, BINOL, or Ag3PO4,
little or no reaction occurred (Table 1, entries 11−13). Finally,
lower catalyst loadings afforded 2b with high yields, indicating
the efficiency of the catalytic system (Table 1, entry 14).12
Once the reaction conditions were optimized, C−H selective
intramolecular aminocarbonylation was studied for different
substrates (Table 2). Phenethylamines 1c and 1d containing a
bicyclic motif (i.e., naphthalene and 1,3-benzodioxole) afforded
the desired products 2c and 2d in useful yields (Table 2, entries
1 and 2). In contrast, the introduction of a substituent at the
ortho-position with respect to the C−H bond markedly
inhibited the process (Table 2, entries 3 and 4). Substrates
1g and 1h containing a methyl (instead of an ethyl) group at
the quaternary carbon gave benzolactams 2g and 2h, albeit in
moderate yields (Table 2, entries 5 and 6). Substrates 1i and 1j
with a silyl-protected alcohol moiety readily underwent the
desired C−H cyclization under the optimized reaction
conditions (Table 2, entries 7 and 8). With the aim to evaluate
the steric influence of a substituent at the α-position with
respect to the amine nitrogen atom, various α,α-dialkylamines
1k−o were employed. Interestingly, the more sterically
hindered the substrate becomes, the more efficiently the C−
H cyclization proceeds (Table 2, entries 9−13). Additionally,
the reactivity of the amine 1p containing both C−H and C−Cl
bonds was investigated. Exclusive formation of 2p resulting
from chemoselective C−H functionalization was observed
(Table 2, entry 14).
functionalization to benzolactam 2aa was achieved in the
presence of CO and Pd(OAc)2/BINAP as a catalytic system. A
change in the reaction conditions (i.e., by adding an oxidant
such as Ag3PO4) allowed for the exclusive formation of
benzolactam 2ab retaining unreacted C−Br bonds with good
yields.
Intrigued by this highly C−H selective cyclization process,
further examination of the reaction parameters was conducted
using the substrate 1b (Table 1). Among the various palladium
Table 1. Optimization of Reaction Parameters for C−H
a
Selective Intramolecular Aminocarbonylation
bc
,
entry
Pd
ligand
BINOL
oxidant
yield (%)
1
Pd(dppe)2
[PdCl(allyl)]2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
none
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
Ag3PO4
AgOAc
Ag2CO3
Cu(OAc)2
Ag3PO4
Ag3PO4
none
67
72
78
(99)
0
2
BINOL
BINOL
BINOL
BINAP
ditbutyl tartrate
IPr·HCl
BINOL
BINOL
BINOL
BINOL
none
3
4
5
6
11
0
7
8
35
41
12
0
With the aim of proving the applicability of the synthetic
method herein proposed, further functionalization of the C−Br
bond was conducted in the cyclized product 2b. Various
palladium-catalyzed coupling reactions were successfully carried
out giving rise to further functionalized benzolactams 3−6 in
good to high yields (Scheme 3).
9
10
11
12
13
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
4
BINOL
BINOL
0
d
14
Ag3PO4
75 (79)
In conclusion, we have developed a highly chemoselective
aminocarbonylation methodology. Selective C−H cyclization of
phenethylamines was efficiently carried out while leaving the
reactive C−Br bond intact by using a palladium catalytic
a
b
Reactions were carried out on a 0.15 mmol scale. Determined by 1H
c
NMR using 1,1,2-trichloroethane as an internal standard. Isolated
yield in parentheses. 5 mol % of Pd(TFA)2 and 20 mol % of BINOL.
d
B
DOI: 10.1021/acs.orglett.6b01171
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 2. Effect of the Substrate in the C−H Selective Intramolecular Aminocarbonylation Process
a
b
c
Reactions were carried out on a 0.15 mmol scale. Isolated yield. Yield based on 1H NMR spectroscopy using 1,1,2-trichloroethane as an internal
standard.
system. In addition, further functionalization of the C−Br bond
in the cyclized benzolactam was successfully conducted making
use of several palladium-catalyzed coupling strategies. Further
studies on similar selective C−H transformations are in
progress in our laboratory.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support by a Grant-in-Aid
for Scientific Research (B) (No. 23390002), a Grant-in-Aid for
Challenging Exploratory Research (No. 25670002), and a
Grant-in-Aid for Scientific Research (C) (No. 25460002) from
Japan Society for the Promotion of Science, a Grant-in-Aid for
Scientific Research on Innovative Areas “Advanced Molecular
Transformations by Organocatalysis” (No. 23105009) and the
project “Platform for Drug Discovery, Informatics, and
Structural Life Science” from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01171.
Experimental procedures, characterization data, and
spectroscopic data (PDF)
REFERENCES
■
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AUTHOR INFORMATION
■
Corresponding Authors
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2009, 48, 4114−4133. (b) Grigg, R.; Mutton, S. P. Tetrahedron 2010,
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Rev. 2011, 40, 4986−5009. (d) Roy, S.; Roy, S.; Gribble, G. W.
Tetrahedron 2012, 68, 9867−9923. (e) Wu, X.-F.; Neumann, H.;
Beller, M. Chem. Rev. 2013, 113, 1−35. (f) Gadge, S. T.; Bhanage, G.
*E-mail: ykondo@m.tohoku.ac.jp.
*E-mail: inamoto@mukogawa-u.ac.jp.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b01171
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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