Synthesis of Aryl Ketoamides via Aryne Insertion into Imides

Article abstract of DOI:10.1021/acs.orglett.6b00994

An insertion of arenes into both imides and anhydrides via reactive aryne intermediates is presented. The reaction is performed under exceptionally mild conditions, and the corresponding ketoamide products are amenable to derivatization to deliver a variety of synthetically useful motifs such as quinolones, indoles, and ketoanilines.

Full text of DOI:10.1021/acs.orglett.6b00994

Letter
pubs.acs.org/OrgLett
Synthesis of Aryl Ketoamides via Aryne Insertion into Imides
Austin C. Wright, Christopher K. Haley, Guillaume Lapointe, and Brian M. Stoltz*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125, United
States
S
* Supporting Information
ABSTRACT: An insertion of arenes into both imides and anhydrides via reactive aryne intermediates is presented. The reaction
is performed under exceptionally mild conditions, and the corresponding ketoamide products are amenable to derivatization to
deliver a variety of synthetically useful motifs such as quinolones, indoles, and ketoanilines.
he insertion of aromatic systems into carbon−carbon and
carbon−heteroatom σ bonds is a desirable transformation
Scheme 2. Derivatization of Aryl Ketoamides
T
in organic synthesis.1 In 2005, our group reported an insertion of
arenes into β-ketoesters to form acyl-alkylated products (Scheme
1A) using arynes generated in situ from ortho-silylphenyl triflates
Scheme 1. Aryne Insertion Methods
amides into arynes afforded similar acyl-aminated products.11
However, the scope of their method was limited to N-arylated
amide substrates, prohibiting subsequent derivatization.
We initiated our synthetic studies by optimizing conditions for
the insertion reaction using acetylacetamide 10 and silylaryl
triflate 1 (Table 1). Implementing CsF as the fluoride source to
trigger aryne generation, we observed a mixture of the desired
Table 1. Reaction Optimization
under mild reaction conditions.2 Following this report, other
aryne insertions were disclosed using a variety of substrates,
including malononitriles,3 α-cyanocarbonyls,4 acylated fluo-
renes,5 and β-ketosulfones.6
More recently, Saito and co-workers developed a procedure
for inserting pyridynes into cyclic ureas to construct various
bicyclic heterocycles.7 Herein, we expand the scope of this aryne
reaction manifold to include acyclic imides and anhydrides to
produce ketoamido- and ketoacyloxyarenes (Scheme 1B). The
ketoamide products accessed by this method have been used to
generate a variety of valuable structural motifs such as quinolones
(7),8 ortho-acylanilines (8),9 and indoles10 (9, Scheme 2). Work
from the Greaney group demonstrated that the insertion of
temperature
yield
(%)
entry
fluoride source
(°C)
solvent
11/12
1
2
3
4
CsF
80
23
23
60
MeCN
THF
49
37
21
62
1.25:1
10:1
KF/18-crown-6
TBAT
THF
10:1
TBAT
PhMe
>20:1
Received: April 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
ketoamide 11 and undesired imide byproduct 12. Presumably,
12 is formed via nucleophilic addition of 10 to the aryne formed
from 1 followed by proton quenching of the resultant aryl anion
intermediate (see Figure 1). Although all three fluoride reagents
Table 3. Aryne Substrate Scope
Figure 1. Plausible mechanism for formation of ketoamide 11 and imide
byproduct 12.
afforded the desired product, KF and tetrabutylammonium
difluorotriphenylsilicate (TBAT) substantially improved selec-
tivity for the desired amide. Additional screening of solvent and
temperature demonstrated that using TBAT in PhMe at 60 °C
maximized product yields and minimized byproduct formation
(entry 4).
With optimized conditions in hand, we explored the substrate
scope with respect to the imide substrate (Table 2). Imides
a
Table 2. Imide Substrate Scope
b
entry
product
R1
R2
X
yield (%)
1
2
3
4
5
6
7
8
9
11
Me
Et
Me
Et
NH
NH
NH
NH
NH
NH
NMe
O
89
88
68
78
79
24
0
a
Reaction conditions: TBAT (2.0 equiv), 10 (0.08 M in PhMe), and
13a
13b
13c
13d
13e
13f
b
14 (1.5 equiv), 60 °C, 16 h. All reported yields are for isolated
products.
Ph
Ph
i-Pr
i-Bu
OMe
Me
Me
Ph
i-Pr
i-Bu
Bn
ketoamide products (15a−d). Furthermore, we observed that
insertion into an unsymmetrical aryne such as 15d occurred with
good regioselectivity. Unfortunately, a substrate bearing
electron-withdrawing fluoride substituents (14e) failed to
undergo insertion.
Me
Me
Ph
13g
13h
54
0
O
a
Reaction conditions: TBAT (2.0 equiv), 4 (0.08 M in PhMe), and 1
(1.5 equiv), 60 °C, 16 h. All reported yields are for isolated products.
b
To demonstrate the synthetic utility of this method, we
elaborated several of these acylamide insertion products to
substituted quinolones via a base-initiated Camps cyclization in a
two-step, one-pot sequence (Figure 2).8 Gratifyingly, quinolones
16a−c were directly produced in moderate yield. Moreover,
formation of 16b and 16c occurred with high regioselectivity for
the aryne insertion, producing a single isolable structural isomer
in each case.
In summary, we developed a method for inserting arynes into
acyclic imides and anhydrides to generate aryl ketoamides and
ketoacyloxyarenes, respectively. These products are capable of
further derivatization to provide an array of useful scaffolds such
as quinolones, indoles, and ketoanilines. Our laboratory is
possessing either aliphatic or aromatic substituents afforded the
corresponding ketoamides in moderate to good yields (entries
1−5). An acylated urethane also undergoes insertion, albeit with
reduced yield (entry 6). However, N-substituted imides afforded
no product (entry 7). Acetic anhydride was found to be a suitable
substrate, delivering the corresponding ketoacyloxyarene (entry
8) in 54% yield. Unfortunately, benzoic anhydride failed to
provide any insertion product (entry 9).
Next, we investigated the tolerance of the reaction to various
aryne precursors (Table 3). Substituted carbocyclic substrates
(14a−d) offered moderate yields of the corresponding aryl
B
DOI: 10.1021/acs.orglett.6b00994
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(8) Jones, C. P.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2007,
72, 7968−7973.
(9) Okabe, M.; Sun, R.-C. Tetrahedron 1995, 51, 1861−1866.
(10) Furstner, A.; Jumbam, D. N.; Weidmann, H. Tetrahedron Lett.
̈
1991, 32, 6695−6696.
(11) Pintori, D. G.; Greaney, M. F. Org. Lett. 2010, 12, 168−171.
Figure 2. Camps cyclization of ketoamide insertion products to provide
quinolones.
pursuing further development of this technology as it relates to
other derivatizations and application in multistep synthesis.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00994.
Experimental procedures and compound characterization
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: stoltz@caltech.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NSF (CCE 1265591), Caltech, and
Amgen for financial support. G.L. is grateful to the Swiss National
Science Foundation (SNSF) for a postdoctoral fellowship. Dr.
Scott C. Virgil (Caltech) is thanked for assistance with
compound isolation. Dr. Mona Shahgholi (Caltech) is acknowl-
edged for help in structural determination and characterizations.
REFERENCES
■
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DOI: 10.1021/acs.orglett.6b00994
Org. Lett. XXXX, XXX, XXX−XXX