A coupling of benzamides and donor/acceptor diazo compounds to form γ-lactams via Rh(III)-catalyzed C-H activation

Article abstract of DOI:10.1021/ja402274g

The coupling of O-pivaloyl benzhydroxamic acids with donor/acceptor diazo compounds provides isoindolones in high yield. The reaction tolerates a broad range of benzhydroxamic acids and diazo compounds, including substituted 2,2,2-trifluorodiazoethanes. Mechanistic experiments suggested that C-H activation is turnover-limiting and irreversible and that insertion of the diazo compound favors electron-deficient substrates.

Full text of DOI:10.1021/ja402274g

Communication
pubs.acs.org/JACS
A Coupling of Benzamides and Donor/Acceptor Diazo Compounds
To Form γ‑Lactams via Rh(III)-Catalyzed C−H Activation
Todd K. Hyster, Kyle E. Ruhl, and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S
* Supporting Information
is the ability to access γ-lactams with the potential to control
ABSTRACT: The coupling of O-pivaloyl benzhydroxamic
acids with donor/acceptor diazo compounds provides
isoindolones in high yield. The reaction tolerates a broad
range of benzhydroxamic acids and diazo compounds,
including substituted 2,2,2-trifluorodiazoethanes. Mecha-
nistic experiments suggested that C−H activation is
turnover-limiting and irreversible and that insertion of
the diazo compound favors electron-deficient substrates.
the stereochemistry of the process. The key to achieving this
reactivity is the identification of a suitable one-carbon
component.
Examples of one-carbon components in Rh(III)-catalyzed
C−H activation reactions are rare. Previously, we found that
amides could be coupled with CO to provide a range of
phthalimides in good yield (eq 2).13 Concurrent work by Zhu
and Falck found isocyanides to be competent coupling partners
in an analogous reaction.14 CO and isocyanides function as
one-carbon components because the carbon has carbenic
character. Elegant work by Yu took advantage of the carbenic
character of electron-deficient diazo compounds to ortho-
functionalize a variety of directing-group-containing arenes (eq
3).15 In view of the importance of γ-lactams, we were interested
in using diazo compounds as one-carbon components in a
cyclization reaction that would provide isoindolones (eq 4).
We believed that a significant barrier to this reactivity would
be the need to inhibit protonation of the metallacycle. The
report by Yu suggested that protonation of the rhodacycle
occurs rapidly when monodentate directing groups are used.15
Fagnou3e and Glorius11 found that use of a bidentate directing
group precludes β-hydride elimination in the synthesis of
dihydroisoquinolones. We imagined that this type of directing
group would also be effective in inhibiting unwanted
protonation events. In a set of initial experiments, we chose
to explore donor/acceptor diazo compounds because they are
less prone to dimerization and can provide interesting products
with a stereogenic carbon.
ulticomponent reactions catalyzed by transition metals
M
represent a powerful approach for the synthesis of
heterocycles.1 This concept has been extensively explored in
the Rh(III)-catalyzed synthesis of nitrogen-containing hetero-
cycles mediated by C−H activation.2 A wide swath of
unsaturated heterocycles can be accessed though coupling of
amides, amines, oximes, and anilines with alkynes to access
isoquinolones,3 pyridones,3d,4 isoquinolines,5 pyridines,5g,6
indoles,7 and pyrroles.7b,8
The ability to access nitrogen-containing heterocycles
bearing stereogenic carbons is important because of their
prevalence in medicinal targets and natural products.9,10
Recently, Glorius11 and Fagnou3e demonstrated that alkenes
can be used to access partially saturated nitrogen-containing
heterocycles (eq 1). In the presence of an enzyme or chiral
Initial coupling of amide 1a with diazo ester 2a using
superstoichiometric CsOPiv in MeOH gave the desired product
in 24% yield, with the remainder of the mass balance being
methanolysis of the pivalate ester in the starting material (Table
1, entry 1). A screen of solvents revealed CH3CN to be ideal,
providing lactam 3a in 78% yield (entry 4). Replacing CsOPiv
with CsOAc gave a comparable yield (entry 5). We were
pleased to find that using a substoichiometric amount of base
did not have a detrimental effect on the yield (entry 6). Finally,
modification of the concentration allowed the desired lactam to
be isolated in 81% yield after 150 min. The catalyst loading can
be decreased to 0.4 mol % when the reaction is performed on a
gram scale (entry 8). The use of O-methyl hydroxamic acid in
place of 1a delivered only a 10% yield of the protonated
product and none of the desired product.
cyclopentadiene ligand, this reaction can be rendered
asymmetric.12 Currently absent from this family of reactivity
Received: March 4, 2013
Published: April 2, 2013
© 2013 American Chemical Society
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Journal of the American Chemical Society
Communication
(3j). Presumably this decrease in regioselectivity can be
attributed to the increase in acidity of the ortho C−H bond.
Increasing the kinetic acidity of the C−H bond overwhelms the
steric bias of the C−H activation, giving a mixture of products.
A gallic acid-derived amide (3k) and a heterocyclic substrate
(3l) also fared well in the reaction, although increased reaction
temperatures were required.
Table 1. Optimization of the Reaction Conditions
a
b
entry
base
solvent
yield (%)
1
2
3
4
5
6
7
CsOPiv (200 mol %)
CsOPiv (200 mol %)
CsOPiv (200 mol %)
CsOPiv (200 mol %)
CsOAc (200 mol %)
CsOAc (20 mol %)
−
MeOH (0.5 M)
EtOH (0.5 M)
TFE (0.5 M)
24
33
59
78
80
We next explored the scope of diazo compounds (Table 3).
Acceptor diazo compounds16 dimerized rapidly under the
MeCN (0.5 M)
MeCN (0.5 M)
MeCN (0.1 M)
MeCN (0.1 M)
MeCN (0.1 M)
a
Table 3. Scope of Donor/Acceptor Diazo Compounds
c
81
0
d
c
8
CsOAc (20 mol %)
75
a
Standard conditions: 1a (1 equiv), 2a (1 equiv), [RhCp*Cl2]2 (1 mol
b
c
d
%). Determined by HPLC. Isolated yield. Catalyst loading 0.4 mol
%
With the ideal conditions in hand, we tested the scope of
isoindolone formation with differentially substituted benzhy-
droxamic acids (Table 2). For a variety of electronically
a
Table 2. Benzhydroxamic Acid Scope
a
b
For the standard reaction conditions, see Table 1. The reaction was
c
conducted at 60 °C. The reaction was conducted at 80 °C.
reaction conditions, while acceptor/acceptor diazo compounds
were almost completely unreactive, with yields of <5% observed
under these reaction conditions. Donor/acceptor diazo
compounds were broadly tolerated with reasonable scope.
Differential substitution on the ester gave the desired products
in high yield (4a, 4b). Cyclic diazo substrates delivered the
desired spiro compounds in high yields under the reaction
conditions (4c, 4d). A wide range of substituents on the
aromatic ring were tolerated.17 While electron-poor substrates
provided the desired product rapidly under the standard
reaction conditions (4e, 4j, 4i), electron-rich substrates were far
more sluggish and required elevated temperatures and
prolonged reaction times (4f, 4h). We were pleased to find
that heteroaryl diazo esters also provided the corresponding
products, albeit in lower yields (4k, 4l). Elevated temperatures
allowed acceptor diazo esters to be incorporated in good yields
(4m, 4n).
a
b
For the standard reaction conditions, see Table 1. Isolated as a 1.1:1
c
d
ratio of regioisomers. The reaction was conducted at 60 °C. Isolated
as a 2:1 ratio of regioisomers.
different para-substituted amides, the reaction afforded the
desired products in high yield (3b−f). Substitution at the meta
position plays an important role in controlling the regiose-
lectivity of the C−H activation event. When m-methyl
benzhydroxamic acid was used (3h), C−H activation occurred
exclusively para to the methyl group, presumably to avoid
sterically disfavored interactions. However, when a methoxy
group was placed at the meta position (3g), a 1.1:1 ratio of
regioisomers was observed. This effect was also observed with
naphthyl amides (3i), where a 2:1 ratio of regioisomers was
observed. By comparison, the less electron-deficient tetrahy-
dronaphthyl benzhydroxamic acid gave a single regioisomer
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Journal of the American Chemical Society
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While screening electron-withdrawing groups on the donor/
acceptor diazo compound, we found that amides and
phosphonates provide very low product yields. In contrast,
we were pleased to find the 1-phenyl-2,2,2-trifluoro diazo-
ethane, as described by Davies and co-workers,18 delivered the
desired product in high yield (Chart 1, 5a). Electron-deficient
experiments were used to determine the electronic preference
of the reaction. When p-bromobenzamide 1c was run in
competition with the unsubstituted amide 1a the reaction
favors the electron deficient amide in a 1.9:1 ratio (Scheme 1a).
This experiment suggest that C−H activation favors more acid
C−H bonds. Indeed, initial rate kinetic isotope studies revealed
a KIE value of 2.6 (Scheme 1b). Together these studies suggest
that C−H activation occurs via a concerted-metalation
deprotonation (CMD) mechanism, and the C−H activation
does not proceed through a Wheland intermediate.20 These
experiments are consistent with the observation that reactions
involving substrates bearing more electron donating groups are
sluggish.
a
Chart 1. Scope of 1-Aryl-2,2,2-trifluoro Diazoethanes
The reversibility of the C−H activation was determined by
removing the diazo compound and running the reaction in the
presence of MeCN-d3 (Scheme 1c). After 15 min, <1%
deuterium incorporation at the ortho positions was observed, as
1
determined by H NMR analysis. After 150 min, the degree of
deuterium incorporation increased to 7%. These results suggest
that C−H activation in largely irreversible on the time scale of
the reaction, which is consistent with previous reports by
Fagnou3e and Glorius.21
a
b
For the standard reaction conditions, see Table 1. The reaction was
A competition experiment was used to determine the
preference of the reaction for electronically different donor/
acceptor diazo compounds (Scheme 1d). When methyl p-
bromophenyl diazo acetate (2e) was used in competition with
2a, the electron-deficient substrate was favored 1.6:1 after 15
min. These results suggest that migratory insertion or reductive
elimination favors the more electron-deficient substrate. Since
reductive elimination should favor a more electron-rich
substrate, it is reasonable to surmise that migratory insertion
favors an electron-deficient diazo substrate because of its
increased electrophilicity.
In conclusion, we have developed a new approach to access
isoindolones bearing a tetrasubstituted carbon. A wide range of
substrates are tolerated, including 1-aryl-2,2,2-trifluoroethyl
diazo compounds. Mechanistic studies revealed that the
reaction operates under a mechanism similar to that for the
synthesis of dihydroisoquinolones.
conducted at 60 °C.
aromatic groups on these trifluoroethyl diazo substrates
functioned well in the reaction, with high yields and short
reaction times (5b and 5d−f). As observed previously, electron-
rich aromatic groups provided substantially lower product
yields even at high temperatures (5c). These products contain
quaternary carbons with a trifluoromethyl group, a substitution
pattern not easily accessed using other methods.19
A series of mechanistic experiments were performed to
elucidate the nuances of the reaction (Scheme 1). Competition
Scheme 1. Mechanistic Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures, characterization data, and
mechanistic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
rovis@lamar.colostate.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NIGMS for generous support of this research
(GM80442). T.R. thanks Amgen and Roche for unrestricted
support and Johnson Matthey for a generous loan of Rh salts.
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