Rhodium-catalyzed oxidative cycloaddition of benzamides and alkynes via C-H/N-H activation

Article abstract of DOI:10.1021/ja103776u

The oxidative cycloaddition of benzamides and alkynes has been developed. The reaction utilizes Rh(III) catalysts in the presence of Cu(II) oxidants, and is proposed to proceed by N-H metalation of the amide followed by ortho C-H activation. The resultant rhodacycle undergoes alkyne insertion to form isoquinolones in good yield. The reaction is tolerant of extensive substitution on the amide, alkyne, and arene, including halides, silyl ethers, and unprotected aldehydes as substituents. Unsymmetrical alkynes proceed with excellent regioselectivity, and heteroaryl carboxamides are tolerated leading to intriguing scaffolds for medicinal chemistry. A series of competition experiments shed further light on the mechanism of the transformation and reasons for selectivity.

Full text of DOI:10.1021/ja103776u

Published on Web 07/13/2010
Rhodium-Catalyzed Oxidative Cycloaddition of Benzamides
and Alkynes via C-H/N-H Activation
Todd K. Hyster and Tomislav Rovis*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
Received May 12, 2010; E-mail: rovis@lamar.colostate.edu
Abstract: The oxidative cycloaddition of benzamides and alkynes has been developed. The reaction utilizes
Rh(III) catalysts in the presence of Cu(II) oxidants, and is proposed to proceed by N-H metalation of the
amide followed by ortho C-H activation. The resultant rhodacycle undergoes alkyne insertion to form
isoquinolones in good yield. The reaction is tolerant of extensive substitution on the amide, alkyne, and
arene, including halides, silyl ethers, and unprotected aldehydes as substituents. Unsymmetrical alkynes
proceed with excellent regioselectivity, and heteroaryl carboxamides are tolerated leading to intriguing
scaffolds for medicinal chemistry. A series of competition experiments shed further light on the mechanism
of the transformation and reasons for selectivity.
Introduction
Metal-catalyzed cycloadditions have proven reliable to form
heterocycles1 with rhodium playing a prominent role.2 We have
previously demonstrated that interception of rhodacyclic inter-
mediates in a [2 + 2 + 2] cycloaddition provides access to
indolizidines and quinolizidines from alkynes and alkene tethered
isocyanates (eq 1).3 Although the described [2 + 2 + 2]
cycloaddition methodology tolerates a range of aryl and alkyl
alkynes, benzyne does not participate in metallacycle formation.
To address this limitation, we imagined accessing similar
products via a C-H activation strategy. Treatment of benza-
mides with catalytic amounts of rhodium(III) would generate
rhodacycle A, which would undergo alkyne insertion to provide
isoquinolones (eq 2).4
dented, with the added advantage of using unfunctionalized
arenes.6 Excellent work by Miura and Satoh7 revealed that
benzoic acid is able to direct C-H insertion in the presence of
alkynes under rhodium(III) catalysis to yield isocoumarins (eq
3). Miura and Satoh expanded on this reactivity by using mildly
acidic N-H bonds as directing groups for rhodium(III) catalyzed
C-H activation, which in the presence of alkynes results in
the cyclized product from a C-H/N-H activation (eqs 4, 6,
and 7).8 In a spectacular application of this approach, Fagnou
has demonstrated a regioselective indole synthesis by coupling
N-aryl acetamides and alkynes under cationic rhodium(III)
conditions (eq 5).9 We envisioned using an amide as a directing
group with selective formation of the isoquinolone motif, a
scaffold found in a variety of natural products.10 Herein, we
provide a complete description of our development of the
Similar intermediates have been invoked in isoquinolone
synthesis from benzotriazones and phthalimides, with concomi-
tant extrusion of either N2 or CO.5 Rhodium(III) catalysis
forming similar metallacycles via C-H activation is prece-
(1) (a) Nakamura, I.; Yamamoto, Y. Chem. ReV. 2004, 104, 2127. (b)
D’Souza, D. M.; Mu¨ller, T. J. J. Chem. Soc. ReV. 2007, 36, 1095.
(2) For recent examples, see: (a) Komine, Y.; Tanaka, K. Org. Lett. 2010,
12, 1312. (b) Saito, T.; Sugizaki, K.; Otani, T.; Suyama, T. Org. Lett.
2007, 9, 1239. (c) Tanaka, K.; Mimura, M.; Hojo, D. Tetrahedron
2009, 65, 9008.
(3) (a) Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 2782–2783. (b)
Yu, R. T.; Rovis, T. J. Am. Chem. Soc. 2006, 128, 12370–12371. (c)
Lee, E. E.; Rovis, T. Org. Lett. 2008, 10 (6), 1231–1234. (d) Yu,
R. T.; Rovis, T. J. Am. Chem. Soc. 2008, 130, 3262–3263. (e) Yu,
R. T.; Lee, E. E.; Malik, G.; Rovis, T. Angew. Chem., Int. Ed. 2009,
48, 2379–2382. (f) Keller Friedman, R.; Rovis, T. J. Am. Chem. Soc.
2009, 131, 10775–10782. (g) Oinen, M. E.; Yu, R. T.; Rovis, T. Org.
Lett. 2009, 12, 4943. (h) Yu, R. T.; Keller Friedman, R.; Rovis, T.
J. Am. Chem. Soc. 2009, 131, 13250. (i) Dalton, D. M.; Oberg, K. M.;
Yu, R. T.; Lee, E. E.; Perreault, S.; Oinen, M. E.; Pease, M. L.; Malik,
G.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 15717. (j) Perreault, S.;
Rovis, T. Chem. Soc. ReV. 2009, 38, 3149.
(6) For a recent stoichiometric example see: Li, L.; Brennessel, W. W.;
Jones, W. D. J. Am. Chem. Soc. 2008, 130, 12414.
(7) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407.
(8) (a) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010,
12, 2068. (b) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura,
M. Chem. Commun. 2009, 5141. (c) Umeda, N.; Tsurugi, H.; Satoh,
T.; Miura, M. Angew. Chem., Int. Ed. 2008, 47, 4019.
(4) For a recent review of rhodium catalyzed C-H activation in C-C bond
formation see: Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem.
ReV. 2010, 110, 624.
(9) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K.
J. Am. Chem. Soc. 2008, 130, 16474. For an additional rhodium
catalyzed cyclization by Fagnou, see: Guimond, N.; Fagnou, K. J. Am.
Chem. Soc. 2009, 131, 12050.
(5) For recent examples, see: (a) Kajita, Y.; Matsubara, S.; Kurahashi, T.
J. Am. Chem. Soc. 2008, 130, 6058. (b) Miura, T.; Yamachi, M.;
Murakami, M. Org. Lett. 2008, 10, 3085.
(10) For a review of isoquinolone synthesis, see: Glushkov, V. A.; Shklyaev,
Y. V. Chem. Heterocycl. Compd. 2001, 37, 663.
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A R T I C L E S
Hyster and Rovis
methodology, a brief derivation of the isoquinolone scaffold,
and some mechanistic insights.
Figure 1. Additive effect.
Chart 1. Benzamide Screen
Table 1. Conditions Screen
entry
catalyst
additive
oxidant
solvent
yield (%)
1
2
3
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
AgSbF6
AgSbF6
none
AgSbF6
AgSbF6
none
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
PhMe
23
65
82
0
65
0
t-AmOH
t-AmOH
t-AmOH
t-AmOH
t-AmOH
4
5a
6b
two alkyne insertions is observed (Figure 1).12 We speculate
that the cationic rhodium is better able to coordinate an
additional equivalent of alkyne resulting in a side pathway
leading to the napthalene product.
a A total of 50 mol % PivOH, and 250 mol % K2CO3 were added.
b A total of 300 mol % Et3N was added.
Substrate Scope. An examination of the scope revealed that
electron-rich and electron-poor N-methyl benzamides participate
in good yield (Chart 1). The reaction is tolerant of aryl bromides
and unprotected aldehydes (3c and 3f). The use of other
substituents on nitrogen is also tolerated including N-ethyl,
N-phenyl, and N-benzyl amides, the latter proceeding in a
depressed yield.13 It is interesting to note that we do not observe
an indole product when subjecting 1g to these reaction condi-
tions, as per the precedent of Fagnou.6 Apparently, benzamide
C-H activation is faster than N-phenyl C-H activation under
these neutral catalyst conditions. Substitution at the meta position
is well tolerated and leads to isoquinolone products as single
regioisomers (3j and 3k). ortho-Methyl benzamide affords the
isoquinolone product in slightly depressed yield.14
Results and Discussion
Initial Conditions Screen. Our studies began with N-methyl
benzamide and diphenylacetylene. When [RhCp*Cl2]2 is used
as catalyst with Cu(OAc)2 as stoichiometric oxidant and AgSbF6
to sequester the halides, the desired isoquinolone product is
obtained in 23% yield (Table 1). t-Amyl alcohol was found to
be the ideal solvent for the reaction providing isoquinolone 3a
in 65% yield. Substitution of Cu(OAc)2 with Cu(OTf)2 resulted
in the exclusive recovery of starting material. However, addition
of pivalic acid and potassium carbonate to the Cu(OTf)2 reaction
affords 3a in 65% yield, suggesting the oxidant is a source of
carboxylate necessary for the reaction to proceed.11 Ultimately,
the exclusion of AgSbF6 gave the optimal conditions with a
yield of 82%. In the course of reaction optimization, we
observed that, when AgSbF6 was added to the reaction, a
naphthalene product resulting from two C-H activations and
(12) Similar reactivity was observed by Miura and Satoh when examining
2-aryl oxazole substrates; see ref 8c
(13) I-Pr and t-Bu benzamides provide no cycloadduct under these
conditions.
(11) This has been suggested in palladium C-H functionalization; see
(14) N-acyl benzyl amines do not undergo the cycloaddition under these
conditions.
Lafrance, M.; Lapointe, D.; Fagnou, K. Tetrahedron 2008, 64, 6015.
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Rh-Catalyzed Oxidative Cycloaddition of Benzamides and Alkynes
A R T I C L E S
Table 2. Alkyne Screen
Figure 2. Competitive isocoumarin formation.
Chart 2. Heteroaryl Screena
a Five mol % RhCp*(MeCN)3(SbF6)2 used as catalyst.
The examination of the benzamide scope revealed three
substrates that afforded anomalous results. Whereas ortho-
methyl benzamide produces the isoquinolone product, the
corresponding ortho-methoxy benzamide leads to clean conver-
sion to the isocoumarin (eq 8, Figure 2). We suggest that this
dichotomy is electronic in nature and that there is an intramo-
lecular hydrogen bond between the amide and the ortho-
methoxy group altering the chemoselectivity of the cyclization
forming an imido ester product (Figure 2). The imido ester is
hydrolyzed to form the isocoumarin product in situ or in the
workup. Furthermore, the use of the more electron-deficient
benzyl or trifluoroethyl amide leads to a mixture of isoquinolone
and isocoumarin products (eq 9, Figure 2).
at the more activated 2-position (5b and 5c, Chart 2). Thiophene
and indolyl carboxamides 4a and 4f provide the corresponding
adducts in excellent yield using the neutral catalyst. However,
2-furyl and 2-pyrrolyl carboxamides lead to low yields under
the neutral precatalyst conditions.16 This situation was rectified
with the use of the more activated cationic precatalyst
[RhCp*(MeCN)3](SbF6)2, leading to products 5d, 5e, and 5g
(Chart 2). The use of unsymmetrical alkynes with heteroaryl
carboxamides led to products 5e-5g as single regioisomers,
paralleling results with those found with benzamides (Chart 2
and see below).
Extension of this reaction to heteroaryl carboxamides proved
successful under these reaction conditions (Chart 2).15 With
3-heteroaryl carboxamides 4b and 4c, the reaction affords a
single regioisomer as product resulting from C-H activation
With respect to the alkyne substituent, the reaction shows
broad substrate tolerance among internal alkynes (Table 2).17
Electron-rich tolanes participate in excellent yield while electron-
(15) Under these conditions, N-methylpyridine-3-carboxamide and N,2-
dimethyloxazole-4-carboxamide afford cycloadduct in 0% and 8%
yield, respectively.
(16) For example, 2-furyl carboxamide 4d leads to 5d in 13% yield using
the [RhCp*Cl2]2 conditions.
(17) Terminal alkynes are not tolerated under the current reaction conditions.
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A R T I C L E S
Hyster and Rovis
Figure 3. Reversible C-H activation.
Figure 5. Alkyne competition experiments.
in nearly equal amounts consistent with the hypothesis that C-H
activation is the first irreversible step (eq 11, Figure 4). If N-H
activation was the first irreversible step, we should see a greater
difference in product distribution given the increased acidity
of amide 1e relative to 1c. Importantly, this suggests a
mechanistic dichotomy between this manifold and Fagnou’s
Rh(III)-catalyzed C-H/N-H activation of N-acetyl anilides
leading to indoles.6
Figure 4. Benzamide competition experiments.
deficient systems are somewhat more recalcitrant (contrast
entries 1 and 2, Table 2). Heteroaryl and aliphatic alkynes are
also tolerated. Acetals are deprotected under the reaction
conditions to yield the corresponding aldehyde (entry 7, Table
2).18 When unsymmetrical alkynes are employed, largely a
single regioisomer is observed. An unsymmetrical dialkyl alkyne
also participates, with 4-methyl-2-pentyne surprisingly affording
3u bearing the bulky isopropyl group distal to the isoquinolone
nitrogen (entry 9, Table 2).
Mechanistic Studies. We conducted a series of experiments
to probe the reaction mechanism. Fagnou has shown that the
C-H insertion step is reversible with electron rich N-phenyl
acetamide.6 When our reaction is conducted in t-AmOD in the
absence of alkyne, 73% deuterium incorporation is observed at
the two ortho positions (Figure 3). If the same reaction is
conducted in the presence of diphenylacetylene, no deuterium
incorporation is observed in unreacted 1a. These experiments
suggest that, under the reaction conditions, the C-H insertion
step is largely irreversible.19
To learn about the subsequent steps in the catalytic cycle,
we conducted a series of competition experiments between
alkynes. Equimolar amounts of 1a, 5-decyne, and diphenyl-
acetylene afford isoquinolone 3a as a single product (eq 12,
Figure 5). A competition experiment between electron-rich (p-
methoxy) and electron-deficient (p-trifluoromethyl) tolanes
provides only the isoquinolone derived from the electron-rich
alkyne (eq 13, Figure 5). Lastly, an unsymmetrical tolane gives
two regioisomeric isoquinolones in good yield (eq 14, Figure
5). Taken together, these results suggest that more electron-
rich alkynes are favored in the insertion event but the regiose-
lectivity of insertion appears to be dictated largely by steric
factors.20
Further support for this step in the mechanism was gained
from a series of competition experiments. Equimolar amounts
of benzamides 1b and 1e were subjected to the standard reaction
conditions with a single equivalent of alkyne. The product
formation favors isoquinolone 3e derived from the more
electron-deficient benzamide (eq 10, Figure 4). These results
suggest that either N-H activation or C-H activation could
be turnover limiting. In order to distinguish between these two
possibilities, we also conducted a competition experiment
between 1c and 1e, two para substituents that have disparate σp
values but similar σm values. In the event, 3c and 3e are formed
In light of these experiments we propose the following
mechanism (Figure 6). The rhodium dimer precatalyst presum-
ably dissociates into the coordinatively unsaturated monomer,
which can exchange ligands to form an acetate-ligated species
with the copper oxidant. Coordination of an equivalent of
benzamide then initiates either N- or O-metalation before a
turnover limiting C-H activation can occur to form a 5-mem-
bered rhodacycle, with concomitant formation of acetic acid.
This rhodacycle has an open coordination site which can
regioselectively and irreversibly insert an equivalent of alkyne
to form a 7-membered rhodacycle with an open coordination
site. If this coordination site is occupied by an equivalent of
alkyne, this can lead to the naphthalene side product; alternately,
the rhodium can reductively eliminate to form the desired
isoquinolone and generate a rhodium(I) species which can
(18) Acetic acid is generated during the course of the reaction and the Cu
salt is used as its hydrate, presumably providing the necessary water
and acid to lead to hydrolysis of the acetal.
(19) This deuteration experiment was also conducted on N-t-Bu benzamide.
In the absence of alkyne, no deuterium incorporation was observed
after 16 h under these conditions suggesting the sterics of the tert-
butyl group negatively affects its ability to metalate by rhodium. This
also suggests that metalation occurs on nitrogen rather than oxygen.
(20) The apparent reversed regioselectivity in product 3u seems to contradict
this model; further studies to address this dichotomy are ongoing.
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Rh-Catalyzed Oxidative Cycloaddition of Benzamides and Alkynes
A R T I C L E S
bered rhodacycle accessed from ortho C-H/N-H activa-
tion.21 We found that heterocycles are well tolerated in the
reaction allowing access to a number of unique molecular
scaffolds. Additionally, unsymmetrical alkynes are tolerated
in high yield and high regioselective with high functional
group tolerance. The mechanism of the reaction was probed
to find that C-H activation is the turnover-limiting step. A
series of competition experiments shed light on this mech-
anism, suggesting alkyne insertion is largely governed by
steric factors and alkyne coordination plays a central role in
product selectivity.
Acknowledgment. We thank NIGMS (GM80442), Amgen, and
Roche for support. We thank Johnson Matthey for a loan of rhodium
salts.
Supporting Information Available: Experimental procedures
and spectral data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JA103776U
Figure 6. Proposed mechanism.
undergo oxidation to regenerate the catalytically active rhod-
ium(III) complex.
(21) During the preparation and review of this manuscript, similar and
complementary studies leading to isoquinolone synthesis were reported
by the groups of Keith Fagnou and Masahiro Miura; see: (a) Guimond,
N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908. (b)
Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem. Lett.
2010, 39, 744.
Conclusion
In conclusion, we have developed a Rh(III) catalyzed
oxidative isoquinolone synthesis using a transient 5-mem-
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