Catalyst-controlled divergent C-H functionalization of unsymmetrical 2-aryl cyclic 1,3-dicarbonyl compounds with alkynes and alkenes

Article abstract of DOI:10.1021/ja404867k

Achieving site-selective, switchable C-H functionalizations of substrates that contain several different types of reactive C-H bonds is an attractive objective to enable the generation of different products from the same starting materials. Herein, we dem

Full text of DOI:10.1021/ja404867k

Article
pubs.acs.org/JACS
Catalyst-Controlled Divergent C−H Functionalization of
Unsymmetrical 2‑Aryl Cyclic 1,3-Dicarbonyl Compounds with
Alkynes and Alkenes
Johnathon D. Dooley, Suresh Reddy Chidipudi, and Hon Wai Lam*
EaStCHEM, School of Chemistry, University of Edinburgh, Joseph Black Building, The King’s Buildings, West Mains Road,
Edinburgh, EH9 3JJ, United Kingdom
S
* Supporting Information
ABSTRACT: Achieving site-selective, switchable C−H func-
tionalizations of substrates that contain several different types
of reactive C−H bonds is an attractive objective to enable
the generation of different products from the same starting
materials. Herein, we demonstrate the divergent C−H func-
tionalization of unsymmetrical 2-aryl cyclic 1,3-dicarbonyl
compounds that contain two distinct, nonadjacent sites for
initial C−H functionalization, where product selectivity is
achieved through catalyst control. By use of a palladium−N-heterocyclic carbene complex as the precatalyst, these substrates
undergo oxidative annulation with alkynes to provide spiroindenes exclusively. In contrast, a ruthenium-based catalyst system
gives benzopyrans as the major products. Examples of divergent, oxidative C−H alkenylations of the same substrates are also
provided.
This prospect led us to consider 3-aryl-4-hydroxyquinolin-
2-ones such as 1a as substrates for oxidative annulation with
alkynes (Scheme 1). However, these compounds present a
complication in that two distinct sites for initial enol/enolate-
directed C(sp2)−H cleavage are now available: at the 3-aryl ring
and at the benzene ring of the quinolin-2-one. C−H cleavage at
the former site (HA) with a metal acetate complex, for example,
would provide a six-membered metallacycle A, which could
then react with an alkyne 2 to give spiroindene 3. Alternatively,
C−H cleavage at the second site (HB) would form a five-
membered metallacycle B, which could react with the alkyne to
give benzopyran 4, a process that has been described by the
group of Satoh and Murai using rhodium catalysis13 and by the
Ackermann group using ruthenium catalysis.14
This situation highlights an inherent challenge in C−H func-
tionalization chemistry resulting from the ubiquity of C−H
bonds in organic compounds: how to control site selectivity
when more than one type of C−H bond can potentially undergo
reaction. One solution to this problem is through catalyst
control. The ability to form one of two possible annulation
products selectively from the same reactants, simply by varying
the catalyst, falls under the area of catalytic selective synthesis,
which has been highlighted by Bode and co-workers in a recent
review.15 Although the area of catalytic C−H functionaliza-
tion has witnessed explosive growth, investigations of catalyst-
controlled divergent C−H functionalizations of distinct C−H
bonds are relatively uncommon.7c,16−19 A greater understanding
of the factors that influence switchable, site-selective C−H
INTRODUCTION
■
Metal-catalyzed C−H functionalization reactions are of sig-
nificant interest because of their potential to streamline organic
synthesis by avoiding the prior preparation of activated substrates
and reducing the quantity of waste byproducts, thereby making
syntheses more step- and atom-economic.1 One important class
of these reactions is the oxidative annulation of alkynes with
substrates containing cleavable C−H/N−H, C−H/O−H, or
C−H/N−O bonds, which enables the preparation of a diverse
range of heterocycles.2−9
The development of corresponding processes for the synthesis
of carbocyclic products would be highly valuable,10 and in this
context, we recently reported the ruthenium-catalyzed oxidative
annulation of alkynes with 2-aryl cyclic 1,3-dicarbonyls or their
enol tautomers (eq 1).11 These reactions proceed via sequential
C(sp2)−H and C(sp3)−H functionalization to give spiroindenes
in generally good yields.12 In that study, only symmetrical 2-aryl
cyclic 1,3-dicarbonyl substrates were studied, which led to the
formation of achiral products. Replacement of these substrates
with unsymmetrical variants would result in chiral spiroindenes,
thus providing the possibility of the development of a catalytic
enantioselective process.
Received: May 15, 2013
© XXXX American Chemical Society
A
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Next, palladium-based precatalysts were investigated,7,10 and
these reactions provided spiroindene 3a as the sole product,21
with none of benzopyran 4a being detected (Table 1, entries
7−10). The use of Pd(OAc)2 (5 mol %) in DMF gave 3a in
76% yield after only 1 h at 120 °C (entry 7). The use of an
N-heterocyclic carbene ligand for palladium22 provided even
better results, and 3a was obtained in 86% yield in the presence of
5 mol % of the PEPPSI-IPr complex developed by Organ and
co-workers (entry 8).23−25 Reduction of the loading of PEPPSI-
IPr to 2.5 mol % gave similar results after a reaction time of 2 h
(entry 9). Although the temperature could be lowered to 90 °C, a
slightly longer reaction time was required, and 3a was obtained in
a slightly lower yield (entry 10). On the basis of these results, the
conditions of entry 9 were used to investigate the scope of the
spiroindene synthesis.
Scheme 1. Divergent Oxidative Annulation of 1a with an
Alkyne
Palladium- and Ruthenium-Catalyzed Oxidative Annula-
tions with Alkynes. Chart 1 presents the results of the palladium-
catalyzed synthesis of spiroindenes from the reaction of various
unsymmetrical 2-aryl cyclic 1,3-dicarbonyls with a range of
alkynes. In addition to diphenylacetylene, which provided 3a in
84% yield, substrate 1a underwent oxidative annulation with
unsymmetrical alkyl/aryl alkynes (spiroindenes 3b and 3c),
Chart 1. Palladium-Catalyzed Oxidative Annulations with
a
Alkynes
functionalizations,20 including catalyst structure, would be
valuable in increasing the utility of these reactions in more com-
plex settings. In this article, we describe the divergent oxidative
annulation of unsymmetrical 2-aryl cyclic 1,3-dicarbonyl com-
pounds with alkynes. Site selectivity in the initial C−H func-
tionalization en route to spiroindene or benzopyran products
may be achieved by the use of palladium- or ruthenium-based
catalysts, respectively. Examples of the oxidative C−H
alkenylation of the same substrates are also provided.
RESULTS AND DISCUSSION
■
Evaluation of Precatalysts in the Oxidative Annulation
with Alkynes. This study began with an evaluation of pre-
catalysts and reaction conditions for the oxidative annulation of
the 4-hydroxy-3-phenylquinolin-2-one 1a with diphenylacety-
lene (2a), using Cu(OAc)2 (2.1 equiv) as the stoichiometric
oxidant (Table 1). First, [RuCl2(p-cymene)]2 was found to favor
the formation of benzopyran 4a in all cases (entries 1−4).14,21
Conditions employed in our previous study of spiroindene
synthesis,11 using 2.5 mol % of [RuCl2(p-cymene)]2 in dioxane at
90 °C for 5 h, gave both possible products 3a and 4a in low yields
(entry 1). An increase in the loading of [RuCl2(p-cymene)]2 to
5 mol % was beneficial, and products 3a and 4a were isolated in
13% and 78% yield, respectively (entry 2). Switching the solvent
to DMF increased the overall yield and the selectivity for 4a
(entry 3). Although the catalyst loading could be reduced to
2.5 mol %, an increase in temperature to 120 °C was required
for reasonable conversions, and the isolated yield of 4a was only
66% (entry 4). [RhCp*Cl2]2 was also a competent precatalyst
and, like [RuCl2(p-cymene)]2, favored the formation of
benzopyran 4a (entries 5 and 6).13 The best result was obtained
using 2.5 mol % of [RhCp*Cl2]2 in DMF at 90 °C (entry 6).
However, on the basis of the lower cost of [RuCl2(p-cymene)]2
compared with [RhCp*Cl2]2, the conditions of entry 3 were
selected for further investigation of the scope of the benzopyran
formation (see Table 2).
a
Reactions were conducted using 0.50 mmol of 1. Unless otherwise
b
stated, cited yields are of pure, isolated material. Using 5.0 mol % of
PEPPSI-IPr and 2.0 equiv of the alkyne. rr = regioisomeric ratio as
determined by H NMR analysis of the unpurified reaction mixture.
c
1
Product was isolated as a 93:7 inseparable mixture of regioisomers.
d
Product 3i was of ∼90% purity.
B
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a
Table 1. Evaluation of Reaction Conditions for the Oxidative Annulation of 1a with Diphenylacetylene
b
yield (%)
entry
[M]
mol %
solvent
temp (°C)
time (h)
3a
4a
1
2
3
4
5
6
7
8
9
10
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RuCl2(p-cymene)]2
[RhCp*Cl2]2
2.5
5
dioxane
dioxane
DMF
90
90
5
5
5
5
5
5
1
1
2
3
5
13
8
15
78
87
66
61
79
0
5
90
2.5
2.5
2.5
5
DMF
120
120
120
120
120
120
90
8
dioxane
DMF
30
13
76
86
87
75
[RhCp*Cl2]2
Pd(OAc)2
DMF
PEPPSI-IPr
5
DMF
0
PEPPSI-IPr
2.5
DMF
0
PEPPSI-IPr
2.5
DMF
0
a
b
Reactions were conducted using 0.25 mmol of 1a. Cited yields are of isolated material.
though 5.0 mol % of PEPPSI-IPr was required in these cases for
reasonable results, and the yields were more modest because of
the presence of unreacted 1a. In these reactions, initial C−H
functionalization resulted in C−C bond formation at the alkyl-
substituted carbon of the alkyne. Spiroindene 3b was formed
as the sole regioisomer, whereas 3c was formed as a 93:7 mixture
of regioisomers that were inseparable by column chromatog-
raphy.26 Substitution at the phenyl group of the 1,3-dicarbonyl
substrate with 4-methoxy or 4-carbomethoxy groups was also
tolerated (spiroindenes 3d and 3e, respectively). The high selec-
tivity of palladium catalysis for spiroindene formation was
demonstrated by the reaction of a substrate 1d containing a
3,5-dimethylphenyl group. Despite the increased steric hin-
drance of C−H functionalization resulting from the m-methyl
substituents, this experiment provided spiroindene 3f in 74%
yield, with none of the alternative benzopyran detected in the
product mixture. As expected, substitution at the benzene ring
of the quinolin-2-one was tolerated (spiroindene 3g). A methyl
group on the nitrogen atom in the substrate is not necessary;
substrate 1f containing a free N−H bond also underwent
oxidative annulation to give 3h in 65% yield. However, the
reaction of 4-hydroxy-3-phenylcoumarin (1g) with diphenyla-
cetylene gave a complex mixture from which the only product
that could be identified was spiroindene 3i, which was isolated
in only 21% yield and in ∼90% purity. Attempted oxidative
annulations of substrate 1a with terminal alkynes such as
phenylacetylene, trimethylsilylacetylene, or 1-hexyne were
unsuccessful, and recovered material consisted of mainly
unreacted 1a, along with small quantities of byproducts.
A more demanding test of the preference for initial C−C bond
formation at the alkyl-substituted carbon of the triple bond of
alkyl/aryl alkynes was provided by the oxidative annulation of
1a with alkyne 2d containing a sterically demanding tert-butyl
group, which was expected to lead to a greater quantity of
the alternative regioisomer (eq 2). Indeed, the alternative
regioisomer 3jb was obtained in 21% yield, though spiroindene
3ja was still produced as the major regioisomer (69% yield).21
Despite the increased steric hindrance resulting from alkyne 2d,
the overall yield of this reaction (90%) was significantly higher
C
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than those obtained using other alkyl/aryl alkynes (Chart 1,
spiroindenes 3b and 3c). The reasons for this observation are not
clear at the present time.
Table 2. Ruthenium-Catalyzed Oxidative Annulations with
Alkynes
a
Since the PEPPSI-IPr complex gives exclusive preference for
spiroindene formation from 3-aryl-4-hydroxyquinolin-2-ones,
the oxidative annulation of substrate 5, from which spiroindene
formation is not possible, was examined. In principle, 5 could
result in the formation of a benzopyran. However, reaction of 5
with diphenylacetylene using the PEPPSI-IPr complex provided
no evidence of benzopyran 6, and recovered material consisted of
a complex mixture of unidentified products. As expected, the
same reaction conducted in the presence of [RuCl2(p-cymene)]2
in place of PEPPSI-Pr provided benzopyran 6 in good yield
(eq 4).14
The oxidative annulation of various unsymmetrical 2-aryl
cyclic 1,3-dicarbonyls with a range of alkynes was then conducted
using the conditions of Table 1, entry 3, to examine the site
selectivity of the ruthenium-based catalyst system in greater
detail (Table 2). These reactions provided benzopyrans 4 as the
major products in 72−88% yield, along with small quantities
of spiroindenes 3. With unsymmetrical aryl/alkyl alkynes,
the regioselectivity was high (entries 2 and 3).21 A 3,5-
dimethylphenyl group in the substrate strongly disfavored the
formation of the spiroindene 3f, and benzopyran 4f was isolated
as the sole product in 88% yield (entry 6). A more stringent test
of the selectivity for benzopyran formation was provided by the
reaction of substrate 1e containing a methyl substituent at the
6-position. As expected, the steric effect of this methyl group
decreased the site selectivity of C−H functionalization, and this
reaction gave benzopyran 4g and spiroindene 3g in 72% and 21%
yield, respectively (entry 7). Although quinolin-2-one 1f
containing a free N−H bond was effective in the palladium-
catalyzed formation of spiroindenes (Chart 1, product 3h), this
substrate was not competent in the ruthenium-catalyzed
oxidative annulation and returned unreacted alkyne along with
a complex mixture of unidentified products (entry 8).27 In con-
trast, while 4-hydroxy-3-phenylcoumarin (1g) was poorly effec-
tive inthe palladium-catalyzed synthesis of spiroindenes (Chart 1),
this compound underwent smooth oxidative annulation with
diphenylacetylene in the presence of [RuCl2(p-cymene)2]/
Cu(OAc)2 to give benzopyran 4i in 80% yield and spiroindene
3i in 11% yield (entry 9). No evidence of oxidative annulation
products was observed in the reactions of substrate 1a with
terminal alkynes such as phenylacetylene, trimethylsilylacety-
lene, or 1-hexyne.
a
Reactions were conducted using 0.50 mmol of 1. Cited yields are of
b
1
pure, isolated material. rr = regioisomeric ratio as determined by H
NMR analysis of the unpurified reaction mixtures. Reaction con-
ducted at 120 °C for better solubility of 1f. Recovered material was
unreacted alkyne and unidentified byproducts.
c
conditions described in Chart 1 but with the omission of the
alkyne and the inclusion of D2O, for reaction times of 15 min
and 2 h (Scheme 2A). These experiments led to recovered
[Dn]1b in which deuteration occurred exclusively at the
4-methoxyphenyl group (12% and 55% D, respectively).
These results indicate that cyclopalladation is reversible in
the absence of an alkyne, and the site of deuterium incorporation
is consistent with the fact that the oxidative annulations pre-
sented in Chart 1 gave spiroindenes exclusively, with no trace of
benzopyran products detected.
Deuteration Experiments. Deuteration experiments were
then conducted to shed further light on these reactions. First,
substrate 1b was treated with PEPPSI-IPr under the
D
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metallacycle B might be expected to be kinetically favored over
the six-membered metallacycle A because of its smaller ring size
(see Scheme 1), and the site selectivity of the ruthenium catalyst
system is consistent with this assumption. However, an explana-
tion for the reluctance of palladium to form metallacycle B will
require further investigation.
Scheme 2. H/D Scrambling Experiments of 1b in the Absence
of an Alkyne
Next, oxidative annulations were conducted in the presence
of D2O (Scheme 3). A reaction of 1b with diphenylacetylene
using the PEPPSI-IPr precatalyst in 6.5/1 DMF/D2O for 15 min
provided recovered 1b and spiroindene 3d in 42% and 34% yield,
respectively, in which no deuterium incorporation was detected
in either compound. An analogous experiment carried out with
[RuCl2(p-cymene)]2 for 5 min gave recovered 1b in 19% yield,
benzopyran 4d in 55% yield, and spiroindene 3d in 3% yield, in
which deuterium incorporation was not detected in any of the
compounds. The lack of deuterium incorporation in these experi-
ments suggests that oxidative annulation is rapid and that both
cyclopalladation and cycloruthenation of 1b are essentially
irreversible in the presence of an alkyne.
Palladium- and Ruthenium-Catalyzed Oxidative An-
nulations with Alkenes. To ascertain whether the high site
selectivities obtained with palladium- and ruthenium-based
precatalysts are maintained in other classes of oxidative C−H
functionalizations, the annulation of 1a with various alkenes
was studied.12,29,30 Reaction of 1a with methyl vinyl ketone,
acrylonitrile, and phenyl vinyl sulfone in the presence of
Pd(OAc)2 (5 mol %) and Cu(OAc)2 (2.1 equiv) in DMF at
120 °C provided benzopyrans 7a−c, respectively, in 79−86%
yield with no trace of other products (Chart 2).12,29a The
oxidative annulations of 1a with internal alkenes such as trans-
methyl crotonate and 2-cyclohexenone were also successful to
provide benzopyrans 7d and 7e, albeit in lower yields (32% and
31%, respectively).
Consistent with earlier results (Table 2), ruthenium-catalyzed
oxidative annulations of 1a with terminal alkenes led to C−H
functionalization at the benzene ring of the quinolin-2-one to
provide benzofurans 8a−c in 63−72% yield (Chart 3). These
reactions were also highly site-selective, and in the reactions with
methyl vinyl ketone and phenyl vinyl sulfone, only trace
quantities (<5%) of the alternative benzopyran products were
In contrast, an analogous experiment performed with
[RuCl2(p-cymene)]2 at 90 °C for 15 min provided recovered
[Dn]1b in which appreciable deuteration (16% D) had occurred
at the benzene ring of the quinolin-2-one but had barely occurred
at the 4-methoxyphenyl ring (Scheme 2B). Repeating this
experiment for a longer duration of 2 h increased the level of
deuterium incorporation at both sites (35% D at the benzene ring
of the quinolin-2-one and 15% D at the 4-methoxyphenyl ring).
Again, these observations are consistent with the results
presented in Table 2, where benzopyrans were obtained as the
major products but where smaller quantities of spiroindenes
were also formed.
The reasons behind the site selectivities exhibited by the
palladium- and ruthenium-based catalyst systems are not clear at
the present time.28 In principle, formation of the five-membered
Scheme 3. Oxidative Annulations of 1b in the Presence of D2O
E
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altering the catalyst offers a broadly useful tool in the late-stage
diversification of molecules and the generation of compound
libraries.1a In this study, the oxidative annulation of alkynes and
alkenes with unsymmetrical 2-aryl cyclic 1,3-dicarbonyl com-
pounds containing two distinct, nonadjacent sites for C−H bond
functionalization has been achieved with high site selectivity
using palladium or ruthenium catalysis. Palladium catalysis
enables the exclusive functionalization of a hydrogen atom five
bonds away from the oxygen of the enol/enolate directing group
in these substrates, leading to spiroindenes 3 or benzopyrans 7
from alkynes or electron-deficient alkenes, respectively. In con-
trast, ruthenium catalysis mainly results in functionalization of a
hydrogen atom four bonds away from the oxygen of the directing
group, which produces benzopyrans 4 or benzofurans 8 from
alkynes or electron-deficient terminal alkenes, respectively.
Efforts to understand the origins of the differing selectivities
exhibited by palladium- and ruthenium-based catalysts, along
with developments in switchable, site-selective C−H function-
alizations of more complex classes of substrates, are topics for
future study in our laboratory.
Chart 2. Palladium-Catalyzed Oxidative Annulations with
Alkenes
a
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, full spectroscopic data for all new
compounds, and crystallographic data in cif format. This material
is available free of charge via the Internet at http://pubs.acs.org.
a
Reactions were conducted using 0.50 mmol of 1a. Cited yields are of
AUTHOR INFORMATION
Corresponding Author
h.lam@ed.ac.uk
Notes
■
isolated material.
Chart 3. Ruthenium-Catalyzed Oxidative Annulations with
Alkenes
a
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the ERC (Starting Grant No. 258580) and the
University of Edinburgh for financial support. The EPSRC is
gratefully acknowledged for the award of a Leadership
Fellowship to H.W.L. We thank Dr. Gary S. Nichol and Jorge
́
Solana Gonzalez at the University of Edinburgh for X-ray
crystallography and assistance in the preparation of substrates,
respectively. We thank the EPSRC National Mass Spectrometry
Facility for high-resolution mass spectra.
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