Rh-catalyzed intermolecular carbenoid functionalization of aromatic C-H bonds by α-diazomalonates

Article abstract of DOI:10.1021/ja305771y

A Rh-catalyzed intermolecular coupling of diazomalonates with arene C-H bonds is reported. The reaction is initiated by electrophilic C-H activation, which is followed by coupling of the arylrhodium(III) complex with the diazomalonate. In most cases, arenes with oximes, carboxylic acids, and amines as directing groups cross-couple with diazomalonates with excellent regioselectivities and functional group tolerance, and thus, this reaction offers a new route to α-aryl carbonyl compounds for specific applications.

Full text of DOI:10.1021/ja305771y

Communication
pubs.acs.org/JACS
Rh-Catalyzed Intermolecular Carbenoid Functionalization of
Aromatic C−H Bonds by α‑Diazomalonates
Wai-Wing Chan, Siu-Fung Lo, Zhongyuan Zhou, and Wing-Yiu Yu*
State Key Laboratory for Chirosciences and Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic
University, Hung Hom, Kowloon, Hong Kong
S
* Supporting Information
heterodiaryl carboxylic acids.8a Migratory carbene insertion is
believed to be the principal step in these carbenoid coupling
reactions.
ABSTRACT: A Rh-catalyzed intermolecular coupling of
diazomalonates with arene C−H bonds is reported. The
reaction is initiated by electrophilic C−H activation, which
is followed by coupling of the arylrhodium(III) complex
with the diazomalonate. In most cases, arenes with oximes,
carboxylic acids, and amines as directing groups cross-
couple with diazomalonates with excellent regioselectivities
and functional group tolerance, and thus, this reaction
offers a new route to α-aryl carbonyl compounds for
specific applications.
Prompted by these achievements, we anticipated that direct
carbenoid cross-couplings with arene C−H bonds via migratory
carbene insertion should be possible. Reactive metal−carbene
complexes are known to insert into saturated C−H bonds with
excellent regio- and enantiocontrol,9 but their reactivity toward
C−H insertion exhibits an order of reactivity of tertiary C−H >
secondary C−H ≫ primary C−H. Notably, direct carbene
functionalization of aryl C−H bonds has limited precedent in
the literature. Recently, Wang, Satoh, and Miura independently
reported the metal-catalyzed C−H bond cross-coupling of 1,3-
azoles with N-tosylhydrazones.10 However, these reactions are
limited to heteroarene C−H bonds, and excess LiOtBu and
high temperatures (110 °C) are required for success. Herein we
report the [Cp*RhIII]-catalyzed direct aryl C−H bond coupling
of diazocarbonyl compounds. This base-free diazo coupling
reaction occurs under mild conditions with excellent
regioselectivity and functional group compatibility. The
reaction is likely initiated by electrophilic C−H metalation,
which is followed by coupling of the diazo compound with the
arylrhodium complex.
To begin, 1a (1 equiv) was treated with [Cp*RhCl2]2 (2.5
mol %), AgOAc (15 mol %), and diazomalonate 2a (1 equiv) in
MeOH (1.5 mL) at 60 °C overnight, and the desired α-aryl
malonate 3a was obtained in 98% yield (Table 1, entry 1). The
structure of 3a was confirmed by X-ray crystallography. The
reaction was equally effective at room temperature under air,
although longer reaction times were required for complete
reaction (entry 2). No product formation was observed with
AgOAc alone in the absence of the Rh catalyst (entry 3). It is
likely that AgOAc provides the acetate ligand for catalytic
turnovers. As expected, effective transformation was observed
when [Cp*Rh(OAc)2] was employed as the catalyst (entry 4).
Other alcoholic solvents such as EtOH and tBuOH were not
suitable for the C−H coupling reaction, and carbene O−H
insertion products were isolated as the major products (entries
5 and 6).11 Little or no product formation was observed with
1,2-dichloroethane (DCE), acetonitrile, tetrahydrofuran
(THF), or toluene as the solvent.12,13 Some acetate additives
were tested; good product yields were obtained with Cu-
(OAc)2, but poor results were obtained with NaOAc (entries 7
and 8). Lowering the Rh catalyst loading to 1.25 mol % and the
atalytic site-selective functionalization of unactivated C−
CH bonds offers an innovative route for atom-economical
C−C and C−heteroatom bond formations.1 Over the past
years, Pd-catalyzed C−H bond functionalizations have achieved
enormous successes.1c−h However, the Pd catalysis is limited in
its substrate scope, must use a high catalyst loading, and often
requires forcing conditions. Recently, several investigations
revealed that [Cp*RhIIICl2]2 and [Cp*RhIII(MeCN)3](SbF6)2
complexes are promising catalysts for direct arene functional-
izations under mild conditions.1i−l It has been established that
[Cp*RhIIICl2]2 undergoes chelation-assisted electrophilic met-
alation of the ortho C(sp2)−H bond to form arylrhodium
complexes,2 which couple with a variety of reagents such as
isocyanates,3a aldehydes/imines,3b,c alkenes, and alkynes.
Recently, the research groups of Glorius,4a,b Ma,4c and Miura4d
achieved the dehydrogenative coupling reaction of allenes and
arenes with arylrhodium(III) complexes using [Cp*Rh]
catalysis. Glorius5 and we6b also independently achieved
[Cp*Rh]-catalyzed direct aryl C−H amination with excellent
regioselectivity and functional group compatibility.
To explore new C−H bond functionalizations, we have been
interested in the coupling reactions of metal−aryl complexes
with carboradicals, nitrenes, and carbenes as unconventional
coupling partners.6 We found that the reactions of arylpalla-
dium complexes with carboradicals and nitrenes result in C−C
and C−N bond formations. Earlier works by the research
groups of Van Vranken, Barluenga, and Wang demonstrated
the Pd-catalyzed cross-coupling reactions of aryl halides with
carbenoid reagents for CC bond formation.7 We also
accomplished the Pd-catalyzed oxidative coupling of arylbor-
onic acids with α-aryldiazoacetates to furnish (E)-diarylacrylates
with excellent stereoselectivity.8 Recently, we achieved the
Rh(I)-catalyzed one-pot coupling of arylboronates with α-
aryldiazoacetates and alkyl halides to afford quarternary
Received: June 14, 2012
Published: August 3, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
slowed the electrophilic C−H activation by the [Cp*Rh]
complex. However, when 1g was treated with 2a via dropwise
addition, 3g was obtained in 93% yield. With the assistance of
the oxime directing groups, the ortho C−H bond was
exclusively functionalized. Nevertheless, the reactions of some
meta-substituted acetophenone oximes produced regiomeric
products. For instance, the reactions of 1j (3-Cl) afforded a
mixture of 3j (33%) and 3j′ (38%); likewise, the reaction of 1k
(3-OMe) gave 3k and 3k′ in 65 and 28% yield, respectively.
According to the literature, rhodium carbenoids can react
with oxygen, nitrogen, and sulfur atoms to afford ylides, which
can undergo a diverse number of chemical tranformations.11 In
this work, when acetothiophene oxime (1l) was treated with 2a
(1 equiv) and the [Cp*Rh] catalyst, the C−H insertion
products 3l and 3l′ were formed exclusively in 74% overall
yield, yet ylide formation was not observed.14 Similarly,
substrates bearing heterocyclic scaffolds were effectively
transformed into their corresponding products (e.g., 3m,
64%; 3n, 55%; 3o, 88%).
The scope of the diazoester coupling partner was also
investigated. With 1a as the substrate, the Rh-catalyzed C−H
coupling reactions with diazoesters 2p−t bearing substituents
such as phenylsulfone, diethyl phosphonate, CF3, and amide
furnished the desired products 3p−t in 51−97% yield (Scheme
1). Similarly, the facile reaction of methyl phenyldiazoacetate
(2u) gave the product 3u in 53% yield under the standard
reaction conditions.
Table 1. Reaction Optimization
b
entry
1
[Rh] (mol %)
additive (mol %)
solvent
yield (%)
[Cp*RhCl2]2 (2.5)
[Cp*RhCl2]2 (2.5)
none
AgOAc (15)
AgOAc (15)
AgOAc (15)
none
MeOH
MeOH
MeOH
MeOH
EtOH
98
93
0
c
2
3
4
Cp*Rh(OAc)2 (2.5)
[Cp*RhCl2]2 (2.5)
[Cp*RhCl2]2 (2.5)
[Cp*RhCl2]2 (2.5)
[Cp*RhCl2]2 (2.5)
[Cp*RhCl2]2 (1.25)
[Cp*RhCl2]2 (0.5)
85
31
0
5
AgOAc (15)
AgOAc (15)
Cu(OAc)2 (15)
NaOAc (15)
AgOAc (7.5)
AgOAc (3)
6
tBuOH
MeOH
MeOH
MeOH
MeOH
7
70
10
8
d
9
96
10
90
a
Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol), [Rh], and
b
additives in solvent (1.5 mL) at 60 °C overnight. Yields were
determined by 1H NMR analysis using 1,2-dibromoethane as an
c
d
internal standard. Reaction was run at room temperature. Isolated
yield.
AgOAc additive to 7.5 mol % gave the optimal reaction
conditions, with an excellent isolated yield of 96% (entry 9).
For the substrate scope study (Table 2), acetophenone
oximes bearing electron-releasing and -withdrawing substitu-
a
Scheme 1. Scope of Diazoesters
Table 2. [Cp*RhIII]-Catalyzed C−H Coupling of Aryl
Ketone Oximes with Diazomalonate
a
a
b
See the SI for experimental details. Catalyst loading = 2.5 mol %;
AgOAc = 15 mol %; 1a = 0.4 mmol; 2 = 0.2 mmol.
To expand the substrate scope further, we examined the
carbenoid C−H coupling reactions of unprotected benzyl-
amines. As shown in Table 3, treatment of N-benzylmethyl-
Table 3. [Cp*RhIII]-Catalyzed C−H Coupling of N-
a
Benzylmethylamines with Diazomalonates
a
See the Supporting Information (SI) for experimental details.
b
Catalyst loading = 2.5 mol %; AgOAc = 15 mol %; 1 = 0.4 mmol;
c
2a = 0.2 mmol. 2a (0.2 mmol) was added dropwise over 10 h under
N2. The regioisomeric ratio was determined by NMR analysis.
d
ents were found to be effective substrates, giving 3b−i in 33−
91% yield. Notably, the 4-bromo-substituted substrate afforded
the expected product in this Rh-catalyzed reaction. The lower
yields for substrates bearing CF3, CO2Et, and SO2Me can be
attributed to their electron-withdrawing properties, which
a
See the SI for experimental details.
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amine derivatives 4 with diazoesters under the standard
conditions afforded isoquinolones 5a−h in 43−89% yield
with excellent functional group compatibility. Isoquinolone
Scheme 4. Proposed Mechanism
15
nuclei are ubiquitous motifs in bioactive alkaloids.
α-Aryl malonates are useful intermediates for organic
synthesis. In this work, 3a, 3p, and 3q were deoximinated by
treatment with concentrated HCl/formaldehyde (Scheme 2a),
Scheme 2. Synthetic Applications
and the corresponding ketones 6 were obtained in good yields
(68−71%). Carboxylate naphthalene-1,3-diol 7 was prepared in
87% yield by the intramolecular Dieckmann condensation of
6a.16
Likewise, isocoumarins are important structural units in
pharmaceutical compounds such as some serine protease
inhibitors.17 In this work, we prepared benzoic acid 8e by the
Rh-catalyzed diazomalonate coupling of 2-naphthoic acid.18
Treatment of 8e with excess thionyl chloride followed by
cyclization of the acid chloride in a basic medium produced
isocoumarin 9 in 78% yield (Scheme 2b).
The carbenoid C−H coupling reaction probably involves
rate-limiting C−H bond cleavage by the Cp*Rh(III) complex,
since a notable primary kinetic isotope effect (KIE) of kH/kD =
3.0 was observed in a competitive experiment using equimolar
amounts of 1a and 1a-d5.19 Treatment of benzo[h]quinoline
with [Cp*RhCl2]2 afforded cyclometalated Rh(III) complex 10,
which reacts with 2a in DCE to afford σ-alkyl−Rh(III) complex
11 in 69% yield (Scheme 3). The structure of 11 was
determined by X-ray crystallography.
possible. In pathway a, extrusion of N2 from II would afford
Rh−carbene III, which would subsequently undergo migratory
insertion to afford IV. Alternatively, intramolecular 1,2-
migratory insertion of the aryl group would give IV (pathway
b).21 The detailed mechanism of the diazo coupling with the
arylrhodium complexes remains unclear. Finally, protonolysis of
IV would generate the desired alkylated product and the active
Rh catalyst.
In summary, we have developed a mild Rh(III)-catalyzed
carbenoid ortho C−H cross-coupling reaction with diazomal-
onates. Except for some meta-substituted substrates, arenes
such as acetophenone oximes, benzoic acids, 2-phenylpyridines,
and unprotected benzylamines can be functionalized in high
yields with excellent regioselectivities and functional group
tolerance. This carbenoid coupling reaction does not require a
strongly basic medium and gives benign N2 as the only
byproduct. The arylated products can readily be converted into
other useful compounds (e.g., naphthalenes and isocoumarins)
for specific applications.
A plausible reaction mechanism is shown in Scheme 4. First,
[Cp*RhCl2]2 undergoes ligand exchange with AgOAc to give
the cationic acetate-ligated species, which undergoes electro-
philic C−H bond cleavage to form a rhodacyclic intermediate.20
Coordination of the diazo compound with I may form the
diazonium intermediate II. At this stage, two pathways are
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, characterization data, and H and 13C
1
Scheme 3. Characterization of the Alkylrhodacycle
Intermediate
NMR spectra of all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
wing-yiu.yu@polyu.edu.hk
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank The Hong Kong Research Grants Council
(PolyU503811P) for financial support.
■
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(13) We noted that the analogous reactions of 2-phenylpyridine in
MeOH gave mono- (67%) and dialkylation (12%) products. However,
the same reaction in DCE afforded the monoalkylation product (85%)
exclusively (Table S2). To account for the overalkylations, we
speculated that the [Cp*RhIII] complex should form a rather stable
metallacycle with 2-phenylpyridine. Compared with DCE, the active
[Cp*Rh(OAc)]+ complex would turnover more readily in MeOH by
protonation of the alkylrhodacycle intermediates. Therefore, the
higher availability of the [Cp*Rh(OAc)]+ complex should favor
further alkylation of the 2-phenylpyridine.
(14) A stable thiophenium ylide has been isolated from the Rh(II)-
catalyzed decomposition of dimethyl diazomalonate with thiophene.
See: Gillespie, R. J.; Murray-Rust, J.; Murray-Rust, P.; Porter, A. E. A. J.
Chem. Soc., Chem. Commun. 1978, 83.
(15) Bentley, K. W. The Isoquinoline Alkaloids; Hardwood Academic:
Amsterdam, The Netherlands, 1998; Vol. 1.
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