RhII-Catalyzed Intermolecular C?H Arylation of Aromatics with Diazo Quinones

Article abstract of DOI:10.1002/chem.201800648

We developed an efficient synthesis of biaryls by a dirhodium(II)-catalyzed aromatic C?H arylation with diazo quinones. The new biaryl synthesis can be performed under mild and neutral conditions and without directing group chelation assistance. The reaction tolerates various functionalities and is applicable to a broad range of aromatics. The regioselectivity of the C?H arylation was often high and predictable. The synthetic utility of the method was demonstrated by the late-stage modifications of a series of pharmaceuticals and functional materials as well as a short synthesis of a transthyretin amyloid inhibitor.

Full text of DOI:10.1002/chem.201800648

A Journal of
Accepted Article
Title: Rh(II)-Catalyzed Intermolecular C-H Arylation of Aromatics with
Diazo Quinones
Authors: Kai Wu, Bei Cao, Cong-Ying Zhou, and Chi-Ming Che
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10.1002/chem.201800648
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COMMUNICATION
Rh(II)-Catalyzed Intermolecular C-H Arylation of Aromatics with Diazo Quinones
Kai Wu, Bei Cao, Cong-Ying Zhou,* and Chi-Ming Che*
Abstract: We developed an efficient synthesis of biaryls by a
dirhodium(II)-catalyzed aromatic C-H arylation with diazo quinones.
The new biaryl synthesis can be performed under mild and neutral
conditions and without directing group chelation assistance. The
reaction tolerates various functionalities and is applicable to a
broad range of aromatics. The regioselectivity of the C-H arylation
was often high and predictable. The synthetic utility of the method
was demonstrated by the late-stage modifications of a series of
pharmaceuticals and functional materials as well as a short
synthesis of a transthyretin amyloid inhibitor.
The development of efficient methods for the construction of biaryls is
very important in organic synthesis, owing to the ubiquity of biaryls in
natural products, pharmaceuticals and organic materials.[1] Transition-
metal-catalyzed cross couplings between aryl halides (Ar-X) and aryl
organometallic reagents (Ar-M) are the most powerful methods for
synthesizing biaryls.[2] Although this approach is highly efficient,
prefunctionalization of both coupling partners is required, and
stoichiometric amounts of organometallic by-products are generated
during the coupling. Metal-catalyzed C-H bond activation has recently
emerged as a more straightforward and atom-economic method for
the construction of biaryls (Scheme 1).[3] Although this strategy
circumvents the prefunctionalization of substrates, controlling the
regioselectivity and achieving enough reactivity for intermolecular
aromatic C-H arylation remains a considerable challenge. This issue
has been elegantly addressed using substrates with directing groups
(DGs) that can facilitate C-H activation via chelation with a metal
catalyst, but installation and removal of the DGs often require additional
synthetic steps. Excess base or stoichiometric amount of oxidants are
often required for metal-catalyzed C-H activation, which limits the
functional-group compatibility. In this regard, the development of new
C-H arylation of aromatics that can proceed efficiently under neutral
(both in redox and acidic/basic terms) and mild conditions with good
functional-group compatibility and high regioselectivity and without
chelation assistance of DGs is highly desirable.
Scheme 1. The methods for the construction of biaryl compounds.
electrophilic addition of a metal quinoid carbene to arenes to give a
Wheland-type intermediate II (Scheme 1) which undergoes a
hydrogen shift and rearomatization to lead to biaryls. The potential side
reactions including Buchner reaction, dimerization of diazo quinone
and over-arylation pose major challenges to achieve the intermolecular
C-H arylation. So far the reports on metal-catalyzed carbene transfer
reactions of diazo quinones are rare.[6,7] While diazo quinones have
recently been reported to undergo aromatic C-H arylation with Rh(III) or
Ir(III) catalyst, the reaction requires chelation assistance of DGs to
facilitate activation of sp2 C-H bond and reaction scope is limited.[7e]
Herein, a new synthesis of biaryls via Rh(II)-catalyzed aromatic C-H
arylation with diazo quinones is described. Mechanistically, this
process is different from metal-catalyzed C-H activation reaction that
proceeds via a metalation of aromatic C-H bond. This reaction does
not involve direct interaction of metal ion with aromatic C-H bond.
Diazo quinones were readily prepared from the diazotization of
aminophenols or functionalization of anilines or phenols according to
the literature.[8] Initially, we examined the C-H arylation of anisole with
diazo quinone 1a at room temperature with a range of catalysts (Table
1, inexpensive anisole was used as both a substrate and a solvent).
The results revealed that Rh2(esp)2 was the most effective catalyst for
the reaction, providing biaryl 3a in 87% yield and with 100% substrate
conversion (entry 3).[9] Other dirhodium carboxylates Rh2(OAc)4,
Rh2(TFA)4, Rh2(piv)4 and Rh2(tpa)4 were less efficient, giving 14-37%
yields of 3a. When Cu(OTf)2, Cu(CH3CN)PF6, AgSbF6,
Ph3PAuCl/AgSbF6, Ru(TTP)(CO) or Co(TTP) was used as catalyst,
the conversion of 1a was 5-51% after 16 h. With Rh2(esp)2 as a
catalyst, the effect of solvents was examined. The use of THF or
α-Diazo carbonyl compounds have been reported to undergo C-H
alkylation of arenes in the presence of transition-metal catalysts
presumable via addition of electron-rich arenes to electrophilic
metal carbenes.[4,5] Diazo quinone, a carbonyl diazo compound
bearing two electron acceptors,[6] is expected to undergo similar
[*]
K. Wu, B. Cao, Dr.C.-Y. Zhou, and Prof. Dr. C.-M. Che
HKU Shenzhen Institute of Research & Innovation, Shenzhen and
State Key Laboratory of Synthetic Chemistry and Department of
Chemistry, The University of Hong Kong, Hong Kong, China.
E-mail: cmche@hku.hk; cyzhou@hku.hk
Prof. Dr. C.-M. Che
HKU Shenzhen Institute of Research and Innovation
Shenzhen, Guangdong, 518053, China
Supporting information for this article is given via a link at the end of the
document
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CH3CN led to 3a in poor yield. Better yields of 49-66% of 3a were
(77% 3j); in this case, diazo quinone 2a, instead of 1a, was used, since
the former could efficiently suppress the undesired over-arylation by
blocking para and ortho position of phenol. Strikingly, even electron-
deficient arenes suchas fluorobenzene and bromobenzenearereactive,
givingcorrespondingbiaryls (3k, 3l) inmoderateyields.
obtainedusingCF3Ph, CH2Cl2 or ClCH2CH2Cl assolvent.
Table 1. Screening of the reaction conditionsa,b,c
Thescope of diazo quinones was examined with anisole as substrate.
Various diazo quinones including para-diazo quinones and ortho-diazo
quinones are effective carbene precursors for the Rh(II)-catalyzed
aromatic C-H arylation affording good to high product yield (58-87%, 3a,
3m-p, Table 2). Thecatalysis is tolerant to various substitutions on diazo
quinones including para-, meta-, ortho- andmulti-substitution (1a-1d, 2a,
2b). The diazo quinones bearing electron-withdrawing groups displayed
higher reactivity than those bearing electron-donating groups, enabling
the C-H arylation to occur at lower temperature and in higher yield (3m,
3nvs 3p).
Table 2. C-H arylation of arenes with diazoquinones [a-e]
The substrate scope of the Rh(II)-catalyzed C-H arylation of arenes
with diazo quinones was examined. As depicted in Table 2, a broad
range of arenes, including benzene, haloarenes, anisoles, N-substituted
anilines, phenols and naphthalenes, reacted efficiently with diazo
quinones to give the corresponding biaryls in good to high yields. The
present C-H arylation often displays good to high regioselectivity with
functionalization at the para or ortho C-H bond of arenes. For electron-
rich arenes such as anisoles, N-substituted anilines and phenols, the
reactions were completed in 2-4 h at room temperature (3a, 3c, 3e-3g).
The use of two or five equivalent such arenes could also lead to C-H
arylation products in good to high yields. When less electron-rich or
sterically hindered arenes were used, longer reaction times (16-24 h)
and higher temperatures (50-70 oC) were required (3b, 3d, and 3i-l).
Such regioselectivity and reactivity of the arylation reaction is consistent
with pattern of electrophilic aromatic substitution (SEAr). Unactivated
arenes such as benzene also underwent C-H arylation in good yields
The present catalysis is applicable to heteroaromatic C-H arylation for
the synthesis of heterobiaryls. As depicted in Table 3, a broad range of
heteroaromatics including indoles, pyrroles, thiophene, benzothiophene,
benzothiazole, benzofuran and furan reacted with diazo quinones to
give heterobiaryls in good to high yields; excellent regioselectivity was
often observed and the site of arylation is predictable, in most cases
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being at the most electron-rich position. For example, a variety of
substituted indoles underwent the C3-H or C2-H aryalation with diazo
quinone 1a in good to high yields and with high regioselectivity (4a-4e).
The site selectivity for C-H arylation of pyrroles could be reversed
through varying the size of N-substituent (4f vs 4g and 4h), indicating
that the reaction is sensitive to steric hindrance. Both thiophene and
benzothiophene were reactive for C-H arylation, giving the
corresponding products in 80% and 70% yields, respectively, and with
excellent regioselectivities. It is worth noting that the present catalysis
was applicable to the arylation of benzofuran and furan leading to 4l
and 4m in 53% and 76% yield, respectively, along with minor
cyclopropane and diene by-products, and the latter were reported to be
major products in a similar reaction with diazoesters.[10] The
heteroaromatic C-H arylation is also compatible with various
substituted quinone diazides (4n-4q).
which is consistent with a sp2 to sp3 hybridization change during the
addition of a rhodium carbene to arene to form a σ-adduct. [5e,16] Control
reaction of diazo quinone 1a with chlorobenzene and anisole was
performed under Meerwein arylation condition and Gomberg-
Bachmann arylation condition, respectively. No reaction was observed.
This result does not support a metal-free radical mechanism for the C-H
arylation(seedetails inSI).
O
The Rh(II)-catalyzed C-H arylation was found to be compatible with
a variety of functionalities, including methoxy, hydroxyl, amino, halide,
nitro and ester (Table 2 and 3). These functional groups are
synthetically useful to enable many further manipulations; for example,
various cross-coupling reactions with aryl halides or sulfonates (derived
from phenol).[2,11] The hydroxyl group on the phenyl ring and its
C4
C3
Rh1-Rh2 2.458 Å
Rh2-C1 1.980 Å
C1-C2 1.436 Å
C2-C3 1.362 Å
C3-C4 1.463 Å
C5
C2
C6
C1
C4-O
Rh2-C1-C6 114.7°
1.236 Å
derivatives can serve as DGs for many useful functionalizations of
Rh2
[13]
arenes, including SEAr,[12] directed ortho-metalation
and metal-
catalyzed C-H bond activation reactions.[14] Additionally, phenols
themselves are common moiety in natural products and versatile
synthons in organic synthesis.[15]
Rh1
Table 3. C-H arylation of heteroaromatics with diazo quinones[a-e]
DFT calculated structure of Rh2(esp)2 quinoid carbene complex Rh-
1a (Figure 1b) shows RhC distance of 1.980 Å comparable to that of
the dirhodium-carbene complexes derived from α-diazoesters
(1.9722.061 Å).[17] DFT calculation (Figure 2) shows that Rh-1a reacts
with anisole to form IntA through TS1, requiring a free-energy barrier of
11.8 kcal/mol. Attempts to locate the transition state of the direct
insertion of Rh-carbene to the sp2 C-H bond of anisole was
To gain insight into the reaction mechanism, the kinetic isotope effect
(KIE) was examined using a 1:1 mixture of MeOPh and MeOPh-d5
(Figure 1a). An inverse isotope effect (kH/kD = 0.87) was observed,
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unsuccessful. Proton migration of IntA leads to IntB via TS2 with an
activation free energy of 3.5 kcal/mol. The unassisted 1,2-proton shift of
IntA to give a biaryl product via TS4 has an activation energy which is
3.0kcal/mol higher thanthat for TS2.
This C-H arylation was highly selective for phenyl ring 2 without the
observed C-H arylation of phenyl ring 1 or 3. Similarly, the C-H arylation
was successfully applied for the functionalization of DH-4T in good yield
(11), thelatter has diverseapplications inmaterials science.
Finally, the Rh(II)-catalyzed C-H arylation was successfully applied
to a short synthesis of a transthyretin amyloid inhibitor (Scheme 2).[18]
Treatment of 1,4-difluorobenzene with 1b in the presence of 2 mol%
Rh2(esp)2 at 45 °C for 14 h afforded the C-H arylation product 12 in
55% yield. Hydrolysis of 12 under basic condition and subsequent
acidification gave transthyretin amyloid inhibitor 13 in 90% yield.
As the aryl moiety is ubiquitous in pharmaceuticals and functional
materials, the application of our C-H arylation to the late-stage
modification of arene-containing compounds provides valuable
opportunities for streamlining the generation of analogues to accelerate
the optimization of potential drugs and functional materials. As shown in
Table 4, nabumetone, a drug used to treat pain or inflammation, reacted
with a variety of diazo quinones to give nabumetone analogues 5-7 in
high yields (89-91%). The methodology provides a rapid approach to
various aryl-nabumetone derivatives. Similarly, C-H arylation of
melatonin, a hormone that anticipates the daily onset of darkness, with
diazo quinone 1b afforded the C2-arylated product 8 in 85% yield.
Chlorambucil (on the World Health Organization’s List of Essential
Medicines) is a chemotherapy drug that has been primarily used in the
treatment of chronic lymphocytic leukemia. Treatment of methyl
chlorambucil with diazo quinone 2a led to the chlorambucil-analogue 9
in 94% yield based on 66% conversion. In addition to the diversification
of drugs, our C-H arylationis also effectivefor thelate-stage modification
of organic functional materials. For example, N,N′-diphenyl-N,N′-di-p-
tolylbenzene-1,4-diamine, a hole-transport material for blue-to-yellow-
emittingOLEDs, was arylatedwith diazo quinone1b in 48% yield(10).
Scheme 2. Synthesis of transthyretin amyloid inhibitor 13
In summary, we have developed an efficient method for the
synthesis of biaryls via the dirhodium(II)-catalyzed C-H arylation of
aromatics with diazo quinones. The C-H arylation could be performed
under mild and neutral conditions without required base or oxidant and
does not need DG assistance. The reaction was applicable to a broad
range of aromatics and tolerated a variety of functionalities. These
advantages promise applications of this method in the construction of
biaryl compounds for pharmaceuticals and materials science, which
was exemplified by the late-stage modifications of a series of
pharmaceuticals and functional materials as well as a short synthesis
of a transthyretin amyloid inhibitor.
Table 4. Late-stage modification of drugs and organic materials[a-c]
Acknowledgements
This work was supported by National Natural Science Foundation of
China (NSFC 21472159, 21272197), Hong Kong Research Grants
Council General Research Fund (17306714, 17303815, 17301817),
and
Basic
Research
Program-Shenzhen
Fund
(JCYJ20170412140251576, JCYJ20150629151046879).
Keywords: arenes • biaryls • carbenoids • C-H bond • rhodium
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Entry for the Table of Contents
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Kai Wu, Bei Cao, Cong-Ying Zhou,* and
Chi-Ming Che*
Page No. – Page No.
Rh(II)-Catalyzed Intermolecular C-H
Arylation of Aromatics with Diazo
Quinones
Text for Table of Contents
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