Divergent Access to 1-Naphthols and Isocoumarins via Rh(III)-Catalyzed C-H Activation Assisted by Phosphonium Ylide

Article abstract of DOI:10.1021/acs.orglett.7b01365

Rh-catalyzed C-H activation of phenacyl phosphoniums in coupling with α-diazocarbonyl compounds has been realized with the assistance of a mutifunctional phosphonium ylidic directing group, providing expedient accesses to 1-naphthols and isocoumarins. Switchable synthesis of 1-naphthols and isocoumarins was realized by substrate control, where these transformations were enabled by initial C-H activation and subsequent intramolecular Wittig reaction or nucleophilic C-O formation.

Full text of DOI:10.1021/acs.orglett.7b01365

Letter
pubs.acs.org/OrgLett
Divergent Access to 1‑Naphthols and Isocoumarins via Rh(III)-
Catalyzed C−H Activation Assisted by Phosphonium Ylide
Yunyun Li,†,‡ Qiang Wang,†,‡ Xifa Yang,†,‡ Fang Xie,† and Xingwei Li*,†
†Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: Rh-catalyzed C−H activation of phenacyl phosphoniums
in coupling with α-diazocarbonyl compounds has been realized with the
assistance of a mutifunctional phosphonium ylidic directing group,
providing expedient accesses to 1-naphthols and isocoumarins. Switchable
synthesis of 1-naphthols and isocoumarins was realized by substrate
control, where these transformations were enabled by initial C−H
activation and subsequent intramolecular Wittig reaction or nucleophilic
C−O formation.
Scheme 1. Transition-Metal-Catalyzed Synthesis of 1-
Naphthols
1-Naphthol scaffolds are an important motif for synthetic
building blocks in natural product synthesis owing to their
ubiquity in numerous biologically relevant compounds that
display a broad spectrum of medicinal properties, such as
antiviral activity1 and antitumor and antibacterial activity,2
among others.3 As a result, numerous routes have been
developed for 1-naphthol synthesis.4 However, these methods
typically suffered from drawbacks, such as harsh reaction
conditions,4b,g employment of highly functionalized starting
materials,4c multiple synthetic steps,4d,f,h and lack of substrate
generality.4i Therefore, more efficient access to 1-naphthol
using simple and easily available starting materials is highly
desirable.
Recently, transition-metal-catalyzed C−H bond functionali-
zation of arenes has been established as an increasingly
important strategy for the construction of complex organic
functional molecules.5 This area further thrived with the high
activity, selectivity, compatibility, and versatility of Cp*Rh(III)
catalysts.6 However, limited systems have been developed to
access 1-naphthols via a C−H bond activation pathway
(Scheme 1). In 2013, Wang and co-workers reported naphthol
synthesis via palladium-catalyzed oxidative annulation of
benzoylacetates with unactivated internal alkynes.7 (Scheme
1a). Zhu’s group recently reported a rhodium-catalyzed
oxidative synthesis of highly functionalized 1-naphthols from
enaminones and alkynes (Scheme 1b).8 Our group recently
reported a redox-neutral coupling of nitrones with cyclo-
propenones to furnish 1-naphthols, where the nitrone acted as
an electrophilic and traceless directing group (DG, Scheme
1c).9 These methods are still limited either to oxidative
conditions or the use of preactivated, less readily available
substrates. To address this limitation and in light of our
previous research on Rh-catalyzed C−H activation of phenacyl
ammoniums,10 we designed simple and easily available
phenacyl phosphonium salts as arenes (Scheme 1d). We
reasoned that a phosphonium ylide DG should be readily
generated from this phosphonium salt upon deprotonation.
Furthermore, the methylene is nucleophilic, but both the
carbonyl and the phosphonium are electrophilic. Ideally, all of
the functional groups of this DG can be utilized to deliver
molecular diversity. Herein, we report diverse C−H activation
of phenacyl phosphoniums, which allowed divergent synthesis
of 1-naphthols and isocoumarins via a C−H activation pathway
with intramolecular Wittig reaction and nucleophilic cycliza-
tion, respectively.
We initiated our studies by examining the reaction
parameters of the coupling of phenacyl phosphonium salt 1
Received: May 7, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01365
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Letter
a
with ethyl α-diazoacetoacetate 2a (Table 1). Several transition-
metal catalysts were initially screened (entries 1−3), among
Scheme 2. Substrate Scope of Phenacyl Phosphoniums
a
Table 1. Optimization Studies
b
entry
X
catalyst (mol %)
[IrCp*Cl2]2 (4)
[Ru(p-cymene)Cl2]2 (4)
[RhCp*Cl2]2 (4)
[RhCp*Cl2]2 (4)
[RhCp*Cl2]2 (4)
[RhCp*Cl2]2 (4)/AgSbF6 (20)
[RhCp*(MeCN)3](SbF6)2 (8)
[RhCp*Cl2]2 (4) /AgSbF6 (20)
[RhCp*Cl2]2 (4) /AgSbF6 (20)
[RhCp*Cl2]2 (4) /AgSbF6 (20)
[RhCp*Cl2]2 (4) /AgSbF6 (20)
solvent
yield (%)
1
OTf
OTf
OTf
OTf
OTf
OTf
OTf
Br
MeCN
MeCN
MeCN
EtOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
<10
<10
11
2
3
4
58
5
55
6
77
7
79
21
8
9
SbF6
BF4
PF6
70
10
11
66
a
64
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), [RhCp*-
a
(MeCN)3](SbF6)2 (8 mol %), CsOAc (2.0 equiv) in ethanol (2 mL)
at 100 °C for 18 h. 120 °C.
Reaction conditions: 1 (0.2 mmol), 2a (0.24 mmol), catalyst, and
b
b
base (2.0 equiv) in a solvent (2 mL) at 100 °C for 18 h. Yields of
isolated products.
a
Scheme 3. Substrate Scope of Diazocarbonyl Compounds
which rhodium catalyst exhibited highest reactivity, and the
expected 1-naphthol was generated likely via a C−H
alkylation11−intramolecular Wittig reaction.12 Ethanol was
identified as the optimal solvent, and introduction of AgSbF6
further improved the reaction efficiency (entry 6). The yield
was reduced when other common anions were used (entries 8−
11). Raising or lowering the reaction temperature all resulted in
a slightly lower yield, and CsOAc proved to be the optimal
base. Thus, the conditions in entry 7 were retained for
subsequent studies, under which a Ph3PO coproduct was also
obtained (87% GC yield). We noted that Rh(III)-catalyzed C−
H activation and annulation of substituted acetophenones have
been reported, but the scope and patterns were limited.13
With the optimal conditions in hand, we then explored the
scope of phenacyl phosphonium salts in the coupling with 2a
(Scheme 2). Phenacyl phosphonium salts bearing various
electron-donating, -withdrawing, and halogen groups at the
para position of the benzene ring all reacted smoothly with 2a
to furnish the corresponding naphthol products in 45−86%
yields (3aa−ha). This carbocyclization also occurred smoothly
when various meta substituents were added (3ia−ka, 43−76%),
and the major regioisomeric product corresponds to C−H
activation at the more hindered ortho position for meta
substituents with a lone pair. In fact, this trend was maximized
for a meta F-substituted substrate (3ja). Moreover, introduction
of ortho OMe and F groups is also tolerated, indicative of
tolerance of steric hindrance. Notably, disubstituted phospho-
nium salts were also viable, affording products in good yields
(3na−oa, 50−70%). The arene ring was not limited to
benzene, and a thiophene-based phosphonium also underwent
smooth coupling (3qa, 120 °C).
a
Reaction conditions: 1a (0.2 mmol), 2 (0.24 mmol), [RhCp*-
(MeCN)3](SbF6)2 (8 mol %), CsOAc (2.0 equiv) in ethanol (2 mL)
at 100 °C for 18 h. With HOAc (2.0 equiv).
b
diketones generally exhibited high chemoselectivity in terms
of the cyclization process (3ai and 3ak). In addition, changing
the diazocarbonyl compounds to those embedded in five- and
seven-membered cyclic β-diketones only attenuated the yields
(3ao and 3ap).
A strinkingly different reaction pattern was observed when
we applied 2-diazocyclohexane-1,3-dione as a coupling partner
(Scheme 4). This reaction delivered an isocoumarin (5aa) in
good yield as a result of C−C bond cleavage.14 In this system,
the stereoelectronic effects (ring size) of the diazocarbonyl
compounds and the electrophilicity of the carbonyl15
contributed to the observed C−O bond formation. The
scope of this coupling system was briefly examined, and all of
the products (5aa−ea and 5ab) were isolated in moderate to
good yields.
The generality of diazocarbonyl substrates was subsequently
investigated. As shown in Scheme 3, the scope of acyclic α-
diazocarbonyls, including α-diazo ketoesters (3ab−af), dike-
tones (3ag−ak), and even diesters (3al−an), proved to be
broad, and all of the corresponding naphthols were isolated in
moderate to high yields. Of note, the coupling of diazocarbonyl
compounds derived from unsymmetrically substituted β-
B
DOI: 10.1021/acs.orglett.7b01365
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a
Scheme 4. Synthesis of Isocoumarins
Scheme 6. Mechanistic Studies
a
Reaction conditions: 1 (0.2 mmol), diazocarbonyl compounds (0.24
mmol), [RhCp*(MeCN)3](SbF6)2 (8 mol %), and CsOAc (2.0 equiv)
in EtOH (2 mL) at 120 °C for 18 h.
Synthetic applications of this protocol have been demon-
strated (Scheme 5). Naphthol 3aa was synthesized in 66% yield
Scheme 5. Gram-Scale Synthesis and Derivatization
Reactions of a Naphthol
performed for this purpose using acetone (Scheme 6d), but still
no olefin or derivative was detected. This result suggests that
initial Wittig olefination seems less likely. Further control
experiments revealed that the corresponding phosphonium
ylide of 1a exhibited comparable activity (69%) in the absence
of any base (Scheme 6e).
On the basis of our mechanistic studies and literature reports,
a plausible catalytic cycle was extracted to depict the synthesis
of 1-naphthols (Scheme 7). O- or C-coordination (shown for
Scheme 7. Proposed Mechanism for the Formation of 1-
Naphthols
on a gram scale even under reduced catalyst loading (Scheme
5a). Derivatization of naphthol 3aa proceeded smoothly in
several peri C−H activation systems. Thus, oxidative coupling
of 3aa with diphenylacetylene16 delivered heterocycle 6, which
has found applications in solid-state fluorescence. Interestingly,
solvent-dependent oxidative olefination17 of 3aa was attained
(Scheme 5b). In MeOH, a trans-olefin 7 was generated. In
contrast, a trisubstituted exocylic (E)-olefin 8 was produced in
cyclohexane via 2-fold oxidation.
A series of experiments have been conducted to elucidate the
mechanism (Scheme 6). H/D exchange experiments were first
performed for 1a in ethanol-d6. The methylene proton was
acidic and was fully deuterated even in the absence of any
catalyst or 2a, but the ortho CH was deuterated (83% D) only
in the presence of a Rh(III) catalyst and the base (Scheme 6a).
In the presence of 2a, H/D exchange was observed at both the
2- and 8-position of product 3aa, suggesting reversibility of
ortho C−H activation. The C−H activation is likely turnover-
limiting as evidenced by a rather large value of kH/kD = 4.0
measured from parallel reactions (Scheme 6b). Reactions
conducted in the presence of H218O or CH3C18O2Na produced
OPPh3 with essentially no 18O incorporation (Scheme 6c),
which is consistent with an intramoelcular Wittig reaction. We
attempted but failed to prepare the diazo-attached olefin species
from 1a and 2a in order to probe the sequence of C−H
activation and Wittig reaction. A control experiment was then
O-coordination only) of the ylidic form of 1a and subsequent
cyclometalation affords a rhodacyclic intermediate A.18
Coordination of a diazocarbonyl substrate to A is followed by
denitrogenation to generate a carbene species B, the Rh−aryl
bond of which would undergo migratory insertion into the
carbene to furnish a six-membered rhodacyclic intermediate C.
Intermediate D was then formed via protonolysis of the Rh−
alkyl bond in C. Ligand dissociation affords intermediate E with
the regeneration of the active catalyst. The final annulated
product 3 is produced upon intramolecular Wittig reaction
together with formation of OPPh3.
In summary, we have realized diversified C−H activation of
phenacyl phosphoniums assisted by a multifunctional ylidic
directing group. Two reaction patterns were realized in the
coupling with α-diazocarbonyls. In most cases, naphthols were
C
DOI: 10.1021/acs.orglett.7b01365
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01365.
General experimental procedures, characterization de-
tails, and 1H, 13C, and 19F NMR spectra of new
compounds (PDF)
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Chem., Int. Ed. 2016, 55, 9384.
AUTHOR INFORMATION
■
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Corresponding Author
*E-mail: xwli@dicp.ac.cn.
ORCID
Xingwei Li: 0000-0002-1153-1558
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The NSFC (Nos. 21525208 and 21472186) and the Dalian
Institute of Chemical Physics, Chinese Academy of Sciences,
are gratefully acknowledged for financial support. This work
was also supported by the Strategic Priority Research Program
of the Chinese Academy of Sciences (XDB17020300).
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