Rhodium(III)-Catalyzed Synthesis of Naphthols via C-H Activation of Sulfoxonium Ylides

Article abstract of DOI:10.1021/acs.orglett.7b01974

Direct and efficient synthesis of 1-naphthols has been realized via Rh(III)-catalyzed C-H activation of sulfoxonium ylides and subsequent annulation with alkynes, where the sulfoxonium ylide functioned as a new traceless bifunctional directing group. This reaction occurred under redox-neutral conditions with a broad substrate scope.

Full text of DOI:10.1021/acs.orglett.7b01974

Letter
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Synthesis of Naphthols via C−H Activation of
Sulfoxonium Ylides
Youwei Xu,†,‡ Xifa Yang,†,‡ Xukai Zhou,†,‡ Lingheng Kong,†,‡ 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: Direct and efficient synthesis of 1-naphthols has
been realized via Rh(III)-catalyzed C−H activation of
sulfoxonium ylides and subsequent annulation with alkynes,
where the sulfoxonium ylide functioned as a new traceless
bifunctional directing group. This reaction occurred under
redox-neutral conditions with a broad substrate scope.
aphthols are among the most versatile organics in organic
synthesis,1 and they are ubiquitously embedded in a large
Scheme 1. Rh-Catalyzed 1-Naphthol Synthesis
N
number of natural products and pharmaceuticals such as
korupensamine A,2 mollugin,3 and gossypol (Figure 1).4 As a
Figure 1. Bioactive compounds containing a 1-naphthol moiety.
consequence, general methods for the synthesis of such
molecules have long been regarded as an important objective
in synthetic organic chemistry.5 Despite the well-established
methodologies, it is attractive to employ the C−H activation
strategy for straightforward and atom-economic access to
naphthols.
Transition metals, especially Cp*Rh(III) complexes, represent
state-of-the-art catalysts for activation of inert C−H bonds6 en
route to eventual annulation and construction of heterocycles7
and carbocycles.8 However, approaches to synthesize naphthols
via C−H activation are still limited. Wang and co-workers
reported Rh(III)-catalyzed oxidative annulation of ortho-
substituted benzoylacetonitrile with alkynes for 1-naphthol
synthesis (Scheme 1).9 Zhu’s group applied enaminones as an
effective arene in the coupling with alkynes to access 2-
formylnaphthol derivatives under oxidative conditions.10 Despite
these important advances, both reaction systems are limited to
the employment of stoichiometric metal oxidants. Very recently,
our group has described redox-neutral coupling of nitrones with
cyclopropenones under redox-neutral Rh(III) catalysis for
efficient construction of 2,3-substituted 1-naphthols.11 However,
access to cyclopropenones is not trivial. Thereafter, we achieved
redox-neutral annulation of phosphonium ylides with reactive
diazo compounds.12 To overcome these limitations and to realize
the construction of naphthols in an economic and green fashion,
development of efficient methods using readily available starting
materials is of great significance. Our strategy is to employ a
carbene synthon for the arene. We now report Rh(III)-catalyzed
C−H activation of sulfoxonium ylides13 and annulation with
simple alkynes as a practical and general method for the synthesis
of 3,4-substituted 1-naphthols.
We initiated our studies by exploring the coupling of ylide 1a
with diphenylacetylene 2a in the presence of [Cp*RhCl2]2 and
AgSbF6 (Table 1). The coupling in DCE at 100 °C afforded the
desired product 3aa in 62% yield (entry 1). With CsOAc or
HOPiv being an additive, the yields of 3aa decreased dramatically
Received: June 28, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01974
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions.
b
entry
catalyst (mol %)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*RhCl2]2 (4)
[Cp*Rh(MeCN)3](SbF6)2 (8)
[Cp*Rh(MeCN)3](SbF6)2 (8)
[Cp*Rh(MeCN)3](SbF6)2 (6)
[Cp*Rh(MeCN)3](SbF6)2 (4)
additive (mol %)
AgSbF6 (16)
solvent
t (°C)
yield (%)
1
2
DCE
DCE
DCE
DCE
DCE
DCM
DCE
DCE
DCE
DCE
DCE
DCE
DCE
100
100
100
100
80
62
15
37
56
75
68
85
92
60
94
89
AgSbF6 (16)/CsOAc (200)
AgSbF6 (16)/HOPiv (200)
AgNTf2 (16)
3
4
5
AgSbF6 (16)
6
AgSbF6 (16)
80
7
AgSbF6 (16)/Zn(OAc)2 (10)
Zn(OAc)2 (10)
80
8
80
9
Cu(OAc)2 (10)
80
10
11
12
13
Zn(OAc)2 (10)
80
Zn(OAc)2 (10)
80
c
Zn(OAc)2 (10)
80
NR
[Cp*RhCl2]2 (4)
Zn(OAc)2 (10)
80
58
a
b
Reaction conditions: 1a (0.2 mmol), 2a (0.22 mmol), catalysis, additives, in solvent (4 mL), sealed tube under N2 for 16 h. Yield of isolated
c
product. No reaction.
ab
,
(entries 2 and 3). A lower yield was delivered when AgNTf2 was
used as a halide scavenger (entry 4). Lowering the reaction
temperature to 80 °C afforded 3aa in 75% yield (entry 5). Then
the effect of the solvent was examined, and DCE gave the best
yield. Introduction of Zn(OAc)2 (10 mol %) as an additive
increased the yield to 85% (entry 7), which likely facilitates C−H
activation and activates the sulfoxonium ylide. Delightfully,
switching the catalyst to [Cp*Rh(MeCN)3](SbF6)2/Zn(OAc)2
afforded 3aa in 92% yield (entry 8), whereas a similar yield was
still obtainable when the catalyst loading was lowered to 6 mol %
(entries 10 and 11). A control experiment revealed that no
reaction occurred in the absence of a rhodium catalyst (entry 12).
Scheme 2. Scope of Sulfoxonium Ylide
−
Moreover, SbF6 proved to be an optimal counterion in this
system (entry 13).
With the optimal reaction conditions in hand, we next sought
to evaluate the scope and generality of the sulfoxonium ylides in
this catalytic system. As given in Scheme 2, a wide range of
sulfoxonium ylides underwent smooth annulation under the
optimal conditions. Ylides with electron-donating and -with-
drawing substituents (including alkyl, halides, nitro and
trifluoromethyl substituents) at the 4-position all reacted with
excellent efficiencies (37−95%). The coupling occurred at the
less hindered ortho site for m-methyl and -bromo-substituted
arenes (3ka and 3la). In addition, the reaction has been extended
to o-substituted sulfoxonium ylides (3ma, 3na, and 3oa),
indicating tolerance of steric hindrance. Furthermore, a
thiophene ring also coupled, albeit in lower yield.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.22 mmol), [Cp*Rh-
(MeCN)3](SbF6)2 (6 mol %) and Zn(OAc)2 (10 mol %) in DCE (4
mL) at 80 °C for 16 h under a N2 atmosphere. Isolated yields.
b
The scope of alkynes was next examined (Scheme 3).
Symmetric diarylacetylenes bearing various electron-donating
and -withdrawing substituents such as methyl, methoxy, halogen,
and trifluoromethyl groups at the 4-position all coupled
smoothly with 1a in excellent yields (3ab−3ag). This reaction
is also compatible with meta-fluoro- or meta-methyl-substituted
diarylacetylene, from which products 3ah and 3ai were isolated
in 91 and 96% yields, respectively. Notably, 1,2-bis(2-
fluorophenyl)ethyne gave an excellent yield (3aj, 99%). The
alkynes can also be extended to heteroaryl substitution, including
1,2-di(thiophen-2-yl)ethyne in good yield (3ak). In addition,
unsymmetric alkyl−aryl alkynes were also applicable, mostly with
good to excellent regioselectivity (3al−3aq). Unfortunately,
alkyl−alkyl alkyne failed to undergo any desired reaction.
To demonstrate synthetic utility of the reaction, a gram-scale
reaction between 1a and 2a has been performed (Scheme 4), and
the product 3aa was isolated in an excellent yield (Scheme 4a).
Moreover, naphthol 3aa was readily converted to the
corresponding triflate 4a in 94% yield, which proved to be a
useful building block in transition-metal-catalyzed cross-
couplings. Thus, both the alkynyl (5a) and alkenyl (5b) groups
could be efficiently installed into the naphthyl motif in excellent
yields via Sonogashira and Heck reactions, respectively (Scheme
4b).
B
DOI: 10.1021/acs.orglett.7b01974
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ab
,
Scheme 3. Scope of Alkynes
Scheme 5. Mechanistic Studies
On the basis of the preliminary mechanistic studies and
previous literature reports on related systems,8e,10,14 a plausible
catalytic cycle for the annulation of 1a and 2a is proposed in
Scheme 6. First, oxygen coordination of 1a is followed by
a
Reaction conditions: 1a (0.2 mmol), alkyne (0.22 mmol), [Cp*Rh-
(MeCN)3](SbF6)2 (6 mol %) and Zn(OAc)2 (10 mol %) in DCE (4
mL) at 80 °C for 16 h under N2. Isolated yields. Only the major
isomer was shown.
b
c
Scheme 6. Proposed Reaction Mechanism
Scheme 4. Gram-Scale Synthesis and Synthetic Applications
Having established the substrate scope and utility of the
product, we next conducted preliminary mechanistic studies.
Several H/D exchange experiments have been carried out
(Scheme 5). Essentially no deuterium incorporation occurred at
the 2-position of the phenyl ring or the α-position of carbonyl
when 1a was allowed to undergo exchange with CD3OD in the
absence of a Rh(III) catalyst. In contrast, both the ortho-CH and
the methine proton underwent slight H/D exchange in the
presence of the Rh(III) catalyst, indicating the reversibility of the
C(aryl)−H bond cleavage. The observed deuterium incorpo-
ration at the methine position may also suggest cyclometalation
and reversible protonation due to the enhanced basicity at this
position. To further probe the C−H activation process, kinetic
isotope effect was measured, and a small value of kinetic isotope
effect (kH/kD = 1.3) obtained from parallel reactions suggests
that C−H bond cleavage is likely not involved in the turnover-
limiting step.
cyclometalation to deliver a five-membered rhodacyclic inter-
mediate. Subsequent coordination of alkyne 2a gives an alkyne
species A, which then undergoes migratory insertion of the aryl
group into alkyne to afford a seven-membered intermediate B.
O-bound to C-bound tautomerization produces an intermediate
C. The intermediate C undergoes α-elimination8e of DMSO to
afford an α-oxo carbenoid species D. The Rh−alkenyl bond
should readily insert into the resultant carbenoid to produce a
Rh(III) alkyl species E. Protonolysis of the Rh−C bond by HX
releases the final product with the regeneration of the active
catalyst.
In summary, we have developed an efficient Rh(III)-catalyzed
annulation of sulfoxonium ylides with alkynes, leading to the
C
DOI: 10.1021/acs.orglett.7b01974
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Organic Letters
Letter
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concise synthesis of 1-naphthols via a C−H activation pathway.
This catalytic system features mild conditions and a wide range of
both ylides and internal alkynes. This new process may add to the
growing arsenal of methods for carboannulation reactions, with
particular application to the increasing demand for the synthesis
of highly functionalized naphthol motifs.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01974.
Detailed experimental procedures, characterization of new
compounds, and copies of NMR spectra (PDF)
(9) Tan, X.; Liu, B.; Li, X.; Li, B.; Xu, S.; Song, H.; Wang, B. J. Am.
Chem. Soc. 2012, 134, 16163.
(10) Zhou, S.; Wang, J.; Wang, L.; Song, C.; Chen, K.; Zhu, J. Angew.
Chem., Int. Ed. 2016, 55, 9384.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xwli@dicp.ac.cn.
ORCID
(11) Xie, F.; Yu, S.; Qi, Z.; Li, X. Angew. Chem., Int. Ed. 2016, 55, 15351.
(12) Li, Y.; Wang, Q.; Yang, X.; Xie, F.; Li, X. Org. Lett. 2017, 19, 3410.
(13) For application of sulfoxonium ylides to organic synthesis, see:
(a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(b) Wang, D.; Schwinden, M. D.; Radesca, L.; Patel, B.; Kronenthal, D.;
Huang, M. H.; Nugent, W. A. J. Org. Chem. 2004, 69, 1629. (c) Dias, R.
M. P.; Burtoloso, A. C. B. Org. Lett. 2016, 18, 3034. (d) Phelps, A. M.;
Chan, V. S.; Napolitano, J. G.; Krabbe, S. W.; Schomaker, J. M.; Shekhar,
S. J. Org. Chem. 2016, 81, 4158. (e) Vaitla, J.; Bayer, A.; Hopmann, K. H.
Angew. Chem., Int. Ed. 2017, 56, 4277.
Xingwei Li: 0000-0002-1153-1558
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NSFC (Nos. 21525208 and
21472186) and the fund for new technology of methanol
conversion of Dalian Institute of Chemical Physics (Chinese
Academy of Sciences) are gratefully acknowledged.
(14) (a) Wang, F.; Jin, L.; Kong, L.; Li, X. Org. Lett. 2017, 19, 1812.
(b) Zeng, X.-P.; Cao, Z.-Y.; Wang, X.; Chen, L.; Zhou, F.; Zhu, F.; Wang,
C.-H.; Zhou, J. J. Am. Chem. Soc. 2016, 138, 416.
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DOI: 10.1021/acs.orglett.7b01974
Org. Lett. XXXX, XXX, XXX−XXX