Ruthenium-catalyzed coupling of α-carbonyl phosphoniums with sulfoxonium ylidesviaC-H activation/Wittig reaction sequences

Article abstract of DOI:10.1039/d1cc00433f

A Ru(ii)-catalyzed coupling of various α-carbonyl phosphoniums with sulfoxonium ylides has been realized for the facile synthesis of 1-naphthols in good to excellent yields. This oxidant-free transformation proceeds through Ru-catalyzed C-H activation of phosphoniums, Ru-carbene insertion, and intramolecular Wittig reaction processes.

Full text of DOI:10.1039/d1cc00433f

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Ruthenium-catalyzed coupling of a-carbonyl
phosphoniums with sulfoxonium ylides via C–H
activation/Wittig reaction sequences†
Cite this: Chem. Commun., 2021,
57, 2665
Received 25th January 2021,
Accepted 2nd February 2021
Tian Chen,a Zhiqiang Ding,a Yuqiu Guan,a Ruike Zhang,a Jinzhong Yao*b and
a
Zhangpei Chen
*
DOI: 10.1039/d1cc00433f
rsc.li/chemcomm
A Ru(II)-catalyzed coupling of various a-carbonyl phosphoniums catalyzed annulation of benzoylacetonitriles or N-(cyanoacetyl)indo-
with sulfoxonium ylides has been realized for the facile synthesis of lines with sulfoxonium ylides through sequential C–C bond forma-
1-naphthols in good to excellent yields. This oxidant-free transforma- tions (Scheme 1b); Fan8 disclosed the reaction of 2-arylindoles with
tion proceeds through Ru-catalyzed C–H activation of phosphoniums, sulfoxonium ylides via Rh(III)-catalyzed C–H activation/annula-
Ru-carbene insertion, and intramolecular Wittig reaction processes.
tion; Wang9 developed Rh(III)-catalyzed C–H functionalization
and annulation between enaminones and sulfoxonium ylides to
Transition-metal-catalyzed C–H activation/annulation reactions generate a series of multi-substituted naphthalenes. Although
have stood out as a highly efficient protocol endowing structu- progress has been achieved in this chemistry, the room for
rally diverse cyclic architectures from simple starting materials.1 further development of efficient strategies in the synthesis of
A variety of substrates with different directing groups (DGs) and carbocyclic compounds with a-carbonyl sulfoxonium ylides
coupling partners have been disclosed to explore new types of through consecutive C–C bonds formation is significant for
C–H activation/annulation reactions, which are significant in synthetic chemistry.
organic synthesis. a-Carbonyl sulfoxonium ylides are one such
On the other hand, 1-naphthols are highly desirable building
example and have received increasing attention due to their blocks and of great importance in the biological, agricultural,
unique reactivities and reaction patterns, which have been pesticides, and dyestuff industries.10 For example, 1-naphthol-
widely employed in synthetic chemistry in recent years.2 Since
the pioneering work of Li on the employment of a-carbonyl
sulfoxonium ylides as the C–H activation substrate in the Rh(III)-
catalyzed C–H activation/annulation with alkynes,3 many efforts
have been devoted to the exploration of different reaction
patterns of such compounds either as a C–H activation substrate
or as a coupling partner.4 As to C–H activation/annulation with
sulfoxonium ylides as the coupling partner, a number of elegant
studies have been reported involving C–C and C–Hetero bond
formations to generate heterocycles (Scheme 1a).5 In contrast,
only limited examples in terms of sequential C–C bond forma-
tions to generate carbocyclic compounds with sulfoxonium
ylides have been reported owing to the immanent difficulty of
constructing two distinct C–C bonds in a single step. For
example, Zhou6 and Li7 independently reported the Rh(III)-
a Center for Molecular Science and Engineering, College of Sciences, Northeastern
University, Shenyang 110819, P. R. China. E-mail: chenzhangpei@mail.neu.edu.cn
b College of Biological, Chemical Sciences and Engineering, Jiaxing University,
Jiaxing 314001, People’s Republic of China. E-mail: jzyao@zju.edu.cn
Scheme 1 Transition-metal-catalyzed C–H activation/annulation with
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
sulfoxonium ylides as the coupling partner.
d1cc00433f
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Table 1 Conditions optimization
containing compounds rubilactone and mollugin are potent
anti-HIV reagents,11 and korupensamine A12 is a promising
antimalarial. Besides, 1-naphthols could be conveniently trans-
formed into numerous useful compounds, such as VANOL,
which is a famous catalyst in organic chemistry.13 Consequently,
developing convenient methods to generate 1-naphthols has
attracted much attention.14 Among them, the C–H activation/
annulation strategy has drawn a special attention, because of
avoiding the additional operations for preparing high-activity
substrates. In this vein, a few examples have been developed and
in most cases alkynes were employed as the coupling partners,
including Rh(III),3,15 Pd(II)16 and Co(III)4g catalysts. In the case of
sulfoxonium ylides, the relatively expensive Rh(III)-catalyst was
needed to promote the corresponding C–H activation process
(Scheme 1b).6,9 Therefore, the exploration of practical and efficient
methods to generate 1-naphthols via C–H activation/annulation
enabled by less expensive catalysts is of great significance. More-
over, the Ru-catalyzed C–H activation/annulation reactions have
drawn increasing attention due to their low cost, high com-
patibility and selectivity compared to Rh(III)-catalysis.17 Thus,
considering that phosphonium ylides could be facilely generated
through the easily available phosphonium salts upon deprotona-
tion and they are compatible in the Rh(III)-catalyzed C–H function-
alization reactions,18 together with promoting the development of
Ru(II)-catalyzed C–H activation/annulation reactions, herein, we
report our findings toward the coupling of various phosphoniums
with sulfoxonium ylides to construct a series of structurally diverse
1-naphthols (Scheme 1c).
Our study began with the annulation between phenacyl
phosphonium salts (1a–d) and sulfoxonium ylides 2a to optimize
the reaction conditions (Table 1). As shown in entry 1 to entry 4,
the counterpart anions have a dramatic effect on the reactivity.
1a with a bromide anion failed to generate the desired
1-naphthol 3Àaa while phosphonium salts (1b–d) bearing OTfÀ,
BF4À, or PF4 anions could produce the product with good to
excellent yields in ethanol by employing [Ru(p-cymene)Cl2]2
(5 mol%) as the catalyst and NaOAc as the base. Next, an array
of solvents were investigated, including 1,2-dichloromethane
(DCE), dioxane, CH3CN, and toluene (entries 5–8), and the
initially used EtOH delivered the best result of 96% yield. Other
bases, such as K2CO3, K3PO4, and KOtBu failed to give a higher
yield (entries 9–11). Notably, the reactivity deteriorated in the
absence of any basic additives (entry 12), and the addition of silver
salt AgSbF6 had little effect on the reactivity (entry 13). Other Ru(II)
complexes, such as Ru(PPh3)3Cl2, failed to achieve a higher reac-
tivity. Further lowering the reaction temperature or reducing the
reaction time resulted in a slightly lower yield, thus, the optimized
reaction conditions were established as: [Ru(p-cymene)Cl2]2,
NaOAc, 120 1C, 10 h in EtOH.
Entrya
X
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Br
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
K2CO3
K3PO4
KOtBu
—
EtOH
EtOH
EtOH
EtOH
DCE
Dioxane
CH3CN
Toluene
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
o5
96
74
90
35
12
21
24
15
8
o5
o5
92
o5
OTf
BF4
PF6
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
9
10
11
12
13c
14d
NaOAc
NaOAc
a
Reaction conditions: 1a–d (0.1 mmol), 2a (0.15 mmol), [Ru(p-cymene)Cl2]2
(5 mol%), base (2.0 equiv.), solvent (1 mL), under a N2 atmosphere at 120 1C
b
c
for 10 h. Isolated yields after column chromatography. AgSbF6
(20 mol%). Ru(PPh3)3Cl2 (5 mol%) instead of [Ru(p-cymene)Cl2]2.
d
a substrate with less steric hindrance could afford the product
with a higher yield (3ca vs. 3da). The electronic properties of
substituted groups in the phenyl group at the para-position of
phosphonium salts had a little effect on the activities and
substrates bearing electron-donating groups showed slightly
higher reactivities (3ca vs. 3fa–3la). Moreover, the substrates
with di-substituents on the phenyl group were also viable,
providing 3ea and 3la with 92% and 54% yields, respectively.
With the optimal conditions in hand, we then explored the
scope of phosphonium salts 1 in coupling with 2a and the
results are summarized in Scheme 2. Generally, a variety of
phosphoniums were smoothly converted into the corres-
ponding 1-naphthols 3 in 54–96% yields. Various functional
groups, including methoxyl, halogen, trifluoromethyl, and
cyano-groups, are tolerated in this reaction. It was noted that
Scheme 2 Scope of phosphonium salts. Reaction conditions: 1 (0.1 mmol),
2a (0.15 mmol), [Ru(p-cymene)Cl2]2 (5 mol%), NaOAc (2.0 equiv.), EtOH
(1 mL), under a N2 atmosphere at 120 1C for 10 h.
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Subsequently, the generality of a-carbonyl sulfoxoniums was
investigated (Scheme 3). The scope of sulfoxonium ylides, including
electron-donating groups (3ab–ad), electron-withdrawing substi-
tuents (3ae), and halides (3af–aj), proved to be broad, and all of
the corresponding 1-naphthols were isolated in 51–94% yields.
Substrates bearing electron-donating groups (3ad vs. 3ae) and
less sterically hindered groups (3ah vs. 3aj) contributed to the
formation of products. In addition, the scope of sulfoxonium
ylides also worked well when the alkyl-substituted sulfoxonium
ylide (3ak) was introduced. Heterocyclic ring systems, such as
furan (3al), thiophene (3am) and polycyclic rings (3an–ao), were
also tolerated in this transformation, affording the desired
products in good yields.
Finally, to further estimate the application possibility of this
strategy, a larger-scale synthesis of 1-naphthol 3aa was conducted,
and a good yield of 91% was obtained on a 2 mmol scale reaction
(Scheme 4a). Moreover, 3aa could be easily transformed into
triflates 4, which then underwent Migita–Kosugi–Stille coupling with
phenyltributyltin and further generated the 1,3-diphenylnaphthalene
5 product in 78% overall yield (Scheme 4b).
Scheme 4 Larger-scale synthesis and derivatization of 3aa.
in the presence of the Ru(II) catalyst, suggesting the ortho C–H
activation. When 2a was introduced, the H/D exchange was
observed at three positions (I–III) of product 3aa; the deuteration
of position I was attributed to the acidity of the methylene proton
of 1b; deuteration of position II further verified the ortho C–H
activation; deuteration of position III suggested that keto–enol
tautomerism existed in the annulation process. Finally, a preli-
minary kinetic isotope effect study revealed a kH/kD value of 2.1 at
100 1C, indicating that the C–H bond cleavage may be involved in
the rate-determining step.
On the basis of these mechanistic studies and literature
reports,5,18 a plausible catalytic cycle was proposed to depict the
synthesis of 1-naphthols (Scheme 6).
To gain insight into the mechanism of this chemistry,
several experiments have been conducted and depicted in
Scheme 5. First, deuterium experiments were performed in
ethanol-d6 with 10 equivalent of D2O (Scheme 5A). The methylene
proton of 1b was acidic and was fully deuterated under these
conditions, and the ortho CH of phenyl was deuterated (495% D)
First, anion exchange may occur between [Ru( p-cymene)Cl2]2
and NaOAc or OTfÀ, generating an active cationic Ru(II) species.
Then, cyclometalation of 1b afforded a chelating Ru(II) inter-
mediate 6, which was supposed to undergo insertion of an
incoming sulfoxonium ylide 2a to afford a five-membered
metallacyclic species 7 and release a molecule of the dimethyl
sulfoxide (DMSO) co-product. Migratory insertion of the
Ru-carbene produced 6-membered metallacyclic species 8. Pro-
tonolysis of the Ru–alkyl bond regenerates the active catalyst to
deliver 9, which was followed by a base promoted intra-
molecular Wittig reaction, furnishing the desired product 3aa
and generating OPPh3. In addition, it should be mentioned that
other possible pathways could not be excluded at this stage.19
To sum up, we have developed an efficient method for the
construction of various 1-naphthols via Ru(II)-catalyzed a-carbonyl
phosphoniums coupling with sulfoxonium ylides. This oxidant-free
Scheme 3 Scope of sulfoxonium ylides. Reaction conditions: 1b (0.1 mmol),
2 (0.15 mmol), [Ru(p-cymene)Cl2]2 (5 mol%), NaOAc (2.0 equiv.), EtOH (1 mL),
under a N2 atmosphere at 120 1C for 10 h.
Scheme 5 Mechanistic studies.
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Scheme 6 Proposed catalytic cycle.
and silver-free transformation occurred through C–H activation,
Ru-carbene insertion, and base promoted Wittig reaction pro-
cesses. This method employed cost-effective [Ru(p-cymene)Cl2]2
as the catalyst, and utilized the easily available phosphonium salts
as the starting material. A broad substrate scope with respect to
both coupling components worked efficiently with up to 96% yield.
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (21702026),
Fundamental Research Funds for the Central Universities
(N2005004 and N180705004), and the Baiqing project of Jiaxing
University (CD70619010).
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Conflicts of interest
There are no conflicts to declare.
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