Pd(0)-Catalyzed Intramolecular "ylide-Ullmann-Type" Cyclization of Carbonyl-Stabilized Phosphonium Ylides and Access to Phosphachromones by Exocyclic P-C Cleavage

Article abstract of DOI:10.1021/acs.orglett.9b03948

An unprecedented palladium-catalyzed intramolecular Ullmann-type cyclization of carbonyl-stabilized phosphonium ylides with aryl bromides was successfully developed. Furthermore, a base-promoted chemoselective hydrolysis of exocyclic P-C bond of the corresponding phosphonium salts delivered various phosphachromones. Excellent selectivity and high efficiency and good functional group tolerance were observed.

Full text of DOI:10.1021/acs.orglett.9b03948

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pd(0)-Catalyzed Intramolecular “Ylide-Ullmann-Type” Cyclization of
Carbonyl-Stabilized Phosphonium Ylides and Access to
Phosphachromones by Exocyclic P−C Cleavage
Shuangshuang Xu, Haiyang Huang,* Zeen Yan, and Qiang Xiao*
Key Laboratory of Organic Chemistry in Jiangxi Province, Institute of Organic Chemistry, Jiangxi Science & Technology Normal
University, Nanchang 330013, China
S
* Supporting Information
ABSTRACT: An unprecedented palladium-catalyzed intramolecular Ullmann-type cyclization of carbonyl-stabilized
phosphonium ylides with aryl bromides was successfully developed. Furthermore, a base-promoted chemoselective hydrolysis
of exocyclic P−C bond of the corresponding phosphonium salts delivered various phosphachromones. Excellent selectivity and
high efficiency and good functional group tolerance were observed.
7
he catalyzed Ullmann-type coupling reactions of aryl
bromides/iodides with alcohols/phenols are widely used
chloride,6 [Et3O]BF4 and MeOTf4c etc., to provide the
corresponding products 2 and 3, respectively (see Scheme 1b).
The reactions of carbonyl-stabilized phosphonium ylides
with highly reactive alkyl iodides/bromides to phosphoniums 2
have been widely reported.4−7 However, none of them
concerned reaction with unactivated aryl halidesthat is,
Ullmann-type reaction of phosphonium ylides as nucleophiles.
Therefore, it is of interest to develop a new catalytic
methodology that could efficiently couple carbonyl phospho-
nium ylides with unactivated aryl halides. In view of catalyzed
Ullmann-type O-arylations, we reasoned that using transition
metals as a catalyst might facilitate the nucleophilic reaction,
although our initial trials for the intermolecular cross couplings
of carbonyl-stabilized phosphonium ylides with aryl halides
failed to provide the desired product under various conditions
(see Table s1 in the Supporting Information). We then
continued to investigate the intramolecular variants, which
successfully furnished heterocyclic phosphonium salts 7
(Scheme 2). Moreover, several interesting phosphachromones
could be readily constructed via highly chemoselective
hydrolysis of exocyclic C−P bond of 7 under mild conditions.
Initially, phosphonium ylide 6a was chosen as a model
substrate to optimize the reaction conditions. A series of
palladium catalysts, such as Pd(Ph3P)4, (Ph3P)2PdCl2, PdCl2,
and Pd(OAc)2, etc. were first investigated. Control experi-
ments revealed that Pd(Ph3P)4 turned out to be a highly
effective catalyst for catalyzing the cyclization; however,
bivalent palladium had little effect (Table 1, entries 1−4).
Reaction solvents, temperatures, and time evaluation then
indicated that toluene as a solvent at 110 °C for 4 h was
optimal for giving the expected product (Table 1, entries 4−9).
T
to afford various aryl ethers.1 However, a strong nucleophilic
group (O−) seems essential for the success of reported O-
arylation reactions.2 Classical phosphonium ylides as mild
nucleophiles have been widely applied in modern Wittig
chemistry.3 Particularly, milder nucleophilic carbonyl-stabilized
phosphonium ylides 1, which have been proven to be a new
type of phosphonium ylide, have been investigated and applied
in very recent synthetic chemistry.4 (see Scheme 1a). It is
Scheme 1. Carbonyl-Stabilized Phosphonium Ylides as
Nucleophiles
important to note that this type of new ylide is an ambident
nucleophile,4c and there exists a tautomeric equilibrium.
Kinetically controlled γ-oxygen could act as a “hard” site,
and, in contrast, thermodynamically controlled α-carbon
became a “soft” site. Both α-carbon atom and γ-oxygen atom
could couple with electron-deficient centers, for instance,
benzhydrylium ions,4a,c alkyl iodides or bromides,5 acyl
Received: November 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03948
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Ullmann-Type Cyclization of Carbonyl
Phosphonium Ylides
Scheme 3. Substrate Scope for 1,4-Addition of Carbonyl
Phosphonium Ylides with Aryl Bromide
a
Table 1. Optimization of Pd-Catalyzed Cyclization Reaction
a
of Carbonyl-Stabilized Phosphonium Ylide
b
temperature
time
(h)
yield
(%)
entry
catalyst
solvent
(°C)
1
2
3
Pd(OAc)2 (8%)
PdCl2 (8%)
(Ph3P)2PdCl2
(8%)
toluene
toluene
toluene
120
120
120
12
12
12
trace
trace
trace
4
5
6
7
8
Pd(Ph3P)4 (8%)
Pd(Ph3P)4 (8%)
Pd(Ph3P)4 (8%)
Pd(Ph3P)4 (8%)
Pd(Ph3P)4 (8%)
Pd(Ph3P)4 (8%)
none
toluene
toluene
toluene
DMF
120
110
120
110
110
110
120
110
110
12
4
4
4
4
4
24
4
78
92
90
34
45
67
trace
87
a
Reaction conditions: phosphonium ylides 6a−6n, 6v−6ab, 6t, 6u (1
mmol) in toluene (5 mL) at 110 °C in an argon atmosphere for 4 h;
6o−6r, 6y (1 mmol) in toluene (5 mL) at 120 °C in an argon
atmosphere for 8 h.
THF
9
dioxane
toluene
toluene
toluene
10
11
12
for the reaction with good reactivity (7u−7aa). More
importantly, to demonstrate the practical synthetic utility of
this newly developed method, gram-scale reaction of 6i (2 g)
was performed under the identical conditions, and 1.85 g of 7i
was obtained in 92% yield without any erosion in the
efficiency. Unfortunately, the substrates cannot be extended
to bromo-ketones bearing an ortho-substituted group, such as
phenyl or alkyl group. The absolute structures of 7a, 7f, 7u,
and 7z were unambiguously confirmed by X-ray crystallog-
raphy (see the Supporting Information).
Pd(Ph3P)4 (3%)
Pd(Ph3P)4 (5%)
4
91
a
Unless otherwise noted, all reactions were performed using 1 mmol
of 6a, 5−8 mol % of catalyst, and 5 mL of solvent. Isolated yield of
7a.
b
Further investigation on the amount of the catalysts shows that
5 mol % seems to be the minimum amount required by
cyclization (Table 1, entries 10−12).
Under the optimized reaction conditions, the generality and
limitation of the intramolecular cyclization of carbonyl
phosphonium ylides was investigated, and the results are
illustrated in Scheme 3. Generally, all of the tested substrates
could react smoothly to deliver the desired cyclic products in
high efficiency and yields. Moreover, all the products can be
easily isolated by simple filtration without time and energy-
consuming chromatography purification manipulation. Several
alkyl carbonyl phosphonium ylides 6a−6c were first evaluated,
the cyclization proceeded smoothly, even with the large steric-
hindrance tertiary butyl group (7c). We then moved to aryl
carbonyl phosphonium ylides. It was found that both electron-
rich and electron-poor phenyl substitutes could be well-
tolerated (7d−7h). Furthermore, a series of halide atoms,
including F, Cl, and Br, were also compatible for the process.
Different positions on the phenyl ring were also tested and no
evident steric influence was noticed (7i−7n). Eventually,
several heteroaryl substitutions, such as furan, thiophene, and
benzothiophene were also examined, and the corresponding
six-members phosphoniums 7o−7s were obtained in good
yields. Note that the ferrocene group could also be tolerated
for the transformation (7t and 7x). Meanwhile, naphthalene
and acenaphthylene skeleton were also appropriate substrates
In light of the experimental results and previous reports,8 a
plausible reaction mechanism is proposed in Scheme 4. First,
oxidation addition of palladium(0) to the C−Br bond
generates Pd(II) intermediate A, and then intramolecular
ligand displacement of one of Ph3P ligands by the carbonyl
group gives rise to intermediate B. Subsequently, enolate
displaces bromide, resulting in palladacycle C. Finally,
Scheme 4. Proposed Mechanism
B
DOI: 10.1021/acs.orglett.9b03948
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Organic Letters
Letter
reductive elimination provided the heterocyclic phosphonium
salt 7, while regenerating active Pd(0) catalyst for the next
catalytic cycle. The cyclization reaction process follows the
To test our hypothesis, aqueous sodium hydroxide was
added to dichloromethane or toluene solution of phosphonium
7a at 0−25 °C. As expected, the experimental results showed
that the new signal of 8a arose and the signal of 7a faded away
within 5 min. Besides, the high chemoselectivity was also
clearly demonstrated by 31P NMR tracing of hydrolysis process
of 7a (Figure 1). Although a trace amount of product 9a of
1
traditional Ullmann-type reaction mechanism.[ ]
It is well-known that phosphonium salts not only constitute
one of the important functional materials that possess special
physicochemical properties,9 but also stand for the main
reactants of phosphoxides.10 Especially, heterocyclic phos-
phoxides are represented as important organic n-type materi-
al11 and pharmaceuticals,12 because of their unique optical,
electrochemical, and biological properties. Hydrolysis of
phosphoniums and phosphonium ylides is one of the most
direct synthetic approaches for phosphoxides by forming
intermediate of the trigonal bipyramidal (TBP) hydroxyte-
traorganophosphorane.13 Recently, the mechanism study of
TBP oxaphosphoranes has attracted special attention, includ-
ing the theoretical computation,14 observation of intermedi-
ates,15 and mechanisms of stereomutuation,16 etc. Until now,
the mechanism for hydrolysis process has been well-
established, which can be summarized by the following three
steps:
(a) nucleophilic attack of hydroxide to electron-deficient
phosphorus center to afford a P(V) intermediate
hydroxytetraorganophosphorane with apical oxygen;
(b) deprotonation by hydroxide to form an oxyanionic
phosphorane (berry pseudorotation (BPR)17 or turnstile
rotation18 may occur in this process); and
Figure 1. 31P NMR tracing of hydrolysis reaction of 7a with NaOH
aqueous at 0 °C in CH2Cl2.
internal P−C bond cleavage can be detected when the
hydrolysis reaction is performed at room temperature (see
Figure s1 in the Supporting Information), almost quantitative
exocyclic C−P bond cleavage is observed to give the expected
phosphachromone skeleton in a ice bath. The improved
selectivity of exocyclic P−C cleavage at lower temperature
proved that the hydrolysis reaction is a kinetically controlled
process. Further optimization of other inorganic and organic
bases, as well as solvents, did not generate better outcomes
(see Table s3 in the Supporting Information).
(c) cleavage of apical P−C bond and electron transfer
provide phosphine oxide product (see Scheme 5a).
Scheme 5. Hydrolysis of Phosphonium Salt
Under mild conditions, the first phosphachromone 8a was
obtained rapidly in excellent yield, which may possess extensive
potential biological activities, because of its similar skeleton to
chromones I (see Figure 2).22 However, compared with the
Because of weak aromaticity caused by the negative
hyperconjugation, ring opening via the hydrolysis reaction of
phophacycles seems easier.11a,15b,20d,e,19 Careful analysis of the
single crystals of 7a, 7f, 7u, and 7z (see the Supporting
Information) showed that the bond length of exocyclic P−C
bonds (1.78−1.80 Å) are longer than internal bonds (1.73−
1.77 Å), and, meanwhile, the internal angle (102°) is larger
than that of the corresponding phosphindolium species
(∼95°).15b,20 Besides, note that pentacoordinate phosphoric
intermediates can self-adjust the position of their substituents
with stronger electronegativity or longer bonds located at
apical sites and bigger bond angles at equatorial sites.16,21
Based on these features, we envisioned that intra-annular P−C
bonds are both self-adjusted to equatorial ligands by
stereomutation of pseudorotation of the trigonal bipyramid
intermediate; on the other hand, one of the phenyl groups
would locate on apical sites, which could act as the leaving
group (Scheme 5b). Thus, it is reasonable to speculate that
chemoselective cleavage of exocyclic P−C bond should be
realized under suitable conditions.
Figure 2. Skeletons of chromones (I), phosphachromones (II), and
phosphaisocoumarins (III).
many literature reports concerning synthetic and applied
research about cognate phosphaisocoumarins III,23 there is
limited synthetic protocols for phosphachromones II.24
Therefore, it is important to develop a general and practical
useful synthetic method toward the direct construction of
phosphachromone frameworks with high efficiency.
Consequently, we set out to investigate the scope of the
hydrolysis reaction using preceding heterocyclic phosphonium
salt products 7 as starting materials (Scheme 6). It is delight to
find that all of the heterocyclic phosphonium salts 7 proved to
be suitable substrates for hydrolysis in the presence of aqueous
sodium hydroxide, either using dichloromethane or toluene as
a solvent. High yields along with excellent chemoselectivity
were obtained under mild conditions to complete the
C
DOI: 10.1021/acs.orglett.9b03948
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Organic Letters
Letter
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Scheme 6. Substrate Scope for Hydrolysis Reaction of Six-
Member Phosphoniums
a
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: huanghaiyang1209@163.com (H. Huang).
*E-mail: xiaoqiang@tsinghua.org.cn (Q. Xiao).
ORCID
Qiang Xiao: 0000-0003-2812-7778
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (No. 21462019, 21676131), the Bureau
of Science & Technology of Jiangxi Province (No.
20143ACB20012), the Education Department of Jiangxi
Province (No. GJJ180625) and the PhD start-up funds of
Jiangxi Science & Technology Normal University (No.
2018BSQD025).
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1
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