Palladium-Catalyzed Ylidyl-Carbonylation of Aryl Halides to Produce α-Acylphosphoranes

Article abstract of DOI:10.1021/acs.orglett.6b02278

An efficient synthesis of α-acylphosphoranes by palladium-catalyzed carbonylation of aryl iodides with carbon monoxide and stabilized phosphonium ylides has been developed. Featuring 44 examples, the protocol displayed a wide substrate scope under mild reaction conditions, showcasing its potential in synthetic organic chemistry.

Full text of DOI:10.1021/acs.orglett.6b02278

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Ylidyl-Carbonylation of Aryl Halides To Produce
α‑Acylphosphoranes
Xiaojun Guo,† Wei Ma,† Dong Xue,*,† Chao Wang,† and Jianliang Xiao*,†,‡
†Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering,
Shaanxi Normal University, Xi’an, 710062, China
‡Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, United Kingdom
S
* Supporting Information
ABSTRACT: An efficient synthesis of α-acylphosphoranes by
palladium-catalyzed carbonylation of aryl iodides with carbon
monoxide and stabilized phosphonium ylides has been
developed. Featuring 44 examples, the protocol displayed a
wide substrate scope under mild reaction conditions, showcasing its potential in synthetic organic chemistry.
α-Acylphosphoranes have attracted considerable attention in
organic synthesis due to their participation in the synthesis of
the Shell Higher Olefin Process (SHOP)-type catalysts,1
carboxylic acids,2 terminal alkynes,3 acetylenic esters,4 vicinal
tricarbonyl compounds,5 2,3-diketo esters,6 halogenated enol
lactones,7 cyclization compounds,8 and heterocycles.9 In
particular, α-acylphosphoranes act as a key intermediate in
the synthesis of GS-493,6b one of the most powerful selective
inhibitors of the protein tyrosine phosphatase SHP2. These
examples highlight the importance of α-acylphosphoranes in
organic synthesis. Traditionally, α-acylphosphoranes have been
synthesized by acylation reaction of carboxylic acid chlorides
with stabilized phosphonium ylides (Scheme 1, a)3a,9b,10 or
compounds. In particular, it has been used for the selective
synthesis of a wide range of aromatic acyl derivatives (Scheme
1, b),14 such as carboxylic acids,15 esters,16 amides,17
anhydrides,18a aldehydes,19 ketones,20 and heterocycles.21
Despite the considerable attention that carbonylation reactions
have received over the past several decades, to the best of our
knowledge, carbonylative reactions of aryl halides with
stabilized phosphonium ylides as nucleophiles via palladium
catalysis to yield α-acylphosphoranes have not been described
before.22 Following our continued interest in palladium-
catalyzed carbonylation reactions,18 herein we describe an
efficient synthesis of α-acylphosphoranes by palladium-
catalyzed ylidyl carbonylation (Scheme 1, c).
We began our investigation by carrying out the reaction of
methyl 4-iodobenzoate 1 (0.5 mmol) with methyl 2-(triphenyl-
phosphoranylidene)acetate 2 (1 equiv) in the presence of DBU
(1 equiv), 2 mol % of Pd(OAc)2, and 4 mol % of
triphenylphosphine in 1,4-dioxane (3 mL) under a CO (6
atm) atmosphere. After reaction at 100 °C for 12 h, to our
delight, the desired product 3 was obtained in 34% isolated
yield (Table 1, entry 1). Control experiments showed that both
the CO and the Pd(OAc)2 catalyst were essential for the
reaction (Table 1, entries 2 and 3). Without the phosphine
ligand and base, the yield of target product decreased compared
to the initial conditions, indicating that the phosphine ligand
and the base are beneficial to the reaction (Table 1, entries 4
and 5). Subsequently, different phosphine ligands (18
examples) were investigated and XantPhos was found to be
the most efficient ligand.23 In the presence of this ligand,
various bases were also surveyed. Compared with organic bases,
the inorganic ones improved the yield further.23 Other Pd
sources were also examined in the presence of 4 mol % of
XantPhos. The results show PdCl2 to be the more effective
catalyst for this reaction compared to Pd(OAc)2, Pd-
(PhCN)2Cl2, and Pd(MeCN)2Cl2.23 In addition, different
Scheme 1. Pd-Catalyzed Carbonylation of Aryl Iodides with
Phosphonium Ylides
using carboxylic acid derivatives,5a,b,8c cyclic anhydrides,11
aldehydes,5a 1,3-dicarbonyl compounds,4d benzoic acid trime-
thylsilyl ester (TMSE),5b and tellurol esters.12 However, an
efficient and simple synthesis of α-acylphosphoranes via
palladium-catalyzed carbonylation under atmospheric CO
pressure has received no attention.
Since its initial discovery by Heck and co-workers in 1974,13
the palladium-catalyzed carbonylation has become an efficient
methodology for synthesizing a variety of highly valued
Received: August 1, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02278
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Organic Letters
Letter
a
investigated. Delightfully, the reaction can work well under
atmospheric CO pressure.23 However, temperatures lower or
higher than 100 °C reduced the yields of the target product.23
Subsequently we varied the ratio of 1 to 2 and found that the
yield of the target product 3 could rise to 93% when the ratio
was 1/1.2 (Table 1, entries 8−11). These results led to the
following optimized reaction conditions: 1 (0.5 mmol), 2 (1.2
equiv), 1 equiv of K2CO3 as the base, and 2 mol % of PdCl2 and
4 mol % of XantPhos as the catalyst in 1,4-dioxane (3 mL) at
100 °C under CO (1 atm) for 12 h.
With the optimized reaction conditions in hand, the substrate
scope of the carbonylation reaction was then explored. As
summarized in Scheme 2, various aryl iodides equipped with
diverse functional groups (ester, ketone, halogen, nitro,
trifluoromethyl) were tolerated in this reaction. The reaction
appears to be affected by the electronic properties of the para
substituent of the aryl iodides with electron-withdrawing groups
providing higher yields (Scheme 2, 3−13). The protocol was
found to work well when the substituent was at the meta
position as well, in which case substrate bearing electron-
withdrawing and -donating groups both afforded the
corresponding α-acylphosphoranes in good to excellent yields
(Scheme 2, 15−21). However, the reaction of methyl 2-
iodobenzoate, 1-iodo-2-methylbenzene, and 1-iodo-2-methox-
ybenzene (Scheme 2, 22, 27, 28) resulted in poor yields, most
likely because of the steric hindrance.24 In contrast, aryl iodides
bearing electron-withdrawing and relatively less sterically
demanding ortho-halogen or ortho-trifluoromethoxy afforded
Table 1. Optimization of Reaction Conditions
b
entry
1
cat.
ligand
PPh3
base
yield (%)
c
Pd(OAc)2
Pd(OAc)2
none
DBU
45/34
d
2
PPh3
DBU
0
3
4
5
6
7
PPh3
DBU
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
none
DBU
36
25
76
81
69
85
93
88
PPh3
none
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
XantPhos
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
ef
,
8
PdCl2
eg
,
9
PdCl2
eh
,
10
11
PdCl2
ei
,
PdCl2
a
1 (0.5 mmol), 2 (0.5 mmol, 1 equiv), base (1 equiv), catalyst (2 mol
%), and ligand (4 mol %) in 3 mL of solvent under CO (6 atm) at 100
b
°C for 12 h. Yield determined by 1H NMR with 1,3,5-
c
d
trimethoxybenzene as internal standard. Isolated yield. Without
CO. CO (1 atm). 0.8 equiv of 2. 1 equiv of 2. 1.2 equiv of 2. 1.4
equiv of 2.
e
f
g
h
i
solvents were examined and dioxane was the best compared
with other solvents.23 Other reaction parameters, such as the
CO pressure and the reaction temperature were also
Scheme 2. Pd-Catalyzed Carbonylation of Aryl Iodides and Methyl 2-(Triphenylphosphoranylidene)acetate
a
PdCl2 (0.01 mmol, 2 mol %), XantPhos (0.02 mmol, 4 mol %), aryl iodides (0.5 mmol, 1 equiv), 2 (0.6 mmol, 1.2 equiv), K2CO3 (0.5 mmol, 1
b
c
d
equiv), and dioxane (3 mL), CO (1 atm), 12 h, 100 °C; isolated yields. 2 (0.8 mmol, 1.6 equiv), 12 h. 2 (0.8 mmol, 1.6 equiv), 24 h. 2 (1.0 mmol,
2 equiv), 24 h.
B
DOI: 10.1021/acs.orglett.6b02278
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Organic Letters
Letter
the target products in good yields (Scheme 2, 23−26).
Disubstituted aryl iodides were also tested, giving the
corresponding products in good yields (Scheme 2, 29−32).
The substrate scope could also be extended to naphthyl or
(hetero)aryl iodides, affording the corresponding products in
moderate to excellent yields (Scheme 2, 33−37). As shown in
Scheme 2, prolonging the reaction time and increasing the
amount of the reactant 2 could achieve high yields for the
substrates with low activity, such as the aryl iodides carrying
electron-donating groups and (hetero)aryl iodides.
Having demonstrated that the process is compatible with a
wide range of aryl iodides, investigation of the scope with
respect to stabilized phosphonium ylides was undertaken. Aside
from the commercially available stabilized phosphonium ylides
(Scheme 2 and Scheme 3, 38), we also synthesized various
Scheme 4. A Gram-Scale Synthesis of 14
α-Acylphosphoranes have been applied to construct various
highly valued compounds.1−9 To highlight the utility of the
products, we performed the transformation of α-acylphosphor-
anes into acetylenic esters, obtaining moderate to good yields
(Scheme 5, 47−51).23 The acetylenic esters are important
Scheme 5. Transformation of α-Acylphosphoranes to
Acetylenic Esters
Scheme 3. Pd-Catalyzed Carbonylation of Methyl 4-
a
Iodobenzoate 1 with Various Phosphonium Ylides
intermediates in organic synthesis. For instance, acetylenic
esters 47 and 48 were vital substrates in the synthesis of α-
pyrone derivatives found in various natural products,26 and 47
and 49 were used in the synthesis of 2,3-diaryl-pyrazolo[1,5-
b]pyridazines derivatives, which are potent and selective
cyclooxygenase-2 inhibitors.27 51 is prepared for the first time
with this methodology.
In summary, we have developed a new and efficient method
for the preparation of α-acylphosphoranes. The palladium-
catalyzed ylide carbonylation allows for the direct trans-
formation of aryl iodides into the corresponding α-
acylphosphoranes under atmospheric CO pressure. The wide
scope, mild reaction conditions, and high yields showcase the
potential of the method in chemical synthesis.
a
PdCl2 (0.01 mmol, 2 mol %), XantPhos (0.02 mmol, 4 mol %), 1
(0.7 mmol, 1.4 equiv), P-ylides (0.5 mmol, 1 equiv), K2CO3 (0.5
mmol, 1 equiv), and dioxane (3 mL), CO (1 atm), 13 h, 100 °C;
isolated yields. 24 h. 1 (1.0 mmol, 2 equiv), 24 h.
b
c
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02278.
■
stabilized phosphonium ylides on gram scale.23 The α-
acylphosphoranes derived from the carbonylation with these
stabilized phosphonium ylides are summarized in Scheme 3.
When the R group was CO2Et, CO2Bn, and cyano, the
corresponding products were obtained in 94%, 87%, and 69%
yields, respectively (Scheme 3, 38−40). When the R group was
PhCO, the target product was also obtained in high yields
(Scheme 3, 41). Electronic effects on the phenyl ring of the R
unit affect the reaction yield significantly. Thus, whilst an
electron-donating group such as methyl and methoxy gave
moderate yields (Scheme 3, 42−43), an electron-withdrawing
group such as the cyano group decreased the yields to less than
40% (Scheme 3, 45). This is in contrast to the effect observed
with the aryl iodides and presumably reflects the ylide as a
nucleophile while the aryl iodide as an electrophile.25
S
Experimental details and spectroscopic data for new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xuedong_welcome@snnu.edu.cn.
*E-mail: j.xiao@liv.ac.uk.
Notes
The authors declare no competing financial interest.
To demonstrate the utility of this palladium-catalyzed
carbonylation, the reaction was carried out on gram scale. As
shown in Scheme 4, methyl 3-oxo-3-phenyl-2-(triphenyl-
phosphoranylidene)propanoate 14 was obtained in 80%
isolated yield, showcasing the potential of the method in
organic synthesis.
ACKNOWLEDGMENTS
■
The work was supported by the National Natural Science
Foundation of China (21372148), Natural Science Foundation
of Shaanxi Province (2015JM2049), 111 projects (B14041),
and the Changjiang Scholar Programme.
C
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