Iridium(III)-Catalyzed C-H Functionalization of Triarylphosphine Oxides with Diazo Dicarbonyl Compounds: Synthesis of α-Aryl 1,3-Dicarbonyl Derivatives

Article abstract of DOI:10.1055/a-1409-1906

A novel (pentamethylcyclopenta-1,3-dienyl)iridium(III)-catalyzed direct C-H functionalization of triarylphosphine oxides with diazo dicarbonyl compounds through carbene insertion has been developed. This strategy provides a simple and efficient route to t

Full text of DOI:10.1055/a-1409-1906

SYNLETT
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 32, A–F
cluster
A
Perspectives on Organoheteroatom and Or-
Q.-X. Lou et al.
Cluster
Synlett
Iridium(III)-Catalyzed C−H Functionalization of Triarylphosphine
Oxides with Diazo Dicarbonyl Compounds: Synthesis of -Aryl
1,3-Dicarbonyl Derivatives
Qin-Xin Lou
[Cp*IrCl2]2 (1.0 mol%)
AgOTf (4.0 mol%)
PivOH (0.5 equiv)
O
O
O
O
Jing-Yu Li
R1
R
R2
Ar
O
R1
R2
+
P
Shang-Dong Yang*
0
0
0
0
-0
0
0
2
-
4
4
8
6
-
8
0
0
X
P(O)Ar2
Ar
DCE, 50 °C
Ar, 24 h
Ar
N2
State Key Laboratory of Applied Organic Chemistry, Lanzhou
University, State Key Laboratory for Oxo Synthesis and Selective
Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences, Lanzhou, 730000, P. R. of China
yangshd@lzu.edu.cn
35 examples
38–95% yield
Published as part of the Cluster
Perspectives on Organoheteroatom and Organometallic Chemistry
SAehtMcaatadneiCeglKom-yeDrarynoegnoLssafpghbSoYdocnai@rdenailngtnzocuger.yseA,douLuftah.Anconpzrhpoliue,d7O3r0g0a0n0i,cPC.hRe.mofisCthryin, aLanzhou University, State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Received: 28.01.2021
Accepted after revision: 05.03.2021
Published online: 05.03.2021
-arylation of 1,3-dicarbonyl derivatives by nonactivated
less-reactive aryl halides or pseudohalides provides a possi-
ble strategy (Scheme 1a).3 Alternatively, 2-diazo-1,3-dicar-
bonyl compounds react with various nucleophilic heteroat-
oms (oxygen, sulfur, or nitrogen) by a Wolff rearrangement,
also potentially providing an effective pathway (Scheme
DOI: 10.1055/a-1409-1906; Art ID: st-2021-l0032-c
Abstract A novel (pentamethylcyclopenta-1,3-dienyl)iridium(III)-cat-
alyzed direct C–H functionalization of triarylphosphine oxides with di-
azo dicarbonyl compounds through carbene insertion has been devel-
oped. This strategy provides a simple and efficient route to the
construction of -arylated 1,3-dicarbonyl compounds, which are im-
portant building blocks in pharmaceutical chemistry.
Table 1 Optimization of the Reaction Conditionsa
catalyst (1.0 mol%)
Ag salt (4.0 mol%)
additive
O
O
Key words triarylphosphine oxides, iridium catalysis, C–H bond acti-
vation, aryl dicarbonyl compounds
O
O
Ph2P
O
+
DCE, 50 °C
Ar, 24 h
P(O)Ph2
N2
-Arylated 1,3-dicarbonyl compounds are important
skeletons in many organic compounds that possess specific
biological activities and pharmacological properties.1 Con-
sequently, concise and efficient catalytic methods for the
arylation of various 1,3-dicarbonyl compounds are highly
desirable and eagerly sought.2 Transition-metal-catalyzed
3
1
2a
Entry
Catalyst
Ag salt
Additive (equiv)
Yieldb,c (%)
1
2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
AgSbF6
AgNTf2
AgPF6
AgBF4
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
PivOH (0.5)
PivOH (0.5)
PivOH (0.5)
PivOH (0.5)
PivOH (0.5)
–
86
47
40
69
90
trace
82
77
75
62
3
(a) Reported methods for the construction of α-arylated 1,3-dicarbonyl compounds
4
X
5
O
O
Ar
O
O
R2-YH
(X = O, S, NR2)
hν or heat
6
R1
R2
O
O
R1
X = halogen
[Pd] or [Cu]
Ar
7
AdCO2Hd (0.5)
TMBzOHe (0.5)
AcOH (0.5)
PivOH (0.5)
R1
R2
N2
1,2-Wolff
Ar
C–C coupling
8
rearrangement
9
(b) P=O-directed CH α-arylation of 1,3-dicarbonyl compounds (this work)
10g
a Reaction conditions: 1 (0.4 mmol), [Cp*IrCl2]2 (1.0 mol%), AgOTf (4.0
mol%), additive, DCE (0.5 mL), 50 °C (oil bath), under Ar, for 24 h, then a
solution of 2a (0.2 mmol) in DCE (1.0 mL) was added over 4 h by using a
peristaltic pump.
O
PR1R2
O
O
Ir(III)
O
O
R3
R4
Ü
O
H
R1
R3
R4
+
P
R
– N2
N2
b Monoarylation occurred exclusively (by NMR spectroscopic analysis).
c Isolated yield.
R2
R
d 1-Adamantanecarboxylic acid.
e 2,4,6-Trimethylbenzoic acid.
Scheme 1 Strategies for the synthesis of -arylated 1,3-dicarbonyl
compounds
f Direct addition of 2a without an injection pump.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Q.-X. Lou et al.
Cluster
Synlett
1a).4 Recently, a transition-metal-catalyzed ortho C−H acti-
vation strategy has been developed and has achieved enor-
mous success through the use of various directing groups
with coordinating properties toward metal species.5 The
participation of diazo carbonyl compounds in ortho C–H
bond activations/carbene insertions has also been success-
fully explored and significant progress has been made.6 For
several years, our research group has been interested in
phosphorus oxide directed C–H functionalizations.7 In
2017, we discovered a novel intermolecular coupling
through Ir(III)-catalyzed direct C–H aromatization of tri-
arylphosphine oxides with diazo compounds under mild
conditions.8 Subsequently, Cramer and co-workers reported
enantioselective C−H bond arylations of biarylphosphine
oxides by quinone diazides catalyzed by iridium(III) com-
plexes containing atropochiral cyclopentadienyl ligands.9 In
2020, our group reported an Ir(III)-catalyzed C–H function-
alization of triphenylphosphine oxide to give 3-aryl oxin-
doles.10 However, no transition-metal-catalyzed C–H aryla-
tion of 2-diazo 1,3-dicarbonyl compounds with triarylphos-
phine oxides through a carbene-insertion process has
previously been reported. In light of the importance of -
arylated 1,3-dicarbonyl molecules in pharmacology and in
organic synthesis, we wished to develop a new method for
the synthesis of various phosphorylated 1,3-dicarbonyl
compounds through Ir(III)-catalyzed C–H functionaliza-
tions of triarylphosphine oxides with 2-diazo 1,3-dicarbon-
yl compounds. Our endeavors were successful, and the re-
sulting ortho-phosphorylated 1,3-dicarbonyl compounds
can be easily transformed into various phosphorus ligands
(Scheme 1b).
We began our studies by using triphenylphosphine ox-
ide (1a) and 2-diazo-4,4-dimethyl-1-phenylpentane-1,3-
dione (2a) as model substrates to determine the optimal re-
[Cp*IrCl2]2 (1.0 mol%)
AgOTf (4.0 mol%)
PivOH (0.5 equiv)
O
R2
O
Ph2P
O
O
R1
O
+
R1
R2
P(O)Ph2
DCE, 50 °C
Ar, 16 h
N2
2b–q
2a'–m'
1
4–32
4
5
6
7
8
9
R = 4-Me
R = 3-Me
R = 2-Me
R = 4-MeO
R = 4-Me2N n.r.
R = 4-F 77%
82%
61%
n.r.
O
O
O
69%
O
O
O
O
O
P(O)Ph2
X
P(O)Ph2
N
P(O)Ph2
R
10 R = 4-Cl
11 R = 4-Br
12 R = 4-CF3
13 R = 4-NO2
14 R = 4-Ac
80%
82%
87%
55%
90%
P(O)Ph2
17 X = S 93%
18 X = O 95%
19, n.r.
16, 88%
15 R = 4-CO2Me 86%
O
O
O
N
O
O
O
O
O
O
N
O
O
O
O
O
O
O
P(O)Ph2
P(O)Ph2
P(O)Ph2
P(O)Ph2
P(O)Ph2
24, 80%, dra = 1:1
23, 38%
20, 86%
21, 70%
22, 48%
O
O
O
O
O
P
O
O
P
O
O
P
O
O
O
O
P(OEt)2
S
O
O
O
O
O
P(O)Ph2
P(O)Ph2
P(O)Ph2
P(O)Ph2
P(O)Ph2
28, 95%
29, n.r.
26, 77%
27, 65%
25, 66%
O
O
O
O O
O
O
O
P
P
O
P(O)Ph2
O
O
O
P(O)Ph2
P(O)Ph2
P(O)Ph2
3, 90%
31, 38%
32, 89%
30, n.r.
Scheme 2 Substrate scope of the diazo 1,3-dicarbonyl compound. Reagents and conditions: 1a (0.4 mmol), [Cp*IrCl2]2 (1.0 mol%), AgOTf (4.0 mol%),
PivOH (0.1 mmol), DCE (0.5 mL), under Ar, stirring, 50 °C (oil bath), 20 min, then a solution of 2 (0.2 mmol) in DCE (1.0 mL) was added over 4 h by using
a peristaltic pump. Isolated yields are reported. n.r. = no reaction. a Determined by 31P NMR.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

C
Q.-X. Lou et al.
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action conditions. We tested various catalysts, solvents, and
carboxylic acids,11 selected examples of which are present-
ed in Table 1. Product 3 was obtained in 86% yield in the
fluoromethyl (12), nitro (13), acetyl (14), and ester groups
(15) were all compatible with the reaction. In addition, dia-
zonium substrates containing 2-naphthyl (16), 2-thienyl
(17), or 2-furyl (18) fragments also reacted efficiently.
However, the reactions with substrates containing an N,N-
dimethyl (8) or 2-pyridyl (19) moiety failed to occur.
We further explored the generality of the present meth-
od by changing the substituents on the backbone of the di-
azo 1,3-dicarbonyl compound. Diazo 1,3-dicarbonyl com-
pounds linked to ester, amide, or diethyl phosphate moi-
eties gave the corresponding products 20–28 in yields of
38–86%. Notably, with an L-proline methyl ester, the ratio of
diastereomers of product 24 was 1:1. Unfortunately, the
protocol did not tolerate p-toluenesulfonyl compounds (29)
or diphosphate esters (30). When the benzene ring of the
benzoyl group in the diazo substrate was replaced by a ben-
zyl (31) or olefin group (32), the reaction proceeded
smoothly. The structure of product 3 was unambiguously
confirmed by X-ray crystallographic analysis.13
presence
of
bis[dichloro(pentamethylcyclopentadie-
nyl)iridium(III)] ([Cp*IrCl2]2), AgSbF6, and pivalic acid in
DCE under argon at 50 ℃ for 24 hours (entry 1). We then
screened various silver salts (entries 2–5) and we found
that the reaction in the presence of AgOTf gave 3 in 90% iso-
lated yield (entry 5).12 Notably, the reaction was far less ef-
ficient in the absence of pivalic acid (entry 6) and, although
the reaction proceeded in the presence of various other car-
boxylic acids (entries 7–9), pivalic acid remained the best
choice for this reaction. Unexpectedly, product 3 was ob-
tained in 62% yield when the diazo compound 2a was add-
ed directly to the reaction vessel without using an injection
pump (entry 10).
Having established the optimal conditions, we tested
the generality of the diazo substrate 2 (Scheme 2). 2-Diazo
1,3-dicarbonyl compounds containing aryl groups with var-
ious electronic properties reacted smoothly to give the cor-
responding products 4–7 and 9–15 in isolated yields of 55–
95%. This transformation showed a broad functional-group
tolerance, as methyl (4 and 5), methoxy (7), halo (9–11), tri-
Next, the scope of the triarylphosphine oxide was inves-
tigated (Scheme 3). A broad range of arenes were tolerated,
with systems containing electron-rich (33 and 34), halo (35
and 36), or heteroaromatic groups (37 and 38) all giving the
O
[Cp*IrCl2]2 (1.0 mol%)
AgOTf (4.0 mol%)
PivOH (0.5 equiv)
O
1R2RP
O
O
O
+
P(O)R1R2
X
DCE, 50 °C
Ar, 16 h
N2
X
n
X = C, S
n = 0, 1
X = C, S
n = 0, 1
1b–m
2a
33–44
O
O
O
O
O
Cl
F
O
O
O
O
O
P
O
O
P
O
P
P
O
Cl
F
O
Cl
F
34, 93%
35, 47%
36, 46%
33, 40%
O
O
O
CF3
Br
O
O
P
O
O
P
O
O
O
S
S
O
O
P
P
F3C
Br
S
CF3
Br
39, trace
37, 40%
38, 55%
40, trace
O
O
O
O
O
O
O
P
O
O
O
O
O
O
P
P
P
O
42, 67%, dra = 1.3:1
44, n.r.
41, 73%
43, trace
Scheme 3 Substrate scope of the triarylphosphine oxide. Reagents and conditions: 1 (0.4 mmol), [Cp*IrCl2]2 (1.0 mol%), AgOTf (4.0 mol%), PivOH (0.1
mmol), DCE (0.5 mL), under Ar, stirring, 50 °C (oil bath), 20 min, then a solution of 2a (0.2 mmol) in DCE (1.0 mL) was added over 4 h by using a
peristaltic pump. Isolated yields are reported. a Determined by 31P NMR.
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

D
Q.-X. Lou et al.
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standard conditions. The resulting value of kH/kD = 6.0 indi-
cates that cleavage of the C−H bond is probably involved in
the turnover-limiting step (Scheme 5a). On the basis of the
above observation and earlier reports in the literature,8–10
we suggest the plausible catalytic cycle shown in Scheme
5b. First, the active Ir(III) catalyst reacts with 1a through C–
H activation to afford the five-membered iridacycle inter-
mediate I. Coordination of the diazo 1,3-dicarbonyl com-
pound 2a gives II and subsequently nitrogen is released to
form the metal–carbenoid intermediate III via intermediate
II. Migratory insertion then generates the six-membered
iridacycle species IV. Finally, product 3 is obtained by pro-
tonation of pivalic acid with regeneration of the catalytical-
ly active Ir(III) species.
(a) Gram-scale synthesis of compound 3
[Cp*IrCl2]2 (1.0 mol%)
AgOTf (4.0 mol%)
PivOH (0.5 equiv)
O
O
O
O
Ph2P
O
+
P(O)Ph2
DCE, 50 °C
Ar, 24 h
N2
1a
1.67 g, 6.0 mmol
2a
3
0.69 g, 3.0 mmol
1.18 g, 82% yield
(b) Transformation of compound 20
O
O
F
O
NaH (1.1 equiv)
NFSI (1.1 equiv)
P(O)Ph2
THF, 0 °C, 2 h
45, 85% yield
In summary, we have developed a novel method for the
arylation of diazo 1,3-dicarbonyl compounds with triaryl-
phosphine oxides through an iridium(III)-catalyzed direct
C−H functionalization. The reaction proceeds under mild
conditions in moderate to excellent yields with a wide vari-
ety of substrates. Moreover, the products can undergo sev-
eral transformations to form intermediates that are highly
valuable in synthetic chemistry. From a broader perspec-
tive, we envision that this direct C–H bond arylation strate-
gy will inspire more research into utilizing phosphorus ox-
ide (P=O)-directed C–H bond functionalization in the devel-
opment of synthetic methodologies.
O
O
O
O
K2CO3 (2.0 equiv)
MeI (2.0 equiv)
O
O
P(O)Ph2
P(O)Ph2
acetone, reflux, 12 h
46, 77% yield
20
N
O
1) NH2OH•HCl (3.0 equiv)
EtOH, reflux, 12 h
O
P(O)Ph2
2) MeI (2.0 equiv)
K2CO3 (1.5 equiv)
acetone, reflux,12 h
Conflict of Interest
47
two steps 67% yield
The authors declare no conflict of interest.
Scheme 4 A gram-scale experiment and derivatizations
Funding Information
corresponding products in yields of 40–93%. However, the
4-bromo (39) and 4-trifluoromethyl (40) derivatives were
ineffective, demonstrating that the reaction was restricted
in the case of triarylphosphine oxides containing electron-
deficient groups. In addition, alkyl-substituted phenylphos-
phine oxides were obtained in good yields when the phenyl
group was substituted by a methyl group (41 and 42). How-
ever, diisopropyl and diethoxy groups were found to be in-
compatible with the reaction (43 and 44).
NSFC (Nos. 21532001) and the Open Fund of the Key Laboratory of
Functional Molecular Engineering of Guangdong Province (2016kf04).
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/a-1409-1906.
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ortingInformati
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To determine whether this reaction is suitable for larg-
er-scale applications, a gram-scale reaction of 1a and 2a
was performed and gave 3 in 82% isolated yield (Scheme
4a). Moreover, to showcase the synthetic potential of the -
aryl 1,3-dicarbonyl compounds bearing an arylphospho-
nate unit as polyfunctional structural intermediates, we ex-
amined the use of 20 as a template material (Scheme 4b).14
Product 20 was fluorinated to give a product 45 in 85%
yield.15 The corresponding methylation product 46 was ob-
tained in 77% yield.16 Subsequently, cyclization and methyl-
ation smoothly gave isoxazolone 47 in two steps.17
References and Notes
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A.; Speight, T. M.; Avery, G. S. Drugs 1983, 26, 279. (b) de Lou-
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To obtain more insight into the transformation mecha-
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© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F

E
Q.-X. Lou et al.
Cluster
Synlett
(a) KIE experiment
O
O
standard conditions
15–75 min
3
or
3-d15
1a
or
1a-d15
+
parallel experiments
N2
2a
KH/KD = 6.0
(b) Possible reaction mechanism
O
O
O
P(O)Ph2
PPh2
[Cp*IrCl2]2
AgOTf PivOH
[Cp*Ir(OPiv)]+
1a
3
PivOH
+
+
O
Ir
Ph2P
Ph2
P
Cp*
O
N2
Cp*
Ir
O
O
I
O
O
N2
2a
IV
+
PPh2
O
Cp*
+
O
Ir
PPh2
O
O
O
N
N
Ir
*Cp
II
O
N2
III
Scheme 5 Kinetic isotope effect study and the proposed reaction mechanism.
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[Cp*IrCl2]2 (2.0 mg, 1.25 mol%), AgOTf (2.6 mg, 10 mol%), and
pivalic acid (10.2 mg, 0.1 mmol, 0.5 equiv) were added to an
oven-dried reaction tube containing a magnetic stirrer bar. The
tube was sealed, DCE (0.3 mL) was added from a syringe, and
the mixture was stirred at 50 °C (oil bath) for 20 min. A solution
of the diazo 1,3-dicarbonyl compound 2a (0.2 mmol, 1.0 equiv)
in DCE (1.0 mL) was then added over 4 h by using a peristaltic
pump. The mixture was stirred for a further 12 h then cooled to
r.t. The solvent was removed in vacuo, and the residue was puri-
fied by chromatography [silica gel, PE–EtOAc (3:1)] to give a
white solid; yield: 86.4 mg (90%).
1H NMR (400 MHz, CDCl3):  = 8.12 (m, 3 H), 7.58–7.36 (m, 11
H), 7.31 (m, 4 H), 7.24–7.18 (m, 1 H), 7.05 (dd, J = 14.4, 7.4 Hz, 1
H), 1.03 (s, 9 H). 13C NMR (101 MHz, CDCl3):  = 209.8, 195.0,
135.9, 134.2 (d, J = 13.1 Hz), 133.1, 132.7 (d, J = 9.7 Hz), 132.3,
132.2 (d, J = 2.8 Hz), 132.2, 132.1, 131.9 (d, J = 2.5 Hz), 131.8,
129.3, 128.9 (d, J = 100.8 Hz), 128.6 (dd, J = 13.6, 12.2 Hz), 128.4,
126.9 (d, J = 12.8 Hz), 58.8 (d, J = 3.6 Hz), 45.6, 27.0. 31P NMR
(162 MHz, CDCl3):  = 34.3. HRMS (ESI): m/z [M + Na]+ calcd for
C31H29NaO3P: 503.1747; found: 503.1747.
(13) CCDC 20127547 contains the supplementary crystallographic
data for compound 3. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/structures
(8) Liu, Z.; Wu, J.-Q.; Yang, S.-D. Org. Lett. 2017, 19, 5434.
(9) Jang, Y.-S.; Woźniak, Ł.; Pedroni, J.; Cramer, N. Angew. Chem. Int.
Ed. 2018, 57, 12901.
(10) Lou, Q.-X.; Niu, Y.; Qi, Z.-C.; Yang, S.-D. J. Org. Chem. 2020, 85,
14527.
(11) Further details of the base optimization, see the Supporting
Information.
(12) 2-[2-(Diphenylphosphoryl)phenyl]-4,4-dimethyl-1-phenyl-
pentane-1,3-dione (3): Typical Procedure
(14) For details, see the Supporting Information.
(15) Kitahara, K.; Mizutani, H.; Iwasa, S.; Shibatomi, K. Synthesis
2019, 51, 4385.
(16) Roy, O.; Riahi, A.; Hénin, F.; Muzart, J. Eur. J. Org. Chem. 2002,
3986.
(17) Zeng, L.; Lai, Z.; Cui, S. J. Org. Chem. 2018, 83, 14834.
Under an Ar atmosphere, Ph3P=O (1; 0.4 mmol, 2.0 equiv),
© 2021. Thieme. All rights reserved. Synlett 2021, 32, A–F