Palladium-Catalyzed Synthesis of 1,2-Diketones from Aryl Halides and Organoaluminum Reagents Using tert-Butyl Isocyanide as the CO Source

Article abstract of DOI:10.1021/acs.orglett.9b04414

In this work, an interesting and practical procedure for the synthesis of 1,2-diketones from aryl halides and organoaluminum reagents has been developed. Employing tert-butyl isocyanide as the CO source and palladium as the catalyst, the desired 1,2-diketones were isolated in good to excellent yields with good functional group tolerance. Concerning the reaction partners, besides aryl halides, both alkyl- A nd arylaluminum reagents were all suitable substrates here.

Full text of DOI:10.1021/acs.orglett.9b04414

pubs.acs.org/OrgLett
Letter
Palladium-Catalyzed Synthesis of 1,2-Diketones from Aryl Halides
and Organoaluminum Reagents Using tert-Butyl Isocyanide as the
CO Source
Bo Chen and Xiao-Feng Wu*
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ABSTRACT: In this work, an interesting and practical procedure
for the synthesis of 1,2-diketones from aryl halides and organo-
aluminum reagents has been developed. Employing tert-butyl
isocyanide as the CO source and palladium as the catalyst, the
desired 1,2-diketones were isolated in good to excellent yields with
good functional group tolerance. Concerning the reaction partners,
besides aryl halides, both alkyl- and arylaluminum reagents were all
suitable substrates here.
1,2-Diketones compose a class of structural motif with
important applications in the synthesis of biologically active
heterocycles and natural products.1,2 Additionally, 1,2-
diketones have also been found to be present in molecules
with antitumor activities.3 Furthermore, they have also been
used as photochemical materials4 and ligands to stabilize
various metal complexes.5 Because of their recognized
importance, many synthetic methods were developed for
their preparation in recent years (Scheme 1). Traditionally,
1,2-diketones can be prepared by the oxidation of ketone
derivatives6 or olefins and internal alkynes (Scheme 1, eqs a
and b).7 Alternatively, 1,2-diketones can also be synthesized
through metal-catalyzed/mediated cross-coupling of arylbor-
onic acids8 or aryl iodides9 with alkynyl carboxylic acids
(Scheme 1, eq c). The reaction proceeds through a
decarboxylative coupling and then an oxidation sequence.
More recently, Blackmond, Dechert-Schmitt and their co-
workers developed an attractive procedure for the synthesis of
unsymmetrical 1,2-diketones from aryl halides and alkyl zincs
employing tert-butyl isocyanide as the CO source (Scheme 1,
eq d).10 Quinoxalines were prepared in moderate to good
yields after reaction with o-phenylenediamine.
Scheme 1. Methodologies for 1,2-Diketone Synthesis
On the other hand, organoaluminum reagents are attractive
coupling partners in synthetic chemistry due to their relatively
low cost and low toxicity as well as the readily availability of
aluminum metal.11 The first report on using organoaluminum
in a transition-metal-catalyzed cross-coupling reaction can be
traced back to 1976 by Negishi and co-workers.12 Since then,
Received: December 9, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04414
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
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Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Synthesis of 1,2-Diketones: Variation of Aryl
a
Iodides
entry
catalyst
ligand
DPPF
DPPF
−
PPh3
solvent
PhMe
base
yield (%)
53
45
42
50
67
41
56
63
30
59
70
58
1
2
3
4
5
6
7
8
Pd2dba3
Pd2dba3
Pd(PPh3)4
Pd(OAc)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
LiOtBu
K2CO3
Et3N
b
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
THF
DPPF
−
DPEphos
Xantphos
DPPM
DPPE
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
DPPP
9
10
11
12
c
13
14
15
16
17
18
19
trace
trace
trace
trace
DBU
d
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
80(77)
PdCl2
PdCl2
PdCl2
PdCl2
56
63
69
9
1,4-dioxane
PhMe
PhMe
e
20
21
f
a
Reaction conditions: 1a (0.5 mmol), 2a (0.7 mmol in pentane), tert-
butyl isocyanide (3 equiv), [Pd] (10 mol %), ligand (10 or 20 mol %),
solvent (2.0 mL), base (0.65 mmol) 100 °C, 16 h, then 1 M HCl, 1 h,
b
c
NMR yield. tert-Butyl isocyanide (2 equiv). 5 mol % PdCl2 and 5
d
e
mol % DPPP. Isolated yield. Bromobenzene instead of 1a.
Chlorobenzene instead of 1a.
f
various examples of cross-coupling reactions with organo-
aluminum reagents were reported.13
For examples, Knochel and co-workers reported a novel
method for preparing organoaluminum reagents in 2010.13i
Promoted by catalytic amounts of selected metallic chlorides in
the presence of LiCl, aluminum powder inserts into the C−X
bond of many unsaturated iodides and bromides. The resulted
organoaluminum reagents were applied in palladium-catalyzed
cross-coupling and acylation reactions. More recently,
Uchiyama, Wang and their co-workers performed a systematic
study on nickel-catalyzed cross-coupling reactions of organo-
aluminum reagents with organic halides as well as phenolic/
alcoholic C−O and ammonium C−N bonds.14 Various C−C
bonds were formed in an effective manner with commercially
available NiCl2(PCy3)2 as the catalyst. However, application of
an organoaluminum reagent in 1,2-diketone synthesis has not
been reported yet.
Under the aforementioned backgrounds, we herein report a
new protocol for the synthesis of 1,2-diketones starting from
organoaluminums and aryl halides. The initial investigations
were carried out with iodobenzene and trimethylaluminum as
the substrates employing tert-butyl isocyanide as the CO
source. To our delight, the target 1-phenylpropane-1,2-dione
3a can be successfully obtained in 53% yield with Pd2dba3 as
the catalyst, DPPF as the ligand, and NaOtBu as the base in
toluene at 100 °C for 16 h, with subsequent use of 1 M HCl
for hydrolysis (Table 1, entry 1). The yield of 3a decreased to
45% if we decrease the loading of tert-butyl isocyanide to 2
a
Reaction scale: 0.50 mmol, isolated yields.
equiv (Table 1, entry 2). Then, different palladium precursors
and ligands were tested and we found PdCl2 and DPPP were
the best catalysis system to give a 70% yield of 3a in this
reaction (Table 1, entries 3−11). Interestingly, we found the
desired product can still be obtained in 41% yield in the
absence of ligand (Table 1, entry 6). The reaction efficiency
decreased significantly if we decrease the loading of palladium
catalyst (Table 1, entry 12). Bases screening disclosed that
KOtBu is the optimal base for this reaction system. The other
tested inorganic and organic bases could not provide any
desired product here (Table 1, entries 13−17). The testing of
different reaction media could not further improve the reaction
outcome (Table 1, entries 18−19). Finally, bromobenzene was
checked as the substrate instead of iodobenzene and the target
product was achieved in 69% yield (Table 1, entry 20).
B
https://dx.doi.org/10.1021/acs.orglett.9b04414
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Scheme 3. Synthesis of 1,2-Diketones: Variation of Aryl
Bromides
Scheme 4. Synthesis of 1,2-Diketones: Variation of
a
a
Organoaluminums
a
Reaction scale: 0.50 mmol, isolated yields.
Scheme 5. Proposed Reaction Mechanism
a
Reaction scale: 0.50 mmol, isolated yields.
However, a very low yield of the target product was obtained
when chlorobenzene was used (Table 1, entry 21). Addition-
ally, a 51% yield of the desired diketone was obtained when
decrease the loading of trimethylaluminum to 1.1 equiv.
With the optimal reaction conditions in hand, we explored
the scope of this new method with various aryl halides and
organoaluminum employing tert-butyl isocyanide as the CO
source. Initially, we tested the generality of substituted aryl
iodides. As shown in Scheme 2, iodobenzenes with
substituents at different positions can be well tolerated,
delivering the desired products in good to excellent yields
C
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(3a−3f). Then we tried substrates with electron-donating and
-withdrawing substituents; the desired products were obtained
with 93% and 87% yields, respectively (3g, 3h). Additionally,
the reaction with 1-iodonaphthalene proceeds smoothly as well
and gave the target product in 75% yield (3i). Gratifyingly,
vinyl-substituted iodobenzene was also well tolerated in this
transformation, delivering the corresponding 1,2-diketones in
75% yield (3j).
To our delight, aryl bromide can be applied as the substrate
for this reaction as well. Under our standard conditions, a wide
range of functional groups with varied electronic properties can
be well tolerated (Scheme 3). The corresponding products
3b′−3r were isolated in 63−82% yields successfully.
Rostock, Germany; orcid.org/0000-0001-6622-3328;
Email: Xiao-Feng.Wu@catalysis.de
Other Author
Bo Chen − Zhejiang Sci-Tech University, Hangzhou,
People’s Republic of China, and Leibniz-Institut fu
̈
r
̈
Katalyse e. V. an der Universitat Rostock, Rostock,
Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04414
Notes
Organoaluminum reagents including aryl- and alkylalumi-
num reagents were tested with aryl iodides as well (Scheme 4).
The applied organoaluminum reagents are either commercially
available or can be easily prepared from aluminum trichloride
and Grignard reagent or organolithium reagent. The reactions
with triisobutylaluminum and tributylaluminum under our
standard reaction conditions proceed well, and the desired
products were obtained in 75% and 75% yields, respectively
(3s, 3t). Subsequently, triphenylaluminum as a representative
arylaluminum reagent was checked. Likewise, the reaction gave
the corresponding benzil derivatives in good yields (3u−3w).
Furthermore, PhB(OH)2 and PhSi(OMe)3 were tested under
our standard conditions as well, instead of an organoaluminum
reagent, but only a trace amount of the target product was
detected.
Concerning the reaction pathway, a plausible reaction
pathway is proposed on the basis of our results and literature
(Scheme 5).10,15 First, the active catalyst A will be generated
from PdCl2 and DPPP. After oxidative addition of aryl halides
to the catalyst A, organopalladium complex B can be obtained.
After the coordination and insertion of isocyanide, complex D
will be formed which will afford complex F after the
coordination and insertion of the second molecule of
isocyanide. Finally, the complex F undergoes a reductive
elimination to yield the diimine product which can deliver the
final 1,2-diketone products after hydrolysis and meanwhile
regenerate the active catalyst A for the next catalytic cycle.
In conclusion, a novel and practical procedure for the
synthesis of 1,2-diketones from aryl halides and an organo-
aluminum reagent has been developed. Employing tert-butyl
isocyanide as the CO source and palladium as the catalyst, the
desired 1,2-diketones were isolated in good to excellent yields
with good functional group tolerance. Notably, both alkyl- and
arylaluminum reagents were all suitable substrates here.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.B. thanks the Chinese Scholarship Council (CSC) for
financial support. The analytical support of Dr. W. Baumann,
Dr. C. Fisher, S. Buchholz, and S. Schareina is gratefully
acknowledged (all at LIKAT).
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General comments, experimental procedures, and
analytic data and NMR spectra for products (PDF)
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