Synthesis of Acyl Alkenylindium Reagents and Their Application in the Synthesis of (Z)-α,β-Unsaturated Ketones via Palladium-Catalyzed Cross-Coupling Reaction

Article abstract of DOI:10.1021/acs.orglett.5b02043

A synthetic method for the preparation of acyl alkenylindium reagents was developed involving the hydroindation reaction of allenyl ketones with indium and indium chloride in methanol under mild conditions. Their synthetic applications were demonstrated from Pd-catalyzed cross-coupling reactions with aryl bromides and iodides and alkenyl and aryl triflates for the synthesis of (Z)-α,β-unsaturated ketones.

Full text of DOI:10.1021/acs.orglett.5b02043

Letter
pubs.acs.org/OrgLett
Synthesis of Acyl Alkenylindium Reagents and Their Application in
the Synthesis of (Z)‑α,β-Unsaturated Ketones via Palladium-
Catalyzed Cross-Coupling Reaction
Youngchul Park, Jiae Min, Dahan Eom, and Phil Ho Lee*
National Creative Research Initiative Center for Catalytic Organic Reactions, Department of Chemistry, Kangwon National
University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: A synthetic method for the preparation of acyl alkenylindium reagents was developed involving the hydroindation
reaction of allenyl ketones with indium and indium chloride in methanol under mild conditions. Their synthetic applications
were demonstrated from Pd-catalyzed cross-coupling reactions with aryl bromides and iodides and alkenyl and aryl triflates for
the synthesis of (Z)-α,β-unsaturated ketones.
indium chloride and their synthetic application in Pd-catalyzed
cross-coupling reactions for the synthesis of α,β-unsaturated
ketones (Scheme 1).
ross-coupling reaction using a variety of organometallic
Creagents in the presence of a transition metal catalyst has
been one of the most significant research subjects for the
formation of C−C and C−heteroatom bonds.1 In particular, the
Pd-catalyzed cross-coupling reaction has been widely used as a
powerful tool in synthetic chemistry.2 To date, development of
new catalysts, organometallic reagents, and electrophilic
coupling partners has been continuously reported to expand
the scope of cross-coupling reactions. Among them, because
organoindium reagents showed advantageous properties related
to their selectivity and reactivity, ease of handling and
preparation, thermal stability, and low toxicity,3 cross-coupling
reactions using organoindium reagents have also been of great
interest. After Pd-catalyzed cross-coupling reactions using
tri(organo)indium reagents were reported by Sarandeses and
co-workers,4 coupling reactions using a large number of
organoindium reagents5 such as allylindiums, allenylindiums,
alkenylindiums, 1,3-butadien-2-ylindiums, tri(naphthyl)indiums,
tetra(organo)indates, indium tri(organothiolates), acylindiums,
β-phosphoryl alkylindiums, arylindiums,6 benzylindiums,7 and
alkylindiums8 have been demonstrated.9 Recently, Loh and co-
workers reported the synthetic method of indium homoenolates
via oxidative addition of indium and indium trichloride to α,β-
enones10 and insertion of indium into a β-halo ester.11 In our
continuing efforts to develop Pd-catalyzed cross-coupling
reactions using organoindium reagents, we envisioned that if
allenyl ketones would be employed in the reaction with In and/or
InCln (n = 1 and 3), the hydroindation reaction would take place
to produce acyl alkenylindium reagents, which can be applicable
in Pd-catalyzed cross-coupling reactions, producing α,β-unsatu-
rated ketones. Herein, we report a novel synthetic method of acyl
alkenylindium reagents from allenyl ketones and indium and
Scheme 1. Synthesis of Acyl Alkenylindium Reagents and
Their Synthetic Application in Pd-Catalyzed Cross-Coupling
Reaction
At the outset, 1-phenylbuta-2,3-dien-1-one (1a) was selected
as the substrate to prepare the organoindium reagent.
Investigation of a wide range of indium reagents such as In,
InCl, InCl3, In/InCl, and In/InCl3 revealed that In and InCl were
the reagents of choice for hydroindation (Table 1). Screening of
solvents revealed that methanol was an optimal solvent, but other
solvents such as CH3CN/H2O, THF/H2O, and MeOH/H2O
gave inferior results. The best result was obtained from a reaction
of 1a (0.2 mmol, 1.0 equiv) with In (1.0 equiv) and InCl (0.8
equiv) in MeOH at 30 °C for 30 min, affording benzoyl
alkenylindium reagent (2a) in 68% isolated yield together with 1-
phenylbut-3-en-1-one (3a) in 19% yield (entry 8).
X-ray diffraction analysis proved that 2a is a benzoyl-
substituted alkenylindium, having a monomeric structure with
chelation of the two carbonyl groups to indium (Figure 1). The
coordination conformation of the central indium metal can be
Received: July 16, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02043
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Organic Letters
Letter
a
a
Table 1. Reaction Optimization
Scheme 2. Scope of Allenyl Ketones
b
yield (%)
time
(h)
entry
conditions (equiv)
solvent
2a
3a
4a
1
2
In (0.8)/InCl3 (0.4)
In (0.8)/InCl3 (0.4)
In (0.8)/InCl3 (0.4)
In (1.2)
CH3CN/H2O
THF/H2O
MeOH/H2O
MeOH
1
1
18
50
34
18
15
34
3
4
4
6
52
70
5
InCl3 (1.2)
MeOH
6
64
6
InCl (1.2)
MeOH
6
15
52
7
In (1.0)/InCl (1.0)
In (1.0)/InCl (0.8)
In (1.0)/InCl (0.6)
In (1.5)/InCl (0.8)
MeOH
0.5
0.5
0.5
0.5
15
19
15
18
c
8
MeOH
68
68
67
9
MeOH
10
MeOH
a
Reactions were carried out with 1a (0.2 mmol, 1 equiv) in solvent
b
(0.8 mL) at 30 °C. NMR yield using CH2Br2 as an internal standard.
c
Isolated yield of 2a.
a
Reactions were carried out using In (0.2 mmol, 1.0 equiv), InCl (0.8
equiv), and allenyl ketone 1 (1 equiv) in MeOH (0.8 mL) at 30 °C.
b
c
All yields are isolated yields. For 30 min. In (0.2 mmol, 1.0 equiv)
d
e
f
and InCl (1.6 equiv) were used. For 10 min. For 20 min. At 40 °C.
For 5 min. In (0.2 mmol, 1.0 equiv) and InCl (1.2 equiv) were used.
g
h
dien-1-one having a methyl group on the terminal sp2 carbon did
not undergo the hydroindation reaction.
We next examined Pd-catalyzed cross-coupling of benzoyl
alkenylindium reagent 2a with ethyl 4-iodobenzoate (5j) (see
Supporting Information). A wide range of solvents such as DMA,
THF, toluene, DMSO, and DMF in the presence of
PdCl2(PPh3)2 (5.0 mol %) were examined in the cross-coupling
reaction, and it was found that DMF was the solvent that
provided optimal yields. It is noteworthy that the E-product was
selectively produced in DMA, while the Z-product was selectively
produced in DMSO. A large number of Pd catalysts, such as
Pd(OAc)2, Pd2(dba)3, Pd(PPh3)4, Pd(PhCN)2Cl2, [Pd(π-allyl)-
Cl]2, and PdCl2(PPh3)2, were screened in DMF. The optimal
reaction conditions were obtained from reactions of 2a (0.7
equiv) with 5j (0.15 mmol, 1 equiv) in the presence of
PdCl2(PPh3)2 (5.0 mol %) and LiCl (2.0 equiv) in DMF (1.0
mL) at 100 °C for 2 h, leading to the formation of α,β-
unsaturated ketone 6j in 86% yield (Z/E = 1.4:1). When LiCl was
not used, the product yield slightly decreased 72% and Z-
selectivity significantly increased (Z/E = 13:1).
To demonstrate the scope and limitation of this cross-coupling
reaction, we investigated the reaction of 2a with a large number
of aryl iodides and bromides under the optimal reaction
conditions (Scheme 3). Electronic modification of substituents
on the aryl ring of 2a did not largely influence the reaction
efficiency. 1-Iodobenzenes with electron-donating 2-methyl and
4-methoxy substituents underwent the cross-coupling reaction,
furnishing the corresponding α,β-unsaturated ketones 6b (60%)
and 6c (72%). The cross-coupling reaction was compatible with
a fluoro group. 3-Trifluoromethylphenyl iodide 5f was coupled
with indium reagent to the desired product 6f. Iodobenzene
having electron-withdrawing groups such as formyl, acetyl,
ethoxycarbonyl, and nitrile are suitable for the cross-coupling
reactions, providing the desired α,β-unsaturated ketones (6g−k)
in good yields, ranging from 68 to 86%. There are no products
arising from the addition of the nucleophilic acyl alkenylindium
Figure 1. X-ray structure of benzoyl alkenylindium (2a).
depicted as a distorted trigonal bipyramid, in which C(9), C(19),
and Cl(1) occupy the equatorial plane and O(1) and O(2)
occupy the apical positions. The average CO bond length is
1.247 Å, and the average CC bond [C(8)−C(9) and C(18)−
C(19)] lengths, which are adjacent to the In−C bonds, are 1.338
Å.
Next, a wide range of allenyl ketones were studied to
demonstrate the scope and limitation of the present method
for the synthesis of acyl alkenylindium reagents under optimal
reaction conditions (Scheme 2). Electronic variation of
substituents on the aryl ring of 1-arylbuta-2,3-dien-1-one (1)
slightly affected the reaction efficiency. For example, acyl
alkenylindium reagents (2b−d) with electron-donating 2-, 3-,
or 4-methyl substituents on the aryl ring were obtained in
moderate to good yields ranging from 60 to 70%. 1-(4-
Methoxyphenyl)buta-2,3-dien-1-one (1e) bearing a strong
electron-donating methoxy group is less reactive, leading to the
formation of 4-methoxybenzoyl alkenylindium reagent 2e in 50%
yield. Likewise, 2-chlorobenzoyl alkenylindium reagent 2f was
prepared from the hydroindation reaction of 1-(2-
chlorophenyl)buta-2,3-dien-1-one (1f) with In and InCl in
MeOH. Hydroindation of 1-(thiophen-2-yl)buta-2,3-dien-1-one
(1g) provided 2g in 60% yield. When alkyl allenyl ketones were
subjected to the hydroindation reaction, the product yields
slightly decreased due to the acidic α-proton of the carbonyl
group. 1-Phenylpenta-3,4-dien-2-one (1h) and 1-phenylhexa-
4,5-dien-3-one (1i) were converted to the corresponding
alkanoyl alkenylindium reagents 2h and 2i in 40 and 48% yields,
respectively. The corresponding allyl ketones were produced in
about 10% yields for all of the allenyl ketones. 1-Phenylpenta-2,3-
B
DOI: 10.1021/acs.orglett.5b02043
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Organic Letters
Letter
a
the present coupling reaction, affording the corresponding dienyl
ketone (6p) in 70% yield (Z/E = 12:1). When phenyl
trifluoromethanesulfonates with 4-chloro and 3,5-dimethyl
groups were employed, the desired α,β-unsaturated ketones 6e
and 6l were obtained in 82 and 76% yields, respectively. 1-
Naphthyl triflate (7m) was compatible with the coupling
reaction conditions.
Scheme 3. Scope of Aryl Iodides and Bromides
With these results in hand, we scrutinized the cross-coupling
reaction of a wide range of acyl alkenylindium reagents 2 with 5j
(Scheme 5). Acyl dialkenylindium reagents (2b−d) bearing
Scheme 5. Scope of Acyl Alkenylindium Reagents in the
a
Coupling Reaction
a
Reactions were carried out with 2a (0.7 equiv), 5 (0.2 mmol, 1
equiv), and LiCl (2.0 equiv) in DMF (1.3 mL) at 100 °C for 2 h.
b
Isolated yield. Numbers in parentheses indicate Z/E ratio. Aryl
bromides were used.
a
Reactions were carried out with 2 (0.7 equiv), 5j (0.2 mmol, 1 equiv),
and LiCl (2.0 equiv) in DMF (1.3 mL) at 100 °C for 2 h. Isolated
yield. Numbers in parentheses indicate Z/E ratio.
reagents to the carbonyls. 1-Iodo-3,5-dimethylbenzene (5l) was
subjected to the cross-coupling reaction to deliver 6l in 70%
yield. When 1-naphthyl iodide was treated with indium reagent
2a, the cross-coupling reaction took place to produce 6m in 61%
yield. Treatment of 3,4-dichloro-1-iodobenzene with 2a afforded
the α,β-unsaturated ketone 6n in 85% yield. 2-Iodothiophene
was applied to the present Pd-catalyzed coupling reaction,
affording 6o in 60% yield. Aryl bromides are less reactive than the
corresponding iodides. For instance, 1-bromo-4-chlorobenzene
gave the desired product 6e in 51% yield. Ethyl 4-bromobenzoate
was also reacted with indium reagent 2a, producing 6j in 61%
yield. (Z)-α,β-Unsaturated ketones were produced as the major
isomer in all of the cross-coupling reactions.
electron-donating 2-, 3-, or 4-methyl substituents on the aryl ring
were reacted with 5j to produce the corresponding α,β-
unsaturated ketones 8a, 8b, and 8c in good yields ranging from
72 to 81%. Indium reagent 2e obtained from 1-(4-
methoxyphenyl)buta-2,3-dien-1-one having a strong electron-
donating methoxy group also worked, leading to the α,β-
unsaturated ketone 8d in 78% yield (Z/E = 25:1). 2-
Chlorobenzoyl alkenylindium reagent 2f prepared from 1-(2-
chlorophenyl)buta-2,3-dien-1-one underwent the cross-coupling
reaction with 5j, resulting in the formation of 8e in 73% yield.
When acyl alkenylindium 2g with a thiophen-2-yl moiety was
employed, the desired α,β-unsaturated ketone 8f was obtained in
82% yield (Z/E = 26:1). The cross-coupling reaction was
amenable to reactions with indium reagents generated from 1-
phenylpenta-3,4-dien-2-one and 1-phenylhexa-4,5-dien-3-one to
afford 8g (62%) and 8h (84%), keeping the high Z-selectivity.
In conclusion, we have developed a synthetic method for the
preparation of acyl alkenylindium reagents from the hydro-
indation reaction of allenyl ketones with indium and indium
chloride in methanol under mild conditions. Their synthetic
applications were demonstrated from Pd-catalyzed cross-
coupling reactions with aryl bromides and iodides and alkenyl
and aryl triflates for the synthesis of (Z)-α,β-unsaturated ketones.
Next, a large number of alkenyl and aryl triflates were
employed in the Pd-catalyzed cross-coupling reactions with 2a
(Scheme 4). 4-tert-Butyl cyclohexen-1-yl triflate was applied to
a
Scheme 4. Scope of Alkenyl and Triflates
ASSOCIATED CONTENT
* Supporting Information
■
S
a
Reactions were carried out with 2a (0.7 equiv), 7 (0.2 mmol, 1
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02043.
equiv), and LiCl (2.0 equiv) in DMF (1.3 mL) at 100 °C for 2 h.
Isolated yield. Numbers in parentheses indicate Z/E ratio.
C
DOI: 10.1021/acs.orglett.5b02043
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental procedures, characterization data, X-ray
Letter
8905. (k) Legros, P. H.; Primault, G.; Fiaud, J. C. Tetrahedron 2001, 57,
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crystallography data (2a), and copies of NMR spectra
for all products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: phlee@kangwon.ac.kr.
Notes
The authors declare no competing financial interest.
(11) Shen, Z.-L.; Goh, K. K. K.; Wong, C. H. A.; Yang, Y.-S.; Lai, Y.-C.;
Cheong, H.-L.; Loh, T.-P. Chem. Commun. 2011, 47, 4778.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
of Korea (NRF) grant funded by the Korea government (MSIP)
(2011-0018355).
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