Tetrasubstituted Furans by PdII-catalyzed three-component domino reactions of 2-(1-alkynyl)-2-alken-1-ones with Nucleophiles and vinyl ketones or acrolein

Article abstract of DOI:10.1002/chem.200901386

A novel Pd^II-catalyzed three-component domino reaction of 2-(1-alkynyl)-2-alken-1-ones with nucleophiles and vinyl ketones, which has provided an efficient, general route to multifunctionalized tetra-substituted furans, was reported. [PdCl

Full text of DOI:10.1002/chem.200901386

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DOI: 10.1002/chem.200901386
Tetrasubstituted Furans by PdII-Catalyzed Three-Component Domino
Reactions of 2-(1-Alkynyl)-2-alken-1-ones with Nucleophiles and Vinyl
Ketones or Acrolein
Renrong Liu[a] and Junliang Zhang*[a, b]
Transition-metal-catalyzed multicomponent domino reac-
tions,[1] which can provide rapid access to architecturally
complex molecules from relatively simple starting materials,
are highly important in synthetic chemistry. Highly substitut-
ed furans are frequently found as subunits in many bioactive
natural products and man-made drugs, and they are also im-
portant building blocks in organic synthesis.[2,3] Recently,
readily available 2-(1-alkynyl)-2-alken-1-ones have demon-
strated their great ability to load various substitutents onto
furans under the catalysis of AuCl3.[4] Very recently, we also
developed a PdII-catalylzed three-component domino reac-
Scheme 1. Previous and current work.
tion of 2-(1-alkynyl)-2-alken-1-ones with nucleophiles and
allylic chlorides, which lead to tetrasubstituted furans
(Scheme 1).[5a]
First, we examined this palladium-catalyzed three-compo-
nent domino reaction under different reaction conditions by
using ketone 1a, MeOH, and vinyl methyl ketone as model
substrates (Table 1). After numerous attempts, the desired
product 5aaa could be obtained in 85% isolated yield after
running the reaction for 9 h at room temperature in CH3CN
In our ongoing efforts to develop cascade reactions to
synthesize heterocyclic compounds,[5] we envisaged that fur-
anyl palladium intermediates A, generated from the cycliza-
tion of ketones 1 and nucleophiles, might react with other
electrophiles such as vinyl ketones or acrolein[6] to afford
terasubstituted furans with 100% atom economy. Herein,
we report a novel, atom-economic PdII-catalyzed three-com-
ponent domino reaction of 2-(1-alkynyl)-2-alken-1-ones with
nucleophiles and vinyl ketones or acrolein, which lead to
multifunctionalized tetrasubstituted furans.[7]
Table 1. Screening reaction conditions.
[a] R. Liu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, Department of Chemistry
East China Normal University, 3663 North Zhongshan Road
Shanghai 200062 (P.R. China)
Fax : (+86)21-6223-3213
E-mail: jlzhang@chem.ecnu.edu.cn
Entry[a] Pd source (5%)
Solvent
Time [h] Isolated yield [%]
1
2
3
4
5
6
7
8
PdCl2
Pd(OAc)2
[Pd2A(dba)3]
[Pd
[PdCl
[PdCl
[PdCl
[PdCl
[PdCl
[PdCl
CH3CN
CH3CN
CH3CN
12
24
24
24
9
83
G
NR
trace
NR
85
R
CHTUNGTRENNUNG
(h3-C3H5)2Cl2] CH3CN
R
2A
2A(CH3CN)2] DMF
2A(CH3CN)2] DMA
2A(CH3CN)2] THF
2A
2A(CH3CN)2] CH3CN
[b] Prof. Dr. J. Zhang
E
N
2.5
9
75
55
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 354 Fenglin Road
Shanghai 200032, (P.R. China)
N
E
T
N
24
81
9
N
(CH3CN)2] 1,4-dioxane 24
65
10[b]
G
C
12
82
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901386 and contains the
preparative procedures and spectroscopic data for all of the new com-
pounds reported.
[a] Unless otherwise specified, vinyl methyl ketone (4 equiv) and MeOH
(4 equiv) were used. [b] Vinyl methyl ketone (2 equiv) and MeOH
(2 equiv) were used. NR=no reaction.
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Table 3. The scope of ketone component 1.
(Table 1, entry 5). Interestingly, different from the results
obtained by Lu et al.,[6] the presence of extra lithium halides
such as LiBr was not necessary for this transformation. It is
not surprising that PdCl2 gave a similar yield in CH3CN.
However, other palladium salts such as Pd
ACHTUNGTRNEN(UNG OAc)2, [Pd2-
A
ACHTUNGTRENNUNG
Other solvents such as DMF, DMA, THF, and 1,4-dioxane
gave relatively lower yields. Further screening indicated that
only two equivalents of methanol and vinyl methyl ketone
were required for this transformation, giving 82% yield of
the corresponding product (Table 1, entry 10).
Next, we investigated the scope and limitation of this
transformation under optimized conditions. We first tested
different nucleophiles and the results are listed in Table 2.
Entry Ketone 1
Time [h] Yield of 5 [%]
R1/R2/R3
1
2
Me/4-MeOC6H4/1-naphthyl (1b)
Me/4-MeOC6H4/Ph (1c)
Me/Ph/nBu (1d)
12
12
12
24
10
30
16
48
16
9
5baa (91)
5caa (70)
5daa (50)
5eaa (78)
5 faa (91)
5gaa (67)
5haa (77)
5iaa (44)
5iaa (60)[b]
5jaa (60)
5kaa (51)
5kaa (64)[b]
5laa (62)
3[a]
4
nBu/Ph/Ph (1e)
5
Ph/Ph/Ph (1 f)
6
7
Ph/Ph/1-cyclohexenyl (1g)
Ph/Ph/nBu (1h)
8[a]
9[a]
10[a]
11[a]
12[a]
13
Ph/Ph/4-NO2C6H4 (1i)
1i
Ph/Ph/4-MeOC6H4 (1j)
Ph/4-MeOC6H4/4-MeOC6H4 (1k) 24
1k
Table 2. Scope of PdII-catalyzed cascade reaction of 1a with various nu-
cleophiles and vinyl ketones.
6
16
Me/nBu/Ph (1l)
[a] Vinyl methyl ketone (4 equiv) and MeOH (4 equiv) were used.
[b] Carried out in DMF.
The generality of this transformation was also investigated
by using the cyclic ketone 7, the chromanone derivative 9,
and aldehyde 11 (Scheme 2). The reaction of ketone 7 gave
Entry
NuH (3)
R=6
Time [h]
Yield of 5 [%]
1
2
3
4
MeOH (3a)
iPrOH (3b)
tBuOH (3c)
BnOH (3d)
4-MeOC6H4OH (3e)
AcOH (3g)
Me (6a)
9
5aaa (82)
5aba (67)
5aca (30)
5ada (76)
5aea (50)
5afa (44)
6a
6a
6a
6a
6a
52
24
26
24
24
5
6[b]
7
6a
12
5aga (81)
8
3a
Ph (6b)
20
5aab (87)
[a] Unless otherwise specified, the reactions were carried out with NuH
(2 equiv) and vinyl ketone (2 equiv); [b] AcOH (4 equiv) was used.
Several points should be noted from these results: 1) The
corresponding products could be obtained in high yields
when MeOH, iso-propanol, and benzyl alcohol were used as
nucleophiles; 2) The treatment of para-methoxyphenol,
bulky tert-butanol, or weak nucleophilic acetic acid with 1a
and 6a could still give the corresponding products in moder-
ate yields; 3) N-Methyl indole could be used as a carbon-nu-
cleophile to give furan 5aga in 81% yield. Furthermore,
vinyl phenyl ketone 6b could also be used as an electrophile
instead of vinyl methyl ketone to afford the corresponding
furan 5aab in excellent yield (Table 2, entry 8).
We next examined the scope of the ketone 1 component
under optimized conditions, and the results are summarized
in Table 3. In general, moderate to high yields were ob-
tained for most substrates under standard conditions. Vari-
ous substitutents could be introduced into the corresponding
furan products. In some cases DMF was found to be a
better solvent than CH3CN based on the yield and reaction
rate (Table 3, entries 8 and 9, and 11 and 12).
Scheme 2. The domino reactions of cyclic ketones 7, 9, and aldehyde 11.
Conditions: MeOH (4 equiv), 6a (4 equiv) and [PdCl2ACHTUNGTRENNUNG(CH3CN)2]
(5 mol%).
the bicyclic 2,3-fused furan 8 in 62% yield, and the reaction
of the ketone 9 produced a tricyclic furan 10 in 50% isolat-
ed yield. The reaction of aldehyde 11 with MeOH and vinyl
methyl ketone at 08C for 36 h gave 53% yield of tetrasubsti-
tuted furan 12 rather than the corresponding trisubstituted
furan, which indicated that the electron-rich trisubstituted
furan would undergo a rapid Friedel–Crafts reaction with
another molecule of vinyl methyl ketone under these reac-
tion conditions. AuIII-catalyzed Friedel–Crafts reactions of
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PdII-Catalyzed Three-Component Domino Reactions
COMMUNICATION
vinyl methyl ketone with furan were first explored by
Hashmi et al., and later extensively studied by He et al..[8]
Furthermore, acrolein could be used as an electrophile in-
stead of vinyl methyl ketone, but the reaction produced an
acetal 13, rather than the free aldehyde, in 70% isolated
yield under the optimized conditions shown in [Eq. (1)].
1-ones with nucleophiles and vinyl ketones, which has pro-
vided an efficient, general, and atom-economic route to
multifunctionalized tetra-substituted furans. It was also in-
teresting to find that when (E)-2-benzylidene-4-phenylbut-3-
ynal was used as substrate, the reaction would undergo a
double addition reaction of two molecules of vinyl methyl
ketones. The reaction produced a furan with an acetal by
acetalization of the aldehyde group when acrolein was used
as the electrophile.
Experimental Section
Typical procedure for the synthesis of 5aaa: [PdCl2ACTHNUGTRNE(UNG CH3CN)2] (6.5 mg,
0.025 mmol) was added to a solution of 1a (123 mg, 0.5 mmol), MeOH
(32 mg, 1.0 mmol) and vinyl methyl ketone (70 mg, 1.0 mmol) in CH3CN
(2 mL) at room temperature. The reaction mixture was stirred for 12 h,
after which 1a was completely consumed according to the TLC analysis,
and then the reaction mixture was concentrated in vacuum. The residue
was purified by column chromatography on silica gel (hexanes/EtOAc=
5:1) to give the desired product 5aaa (142 mg) as a colorless oil. Yield=
82%; 1H NMR (300 MHz, CDCl3): dH =7.58 (d, 2H, J=7.8 Hz), 7.33–
7.43 (m, 6H), 7.21–7.30 (m, 2H), 5.35 (s, 1H), 3.44 (s, 3H), 2.80–2.91 (m,
1H), 2.64–2.75 (m, 1H), 2.40–2.52 (m, 1H); 2.39 (s, 3H), 2.07–2.15 (m,
1H), 2.05 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): dC =207.90, 148.93,
147.06, 141.25, 131.28, 128.43, 128.08, 126.98, 126.56, 126.14, 124.75,
120.48, 119.82, 77.00, 56.34, 42.77, 29.40, 18.12, 12.00 ppm; MS (70 eV):
m/z (%): 348 (47.59), 258 (100); HRMS calcd for C23H24O3 [M]+:
348.1725; found: 348.1722.
The reaction of ketone 1a, vinyl phenyl ketone 6b, and
deuterated methanol produced the corresponding [D1]5aab
in excellent yield, and about 56% of deuterium was incor-
porated at the a carbon of the ketone as shown in [Eq. (2)].
This result led us to propose a plausible mechanism for
this PdII-catalyzed three-component domino reaction
(Scheme 3). The reaction of a nucleophile with ketone 1
Acknowledgements
Financial support from NSFC (20702015), STCSM (07DZ-22937,
08dj1400101), Shanghai Shuguang Program (07SG27), Shanghai Pujiang
Program (07pj14039), and Shanghai Leading Academic Discipline Project
(B409) is greatly appreciated.
Keywords: cyclization
·
domino reactions
·
furans
·
multicomponent reactions · palladium
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Chem. Eur. J. 2009, 15, 9303 – 9306
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Received: May 25, 2009
Published online: August 4, 2009
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