Tetrasubstituted furans by a PdII-catalyzed three-component Michael addition/cyclization/cross-coupling reaction

Article abstract of DOI:10.1002/anie.200704531

(Chemical Equation Presented) Dual personalities: Pd^II-catalyzed three-component Michael addition/cyclization/ cross-coupling reaction provides an efficient route to functionalized tetraubstituted furans (see scheme). The [PdCl₂-(CH₃CN)₂] catalyst plays a dual role in this transformation as both a Lewis acid and a transition-metal center.

Full text of DOI:10.1002/anie.200704531

Angewandte
Chemie
DOI: 10.1002/anie.200704531
Furan Synthesis
Tetrasubstituted Furans by a PdII-Catalyzed Three-Component
Michael Addition/Cyclization/Cross-Coupling Reaction **
Yuanjing Xiao and Junliang Zhang*
The design and discovery of new reactions for the synthesis of
highly substituted furans has been stimulated by their
appearance in many bioactive natural products and important
pharmaceuticals.[1,2] There has been recent focus on the
development of metal-catalyzed one- or two-component
reactions for synthesis of these types of compounds, including
the cyclization of allenyl ketones,[3] 3-alkyn-1-ones,[3k,4] 1-(1-
alkynyl)-cyclopropyl ketones,[5] (Z)-2-en-4-yn-1-ols,[6] and 2-
(1-alkynyl)-2-alken-1-ones,[7] and cycloisomerization of cyclo-
propyl ketones[8]/cyclopropenyl ketones.[9] Recently, the
design of multicomponent reactions[10] that preserve atom
economy in a one-pot reaction has attracted attention
becasue of the application to efficient construction of
molecular structures. Herein we report results of a PdII-
catalyzed three-component Michael addition/cycliztion/cross-
coupling reaction to afford highly functionalized tetrasubsti-
tuted furans.[11]
As a continuation of our interest in the design and
Scheme 1. a) General reaction scheme for the PdII-catalyzed three-
component reaction to afford highlysubstituted furans. b) Propsed
reaction pathwayfor the reaction in (a). In the first step the Pd II serves
as a Lewis acid and a transition metal, and in subsequent steps the
PdII serves as a transition metal.
discovery of new reactions for the synthesis of highly
substituted furans,[5,8,9b] we envisioned that 2-(1-alknyl)-2-
alken-1-ones might react with nucleophiles and an allyl halide
in the presence of a catalytic PdII species that might exhibit
dual roles, serving simultaneously as a Lewis acid and a
transition metal (Scheme 1). First, PdII acts as a Lewis acid
and a transition metal to facilitate both the nucleophilic
addition step and the cyclization step[12] to afford a furanyl–
palladium intermediate, which then reacts with the allyl
halide by insertion and subsequent b-halide elimination to
provide product furans and regenerate the PdX2 catalyst. To
the best of our knowledge, only one example of Pd(OAc)2
serving as a dual role catalyst exists.[13] Herein we present our
recent results on the [PdCl2(CH3CN)2]-catalyzed three-com-
ponent Michael addition/cyclization/cross-coupling of 2-(1-
alkynyl)-2-alken-1-ones 1 with various nucleophiles and allyl
chlorides.
First, we examined the reaction of 2-phenylethynyl-3-
phenyl-2-butylene-1-one (1a) with MeOH and allyl chloride
(3a) under different reaction conditions. After numerous
attempts, we isolated the desired product 4aaa in 75% yield
after running the reaction for 24 hours at room temeprature in
CH3CN with [PdCl2(CH3CN)2] (5 mol%) as the catalyst,
methanol (4.0 equiv) as the nucleophile, allyl chloride
(4.0 equiv) as the allylating reagent, and K2CO3 (4.0 equiv)
as the base. Only trace amounts (< 1%) of the furan
generated by the competitive side reaction from protonation
could be detected by 1H NMR spectra analysis (Table 1,
entry 6). Alternate conditions, such as lowering the equiv-
alents of the base, MeOH, or allylic chloride or changing the
solvent or the base lead to a lower yield of the product
(Table 1, entries 1–12). Surprisingly, when allyl bromide (even
10 equiv) was used instead of allyl chloride, the reaction
proceeded slowly to give the desired furan in 37% yield
[*] Dr. Y. Xiao, Prof. Dr. J. Zhang
Shanghai KeyLaboratoryof Green Chemistryand Chemical
Processes
1
Department of Chemistry
East China Normal University
3663 N. Zhongshan Road, Shanghai 200062 (P.R. China)
Fax: (+86)21-6223-3213
E-mail: jlzhang@chem.ecnu.edu.cn
(determined by H NMR spectroscopy) after 48 hours. We
deduced that relative to [PdCl2(CH3CN)2], the weak Lewis
acid [PdBr2(CH3CN)2] that is generated in the reaction is not
strong enough to activate the substrate. To support this
deduction, two control reactions were carried out under the
standard conditions with the exception that 20 mol% of Ph3P
(Table 1, entry 14) or 1 equivalent of KBr (Table 1, entry 15)
was added; neither of the reactions worked well and the yield
of the product was not more than 20%, thus, further verifying
that [PdCl2(CH3CN)2] is a stronger Lewis acid than [PdBr2-
[**] Financial support from the National Science Foundation of China
and East China Normal Universityis greatlyappreciated. This work
was sponsored bythe Shanghai Pujiang Program (07pj14039) and
the Shanghai Leading Academic Discipline Project (B409).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
Table 1: Screening of reaction conditions for the three-component
Michael addition/cyclization/cross-coupling reaction.[a]
Table 2: Scope of the [PdCl2(CH3CN)2]-catalyzed three-component
Michael addition/cyclization/cross-coupling of 1a.[a]
EntryNuH (
1
2)
3
t [h] Yield (4)[a]
EntryBase
(equiv)
2a/3a
[equiv]
Solvent
t [h]
Yield [%][b]
1
none
4.0/4.0
4.0/4.0
4.0/4.0
4.0/4.0
4.0/4.0
4.0/4.0
4.0/4.0
2.0/2.0
2.0/4.0
4.0/4.0
4.0/4.0
4.0/4.0
4.0/4.0
4.0/4.0
4.0/4.0
4.0/4.0
4.0/4.0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
36
36
36
36
24
24
24
24
24
24
24
24
24
24
24
48
48
0
MeOH
14
2
3
4
5
6
7
8
9
10
11
12
13[c]
14[d]
15[e]
16[f]
17[g]
Na2CO3(4.0)
NaHCO3(4.0)
K3PO4 (4.0)
Cs2CO3 (4.0)
K2CO3(4.0)
K2CO3(2.0)
K2CO3(2.0)
K2CO3(2.0)
K2CO3(4.0)
K2CO3(4.0)
K2CO3(4.0)
K2CO3(4.0)
K2CO3(4.0)
K2CO3(4.0)
K2CO3(4.0)
K2CO3(4.0)
41
50
62
42
88(75)
80
53
62
52
68
69
0
2a
2a
3b
3c
R=Me, 4aab,[f] 66%
2[b]
36 R=CO2Me, 4aac, 70%
1,4-dioxane
DMF
3
2a
48
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0
3d
3a
4aad, 89%
20
37
78
4[b,c]
iPrOH
[a] Reactions run with 1a (0.5 mmol) at room temperature. [b] Yields
were determined by H NMR spectroscopyusing CH Br2 as an internal
2b
72
1
2
standard; yields of isolated product are shown in parentheses.
[c] 5 mol% of [Pd(PPh3)4] was used. [d] 20 mol% of Ph3P was added.
[e] 1.0 equiv of KBr was added. [f] 10 equiv of allyl bromide used instead
of allyl chloride. [g] 5 mol% of allylpalladium chloride dimer was used.
R=iPr, 4aba, 42%
5
6
BnOH
2c
3a
3a
24 R=Bn, 4aca, 63%
24 R=Ph, 4ada, 66%
PhOH
2d
(CH3CN)2] and [PdCl2(PPh3)2] (generated by adding Ph3P to
the mixture). In addition, no reaction occurred when [Pd-
(PPh3)4] was employed as the catalyst instead of [PdCl2-
(CH3CN)2]. All these observations indicate that [PdCl2-
(CH3CN)2], acting simultaneously as a Lewis acid and a
transition-metal catalyst, is the key to making this trans-
formation work well.[14]
To determine the scope of this transformation, we studied
the reaction of 1a with various nucleophiles 2 and allyl
chlorides 3, and the results are listed in Table 2. Notably:
1) Alcohols other than methanol, such as isopropanol, benzyl
alcohol, and phenol, can act as O nucleophiles to give
tetrasubstituted furans in moderate to excellent yields
(Table 2, entries 1–6); 2) Dimethyl malonate can act as a
nucleophilic component to allow the introduction of more
functional groups (Table 1, entries 7–11); 3) Substituted allyl
chlorides, such as 3b–d, can be used as allylating reagents to
give more functionalized furans in good yields (Table 2,
entries 1–3, 8–11); 4) The coupling occurs exclusively at the
less substituted terminus of the allyl chloride and the
7[d]
3a
10
2e
2e
2e
R=H, R’=H , 4aea, 91%
8[d]
9[d]
3b
3c
12 R=Me, R’=H, 4aeb,62%
20 R=CO2Me, R’=H, 4aec,
54%
10[d,e]
2e
2e
24 R=H, R’=Ph, 4aee, 79%
3e
3d
11[d]
24
4aed, 85%
=
configuration of the C C bond in 3-phenyl-2-propenyl
[a] Unless otherwise specified, reactions were carried out under standard
conditions. Reported yields are of the isolated product. [b] Additional
[PdCl2(CH3CN)2] (5 mol%) was added after the reaction was stirred for
24 h. [c] Used iPrOH (6.0 equiv) and allyl chloride (6.0 equiv).
[d] 2.0 equiv of dimethyl malonate were used. [e] Additional 0.5 equiv
of dimethyl malonate was added after the reaction was stirred for 12 h.
[f] The designation 4aab for the product indicates that the reactants
used were 1a, 2a, and 3b, respectively.
chloride 3e remained intact when it was introduced as the
allylating agent (Table 2, entry 10), a result that was consis-
tent with previous findings.[3g]
This transformation can be successfully extended to a
variety of 2-(1-alkynyl)-2-alken-1-ones 1 leading to the
generation of the corresponding tetrasubstituted furan in
40–91% yield (Table 3, entries 1–7). The substituents on the
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Table 3: [PdCl2(CH3CN)2]-catalyzed three-component Michael addition/
cyclization/cross-coupling of various 2-(1-alkynyl)-2-alken-1-ones 1 with
MeOH and allyl chloride.[a]
alkynes can affect the reaction; for example, alkynes bearing
aryl groups afford relatively higher yields than those bearing
alkyl groups (Table 3, compare entry 1 to entry 4). The type of
nucleophile also affects the yield and the rate of the reaction
(compare entries 4–7 in Table 2). Cyclic substrate 1h also
affords a fused furan in 57% yield under these reaction
conditions (Table 3, entry 7). The results in Tables 2 and 3
clearly show that our new approach to tetrasubstituted furans
allows easy introduction of various functional groups, such as
alkoxy groups, aryloxy groups, and dimethyl malonate groups,
as well as various types of allylic groups directly incorporated
into the furan ring. The new method provides opportunities
for further elaboration of the functional groups on the
polysubstitued furans.
Entry
1
1
t [h]
Yield 4[b]
30
1b
4baa, 77%
In conclusion, we have developed a [PdCl2(CH3CN)2]-
catalyzed three-component Michael addition/cyclization/
cross-coupling reaction that provides an efficient route to
functionalized tetrasubstituted furans. We found that [PdCl2-
(CH3CN)2] plays a dual role in this transformation. This
finding will be helpful to other cases in which activation of a
carbonyl group or related functional group, such as enone
(Lewis acid role), and activation of a double or triple bond
(transition-metal role) are desired to occur simultaneously.
As all three starting materials are readily available, this
method may allow the synthesis of more complex furans.
Further studies on the scope and synthetic applications of this
methodology are currently being carried out in our labora-
tory.
2
3
24
24
1c
1d
4caa, 80%
4daa, 91%
4[c]
43
36
1e
4eaa, 40%
Experimental Section
Typical procedure for the synthesis of 4aaa (Table 1, entry 6):
[PdCl2(CH3CN)2] (6.0 mg, 0.025 mmol) was added to a mixture of
1a (123.0 mg, 0.5 mmol), MeOH (64.0 mg, 2.0 mmol), allyl chloride
(153.0 mg, 2.0 mmol), and K2CO3 (276.0 mg, 2.0 mmol) in CH3CN
(2.0 mL) at room temperature. The reaction mixture was stirred for
24 h, at which time 1a was consumed completely according to TLC
analysis, and then concentrated in vacuo after filtration. The residue
was purified by column chromatography on silica gel (petroleum
ether/Et2O = 10:1) to give desired product 4aaa (119 mg) in 75%
yield as a colorless oil. 1H NMR (500 MHz, CDCl3) : d = 7.66–7.59 (m,
2H), 7.40–7.34 (m, 6H), 7.28–7.20 (m, 2H), 5.90–5.78 (m, 1H), 5.29 (s,
1H), 5.04–4.96 (m, 2H), 3.41 (s, 3H) 3.29–3.25 (m, 2H), 2.30 ppm (s,
3H); 13C NMR (125 MHz, CDCl3): d = 149.04, 148.00, 141.30, 135.86,
131.43, 128.43, 128.20, 127.19, 126.72, 126.64, 125.36, 120.86, 118.36,
115.45, 77.38, 56.78, 28.29, 12.58 ppm; MS (70 eV): m/z (%):318 (3.10)
[M+], 105 (100) [C6H5CO]+, HRMS calcd for C22H22O2: 318.1620,
found: 318.1620.
5
1 f
4 faa, 73%
6
7
18
24
1g
1h
4gaa, 65%
4haa, 57%
Received: October 2, 2007
Revised: December 6, 2007
Published online: January 29, 2008
Keywords: cyclization · domino reactions · furans ·
multicomponent reactions · palladium
.
8
72
1i
4iaa, 63%
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alternative reaction mechanism that is depicted below. We want
to thank the reviewer.
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