Synthesis of difurylmethane derivatives via the gold-catalyzed tandem cycloisomerization/dimerization of epoxide alkynes

Article abstract of DOI:10.1002/adsc.200800130

A simple and convenient synthetic approach to difurylmethane derivatives has been developed via gold-catalyzed cycloisomerization of 1-oxiranyl-2-alkynyl esters and dimerization of the 2-(α-hydroxyalkyl)furans. The reaction takes place in the presence of 2 mol% of tetrachloroauric acid tetrahydrate (HAuCl₄·4H₂O) under very mild conditions.

Full text of DOI:10.1002/adsc.200800130

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DOI: 10.1002/adsc.200800130
Synthesis of Difurylmethane Derivatives via the Gold-Catalyzed
Tandem Cycloisomerization/Dimerization of Epoxide Alkynes
Ke-Gong Ji,a Yong-Wen Shen,a Xing-Zhong Shu,a Hui-Quan Xiao,a
Yong-Jiang Bian,a and Yong-Min Lianga,b,*
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, Peopleꢀs Republic of China
State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Science,
b
Lanzhou 730000, Peopleꢀs Republic of China
Fax : (+86)-931-891-2582; phone: (+86)-931-891-2593; e-mail: liangym@lzu.edu.cn
Received: March 1, 2008; Revised: March 22, 2008; Published online: May 16, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A simple and convenient synthetic ap-
proach to difurylmethane derivatives has been de-
veloped via gold-catalyzed cycloisomerization of 1-
oxiranyl-2-alkynyl esters and dimerization of the 2-
(a-hydroxyalkyl)furans. The reaction takes place in
the presence of 2 mol% of tetrachloroauric acid tet-
rahydrate (HAuCl4·4H2O) under very mild condi-
tions.
itself.[5] Only few publications have reported the em-
ployment of transition metals-catalyzed cycloisomeri-
zation reactions,[6] which have been proved as an effi-
cient way to construct the furan ring systems.[7] For in-
stance, Marson has reported that mercury(II)-cata-
lyzed isomerization of alkynyl epoxides to afford di-
furylmethanes.[6a] Consequently, the transition metal-
catalyzed cycloisomerization route to difurylmethanes
remains largely unexplored.
Keywords: cycloisomerization; dimerization; epoxy-
ACHTREUNGalkynes; furans; gold
Recently, it was reported that carbon-carbon and
carbon-heteroatom bonds can be formed under mild
conditions using gold catalysts.[8] Their ability to acti-
vate alkynes and promote the addition of nucleo-
philes has spurred growing investigations for the dis-
covery of selective reactions.[9] Several gold-catalyzed
Furan rings occur widely as key structural subunits in cycloisomerizations for the preparation of furans have
numerous natural products, such as pseudopterolide been developed, among which we have described the
A[1] and pseudopteranolide kallolide B,[2] while difur- gold-catalyzed tandem cycloisomerization of 1-oxiran-
ylmethanes look quite attractive. Difurylmethanes are yl-2-alkynyl esters 1 with nucleophiles to give 2,5-di-
of interest to the food industry as they are present as
substituted furans 4 (Scheme 1).[10] Without the addi-
ACHTREUNG
natural compounds in foods and beverages, such as tion of nucleophiles, water may play an important
licorice.[3] Furthermore, they are important intermedi- role in the cycloisomerization to give the 2-(a-hyd-
ates in the synthesis of various heterocyclic macromo-
ACHTRErUNG oxyalkyl)furans. Then, under the gold catalysts, the
lecules.[4] Consequently, the construction of this type latter may afford difurylmethanes through the dimeri-
of furan ring enjoys the continued development of zation process, which is an efficient approach to the
À
new methods. However, most attention has been paid formation of a C C bond.
to the classical route to the difurylmethanes, which
must contain the structure of the 2-substituted furan
Herein, we report the gold-catalyzed tandem cyclo-
AHCTREUNG
Initially, we started out our investigation by using
0.5 mmol of 1-oxiranyl-2-alkynyl ester 1a and 2 mol%
of HAuCl4·4H2O in 1,4-dioxane/H2O systems at room
temperature. Gratifyingly, the desired difurylmethane
2a was formed, along with undimerized 2-(a-hydroxy-
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Ke-Gong Ji et al.
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Scheme 1.
ACHTREUNG
tained in 68% yield after 10 min (Table 1, entry 3). this reaction was then examined, as depicted in
With other gold catalysts, such as NaAuCl4·2H2O, Table 2. We first investigated a range of esters of 1-
(PPh3)Cl/AgBF4, no superior re- oxiranyl-2-alkyn-1-ols.[11] The reaction works well with
AuCl3, AuCl and AuACHTREUNG
sults were obtained (Table 1, entries 4–7). Other tran- aromatic R2 groups (entries 1–3). Electron-rich aryl
sition metal catalysts such as AgBF4, PtCl2 and PdCl2 groups showed equal results to those with an elec-
were ineffective (entries 6–10). Protic acids such as tron-withdrawing groupin this cycloisomerization and
TFA and TsOH have also been applied to the reac- dimerization process (entries 2 vs. 3). While substrates
tion under identical conditions, but no reaction oc- like 1d and 1e gave the corresponding products in
curred (entries 11 and 12). Other solvents such as lower yields (entries 4 and 5), compounds having an
THF, ether and 1,2-dimethoxyethane produced lower aliphatic or H R2 groupwould be less stabilized for
yields of the desired products (entries 13–15). Thus, forming the intermediates C and the process of dime-
the use of HAuCl4·4H2O (2 mol%) in wet 1,4-dioxane rization (vide infra). Various aryl substituents on the
Table 1. Efficiency of transition-metal catalysts for the transformation of 1a to 2a.[a]
Solvent
Catalyst
Solvent
Time
Yield [%][b]
2a
3a
1
2
3
4
5
6
7
8
HAuCl4·4H2O
HAuCl4·4H2O
HAuCl4·4H2O
NaAuCl4·2H2O
AuCl3
1,4-dioxane/H2O=1:1
1,4-dioxane/H2O=10:1
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
12 h
12 h
20
25
68
64
38
61
60
0
30
28
0
0
0
0
0
0
10 min
30 min
25 min
30 min
30 min
2 h
AuCl
Au
A
AgBF4
9
PtCl2
1,4-dioxane
2 h
0
0
10
11
12
13
14
15
PdCl2
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
2 h
2 h
2 h
10 min
20 min
30 min
0
0
0
50
60
29
0
0
0
0
0
0
10 mol% TFA
10 mol% TsOH
HAuCl4·4H2O
HAuCl4·4H2O
HAuCl4·4H2O
ether
1,2-dimethoxyethane
[a]
Conditions: 0.5 mmol of 1a with 2 mol% of catalyst in wet 1,4-dioxane (2.0 mL) at room temperature (23–258C).
Isolated yield.
[b]
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Synthesis of Difurylmethane Derivatives
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Table 2. AuACHTREUNG
(III)-catalyzed synthesis of difurylmethanes 2 by cyclization of esters of 1-oxiranyl-2-alkyn-1-ols 1.[a]
Entry
1[b]
R1
R2
R3
Time [min]
2
Yield [%][c]
1
2
3
4
5
6
7
8
1a (7:5)
1b (10:7)
1c (2:1)
1d (2:1)
1e (9:7)
1f (16:7)
1g (7:5)
1h (2:1)
1i (2:1)
1j (2:1)
1k (1:0)
1l (1:0)
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
CH3
CH3
Et
10
10
10
20
20
10
10
20
25
10
10
10
20
2a
2b
2c
2d
2e
2f
2g
2h
2i
68
72
p-CH3-C6H4
p-Cl-C6H4
CH3
H
Ph
Ph
Ph
Ph
Ph
70
55[d]
49[d]
61
Ph
p-CH3-C6H4
m-CH3-C6H4
m-Cl-C6H4
p-Cl-C6H4
2-thienyl
Ph
62
64
61
60
70
72
55
9
10
11
12
13
2j
2k
2l
Ph
p-Cl-C6H4
Ph
Ph
Ph
1m (1:0)
2m
[a]
Conditions: 0.5 mmol of 1 with 2 mol% of catalysts in wet 1,4-dioxane (2.0 mL) at room temperature (23–258C).
syn/anti mixtures of the substrate were used; syn:anti ratio determined by H NMR.
Isolated yield.
Reaction run with 10 mol% catalyst loading.
[b]
[c]
[d]
1
alkyne moiety, including electron-rich, electron-poor alkyn-1-ols with different protective groups, as shown
and heteroaromatic ones such as the 2-thienyl group, in Table 3. The reaction works well with carbonate
were compatible with this reaction and generally protective groups (entries 1–3), while it affords the
good yields of the corresponding difurylmethanes desired product in lower yields when using 1-oxiranyl-
were obtained (entries 6–10). We have also investigat- 2-alkyn-1-ols that bear an aliphatic protective group
ed the reactions of alkynyloxiranes containing differ- (entries 4 and5). Substrates such as 1p bearing a
ent R3 which afforded the desired products in good methyl as protective group, only afford the desired
yields (entries 11–13).
product in 35% yield.
Furthermore, considering the impact of the leaving
In order to uncover the mechanism for the reaction,
groups on the reaction, we examined 1-oxiranyl-2- we started out our investigation by using esters of 1-
Table 3. Synthesis of difurylmethanes 2 by cyclization of 3-phenyl-1-(3-phenyloxiran-2-yl)prop-2-yl-1-ol (1) bearing different
protective groups.[a]
Entry
1[b]
R
Time [min]
Yield [%][c]
1
2
3
4
5
1a (7:5)
1n (2:1)
1o (1:1)
1p (1:1)
1q (1:1)
COCH3
COOCH3
10
20
10
60
25
68
66
65
35
40
COOC
Me
ACHTRE(UNG CH3)3
CH2CH=CH2
[a]
Conditions: 0.5 mmol of 1 with 2 mol% of catalysts in wet 1,4-dioxane (2.0 mL) at room temperature (23–258C).
syn/anti mixtures of the substrate were used; syn:anti ratio determined by H NMR.
Isolated yield.
[b]
[c]
1
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Ke-Gong Ji et al.
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On the basis of the above observations, a possible
reaction mechanism is proposed as shown in
Scheme 3, which may involve the following steps: (i)
coordination of the alkynyl moiety of A to the Au
catalyst gives the complex B, (ii) attack of the trace
amounts of water, anti-endo-dig cyclization affords
the organogold intermediate E, (iii) protonation of E
yields 2,3-dihydrofuran F and regenerates the catalyst
Au, (iv) F undergoes direct reductive elimination of
acetic acid, presumably via the corresponding oxoni-
um ion, to afford the 2-(a-hydroxyalkyl)furans G,[12]
(v) under the gold catalysis, G eliminates one mole-
cule water to afford ion intermediate H, (vi) ion inter-
mediate H attacks another molecule G to afford the
difurylmethanes I[6b] with loss of one molecule of al-
dehyde, which is an intermolecular Friedel–Crafts-
type reaction.[13] Alternatively, the reaction may in-
volve an oxonium ion C,[12] which is formed by attack
of trace amounts of H2O on the epoxide oxygen to
afford the gold-coordinated alkynes.[10,14] The oxonium
ion C then undergoes subsequent reaction with traces
of water followed by protonation to regenerate the
Au catalyst and eliminate one molecule of acetic acid
Scheme 2.
oxiranyl-2-alkyn-1-ols 1a in 1,4-dioxane/H2O systems to produce 2,3-dihydrofuran F.
under 2 mol% of HAuCl4·4H2O; the 2-(a-hydroxyal-
In summary, a novel and flexible method for the
kyl)furan 3a was formed along with difurylmethane synthesis of difurylmethanes has been developed
2a. Next we investigated 3a under the standard condi- through the cycloisomerization/dimerization of esters
tions and the desired product 2a was formed in 93% of 1-oxiranyl-2-alkyn-1-ols at room temperature
yield after 1 min. In the presence of 2 mol% of under gold catalysis. The starting materials are easily
NaAuCl4·2H2O, AuCl3 or AuCl, the reaction also accessible. Further studies, including detailed investi-
gave desired product 2a smoothly in high yields. TFA, gations into the mechanism and the scope of this reac-
chloroacetic acid and acetic acid have also been tion, are in progress in our laboratory.
tested, among which only TFA was effective
(Scheme 2).
Scheme 3. Proposed reaction mechanism for Au-catalyzed cyclization.
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Synthesis of Difurylmethane Derivatives
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Marshall, W. J. DuBay, J. Org. Chem. 1994, 59, 1703–
1708.
Experimental Section
[3] C. Frattini, C. Bicchi, C. Barettini, G. M. Nano, J.
Agric. Food Chem. 1977, 25, 1238–1241.
[4] a) A. Gandini, Adv. Polym. Sci. 1977, 25, 47; b) Chem.
General Remarks
Column chromatography was carried out on silica gel.
1H NMR spectra were recorded at 300 MHz in CDCl3 and
13C NMR spectra were recorded at 75 MHz in CDCl3. IR
spectra were recorded on an FT-IR spectrometer and only
major peaks are reported in cmÀ1. Melting points were de-
termined on a microscopic apparatus and are uncorrected.
All compounds were further characterized by elemental
Abstr. 1978, 88, 90046p.
[5] a) A. V. Butin, V. T. Abaev, V. V. Mel’chin, A. S. Dmi-
triev, Tetrahedron Lett. 2005, 46, 8439–8441; b) D. J.
Macquarrie, S. J. Tavener, M. A. Harmer, Chem.
Commun. 2005, 18, 2363–2365; c) S. Onitsuka, H.
Nishino, Tetrahedron 2003, 59, 755–765; d) A. V.
Gutnov, V. T. Abaev, A. V. Butin, A. S. Dmitriev, J.
Org. Chem. 2001, 66, 8685–8686; e) A. S. K. Hashmi,
M. C. Blanco, Eur. J. Org. Chem. 2006, 19, 4340–4342;
f) V. Nair, N. Vidya, K. G. Abhilash, Tetrahedron Lett.
2006, 47, 2871–2873; g) A. S. K. Hashmi, L. Schwarz, P.
Rubenbauer, M. C. Blanco, Adv. Synth. Catal. 2006,
348, 705–708; h) V. Nair, K. G. Abhilash, N. Vidya,
Org. Lett. 2005, 7, 5857–5859; i) T. Li, S. Cheng, J.-F.
Lee, L.-Y. Jang, J. Mol. Catal. A: Chem. 2003, 198,
139–149; j) V. Nair, N. Vidya, K. G. Abhilash, Synthesis
2006, 21, 3647–3653; k) A. Riad, Z. Mouloungui, M.
Delmas, A. Gaset, Synth. Commun. 1989, 19, 3169–
3173; l) I. G. Lovel, Yu. Sh. Gol’dberg, M. V. Shiman-
skaya, Khim. Geterotsikl. Soedin. 1989, 6, 746–749;
m) M.-E. Schwenter, P. Vogel, Chem. Eur. J. 2000, 6,
4091–4103.
analysis; copies of their H NMR and 13C NMR spectra are
1
provided in the Supporting Information. Room temperature
is 23–258C. Commercially available reagents and solvents
were used without further purification. THF was distilled
immediately before use from Na/benzophenone.
General Procedure for Cycloisomerization/
DimeriACHTREUNGzation at Room Temperature in Wet 1,4-
Dioxane
To a solution of the esters of 1-oxiranyl-2-alkyn-1-ols 1
(0.50 mmol) in wet 1,4-dioxane (2.0 mL) was added 4.00 mg
(0.01 mmol, 2 mol%) of HAuCl4·4H2O under air at room
temperature. When the reaction was considered complete as
determined by TLC analysis, the reaction mixture was dilut-
ed with ethyl ether (40 mL), washed with water, saturated
brine, dried over Na2SO4 and evaporated under reduced
pressure. The residue was purified by chromatography on
silica gel to afford corresponding difurylmethanes 2.
[6] a) C. M. Marson, S. Harper, J. Org. Chem. 1998, 63,
9223–9231; b) J. A. Marshall, X. j. Wang, J. Org. Chem.
1991, 56 ,960–969.
[7] a) S. F. Kirsch, Org. Biomol. Chem. 2006, 4, 2076–
2080; b) R. C. D. Brown, Angew. Chem. 2005, 117,
872–874; Angew. Chem. Int. Ed. 2005, 44, 850–852;
c) T. Eicher, S. Hauptmann, A. Speicher, The Chemis-
try of Heterocycles, 2nd edn., Wiley-VCH, Weinheim,
2003, pp 57–62; d) A. Jeevanandam, A. Ghule, Y.-C.
Ling, Curr. Org. Chem. 2002, 6, 841–864; e) S. Cacchi,
G. Fabrizi, A. Goggiomani, Heterocycles 2002, 56, 613–
632.
[8] For recent reviews on gold catalysis, see: a) A. S. K.
Hashmi, Angew. Chem. 2005, 117, 7150–7154; Angew.
Chem. Int. Ed. 2005, 44, 6990–6993; b) A. Hçffmann-
Rçder, N. Krause, Org. Biomol. Chem. 2005, 3, 387–
391; c) A. S. K. Hashmi, G. J. Hutchings, Angew. Chem.
2006, 118, 8064–8105; Angew. Chem. Int. Ed. 2006, 45,
7896–7936; d) E. JimØnez-NfflÇez, A. M. Echavarren,
Chem. Commun. 2007, 333–346; e) D. J. Gorin, F. D.
Toste, Nature 2007, 446, 395–403; f) A. S. K. Hashmi,
Chem. Rev. 2007, 107, 3180–3211.
General Procedure for Cycloisomerization at Room
Temperature in 1,4-Dioxane/H2O (1:1)
To a solution of the acetate of 1-oxiranyl-2-alkyn-1-ol 1a
(0.50 mmol) in 1,4-dioxane/H2OCAHTRE(UNG 1:1) was added 4.00 mg
(0.01 mmol, 2 mol%) of HAuCl4·4H2O under air at room
temperature. After 12 h, the reaction mixture was diluted
with ethyl ether (40 mL), washed with water, saturated
brine, dried over Na2SO4 and evaporated under reduced
pressure. The residue was purified by chromatography on
silica gel to afford 2-(a-hydroxyalkyl)furan 3a in 30% yield
as a solid, along with difurylmethane 2a in 20% yield.
Acknowledgements
We thank the NSF (NSF-20621091, NSF-20732002) for finan-
cial support.
[9] a) Y. Liu, F. Song, Z. Song, M. Liu, B. Yan, Org. Lett.
2005, 7, 5409–5412; b) A. S. K. Hashmi, P. Sinha, Adv.
Synth. Catal. 2004, 346, 432–438; c) A. S. K. Hashmi,
L. Schwarz, J.-H. Choi, T. M. Frost, Angew. Chem.
2000, 112, 2382–2385; Angew. Chem. Int. Ed. 2000, 39,
2285–2288; d) C.-Y. Zhou, P. W. H. Chan, C.-M. Che,
Org. Lett. 2006, 8, 325–328; e) J. Zhang, H.-G.
Schmalz, Angew. Chem. 2006, 118, 6856–6859; Angew.
Chem. Int. Ed. 2006, 45, 6704–6707; f) T. Yao, X.
Zhang, R. C. Larock, J. Org. Chem. 2005, 70, 7679–
7685; g) T. Yao, X. Zhang, R. C. Larock, J. Am. Chem.
Soc. 2004, 126, 11164–11165; h) X. Liu, Z. Pan, X. Shu,
X. Duan, Y. Liang, Synlett 2006, 1962–1964; i) X.-Z.
References
[1] a) M. M. Bandurraga, F. William, S. F. Donovan, J.
Clardy, J. Am. Chem. Soc. 1982, 104, 6463–6465;
b) J. A. Marshall, L. M. McNulty, D. Zou, J. Org.
Chem. 1999, 64, 5193–5200; c) J. A. Marshall, J. Liao, J.
Org. Chem. 1998, 63, 5962–5970; d) J. A. Marshall
E. M. Wallace 1, J. Org. Chem. 1995, 60, 796–797.
[2] a) S. A. Look, M. T. Burch, W. Fenical, Z. Qi-tai, J.
Clardy, J. Org. Chem. 1985, 50, 5741–5746; b) J. A.
Adv. Synth. Catal. 2008, 350, 1275 – 1280
ꢁ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1279

Ke-Gong Ji et al.
COMMUNICATIONS
Shu, X.-Y. Liu, H.-Q. Xiao, K.-G. Ji, L.-N. Guo, Y.-M.
Liang, Adv. Synth. Catal. 2008, 350, 243–248.
[10] X.-Z. Shu, X.-Y. Liu, H.-Q. Xiao, K.-G. Ji, L.-N. Guo,
C.-Z. Qi, Y.-M. Liang, Adv. Synth. Catal. 2007, 349,
2493–2498.
[13] According to the refereeꢀs opinion to further uncover
the mechanism and enhance the synthetic utility, we in-
vestigated the reaction of epoxyalkyne 1a with furan
under the standard conditions. The desired asymmetric
product
2-[furan-2-ylACHTRE(UNG phenyl)methyl]-5-phenylfuran
[11] syn/anti Mixtures of the substrate esters of 1-alkynyl-
2,3-epoxy alcohols were used. The reaction products
were not found to be affected by the stereochemical
configuration of the substrate. For a full explanation
and definition of the terms syn and anti as used herein
see: C. M. Marson, D. W. M. Benzies, A. D. Hobson,
Tetrahedron 1991, 47, 5491–5506.
was obtained. This is consistent with the proposed
mechanism in Scheme 3. After losing one molecule of
H2O, 2-(a-hydroxyalkyl)furans G might lead to the for-
mation of the cation intermediates H, which undergo
the Friedel–Crafts-type reaction to afford the difuryl-
methanes I.
[12] Similar intermediates have been reported by Sarpong,
see: a) B. G. Pujanauski, B. A. Bhanu Prasad, R. Sar-
pong, J. Am. Chem. Soc. 2006, 128, 6786–6787; for the
transition metal-catalyzed oxonium ion formation, see:
b) N. Asao, K. Takahashi, S. Lee, T. Kasahara, Y. Ya-
mamoto, J. Am. Chem. Soc. 2002, 124, 12650–12651;
c) N. Asao, T. Nogami, S. Lee, Y. Yamamoto, J. Am.
Chem. Soc. 2003, 125, 10921–10925; d) N. Asao, H.
Aikawa, Y. Yamamoto, J. Am. Chem. Soc. 2004, 126,
7458–7459; e) J. Zhu, A. R. Germain, J. A. J. Porco,
Angew. Chem. 2004, 116, 1259–1263; Angew. Chem.
Int. Ed. 2004, 43, 1239–1243; f) K. Sato, S. S. Yudha, N.
Asao, Y. Yamamoto, Synthesis 2004, 9, 1409–1412;
g) H. Kusama, H. Funami, M. Shido, Y. Hara, J.
Takaya, N. Iwasawa, J. Am. Chem. Soc. 2005, 127,
2709–2716.
[14] Asimilar mechanism has been reported by Marson,
see: C. M. Marson, J. Campbell, Tetrahedron Lett. 1997,
38, 7785–7788.
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