Gold(III)-catalyzed tandem reaction of O-arylhydroxylamines with 1,3-dicarbonyl compounds: Highly selective synthesis of 3-carbonylated benzofuran derivatives

Article abstract of DOI:10.1021/jo101357d

Figure presented. A highly regioselective protocol for the synthesis of 3-carbonylated benzofuran derivatives has been developed involving the gold(III)-catalyzed tandem condensation/rearrangement/cyclization reaction of O-arylhydroxylamines with 1,3-dicarbonyl compounds.

Full text of DOI:10.1021/jo101357d

pubs.acs.org/joc
patterns,3-5 among which, however, those related to the
Gold(III)-Catalyzed Tandem Reaction of
O-Arylhydroxylamines with 1,3-Dicarbonyl
Compounds: Highly Selective Synthesis of
3-Carbonylated Benzofuran Derivatives
synthesis of 3-CBFs have a lack of development. Represen-
tative methods include Pd-catalyzed cascade carbonylative
annulation of o-hydroxyarylacetylenes in the presence of CO
gas,4a-c tandem Michael addition/cyclization of quinones
with 1,3-dicarbonyl compounds or β-(dimethylamino)vinyl
ketones,4d-f CuI-catalyzed coupling of 1-bromo-2-iodoben-
zenes and β-keto esters,4g and BBr3-mediated domino ring
cleavage/deprotection/annulation reaction of 2-alkylidenet-
etrahydrofurans.4h Unfortunately, most of these procedures
suffer from one or more limitations such as the requirement
of highly toxic CO gas, multistep processes, high catalyst
loading, and/or not easy availability of starting materials.
Recently, oxidative annulation protocol has been developed
as an alternative to 3-CBFs with high efficiency, as exempli-
fied in the FeCl3-mediated ring closure of R-arylketones4i
and the Fe(III)-catalyzed tandem oxidative coupling/cycli-
zation reaction of phenols with β-keto esters.4j However,
harsh reaction conditions and using external oxidants re-
present the main drawbacks. Li4k and co-workers have
Yunkui Liu,* Jianqiang Qian, Shaojie Lou, and
Zhenyuan Xu*
State Key Laboratory Breeding Base of Green
Chemistry-Synthesis Technology, Zhejiang University of
Technology, Hangzhou 310014, People’s Repubilc of China
ykuiliu@zjut.edu.cn; greensyn@zjut.edu.cn
Received July 10, 2010
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A highly regioselective protocol for the synthesis of
3-carbonylated benzofuran derivatives has been developed
involving the gold(III)-catalyzed tandem condensation/
rearrangement/cyclization reaction of O-arylhydroxyla-
mines with 1,3-dicarbonyl compounds.
3-Carbonylated benzofuran (3-CBF) derivatives represent
an important class of members in the benzofuran1 family
exhibiting unique biological and pharmacological activities.2
To date, many approaches have been explored for the con-
struction of benzofuran scaffold with different functional
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Published on Web 08/13/2010
DOI: 10.1021/jo101357d
r
2010 American Chemical Society

Liu et al.
JOCNote
TABLE 1. Optimization of Reaction Conditionsa
On the other hand, the study of recently popularized
gold6-catalyzed tandem reactions7 has resulted in significant
achievements in the construction of various heterocycles.3a,8
In this regard, we once reported an efficient and highly
selective approach to 4H-chromene derivatives via gold(III)-
catalyzed condensation/annulation tandem reaction of
ketones with phenols,8h and a temperature-controlled highly
regioselective synthesis of 3,4-dihydrocoumarin derivatives
via gold(III)-catalyzed tandem rearrangement/cyclization of
(E)-2-(aryloxymethyl)alk-2-enoates.8i Recently, Tomkinson5h
and Naito5v have developed efficient methods for the synth-
esis of benzofurans involving methanesulfonic acid (2 equiv)
or trifluoroacetyl triflate (5 equiv)-triggered [3,3]-sigmatro-
pic rearrangement of oxime ethers generated from the con-
densation of O-arylhydroxylamines with monoketones. In
light of their reports, we envisioned that 3-CBFs might be
accessed when 1,3-dicarbonyl compounds were used as sub-
strates. Herein, we present a gold(III)-catalyzed (only with
3 mol %) highly selective protocol for the synthesis of 3-CBFs
via one-pot tandem reaction of O-arylhydroxylamines with
1,3-dicarbonyl compounds.
Initially, the model reaction between O-phenylhydroxyla-
mine 1a and acetylacetone 2a was investigated under a broad
range of reaction conditions (Table 1; Table 1S in the SI).
When 1a was subjected to react with 2a in the presence of
AuCl3/3AgOTf (3 mol % based on 1a) in DCE at 90 °C for 3 h,
the target product 3aa was isolated in 46% yield (entry 1).
The AuCl3/3AgOTf catalytic system showed the best per-
formance in nitromethane among several solvents examined,
affording 3aa in 78% yield (entry 1). It was found that silver
salts had profound effects on the tandem reaction.9 While
employment of AgBF4, AgCN, AgNO2, or AgF in combina-
tion with AuCl3 showed a modest catalytic activity for the re-
action (Table 1S, SI), a combination of AgNTf2 with AuCl3
displayed almost equal effectiveness as AuCl3/3AgOTf
(entry 2 vs 1), and a AuCl3/3AgSbF6 combined system was
identified to be the best choice for the reaction (entry 3). A
combined system of AuCl3 and AgSbF6 with a molar ratio of
1:1 was less effective than the AuCl3/3AgSbF6 system(entry4).
Cationic Au(I) catalysts were not suitable for the reaction
(entries 7-10). The reaction could hardly take place without
a catalyst (entry 19), or in the presence of AuCl3 or AgSbF6
alone (entries 6, 11). Using a range of other conventional
Lewis or Brønsted acids as catalyst resulted in far less effecti-
veness even at a catalyst loading of 30 mol % (entries 12-18),
indicating that cationic gold(III) species were indispensable
in reaching high reactivity for the tandem reaction.
entry
1
catalyst (0.03 mmol)
AuCl3/3AgOTf
solvent
DCEb
dioxane
yield (%)
46
58
45
22
5
78
79
82
73
67
10
51
40
31
46
0
41
25
36
7
0
<3
0
THFc
toluene
CH3CNc
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
AuCl3/3AgNTf2
AuCl3/3AgSbF6
AuCl3/AgSbF6
AuCl3/3AgBF4
AuCl3
AuCl/AgOTf
AuCl/AgSbF6
PPh3AuCl/AgOTf
PPh3AuNTf2
d
AgSbF6
e
AlCl3 e
ZnCl2
e
FeCl3
Cu(OTf)2
e
HCle,f
HOTfe
MeSO3He
none
0
aCarried out on 1 mmol of 1a and 1.2 mmol of 2a in the presence of
catalyst in solvent (3 mL) at 90 °C for 3 h. bDCE = 1,2-dichloroethane.
cThe reaction temperature at reflux. dThe amount of catalyst is 0.09
mmol. The amount of catalyst is 0.3 mmol. Aqueous HCl (37 wt %)
was used.
e
f
developed a mild and general route for the synthesis of 3-CBFs
involving cycloaddition of arynes with iodonium ylides. De-
spite significant advance, a stoichiometric amount of iodoben-
zene byproduct is generated in the method. Owing to their
importance in medicinal chemistry, it is still highly desirable to
develop general and efficient new approaches to 3-CBFs.
(6) For reviews on gold catalysts, see: (a) Hashmi, A. S. K.; Rodolph, M.
ꢀ
ꢀ~
Chem. Soc. Rev. 2008, 37, 1766. (b) Jimenez-Nunez, E.; Echavarren, A. M.
Chem. Rev. 2008, 108, 3326. (c) Marion, N.; Nolan, S. P. Chem. Soc. Rev.
2008, 37, 1776. (d) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239.
(e) Arcadi, A. Chem. Rev. 2008, 108, 3266. (f) Skouta, R.; Li, C.-J. Tetra-
hedron 2008, 64, 4917. (g) Muzart, J. Tetrahedron 2008, 64, 5815. (h) Hashmi,
A. S. K. Chem. Rev. 2007, 107, 3180. (i) Jimenez-Nunez, E.; Echavarren,
A. M. Chem. Commun. 2007, 333. (j) Hashmi, A. S. K.; Hutching, G. J.
Angew. Chem., Int. Ed. 2006, 45, 7896.
ꢀ
ꢀ~
(7) For reviews on tandem reactions, see: (a) Enders, D.; Grondal, C.;
Subsequently, the scope of 1,3-dicarbonyl compounds was
investigated under the optimized reaction conditions by
fixing O-phenylhydroxylamine 1a as a model substrate
(Table 2). Both acyclic (entries 1, 2, and 5-10) and cyclic
1,3-diketones (entries 3, 4) are suitable substrates for the
reaction, generally furnishing desired products in good to
excellent yields (81-93%, entries 1-10 except 2). For un-
symmetrical aryl alkyl 1,3-diketones, the present reaction
€
Huttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570. (b) Tietze, L. F.; Bell,
H. P.; Brasche, G., Eds. Domino Reactions in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2006. (c) Nicolaou, K. C.; Montagnon, T.; Snyder,
S. A. Chem. Commun. 2003, 551. (d) Tietze, L. F. Chem. Rev. 1996, 96, 115.
(8) For recent examples on the synthesis of heterocylces via gold-cata-
lyzed tandem reactions, see: (a) Ye, L.; Cui, L.; Zhang, G.; Zhang, L. J. Am.
Chem. Soc. 2010, 132, 3258. (b) Zhang, Q.; Cheng, M.; Hu, X.; Li, B.-G.; Ji,
J.-X. J. Am. Chem. Soc. 2010, 132, 7256. (c) Kothandaraman, P.; Rao, W.;
Foo, S. J.; Chan, P. W. H. Angew. Chem., Int. Ed. 2010, 49, 4619.
(d) Nakamura, I.; Okamoto, M.; Terada, M. Org. Lett. 2010, 12, 2453.
(e) Ueda, M.; Sato, A.; Ikeda, Y.; Miyoshi, T.; Naito, T.; Miyata, O. Org.
Lett. 2010, 12, 2594. (f) Liu, Y.; Xu, W.; Wang, X. Org. Lett. 2010, 12, 1448.
(g) Zhou, Y.; Zhai, Y.; Ji, X.; Liu, G.; Feng, E.; Ye, D.; Zhao, L.; Jiang, H.;
Liu, H. Adv. Synth. Catal. 2010, 352, 373. (h) Liu, Y.; Qian, J.; Lou, S.; Zhu,
J.; Xu, Z. J. Org. Chem. 2010, 75, 1309. (i) Liu, Y.; Qian, J.; Lou, S.; Xu, Z.
Synlett 2009, 2971. (j) Shi, Y.; Roth, K. E.; Ramgren, S. D.; Blum, S. A.
J. Am. Chem. Soc. 2009, 131, 18022. (k) Aponick, A.; Li, C.-Y.; Palmes, J. A.
Org. Lett. 2009, 11, 121. (l) Luo, T.; Schreiber, S. L. J. Am. Chem. Soc. 2009,
131, 5667. (m) Uemura, M.; Watson, I. D. G.; Katsukawa, M.; Toste, F. D.
J. Am. Chem. Soc. 2009, 131, 3464.
(9) For an excellent review on ligand effects in homogeneous gold
catalysis, see: (a) Grorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. Rev.
2008, 108, 3351. For silver salt additives in gold catalysis, see for examples:
ꢁ
(b) Lemiere, G. G.; Gandon, V.; Agenet, N.; Goddard, J.-P.; de Kozak, A.;
Aubert, C.; Fensterbank, L.; Malacria, M. Angew. Chem., Int. Ed. 2006, 45,
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7596. (c) Nieto-Oberhuber, C.; Munoz, M. P.; Bunuel, E.; Nevado, C.;
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~
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(d) Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 5964.
J. Org. Chem. Vol. 75, No. 18, 2010 6301

Liu et al.
JOCNote
TABLE 2. Au(III)-Catalyzed Tandem Reaction of O-Phenylhydroxy-
TABLE 3. Au(III)-Catalyzed Tandem Reaction of Acetylactone 2a
lamine 1a with Different 1,3-Dicarbonyl Compounds 2a
with Different O-Arylhydroxylamines 1a
aReaction conditions: 1 (1 mmol), 2a (1.2 mmol), AuCl3/3AgSbF6
(0.03 mmol), CH3NO2 (3 mL), 90 °C. bThe reaction temperature at
100 °C. cThe ratio of 3ka to 30ka; determined on the basis of 1H NMR
analysis.
(100% for 3ae-h, entries 5-8; 93% for 3ai, entry 9). When
unsymmetrical dialkyl 1,3-diketone 2j was subjected to react
with 1a, two regioisomeric products 3aj and 30aj in a ratio of
55:45 were isolated in a total yield of 81% (entry 10). The
reactions of β-keto esters with 1a resulted in regiospecific
formation of 3-alkoxycarbonyl-substituted benzofurans in
modest yields (45-56%, entries 11-13). In these cases, a
small amount of phenol was detected as the minor product.
Monoketones as well as their preparative O-phenyloxime
ethers were also examined for the reaction (entries 14 and 15).
Unfortunately, none of the desired product was obtained
while phenol was always detected as the major product,
suggesting the decomposition of reaction intermediates.
Next, the substitution variation of O-arylhydroxylamines
1 was investigated (Table 3). Both para- and ortho-substi-
tuted O-arylhydroxylamines 1 were able to react with 2a
affording target products in moderate to good yields (entries
1-3 and 5-9). Meta-substituted 1 gave predominantly one
isomer within which the carbon at the less sterically hindered
aReaction conditions: 1a (1 mmol), 2 (1.2 mmol), AuCl3/3AgSbF6
(0.03mmol), CH3NO2(3 mL), 90°C. bThe reactiontemperature at100°C.
cThe ratio of 3ai to 30ai; determined on the basis of 1H NMR analysis.
dPhenol was detected as minor product. ePhenol was detected as major
product. fPreparative O-phenyloxime ether was directly used as substrate.
exhibited excellent regioselectivity for the formation of 2-
alkyl-3-aroyl-substituted benzofuran isomer predominantly
6302 J. Org. Chem. Vol. 75, No. 18, 2010

Liu et al.
JOCNote
SCHEME 1
with 2 is depicted in Scheme 2. First, gold(III)-catalyzed con-
densation of 1 and 2 formed intermediate 4,10 which might be
isomerized into 40 under the reaction conditions.10a,11 Either
the oxygen atom (path a) or the nitrogen atom (path b) in the
arylhydroxylamine moiety would coordinate to the cationic
Au(III) center and then trigger the [3,3]-σ rearrangement
of 40.5h,v,8i Since electron-deficient O-arylhydroxyamines 1
showed better reactivity than their electron-rich counter-
parts, 40 undergoing [3,3]-σ rearrangement via path a is more
likely to give 5. Intramolecular annulation of 5 followed
by elimination of one molecule of NH3 from 6 eventually
furnished 3.
SCHEME 2. Proposed Mechanism
In summary, we have developed a unique gold(III)-cataly-
zed tandem reaction of O-arylhydroxyamines with 1,3-
dicarbonyl compounds, which furnished a variety of 3-carbony-
lated benzofuran derivatives with excellent regioselectivity.
Experimental Section
AuCl3 (9.1 mg, 0.03 mmol), AgSbF6 (30.8 mg, 0.09 mmol),
and CH3NO2 (2 mL) were added to a 10-mL flask in a glovebox.
The mixture was stirred at rt for 5 min before a CH3NO2
solution (1 mL) of 1a (1.0 mmol, 0.11 g) and 2a (1.2 mmol,
0.12 g) was added. Then the reaction mixture was stirred at
90 °C. Upon completion, the resulting mixture was diluted with
CH2Cl2 (10 mL) and filtered through Celite. After evaporation
of the solvent under vacuum, the residue was purified by column
chromatography on silica gel (200-300 mesh) with petroleum
ether-EtOAc (6:1) as eluent to give pure 3aa (143 mg, 82%).
Yellow oil; Rf 0.35 (cyclohexane-EtOAc, 6:1); IR (neat, cm-1) ν
1661; 1H NMR (CDCl3/TMS, 500 MHz) δ 7.95-7.93 (m, 1H),
7.46-7.44 (m, 1H), 7.33-7.28 (m, 2H), 2.78 (s, 3H), 2.64 (s, 3H);
13C NMR (CDCl3/TMS, 125 MHz) δ 194.3, 162.8, 153.6, 126.1,
124.4, 124.0, 121.4, 117.6, 111.0, 31.2, 15.4; MS (EI, 70 eV) m/z (%)
174 (40) [Mþ], 159 (100). For more details, see the Supporting
Information.
position was incorporated into the benzofuran scaffold
(>99% for 3ea, entry 4; 92% for 3ka, entry 10). Generally,
electron-deficient O-arylhydroxylamines 1 reacted with 2a
more smoothly than those substituted with electron-donating
groups and afforded higher yields of desired products (entries
1-7 vs entries 8-10). A range of functional groups including
halo (F, Cl, and Br), methyl, trifluoromethyl, and ester groups
were well tolerated under the reaction conditions.
Acknowledgment. Financial support from the Natural
Science Foundation of Zhejiang Province (No. Y407168),
the Foundation of Education of Zhejiang Province (No.
Z200803599), and the Opening Foundation of Zhejiang
Provincial Top Key Discipline is gratefully acknowledged.
Finally, preliminary mechanistic experiments revealed
that the condensation intermediate, i.e. β-phenoxyimino
ketone 4aa, was able to be isolated in 90% yield upon treat-
ment of 1a and 2a in nitromethane at 25 °C for 30 min in the
presence of 3 mol % of AuCl3/3AgSbF6. Subsequent em-
ployment of 4aa under the standard reaction conditions for
2 h also afforded the desired product 3aa in 84% yield
(Scheme 1). On the basis of these facts, a proposed mechan-
ism regarding the gold(III)-catalyzed tandem reaction of 1
Supporting Information Available: Experimental proce-
dures and characterization data of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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F.; Rossi, E. J. Org. Chem. 2003, 68, 6959. (b) Arcadi, A.; Bianchi, G.; Di
Giuseppe, A.; Marinelli, F. Green Chem. 2003, 5, 64.
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