Gold-catalyzed cascade reactions of furan-ynes with external nucleophiles consisting of a 1,2-rearrangement: Straightforward synthesis of multi-substituted benzo[b]furans

Article abstract of DOI:10.1002/chem.201400112

A gold-catalyzed cycloisomerization of silyl-protected 2-(1-alkynyl)-2- alken-1-(2-furanyl)-1-ols with various nucleophiles including water, alcohol, aniline, sulfonamide, and electron-rich arene has been developed. The method provides a highly efficient access to 5,7-disubstituted or 2,5,7-trisubstituted benzo[b]furans with a wide diversity of substituents under mild reaction conditions, which are not easily available by other methods. Remarkably, an interesting rearrangement of the alkyl group from C2 to the C3 position of the furan ring takes place during the cyclization process. The following gold-assisted allylic substitution enables an elaboration of benzo[b]furans on its side chain of the C5 position with a wide range of functional groups.

Full text of DOI:10.1002/chem.201400112

DOI: 10.1002/chem.201400112
Full Paper
&
Cyclization
Gold-Catalyzed Cascade Reactions of Furan-ynes with External
Nucleophiles Consisting of a 1,2-Rearrangement: Straightforward
Synthesis of Multi-Substituted Benzo[b]furans
Ning Sun, Xin Xie, and Yuanhong Liu*[a]
Abstract: A gold-catalyzed cycloisomerization of silyl-pro-
tected 2-(1-alkynyl)-2-alken-1-(2-furanyl)-1-ols with various
nucleophiles including water, alcohol, aniline, sulfonamide,
and electron-rich arene has been developed. The method
provides a highly efficient access to 5,7-disubstituted or
2,5,7-trisubstituted benzo[b]furans with a wide diversity of
substituents under mild reaction conditions, which are not
easily available by other methods. Remarkably, an interesting
rearrangement of the alkyl group from C2 to the C3 position
of the furan ring takes place during the cyclization process.
The following gold-assisted allylic substitution enables an
elaboration of benzo[b]furans on its side chain of the C5 po-
sition with a wide range of functional groups.
Introduction
The benzo[b]furans constitute an important class of heterocy-
clic compounds that widely occur as a core structural motif in
biologically active natural products and pharmaceutical
agents.[1] For example, obovaten is one of the characteristic
member of the neolignan family, which is known as an active
antitumor agent.[2] 2-Aminoethylbenzofurans such as “a” in
Figure 1 represent a new class of non-imidazole H3 antagonists,
can operate under mild reaction conditions, is highly desired.
Most of the synthetic approaches concentrated on the con-
struction of the furan framework by using ortho-functionalized
phenols,[5,6] such as palladium-catalyzed tandem reaction of o-
halophenols with terminal alkynes,[6] whereas there are few re-
ports based on the aromatic benzene ring formation.[7] The de-
velopment of the new strategy through formation of the ben-
zene ring of benzofurans would be quite useful because it
may allow the introduction of the substituents on the phenyl
ring in a highly regioselective manner. Recently, we carried out
a series of gold-catalyzed[8] cascade reactions of furan-ynes
through an endo-dig-type cyclization leading to a variety of
functionalized products such as benzenes, phenanthrenes, and
fulvenes.[9] The methodology has been applied to the synthesis
of 1-naphthol derivatives from tert-butyldimethylsilyl (TBS)-pro-
tected (o-alkynyl)phenyl 2-furylcarbinols.[10] Inspired by these
results and during our further study on gold-catalyzed forma-
tion of fulvenes[9c] (Scheme 1, [Eq. (1)]), we envisioned that the
use of more readily available substrate of silyl-protected 2-(1-
alkynyl)-2-alken-1-(2-furanyl)-1-ols 1 compared with the sub-
strates shown in Scheme 1, Equation (1), might also undergo
a similar type of cyclization to furnish siloxy-substituted ful-
venes. However, to our surprise, the reaction proceeded effi-
ciently to generate the benzo[b]furan 2 through construction
of the benzene ring in the presence of external nucleophiles
instead of fulvene (Scheme 1, [Eq. (2)]). Interestingly, a rear-
rangement of the C2 alkyl group on the furan ring was in-
volved in these reactions. Recently, Hashmi et al. reported
a 2,3-shift reaction of furans tethered with aryl- or heteroaryl-
substituted alkynes leading to 2,7-disubstituted benzo[b]furan-
s[7a] (Scheme 1, [Eq. (3)]). Our reaction presented here allows
a facile synthesis of 5,7-disubstituted and 2,5,7-trisubstituted
benzo[b]furans with a wider reaction scope. Moreover, the side
Figure 1. Biologically active benzo[b]furans.
which retain high potency at human and rat receptors with ef-
ficient CNS penetration.[3] The 2,7-disubstituted benzofuran
b can be used for the treatment of type II diabetes (Figure 1).[4]
Therefore, the development of general and efficient methodol-
ogies for the synthesis of benzo[b]furans, especially those that
[a] N. Sun, X. Xie, Prof. Dr. Y. Liu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences, 345 Lingling Lu
Shanghai 200032 (P.R. China)
Fax: (+86)021-64166128
E-mail: yhliu@mail.sioc.ac.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201400112.
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Table 1. Optimization studies for the formation of benzo[b]furan 2a.
Entry Substrate Catalyst
[5 mol%]
Solvent H2O
t
Yield of
2a[a] [%]
[equiv] [h]
1
1a
1a
1a
1a
1a
1a’
1a
1a
1a
1a
1a
1a
1a
1a
1a
A
A
A
A
A
A
A
A
THF
THF
THF
THF
THF
THF
DCE
toluene
–
–
–
2
5
5
5
5
5
5
5
5
5
5
5
14
5
9
38
2[b]
3[b,d]
4
–
–
[c]
[e]
3
89
5
6
7
8
1.5 93
6.5 75
9
6
35
58
72
56
72
24
12
9
[Au(PPh3)][SbF6] THF
[Au(PPh3)][NTf2] THF
[Au(IPr)][SbF6]
[Au(PPh3)(OTf)] THF
[AuCl3]
40
9
22
16
15
5
10
11
12
13
14
15
THF
THF
THF
THF
[f]
Scheme 1. Gold-catalyzed transformation of furan-ynes.
[Au(PPh3)Cl]
[AgSbF6]
–
3.5 NR[g]
[a] Yields of the isolated products. [b] In the presence of 4 ꢁ MS. [c] A
yield of 96% of 1a was recovered. [d] T=808C, in a sealed tube. [e] A
yield of 97% of 1a was recovered. [f] A yield of 98% of 1a was recov-
ered. [g] NR=No reaction.
chain of the C5 substituent of the benzofuran products can be
further elaborated by using a variety of functional groups.
Results and Discussion
The requisite substrates are easily synthesized by the addition
of a (2-furanyl)lithium reagent to an enynyl aldehyde followed
by protection with silyl chloride or through Sonogashira cou-
pling of the corresponding aryl or vinyl halides with terminal
alkynes.[11] Our studies began with the investigation of the pos- The frequently used gold(I) complexes such as [Au(PPh3)]-
sible cyclization of tert-butyldiphenylsilyl (TBDPS)-protected 2- [SbF6], [Au(PPh3)][NTf2], or [Au(IPr)][SbF6] (IPr=2,6-bis(diisopro-
furylcarbinol 1a. In light of the superior catalytic activity of pylphenyl)imidazol-2-ylidene; NTf2 =bis(trifluoromethanesulfo-
JohnPhos(MeCN)AuSbF6 (catalyst A) bearing a biarylphosphine nyl)imidate) could also catalyze this cycloisomerization reaction
ligand in various gold-catalyzed reactions,[12] catalyst
A
to afford moderate to good yields of 2a (Table 1, entries 9–11),
(5 mol%) was first employed as the catalyst. The reaction pro- however, the use of less electrophilic [Au(PPh3)][OTf] (OTf=tri-
ceeded at room temperature in THF to give benzo[b]furan 2a fluoromethanesulfonate) only led to 24% yield of 2a (Table 1,
in 38% yield after 14 h (Table 1, entry 1). The presence of an entry 12). Control experiments with [AuCl(PPh3)] or [AgSbF6]
OH group indicated that 2a might be formed by the reaction could not afford the desired benzofuran 2a (Table 1, entries 14
of 1a with a small amount of water contained in the reaction and 15). The use of non-protected 2-furylcarbinol such as (E)-2-
system. In the presence of 4 ꢁ molecular sieves (MS), no reac- benzylidene-1-(5-methylfuran-2-yl)-4-phenylbut-3-yn-1-ol only
tion occurred at room temperature or at 808C, because most afforded a complicated mixture under gold-catalyzed condi-
of 1a was recovered (Table 1, entries 2 and 3). As expected, ad- tions shown in Table 1, entry 5. To our surprise, X-ray crystal
dition of H2O (2.0 equiv) to the reaction mixture led to a drastic analysis of analogous products 2i and 3i[13] (see below) indi-
improvement in which 89% of 2a could be obtained within cated that the structure of 2a is a 2,5,7-trisubstituted benzo-
3 h (Table 1, entry 4). Increasing the amount of H2O to furan, but not a 2,4,6-trisubstituted benzofuran 2a’ formed by
5.0 equiv resulted in a shorter reaction time and higher prod- direct hydroarylation of the furan ring through its C3 position
uct yield (93%, Table 1, entry 5). When the TBS-protected sub- followed by subsequent allylic substitution. The results indicat-
strate 1a’ was employed, the yield of 2a decreased to 75%, ed that a rearrangement of the alkyl group from C2 to the C3
possibly due to the lower stability of 1a’ compared with 1a in position of the furan ring occurred during the cyclization pro-
acidic medium (Table 1, entry 6). Changing the solvent to 1,2- cess. The substituent “castling” process[14] to form a 2,7-disub-
dichloroethane (DCE) or toluene resulted in lower yields of 2a stituted benzofuran was also observed by Hashmi et al. as
(35–58%, Table 1, entries 7 and 8). Thus, THF was proved to be shown in Scheme 1, Equation (3).[7a]
the best solvent, possibly due to the fact that it can stabilize
Next, we investigated the substrate scope under the reac-
the cationic intermediate formed during the reaction process. tion conditions shown in entry 5, Table 1, and the results are
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tive yield. The strong electron-
withdrawing ÀNO2 functionality
was also compatible for this re-
action, however, only 60% of 2h
was obtained after stirring at
room temperature for 20 h using
10 mol% of catalyst A. The
thienyl group was well-tolerated,
leading to 2i in 84% yield. In
particular, a range of alkyl-substi-
tuted alkynes such as n-butyl,
cyclopropyl, or benzyloxymethyl-
substituted alkynes were effi-
ciently transformed into benzo-
furans 2j–2l in 66–86% yields.
The alkyl-substituted furan-ynes
were not mentioned in Hashmi’s
work[7a] described in Scheme 1.
Our reactions enlarged the reac-
tion scope significantly for this
chemistry. Next, the substituents
on the alkene terminus (R1) were
examined.
Methyl-substituted
substrates, either with an aryl or
alkyl group on its alkyne termi-
nus, underwent the cyclization
smoothly to provide 2m and 2n
in 83 and 77% yields, respective-
ly. The alkene substituent could
also be a hydrogen, and the cor-
responding 2o was obtained in
80% yield with a ÀCH2OH func-
tionality. The substituent effects
on the furanyl moiety (R3) were
also investigated. The 5-phenyl-
substituted furan 1p with
a phenyl group on the alkene
Scheme 2. Synthesis of benzo[b]furans by the gold-catalyzed cascade reaction of furan-ynes 1. [a] Yields of the iso-
lated products. [b] 10 mol% of catalyst A was used. [c] Complex mixture.
summarized in Scheme 2. The reaction proved to be quite gen-
eral with respect to substitution of R1–R3, since aryl, alkyl, and
hydrogen groups were all suitable for R1 and R3, and aryl, het-
eroaryl, and alkyl groups were suitable for R2 substituents, pro-
viding a broad diversity of the products. Gold catalyst A
showed high catalytic performance in this system, since most
of the reactions could be completed within several hours at
room temperature, and the desired benzo[b]furans were ob-
tained in moderate to high yields. The substituent effects on
the alkyne terminus (R2) were examined first. The reactions tol-
erated both electron-rich (p-MeO, o-MeO, m-MeO, 3,4,5-tri-
(MeO)) and electron-poor (p-Cl, p-CF3, p-NO2) aryl substituents,
furnishing the corresponding benzofuran derivatives 2b–2h in
60–99% yields. Usually, electron-rich alkynes made the reaction
faster than the electron-poor ones. Interestingly, a sterically en-
cumbered o-MeO-substituted substrate 1c was smoothly con-
verted into the corresponding 2c in a high yield of 88%, possi-
bly due to the weak interaction of the MeO group with gold
catalyst, which facilitates the formation of a gold-alkyne com-
plex. The 3,4,5-tri(MeO)-substituted 1e afforded 2e in quantita-
moiety was also suitable under the reaction conditions, fur-
nishing multi-substituted benzofuran 2p in 74% yield. We also
studied the reactivity of unsubstituted furan substrates 1q–1s.
It was found that the nature of the substituents on the alkene
terminus had a marked influence on the cyclization process.
Substrates 1q and 1r with alkyl or aryl groups on the alkene
moiety reacted with water without problem to give 2q and 2r
in 50 and 91% yields, respectively. However, substrate 1s with
a terminal alkene moiety did not deliver the desired benzofur-
an, but instead, a complicated reaction mixture was observed.
We proceeded to examine the reactions with a range of nu-
cleophiles using 1a or 1p as the furan-yne component, and
the results are summarized in Table 2. It was found that a varie-
ty of alcohols could be used as effective nucleophiles for this
reaction. For example, treatment of 1a with methanol or etha-
nol afforded the corresponding cycloisomerization products
3a and 3b in 70 and 80% yields, respectively (Table 2, entries 1
and 2).[15] Benzyl alcohol or allyl alcohol were also well-suited,
leading to 3c and 3d in 79 and 62% yields, respectively
(Table 2, entries 3 and 4). Anilines were also successfully em-
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tron-rich arenes such as 1,3,5-trimethoxybenzene also reacted
with 1a in the presence of 10 mol% catalyst A to afford 3j in
62% yield (Table 2, entry 10). So far, no positive results were
obtained by using 1,3-dicarbonyl compounds such as pentane-
2,4-dione or 1,3-diphenylpropane-1,3-dione.
Table 2. Gold-catalyzed cyclization of furan-ynes 1 with various nucleo-
philes.
A proposed reaction mechanism[17] for this gold-catalyzed
cycloisomerization of furan-ynes in the presence of external
nucleophiles is depicted in Scheme 3. The reaction starts with
the activation of the alkyne moiety in 1 through coordination
with the gold catalyst. This is followed by attack of the C2 po-
sition of furan ring to the triple bond in a manner of 5-endo-
dig cyclization to give a spirocyclic intermediate 5. Then,
a Wagner–Meerwein rearrangement[7a,18] of the alkyl group fol-
lowed by elimination of a proton gives intermediate 7. Proto-
deauration of 7 delivers intermediate 8. Allylic substitution of 8
with external nucleophile, possibly assisted by gold catalyst,[19]
affords the benzo[b]furans 2 or 3.
Entry
Enyne
NuH
t
[h]
Product
Yield
[%][a]
1
2
3
1a
1a
1a
MeOH
EtOH
1
1
1
3a
3b
3c
70
80
79
4
1a
1
3d
62
5
1a
1
3e
96
6
7
1a
1a
1
2
3 f
78
3g
81[b]
Conclusion
8
9
1a
1p
14
2
3h
3i
75[c]
47[d]
We have developed a gold-catalyzed cycloisomerization of
furan-ynes bearing a silyloxy group at the a-position of the
furan rings with various nucleophiles, which provides a highly
efficient route for the synthesis of multi-substituted benzo[b]-
furans. The reactions tolerate a wide variety of functional
groups both on the furanyne substrates and the nucleophiles,
making this approach highly attractive. The method is useful
to pharmaceutical chemists for drug discovery and develop-
ment. Mechanistically, it is suggested that the formation of
a spirocyclic cationic intermediate followed by 1,2-rearrange-
ment and gold-catalyzed allylic substitution is involved in the
reaction process. It is anticipated that the use of other hetero-
cycles such as thiophene, pyrrole, indole, and so on, instead of
the furan moiety might also be suited for this chemistry. Fur-
ther extensions toward this subject are in progress.
TsNH2
10
1a
3
3j
62[e]
[a] Yields of the isolated product. [b] T=508C, in THF. [c] T=808C, in tolu-
ene. [d] 3.0 equiv of TsNH2 was used, 508C, in toluene. [e] 10 mol% cata-
lyst A was used, 608C, in toluene.
ployed as nucleophiles for this cyclization;[16] for example, ani-
lines bearing strong electron-withdrawing 4-NO2 or 2,4-diNO2-
substituent afforded the corresponding benzofurans 3e and
3 f in 96 and 78% yields, respectively, within 1 h (Table 2, en-
tries 5 and 6). The use of p-CN-substituted aniline afforded 3g
in 81% yield at 508C (Table 2, entry 7). A weak electron-with-
drawing p-Cl-substituted aniline underwent the reaction only
at higher reaction temperature (808C) to give 3h in 75% yield
(Table 2, entry 8). This might be due to the coordination of
amine to the metal center, which decreased the activity of the
catalyst. When TsNH2 was employed as a nucleophile, a moder-
ate yield of 3i (47%) could be obtained (Table 2, entry 9). Elec-
Experimental Section
General procedure for the synthesis of benzo[b]furans 2
and 3
The nucleophile (for the amount, see Scheme 2 and Table 2) and
catalyst A (11.6 mg, 0.015 mmol) were added to a solution of
furan-yne
1 (0.3 mmol) in THF
(6 mL). The resulting mixture was
stirred at room temperature or in-
dicated temperature until the reac-
tion was complete as monitored
by thin-layer chromatography. The
solvent was evaporated under the
reduced pressure and the residue
was purified by column chroma-
tography on silica gel to afford the
product 2 or 3.
(2-Methyl-7-phenylbenzofuran-5-
yl)(phenyl)methanol (2a): Scale=
0.3 mmol. Column chromatogra-
phy on silica gel (petroleum ether:
Scheme 3. Proposed reaction mechanism
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2005, 127, 15024; c) I. Nakamura, Y. Mizushima, Y. Yamamoto, J. Am.
Chem. Soc. 2005, 127, 15022; d) D. Yue, T. Yao, R. C. Larock, J. Org.
Chem. 2005, 70, 10292; e) E. Genin, R. Amengual, V. Michelet, M. Savi-
gnac, A. Jutand, L. Neuville, J.-P. GenÞt, Adv. Synth. Catal. 2004, 346,
1733.
ethyl acetate=10:1) afforded the title product isolated in 93%
yield (87.7 mg) as a yellow solid. H NMR (400 MHz, CDCl3, Me4Si):
1
d=7.79 (d, J=7.6 Hz, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.36–7.31 (m,
5H), 7.28–7.25 (m, 2H), 7.21–7.18 (m, 1H), 6.30 (s, 1H), 5.83 (s, 1H),
2.72 (brs, 1H), 2.39 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
156.13, 151.30, 144.06, 138.80, 136.45, 129.99, 128.53, 128.44,
128.31, 127.49, 127.27, 126.38, 124.47, 121.58, 117.32, 102.90, 76.25,
14.12 ppm; IR (neat): n˜ =3571, 3398, 3059, 2919, 1953, 1607, 1494,
1450, 1406, 1337, 1264, 1206, 1077, 1033, 940, 877, 818, 770, 734,
696 cmÀ1; HRMS (EI): m/z calcd for C22H18O2: 314.1307; found:
314.1305.
[7] a) A. S. K. Hashmi, W. Yang, F. Rominger, Angew. Chem. 2011, 123, 5882;
Angew. Chem. Int. Ed. 2011, 50, 5762; b) M. Shi, X. Y. Tang, Y. H. Yang, J.
Org. Chem. 2008, 73, 5311; c) Y. Liu, J. Liu, M. Wang, J. Liu, Q. Liu, Adv.
Synth. Catal. 2012, 354, 2678; d) T. Wang, S. Shi, M. H. Vilhelmsen, T.
Zhang, M. Rudolph, F. Rominger, A. S. K. Hashmi, Chem. Eur. J. 2013, 19,
12512; e) A. S. K. Hashmi, M. Rudolph, J. W. Bats, W. Frey, F. Rominger, T.
Oeser, Chem. Eur. J. 2008, 14, 6672; f) A. S. K. Hashmi, M. Wçlfle, F. Ata,
M. Hamzic, R. Salathꢂ, W. Frey, Adv. Synth. Catal. 2006, 348, 2501.
[8] For reviews on gold-catalyzed reactions, see: a) A. S. K. Hashmi, G. J.
Hutchings, Angew. Chem. 2006, 118, 8064; Angew. Chem. Int. Ed. 2006,
45, 7896; b) D. J. Gorin, F. D. Toste, Nature 2007, 446, 395; c) A. S. K.
Hashmi, Chem. Rev. 2007, 107, 3180; d) A. Fꢄrstner, P. W. Davies, Angew.
Chem. 2007, 119, 3478; Angew. Chem. Int. Ed. 2007, 46, 3410; e) E. Jimꢂ-
nez-NfflÇez, A. M. Echavarren, Chem. Commun. 2007, 333; f) B. H. Lip-
shutz, Y. Yamamoto, Chem. Rev. 2008, 108, 2793; g) E. Jimꢂnez-NfflÇez,
A. M. Echavarren, Chem. Rev. 2008, 108, 3326; h) D. J. Gorin, B. D. Sherry,
F. D. Toste, Chem. Rev. 2008, 108, 3351; i) A. Arcadi, Chem. Rev. 2008,
108, 3266; j) N. T. Patil, Y. Yamamoto, Chem. Rev. 2008, 108, 3395; k) Z.
Li, C. Brouwer, C. He, Chem. Rev. 2008, 108, 3239; l) J. Muzart, Tetrahe-
dron 2008, 64, 5815; m) H. C. Shen, Tetrahedron 2008, 64, 3885; n) N.
Shapiro, D. Toste, Synlett 2010, 675; o) A. Corma, A. Leyva-Pꢂrez, M. J.
Sabater, Chem. Rev. 2011, 111, 1657.
5-(Methoxy(phenyl)methyl)-2-methyl-7-phenylbenzofuran (3a):
Scale=0.2 mmol. Column chromatography on silica gel (petroleum
ether/ethyl acetate=100:1) afforded the title product isolated in
70% (46.2 mg) yield as a light-yellow liquid. 1H NMR (400 MHz,
CDCl3, Me4Si): d=7.83 (d, J=7.6 Hz, 2H), 7.48–7.20 (m, 10H), 6.36
(s, 1H), 5.36 (s, 1H), 3.41 (s, 3H), 2.43 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=156.11, 151.39, 142.48, 136.87, 136.60, 130.02,
128.59, 128.47, 128.34, 127.51, 127.30, 126.79, 124.53, 121.93,
117.76, 102.90, 85.58, 57.00, 14.18 ppm; IR (neat): 3089, 3057, 3030,
2923, 2820, 2049, 1949, 1881, 1732, 1607, 1494, 1451, 1405, 1338,
1244, 1204, 1114, 1091, 1074, 1030, 940, 877, 821, 769, 718,
695 cmÀ1; HRMS (EI): m/z calcd for C23H20O2: 328.1463; found:
328.1459.
[9] a) Y. Chen, Y. Lu, G. Li, Y. Liu, Org. Lett. 2009, 11, 3838; b) Y. Chen, G. Li, Y.
Liu, Adv. Synth. Catal. 2011, 353, 392; c) Y. Chen, Y. Liu, J. Org. Chem.
2011, 76, 5274.
[10] C. Wang, Y. Chen, X. Xie, J. Liu, Y. Liu, J. Org. Chem. 2012, 77, 1915.
[11] See the Supporting Information.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant Nos. 21125210, 21121062, 21372244), the Chinese Acad-
emy of Science, and the Major State Basic Research Develop-
ment Program (Grant No. 2011CB808700) for financial support.
[12] a) C. Nieto-Oberhuber, P. Pꢂrez-Galµn, E. Herrero-Gómez, T. Lauterbach,
C. Rodriguez, S. López, C. Bour, A. Rosellón, D. J. Cµrdenas, A. M. Echa-
varren, J. Am. Chem. Soc. 2008, 130, 269; b) S. Porcel, V. López-Carrillo,
C. García-Yebra, A. M. Echavarren, Angew. Chem. 2008, 120, 1909;
Angew. Chem. Int. Ed. 2008, 47, 1883; c) M. Gaydou, A. M. Echavarren,
Angew. Chem. 2013, 125, 13710; Angew. Chem. Int. Ed. 2013, 52, 13468;
d) Y. Chen, M. Chen, Y. Liu, Angew. Chem. 2012, 124, 6285; Angew.
Chem. Int. Ed. 2012, 51, 6181; e) Y. Chen, M. Chen, Y. Liu, Angew. Chem.
2012, 124, 6599; Angew. Chem. Int. Ed. 2012, 51, 6493; f) W. Rao, M. J.
Koh, P. Kothandaraman, P. W. H. Chan, J. Am. Chem. Soc. 2012, 134,
10811.
Keywords: alkynes
· cyclization · gold · heterocycles ·
rearrangement
[1] a) M. d’Ischia, A. Napolitano, A. Pezella, in Comprehensive Heterocyclic
Chemistry III, Vol. 2 (Eds.: C. A. Ramsden, E. F. V. Scriven, R. J. K. Taylor),
Pergamon Press, London, 2008, p. 353; b) B. A. Keay, J. M. Hopkins, in
Comprehensive Heterocyclic Chemistry III, Vol. 2, (Eds.: C. A. Ramsden,
E. F. V. Scriven, R. J. K. Taylor), Pergamon Press, London, 2008, p. 571.
[2] I.-L. Tsai, C.-F. Hsieh, C.-Y. Duh, Phytochemistry 1998, 48, 1371.
[3] M. Cowart, J. K. Pratt, A. O. Stewart, Y. L. Bennani, T. A. Esbenshade, A. A.
Hancock, Bioorg. Med. Chem. Lett. 2004, 14, 689.
[4] P. Michael, R. Gerd, S. Theo (Eli Lilly Co.), WO2000078726A1, 2000.
[5] For a review of the synthesis of benzo[b]furans, see: a) L. De Luca, G.
Nieddu, A. Porcheddu, G. Giacomelli, Curr. Med. Chem. 2009, 16, 1. For
recent examples, see: b) C. Chen, D. R. Lieberman, R. D. Larsen, T. R. Ver-
hoeven, P. J. Reider, J. Org. Chem. 1997, 62, 2676; c) H. Zhang, E. M. Fer-
reira, B. M. Stoltz, Angew. Chem. 2004, 116, 6270; Angew. Chem. Int. Ed.
2004, 43, 6144; d) B. Zhao, X. Lu, Org. Lett. 2006, 8, 5987; e) A. C. Tadd,
M. R. Fielding, M. C. Willis, Tetrahedron Lett. 2007, 48, 7578; f) B. Lu, B.
Wang, Y. Zhang, D. Ma, J. Org. Chem. 2007, 72, 5337; g) E. M. Ferreira, H.
Zhang, B. M. Stoltz, Tetrahedron 2008, 64, 5987; h) C. Eidamshaus, J. D.
Burch, Org. Lett. 2008, 10, 4211; i) M. Csꢂkei, Z. Novak, A. Kotschy, Tetra-
hedron 2008, 64, 8992; j) X. Guo, R. Yu, H. Li, Z. Li, J. Am. Chem. Soc.
2009, 131, 17387; k) J. Farago, A. Kotschy, Synthesis 2009, 85; l) C. Li, Y.
Zhang, P. Li, L. Wang, J. Org. Chem. 2011, 76, 4692; m) L. Zhou, Y. Shi, Q.
Xiao, Y. Liu, F. Ye, Y. Zhang, J. Wang, Org. Lett. 2011, 13, 968; n) A. S. K.
Hashmi, T. M. Frost, J. W. Bats, Org. Lett. 2001, 3, 3769; o) A. S. K.
Hashmi, E. Enns, T. M. Frost, S. Schꢃfer, W. Frey, F. Rominger, Synthesis
2008, 2707; p) M. C. Blanco Jaimes, V. Weingand, F. Rominger, A. S. K.
Hashmi, Chem. Eur. J. 2013, 19, 12504.
[13] CCDC-978477 (2i) and -978478 (3i) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
[14] For gold-catalyzed substituent “castling” reactions observed in alkynes
tethered with a thiophene, pyrrole, or indole system, see: a) M. Gruit, D.
Michalik, A. Tillack, M. Beller, Angew. Chem. 2009, 121, 7348; Angew.
Chem. Int. Ed. 2009, 48, 7212; b) A. S. K. Hashmi, W. Yang, F. Rominger,
Adv. Synth. Catal. 2012, 354, 1273; c) A. S. K. Hashmi, W. Yang, F. Ro-
minger, Chem. Eur. J. 2012, 18, 6576. For gold-catalyzed substituent
“castling” reactions observed in allenes tethered with indole, see: d) E.
lvarez, P. García-García, M. A. Fernµndez-Rodríguez, R. Sanz, J. Org.
Chem. 2013, 78, 9758. For the only reference on an open-chained, non-
spirocyclic intermediate, see: e) A. S. K. Hashmi, T. Hꢃffner, W. Yang, S.
Pankajakshan, S. Schꢃfer, L. Schultes, F. Rominger, W. Frey, Chem. Eur. J.
2012, 18, 10480.
[15] For the recent use of different alcohol nucleophiles in gold catalysis,
see: a) J. Liu, Y. Liu, Org. Lett. 2012, 14, 4742; b) K. Graf, P. D. Hinden-
berg, Y. Tokimizu, S. Naoe, M. Rudolph, F. Rominger, H. Ohno, A. S. K.
Hashmi, ChemCatChem 2014, 6, 199.
[16] For the recent use of anilines as nucleophiles, see: a) A. S. K. Hashmi, M.
Bꢄhrle, M. Wçlfle, M. Rudolph, M. Wieteck, F. Rominger, W. Frey, Chem.
Eur. J. 2010, 16, 9846; b) X. Du, S. Yang, J. Yang, Y. Liu, Chem. Eur. J.
2011, 17, 4981.
[17] A. S. K. Hashmi, Angew. Chem. 2010, 122, 5360; Angew. Chem. Int. Ed.
2010, 49, 5232.
[6] a) K. W. Anderson, T. Ikawa, R. E. Tundel, S. L. Buchwald, J. Am. Chem.
Soc. 2006, 128, 10694; b) A. Fꢄrstner, P. W. Davies, J. Am. Chem. Soc.
[18] For gold-catalyzed reactions involving the formation of oxonium ion in-
termediates that undergo Wagner–Meerwein rearrangement, see:
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
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a) S. F. Kirsch, J. T. Binder, C. Liebert, H. Menz, Angew. Chem. 2006, 118,
6010; Angew. Chem. Int. Ed. 2006, 45, 5878; b) J. Zhang, H. G. Schmalz,
Angew. Chem. 2006, 118, 6856; Angew. Chem. Int. Ed. 2006, 45, 6704;
c) S. Labsch, S. Ye, A. Adler, J.-M. Neudçrfl, H.-G. Schmalz, Tetrahedron:
Asymmetry 2010, 21, 1745.
[19] For gold-catalyzed amination of allylic alcohols, see: S. Guo, F. Song, Y.
Liu, Synlett 2007, 964.
Received: January 10, 2014
Revised: March 18, 2014
Published online on && &&, 2014
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FULL PAPER
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Cyclization
N. Sun, X. Xie, Y. Liu*
&& – &&
Gold-Catalyzed Cascade Reactions of
Furan-ynes with External Nucleophiles
Consisting of a 1,2-Rearrangement:
Straightforward Synthesis of Multi-
Substituted Benzo[b]furans
Substituent “castling”: A gold-catalyzed
cyclization of silyl-protected 2-(1-alkyn-
yl)-2-alken-1-(2-furanyl)-1-ols with vari-
ous nucleophiles has been developed,
providing a highly efficient access to
5,7-disubstituted or 2,5,7-trisubstituted
benzo[b]furans under mild reaction con-
ditions with a wide diversity of substitu-
ents (see scheme; TBDPS=tert-butyldi-
phenylsilyl). A mechanistic proposal for
these transformations involving a 1,2-re-
arrangement and allylic substitution is
presented.
Chem. Eur. J. 2014, 20, 1 – 7
www.chemeurj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ