Gold(I)-catalyzed, highly diastereoselective, tandem heterocyclizations/ [3+2] cycloadditions: Synthesis of highly substituted cyclopenta[c]furans

Article abstract of DOI:10.1002/chem.201003363

The domino effect: A novel, cationic, gold(I)-catalyzed [3+2], tandem bicyclization, which provides rapid, efficient, and diastereoselective access to highly substituted cyclopenta[c]furans from simple, readily available 2-(1-alkynyl)-2-alken-1-ones and 3-styrylindoles under mild conditions, is described (see scheme).

Full text of DOI:10.1002/chem.201003363

DOI: 10.1002/chem.201003363
Gold(I)-Catalyzed, Highly Diastereoselective, Tandem
Heterocyclizations/[3+2] Cycloadditions: Synthesis of Highly Substituted
Cyclopenta[c]furans
AHCTUNGTRENNUNG
Hongyin Gao,[a] Xingxing Wu,[a] and Junliang Zhang*[a, b]
Carbo- and heterocyclic compounds play an irreplaceable
yl imine 2a, might also undergo a similar tandem heterocyc-
lization and formal [4+3] cycloaddition reaction through in-
termediate A to give cyclohepta[c]furan (Scheme 1).
role as lead candidates in drug discovery. Thus, highly effi-
cient design and synthesis of these compounds are highly de-
sirable in synthetic chemistry. Transition-metal-catalyzed cy-
cloaddition reactions provide efficient tools for the chemo-,
regio-, and diastereoselective construction of highly substi-
tuted medium-sized ring systems from simple acyclic starting
materials.[1] In particular, transition-metal-catalyzed [3+2]
cycloadditions provide access to five-membered rings,[2]
which are difficult to achieve by alternative approaches,
such as intramolecular substitution reactions. Herein, we
report a novel approach to highly substituted cyclopenta[c]-
furans by a gold(I)-catalyzed, highly regio- and diastereose-
lective, tandem heterocyclization/
ACHTUNGERTN[NUNG 3+2] cycloaddition reac-
tion.[3]
Because of the recent attention given to cascade reac-
tions,[4] an increasing number of studies have highlighted the
utility of 2-(1-alkynyl)-2-alken-1-ones,[5] which were first re-
ported by Larock in 2004,[5a] as substrates in transition-
metal-catalyzed carbon–carbon or carbon–hetero atom
bond-formation reactions. For example, we have recently re-
ported an efficient and convenient synthetic route to fused
Scheme 1. Previous work and projected reaction pattern of ketones 1a
with 3-styrylindole 4a (Ts=tosyl).
With this hypothesis in mind, we began our study by ex-
amining the reaction of 1a and 4a catalyzed by various
metal complexes. Unfortunately, the reaction products
always contained impurities and failed to give any major
products under the different reaction conditions investigat-
ed. We reasoned that this may result from the weak nucleo-
philicity of 4a due to the electron-withdrawing Ts group.
The more electron-rich (E)-1-methyl-3-styryl-1H-indole
(4b) was then proposed and tested as a substrate. Luckily,
the reaction proceeded smoothly at RT in 1,2-dichlorethane
(DCE) catalyzed by 5 mol% Ph3PAuOTf (generated from
the 1:1 ratio of Ph3PAuCl/AgOTf, Table 1, entry 1). Howev-
er, to our surprise, the product is the 5,5-fused cyclopen-
ta[c]furan 6ab with a high diastereo-selectivity rather than
the expected 5,7-fused cyclohepta[c]furan 5ab. The structure
of 6ab was confirmed by single-crystal X-ray diffraction.[8]
heterobicyclic furoACHTUNGTRENNUNG[3,4-c]azepines by a gold-catalyzed, highly
diastereoselective, tandem, double heterocyclizations and
1,2-alkyl migrations.[6,7] During the course of this investiga-
tion, we found that the Ph3PAuOTf-catalyzed (OTf=tri-
flate) reaction of 2-(1-alkynyl)-2-alken-1-ones (1a) with het-
eroaryl imine 2a underwent the formal [4+3] cycloaddition
without 1,2-alkyl migration.[6h] As part of an ongoing pro-
gram to develop this type of synthetic approaches to polyhe-
terocyclic compounds, we reasoned that readily available
(E)-1-tosyl-3-styryl-1H-indole (4a), an analogue of heteroar-
[a] H. Gao, X. Wu, Prof. Dr. J. Zhang
Shanghai Key Laboratory of Green Chemistry
and Chemical Processes, Department of Chemistry
East China Normal University, 3663 N. Zhongshan Road
Shanghai 200062 (P.R. China)
With AgOTf or InACTHNUTRGNEUNG(OTf)3 as catalysts the yield and diaste-
Fax : (+86)21-6223-5039
E-mail: jlzhang@chem.ecnu.edu.cn
reoselectivity decreased drastically(Table 1, entries 2 and 3).
There was no improvement in yield or diastereoselectivity,
[b] Prof. Dr. J. Zhang
when Cu
ACHUTGTNNERNUG(OTf)2 or FeACHTGNUTRENNUNG
State key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences (P.R. China)
(Table 1, entries 4 and 5). PtCl2 and ScAHCNUTGTRENNUNG
cient catalysts for this transformation (Table 1, entries 6 and
7). Finally, we were pleased to find that Cy3PAuCl/AgOTf
was the best catalyst system and the reaction gave 6ab in
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003363.
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Chem. Eur. J. 2011, 17, 2838 – 2841

COMMUNICATION
Table 1. Optimization of the reaction conditions for the [3+2] tandem
cycloaddition between 1a and 4b.[a]
better diastereoselectivity than aromatic-substituted ones
(Table 2, entries 1–11 vs. entries 12–14). Not only electron-
rich and electron-deficient aromatic substituents, but also
cyclic and acyclic aliphatic substituents can be introduced as
R3 (Table 2, entries 2,3,7,8, and 4–6, respectively). Both a
cyclopropyl group as R3 and a halogen atom on the aromatic
ring of R2 are compatible with this catalytic system (Table 2,
entries 5 and 14).
Entry
Catalyst
6ab Yield [%][b]
d.r.[c]
To expand the generality of this process, other substituted
3-styrylindoles were tested and the results are summarized
in Table 3. To our delight, a diverse array of highly substitut-
1
2
3
4
5
6
7
8
Ph3PAuCl/AgOTf
AgOTf
88
38
28
45
8.3:1
1:1.4
1:1.8
1:1
1:1.2
-
In
Cu
Fe(OTf)3
PtCl2
Sc(OTf)3
Cy3PAuCl[d]/AgOTf
T
E
R
52
Table 3. Diastereoselective synthesis of highly substituted cyclopenta[c]-
furan through variation of 3-styrylindole 4.[a]
trace
trace
93
A
-
>20:1
[a] 1a (0.3 mmol), 4b (0.36 mmol), and DCE (3 mL) were employed at
RT. [b] Yield of the isolated product. [c] d.r.=diastereomeric ratio, deter-
1
mined by H NMR analysis of the crude product. [d] Cy=cyclohexyl.
Entry
R4/R5
6 Yield [%][b]
d.r.[c]
1
2
3
4
5
6
7
8
9
4-MeC6H4/H (4c)
4-MeOC6H4/H (4d)
4-CNC6H4/H (4e)
4-NO2C6H4/H (4 f)
4-ClC6H4/H (4g)
4-BrC6H4/H (4h)
Ph/OMe (4i)
6ac: 89
6ad: 87
6ae: 87
6af: 89
6ag: 84
6ah: 92
6ai: 96
6aj: 96
6ak: 93
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
93% yield and excellent diastereoselectivity (>20:1,
Table 1, entry 8).
With the optimal conditions in hand, we turned our atten-
tion to the reaction scope of this gold-catalyzed tandem
transformation by varying the 2-(1-alkynyl)-2-alken-1-one
(Table 2). In general, various substituents (R1, R2, and R3)
at all three positions of ketone 1 are well-tolerated. Sub-
stituent R1, which can be either an aliphatic or aromatic
group, has little impact on the yield, but remarkable impact
on the diastereoselectivity (Table 2, entries 1 vs. 12, entries 6
vs. 13). The R1 alkyl-substituted substrates can achieve
Ph/Me (4j)
Ph/Br (4k)
[a] All reactions were carried out with 1a (0.3 mmol) under standard con-
ditions. [b] Yield of the isolated product. [c] Determined by 1H NMR
analysis of the crude product.
ed cyclopenta[c]furans was easily constructed in good to ex-
cellent yields with excellent diastereoselectivities. Two
points are noteworthy: 1) not only electron-rich, but also
electron-deficient aromatic substituents can be introduced at
R4; this has little impact on the yield and diastereoselectivity
(Table 3, entries 1–6), and 2) a halogen substituent on either
of the two aromatic rings is tolerated (Table 3, entries 3, 5,
6, and 9).
Table 2. Diastereoselective synthesis of highly substituted cyclopenta[c]-
furans through variation of ketone 1.[a]
To gain insight into the mechanism and check whether
the stereochemistry of the dipolarophile 4 affects the stereo-
chemistry of the product, the Z isomer of 4b ((Z)-4b) was
subjected to the reaction under the standard conditions, the
same product as for the E isomer (6ab) was isolated in 74%
yield with 10:1 diasteroselectivity after 2 h at room tempera-
ture, indicating that the reaction proceeds through a step-
wise, formal [3+2] cycloaddition reaction pathway [Eq. (1)].
Entry
R1/R2/R3
6 Yield [%][b]
d.r.[c]
1
2
3
4
5
6
7
8
Me/Ph/Ph
Me/Ph/4-MeOC6H4 ACTHNGUTERNNU(G 1b)
Me/Ph/4-MeC6H4 (1c)
(1a)
6ab: 93
6bb: 82
6cb: 87
6 db: 67
6eb: 68
6 fb: 72
6gb: 87
6hb: 94
6ib: 81
6jb: 85
6kb: 92
6lb: 89
6mb:80
6nb: 83
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
10:1
>20:1
>20:1
>20:1
3.7:1
Me/Ph/1-Cyclohexenyl (1d)
Me/Ph/1-Cyclopropyl (1e)
Me/Ph/nBu (1 f)
Me/Ph/4-NO2C6H4 (1g)
Me/Ph/1-Naphthyl (1h)
Me/4-MeOC6H4/Ph (1i)
Me/4-MeOC6H4/4-MeOC6H4 (1j)
Me/4-MeOC6H4/1-Naphthyl (1k)
9
10
11
12
13
14
Ph/Ph/Ph
Ph/Ph/nBu
Ph/4-ClC6H4/Ph
ACHTUNGTRENNUNG
E
3.4:1
4.5:1
N
[a] All reactions were carried out with 1 (0.3 mmol) under standard con-
ditions. [b] Yield of the isolated product. [c] Determined by 1H NMR
analysis of the crude product.
Chem. Eur. J. 2011, 17, 2838 – 2841
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www.chemeurj.org
2839

J. Zhang et al.
(400 MHz, CDCl3): d=7.30 (d, J=8.0 Hz, 2H), 7.22–7.06 (m, 13H),
7.05–7.00 (m, 2H), 6.97–6.90 (m, 1H), 6.85 (t, J=7.2 Hz, 1H), 6.65 (s,
1H), 4.78 (d, J=8.4 Hz, 1H), 4.32 (d, J=8.4 Hz, 1H), 3.83 (t, J=8.4 Hz,
1H), 3.48 (s, 3H), 2.08 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
143.1, 142.7, 142.3, 142.1, 137.3, 131.0, 130.4, 128.31, 128.25, 127.99,
127.95, 127.7, 126.93, 126.87, 126.5, 126.3, 125.6, 124.3, 121.1, 119.8, 118.4,
115.0, 108.9, 73.3, 51.7, 44.8, 32.5, 12.5 ppm; MS (EI): m/z (%): 479 [M+]
(2.90), 84 (100); HRMS: calcd for C35H29NO: 479.2249, found: 479.2248.
For preparative procedures and spectroscopic data for all new com-
pounds, see the Supporting Information.
A proposed stepwise mechanism that accounts for this
gold(I)-catalyzed [3+2] tandem bicyclizations is depicted in
Scheme 2. The furanyl gold intermediate IA would be af-
Acknowledgements
Financial support from the 973 program (2009CB825300), NSFC
(20972054), Ministry of Education of PRC, Science and Technology
Commission of Shanghai Municipality (08dj1400100) and the PhD Pro-
gram Scholarship Fund of ECNU (2010032) are greatly appreciated.
Keywords: cycloaddition
·
cyclopenta[c]furans
·
diastereoselectivity · domino reactions · gold
Scheme 2. Plausible mechanism.
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intramolecular 1,5-cyclization leading to the final formal
[3+2] cycloaddition-product 6 and regenerate the gold cata-
lyst.
In conclusion, we have demonstrated that highly substitut-
ed cyclopenta[c]furans can be efficiently constructed from
readily available 2-(1-alkynyl)-2-alken-1-ones and 3-styrylin-
doles in a one-pot manner by employing a gold-catalyzed
tandem cyclization. Mild reaction conditions, ease of opera-
tion, high yields, high diastereoselectivities, and a wide func-
tional-group tolerance are several merits of this highly effi-
cient protocol. Further investigations to extend the scope of
this reaction, asymmetric catalysis, as well as biological eval-
uation of these compounds are currently underway in our
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Experimental Section
Synthesis of 6ab: AgOTf (3.8 mg, 0.015 mmol) was added to a solution
of Cy3PAuCl (7.8 mg, 0.015 mmol) in DCE (1 mL) under an Ar atmos-
phere. The mixture was stirred for 10 min at room temperature. Then the
solution of ketone 1a (73.8 mg, 0.3 mmol) and 4b (83.9 mg, 0.36 mmol)
in DCE (2 mL) was added to this mixture. After stirring for 2 h at room
temperature, ketone 1a was consumed completely according to TLC
analysis. The mixture was passed through a short silica-gel column and
then concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel to afford the pure product
6ab (133.2 mg) in 93% yield as a white solid. M.p. 212–2138C; 1H NMR
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Gold(I)-Catalyzed [3+2] Cycloadditions
COMMUNICATION
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Received: November 22, 2010
Published online: February 3, 2011
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www.chemeurj.org
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