Gold(I)-catalyzed reaction of 1-(1-alkynyl)-cyclopropyl ketones with nucleophiles: A modular entry to highly substituted furans

Article abstract of DOI:10.1002/anie.200601252

(Chemical Equation Presented) Ring round: 1-Acyl-1-alkynyl-cyclopropanes smoothly react with nucleophiles in the presence of a gold(I) catalyst to afford substituted furans in a fully atom-economical fashion (see scheme; Nu = nucleophile, Tf=trifluorometh

Full text of DOI:10.1002/anie.200601252

Communications
Furan Synthesis
DOI: 10.1002/anie.200601252
Gold(I)-Catalyzed Reaction of 1-(1-Alkynyl)-
cyclopropyl Ketones with Nucleophiles: A
Modular Entry to Highly Substituted Furans**
Junliang Zhang and Hans-Günther Schmalz*
Highly substituted furans are found as key structural elements
in many bioactive natural products and important pharma-
ceuticals. They also represent versatile building blocks for the
synthesis of more elaborate heterocyclic compounds.[1,2] The
search for efficient general routes to substituted furans is an
important, continuing goal of organic synthesis. Several
studies have focused on metal-catalyzed methods for furan
synthesis (Scheme 1). These include the cyclization of allenyl
ketones,[3] 3-alkyn-1-ones,[4] or 2-(1-alkynyl)-2-alken-1-ones[5]
through nucleophilic attack of the carbonyl oxygen atom to a
À
transition-metal-coordinated C C double or triple bond
(Mode A, Scheme 1). Alternatively, alkylidene cyclopropyl
ketones[6] or cyclopropenyl ketones[7] are prone to metal-
catalyzed cycloisomerization to afford furans through (regio-
selective) cleavage of the three-membered ring and subse-
quent cyclization (Mode B, Scheme 1).
As cyclopropanes are readily accessible and reactive
because of their ring strain,[8,9] we designed 1-(1-alkynyl)-
cyclopropyl ketones 1 (Scheme 2) that contain both an alkyne
and a cyclopropane unit as starting materials for cyclization
reactions catalyzed by transition metals. Although both
modes A and B (to form 2,3-dihydrofurans[10]) are potentially
possible pathways for metal-mediated reactions involving 1,
we envisioned that furan formation through attack of the
carbonyl oxygen atom on the alkyne (Mode A) seemed to be
particularly feasible.
Herein, we present a mild and efficient method for the
synthesis of multiply substituted furans starting from com-
pounds of type 1. In particular, we show that the atom-
economical gold(I)-catalyzed cascade process allows access to
condensed ring systems (for example, furo[b]cycloheptenes)
under ring expansion.
First, we examined the reaction of (racemic) ketone 2a
using different metal catalysts (5 mol%) with MeOH
(2 equiv) in CH2Cl2 (Table 1). Remarkably, the ring-
expanded bicyclic cycloheptafuran 3aa was formed regiose-
[*] Dr. J. Zhang, Prof. Dr. H.-G. Schmalz
Institut für Organische Chemie
Universität zu Köln
Greinstrasse 4, 50939 Köln (Germany)
Fax: (+49)221-470-3064
E-mail: schmalz@uni-koeln.de
[**] This work was supported by the Alexander von Humboldt Stiftung
(postdoctoral fellowship to J.Z.) and the Fonds der Chemischen
Industrie.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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using AuCl, AuCl3, and AgOTf as the catalyst;[11]
AgOTf afforded the product in a respectable 85%
yield after 1 h. Significantly, we found that
(Ph3P)AuOTf[12] is a particularly efficient catalyst for
this reaction. With only 1 mol% of this catalyst, the
cascade ring expansion/furan formation was complete
after less than ten minutes at room temperature to
afford pure 3aa in 91% yield (Table 1, entry 11). No
trace of the isomeric product (4aa) could be detected.
Two plausible mechanisms can be envisioned for
this novel AuI-catalyzed transformation (Scheme 3).[11]
In cycle A (Scheme 3), a cationic AuI species first
coordinates to the triple bond to generate an inter-
mediate 5. Nucleophilic attack of the carbonyl oxygen
atom on the activated triple bond with concomitant
(regioselective) cleavage of the cyclopropane would
generate a carbocation 6, which can be trapped by a
nucleophile (MeOH). Protonolysis of the resulting
organogold intermediate 7 gives product 3 and regen-
Scheme 1. Transition-metal-catalyzed synthesis of furans. Nu=nucleophile.
Scheme 2. Two possible modes of reaction for the cyclization of 1.
[TM]=transition metal reagent.
Table 1: Effect of catalyst on the reaction of 2a to give 3aa.
Scheme 3. Possible mechanisms of the Au-catalyzed transformation.
L=ligand.
erates the AuI catalyst. Alternatively (cycle B, Scheme 3), a
chelate complex 8 could form as a primary intermediate,
which could be attacked by the nucleophile (MeOH) in a
regioselective homo-Michael-type addition to generate an
Au–enolate 9, which then undergoes cycloisomerization to
afford intermediate 7.
To probe the scope of the reaction, we performed a series
of experiments with different ketones of type 2 and also
varied the nucleophile (Table 2). While (Ph3P)AuOTf was
used as it was found to be the most effective catalyst, some
reactions were also studied using AgOTf for comparative
purposes.
A variety of O nucleophiles, such as alcohols (including
tert-butanol),[13] phenols, or acetic acid, react smoothly to
afford the desired products (Table 2). An N-nucleophilic 2-
pyrrolidone could also be employed to give the corresponding
N-alkylated product (Table 2, entry 10); however, the reac-
tion was slower than those performed using alcohols as the
nucleophiles. When indole was used as the nucleophile, the
C3 alkylation product was formed selectively in good yield
(Table 2, entry 7). The reaction tolerates a wide range of R
Entry
Catalyst
(Amount)
Time
Yield [%]
1
2
3
4
5
6
7
8
9
none
–
24 h
16 h
22 h
16 h
18 h
24 h
1 h
1 h
1 h
0
74
41
55
63
70
66
68
85
90
91
Cu(OTf)2
In(OTf)3
Ga(OTf)3
Sc(OTf)3
Yb(OTf)3
AuCl
AuCl3
AgOTf
(PPh3)AuOTf
(PPh3)AuOTf
(5 mol%)
(5 mol%)
(5 mol%)
(5 mol%)
(5 mol%)
(5 mol%)
(5 mol%)
(5 mol%)
(5 mol%)
(1 mol%)
10
11
<5 min
<10 min
Tf =triflate=trifluoromethanesulfonyl.
lectively in all cases as the only major product. Lewis acids
such as Cu(OTf)2, In(OTf)3, Ga(OTf)3, Sc(OTf)3, and Yb-
(OTf)3 were active, but only modest yields were obtained
after long reaction times. Faster reactions were observed
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Table 2: AuI-catalyzed ring expansion/cyclization reactions of substrates
2 with different nucleophiles.[a]
Entry Ketone
R
Prod. Yield [%][b]
À
Nu H
1
2
3
4
5
6
7
8
9
10
11
12
13
2a
2a
2a
2a
2a
2a
2a
2b
2c
2c
2d
2e
2 f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
MeOH
iPrOH
tBuOH
ꢀ
3aa
3ab
3ac
91 (85)
90 (85)
85 (77)
77 (88)
84
84 (61)
73 (31)
80
82
68 (59)
86
76
35
Ph-C C-CH2OH 3ad
p-MeO-C6H4-OH 3ae
AcOH
indole
3af
3ag
3ba
3ca
3ch
3da
3ea
3ea
1-cyclohexenyl MeOH
cyclopropyl
cyclopropyl
n-butyl
H
MeOH
2-pyrrolidone
MeOH
MeOH
MeOH
TMS
[a] Unless otherwise specified, reactions were carried out as follows: a
solution of (racemic) ketone 2 (0.5 mmol), (Ph3P)AuOTf (1 mol%), and
nucleophile (2.0 equiv) in CH2Cl2 (2.8 mL) was stirred at RT for 15 min.
[b] Yields of isolated products; yield given in parenthesis refer to
reactions performed with AgOTf (5 mol%, 1 h). [c] Indole (1.5 equiv).
[d] 6h. TMS=trimethylsilyl.
Scheme 4. The generality of the reaction. Conditions: a) (Ph3P)AuOTf
(1 mol%), MeOH (2.0 equiv), CH2Cl2, RT.
and AgOTf, with AgCl filtered off) in CH2Cl2 (0.00625m, 0.8 mL,
0.005 mmol). The mixture was stirred for 15 min at room temper-
ature. After evaporation of the solvent, the residue was purified by
column chromatography on silica gel (cyclohexane/ethyl acetate 10:1)
to afford 110 mg of 3aa (91%) as a light yellow oil; 1H NMR
(300 MHz, CDCl3): d = 7.63–7.59 (m, 2H), 7.40–7.32 (m, 2H), 7.25–
7.18 (m, 1H), 6.48 (s, 1H), 3.41 (s, 3H), 3.35 (tt, J = 9.3, 2.7 Hz, 1H),
2.96–2.82 (m, 2H), 2.81–2.70 (m, 1H), 2.61 (dd, J = 15.6, 9.6 Hz, 1H),
2.30–2.16 (m, 1H), 2.08–1.96 (m, 1H), 1.82–1.54 ppm (m, 2H);
13C NMR (75.4 MHz, CDCl3): d = 153.12, 150.23, 131.06, 128.52,
126.58, 123.17, 116.67, 108.90, 79.69, 56.18, 35.76, 31.17, 28.34,
22.77 ppm; IR (neat): n = 2926, 2850, 1600, 1580, 1551, 1485, 1444,
1091, 757 cmÀ1; MS (70 eV): m/z (%): 242 (100) [M+]; HRMS calcd
for C16H18O2 [M+]: 242.1307, found: 242.131. For preparative
procedures and spectroscopic data for all new compounds, see the
Supporting Information.
groups on the alkyne in substrate 2.[13] Besides phenyl, alkyl,
and alkenyl substituents, even a cyclopropyl unit is tolerated
(Table 2, entries 9 and 10). This result demonstrates the
remarkable chemoselectivity of the reaction.
The generality of the method was also investigated using
the cycloheptane derivative 10, the 2,3-methanochromanone
derivative 12, and the monocyclic 1-(1-alkynyl)cyclopropyl
ketones 14 and 16, all of which afforded the expected products
(11, 13, 15, and 17) in good yields (Scheme 4). In the case of
16, nucleophilic addition occurs at the more substituted
position of the cyclopropane ring.
Remarkably, no reaction took place when 16 was sub-
jected to the standard reaction conditions (1 mol% of
(Ph3P)AuOTf, CH2Cl2, RT) in the absence of a nucleophile.
Furthermore, no reaction was observed when Et3SiH was
used as a potential hydride source in place of a nucleophile.
These facts contradict a mechanism involving a carbocation
intermediate; however, further studies are necessary to obtain
deeper mechanistic insights.
In conclusion, a gold-catalyzed cascade reaction was
developed which provides efficient access to highly substi-
tuted furans under mild conditions. The substrates can be
readily prepared from the corresponding enones through
cyclopropanation.[14] Further studies concerning both the
mechanism and possible synthetic applications of the meth-
odology are currently being carried out.
Received: March 30, 2006
Revised: August 2, 2006
Published online: September 20, 2006
Keywords: cyclopropanes · furans · gold · ring expansion ·
.
transition metals
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Angew. Chem. Int. Ed. 2006, 45, 6704 –6707
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