Angewandte
Chemie
In a catalyst screening, model substrate 6a could be
converted into the tetracyclic system 7a within minutes by the
use of the air-stable [Mes3PAu]NTf2 catalyst in chloroform
(Mes = mesityl, Tf = triflyl; the X-ray crystal-structure anal-
ysis[9] of this complex is shown in the Supporting Informa-
tion). The use of AuCl3 or [Ad2(nBu)PAu]NTf2[10] (Ad = ada-
mantyl) led to decomposition, whereas silver tetrafluorobo-
rate and para-toluenesulfonic acid did not show any con-
version (Table 1). The structure of the tetracyclic product 7a
could be unambiguously determined by X-ray crystal-struc-
ture analysis (Figure 1).[9]
Again, as with 6e, adding an electron-donating methyl group
on the 5-position of the furan ring of 6g prevented the
formation of 7g (Table 2, entry 6).
Thus we returned to substrates with monosubstituted
furan rings, used the para-methoxyphenyl group as in 6 f but
added a chiral center in propargylic positions. For the small
propargylic methyl group in 6h these 1,4-inductions only led
to a diastereoselectivity of 71:29 in 7h (Table 2, entry 7). With
the larger ethyl group in 6i, as expected, the diastereoselec-
tivity increased to 90:10 for 7i (Table 2, entry 8), but then
unexpectedly with the tert-butyl substituent in 6j dropped to
80:20 for 7j (Table 2, entry 9). Fortunately, for both diaste-
reomers of 7j crystals suitable for X-ray structure analysis
could be grown (Figure 2).[9] The main diastereomer shows a
trans-arrangement of the tert-butyl group and the dihydro-
furan ring.
Table 1: Screening of different catalysts.
For the furan systems discussed above, the conversions
were complete in minutes, but in the case of the disubstituted
propargylic position in 6k, the substrate decomposed
(Table 2, entry 10). On the other hand, combining this
propargylic disubstitution with a sterically demanding ortho-
nitrophenyl group at the R8-position in substrate 6l led to a
successful conversion, however, the reaction time increased to
4 h (Table 2, entry 11). Substrate 6m which contains a
stereogenic center in the furyl position for the investigation
of a potential 1,2-induction, also led to a decomposition of the
substrate. The higher stability of a secondary propargylic
cation might account for this observation (Table 2, entry 12).
The only substrate that showed no conversion at all was
substrate 6n (Table 2, entry 13). In this case, the methyl group
in the 3-position of the furan (which is very close to the
evolving spiro center and at the position which then has to
attack the phenyl group) seems to be a steric problem.
g-Alkynylpyrroles without an ether moiety on the alkyne
undergo a hydroarylation reaction rather than the phenol
synthesis.[3h] With the arylether group, even for the N-
tosylpyrroles 6o and 6p, a formation of the desired tetracyclic
systems 7o and 7p was observed in high yields (Table 2,
entries 14 and 15). Even the thiophene substrate 6q could be
perfectly converted without any sign of catalyst deactivation
(Table 2, entry 16). This is one of the few conversions of low-
valent sulfur-containing compounds in gold catalysis,[11] and it
is remarkable that in the course of the reaction the
aromaticity is broken, not only in the furan ring with its low
aromatic character, but also in the pyrrole, and even the
thiophene ring.[12]
Entry
Catalyst
t
Solvent
Yield of 7a
[a]
1
2
3
4
5
6
AuCl3
10 min
10 min
10 min
3 h
1 day
1 day
CH3CN
CH2Cl2
CHCl3
CH2Cl2
CHCl3
CH2Cl2
–
[a]
[Ad2(nBu)PAu]NTf2
[Mes3PAu]NTf2
[Mes3PAu]NTf2
p-TsOH
–
54%
44%
–
AgBF4
–
[a] Decomposition of the starting material.
Figure 1. Ortep plot of the solid-state structure of 7a.
Encouraged by this result, we examined the conversion of
substrates 6b–6q under the optimized reaction conditions
(Table 2). Even without the activating methoxy group on the
phenyl ring of 6a the cycloisomerization readily proceeds, as
demonstrated by the reaction of 6b (Table 2, entry 1). On the
other hand, the electron-withdrawing CF3 group on the
phenyl group of 6c (Table 2, entry 2) led to a decomposition
of the starting material. Not unexpectedly, the blocking of
both ortho-positions of the phenyl group 6d (Table 2, entry 3)
also led to a decomposition of the substrate. Further limits are
electron-rich furan derivatives, such as 6e (Table 2, entry 4),
which like 6a have the activating methoxy group on the
phenyl group but in addition a methyl-donor on the 5-position
of the furan ring.
We could extend this method to non-heterocyclic, olefinic
systems. Substrate 8 with a prenyl side-chain delivered the
tricyclic heterocycle 9 in good yield (Scheme 4).
A mechanistic proposal for this reaction is given in
Scheme 5. As a result of the electronic properties of the
alkynylether moiety, the initiation step is a 6-endo-dig
cyclization, leading to the stabilized cation H (which poten-
tially could also be a carbenoid system I; there is an ongoing
discussion on the nature of these intermediates).[13] The
reaction cascade continues by a Friedel–Crafts-like aryla-
tion,[14] followed by protodemetallation to form the products
7. The failure of the methyl-substituted furans 6e and 6g to
undergo a selective cyclization (Table 2, entries 4 and 6) might
Returning to a monosubstituted furan ring and shifting
the activating methoxy group on the phenyl group to the para-
position in 6 f (Table 2, entry 5) delivered 7 f in good yield.
Angew. Chem. Int. Ed. 2009, 48, 5848 –5852
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Hashmi, A. Stephen K.
