Gold(I)-catalyzed annulation of salicylaldehydes and aryl acetylenes as an expedient route to isoflavanones

Article abstract of DOI:10.1002/anie.200603495

(Chemical Equation Presented) The value of gold 'n' rings: An isoflavanone moiety is the key structural feature of many complex natural products. It is now shown that such structures can be generated efficiently and atom economically by the annulation of

Full text of DOI:10.1002/anie.200603495

Angewandte
Chemie
DOI: 10.1002/anie.200603495
Transition-Metal Catalysis
Gold(I)-Catalyzed Annulation of Salicylaldehydes and Aryl
Acetylenes as an Expedient Route to Isoflavanones**
Rachid Skouta and Chao-Jun Li*
Isoflavanones are widely present in nature; the isoflavanone
moiety is the key structural feature of many complex natural
products, such as the pterocarpenoids and eriotrichin B
(Scheme 1).[1] The classical methods for synthesizing isofla-
reported an efficient gold(III)-catalyzed multicomponent
coupling that leads to propargylamines and benzylamines,[14]
a highly efficient gold(III)-catalyzed annulation of phenols
with dienes,[15a,c] and a gold(I)-catalyzed addition–cyclization
cascade of terminal alkynes with ortho-alkynyl aryl alde-
hydes.[15b] Methodologies based on the reaction of C H bonds
À
provide more direct syntheses of complex molecules from
relatively simple starting materials.[16] In 1997, Miura and co-
À
workers reported a rhodium-catalyzed activation of the C H
bond of aldehydes.[17] Jun and co-workers have described
rhodium-catalyzed hydroacylations of terminal olefins[18] and
alkynes.[19]
Herein, we report a novel annulation of simple hydrox-
yaldehydes with alkynes under gold catalysis to give isofla-
vanone-type structures 3 directly and efficiently (Scheme 2).
The isoflavanone derivative 3a is a known compound. Its
Scheme 1. The isoflavanone structure contained in manynatural
products, including eriotrichin B, a compound isolated from
Erythrina eriotricha.[1b]
vanones are 1) the reduction of alkoxy isoflavones by using a
complex metal hydride;[2,3] 2) the hydroboration of 3-phenyl-
coumarin or 4-hydroxy-3-phenylcoumarin followed by oxida-
tion with chromic acid;[4] 3) Heck arylation of 4-acyloxy
2H-chromenes with aryl mercury(ii) compounds in the
presence of catalytic amounts of palladium acetate;[5] 4) the
treatment of 2-hydroxyalkoxy deoxybenzoines with methyl-
ene iodide;[4] and 5) the Mannich reaction of 2-hydroxyalkoxy
deoxybenzoines with paraformaldehyde in the presence of
secondary amines, such as piperidine or dimethylamine, in
boiling methanol.[6] However, these methods are limited by
the use of expensive starting materials and, in some cases,
toxic reagents.[5]
Gold catalysis has emerged recently as a powerful tool in
synthesis.[7,8] For example, heterobicyclic molecules,[9] highly
substituted pyrroles,[10] furans,[11] and chromanols[12] have
been synthesized expediently by gold-based catalysis. A
gold-catalyzed reaction has also been used as a key step in
the total synthesis of angucyclinone antibiotics.[13] We have
Scheme 2. Gold-catalyzed annulation of salicylaldehyde with
phenylacetylene.
spectral data are consistent with those reported in the
literature.[20] A doublet (J = 7.1 Hz) is observed in the
1H NMR spectrum at d = 4.68 ppm for the two hydrogen
atoms a to the oxygen atom of the ether group, and a triplet
(J = 7.1 Hz) is observed at d = 4.02 ppm for the hydrogen
atom a to the carbonyl group.
In our initial studies, salicylaldehyde (1a) was treated with
phenylacetylene (2a) under various conditions (Table 1). The
inclusion of AuIII/PBu3 as a potential catalyst combination led
only to the recovery of starting material (Table 1, entries 1
and 2). With different ratios of AuI/PBu3 the desired product
was formed in low to good yields (Table 1, entries 3–6 and
9–12). The best conditions found, which led to the isolation of
3a in 78% yield, were the use of 1 mol% of an AuI source and
25 mol% of PBu3 (Table 1, entry 13). Finally, AuI or PBu3
alone provided none or only a trace amount of the desired
product (Table 1, entries 7 and 8, respectively). When the
alternative ligands triethylphosphane, tricyclohexylphos-
phane, and trimethylphosphane were used, the yield of the
product decreased to 36, 19, and < 5%, respectively (Table 2,
entries 2, 4, and 1). Among the organophosphine ligands
examined for the annulation of hydroxyaldehydes with
[*] R. Skouta, Prof. Dr. C.-J. Li
Department of Chemistry
McGill University
801 Sherbrooke Street West, Montreal QC H3A2K6 (Canada)
Fax: (+1)514-398-3739
E-mail: cj.li@mcgill.ca
[**] We are grateful to the Canada Research Chair (Tier I) Foundation
(C.J.L.), the CFI, and NSERC for support of our research.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 1117 –1119
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
Table 1: The reaction of salicylaldehyde with phenylacetylene under various conditions.[a]
lene derivative (because the hydroxy group
should add with Markovnikov regioselectiv-
ity, as reported by Yang and He:[21] the
incorrect regioselectivity for the formation
of compound 3a); and 2) initial reaction of
the terminal carbon atom of the alkyne with
the aldehyde group, as described previously
by us,[15b] followed by a Rupe[22] rearrange-
ment to the a,b-unsaturated ketone and an
intramolecular conjugate addition (because
the phenyl substituent would then be b and
not a to the carbonyl group). Thus, only a
Entry[b]
1a [mmol]
2a [mmol]
t [h]
T [8C]
Yield of 3a [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
AuBr3/PBu3 (10/50)
AuCl3/PBu3 (10/50)
AuI/PBu3 (10/50)
AuCl/PBu3 (10/50)
AuCN/PBu3 (10/50)
AuCN/PBu3 (10/50)
AuCN (10)
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.50
0.50
0.50
0.50
0.50
1.00
0.50
0.50
0.75
0.75
0.75
0.75
0.75
0.75
17
17
17
17
17
17
17
17
36
36
36
36
36
36
100
100
100
100
100
150
150
150
150
150
150
150
150
150
no reaction
no reaction
11 (19)
19 (69)
21 (77)
46 (75)
no reaction
trace (low)
38 (98)
PBu3 (50)
AuCN/PBu3 (10/50)
AuCN/PBu3 (15/50)
AuCN/PBu3 (1/50)
AuCN/PBu3 (2.5/25)
AuCN/PBu3 (1/25)
AuCN/PBu3 (1/5)
38 (98)
20 (98)
66 (88)
78 (81)
À
mechanism based on C H activation of the
aldehyde, possibly assisted by chelation,
remains open to consideration.[19]
<5 (low)
A tentative mechanism for the novel
[a] All reactions were conducted in a sealed tube in toluene (1 mL). [b] Catalyst combination and (in
parentheses) amount of the components in mol%. [c] Based on 1H NMR spectroscopic analysis with an annulation is proposed in Scheme 3:
internal standard; reaction conversion is shown in parentheses.
Table 3: Gold-catalyzed annulation of aldehydes with alkynes.[a]
Entry Aldehyde
Alkyne
Product
Yield [%][b]
78 (75)
Table 2: The effect of various ligands on the gold-catalyzed annulation.[a]
EntryLigand (25 mol%)
Yield of
3 [%][b]
1
1
2
3
4
5
6
7
8
9
trimethylphosphane
triethylphosphane
tributylphosphane
tricyclohexylphosphane
tri-tert-butylphosphane
triphenylphosphane
tri-o-tolylphosphane
tri-2-furylphosphane
triphenyl phosphite
<5
36
78
19
2
1a
73 (63)
no reaction
no reaction
no reaction
no reaction
no reaction
3
4
5
6
1a
1a
1a
60 (57)
71 (69)
59 (55)
75 (55)
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.75 mmol, AuCN
(1 mol%), ligand (25 mol%), toluene (1 mL); all reactions were carried
out at 1508C for 36 h in a sealed tube under nitrogen. [b] Based on
1H NMR spectroscopic analysis with an internal standard.
alkynes, PBu3 appeared to be the most effective
(Table 2, entry 3).
2a
2b
Subsequently, the reaction was examined with a
range of substrates under the optimized conditions
given in Scheme 2 (Table 3). The presence of a
phenyl or electron-withdrawing substituent on the
alkyne appears to be more beneficial (Table 3,
entries 2 and 4) than the presence of an electron-
donating substituent (Table 3, entries 3 and 5). On
the other hand, no significant effect of substituents
(H, MeO, Cl) on the hydroxyaldehyde was observed,
and good yields were obtained in all cases. 2-
Hydroxy-1-naphthaldehyde (1d) also reacted effi-
ciently with 2a to give the desired annulation product
(Table 3, entry 10). The use of an aliphatic alkyne, 1-
hexyne, under the same conditions led to the
recovery of starting material.
7
1b
1b
65 (52)
8
9
2c
2a
75 (65)
73 (65)
10
2a
70 (68)
On the basis of the structure of compound 3a as
confirmed by 1H NMR spectroscopy and thus the
regioselectivity of the reaction, the following two
mechanisms can be excluded: 1) initial reaction of
the phenolic hydroxy group with the phenyl acety-
[a] Reaction conditions: aldehyde (0.25 mmol), alkyne (0.75 mmol), AuCN
(1 mol%), PBu3 (25 mol%), toluene (1 mL); all reactions were carried out at
1508C for 36 h in a sealed tube under nitrogen. [b] Based on 1H NMR spectroscopic
analysis with an internal standard; the yield of the isolated product is shown in
parentheses.
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Chemie
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Scheme 3. Tentative mechanism for the gold-catalyzed annulation of
salicylaldehyde with phenylacetylene.
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Complexation of the gold(I) catalyst with salicylaldehyde
À
followed by oxidative addition of the aldehyde C H bond
generates an acyl gold(III) hydride. This intermediate com-
plexes with phenylacetylene, which undergoes hydrometala-
tion. A subsequent conjugate addition of the hydroxy group
to the a,b-unsaturated ketone now generated by reductive
elimination gives the desired isoflavanone derivative and
regenerates the gold catalyst. Alternatively, a gold–carbene
intermediate[23] might be involved.
In conclusion, we have developed an annulation catalyzed
by gold(I) of simple o-hydroxyaldehydes with alkynes. The
annulation efficiently generates isoflavanone-type structures,
which have many possible applications in the synthesis of
isoflavanone natural products. Furthermore, this annulation
incorporates all atoms in both starting materials into the
product and thus has a theoretical atom economy of 100%.[24]
The scope, mechanism, and synthetic applications of this
reaction are under investigation in our laboratory.
Experimental Section
Typical procedure: A mixture of AuCN (0.6 mg, 0.0025 mmol), PBu3
(15.4 mL, 0.0625 mmol), 1a (26.6 mL, 0.25 mmol), and 2a (82.5 mL,
0.75 mmol) in freshly distilled toluene (1 mL) was stirred in a sealed
tube at 1508C for 36 h under an atmosphere of nitrogen. The reaction
mixture was then cooled to room temperature, and the solvent was
evaporated in vacuo. The residue was purified by flash column
chromatography on silica gel (hexane/ethyl acetate 15:1) to give 3a
(Rf = 0.2; 42 mg, 75%).
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Received: August 26, 2006
Revised: October 24, 2006
Published online: December 19, 2006
Keywords: alkynes · annulation · gold · homogeneous catalysis ·
.
isoflavanones
[1]a) P. M. Dewich in The Flavanoids: Advances in Research (Ed.:
J. B. Harborne, T. J. Mabry), Chapman and Hall, London, 1982,
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