Gold catalysis: Synthesis of 3-acylindenes from 2-alkynylaryl epoxides

Article abstract of DOI:10.1002/adsc.200800385

A series of 2-alkynylaryl epoxides were prepared by a sequence of Sonogashira coupling, Wittig olefination and epoxidation or a Darzens' glycid ester synthesis. The conversion of these substrates with gold(I) catalysts furnished 3-acylindenes and, in occa

Full text of DOI:10.1002/adsc.200800385

FULL PAPERS
DOI: 10.1002/adsc.200800385
Gold Catalysis: Synthesis of 3-Acylindenes from2-Alkynylaryl
Epoxides
A. Stephen K. Hashmi,a,* Miriam Bührle,a Ralph SalathØ,a and Jan W. Batsb
a
Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg,
Germany
Fax : (+49)-6221-54-4205; phone: (+49)-6221-54-8413; e-mail: hashmi@hashmi.de
Institut für Organische Chemie und Chemische Biologie, Johann Wolfgang Goethe-Universität Frankfurt,
b
Marie-Curie-Str. 11, 60439 Frankfurt/Main, Germany (crystallographic investigation)
Received: June 19, 2008; Published online: August 19, 2008
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800385.
Abstract: A series of 2-alkynylaryl epoxides were ucts of an isomerization of the oxirane ring to a
prepared by a sequence of Sonogashira coupling, ketone. Isotope labelling of the epoxide oxygen indi-
Wittig olefination and epoxidation or a Darzensꢀ cates an intramolecular oxygen transfer.
glycid ester synthesis. The conversion of these sub-
strates with gold(I) catalysts furnished 3-acylindenes Keywords: alkynes; gold; homogeneous catalysis; in-
and, in occasional cases as side-products, the prod- denes; isotope labelling; oxiranes
Introduction
We then became interested in using alternative pre-
cursors for oxepines in gold catalysis. Based on our
Homogeneous gold catalysis[1] is a fast growing field, previous experience with oxiranes,[5] we assumed that
one of the most reliable transformations in this field an activation of the alkyne in 5 by an electrophilic
is the phenol synthesis,[2] a special sub-type of the gold catalyst initiates a nucleophilic attack of the ep-
enyne cycloisomerization (Scheme 1). The synthetic oxide oxygen, opening of the strained ring should be
À
aspects of this reaction have been explored, from selective for the benzylic C O bond to deliver the
easily accessible furan derivatives 1 a broad range of more stable benzylic cation 6. Then elimination of a
benzo-anellated carbo- and heterocycles 2 can be pre- proton at the position neighbouring to the carbenium
pared by this methodology.[3] In addition, the unique ion and a proto-desauration would lead to the benzo-
mechanism was investigated,[4] experimental proof for anellated oxepine 7. If the reaction would proceed
oxepin (3) and arene oxide (4) intermediates was ob- from 7 in analogy to the corresponding steps of the
tained.[3h,4c–e]
phenol synthesis, one could ultimately expect the
naphthols 9 and/or 10 as products (Scheme 2).
Here we report our observations on the gold-cata-
lyzed conversions of substrates of type 5.
Results and Discussion
The step-wise assembly of the three components, 2-
bromobenzaldehyde (11) with different terminal al-
kynes by a Sonogashira coupling and a subsequent
Wittig reaction with phosphorus ylides delivered (12)
the enynes 13 as an (E/Z) mixture. We did not ad-
dress the double bond geometry in order to keep the
synthetic approach as simple as possible, and we ex-
pected both diastereomers to ultimately form the
same product. The alkenes were epoxidized with m-
Scheme 1. Oxepines and arene oxides as intermediates in
the gold-catalyzed phenol synthesis.
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A. Stephen K. Hashmi et al.
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Scheme 2. Substrates 5 as potential precursors for oxepines.
Table 1. A variety of substrates 14 from three components, 2-bromobenzaldehyde, a terminal alkyne and a phosphorus
ylide.
Entry
R1
12 (Yield)
12a (89%)
R2
13 (Yield, E:Z)
14 (Yield, trans:cis)
1
2
n-Bu
n-Pr
H
13a (82%, 1:1.3)
13b (80%)
14a (75%, 1:1.3)
14b (51%)
3
4
5
6
7
8
9
10
11
12
13
14
15
n-Hex
12b (96%)
n-Pr
i-Pr
n-Bu
n-Pe
Me
Me
n-Pr
Me
n-Pr
Me
n-Pr
Me
13c (92%, 1:1)
13d (46%, 1:0.6)
13e (49%, 1:0.9)
13f (51%, 1:1)
13g (67%, 1:0.9)
13h (87%, 1:0.8)
13i (59%, 1:0.7)
13j (74%, 1:0.8)
13k (79%, 1:0.9)
13l (69%, 1:0.7)
13m (75%, 1:0.5)
14c (73%, 1:0.9)
14d (86%, 1:0.5)
14e (76%, 1:0.8)
14f (86%, 1:0.9)
14g (72%, 1:0.7)
14h (75%, 1:0.9)
14i (95%, 1:0.5)
14j (89%, 1:0.7)
14k (76%, 1:0.8)
14l (85%, 1:0.7)
14m (78%, 1:0.5)
14n[a] (79%, 1:0.7)
14o[b] (39%)
Ph
t-Bu
CH2CH2Ph
12c (91%)
12d (96%)
12e (99%)
TMS
TBS
H
12f (88%)
12g (99%)
Bu
CO2Et
[a]
From 14l by desilylation.
From 12a by Darzensꢀ glycid ester synthesis.
[b]
CPBA (Table 1), again a mixture of the cis/trans dia- 14l (entry 14). For the ester-substitued oxirane 14o
stereomers was obtained. Compound 14n was pre- Darzensꢀ glycid ester synthesis was a convenient short
pared by desilylation of the TMS-substituted alkyne cut (entry 15).
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Gold Catalysis: Synthesis of 3-Acylindenes from 2-Alkynylaryl Epoxides
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Table 2. Gold(I)-catalyzed conversion of 14.
Entry
Substrate
R1
R2
Amount of catalyst [mol%]
Product (yield)
1
2
3
4
5
6
7
8
14a
14b
14c
14d
14e
14f
14g
14h
14i
14j
14k
14l
14m
14n
14o
n-Bu
n-Bu
n-Pr
H
n-Pr
i-Pr
n-Bu
n-Pent
Me
Me
n-Pr
Me
n-Pr
Me
n-Pr
Me
5
5
5
5
5
5
5
3
5
3
5
5
5
5
5
15a (80%)
–
15c (85%)
15d (56%)
15e (66%)
15f (64%)
15g (67%)
15h (37%)
16a (7%)
16b (48%)
16c (8%)
–
–
–
–
16h (18%)
–
–
–
n-Hex
n-Hex
n-Hex
n-Hex
n-Hex
Ph
9
t-Bu
–
10
11
12
13
14
15
CH2CH2Ph
CH2CH2Ph
TMS
TBS
H
15j (90%)
15k (68%)
–
–
–
–
–
16m (13%)
–
–
n-Bu
CO2Et
Initial testing of several different gold catalysts in- rings. These dimers also are stabilized by additional
dicated that Gagoszꢀs catalyst[6] [(Ad)
2A
(benzene)
interactions.
The
À
PAu]NTf2
gave
the
best
results
À
AuCl2[picolinate] and {[Mes3PAu]2Cl}BF4 gave only connected by rather long intermolecular C H···p in-
an unselective reaction and low conversion). Thus the teractions.
substrates 14a–o were subjected to this gold(I) cata-
A competing process is the simple isomerization of
lyst (Table 2). Interestingly, rather than the expected the epoxide by initial opening of the benzylic epoxide
products, in most cases the acylindenes 15 were bond (whether this is initated intermolecularly by a
formed, in some examples in excellent yields. Due to direct gold-oxygen interaction or intramolecularly by
the absence of stereogenic elements in 15, both dia- an interaction of the gold-alkyne complex with the
stereomers of 14 converge to the same product.
epoxide, hydride shift from intermediate 18, and elim-
The structure of 15, especially the position of the ination to re-form the alkyne, is as yet unknown).
carbonyl group, was initially based on spectroscopic This was observed in the case of the unsubstituted ep-
evidence. Apart from characteristic data for the a,b- oxide 14b (entry 2), here only 16b was obtained. In
1
unsaturated carbonyl unit, the H NMR nicely shows the case of the substrates 14a, 14c and 14h the ke-
that the group R1 is attached to the carbonyl group tones 16a, 16c and 16h were only formed as side-prod-
and R2 is attached to the double bond. For example, ucts (entries 1, 3 and 8).
in the substrates 15g, 15h and 15j with R2 =Me the
The limitations become visible, too. With a sterical-
methyl group shows as a singlet at 2.34, 2.08 and ly demanding group on the alkyne, the reaction com-
2.35 ppm, respectively, typical for an allylic methyl pletely failed (t-Bu group in 14l, entry 9) or gave only
group. For the first CH2 group of the other side chain a low yield of epoxide ring opening (TBS group in
R1, 2.84 ppm for the hexyl group in 15g and 3.05 ppm 14m, entry 13). Terminal alkynes completely fail
for the CH2CH2Ph substituent in 15j show as triplets (entry 14), another (maybe related) problem is the
with coupling constants of 7.3–7.5 Hz. This assignment TMS-substituted alkyne which is easily desilylated
was ultimately confirmed by a crystal structure analy- under the electrophilic reaction conditions (entry 12).
sis of 15j (Figure 1).[7] It shows a planar indene skele- Most unfortunately, the easily accessible ester-substi-
ton (mean deviation from plane: 0.003 Š) with a co- tuted expoxide 14o (entry 15) also does not react.
planar keto group (angle between planes: 4.28). There
Control experiments with 5 mol% AgBF4 or 5
is a short intramolecular contact distance of 2.39 Š mol% p-TsOH under the same conditions gave no
between O1 and the hydrogen atom at C8. The mole- conversion of the substrates.
cules form centrosymmetric dimers with p···p contacts
of about 3.50 Š between the parallel five-membered belled derivative of 14j. The product 15j still con-
Regarding the mechanism, we prepared the 18O-la-
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Figure 1. The X-ray crystal structure analysis of 15j confirmed the structural assignment.
broken and an even more delocalized carbenium ion
19 can be formed. In Scheme 3 the pentadienyl cation
structure of 19 is emphasized, and in analogy to the
gold-catalyzed Rautenstrauch rearrangement[10] a ring
closure to the allyl cation 20 could follow. Here the
allyl cation in 20 would be part of a well-stabilized
benzylic cation. Elimination of the gold catalyst to 21
and isomerization of the double bond finally would
deliver the product 15.
Figure 2. Labelling studies suggest an intramolecular trans-
fer of the oxygen atom.
Conclusions
tained the 18O-label (Figure 2), which proves an intra-
molecular oxygen transfer and excludes external This new conversion nicely complements the few
water molecules as nucleophiles. For example, the known routes to 3-acylindenes.[11] Furthermore, the
possibility of an epoxide isomerization to 16, a hydra- mechanistic study proofs an intramolecular oxygen
tation of the triple bond to the benzyl ketone, as dis- transfer and points towards a pentadienyl cation to
cussed in work by Liu,[8] and a final intramolecular cyclopentenyl cation cyclization as a key step and not
condensation of the two carbonyl side-arms, can be a hydrative carbocyclization or the participation of vi-
ruled out. The same is true for a potential hydratation nylidene-metal species. Future optimization of the
to a vinylgold intermediate and a reaction of the catalyst and the reaction conditions is necessary to
latter with the epoxide. Similarly, a cross-over experi- completely suppress the side product 16.
ment of a mixture of 18O-14j and 14a gave 18O-15j
and 15j and no evidence for 18O-15j (MS detection).
Furthermore, the fact that internal alkynes react,
excludes the participation of vinylidene-metal species
as suggested by Liu et al. for related reactions of simi-
lar substrates with ruthenium catalysts (leading to dif-
ferent products).[9]
Experimental Section
General Procedure A: Sonogashira Coupling
1.2 equivalents alkyne, 1 equivalent bromobenzaldehyde 11
and PdCl2ACTHER(UNG PPh3)2 were dissolved in degassed triethylamine,
and after 1 min, copper(I) iodide was added. The mixture
was stirred at 658Cfor 16 h and was then concentrated
under reduced pressure. The crude product was purified by
A mechanistic proposal is shown in Scheme 3.
After coordination of the alkyne to the catalyst (17)
and electrophilic attack at the oxirane oxygen atom,
the benzylic cation 18 could be generated. Then, the
À
remaining C O bond of the former epoxide ring is flash chromatography on silica gel.
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Gold Catalysis: Synthesis of 3-Acylindenes from 2-Alkynylaryl Epoxides
FULL PAPERS
Scheme 3. Possible reaction mechanism for the gold-catalyzed conversion of 14 to 15.
General Procedure B: Wittig Reaction B
Acknowledgements
1.3 equivalents n-butyllithium were added slowly to a solu-
This work was supported by Umicore AG & Co. KG and by
the Deutsche Forschungsgemeinschaft (HA 1932/10-1).
tion of 1.5 equivalents Wittig reagent in THF at 08C. At this
temperature the mixture was stirred for 30 min. Then the
substituted benzaldehyde 12 was added and the mixture
again stirred at 08Cfor 4 h. Afterwards the mixture was hy-
drolyzed with brine, extracted three times with diethyl
ether, dried over MgSO4 and filtered. The solvent was re-
moved under reduced pressure and the crude product was
purified by flash chromatography on silica gel.
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A. Stephen K. Hashmi et al.
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