Gold-catalyzed annulations of 2-alkynyl benzaldehydes with vinyl ethers: Synthesis of dihydronaphthalene, isochromene, and Bicyclo[2.2.2]octane derivatives

Article abstract of DOI:10.1002/chem.201203841

With the suitable selection of a gold catalyst as well as the appropriate control of the reaction conditions, various new gold-catalyzed cyclizations of 2-alkynyl benzaldehyde with acyclic or cyclic vinyl ethers have been developed. Acetal-tethered dihydronaphthalene and isochromenes were obtained from the reactions of 2-alkynyl benzaldehydes with acyclic vinyl ethers under mild conditions. And, more interestingly, the gold-catalyzed reactions of 2-alkynyl benzaldehyde with a cyclic vinyl ether afforded the bicyclo[2.2.2]octane derivative involving two molecules of cyclic vinyl ethers. These products contain interesting substructures that have been found in many biologically active molecules and natural products. In addition, a gold-catalyzed homo-dimerization of 2-phenylethynyl benzaldehyde 1 a was observed when the reaction was carried out in the absence of vinyl ether, affording a set of separable diastereomeric products. Plausible mechanisms for these transformations are discussed; a gold-containing benzopyrylium was regarded as the crucial intermediate by which a number of these new transformations took place. The (mild) Midas touch: The gold-catalyzed reactions of 2-alkynyl benzaldehydes with acyclic or cyclic vinyl ethers afforded acetal-tethered dihydronaphthalene 1, isochromene 2, and bicyclo[2.2.2]octane 3 under mild reaction conditions (see scheme). Plausible mechanisms for the formations of these interesting compounds are discussed. Copyright

Full text of DOI:10.1002/chem.201203841

FULL PAPER
DOI: 10.1002/chem.201203841
Gold-Catalyzed Annulations of ACTHNUGRTENUNG2-Alkynyl Benzaldehydes with Vinyl Ethers:
Synthesis of Dihydronaphthalene, Isochromene, and Bicyclo
Derivatives
ACHTUNGTREN[NUNG 2.2.2]octane
Deepika Malhotra, Le-Ping Liu, Mark S. Mashuta, and G. B. Hammond*[a]
Dedicated to Chancellor Professor Emeritus Chang Ning Wu
Abstract: With the suitable selection of
a gold catalyst as well as the appropri-
ate control of the reaction conditions,
various new gold-catalyzed cyclizations
of 2-alkynyl benzaldehyde with acyclic
or cyclic vinyl ethers have been devel-
oped. Acetal-tethered dihydronaphtha-
lene and isochromenes were obtained
from the reactions of 2-alkynyl benzal-
dehydes with acyclic vinyl ethers under
mild conditions. And, more interesting-
ly, the gold-catalyzed reactions of 2-al-
kynyl benzaldehyde with a cyclic vinyl
ether afforded the bicyclo[2.2.2]octane
dition, a gold-catalyzed homo-dimeri-
zation of 2-phenylethynyl benzalde-
hyde 1a was observed when the reac-
tion was carried out in the absence of
vinyl ether, affording a set of separable
AHCTUNGTRENNUNG
derivative involving two molecules of
cyclic vinyl ethers. These products con-
tain interesting substructures that have
been found in many biologically active
molecules and natural products. In ad-
diastereomeric
products. Plausible
mechanisms for these transformations
are discussed; a gold-containing benzo-
pyrylium was regarded as the crucial
intermediate by which a number of
these new transformations took place.
Keywords: annulation · cyclization ·
gold · reaction mechanisms · syn-
thetic methods
Introduction
For more than a decade now, gold-catalyzed transformations
have been used extensively in the field of synthetic organic
chemistry to rapidly and effectively construct interesting or-
ganic frameworks.[1] The development of gold catalysts with
improved catalytic activity and stability has also attracted in-
terest.[2] Selected recent notable examples include N,O-che-
lating goldACHTUNGTRENNUNG
(III) catalysts,[3] N-heterocyclic carbene (NHC) or
acyclic carbene gold catalysts,[4] cationic gold acetonitrile
complexes[5] containing Buchwald-type phosphine ligands[6]
and cationic gold-triazole complexes.[7] On the other hand,
counteranions, such as super acid anions including the bis(-
trifluoromethanesulfonyl)imide (NTf2),[8] phosphates,[9] and
even hydroxide,[10] have been found to play a significant role
in the catalytic activities of gold catalysts. (Scheme 1)
Scheme 1. Selected examples of recently developed gold catalysts.
Due to their easy activation by various transition-metal
catalysts and Lewis acids, the readily available 2-alkynyl
benzaldehyde 1 has served as versatile scaffold in a number
of transformations[11] of which gold-catalyzed annulations
stand out.[12] Notably, Yamamoto and co-workers reported a
gold-catalyzed benzannulation of 2-alkynyl benzaldehyde
with an alkyne, furnishing naphthalene derivative 2 in a
highly efficient manner.[13]
A formal Diels–Alder-type
[4+2]-cycloaddition mechanism for this gold-catalyzed annu-
lation was proposed, but a stepwise mechanism via inter-
mediate B was also suggested and supported by substituent
effects. When copper was used as catalyst decarbonylation
occurred to yield 3 as the main product.[14] The group of Ya-
mamoto extended their formal [4+2]-cycloaddition protocol
to alkenes, obtaining dihydronaphthalene derivative 4, but
in this case the copper catalyst exhibited better catalytic ac-
tivity than gold.[15] Carbocation intermediate B was called
for to account for the observed regio- and stereoselectivities.
However, when vinyl ether was employed in the annulation
[a] D. Malhotra,+ Dr. L.-P. Liu,+ Dr. M. S. Mashuta,
Prof. Dr. G. B. Hammond
Department of Chemistry, University of Louisville
2320 South Brook Street, Louisville, Kentucky 40208 (USA)
Fax : (+1)502-852-3899
E-mail: gb.hammond@louisville.edu
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203841.
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with 2-alkynyl benzaldehyde, the reaction yielded nathpha-
lene 2, rather than dihydronaphthalene 4; this result has
been ascribed to the elimination of alcohol. This outcome
was corroborated by work reported by the Porco group.[16]
Aldehydes or acetals having a-protons have been effectively
involved in this gold-catalyzed annulation, but these sub-
strates served as an enol source instead of a carbonyl
source, affording the naphthalene product 2, once again,
due to the elimination of a water molecule (Scheme 2).[17]
Scheme 3. New developments on gold-catalyzed annulations of 2-alkynyl
benzaldehydes with vinyl ethers.
Scheme 2. Yamamotoꢁs group pioneered the gold or copper-catalyzed an-
nulation of 2-alkynyl benzaldehyde with alkyne, alkene, vinyl ether, or al-
dehyde. R4 is H or alkyl in B.
In line with our continuing interest in gold catalysis and
ligand effects,[18] we posited that a gold catalyst containing a
suitable ligand may help to stabilize the carbocation inter-
mediate and veer the reaction toward new synthetic paths.
Recently, we reported the gold-catalyzed intramolecular an-
nulations of 2-(ynol)aryl aldehydes, in which different gold
catalysts furnished benzochromanes or benzobicyclo-
Scheme 4. Selected examples of biologically active compounds containing
dihydronaphthalene, isochromene, or bicycloACTHNUTRGNEU[GN 2.2.2]octane substructures.
ACHTUNGTRENNUNG
[4.3.1]acetals (Scheme 3).[19] Thus, we envisioned that the re-
action of 2-alkynyl benzaldehyde with a vinyl ether might
yield a synthetically interesting product if a suitable gold
catalyst could be found. Herein, we are pleased to report
that, by selecting Au-1 as the catalyst, the reaction of 2-al-
kynyl benzaldehyde with vinyl ether produced acetal-teth-
ered dihydronaphthalene 5 and isochromene 6, rather than
Results and Discussion
Although for the most part the selection of gold catalysts
relies on an empirical trial and error approach, some pat-
terns on ligand effect in gold catalysis have emerged recen-
tly.[18a–c] For example, the cationic gold complex Au-1, devel-
oped by Echavarren and co-workers, exhibited excellent sta-
bility and catalytic activity in the cycloisomerization of
enynes due to its bulky and electron-rich phosphine
ligand.[27] Accordingly, we first employed Au-1 as the cata-
lyst in the reaction of 2-phenylethynyl benzaldehyde with
ethyl vinyl ether. To our delight, along with Yamamotoꢁs
naphthalene product 2a, which was obtained in low yield,
we isolated the acetal-tethered dihydronaphthalene deriva-
tive 5a as the major product, under mild conditions
(Table 1, entry 1). Other traditional gold catalysts were also
investigated in this reaction, but only phosphine gold chlor-
ide with silver activators showed good catalytic activities
(Table 1, entries 2 and 3); other catalysts such as AuCl,
naphthalene 2. Furthermore,
a
symmetrical bicyclo-
ACHTUNGTRENNUNG[2.2.2]octane 7 was produced from the reaction of 2-alkynyl
benzaldehyde with a cyclic vinyl ether. By using (iPr)Au as
the catalyst, a homo-dimerization of 2-alkynyl benzaldehyde
took place, affording a set of separable diastereomers 9
(Scheme 3). These interesting cyclic products are potentially
useful synthetic templates of biologically active molecules
and natural products such as codeine,[20] CJ-17493,[21] psy-
chorubrin,[22] trioxifene,[23] regalamine, robustamine,[24] and
the trypticene analogue TT13[25] (Scheme 4). To the best of
our knowledge, the synthesis of similar cyclic compounds
are rare, and, normally, harsh reaction conditions are
needed.[26]
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Gold-Catalyzed Annulations
FULL PAPER
Table 1. Discovery of a new gold-catalyzed annulation of 2-alkynyl ben-
zaldehyde with vinyl ether.[a,c]
Table 2. Scope of the gold-catalyzed annulation of 2-alkynyl benzalde-
hyde with vinyl ether.[a]
Entry
Substrate
Product
Yield
[%][b]
Entry
Au cat.
Yield [%][b]
1
2
3
4
5
6
7
8
Au-1
52 (9)
50 (20)
50 (10)
complex
complex
complex
complex
complex
PPh3AuCl/AgOTf
PPh3AuCl/AgNTf2
AuCl
AuCl3
triazole Au
1[c]
67
56
ACHTUNGTRENNUNG
[a] General reaction conditions: 2-(phenylethynyl)benzaldehyde 1a
(0.2 mmol), ethyl vinyl ether (1.0 mmol), Au (5 mol%), CH2Cl2 (1.0 mL).
[b] Yields of the isolated product; the yields of product 2a are presented
in parentheses. [c] Reaction of 1a with TfOH (5 mol%) gave a complex
reaction mixture along with unreacted 1a.
2
3
4
5
51[d]
53[d]
41
AuCl3, triazole gold, and (iPr)AuCl/AgOTf, as well as
AgOTf failed to give any identifiable product (Table 1, en-
tries 4–7). The fragility of this reaction may be due to the in-
stability of ethyl vinyl ether to acidic conditions.[28] Next,
various 2-alkynyl benzaldehyde substrates with different
substituents on the aromatic ring were prepared for use in
this new gold-catalyzed annulation with vinyl ether, and the
results are summarized in Table 2. All the reactions gave the
desired dihydronaphthalene derivatives in moderate yields
at, or below, room temperature. Mechanistically, the teth-
ered acetal might have been generated from an oxonium in-
termediate reacting with an alkoxide anion.[29]
Thus, we wondered if the oxonium intermediate could be
intramolecularly trapped by an adjacent phenolic hydroxyl
group or if the desired product would be formed preferably
in the presence of additional ethanol. To our satisfaction,
when substrate 1 f was employed in this reaction, the reac-
tion intermediate was indeed trapped by the adjacent phe-
nolic hydroxyl group, furnishing the structurally interesting
tricyclic compound 5 f as the main product (Table 2,
entry 5).[30] However, when two equivalents of ethanol were
added to the reaction, a new acetal-tethered isochromene
6a, rather than the corresponding dihydronaphthalene de-
rivative, was obtained in good yield (Table 3, entry 1).
Since isochromene derivatives are also attractive sub-
strates in organic chemistry, we investigated the gold-cata-
lyzed annulation of 2-alkynyl benzaldehydes with vinyl
ether in the presence of alcohol. Our results are outlined in
Table 3. All the desired products were obtained in good
yields. It should be noted that, for substrate 1 f, the intramo-
lecular trapping was bypassed by an intermolecular quench-
ing with ethanol (Table 3, entry 6), which could be explained
by the fact that alkoxide is a stronger nucleophile than
phenoxide. Other alcohols such methanol and isopropanol
were tested in this reaction, and similar products were ob-
tained in good yields (Table 3, entries 7 and 8).
[a] General reaction conditions: 2-alkynyl benzaldehyde 1 (0.145 mmol),
ethyl vinyl ether (0.72 mmol), Au-1 (5 mol%), CH2Cl2 (1.0 mL). [b] Yield
of the isolated product. [c] Reaction time: 15 min. [d] Ethyl vinyl ether
(1.45 mmol) was used and the reaction was carried out at 08C.
Plausible mechanisms for the formations of these new
products have been proposed, as outlined in Scheme 5. The
generation of intermediate A from a gold catalyst and 2-al-
kynyl benzaldehyde substrate is well-accepted,[31] whereas
the subsequent annulation with vinyl ether to form C is not
clear. It could be either a concerted step, as in a Diels–
Alder-type reaction, or in stepwise fashion, beginning with
the formation of B. According to previous literature reports,
the existence of B is supported by substituent effects, regio-
and stereoselectivities.[13–17] In our case, the formation of
acetal-tethered isochromene 6 in the presence of alcohol
also implies the generation of intermediate B. However, in-
termediate A was not trapped by alcohol before the forma-
tion of B, demonstrating the different catalytic activity of
the gold catalyst.[32] Once intermediate C was formed, it
could transform into D, which reacted with another mole-
cule of vinyl ether, generating intermediate E. Gold and
ethoxide elimination and quenching of the oxonium ion
with ethoxide took place in E, affording 5 as the product
and re-generating the gold catalyst.[33,28] A competitive elim-
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4045

G. B. Hammond et al.
Table 3. Gold-catalyzed annulation of 2-alkynyl benzaldehyde with vinyl
ether in the presence of alcohol.[a]
Entry
1
Substrate
Product
Yield
[%][b]
86
82
2[c]
3
71
4
54[d]
5
6
7
8
51[d]
56
Scheme 5. Proposed mechanisms for the gold-catalyzed annulations of 2-
alkynyl benzaldehyde with vinyl ether.
as the cyclic vinyl ether due to its easy availability, and the
corresponding product 7j was obtained in moderate yield.[35]
89
1
The structure of product 7 was determined by using H,
13C, DEPT, gCOSY, HMQC, and HMBC NMR spectrosco-
py as well as HRMS, and finally confirmed by using X-ray
crystallography (the ORTEP-3 diagram of 7a is shown in
Figure 1).
81
[a] General reaction conditions: 2-alkynyl benzaldehyde 1 (0.145 mmol),
ethyl vinyl ether (0.72 mmol), alcohol (0.29 mmol), Au-1 (5 mol%),
CH2Cl2 (1.0 mL). [b] Yield of the isolated product. [c] Reaction time:
10 min. [d] The reaction was carried out at 08C.
A plausible mechanism for the formation of the bicyclo-
AHCTUNGTREG[NNUN 2.2.2]octane derivative is outlined in Scheme 6. After inter-
mediate A is generated, a formal [4+2] cycloaddition to 2,3-
dihydrofuran could take place either through a concerted or
stepwise fashion to yield intermediate G. Intermediate G
could transform itself into H, which then reacts with a
second molecule of 2,3-dihydrofuran, generating I, before fi-
nally furnishing product 7 and regenerating the gold cata-
lyst. However, an alternative possibility should also be
taken into account, namely, elimination of gold catalyst
from H could generate tetrahydronaphthofuran derivative 8,
which would then undergo an inverse-electron-demand
Diels–Alder reaction with the second molecule of 2,3-dihy-
drofuran, furnishing the final product 7.[36]
ination in D also occurred, furnishing naphthalene 2 as the
product. With the selection of an appropriate gold catalyst,
the elimination could be controlled.
Because gold alkoxide elimination took place at the stage
of intermediate E, we envisioned that this elimination might
have been prevented if a cyclic vinyl ether was chosen as
the annulation partner. Thus, the readily available 2,3-dihy-
drofuran was employed in the reaction, and as expected, the
gold alkoxide elimination was successfully prevented; in-
stead, a new bicycloACHTUNGTRENNUNG[2.2.2]octane derivative 7 was produced,
in which two molecules of cyclic vinyl ether were involved.
Catalyst Au-2[34] showed the best catalytic activity and there-
fore it was selected for subsequent reactions. Various sub-
strates, having different substituents on the aromatic rings,
were employed in this new gold-catalyzed annulation with
2,3-dihydrofuran, and the corresponding products 7a–i were
isolated (Table 4). 3,4-Dihydro-2H-pyran was also employed
During our investigations on these gold-catalyzed annula-
tions, homo-dimerization of 2-alkynyl benzaldehyde was ob-
served when (iPr)AuCl/AgOTf was employed as the cata-
lyst, in the absence of vinyl ether (Scheme 7).[16] A set of
separable diastereoisomers 9a and 9b was obtained in good
yield, in a 3:5 ratio. The formation of this dimer has been as-
cribed to a gold-catalyzed hydrolysis of the 2-alkynyl benzal-
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Gold-Catalyzed Annulations
FULL PAPER
Table 4. Gold-catalyzed annulation of 2-alkynyl benzaldehyde with cyclic vinyl
ether.[a]
very mild conditions, and found a number of syn-
thetically interesting transformations. With the se-
lection of an appropriate gold catalyst, the reactions
of various 2-alkynyl benzaldehydes with acyclic
vinyl ethers afforded dihydronaphthalene deriva-
tives as the products, whereas acetal-tethered iso-
chromenes were obtained when the reaction was
conducted in the presence of alcohol. Interestingly,
Reactant
Product[b]
Reactant
Product[b]
a new bicycloACTHUNTGRNEUNG[2.2.2]octane derivative was isolated
from the reaction of 2-alkynyl benzaldehyde with
cyclic vinyl ether. The various mechanisms of for-
mation of these reactions have been discussed.
Lastly, it was found that 2-alkynyl benzaldehyde un-
dergoes dimerization under gold catalysis in the ab-
sence of vinyl ether.
Experimental Section
General methods: 1H and 13C NMR spectra were recorded at
500 and 126 (or 400 and 101) MHz, respectively, by using
CDCl3 as a solvent. The chemical shifts are reported in d
(ppm) values (1H and 13C NMR relative to CHCl3, d=
7.26 ppm for 1H NMR and d=77.0 ppm for 13C NMR and
CFCl3 (d=0 ppm for 19F NMR), multiplicities are indicated by
s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), h
(hextet), m (multiplet) and br (broad). Coupling constants, J,
are reported in Hertz (Hz). Solvents (tetrahydrofuran, ether,
dichloromethane and DMF) were dried using a commercial
solvent purification system. All other reagents and solvents
were employed without further purification. The products
were purified using a commercial flash chromatography system
or a regular glass column. TLC was developed on silica gel 60
F254 aluminum sheets. Exact molecular weight of new com-
pound was obtained by high-resolution electrospray ionization
mass spectrometry (HREIMS).
General procedure for the formation of dihydronaphthalenes
(5): Catalyst Au-1 (5.61 mg, 0.0072 mmol) was added to the
solution of 2-phenylethynyl benzaldehyde 1a (30 mg,
0.145 mmol) and ethyl vinyl ether (70 mL, 0.72 mmol) in
CH2Cl2 (1.0 mL). The mixture was stirred for 30 min at room
temperature; afterwards the reaction mixture was quenched
with water and extracted with CH2Cl2. The solvent in the or-
ganic layer was removed under reduced pressure and the resi-
due was subjected to flash column chromatography (eluent:
ethyl acetate/n-hexane=1:10) to give product 5a (26.5 mg,
52%) as a colorless oil. 1H NMR (CDCl3, 400 MHz): d=1.13–
1.16 (3H, t, J=7.2 Hz), 1.23–1.26 (3H, t, J=7.2 Hz), 1.84–1.88
(1H, m), 1.93–2.0 (1H, m), 2.42–2.49 (1H, m), 2.68–2.74 (1H,
m), 3.01–3.06 (1H, m), 3.39–3.59 (3H, m), 3.63–3.71 (1H, m),
4.44–4.47 (1H, t, J=6.4 Hz), 6.39–6.42 (1H, dd, J=6.4,
3.2 Hz), 7.12–7.17 (1H, m), 7.19–7.20 (2H, m), 7.27–7.30 (1H,
[a] General reaction conditions: 2-alkynyl benzaldehyde 1 (0.145 mmol), 2,3-dihydro-
furan (0.72 mmol), Au-2 (5 mol%), and CH2Cl2 (1.0 mL). [b] Yield of the isolated
product. [c] 3,4-Dihydro-2H-pyran was used as cyclic vinyl ether.
dehyde substrate, generating ketone 10, which then serves
d, J=8.0 Hz), 7.40–7.44 (2H, t, J=7.8 Hz), 7.52–7.56 (1H, t, J=7.4 Hz),
7.83–7.85 ppm (2H, d, J=7.2 Hz); 13C NMR (CDCl3, 101 MHz): d=15.3,
15.4, 29.0, 33.3, 37.3, 60.8, 61.0, 101.1, 126.3, 126.8, 127.8, 127.9, 128.3,
129.8, 131.1, 132.8, 135.2, 138.0, 138.3, 138.8, 196.7 ppm; HRMS (ESI)
calcd for C23H26NaO3+: 373.1774 [M+Na+]; found: 373.1775.
as a nucleophile for attacking the electrophilic intermediate
A. The structure of the dimer was also confirmed by X-ray
crystallography. The ORTEP-3 diagram of the anti-isomer
9b is shown in Figure 2.
General procedure for the formation of isochromenes (6): Catalyst Au-1
(5.61 mg, 0.0072 mmol) was added to the solution of 2-phenylethynyl
benzaldehyde 1a (30 mg, 0.145 mmol, ethyl vinyl ether (70 mL,
0.72 mmol), and ethanol (17 mL, 0.29 mmol) in CH2Cl2 (1.0 mL). The
mixture was stirred for 30 min at room temperature; afterwards the reac-
tion mixture was quenched with water and extracted with CH2Cl2. The
solvent in the organic layer was removed under reduced pressure and the
Conclusion
We have investigated the gold-catalyzed annulations of 2-al-
kynyl benzaldehyde with acyclic or cyclic vinyl ethers under
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4047

G. B. Hammond et al.
Scheme 7. Gold-catalyzed homo-dimerization of 2-alkynyl benzaldehyde
and the proposed mechanism.
Figure 1. ORTEP-3 diagram of bicycloACTHNUTRGNEUGN[2.2.2]octane derivative 7a, show-
ing 40% probability ellipsoids. H atoms are shown as small spheres of ar-
bitrary radii. Selected bond lengths [ꢂ] and angles [8]: O1-C2,
1.4285(17); O1-C3, 1.4380(18); O2-C9, 1.4419(18); O2-C10, 1.4338(16);
O3-C17, 1.2100(18); O2-C10-C1, 111.15(11); O1-C2-C3, 111.78(11); C2-
C1-C10, 104.06(11).
Figure 2. ORTEP-3 diagram of product 9b, showing one diastereoisomer
of the racemic mixture at 40% probability ellipsoids. H atoms are shown
as small spheres of arbitrary radii. Selected bond lengths [ꢂ] and angles
[8]: O1-C7, 1.3795(15); O1-C15, 1.4447(15); O2-C17, 1.2157(15); O3-C30,
1.2117(16); C15-C16, 1.5531(17); C7-O1-C15, 114.70(9); O1-C7-C8,
121.07(11); O1-C15-C16, 106.72(9).
m), 3.61–3.71 (2H, m), 3.76–3.84 (1H, m), 4.90–4.93 (1H, dd, J=7.6,
3.8 Hz), 5.50–5.53 (1H, dd, J=9.6, 4.0 Hz), 6.47 (1H, s), 7.09–7.13 (2H, t,
J=8.0 Hz), 7.18–7.27 (2H, m), 7.34–7.43 (3H, m), 7.76–7.78 ppm (2H,
m); 13C NMR (CDCl3, 101 MHz): d=15.39, 15.41, 37.9, 60.9, 62.2, 75.0,
99.9, 100.6, 123.7, 124.0, 124.9, 126.6, 128.0, 128.4, 128.7, 130.9, 131.0,
134.6, 151.3 ppm; HRMS (ESI) calcd for C21H24NaO3+: 347.1618 [M+
Na+]; found: 347.1622.
Scheme 6. Proposed mechanism for the gold-catalyzed annulation of 2-al-
kynyl benzaldehyde with cyclic vinyl ether.
residue was subjected to flash column chromatography (eluent: ethyl ace-
tate/n-hexane=1:10) to give product 6a (41 mg, 87%) as a colorless oil.
1H NMR (CDCl3, 400 MHz): d=1.21–1.24 (3H, t, J=7.6 Hz), 1.27–1.31
(3H, t, J=7.2 Hz), 2.09–2.16 (1H, m), 2.42–2.49 (1H, m), 3.51–3.59 (1H,
General procedure for the formation of bicyclo
ACHTUNGERTN[NUNG 2.2.2]octanes (7): Cata-
lyst Au-2 (6.93 mg, 0.0072 mmol) was added to the solution of 2-phenyl-
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Gold-Catalyzed Annulations
FULL PAPER
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quenched with water and extracted with CH2Cl2. The solvent in the or-
ganic layer was removed under reduced pressure and the residue was
subjected to a flash column chromatography (eluent: ethyl acetate/n-
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hexane=1:10) to give product 7a (26 mg, 51%) as
a white solid.
1H NMR (CDCl3, 400 MHz): d=1.13–1.21 (2H, m), 1.81–1.89 (2H, m),
2.54–2.61 (2H, m), 2.91–2.97 (3H, m), 3.29–3.35 (2H, q, J=7.2 Hz), 4.48–
4.50 (2H, d, J=8.4 Hz), 7.05–7.18 (3H, m), 7.30–7.34 (2H, t, J=7.6 Hz),
7.38–7.41 (1H, t, J=6.8 Hz), 7.58–7.59 (1H, d, J=7.2 Hz), 7.83–7.85 ppm
(2H, d, J=8.4 Hz); 13C NMR (CDCl3, 101 MHz): d=30.3, 43.8, 44.2,
62.2, 68.5, 81.0, 126.4, 126.8, 127.3, 127.6, 129.0, 129.6, 130.8, 134.9, 137.8,
140.3, 204.0 ppm; HRMS (ESI) calcd for C23H23O3+: 347.1642 [M+H+];
found: 347.1642.
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1
16.3 mg, 52%) as a white solid. For 9a: H NMR (CDCl3, 400 MHz): d=
6.28–6.31 (1H, d, J=9.6 Hz), 6.60 (1H, s), 6.99–7.08 (4H, m), 7.12–7.27
(8H, m), 7.36–7.50 (3H, m), 7.60–7.64 (1H, t, J=7.4 Hz), 7.85–7.87 (2H,
d, J=8.4 Hz), 7.99–8.01 (1H, d, J=7.6 Hz), 9.64 ppm (1H, s); 13C NMR
(CDCl3, 101 MHz): d=49.1, 79.8, 101.0, 124.4, 124.5, 126.0, 126.5, 127.6,
127.9, 128.36, 128.4, 128.6, 128.7, 129.6, 129.8, 130.4, 133.2, 133.5, 133.8,
134.7, 135.1, 136.9, 150.7, 192.9, 198.5 ppm; HRMS (ESI) calcd for
C30H22NaO3+: 453.1461 [M+Na+]; found: 453.1465. For 9b: 1H NMR
(CDCl3, 400 MHz): d=5.92–5.94 (1H, d, J=7.6 Hz), 6.17–6.20 (1H, d,
J=9.6 Hz), 6.58 (1H, s), 6.65–6.68 (1H, t, J=7.4 Hz), 7.03–7.11 (3H, m),
7.18–7.19 (3H, m), 7.24–7.28 (2H, t, J=7.2 Hz), 7.35–7.39 (2H, t, J=
7.6 Hz), 7.46–7.55 (4H, m), 7.77–7.80 (1H, d, J=8.0 Hz), 7.98–8.00 (2H,
d, J=8.0 Hz), 9.57 ppm (1H, s); 13C NMR (CDCl3, 101 MHz): d=46.1,
79.9, 100.5, 123.8, 125.1, 125.2, 125.4, 127.0, 128.0, 128.1, 128.2, 128.57,
128.66, 128.68, 129.3, 131.3, 133.2, 133.6, 134.0, 134.5, 135.5, 136.9, 150.7,
191.9, 198.2 ppm; HRMS (ESI) calcd for C30H22NaO3+: 453.1461 [M+
Na+]; found: 453.1464.
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We are grateful to the National Science Foundation for financial support
(CHE-1111316). D.M. acknowledges with gratitude a graduate student
fellowship from the Institute of Molecular Diversity and Drug Design of
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knowledge the support provided by the CREAM Mass Spectrometry Fa-
cility (University of Louisville) funded by NSF/EPS CoR (EPS-0447479).
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Received: October 27, 2012
Revised: December 11, 2012
Published online: January 30, 2013
4050
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Chem. Eur. J. 2013, 19, 4043 – 4050