GoId(I) catalysis: Selective synthesis of six- or seven-membered heterocycles from epoxy alkynes

Article abstract of DOI:10.1002/ejoc.200900210

Gold(I)-catalyzed intramolecular cycloisomerization of ketone-substituted epoxides with alkynes to six- or sevenmembered heterocyclic compounds is firstly introduced in this paper. This procedure involves a cascade isomerization of the ketone-substituted.

Full text of DOI:10.1002/ejoc.200900210

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900210
Gold(I) Catalysis: Selective Synthesis of Six- or Seven-Membered Heterocycles
from Epoxy Alkynes
Lun-Zhi Dai[a] and Min Shi*[a]
Keywords: Gold / Alkynes / Domino reactions / Heterocycles / Isomerization
Gold(I)-catalyzed intramolecular cycloisomerization of
ketone-substituted epoxides with alkynes to six- or seven-
membered heterocyclic compounds is firstly introduced in
this paper. This procedure involves a cascade isomerization
of the ketone-substituted epoxides into 1,3-diketones in the
presence of a Lewis acid and subsequent gold(I)-catalyzed
selective intramolecular addition of an oxygen or a carbon
nucleophile to the alkynes.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Six- and seven-membered oxygen-containing hetero-
cycles are abundant in nature and have attracted much syn-
thetic interest in recent years because of their diverse and
important biological properties.[1] Among them, the ad-
dition of 1,3-diketones to alkynes plays an important role
in organic chemistry. For example, In-,[2] Pd-,[3] and Zn[4]-
catalyzed transformations have been well documented be-
fore. Toste[5] and co-workers have reported an efficient gold-
catalyzed intramolecular addition of β-keto esters to inacti-
vated alkynes, providing the cyclization products derived
from the carbon nucleophiles. Later on, Sawamura[6] also
reported a similar reaction assisted by “holey phosphines”
to give six- or seven-membered rings (Scheme 1). Moreover,
some other groups have also reported the nucleophilic ad-
dition of 1,3-dicarbonyl compounds to propargyl carboxyl-
ates and unactivated olefins catalyzed by gold to give the
adducts in good yields.[7] All of these gold-catalyzed reac-
tions have the same feature that the 1,3-diketones act as
carbon nucleophiles. Herein, we wish to introduce another
new reaction catalyzed by gold to produce six- and seven-
membered heterocyclic compounds, in which the alkynes
are attacked by 1,3-diketones acting as carbon or oxygen
nucleophiles selectively, depending on the employed sub-
strates.
Scheme 1. Previous examples of AuI-catalyzed carbocyclization of
β-keto esters with alkynes.
forts to develop cascade reactions using epoxy alkynes as
substrates,[10] we envisaged that ketone-substituted epoxides
1 in the presence of acid might undergo isomerization to
give 1,3-diketones 1Ј (Scheme 2, step I). Subsequent cycliza-
tion could occur by two pathways involving either (1) ad-
dition of an oxygen nucleophile to the alkyne to afford 2
(Scheme 2, step II, path a) or (2) addition of a carbon nu-
cleophile to the alkyne to afford 3 (Scheme 2, step II,
path b), which was similar to the results reported by Toste
and Sawamura (Scheme 1).
It is well known that cyclizations of epoxy alkynes have
provided rapid access to complex structures in easy one-
pot processes.[8] Moreover, gold as an effective catalyst to
promote the isomerization of epoxy alkynes has been exten-
sively reported recently.[9] In the context of our ongoing ef-
[a] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
Fax: +86-21-64166128
E-mail: Mshi@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900210.
Scheme 2. Hypotheses for the one-pot conversion of epoxy alkynes
1 to seven-membered heterocycles.
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L.-Z. Dai, M. Shi
SHORT COMMUNICATION
With the optimized reaction conditions in hand, the
scope of this one-pot, two-step reaction was then examined
as depicted in Table 2. By examining the influence of the R1
substituents on the benzene rings we found that substrates
bearing electron-donating groups (Me, OMe) or electron-
withdrawing ones (F, Cl, Br) were smoothly transformed
into products 2 in moderate yields (Table 2, Entries 1–5).
However, when R1 was p-NO2C6H4 or the pyridyl group,
no reaction occurred, presumably as a result of the difficult
1,2-aryl transfer of the strongly electron-deficient aromatic
ring in the presence of a Lewis acid, as shown in step I of
Scheme 3 (Table 2, Entries 6 and 7).[12] Upon further ex-
ploring the applicability of this one-pot cycloisomerization
to epoxy alkyne 1i bearing a Br atom at the terminus of the
alkyne, we found that the reaction also proceeded smoothly
to give products (E)-2i and (Z)-2i in 28 and 18% yield,
respectively (Table 2, Entry 8).
Results and Discussion
To probe these hypotheses, we initially started our inves-
tigation by using 0.3 mmol of substrate 1a and 5 mol-% of
Au(PPh3)Cl/AgOTf in CH2Cl2 at room temperature. To our
disappointment, although the reaction gave a small amount
1
of 2a on the basis of H NMR spectroscopy, the product
could not be cleanly separated from some unidentified by-
products (Table 1, Entry 1). After 30 min at 40 °C 1a was
consumed completely upon treatment with 10 mol-% of
Yb(OTf)3. Then, 5 mol-% of Au(PPh3)Cl/AgOTf was fur-
ther added at room temperature (20 °C). After 36 h, we
found that (E)-2a and (Z)-2a were obtained in 36 and 16%
yield, respectively (Table 1, Entry 2), along with some impu-
rities (see the Supporting Information). The structure of
(E)-2a was unambiguously determined by X-ray diffrac-
tion.[11] By increasing the reaction temperature to 60 °C in
the first step, the overall yield of (E)-2a and (Z)-2a became
slightly lower (Table 1, Entry 3). Changing Yb(OTf)3 to
Sc(OTf)3 or In(OTf)3 afforded 2a in lower yields (Table 1,
Entries 4 and 5). By using Brønsted acids such as trifluoro-
methanesulfonic acid (HOTf) as a cocatalyst to the reac-
tion, complex product mixtures were obtained (Table 1, En-
try 6). Switching the CH2Cl2 solvent to CH3NO2 gave the
best result, affording (E)-2a in 46% yield and (Z)-2a in 14%
yield, respectively (Table 1, Entry 7). Subsequently, the use
of Yb(OTf)3 as the sole catalyst afforded 1aЈ in 74% yield
as a sole product (Table 1, Entry 8). Therefore, we believe
the use of Yb(OTf)3 as the Lewis acid was beneficial to
promote the rearrangement of oxiranes to form 1,3-dike-
tones.
Table 2. The scope of Yb(OTf)3 and gold(I) cocatalyzed cycloisom-
erization.
Table 1. Screening of reaction conditions for the transformation of
1a into a seven-membered heterocycle.
[a] Isolated yield. [b] Isolated yield, but containing a trace amount
of the corresponding (E)-2. [c] Some unidentified impurities could
not be separated from (Z)-2c. [d] Distilled CH3NO2 was not further
dried with 4 Å MS.
[a] The concentration of substrate was 0.15 . [b] Isolated yield.
[c] Complex reaction mixture.
Scheme 3. Proposed mechanism for the formation of seven-mem-
bered heterocycles.
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Eur. J. Org. Chem. 2009, 3129–3133

Gold(I)-Catalyzed Selective Synthesis of 6- or 7-Membered Heterocycles
On the basis of the above observations, a plausible
Inspired by the above results, we next examined the pos-
mechanism for the formation of the seven-membered sibility of the reaction by using epoxy alkynes 6 under iden-
heterocycles is proposed in Scheme 3. In step I, the coordi- tical conditions. Unexpectedly, it was found that the use of
nation of Yb(OTf)3 to the epoxy moiety of 1a affords com- 6a as the starting material gave product 7a in 65% yield,
plex A. Subsequent 1,2-transfer of the aryl group leads to resulting from carbon nucleophilic addition to the alkyne,
intermediate 1aЈ. In the second step, unlike the results in- along with the formation of byproduct 9a in 13% yield
volving carbon nucleophilic addition reported by Toste and (Table 3, Entry 1).[13] Further systematic screening of the
Sawamura, the addition of an oxygen nucleophile to the catalysts and solvents revealed that Au(PPh3)Cl/AgOTf was
alkyne moiety takes place by adding a gold catalyst to the the best catalyst and CH2Cl2 was the best solvent for the
system, resulting in the formation of products (E)-2a and reaction (Table 3, Entry 7). It should be mentioned that in
(Z)-2a. In comparison to the example reported by Sawa- toluene, 1,3-diketone 8 was obtained as the major product
mura, it is conceivable that the two aryl groups in 1,3-dike- (Table 3, Entry 5).
tones would promote the enolization of 1aЈ, which might
be the driving force for the addition of the oxygen nucleo- was C6H5, β-naphthyl, and p-ClC6H4, desired products 7
phile to the alkyne moiety. were obtained in moderate yield along with minor products
The scope of this reaction was also explored. When R
In addition to epoxy alkynes, epoxy alkene 4 was also 9 (Table 4, Entries 1–3). However, when R was o-CH3C6H4,
examined to obtain the corresponding seven-membered het- 9e was obtained as the major product in 47% yield, presum-
erocycle, which would be formed by nucleophilic addition ably as a result of the electron-donating group on the ben-
of the resulting 1,3-diketone to the double bond cocata- zene ring, which would increase the electronic density of the
lyzed by Yb(OTf)3 and gold(I). However, the reaction did aryl group, resulting in the formation of product 9e in a
not proceed in accordance with our expectation, and it was much easier way (Table 4, Entry 4). The yield of 7a (77%)
found that only product 5 was formed in 72% yield. By was higher than those of 7b–e (13–52%), indicating that the
further examination of the role of the catalysts, we found aryl group would promote the enolization of intermediate
that addition of 10 mol-% of Yb(OTf)3 to a solution of 4 8 more easily (Scheme 5), which was beneficial to the intra-
in dry CH3NO2 resulted in the transformation of substrate molecular addition of 1,3-diketones to alkynes.
4 into product 5 in 77% yield within 12 h (Scheme 4).
To gain some insight into the mechanism, a control ex-
Moreover, substrate 1j could also be transformed into 5 un- periment was carried out by subjecting isolated 8a under
der the similar conditions. This might be due to the fact the catalysis of Au(PPh3)Cl/AgOTf (5 mol-%) in dichloro-
that an aryl group at the end of the alkyne would weaken methane. It was found that 7a and 9a were obtained in 82
the C1–O bond and increase the nucleophilicity of the oxy- and 9% yield, respectively. On the basis of this control ex-
gen atom, as it would be more negatively charged. More- periment, a proposed mechanism was shown in Scheme 5.
over, the phenyl substituent stabilized the propargyl carbo- Being similar to the mechanism described in Scheme 3, in
cation that is eliminated in the transformation.[7a] There- the presence of gold complex, 6a easily rearranges into 1,3-
fore, the intramolecular nucleophilic ring opening of oxir- diketone 8a through intermediate F. Subsequent addition of
ane can take place prior to its rearrangement (Scheme 4).
a carbon nucleophile to the alkyne–gold complex produces
Scheme 4. Cycloisomerization of 4 or 1j.
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L.-Z. Dai, M. Shi
SHORT COMMUNICATION
Table 3. Screening of the reaction conditions for the transformation six-membered product 7a via intermediates G and H
(Scheme 5).[14]
of 6a.
Conclusions
In summary, we have developed a novel synthetic ap-
proach to six- and seven-membered heterocycles from ep-
oxy alkynes catalyzed by gold(I) or Yb(OTf)3/gold(I) in a
mild and efficient way through selective carbon or oxygen
nucleophilic addition to alkynes. Further investigation on
the scope and limitations of this reaction is in progress in
our lab.
Experimental Section
General Remarks: Melting points are uncorrected. 1H and 13C
NMR spectra were recorded at 300 and 75 MHz respectively. Mass
and HRMS spectra were recorded by EI methods. Organic solvents
used were dried by standard methods when necessary. Satisfactory
CHN microanalyses were obtained with an analyzer. Commercially
obtained reagents were used without further purification. All reac-
tions were monitored by TLC with silica gel coated plates. Flash
column chromatography was carried out using silica gel at in-
creased pressure.
[a] Isolated yield. [b] 10 mol-% of Yb(OTf)3 was added firstly at
40 °C, and after 30 min, 5 mol-% of Au(PPh3)Cl/AgOTf was added
further. [c] 61% of 6a was recovered. [d] 5 mol-% of catalyst was
used.
Procedure for the Preparation of 2a: To a solution of [3-(4-chlo-
Table 4. The scope of the reaction for the synthesis of 7.
rophenyl)oxiran-2-yl][2-(prop-2-ynyloxy)phenyl]methanone
(1a;
93.6 mg, 0.3 mmol) in freshly distilled nitromethane (2.0 mL) at
40 °C was added Yb(OTf)3 (0.03 mmol) under an atmosphere of
argon for about 30 min. Then, Au(Ph3P)Cl (0.015 mmol) and Ag-
OTf (0.015 mmol) were added. The reaction mixture was moni-
tored by TLC. When the reaction was complete, the mixture was
diluted with EtOAc and evaporated under reduced pressure, and
the residue was purified by flash column chromatography (EtOAc/
petroleum ether, 1:30). Compound 2a (56.2 mg) was isolated in
60% yield.
(2E)-(4-chlorophenyl)(3-methylene-2,3-dihydro-5H-1,4-benzodioxepin-
5-ylidene)acetaldehyde [(E)-2a]: Yield: 43.1 mg (46%). White solid.
[a] Isolated yield and the ratio of 7 and 9 was determined by 1H
NMR spectroscopy.
M.p. 139–141 °C. IR (NaCl): ν = 3064, 2927, 2861, 2757, 1664,
˜
1590, 1492, 1321, 1230, 1114 cm–1. 1H NMR (300 MHz, CDCl3,
TMS): δ = 4.80 (s, 2 H), 4.80 (s, 1 H), 4.93 (s, 1 H), 7.14–7.26 (m,
2 H), 7.32–7.43 (m, 5 H), 7.50–7.55 (m, 1 H), 9.57 (s, 1 H) ppm.
13C NMR (75 MHz, CDCl3, TMS): δ = 74.4, 106.0, 121.5, 122.4,
123.6, 123.7, 128.2, 130.1, 131.9, 133.46, 133.52, 134.1, 152.5,
155.8, 170.0, 191.0 ppm. MS (EI): m/z (%) = 89 (16.3) [M+ – 223],
165 (31.4) [M+ – 147], 228 (27.9) [M+ – 84], 273 (24.9) [M+ – 39],
312 (100.0) [M+], 314 (34.5) [M+ + 2]. HRMS: calcd. for
C18H13ClO3 312.0553; found 312.0550.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed procedure and characterization data for the starting
materials and products.
Acknowledgments
Financial support from the Shanghai Municipal Committee of Sci-
ence and Technology (04JC14083, 06XD14005), National Basic
Research Program of China ((973)-2009CB825300), and the
National Natural Science Foundation of China (20872162,
20672127, 20732008, 20821002, and 20702013) are greatly acknowl-
edged.
Scheme 5. Proposed pathway for the formation of six-membered
heterocycles.
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Gold(I)-Catalyzed Selective Synthesis of 6- or 7-Membered Heterocycles
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Received: March 2, 2009
Published Online: May 14, 2009
Eur. J. Org. Chem. 2009, 3129–3133
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