Au(I)-catalyzed hydrative rearrangement of 1,1-diethynylcarbinol acetates to functionalized cyclopentenones and allenones

Article abstract of DOI:10.1021/jo802103g

(Chemical Equation Presented) Atom-economical syntheses of isomeric 5-acetoxy-2-alkyl-2-cyclopentenones (2) and acetoxymethyl α-alkylallenones (3) have been described via Au-catalyzed hydrative rearrangement of 1,1-diethynylcarbinol acetates (1). In anhyd

Full text of DOI:10.1021/jo802103g

Au(I)-Catalyzed Hydrative Rearrangement of 1,1-Diethynylcarbinol
Acetates to Functionalized Cyclopentenones and Allenones
Chang Ho Oh* and Swastik Karmakar
Department of Chemistry, Hanyang UniVersity, Sungdong-Gu, Seoul 133-791, South Korea
changho@hanyang.ac.kr
ReceiVed September 24, 2008
Atom-economical syntheses of isomeric 5-acetoxy-2-alkyl-2-cyclopentenones (2) and acetoxymethyl
R-alkylallenones (3) have been described via Au-catalyzed hydrative rearrangement of 1,1-diethynyl-
carbinol acetates (1). In anhydrous condition, Au(I)-catalyzed [3,3]-rearrangement of 1 afforded the
3-alkynylallenyl acetate 4 in low yield. Treatment of 1 with Au(I) catalyst in wet CH2Cl2 produced
either 2 or 3 as a major product depending on the temperature, reaction time, and catalyst loading. D has
been proposed as an intermediate, which might be formed via Au(I)-induced internal oxacyclization of
the intermediate 4 followed by chemoselective nucleophilic attack by the water molecule. Formation of
2 or 3 might be explained via sequential 1,3-dioxole ring opening and gold-promoted 5-endo-dig
carbocyclization or simple protonation of the intermediate D, respectively.
Introduction
ate functionalization are of utmost interest of cyclopentenone
construction strategy. Specially, introduction of an alkyl group
at the R-position of R,ꢀ-unsaturated carbonyl compounds is still
challenging in organic synthesis,2d as many pharmaceuticals
(e.g., Prostaglandins, Limaprost, Misoprostol, etc.)1f and floral
odorants (e.g., Hedione, (+)-(1R,2S)-methyl epi-jasmonate,
etc.)2a contain an alkyl substituent at the R-position of their
cyclopentenone skeleton. Now, we intend to introduce a new
methodology for the construction of R-alkyl R′-acetoxy cyclo-
pentenone (2), which could be a valuable intermediate in organic
synthesis. Additionally, another product, acetoxymethyl R-alky-
lallenone (3), could be an effective building block for the
Substituted cyclopentenones are the important building blocks
for the synthesis of a wide array of pharmaceuticals1 and
interesting natural products.2 Therefore, popular strategies have
been developed for the construction of this five-membered ring
system, which include the intramolecular aldol reaction,3 the
electrocyclizations such as Nazarov cyclization4 and Rauten-
strauch rearrangement,5 and the cycloadditions such as Pauson-
Khand reaction6 and [2 + 3]- or [4 + 1]-cycloadditions.7,8
Judicious placement of double bonds and the scope of appropri-
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370 J. Org. Chem. 2009, 74, 370–374
10.1021/jo802103g CCC: $40.75 2009 American Chemical Society
Published on Web 11/21/2008

HydratiVe Rearrangement of 1,1-Diethynylcarbinol Acetates
TABLE 1. Optimization of Catalysts To Construct Cyclopentenone and Allenone
temp (°C)/
time (h)
product (%
isolated yield)
entry
catalyst
AuCl (5 mol %)
solventa
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCM/water
DCM/water
DCM/water
DCM/water
DCM/water
DCM/water
DCM/water
1
0/0.5
0/0.5
0/0.25
rt/3
0/0.5
0/0.5
rt/3
rt/1.0
rt/1.0
rt/1
0/0.25
rt/4
4a (5)
4a (5)
4a (20)
no reaction
4a (10)
4a (8)
complex mixture
3a (30)
3a (25)
2a (82), 3a (5)
3a (70)
2
AuCl(PPh3) (5 mol %)
3
4
5
AuCl(PPh3)/AgSbF6 (5 mol %)
AuCl(Me2S)/AgSbF6 (5 mol %)
AuBr3 (3 mol %)
6
7
NaAuCl4 ·2H2O (3 mol %)
AgSbF6 (3 mol %)
8
AuBr3 (3 mol %)
9
NaAuCl4 ·2H2O (3 mol %)
AuCl(PPh3)/AgSbF6 (3 mol %)
AuCl(PPh3)/AgSbF6 (6 mol %)
CF3CO2H (10 mol %)
p-toluenesulfonic acid (10 mol %)
CF3SO3H (10 mol %)
10
11
12
13
14
no reaction
no reaction
no reaction
rt/4
rt/4
a DCE and DCM are abbreviations of 1,2-dichloroethane and dichloromethane, respectively.
numerous elegant transformations as well as for the synthesis
of some important natural products and medicinally valuable
compounds.9
electrocyclization of pentadienyl cation must proceed with the
conservation of orbital symmetry, the ability to create new
carbon-carbon bonds requires the proximity between two
reacting triple bonds.12 Herein, we wish to report a new and
facile approach toward the gold-catalyzed water-assisted chemose-
lective syntheses of structurally isomeric R-alkyl R′-acetoxy
cyclopentenones (2) and allenones (3) utilizing 1,1-diethynyl-
carbinol acetates as starting material. The excellent alkynophi-
licity of gold has been well-documented, and propargylic
acetates upon treatment with gold catalyst can be activated for
the 1,2- and/or 1,3-acetate shift depending on the substrates and
reaction conditions.13 To date, numerous novel endeavors have
been made for establishing the central factors which govern such
type of regioselective activation of the propargylic acetates.12a,14
During the course of our studies,10 we became interested in
exploring an efficient transformation involving rearrangement
of 1,1-diethynylcarbinol acetate11 by gold catalysis. Since the
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Results and Discussion
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All 1,1-diethynylcarbinol acetates 1a-h were prepared from
the corresponding esters via Grignard reaction with ethynyl-
magnesium bromide followed by acetylation. We initiated our
investigation by treating 1a with various gold catalysts, and those
results are summarized in Table 1.
Initially, 1a was treated with different Au(I) catalysts (AuCl,
AuCl(PPh3), AuCl(PPh3) with AgSbF6, AuCl(SMe2) with AgS-
bF6) and Au(III) catalysts (AuBr3 and NaAuCl4 ·2H2O) in dry
1,2-dichloroethane (DCE) at low temperature (0 °C to room
temperature). Allenyne acetate 4a was the only isolated product
in low yields (5-20%). Among Au(I) and Au(III) catalysts,
AuCl(PPh3) with AgSbF6 (entry 3) catalyzed this conversion
significantly. Formation of 4a can be understood by Au-
catalyzed [3,3]-sigmatropic shift of the acetate group (Scheme
1).4h Catalysts AuCl(Me2S) with AgSbF6 (entry 4) and AgSbF6
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J. Org. Chem. Vol. 74, No. 1, 2009 371

Oh and Karmakar
SCHEME 1. Plausible Mechanism for Au(I)-Catalyzed
Syntheses of Isomeric Cyclopentenone and r-Allenone
reaction time (10-20 min). Additionally, as there are several
examples that gold- and platinum-catalyzed transformations
sometimes can be carried out by simple Brønsted acid
catalysis,14d,15 the substrate 1a was treated with the catalytic
amount (10 mol %) of Brønsted acids (entries 12-14) in wet
CH2Cl2 at room temperature to make an investigation of any
probable rearrangement. Notably, 1a was recovered unchanged
under these conditions (entries 12-14). Thus, this rearrangement
cannot be catalyzed by simple Brønsted acids. Control experi-
ments were made to get more insight into the mechanism. First
of all, when we started the reaction by treating 1a with
AuCl(PPh3)/AgSbF6 at 0 °C with low catalyst loading (3 mol
%) and allowed it to stay at room temperature for 2.5 h, we
obtained only 2a in moderate yield (55%). Second, when the
product 3a was treated under the same conditions, cyclization
to 2a did not occur (eq 1). From those two controlled
experimentations, we could get a mechanistic insight, where
3a might not be the intermediate to 2a.
itself (entry 7) were incompetent to result in either no reaction
or decomposition due to overreaction.
Mechanistic consideration revealed that any nucleophilic
additive might be necessary to bring two reacting partners in
close proximity in order to achieve a new C-C bond formation
intramolecularly. In this context, Zhang and Wang4h showed
that Au(I)-catalyzed [3,3]-rearrangement of propargylic acetates
could be accomplished effectively in wet dichloromethane
(DCM). Notably, water did not participate as a nucleophile in
their transformation, rather it acted as a proton shuttle in the
proton-transport catalysis strategy.12a We, however, considered
the possibility of the chemoselective nucleophilic attack by the
water molecule on the allenyne acetate 4a followed by new C-C
bond formation leading to any probable cyclization. Again,
substrate 1a was treated with gold(III) catalysts (AuBr3 and
From the synthetic point of view, the condition 10 (Table 1)
was applied to diverse 1,1-diethynylcarbinol acetates in order
to investigate the generality of this reaction condition (Table
2). Interestingly, 1,1-diethynylcarbinol acetates, having an
arylmethylene chain, worked well under the reaction condition
(entries 1-4). p-Tolylmethylene and naphthylmethylene-
substituted 1,1-diethynylcarbinol acetates 1b and 1d (entries 2
and 4) on treatment with AuCl(PPh3)/AgSbF6 (3 mol %) in wet
CH2Cl2 underwent smooth conversion to the corresponding
cyclopentenones 2b and 2d in 80 and 75% yields, respectively.
Rearrangement of 3,4-dimethoxybenzylmethyl 1,1-diethynyl-
carbinol acetate (1c) required relatively longer reaction time (2
h) to afford 2c in 73% yield (entry 3). Notably, R-allenone
acetates 3a-d were isolated as minor products (5-20%).
R-Alkyl-substituted cyclopentenones 2e and 2f were also
obtained by this method in 60 and 65% yields, respectively
(entries 5 and 6). The substrates 1g and 1h, having a hydroxyl-
protected long alkyl chain, underwent a similar type of cycliza-
tion to provide 2g and 2h in moderate yields (58 and 50%,
respectively; entries 7 and 8). Especially, 1g required higher
catalyst loading (5 mol %) for this conversion.
R-Allenones can usually be synthesized by Dess-Martin
periodinane oxidation of the homopropargylic alcohol or Swern
oxidation of the allenic alcohol, and in the past decade, some
new methodologies have been developed for their construc-
tions.16 Considering their wide applicability, we decided to
explore the generality of the reaction condition 11 (entry 11 in
Table 1). We treated all 1,1-diethynylcarbinol acetates (1a-h)
under that condition. Surprisingly, all the substrates except 1g,
on treatment with AuCl(PPh3) with AgSbF6 (6 mol %) in wet
CH2Cl2 at 0 °C, smoothly converted into the corresponding
R-allenone acetates (3a-f and 3h) within 10 to 15 min in good
to excellent yields (55-85%) (Table 3). However, relatively
4h
NaAuCl4 ·2H2O) in wet CH2Cl2 at room temperature for 1 h
(entries 8 and 9). In both experiments, any cyclization was not
observed; instead 3a was isolated in 30 and 25% yields (entries
8 and 9). Gratifyingly, when only 3 mol % of AuCl(PPh3) with
AgSbF6 was used as a catalyst system in wet CH2Cl2 (entry
10) at room temperature, cyclopentenone 2a was isolated in 82%
yield within 1 h along with 3a in 5% yield. Since the substituted
allenones have been remarkably utilized as building blocks for
various transformations,9 we were in quest of an optimum
condition for the synthesis of 3a. Surprisingly, when the reaction
was carried out with high catalyst loading (6 mol %) using
AuCl(PPh3) with AgSbF6 as catalyst in wet CH2Cl2 at low
temperature (0 °C) for 15 min, 3a was isolated in 70% yield
(entry 11). By TLC monitoring of the reaction, formation of
2a was not observed within that reaction time. The observed
results (entries 10 and 11) might lead to a conclusion that
generation of 2a required low catalyst loading (3 mol %),
relatively high activation energy (rt), and long reaction time (1
h), while formation of 3a demanded relatively high catalyst
loading (6 mol %), low activation energy (0 °C), and short
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372 J. Org. Chem. Vol. 74, No. 1, 2009

HydratiVe Rearrangement of 1,1-Diethynylcarbinol Acetates
TABLE 2. Au(I)-Catalyzed Hydrative Isomerization of Various
1,1-Diethynylcarbinol Acetates 1a-h
coordinates with the triple bond, which induces oxacyclization/
1,3-dioxolium ion generation via internal nucleophilic attack
by the carbonyl oxygen of the acetoxy group at the C-2 of allene
to furnish B. A water molecule is expected to be involved at
this stage to form an intermediate C, which is then converted
into D by simple protodemetalation. Interestingly, Au(I) further
activates the allene functionality,17 which induces the sequential
1,3-dioxole ring opening and 5-endo-dig carbocyclization to
furnish the gold-coordinated cyclopentenone E via route a
(Scheme 1).18 The latter on prodemetalation can be converted
into the cyclopentenone 2. On the other hand, depending on
the reaction condition, the intermediate D can rearrange into
R-allenone acetates 3 via hydrative 1,3-dioxole ring opening
followed by protonation (route b).
Conclusions
We have developed a new and general method for the
synthesis of isomeric 5-acetoxy-2-alkyl-2-cyclopentenones (2)
and acetoxymethyl R-alkylallenones (3). Former was formed
via Au(I)-catalyzed 5-endo-dig carbocyclization of a plausible
intermediate D derived from gold-catalyzed hydrative rear-
rangement of the allene yne acetate 4 (Scheme 1), whereas
formation of 3 might be realized by sequential 1,3-dioxole ring
opening and protonation of the same intermediate. In a wider
sense, reactions described herein may take a modular entry to
a metal-mediated rearrangement of the allene yne acetoxy
system in the presence of a nucleophile, and this methodology
can be useful to construct some important building blocks, such
as R,R′-substituted cyclopentenones 2 and R-allenones 3.
Experimental Section
General Experimental Procedure for Compound 2. In a 5
mL new test tube, 3 mol % (in case of 1g, 5 mol %) of AuCl(PPh3)
and AgSbF6 was taken in 1.0 mL of wet dichloromethane19 at 0
°C. It was then allowed to reach room temperature (25 °C) followed
by addition of 1,1-diethynylcarbinol acetate (1a-h) (0.2 mmol)
dissolving in a minimum volume of wet dichloromethane. The
resulting mixture was stirred for 1-3 h (as stated in Table 2) at
room temperature by monitoring TLC of the reaction periodically.
Upon completion, the solvent was removed under vacuum and the
crude product was subjected to flash column chromatography (10:1
hexane/EtOAc) to afford the pure products 2a-h.
3-Benzyl-2-oxocyclopent-3-enyl acetate (2a). Compound 2a (45
mg, 0.19 mmol) was synthesized following the general procedure
starting from 1a (50 mg, 0.23 mmol): IR (film, cm-1) 1744, 1718,
1627; 1H NMR (400 MHz, CDCl3) δ 7.32-7.18 (m, 5H), 7.06 (s,
1H), 5.17 (dd, J ) 6.6, 3.0 Hz, 1H), 3.52 (s, 2H), 3.04 (d, J ) 18.8
Hz, 1H), 2.47 (dm, J ) 18.8, 2.4 Hz, 1H), 2.14 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 203, 171, 156, 145, 138, 129, 129, 127, 72,
34, 32, 21; HRMS calcd for C14H14NaO3 253.0841; found,
253.0835.
TABLE 3. Rapid Formation of r-Alkyl r′-Acetoxy Allenones 3
entry
substrates
mol (%)
time (min)
products 3 (% yield)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
6
6
6
6
6
6
8
6
15
15
15
15
15
15
5
3a (70)
3b (70)
3c (65)
3d (70)
3e (80)
3f (85)
3g (70)
3h (55)
1g
1h
10
high catalyst loading (8 mol %) was essential to obtain 3g in
70% yield within 5 min in wet CH2Cl2 at 0 °C.
General Experimental Procedure for Compound 3. In a 5
mL new test tube, 6 mol % (in the case of 1g 8 mol %) of
To rationalize our observations, a plausible mechanistic
manifold for the formations of isomeric R,R′-substituted cyclo-
pentenones and R-allenones acetates was hypothesized in
Scheme 1. Due to extraordinary alkynophilicity of gold, Au(I)
activates the triple bond, which promotes 3,3-sigmatropic shift
of the acetate functionality via cationic vinyl gold intermediate
A to furnish the alkyne allene acetate 4. Now, Au(I) plays a
central role in activating alkyne functionality. Initially, Au(I)
(17) Gandon, V.; Lemie`re, G.; Hours, A.; Fensterbank, L.; Malacria, M.
Angew. Chem., Int. Ed. 2008, 47, 7534–7538.
(18) (a) Funami, H.; Kusama, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2007,
46, 909–911. (b) Lee, J. H.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 912–
914. (c) Dolaine, R.; Gleason, J. L. Org. Lett. 2000, 2, 1753–1756. (d)
Ramanathan, B.; Keith, A. J.; Armstrong, D.; Odom, A. L. Org. Lett. 2004, 6,
2957–2960. (e) Madhushaw, R. J.; Lin, M. Y.; Sohel, S. M. A.; Liu, R. S. J. Am.
Chem. Soc. 2004, 126, 6895–6899. (f) Zhang, L.; Kozmin, S. A. J. Am. Chem.
Soc. 2005, 127, 6962–6963. (g) Sun, J.; Kozmin, S. A. J. Am. Chem. Soc. 2005,
127, 13512–13513. (h) Oppenheimer, J.; Johnson, W. L.; Tracey, M. R.; Hsung,
R. P.; Yao, P. Y.; Liu, R.; Zhao, K. Org. Lett. 2007, 9, 2361–2364.
(19) Prepared by shaking distilled dichloromethane with deionized water in
a separatory funnel.
(16) (a) Mandai, T.; Kunitomi, H.; Higashi, K.; Kawada, M.; Tsuji, J. Synlett
1991, 697–698. (b) Santelli-Rouvier, C.; Lefrere, S.; Mamai, M.; Santelli, M.
Tetrahedron Lett. 1995, 36, 2459–2460. (c) Cunico, R. F.; Zaporowski, L. F.;
Rogers, M. J. Org. Chem. 1999, 64, 9307–9309.
J. Org. Chem. Vol. 74, No. 1, 2009 373

Oh and Karmakar
AuCl(PPh3) and AgSbF6 was taken in 0.5 mL of wet dichlo-
romethane at 0 °C followed by addition of 1,1-diethynylcarbinol
acetate (1a-h) (0.2 mmol) dissolving in a minimum volume of
wet dichloromethane. The resulting mixture was stirred for 10-15
min at 0 °C and the reaction monitored by TLC periodically. Upon
completion, the solvent was removed under vacuum and the crude
product was subjected to flash column chromatography (10:1
hexane/EtOAc) to afford the pure products 3a-h.
129, 128.6, 127, 106, 82, 66, 33, 21; HRMS calcd for C14H14NaO3
253.0841; found, 253.0835.
Acknowledgment. We gratefully acknowledge the Korea
Science and Engineering Foundation (KOSEF R01-2007-000-
20315-0) and BK21 for the support of this research.
r-Benzyl-r/-acetoxy allenone (3a). Compound 3a (37 mg, 0.161
mmol) was synthesized following the general procedure starting
from 1a (50 mg, 0.23 mmol): IR (film, cm-1) 1950, 1925, 1745,
Supporting Information Available: General experimental
procedures for the synthesis of compounds 2 and 3 and spectral
data for all new compounds This material is available free of
charge via the Internet at http://pubs.acs.org.
1
1690, 1554; H NMR (400 MHz, CDCl3) δ 7.29-7.18 (m, 5H),
5.24 (t, J ) 2.6 Hz, 2H), 4.99 (s, 2H), 3.54 (t, J ) 2.4 Hz, 2H),
2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 216, 192, 171, 139,
JO802103G
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