Gold-catalyzed cyclization of allenyl acetal derivatives

Article abstract of DOI:10.3762/bjoc.9.202

The gold-catalyzed transformation of allenyl acetals into 5-alkylidenecyclopent-2-en-1-ones is described. The outcome of our deuterium labeling experiments supports a 1,4-hydride shift of the resulting allyl cationic intermediates because a complete deuterium transfer is observed. We tested the reaction on various acetal substrates bearing a propargyl acetate, giving 4-methoxy-5-alkylidenecyclopent-2-en-1-ones 4 via a degradation of the acetate group at the allyl cation intermediate.

Full text of DOI:10.3762/bjoc.9.202

Gold-catalyzed cyclization of
allenyl acetal derivatives
Dhananjayan Vasu, Samir Kundlik Pawar and Rai-Shung Liu*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1751–1756.
Department of Chemistry, National Tsing Hua University, Hsinchu,
30013, Taiwan (ROC)
doi:10.3762/bjoc.9.202
Received: 18 June 2013
Accepted: 07 August 2013
Published: 27 August 2013
Email:
Rai-Shung Liu* - rsliu@mx.nthu.edu.tw
* Corresponding author
This article is part of the Thematic Series "Gold catalysis for organic
synthesis II".
Keywords:
allenyl acetals; 5-alkylidenecyclopent-2-en-1-ones; cyclization; gold
catalysis
Guest Editor: F. D. Toste
© 2013 Vasu et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The gold-catalyzed transformation of allenyl acetals into 5-alkylidenecyclopent-2-en-1-ones is described. The outcome of our
deuterium labeling experiments supports a 1,4-hydride shift of the resulting allyl cationic intermediates because a complete
deuterium transfer is observed. We tested the reaction on various acetal substrates bearing a propargyl acetate, giving 4-methoxy-5-
alkylidenecyclopent-2-en-1-ones 4 via a degradation of the acetate group at the allyl cation intermediate.
Introduction
Gold-catalyzed cyclization/cycloaddition reactions [1-5] are ated allyl cation intermediates I. In the case of electrophilic
useful synthetic methods to construct complicated carbo- and nitrones, allyl cations I release a proton to form reactive
oxacyclic frameworks. Such cascade reactions have been well 1-methoxyfulvenes II to achieve a [3 + 2]-nitrone cycloaddi-
studied on various difunctionalized molecules including tion. The versatility of cationic intermediates I encourages us to
oxoalkynes [6-13], oxoallenes [14], oxoalkenes [15] and allenyl understand their behavior in the absence of a dipolarophile. This
acetals [16-18]. In this cascade sequence, two new rings and work reports gold-catalyzed intramolecular cyclizations of these
three chemical bonds are generated in a one-pot procedure. We allenyl acetals [19].
previously reported gold-catalyzed reactions of allenyl acetals
with suitable dipolarophiles such as 1,3-diones to chemoselec- Results and Discussion
tively produce the cycloaddition product 2 [17] (Scheme 1). We first tested the intramolecular cyclizations of allenyl acetal
Similar reactions with nitrones stereoselectively delivered 1a with PPh3AuCl/AgSbF6 (5 mol %), which was shown to be
distinct formal cycloadducts 3 [18]. We postulate that com- an active catalyst in the two cascade reactions, as depicted in
pounds 2 arise from the attack of 1,3-diones at initially gener- Scheme 1 [17,18]. As shown in Table 1, the treatment of com-
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Beilstein J. Org. Chem. 2013, 9, 1751–1756.
Scheme 1: Reported cascade reactions on allenyl acetals.
pound 1a with this gold catalyst (5 mol %) in dichloromethane produced with satisfactory yields (68–82%). We also tested the
(DCM, 28 °C, 0.5 h) afforded 5-isopropylidenecyclopent-2-en- reaction on acyclic allenyl acetal 1e (E/Z = 3:1), and afforded
1-one derivative 4a in 65% yield (Table 1, entry 1). With a the desired product 4e in 52% yield according to initial
change of the counter anion as in PPh3AuCl/AgOTf, the prod- E-configured 1e. The structure of compound 4e was deter-
uct yield increased to 89% (Table 1, entry 2). PPh3AuCl/ mined by 1H NMR NOE spectra. The reaction was still oper-
AgNTf2 was also active to give the same product in 83% yield able with 1f, bearing a 1,2-disubsituted allene, giving the
(Table 1, entry 3). Under the same conditions, AgOTf alone desired 4f in moderate yield (49%). Its E-configuration was
gave the desired 4a in 48% yield (Table 1, entry 4). AuCl3 and determined by NOE measurements, and assignable to other
PtCl2 enabled a complete consumption of the starting material products including 4g and 4h. The reaction worked well with
1a, but the yields of compound 4a were 51% and 30%, respect- substrates bearing a different trisubstituted allenes, giving the
ively (Table 1, entries 5 and 6).
desired cyclopentenone 4g and 4h in 82–83% yields.
The preceding cyclization is mechanistically interesting because
it involves a cleavage of the C–H bond of the acetal group. We
prepared d1-1a bearing a deuterium (>98%, Scheme 2, reaction
1) at its acetal group. The resulting product d1-4a has almost
one full deuterium (X = 0.98 D) at one of the methylene protons
according to DEPT 13C NMR analysis. In the presence of added
D2O, undeuterated 1a gave the product without deuterium
content (Scheme 2, reaction 2). The results of these labeling
experiments reveal a 1,4-hydrogen shift [20-22] in the
d1-1a→d1-4a transformation.
Table 1: Catalyst screening over various acid catalysts.
Entrya Catalyst
Time (h)
Yield (%)b
1
2
3
4
5
6
PPh3AuCl/AgSbF6
0.5
0.5
0.5
2.0
1.5
1.5
65
89
83
48
51
30
PPh3AuCl/AgOTf
PPh3AuCl/AgNTf2
AgOTf
AuCl3/CO
PtCl2/CO
a[1a] = 0.1 M. bIsolated yields.
Table 2 shows the substrate scope including additional allenyl
acetals 1b–1h. The reactions were catalyzed by PPh3AuCl/
AgNTf2 (5 mol %) in DCM. As shown in entries 1–3, this
cyclization was applicable to allenyl acetals 1b–1d bearing a
cyclopentyl bridge. The resulting products 4b–4d were
Scheme 2: Gold-catalyzed cyclization of deuterated d1-1a.
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Table 2: Gold-catalyzed cyclization of allenyl acetals.
Entry
Substratesa
Time/min
Product (yield)b
1
15
4b (82%)
4c (68%)
4d (70%)
1b
1c
1d
2
3
10
10
4c
30
30
30
4e (52%)
4f (49%)
4g (82%)
1e
1f
5
6
1g
1h
7
10
4h (83%)
a5 mol % AuClPPh3/AgOTf, [1] = 0.1 M, 25 °C, DCM. bIsolated yield. c10 mol % of gold catalyst.
Scheme 3 shows a plausible mechanism to rationalize the trans- acetal group. Accordingly, we postulate a 1,4-hydride shift
formation of the allenyl acetal 1e into the observed cyclopen- [21,22] for the intermediate transformation B→C. We excluded
tenone 4e. The deuterium labeling experiment of the an alternative route involving the protonation of the fulvene
d1-1a→d1-4a transformation (Scheme 2, reaction 1) indicates intermediate D because this route would water as a proton
that one methylene proton of 4a is derived from the original source. The formation of the fulvene intermediate D from allyl
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Beilstein J. Org. Chem. 2013, 9, 1751–1756.
Scheme 3: A plausible reaction mechanism.
cation B is assisted by a weak base like nitrone [18]. We We prepared the additional substrates 5b–5g bearing an acetate
envisage that a 1,2-hydrogen shift for the allyl cation B fails to group to examine the scope of the reaction, results are shown in
explain a complete deuterium transfer for the d1-1a→d1-4a Table 3. This gold-catalyzed cyclization was applicable to com-
transformation because its resulting cyclopent-3-en-1-one pound 5b bearing a cyclopentyl bridge, giving the desired 6b in
derivative became isomerized to the final product 4a with a loss 96% yield. The reaction worked also with 5c and 5d bearing a
of deuterium content.
cyclohexyl bridge, delivering the desired products 6c and 6d in
78% and 72% yields, respectively (Table 3, entries 2 and 3). We
We also prepared the substrate 5a bearing a propargyl acetate tested the reaction with the benzenoid substrates 5e–5g, giving
moiety because this functionality can be transferred to the the corresponding enones 6e–6g in 63–78% yields.
allenyl acetate 5a’ by a gold catalyst [23,24]. As shown in
Scheme 4, the treatment of species 5a with PPh3AuOTf Conclusion
(5 mol %) in dichloromethane (28 °C, 5 min) gave 4-methoxy- In summary, we report a gold-catalyzed transformation of
5-isopropylidenecyclopent-2-en-1-one 6a in 76% yield. The allenyl acetals 1 into 5-alkylidenecyclopent-2-en-1-ones 4. Our
structure of compound 6a was determined by an X-ray diffrac- deuterium labeling experiments support a 1,4-hydride shift for
tion study (crystallographic data are provided in Supporting the resulting allyl cation because of a complete deuterium
Information File 1). Formation of this product is postulated to transfer. This observation excludes the pathway involving the
arise from the attack of the methoxy anion at the acetyl group of protonation of a 1-methoxyfulvene species. We tested the reac-
the corresponding allyl cation E, a process not involving a 1,4- tions of acetal substrates 5 bearing a propargyl acetate to afford
hydride shift. This alternative pathway highlights the diversi- 4-methoxy-5-alkylidenecyclopent-2-en-1-ones 6. The forma-
fied mechanism of such oxidative cyclizations.
tion mechanism involves a degradation of the acetate group at
the corresponding allyl cation.
Experimental
General procedure for the gold-catalyzed
carbocyclization
General procedure for the the gold(I)-catalyzed carbocy-
clization of vinylallenyl acetal: A two-necked flask was
charged with chloro(triphenylphosphine)gold(I) (11.1 mg,
0.022 mmol) and silver triflate (5.8 mg, 0.022 mmol), and to
this mixture CH2Cl2 (2.0 mL) was added. The resulting solu-
tion was stirred at room temperature for 10 min. To this mix-
ture a solution of vinylallenyl acetal 1a (100 mg, 0.45 mmol) in
CH2Cl2 (2.5 mL) was added dropwise, and the mixture was
kept stirring at 25 °C for 30 min before it was filtered over a
short silica bed. The solvent was evaporated under reduced
pressure. The crude product was eluted through a short silica
Scheme 4: The reaction of propargyl acetate 5a.
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Beilstein J. Org. Chem. 2013, 9, 1751–1756.
Table 3: Gold-catalyzed carbocyclization of propargylic esters.
Entry
Substratesa
Time/min
Product (yield)b
1
5
6b (96%)
5b
5c
5d
5e
5f
2
3
4
5
6
5
6c (78%)
5
6d (72%)
6e (78%)
6f (68%)
6g (63%)
10
10
10
5g
a5 mol % AuClPPh3/ AgOTf, [5] = 0.1 M, 25 °C, DCM. bIsolated yield.
column (3% ethyl acetate in hexane) to afford the desired 0.016 mmol) were added to a dried Schlenk tube under an N2
ketone 4a (70.6 mg, 0.40 mmol, 89%) as a pale yellow oil. atmosphere, and freshly distilled CH2Cl2 (1.0 mL) was intro-
duced by a syringe. The resulting mixture was stirred at room
General procedure for the gold(I)-catalyzed carbocycliza- temperature for 10 minutes before the addition of propargylic
tion of propargylic ester acetals: Chloro(triphenylphos- ester acetal 5a (100 mg, 0.32 mmol) in CH2Cl2 (2.2 mL). The
phine)gold(I) (8.0 mg, 0.016 mmol) and silver triflate (4.2 mg, reaction mixture was stirred for additional 5 minutes at 25 °C.
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Beilstein J. Org. Chem. 2013, 9, 1751–1756.
19.Nakamura, I.; Mizushima, Y.; Gridnev, I. D.; Yamamoto, Y.
After the completion of reaction, the brown suspension was
filtered through a short bed of silica gel. The solvent was
removed under reduced pressure. The crude product was puri-
fied by flash chromatography to afford the desired ketone 6a
(58 mg, 0.25 mmol, 76%) as a dark yellow oil.
J. Am. Chem. Soc. 2005, 127, 9844. doi:10.1021/ja051114j
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doi:10.1021/ol005964
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22.Bolte, B.; Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc. 2010, 132,
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Supporting Information
23.Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804. doi:10.1021/ja056419c
24.Marion, N.; Díez-González, S.; de Frémont, P.; Noble, A. R.;
Nolan, S. P. Angew. Chem., Int. Ed. 2006, 45, 3647.
doi:10.1002/anie.200600571
Supporting Information File 1
Experimental details.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-202-S1.pdf]
License and Terms
Acknowledgements
This is an Open Access article under the terms of the
Creative Commons Attribution License
We thank the National Science Council, Taiwan, for financial
support of this work.
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
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