Highly efficient Bronsted acid-catalyzed cycloisomerizations of alkynes bearing bis(acetoxy) groups to indenyl ketones

Article abstract of DOI:10.1002/adsc.200800037

A Bronsted acid-catalyzed cycloisomerization of functionalized alkynes is described, which is assumed to be initiated through the formation of a benzylic cation intermediate. The reaction offers a highly efficient and straightforward route to indenyl ketones with a wide range of substituents under mild conditions.

Full text of DOI:10.1002/adsc.200800037

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DOI: 10.1002/adsc.200800037
Highly Efficient Brønsted Acid-Catalyzed Cycloisomerizations of
Alkynes Bearing Bis(acetoxy) Groups to Indenyl Ketones
G
Yuanhong Liu,a,* Shaolin Zhou,a Guijie Li,a Bin Yan,a Shenghai Guo,a
Yebing Zhou,a Hao Zhang,a and Peng George Wangb
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: yhliu@mail.sioc.ac.cn
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA
b
Received: January 18, 2008; Published online: March 31, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A Brønsted acid-catalyzed cycloisomeri-
zation of functionalized alkynes is described, which
is assumed to be initiated through the formation of
a benzylic cation intermediate. The reaction offers
a highly efficient and straightforward route to in-
denyl ketones with a wide range of substituents
under mild conditions.
ed the HNTf2-promoted cyclization of siloxyalkynes
with arenes, alkenes, or alkynes via the intermediacy
of highly reactive ketenium ions.[2a–b] Hsung et al. re-
ported a stereoselective arene-ynamide cyclization via
a novel keteniminium Pictet–Spengler cyclization.[2c]
Brønsted acid-catalyzed metathesis reactions of
enynes bearing electron-withdrawing groups on the
alkyne entity can be also found in the literature.[2d]
However, special substituents (OR, NR1R2, or EWG)
on the alkyne terminus were usually required for
these cyclizations. We anticipated that a new domino
process initiated by Lewis- or Brønsted acid-induced
carbocation formation followed by subsequent nucle-
ophilic attack (Scheme 1) might be achieved. In this
Keywords: alkynes; Brønsted acids; cycloisomeriza-
tion; indenyl ketones; propargyl esters
The intramolecular cyclization of alkynes bearing communication, we describe our discovery and inves-
proximate C, O, N nucleophiles has proven to be a tigation of the Brønsted acid-catalyzed cycloisomeri-
powerful synthetic route to the wide variety of carbo- zation of alkynes bearing bis
and/or heterocycles. Although much progress has denyl ketones.
ACHTRE(UNG acetoxy) groups to in-
been achieved, most of this chemistry has concentrat-
The substrates, diesters 1a and 2a, which were
ed on transition metal-catalyzed strategies through easily prepared in high yields as a diastereomeric mix-
the regio- and stereoselective addition of a nucleo- ture through acetylide addition to phthalaldehyde,[3]
phile to the activated carbon-carbon triple bond.[1] were chosen to test the hypothesis. In light of the effi-
There are only few examples for the Brønsted acid- cient activation of alkynes by gold catalysts[4–6] and
catalyzed cyclization or cycloisomerization reactions our recent report on the gold-catalyzed direct amina-
of alkynes.[2] From both an economical and an envi- tion of allylic alcohols,[6c] we first examined the reac-
ronmental point of view, the development of a metal- tivity of 1a in the presence of various gold catalysts.
free methodology for these type of reactions is highly However, only disappointing results were obtained
desirable. Several successful approaches for the (Table 1, entries 1 and 2). After many efforts, we were
Brønsted acid-catalyzed transformation of alkynes to delighted to find that, in the presence of 5 mol% of
cyclic rings have been reported. Kozmin et al. report- AgSbF6, 1a cyclized smoothly in CH2Cl2 to afford in-
Scheme 1.
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Yuanhong Liu et al.
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Table 1. Optimization studies for the Lewis or Brønsted
acid-catalyzed cycloisomerization of alkyne 1a or 2a.
as major product in these cases (isomeric purity
>98% except 4m).[9] Treatment of diacetate 1g bear-
ing phenyl groups on the alkyne and at the benzylic
position with 5 mol% of TfOH in CH2Cl2 for 1 min
afforded indenyl ketone 4g in 81% yield (Table 2,
entry 7). The aromatic groups at R1 and/or R2 bearing
various substituents were well accommodated, and
the corresponding products 4h–o were formed in 36–
95% yields. The structures of 3 and 4 were unambigu-
ously confirmed by X-ray single-crystal analyses of 3f
and 4l.[10]
Substrate 5 with a methyl substituent on the aro-
matic ring was studied to investigate the electronic ef-
fects of the substitution on the efficiency of the cycli-
zation reaction (Scheme 2). The cyclization proceeded
with complete regioselectivity to give 2,3,6-trisubsti-
tuted indene 6 in 73% yield, while its regioisomer 7
was not observed. The structure of 6 was determined
by collateral evidence of H-1H COSY and HMBC
1
spectra.[11] This experimental result supported a cat-
ionic mechanism, since a more stable benzyl cation
para to the methyl group would be formed preferen-
tially. Interestingly, the presented method could be
readily extended to the synthesis of tricyclic ketone 9
or its isomer 10 (Scheme 2), and good yields were ob-
tained in each case.
[a]
NMR yields.
Complicated reaction mixture was observed.
NR=no reaction.
Isolated yield is 65%.
We did observe some transformation in this case, howev-
er, this reaction was not clean, and we could not obtain
pure products.
[b]
[c]
[d]
[e]
On the basis of the above observations, a possible
reaction mechanism is proposed in Scheme 3. As the
denyl ketone 3a[7] incorporating an alkynyl group in first step, protonation followed by elimination of a
89% NMR yield after stirring at room temperature leaving group in 1 is proposed to generate a benzyl
for 20 h (Table 1, entry 3). Interestingly, using 5 mol% cation intermediate 11.[12] The stability of benzyl cat-
of ScACHTREUNG(OTf)3 reduced the reaction time to 6 h, and a ions is well documented and has been the subject of
high yield of 97% of 3a was obtained. Further studies theoretical and experimental study.[13] Benzyl cation-
revealed that the conjugate acid of the metal triflates, initiated cyclization via an intramolecular Friedel–
TfOH, showed excellent catalytic activities to afford Crafts reaction is also well precedent.[14] Attack of the
>99% NMR yields of the desired product within one alkyne moiety onto the resulting carbocation leads to
minute (Table 1, entries 6 and 7)![8] The efficiency of cyclization and affords the alkenyl cation 12. Nucleo-
TfOH was demonstrated also through a comparison philic attack of HOAc onto 12 followed by deproto-
with other Brønsted acids such as CF3COOH or nation gives enol acetate 13. HOAc may also attack
TsOH (Table 1, entries 8 and 9).
the alkyne moiety in 11 directly to furnish 13. Decom-
Encouraged by these results, we next examined the position of the unstable enol acetate, presumably
scope of this cycloisomerization in terms of the through an oxocarbonium intermediate 15, then gives
alkyne substituent (Table 2, entries 1–6). We were indenyl ketone 4. Isomerization of 4 upon column
pleased to find that the functionalities like Me, MeO, chromatography affords the thermodynamically more
and Cl groups on the aromatic ring were well tolerat- stable 2,3-disubstituted indene 3 in the cases of bisal-
ed during the reaction, furnishing the corresponding kynes.
products 3b–d in 61–76% yields. However, the diace-
To probe the mechanistic hypotheses, we next
tate 1e, bearing an o-CF3 group on the aromatic ring, monitored the reaction of 1d by NMR. 1H NMR
afforded a low yield (32%) of 3e (Table 2, entry 5). showed a complete conversion to 4d along with small
The procedure was also compatible with alkyl-substi- amounts of 3d. In addition, Ac2O could also be de-
tuted alkyne 1f to afford 3f in 51% yield using 15% tected in 95% NMR yield (Scheme 4).[15]
of TfOH (Table 2, entry 6).
In conclusion, we have developed a highly efficient
It should be noted that this cycloisomerization pro- method for the synthesis of indenyl ketones via a
cess was not limited to bisalkynes, monoalkynes of Brønsted acid-catalyzed cycloisomerization of func-
1g–1o also underwent similar cyclization reactions tionalized alkynes under extremely mild conditions.
smoothly (Table 2, entries 7–15). However, a double The indene derivatives are useful synthetic intermedi-
bond isomer of 1,2-disubstituted indene 4 was formed ates, especially as valuable ligand precursors for tran-
798
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Highly Efficient Brønsted Acid-Catalyzed Cycloisomerizations of Alkynes
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Table 2. TfOH-catalyzed cycloisomerization reactions of alkynes.
[a]
Isolated yields after column chromatography.
Isolated yields after further purification by recrystallization or washing with
organic solvents.
The product was obtained as a mixture of two double bond isomers in a ratio
of 8:1, 4m is the major isomer.
[b]
[c]
Scheme 2.
Adv. Synth. Catal. 2008, 350, 797 – 801
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Yuanhong Liu et al.
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Scheme 3.
Scheme 4.
followed by recrystallization in petroleum ether/CH2Cl2 af-
forded the title compound as a yellow solid; yield: 104 mg
(0.5 mmol scale; 65%); mp116–1188C. 1H NMR (CDCl3,
Me4Si): d=4.05 (s, 2H), 7.03–7.06 (m, 2H), 7.21–7.30 (m,
3H), 7.42–7.51 (m, 4H), 7.55–7.58 (m, 2H), 7.75–7.77 (m,
1H), 7.91–7.94 (m, 2H); 13C NMR (CDCl3, Me4Si): d=39.66,
82.88, 101.68, 121.99, 122.47, 124.20, 127.13, 128.04, 128.17,
128.38, 129.09, 129.60, 131.92, 132.20, 132.40, 138.76, 142.86,
143.43, 145.53, 193.73; HR-MS (EI): m/z=320.1209, calcd
for C24H26O: 320.1201.
sition metal complexes.[16] Further studies to elucidate
the reaction mechanism and to extend the scope and
synthetic utility are in progress in our laboratory.
Experimental Section
General Procedure for TfOH-Catalyzed
Cycloisomerization of Alkynes Bearing Bis
Groups to Indenyl Ketone
ACHTRE(UGN acetoxy)
Supporting Information
To a solution of diacetate 1 (0.4 mmol, in 4 mL dry CH2Cl2)
was added TfOH (0.02 mmol, 1.8 mL), the color changed im-
mediately to deep brown, and the mixture was stirred at
room temperature for 1~5 min. An appropriate amount of
silica gel was added to the mixture and the solvent was
evaporated under vacuum at room temperature (in some
cases, evaporation at higher temperature such as 508Cre-
sulted in a partial decomposition of the product). The resi-
due was purified by flash chromatography on silica gel
(eluent: petroleum ether/ethyl acetate) to afford the desired
indenyl ketone 3 or 4. Note: For alkynyl-substituted indenyl
ketones 3a–3f, further purification by recrystallization or by
washing with the organic solvents was needed to remove the
coloring matter.
Experimental details and spectroscopic characterization of
all new compounds and X-ray crystal structure of com-
pounds 3f and 4l are available as Supporting Information.
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant Nos. 20672133, 20732008), the Chinese Academy of
Science and Technology Commission of Shanghai Municipal-
ity (Grant No. 07JC14063) and the Major State Basic Re-
search Development Program (Grant No. 2006CB806105)
for financial support.
Phenyl-(3-phenylethynyl-1H-inden-2-yl)-methanone (3a):
Purification of the crude product by flash column chroma-
tography on silica gel (petroleum ether/ethyl acetate=5:1)
800
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Highly Efficient Brønsted Acid-Catalyzed Cycloisomerizations of Alkynes
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(the detailed procedure is shown in the Supporting In-
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[8] We have also tried TfOH-catalyzed reaction of 1a in
the presence of water as suggested by one reviewer. It
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Adv. Synth. Catal. 2008, 350, 797 – 801
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