Bismuth(III) chloride catalyzed cycloisomerization of enynes

Article abstract of DOI:10.1002/ejoc.200900819

Several simple bismuth(III) salts were screened for the suitability to catalyze the cycloisomerization of enynes. Among them, BiCl₃ gave the best results. Under the optimized reaction conditions, eight substrates were studied, and acceptable to

Full text of DOI:10.1002/ejoc.200900819

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900819
Bismuth(III) Chloride Catalyzed Cycloisomerization of Enynes
Zezhou Wang[a] and Shiyue Fang*[a]
Keywords: Bismuth / Lewis acids / Cycloisomerization / Enynes / Pyrrolidine
Several simple bismuth(III) salts were screened for the suit-
ability to catalyze the cycloisomerization of enynes. Among
them, BiCl3 gave the best results. Under the optimized reac-
tion conditions, eight substrates were studied, and accept-
able to excellent isolated yields were obtained. Consistent
with data in the literature, electron-deficient alkynes were
found to be better substrates for the reaction than electron-
rich ones. Because BiCl3 is readily available, inexpensive and
environmentally benign, this soft Lewis acid catalyzed isom-
erization reaction is expected to be a good choice for organic
chemists to prepare pyrrolidine derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
nucleophile attack. Subsequent rearrangements usually give
valuable highly functionalized carbocyclic and heterocyclic
compounds. In this field, we have found that several alkynyl
epoxides and an alkyl alcohol could be isomerized to di-
hydro-1,4-oxazine derivatives using PtCl2 as the catalyst.[11]
In searching less expensive catalysts for the reaction, bis-
muth(III) salts attracted our attention as ideal candidates.
Unfortunately, these salts including triflate, bromide, chlo-
ride and fluoride were not active for the transformation.
However, we found that BiCl3 was capable of catalyzing the
cycloisomerization of enynes, which were our precursors to-
ward alkynyl epoxides.[11] In this communication, we report
our results on this study.
Introduction
The transition-metal-catalyzed cyclization of 1,6-enynes
to five-membered rings is one of the most studied reactions
in the literature. The starting materials of the reaction are
readily available, and the products are highly functionalized
carbocycles or heterocycles, which are valuable intermedi-
ates in organic synthesis.[1] The reaction can proceed either
with the participation of another reactant such as carbon
monoxide or through an isomerization. Precious late transi-
tion metals such as gold,[2] palladium[3] and rhodium[4] are
usually used as catalysts for the reaction. However, for in-
dustrial applications, the use of inexpensive and nontoxic
metals as the catalyst is highly desired. To this end, several
catalysts based on inexpensive metals were developed,
which include titanocene catalysts,[5] low-valent iron com-
plexes[6] and in-situ generated Ni0.[7] Although readily avail-
able metals were used, these catalysts are not expected to
be inexpensive when the costs associated with the prepara-
tion of the complexes are considered. Beside these com-
plexes, mercuric triflate, which is toxic but simple to pre-
pare, was also found suitable for catalyzing the reaction.[8]
Although a heavy metal, unlike its neighbors in the per-
iodic table such as mercury, thallium and lead, bismuth is
relatively nontoxic due to its low bioavailability.[9] In ad-
dition, despite a lone pair on the metal atom, bismuth(III)
salts such as its chloride and triflate have been found cap-
able of serving as Lewis acids to catalyze many transforma-
tions.[9,10] We recently became interested in the soft Lewis
acid catalyzed isomerization reactions of alkynyl com-
pounds. In this type of reactions, the soft Lewis acid coordi-
nates a carbon–carbon triple bond and activates it toward
Results and Discussion
As shown in Table 1, we first tested the isomerization of
enyne 1[12] in CH2Cl2 with BiCl3 as the catalyst. At room
temperature, no reaction was observed according to TLC
even after 6 h with vigorous stirring. Heating of the reac-
tion mixture to reflux did also not result in any conversion
of the starting material (Entry 1). In order to increase the
reaction temperature, benzene was next used as the solvent
(Entry 2). At reflux temperature, we did see some conver-
sion after 12 h. The product was identified to be the five-
membered cycle 2,[13] but the yield was only 20%. Further
increase of the reaction temperature by changing the sol-
vent to toluene did not increase the yield significantly (En-
try 3). In addition, an increase of the catalyst loading from
10 mol-% to 20 mol-% still did not give satisfactory results
(Entry 4). Change of the solvent to 1,2-dichloroethane and
use of 10 mol-% of catalyst gave a slightly higher yield
(32%; Entry 5). However, when the catalyst loading was in-
creased to 20 mol-%, with 1,2-dichloroethane as the sol-
vent, at only 60 °C, the starting material was completely
consumed within 12 h, and the product 2 was obtained in
[a] Department of Chemistry, Michigan Technological University,
1400 Townsend Drive, Houghton, MI 49931, USA
E-mail: shifang@mtu.edu
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900819.
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Z. Wang, S. Fang
SHORT COMMUNICATION
Table 1. Optimization of reaction conditions for the bismuth(III)-catalyzed isomerization of enynes.[a]
Entry
Catalyst
Catalyst loading
Solvent
Temperature[b]
Yield[c]
1
2
3
4
5
6
7
8
9
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
Bi(OTf)3
BiF3
BiI3
BiCl3
10 mol-%
10 mol-%
10 mol-%
20 mol-%
10 mol-%
20 mol-%
20 mol-%
20 mol-%
20 mol-%
CH2Cl2
PhH
PhMe
reflux
reflux
reflux
reflux
60 °C
60 °C
reflux
reflux
reflux
0%
20%
25%
30%
32%
66%
25%
10%
10%
50%
0%[d]
PhMe
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl (wet)
ClCH2CH2Cl
10
11
20 mol-%
60 °C
BiCl3/AgSbF6
20 mol-%/20 mol-%
room temp.
[a] Reaction conditions: 1, catalyst, solvent, stirred under N2 for 12 h. [b] The reactions were first tested at room temp., if no reaction
occurred within 6 h, the temperature was raised to 60 °C; if still no reaction occurred or the reaction was slow, reflux temperature was
used. Indicated temperatures are the highest ones. [c] Isolated yield. [d] Deprenylation product was obtained.
66% isolated yield (Entry 6). In order to see if other bis- group at this position, substrate 9[14] was converted to 10[14]
muth(III) salts could give better yields for the reaction un- in 71% yield (Entry 4).
der similar conditions, Bi(OTf)3, BiF3 and BiI3 were scre-
In our previous studies on the soft Lewis acid catalyzed
ened, but all gave inferior results (Entries 7–9). In our ear- isomerization of alkynyl epoxides, we observed that alkynes
lier studies on the isomerization of alkynyl alcohols with with an electron-withdrawing group were better substrates
PtCl2 as catalyst, we found that a small amount of water for the reaction.[11] Similar observations were also made
could improve the yield of the desired product.[11] To see if previously by Fürstner and co-workers in their work.[15] In
the current reaction could also benefit from the presence of the present study, substrates with electron-deficient alkynes
water, 1,2-dichloroethane saturated with water was used as also gave higher yields of the desired isomerization prod-
the solvent. Under similar conditions with 20 mol-% BiCl3 ucts. As shown in Table 2, enyne 11[11] was isomerized to 12
as catalyst, 1 was isomerized to 2 in 50% isolated yield (En- in 70% isolated yield under the optimized conditions for
try 10). Although the yield was not as good as that under the isomerization of 1. If recovered starting material was
anhydrous conditions (compare Entries 10 and 6), this ex- subtracted from the initial substrate quantity, the yield was
periment showed that the reaction could tolerate a signifi- as high as 94% (Entry 5). Significantly, only one stereoiso-
cant amount of moisture, which may be important for some mer (12) concerning the trisubstituted double bond was
applications. Finally, we hoped to see if AgSbF6 could ab- formed under these reaction conditions. The (Z) geometry
stract a chloride ion from BiCl3 and increase the yield of of this double bond was established by NOE experiments,
the reaction. However, in 1,2-dichloroethane, even at room in which NOEs were observed between the vinyl proton of
temperature, the starting material was all converted into the the trisubstituted alkene (δ = 5.62 ppm) and the proton on
deprenylation product 4-methyl-N-(prop-2-yn-1-yl)benzene- C-4 of the pyrrolidine ring (δ = 3.43 ppm), and between the
sulfonamide; no desired product 2 was formed (Entry 11). vinyl proton (δ = 5.62 ppm) and the protons of the methyl
After these studies, we decided to use the conditions shown group attached to the vinyl group (δ = 1.54 ppm). With sub-
in Entry 6 of Table 1 to explore the scope of the reaction.
strates 13 and 15, both of which also contain an electron-
As shown in Table 2, with an electron-donating group on deficient alkyne, excellent isolated yields of five-membered
the phenyl ring of the benzenesulfonyl group, substrate 3[11] cyclic isomerization products were achieved (Entries 6 and
was isomerized to product 4 in 52% yield (Entry 1), which 7). Significantly, these yields were even higher than those of
was lower than that for the isomerization of 1 to 2. How- the isomerization of similar enynes with a palladium cata-
ever, when substrate 5[11] was used, which has an electron- lyst (70–80% vs. 60%).[16] Like the isomerization of 11, the
withdrawing group, the yield was not improved as well (En- isomerization of 13 and 15 also gave only the (Z) stereoiso-
try 2). One hypothesis was that the electronic effect did not mers concerning the trisubstituted double bond. In order
play an important role in these reactions; instead, the larger to further probe the electronic effects of the substitution
sizes of the methoxy and nitro groups compared to that of groups on the alkyne, substrates with a phenyl and a methyl
the methyl group might be more responsible for the lower group attached to the alkyne were prepared and subjected
yields in the isomerization of 3 and 5. Indeed, when 7[11] to the optimized isomerization conditions. Unfortunately,
was used as the substrate, which has a phenyl group on none of the trials gave any conversion, even after long reac-
the phenyl ring of the benzenesulfonyl group, the yield was tion times. Heating of the reaction mixtures to reflux tem-
further lowered to 19% (Entry 3). With no substitution perature for long times gave complex mixtures.
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Eur. J. Org. Chem. 2009, 5505–5508

Bismuth(III) Chloride Catalyzed Cycloisomerization of Enynes
Table 2. Substrate scope study of BiCl3-catalyzed isomerization of enynes.[a]
[a] Reaction conditions: 1, BiCl3 (20 mol-%), ClCH2CH2Cl, 60 °C, 12 h. [b] Isolated yield. [c] Isolated yield after subtraction of unreacted
starting material.
Based on literature information on the soft Lewis acid tion product 19. According to this mechanism, when sub-
catalyzed isomerization of alkynyl compounds[10,17] and our strates 11, 13 and 15 were used, products with an (E) trisub-
previous study on the isomerization of alkynyl epoxides and stituted double bond were expected. This was contrary to
an alkynyl alcohol,[11] the following mechanism was pro- the observed results. A potential explanation is that (E)
posed for the current BiCl3-catalyzed isomerization of en- products were initially formed. However, due to the steric
ynes (Scheme 1). The BiIII salt coordinates to the π-elec- hindrance between the ethyl ester group and the 1-methylvi-
trons of the alkyne of an enyne to form intermediate 17. nyl group, under the acidic reaction conditions, the (E)
The sulfonamide group may help to stabilize the complex. products were isomerized to the more stable (Z) products.
The alkene of the enyne serves as a nucleophile and attacks
the activated alkyne intramolecularly to give intermediate
18, which undergoes proton transfers to give the isomeriza-
Conclusions
We have found that BiCl3 could be used as soft Lewis
acid to catalyze the isomerization of several enynes. The
reaction can tolerate a significant amount of moisture. Ac-
ceptable to excellent isolated yields of isomerization prod-
uct were obtained. We also found that electron-deficient al-
kynes were more suitable substrates for the reaction, and in
the examples studied, only one stereoisomer was formed in
all cases. Although the catalyst loading was quite high un-
der the conditions we used, considering the low price of the
catalyst, its environmental friendliness and low toxicity, we
believe that BiCl3 will be one of the choices of chemists in
the pharmaceutical industry to catalyze the isomerization
of enynes.
Scheme 1. Potential mechanism of the BiCl3-catalyzed isomeriza-
tion of enynes.
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Z. Wang, S. Fang
SHORT COMMUNICATION
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Experimental Section
General Procedure for the BiCl3-Catalyzed Cycloisomerization of
Enynes: A round-bottomed flask was charged with the enyne and
BiCl3, and 1,2-dichloroethane was added via syringe (for amounts
of reagents and solvents, see Supporting Information). The mixture
was heated to 60 °C under nitrogen for 12 h. After cooling to room
temp., volatile components were removed under reduced pressure.
The residue was partitioned between water and CH2Cl2, and the
aqueous phase was further extracted with CH2Cl2 for at least three
times. The combined organic phases were dried with anhydrous
Na2SO4, filtered, and the solvent was removed under reduced pres-
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Acknowledgments
Financial support from U. S. NSF (CHE-0647129), Michigan Uni-
versities Commercialization Initiative Challenge Fund and MTU
Chemistry Department; the assistance from Mr. Jerry Lutz
(NMR), Mr. Shane Crist (computation) and Mr. Dean Seppala
(electronics); and an NSF equipment grant (CHE-9512445) are all
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Received: July 22, 2009
Published Online: October 5, 2009
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