FeCl3-catalyzed nucleophilic substitution of propargylic acetates with enoxysilanes

Article abstract of DOI:10.1021/jo701782g

(Chemical Equation Presented) An efficient FeCl₃-catalyzed substitution reaction of propargylic acetates with enoxysilanes under mild conditions to afford corresponding γ-alkynyl ketones has been developed. The substitution reaction is followed

Full text of DOI:10.1021/jo701782g

yashi6 and co-workers described an efficient coupling of
propargylic alcohols with ketones for the formation of γ-alkynyl
ketones and the straightforward synthesis of substituted furans
in the presence of a catalytic amount of a ruthenium catalyst.
Nevertheless, with this method, the substrate is generally limited
to the propargylic alcohols bearing a terminal alkyne group.
Matsuda’s team7 reported that iridium complex [Ir(cod)-
{P(OPh)3}2]OTf serves as a catalyst for the transformation to
γ-alkynyl ketones by the coupling of propargylic esters with
enoxysilanes. However, the peculiarity and high cost of such
catalysts make a barrier to their large-scale use.
FeCl3-Catalyzed Nucleophilic Substitution of
Propargylic Acetates with Enoxysilanes
Zhuang-ping Zhan,* Xu-bin Cai, Shao-pei Wang,
Jing-liang Yu, Hui-juan Liu, and Yuan-yuan Cui
Department of Chemistry, College of Chemistry and Chemical
Engineering, Xiamen UniVersity, Xiamen 361005, Fujian,
People’s Republic of China
zpzhan@xmu.edu.cn
We have recently developed a highly efficient iron(III)- or
bismuth(III)-catalyzed propargylic substitution of propargylic
alcohols or esters with various heteroatom- and carbon-centered
nucleophiles.8 Naturally, we intended to extend this method to
the route to γ-alkynyl ketones. However, no propargylation
occurred while using ketones as the nucleophiles under our
reaction conditions, probably due to the weak nucleophilicity
of the R-C of the ketones. Gratifyingly, enoxysilanes as the
carbon-centered nucleophiles exhibited strong nucleophilicity.
The nucleophilic substitution reaction of propargylic acetates
with enoxysilanes proceeded rapidly in the presence of 5 mol
% of FeCl3 and efficiently afforded corresponding γ-alkynyl
ketones in high yields. Herein we reported the successful results
and scope of the reactions, and this iron(III)-catalyzed reaction
allows for the straightforward synthesis of tri- or tetrasubstituted
furans.
ReceiVed August 19, 2007
An efficient FeCl3-catalyzed substitution reaction of prop-
argylic acetates with enoxysilanes under mild conditions to
afford corresponding γ-alkynyl ketones has been developed.
The substitution reaction is followed by a TsOH-catalyzed
cyclization without purification of the γ-alkynyl ketone
intermediates, offering a straightforward synthetic route to
tri- or tetrasubstituted furans.
Reaction of propargylic acetate 1a and enoxysilane 2a was
first carried out employing FeCl3 as the catalyst. γ-Alkynyl
ketone 3aa was obtained in 83% isolated yield at room
temperature within just 5 min by simple stirring of 1a (0.5
mmol), enoxysilane 2a (1.5 mmol), and FeCl3 (0.025 mmol) in
acetonitrile. With the conditions in hand, various propargylic
acetates were treated with the enoxysilane 2a in the presence
of 5 mol % of FeCl3and all the reactions gave the desired
coupling products in moderate to high yields. Typical results
are summarized in Table 1. The reaction proceeded smoothly
without exclusion of moisture or air from the reaction mixture.
Both electron-donating (1m) and electron-withdrawing (1k, 1l)
The acetylenic carbon-carbon triple bond plays a pivotal role
in a variety of functional group transformations,1 which has
resulted in the steady growth in the synthesis of propargylic
derivatives. An efficient route to propargylic derivatives is
through propargylic substitution reactions. Reactions of this type
have been traditionally carried out by using the classical
Nicholas reaction but with some drawbacks: more than a
stoichiometric amount of [Co2(CO)8] is required, and several
steps are necessary to obtain propargylic products from prop-
argylic alcohols via cationic propargylic complexes [Co2(CO)6-
(propargyl)]+.2,3 Some transition metal complexes were devel-
oped to catalyze the propargylic substitution reactions of
propargylic alcohols with nucleophiles,4,5 where most of the
nucleophiles were heteroatom-centered such as alcohols, thiols,
amides, and so on. However, the carbon-centered nucleophiles
were unfortunately limited to allyl silanes for the construction
of sp3-sp3 C-C bonds in the reaction.4b,5h Recently, Nishiba-
(5) (a) Nishibayashi, Y.; Wakiji, I.; Hidai, M. J. Am. Chem. Soc. 2000,
122, 11019. (b) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.;
Uemura, S. J. Am. Chem. Soc. 2002, 124, 11846. (c) Nishibayashi, Y.;
Milton, M. D.; Inada, Y.; Yoshikawa, M.; Wakiji, I.; Hidai, M.; Uemura,
S.; Chem. Eur. J. 2005, 11, 1433. (d) Nishibayashi, Y.; Inada, Y.; Hidai,
M.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 7900. (e) Nishibayashi, Y.;
Inada, Y.; Yoshikawa, M.; Hidai, M.; Uemura, S. Angew. Chem., Int. Ed.
2003, 42, 1495. (f) Inada, Y.; Nishibayashi, Y.; Hidai, M.; Uemura, S. J.
Am. Chem. Soc. 2002, 124, 15172. (g) Sherry, B. D.; Radosevich, A. T.;
Toste, F. D. J. Am. Chem. Soc. 2003, 125, 6076. (h) Georgy, M.; Boucard,
V.; Campagne, J. M. J. Am. Chem. Soc. 2005, 127, 14180. (i) Mahrwald,
R.; Quint, S.; Scholtis, S. Tetrahedron 2002, 58, 9847. (j) Liu, J. H.; Muth,
E.; Flo¨rke, U.; Henkel, G.; Merz, K.; Sauvageau, J.; Schwake, E.; Dyker,
G. AdV. Synth. Catal. 2006, 348, 456.
(6) (a) Nishibayashi, Y.; Wakiji, I.; Ishii, Y.; Uemura, S.; Hidai, M. J.
Am. Chem. Soc. 2001, 123, 3393. (b) Inada, Y.; Nishibayashi, Y.; Uemura,
S. Angew. Chem., Int. Ed. 2005, 44, 7715. (c) Milton, M. D.; Inada, Y.;
Nishibayashi, Y.; Uemura, S. Chem. Commun. 2004, 2712. (d) Nishibayashi,
Y.; Yoshikawa, M.; Inada, Y.; Milton, M. D.; Hidai, M.; Uemura, S. Angew.
Chem., Int. Ed. 2003, 42, 2681.
* To whom correspondence should be addressed. Phone/fax: +86(592)
2180318.
(1) (a) Hudrlik, P. F.; Hudrlik, A. M. In The Chemistry of the Carbon-
Carbon Triple Bond; Patai, S., Ed.; John Wiley & Sons: Chester, UK, 1978;
Chapter 7, p 199. (b) Trost, B. M.; Fleming, I., Eds: Comprehensive
Organic Synthesis; Pergamon Press: Oxford, UK, 1991; Vol. 4.
(2) Review articles: (a) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207.
(b) Caffyn, A. J. M.; Nicholas, K. M. ComprehensiVe Organometallic
Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, J., Eds.; Pergamon
Press: Oxford, UK, 1995; Vol. 12, Chapter 7.1, p 685. (c) Green, J. R.
Curr. Org. Chem. 2001, 5, 809. (d) Teobald, B. J. Tetrahedron 2002, 58,
4133. (e) Kuhn, O.; Rau, D.; Mayr, H. J. Am. Chem. Soc. 1998, 120, 900.
(3) Nicholas, K. M.; Mulvaney, M.; Bayer, M. J. Am. Chem. Soc. 1980,
102, 2508.
(7) Matsuda, I.; Komori, K.; Itoh, K. J. Am. Chem. Soc. 2002, 124, 9072.
(8) (a) Zhan, Z. P.; Yu, J. L.; Liu, H. J.; Cui, Y. Y.; Yang, R. F.; Yang,
W. Z.; Li, J. P. J. Org. Chem. 2006, 71, 8298. (b) Zhan, Z. P.; Yang, W.
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10.1021/jo701782g CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/13/2007
9838
J. Org. Chem. 2007, 72, 9838-9841

TABLE 1. FeCl3-Catalyzed Substitution of Various Propargylic
Acetates 1 with Enoxysilanes 2aa
TABLE 2. FeCl3-Catalyzed Substitution of Various Propargylic
Acetates 1 with Nucleophiles 2a
substrate
isolated yields
entry
R1; R2; R3
product
of 3 (%)
1
2
1a: Ph; H; n-Bu
1b: Ph; H; Ph
1c: Ph; H; TMS
1d: CH3; CH3; Ph
1e: -(CH2)5-; Ph
1f: Ph; CH3; Ph
1g: Ph; H; H
1h: Ph; Ph; Ph
1i: CH3; H; Ph
1j: H; H; Ph
3aa
3ba
3ca
3da
3ea
83
95
90
92
3
4f
5f
6
82
3fa
83
7
3ga
3ha; 4ha
3ia
3ja
3ka
3la
82b
8c
9
53, 38(4ha)
0(33)d,f
0(0)d,f
81
10
11
12
13
1k: 4-Cl-C6H4; H; n-Bu
1l: 4-CN-C6H4; H; n-Bu
1m: 2-MeO-C6H4; H; n-Bu
77e
86
3ma
a The reactions of 1 (0.5 mmol) with enoxysilane 2a (1.5 mmol) were
carried out in the presence of FeCl3 (0.025 mmol) in CH3CN (1.0 mL) at
room temperature for 5 min. b At 40 °C for 1 h. c Allenyl isomer 4ha was
concomitantly formed in the reaction. d The propargylic phosphate 1iP or
1jP was used instead of propargylic acetates as the substrate, at 60 °C for
30 min. e At rt, 30 min. f The structures of 5d, 5e, 1iP, and 1jP are the
following:
a The reactions of 1 (0.5 mmol) with enoxysilane 2 (1.5 mmol) were
carried out in the presence of FeCl3 (0.025 mmol) in CH3CN (1.0 mL) at
room temperature for 5 min. b At 40 °C for 1 h. c The propargylic phosphate
1iP was used as the substrate, at 60 °C for 15 min. d The propargylic
phosphate 1jP was used as the substrate, at 60 °C for 3 h. e Two
diastereoisomers were formed with the isomer ratio of 2:1. f Two diaste-
reoisomers were formed with the isomer ratio of 1.3:1. g At 40 °C for 1 h.
Two diastereoisomers were formed with the isomer ratio of 1.5:1. h Two
diastereoisomers were formed with the isomer ratio of 1.5:1. i Two
diastereoisomers were formed with the isomer ratio of 1.6:1.
aromatic substrates reacted smoothly with enoxysilane 2a
affording the corresponding alkylated products in high yields
(Table 1, entries 11-13). Functional groups such as chloro,
cyano, and methoxyl in the substrates did not affect the coupling
of sp3-sp3 C-C bonds, but the electron-withdrawing substrates
require a relatively longer time for completion (Table 1, entry
12). Variation in the alkyne substituent from an aryl to an n-Bu,
trimethylsilyl, or H (1a-1c, 1g) is well tolerated. This is in
sharp contrast to the Ru-catalyzed substitution6 where the
substrates were limited to the propargylic alcohols bearing a
terminal alkyne group. Coupling of secondary benzylic prop-
argylic acetates with 2a was completed at room temperature
within 5 min furnishing corresponding products in 77-95%
yields (Table 1, entries 1-3, 7, 11-13). However, the secondary
aliphatic propargylic acetate (R1 ) CH3, R2 ) H, R3 ) Ph) 1i
did not react at all with 2a. The starting 1i was recovered intact.
The desired transformation was accomplished by using corre-
sponding phosphate 1iP as the substrate under forcing condi-
tions, with low yield (Table 1, entry 9). The primary aliphatic
propargylic phosphate 1jP did not undergo the substitution even
under fierce reaction conditions (Table 1, entry 10). On the other
hand, tertiary aliphatic propargylic acetates allow for the
construction of sp3-sp3 C-C bonds in high yields (Table 1,
entries 4, 5). The experimental results suggest a mechanism
through the formation of a propargylic cation intermediate.
Instability of the propargylic cation intermediate clearly made
the substitution reaction less favorable. Unfortunately, allenyl
isomer was concomitantly formed in 38% yield in the example
of more hindered substrate 1h, which has two phenyl groups
on the propargylic carbon (Table 1, entry 8). This shows that
an increase in steric bulk at the electrophilic site can alter the
regiochemistry of the nucleophilic attack. It is noteworthy that
the corresponding γ-alkynyl ketones were obtained in good
yields in the examples involving the substrates 1d and 1e which
have alkyl groups on the propargylic carbon, and the elimination
product enynes 5d and 5e were not observed in the reaction
(Table 1, entries 4, 5). This is in contrast to the Ir-catalyzed
procedure of Matsuda,7 where the enynes 5d and 5e were formed
as the major products at 25 °C. The iron(III)-catalyzed substitu-
tion is complete in several minutes while other methodologies6,7
require several hours. These results show the superiority of FeCl3
as a catalyst for this reaction.
With these preliminary results available, the scope of the
nucleophiles in this reaction was investigated (Table 2). Enox-
ysilanes 2b, 2c, and 2d were proved to be efficient for the
present transformation as well. The regioselectivity that preferred
the propargylic products 3 was retained in examples involving
2b as the nucleophile (Table 2, entries 1-7). Allenyl isomer
4hb (3hb:4hb ) 42:51) was concomitantly formed only in the
reaction of sterically encumbered substrate 1h (Table 2, entry
8). The primary propargylic acetate 1j (R1, R2 ) H) failed to
give coupling product in the reaction with 2b; the substitution
was achieved by employing the corresponding phosphate 1jp
at higher temperature but lower yield (Table 2, entry 10). In
the reactions involving cyclohexenoxysilane 2c, the ratio of
product 3 and 4 was obviously affected by the steric bulkiness
J. Org. Chem, Vol. 72, No. 25, 2007 9839

TABLE 3. Synthesis of Substituted Furans from Propargylic Acetates 1 and Enoxysilane 2a
a The solution of propargylic acetates 1 (0.5 mmol), enoxysilanes 2 (1.5 mmol), and FeCl3 (0.025 mmol) was stirred in CH3CN (1.0 mL) at rt for 5 min
or at 40 °C for 1 h (for substrate 1g), or at rt for 30 min (for substrate 1l). Acetonitrile was then removed, followed by the addition of TsOH (0.5 mmol)
and toluene (6.0 mL). Cyclization proceeded under refluxing for 0.5-2.0 h.
of the propargylic acetates 1. γ-Alkynyl ketones 3 were the sole
products in the reactions of secondary propargylic acetates 1c
and 1g. No allenyl isomers 4 were detected (Table 2, entries
11, 15). But by changing the substrates to tertiary propargylic
acetates 1d, 1e, and 1f, the yields of substitution product 3
decreased and the allenyl isomer 4 was respectively obtained
in 24%, 29%, and 14% yields (Table 2, entries 12-14).
Especially, the allenyl isomer 4hc was isolated as the sole
product in 83% yield in the reaction of 1h with 2c (Table 2,
entry 16). Ketene acetal 2d retained the preferential formation
of 4hd in reaction with 1h (Table 2, entry 18). The regiose-
lectivity of the substitution was also affected by the steric
bulkiness of the nucleophile 2. For example, γ-alkynyl ketone
3fa or 3fb was the sole product in the reaction of 2a or 2b with
1f (Table 1, entry 6; Table 2, entry 6). Allenyl isomer 4fc (3fc:
4fc ) 75:14) was concomitantly formed in the reaction of 2c
with 1f (Table 2, entry 14). This implies that the bulkiness at
the nucleophile site affects the regioselectivity of substitution.
In addition, â-diketone ester 2e can be directly used for the
propargylic substitution giving corresponding alkylated products
in good yields (Table 2, entries 19, 20).
The FeCl3-catalyzed propargylic substitution allows for the
straightforward synthesis of tri- or tetrasubstituted furans by the
sequential cyclization reaction of γ-alkynyl ketone intermediates
in a one-pot procedure. The mixture of secondary propargylic
acetates 1, enoxysilanes 2, and 5 mol % of FeCl3 was simply
stirred in acetonitrile. Upon reaction completion, acetonitrile
was then removed in vacuo, followed by the addition of toluene
and a stoichiometric amount of 4-methylbenzenesulfonic acid
(TsOH). Highly substituted furans were conveniently furnished
in good yields within no more than 2 h under refluxing
condition9 (Table 3). Reactions of enoxysilane 2a with various
9840 J. Org. Chem., Vol. 72, No. 25, 2007

propargylic acetates afforded corresponding 2,3,5-trisubstituted
furans in high yields (Table 3, entries 1, 5-8, 11). Functional
groups such as chloro, cyano, and methoxyl in the substrates
were tolerant in the TsOH-catalyzed cyclization, which allows
access to other functionalized furans. The use of 2b also gave
good results under the same conditions (Table 3, entries 2, 9).
Starting with cyclohexenyloxytrimethylsilane 2c and propargylic
acetates 1a, 1g, and 1c, tetrasubstituted furans were isolated in
75%, 61%, and 80% yields, respectively (Table 3, entries 3,
10, 12). The trimethylsilyl group undergoes protodesilylation
under the acidic cyclization conditions and so the same products
were obtained in the examples involving 1g and 1c (Table 3,
entries 8 and 11, 10 and 12). Treatment of propargylic acetate
1a with â-diketone ester 2e gave the 3-carboxylated tetrasub-
stituted 6ae in moderate yield (Table 3, entry 4). In the
sequential process, the intermediates γ-alkynyl ketones, obtained
by the coupling of propargylic acetates with nucleophiles in
the first step, can be directly used for the next cyclization without
purification, which would lessen the yield loss of the furan
products. Nishibayashi’s team6d reported novel ruthenium- and
platinum-catalyzed sequential reactions to afford the corre-
sponding tri- and tetrasubstituted furans by the direct use of
propargylic alcohols as substrates and ketones as carbon-
centered nucleophiles under N2. However, the substrates were
limited to propargylic alcohols bearing a terminal alkyne group
and the reaction required a rather long time for completion. In
contrast, propargylic acetates bearing both a terminal alkyne
group and an internal alkyne group are available, and the
reaction proceeded much more rapidly without the protection
inert gases. However, more active enoxysilanes of ketones as
nucleophiles were required in our procedure.
available methods for the preparation of γ-alkynyl ketones.
Additionally, the FeCl3-catalyzed substitution reaction can be
followed by a TsOH-accelerated cyclization without purification
of the γ-alkynyl ketone intermediates, offering a straightforward
synthetic route to polysubstituted furans in an air atmosphere.
Experimental Section
A typical experimental procedure for the reaction of 1-phenyl-
hept-2-ynyl acetate (1a) with enoxysilane (2a) catalyzed by 5 mol
% FeCl3 is described below: To a 5-mL flask were successively
added 1-phenylhept-2-ynyl acetate (1a, 115 mg, 0.5 mmol),
enoxysilane (2a, 195 mg, 1.5 mmol), CH3CN (1.0 mL), and FeCl3
(4 mg, 0.025 mmol). The reaction mixture was stirred at room
temperature and monitored periodically by TLC. After 5 min, the
reaction was completed, the solvent was removed under reduced
pressure by an aspirator, and then the residue was purified by silica
gel column chromatography (EtOAc/hexane) to afford the corre-
sponding γ-alkynyl ketone (3aa) as a yellow oil (95 mg, 83% yield).
A typical experimental procedure for the synthesis of substituted
furan 5-methyl-2-pentyl-3-phenylfuran (6aa) is described here: To
a 25-mL flask were successively added 1-phenylhept-2-ynyl acetate
(1a, 115 mg, 0.5 mmol), enoxysilane (2a, 195 mg, 1.5 mmol), CH3-
CN (1.0 mL), and FeCl3(4 mg, 0.025 mmol), then the reaction
mixture was stirred at room temperature for 5 min and monitored
periodically by TLC. Upon completion of the reaction, the solvent
was removed under reduced pressure by an aspirator, followed by
the addition of toluene (6.0 mL) and a stoichiometric amount of
4-methylbenzenesulfonic acid (86 mg, 0.5 mmol). The reaction was
heated to reflux for 0.5 h and monitored by TLC. When complete,
the toluene was removed under reduced pressure by an aspirator,
and then the residue was purified by silica gel column chromatog-
raphy (hexane) to afford the corresponding furan (6aa) as a colorless
oil (92 mg, 81% yield).
In conclusion, we have developed a novel and efficient FeCl3-
catalyzed propargylic substitution of propargylic acetates with
enoxysilanes to afford corresponding γ-alkynyl ketones in good
to high yields. The reaction proceeds under mild conditions and
air or moisture is tolerated. The broad scope, mild reaction
conditions, short reaction time, and experimental ease of this
transformation have made it a valuable alternative to current
Acknowledgment. The research was financially supported
by the National Natural Science Foundation of China (Nos.
20772098 and 30572250), the Natural Science Foundation of
Fujian province of China (No. C0510002), and the Program
for New Century Excellent Talents in Fujian Province Univer-
sity.
Supporting Information Available: Experimental procedures
and spectra data for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(9) Cyclization reaction of γ-alkynyl ketones did not proceed in
acetonitrile. The FeCl3-catalyzed propargylic substitution reaction also did
not proceed in toluene. So it is necessary that toluene displace acetonitrile
as solvent for the cyclization reaction.
JO701782G
J. Org. Chem, Vol. 72, No. 25, 2007 9841