A general and efficient FeCl3-catalyzed nucleophilic substitution of propargylic alcohols

Article abstract of DOI:10.1021/jo061234p

A general and efficient FeCl₃-catalyzed substitution reaction of propargylic alcohols with carbon- and heteroatom-centered nucleophiles such as allyl trimethylsilane, alcohols, aromatic compounds, thiols, and amides, leading to the construction of C-C, C-O, C-S and C-N bonds, has been developed.

Full text of DOI:10.1021/jo061234p

metal-catalyzed propargylic substitution reactions have been
recently reported. Among them, a ruthenium-catalyzed process
is a versatile and direct method.4 A wide variety of nucleophiles
such as alcohols, amines, amides, and thiols are available for
this reaction. Nevertheless, with this method, the substrate is
generally limited to the propargylic alcohols bearing terminal
alkyne group.5 More recently, Toste6 and Campagne7 have
respectively described efficient nucleophilic substitution of
propargylic alcohols in the presence of catalytic amounts of
rhenium [(dppm) ReOCl3] and/or gold [NaAuCl4‚2H2O] cata-
lyst. However, the peculiarity and high cost of such catalysts
make a barrier to their large-scale use. Therefore, development
of a general, efficient, cheap, and readily available catalyst for
propargylic substitution is highly desirable.
A General and Efficient FeCl3-Catalyzed
Nucleophilic Substitution of Propargylic Alcohols
Zhuang-ping Zhan,* Jing-liang Yu, Hui-juan Liu,
Yuan-yuan Cui, Rui-feng Yang, Wen-zhen Yang, and
Jun-ping Li
Department of Chemistry and The Key Laboratory for Chemical
Biology of Fujian ProVince, College of Chemistry and Chemical
Engineering, Xiamen UniVersity, Xiamen 361005, P. R. China
zpzhan@xmu.edu.cn
ReceiVed June 15, 2006
Herein, we wish to report an efficient FeCl3-catalyzed
nucleophilic substitution reaction of propargylic alcohols bearing
not only terminal alkyne group but also internal alkyne group
with various carbon- and heteroatom-centered nucleophiles to
afford the corresponding products in high yields with complete
regioselectivities under mild reaction conditions.
At first, we investigated the FeCl3-catalyzed coupling reac-
tions of various propargylic alcohols with allyl trimethylsilane.
We were pleased to find that 5 mol % FeCl3 in acetonitrile at
room temperature cleanly produced the substituted 1,5-enynes
in excellent yields and no R,â-unsaturated compounds via the
Meyer-Schuster-type rearrangement were detected.8 Various
aryl- and alkyl-substituted propargylic alcohols (1a-i) ef-
fectively underwent the FeCl3-catalyzed substitution. Typical
results are shown in Table 1. The reaction proceeded smoothly
without exclusion of moisture or air from the reaction mixture.
Both electron-rich and electron-poor aromatic substrates (1g-
i) reacted smoothly with allyltrimethylsilane affording the
corresponding allylated products in high yields (Table 1, entries
7-9). Functional groups, such as methoxyl, bromo, and cyano
A general and efficient FeCl3-catalyzed substitution reaction
of propargylic alcohols with carbon- and heteroatom-centered
nucleophiles such as allyl trimethylsilane, alcohols, aromatic
compounds, thiols, and amides, leading to the construction
of C-C, C-O, C-S and C-N bonds, has been developed.
Transition-metal-catalyzed allylic substitution reaction of
allylic alcohol derivatives with nucleophiles has become an
important chemical transformation, as it provides a direct and
reliable approach to a wide variety of allylated products.1 In
contrast, related transition-metal-catalyzed propargylic substitu-
tion reactions of propargylic alcohol derivatives with nucleo-
philes are relatively rare. The flexibility of the alkyne functional
group in organic synthesis makes the propargylic substitution
reaction a desirable method for development. In addition to
allowing access to saturated products by hydrogenation, the
alkyne moiety offers a handle for transformation into various
other functional groups.
The Nicholas reaction has been widely accepted as a powerful
tool for propargylic substitution reaction2 but has some draw-
backs: a stoichiometric amount of [Co2(CO)8] is required, and
several steps are necessary to obtain propargylic product from
propargylic alcohols via cationic propargylic complexes [Co2-
(CO)6(propargyl)]+.2,3 On the other hand, several transition-
(4) (a) Nishibayashi, Y.; Wakiji, I.; Hidai, M. J. Am. Chem. Soc. 2000,
122, 11019-11020. (b) Nishibayashi, Y.; Wakiji, I.; Ishii, Y.; Uemura, S.;
Hidai, M. J. Am. Chem. Soc. 2001, 123, 3393-3394. (c) Nishibayashi, Y.;
Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2002,
124, 11846-11847. (d) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton,
M. D.; Hidai, M.; Uemura, S. Angew. Chem., Int. Ed. 2003, 42, 2681-
2684. (e) Milton, M. D.; Inada, Y.; Nishibayashi, Y.; Uemura, S. Chem.
Commun. 2004, 2712-2713. (f) Nishibayashi, Y.; Milton, M. D.; Inada,
Y.; Yoshikawa, M.; Wakiji, I.; Hidai, M.; Uemura, S. Chem.sEur. J. 2005,
11, 1433-1451. (g) Nishibayashi, Y.; Inada, Y.; Hidai, M.; Uemura, S. J.
Am. Chem. Soc. 2002, 124, 7900-7901.
(5) The ruthenium-catalyzed propargylic substitution was reported to run
via allenylidene complex intermediates which can be produced only from
the propargylic alcohols bearing terminal alkyne group; see ref 4. On the
other hand, ruthenium-catalyzed substitution of propargylic alcohols bearing
internal alkyne group were also investigated; see: (a) Nishibayashi, Y.;
Inada, Y.; Yoshikawa, M.; Hidai, M.; Uemura, S. Angew. Chem., Int. Ed.
2003, 42, 1495-1498. (b) Inada, Y.; Nishibayashi, Y.; Hidai, M.; Uemura,
S. J. Am. Chem. Soc. 2002, 124, 15172-15173.
(6) (a) Luzung, M. R.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 15760-
15761. (b) Sherry, B. D.; Radosevich, A. T.; Toste, F. D. J. Am. Chem.
Soc. 2003, 125, 6076-6077. (c) Kennedy-Smith, J. J.; Young, L. A.; Toste,
F. D. Org. Lett. 2004, 6, 1325-1327.
(7) Georgy, M.; Boucard, V.; Campagne, J. M. J. Am. Chem. Soc. 2005,
127, 14180-14181.
(8) Several catalysts have been employed to carry out the conversion of
propargyl alcohols to enones (Meyer-Schuster rearrangement); see: (a)
Narasaka, K.; Kusama, H.; Hayashi, Y. Tetrahedron 1992, 48, 2059-2068.
(b) Yoshimatsu, M.; Naito, M.; Kawahigashi, M.; Shimizu, H.; Kataoka,
T. J. Org. Chem. 1995, 60, 4798-4802. (c) Lorber, C. Y.; Osborn, J. A.
Tetrahedron Lett. 1996, 37, 853-856.
* To whom correspondence should be addressed. Tel: +86(592) 2180318.
Fax: +86(592) 2185780.
(1) For recent reviews, see: (a) Tsuji, J. Palladium Reagents and
Catalysts; John Wiley & Sons: New York, 1995. (b) Trost, B. M.; Van
Vranken, D. L. Chem. ReV. 1996, 96, 395-422. (c) Trost, B. M.; Lee, C.
In Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York,
2000; Chapter 8E.
(2) Review articles: (a) Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207-
214. (b) Caffyn, A. J. M.; Nicholas, K. M. In Comprehensive Organome-
tallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, J., Eds.;
Pergamon Press: Oxford, 1995; Vol. 12, Chapter 7.1, p 685. (c) Green, J.
R. Curr. Org. Chem. 2001, 5, 809-826. (d) Teobald, B. J. Tetrahedron.
2002, 58, 4133-4170. (e) Kuhn, O.; Rau, D.; Mayr, H. J. Am. Chem. Soc.
1998, 120, 900-907.
(3) Nicholas, K. M.; Mulvaney, M.; Bayer, M. J. Am. Chem. Soc. 1980,
102, 2508-2510.
10.1021/jo061234p CCC: $33.50 © 2006 American Chemical Society
Published on Web 09/13/2006
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J. Org. Chem. 2006, 71, 8298-8301

TABLE 1. FeCl3-Catalyzed Substitution of Various Propargylic
Alcohols 1 with Allyltrimethylsilane 2a
propargylic ethers were obtained in good yields with complete
regioselectivity (Table 2, entries 1-10). Functional groups such
as alkenyl (Table 2, entries 2 and 4) and chloro (Table 2, entries
1, 3, and 5) in the alcohol were readily carried through the
reaction, allowing for the subsequent elaboration of the products
after the propargylic etherification event. The reaction is not
limited to benzylic substrates. For example, tertiary alcohol (1d)
readily undergoes propargylic etherification to afford tertiary
ether in 64% and 82% isolated yields, respectively (Table 2,
entries 5 and 10). Notably, the use of ethanol as the nucleophile
did not lead to the formation of the rearranged enone, which
was obtained as the main product in the process catalyzed by
gold(III) (Table 2, entries 8-10).7
Similarly, reactions of propargylic alcohols bearing a terminal
alkyne group or internal alkyne group with various aromatic
compound nucleophiles were also carried out (Table 2, entries11-
19). The corresponding Friedel-Crafts arylated products were
obtained from heteroaromatic compounds furan and pyrrole in
good yields with complete regioselectivity (Table 2, entries14-
16). Propargylation occurred selectively at the R-position of the
heterocyclic rings. Electron-rich aromatic compounds such as
anisole, 1,3-dimethoxybenzene, phenol, â-naphthol, and 2-meth-
oxynaphthalene reacted smoothly with propargylic alcohols
affording the corresponding propargylated compounds in mod-
erate to excellent yields (Table 2, entries 11-13 and 17-19).
The high-yield formation of Friedel-Crafts arylated products
were obtained in the reaction of phenol, â-naphthol, and
2-methoxynaphthalene with 1,3-diphenylprop-2-yn-1-ol (1b)
(Table 2, entries13, 17, and 18). In the processes involving furan
and â-naphthol, the substrate-bearing terminal alkyne group gave
the propargylic adduct in lower yields (Table 2, entry 15 vs
14; entry 19 vs 17). In all cases, propargylation occurred
selectively at the electron-rich position of aromatic compounds.
The results indicated that the reactions proceed electrophilically.
Lewis acid BF3‚Et2O also efficiently catalyzed the substitution
of propargylic alcohols with arenes, and the corresponding
Friedel-Crafts arylated products were obtained in excellent
yields. However, the catalyst loading is very high (100%
equiv).10
Transition-metal-catalyzed substitution of propargylic alcohols
with thiols has been considered difficult to achieve, probably
due to that sulfur-containing compounds are catalyst-poison
because of their strong coordinating properties.11,5b Gratifyingly,
by employing 5 mol % of FeCl3 as the catalyst, the construction
of sp3 C-S bonds was achieved by the nucleophilic substitution
of propargylic alcohols with a series of thiols. Propargylic
alcohols possessing an alkyl or aryl substituent on the alkyne
part reacted rapidly with various thiols such as ethyl 2-mer-
captoacetate, benzenethiol, and mercaptoethanol affording the
corresponding sulfide products in excellent yields with complete
regioselectivity (Table 2, entries 20, 21, 23, and 24). In contrast
to the result obtained by using phenol as nucleophile, no
Friedel-Crafts arylated product was detected while using
benzenethiol as the nucleophile, and the propargylic sulfide was
the only product (Table 2, entry 21 vs 13). Remarkably, the
hydroxyl moiety is well tolerant in the reaction; 5 mol % of
FeCl3 efficiently catalyzed the propargylation of mercaptoet-
hanol while avoiding competitive O-alkylation and the formation
isolated yield (%)
entry
R1; R2; R3
product
of 3
1
2
3
4
5
6
7
8
9
1a, Ph; H; n-Bu
1b, Ph; H; Ph
1c, Ph; H; TMS
1d, CH3; CH3; Ph
1e, Ph; H; H
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
90
95
86
61b
70
15c
83
90
85
1f, CH3; H; Ph
1g, o-MeOC6H4; H; n-Bu
1h, p-BrC6H4; H; n-Bu
1i, p-CNC6H4; H; n-Bu
a The reactions of 1 (1 mmol) with allyltrimethylsilane 2 (3 mmol) were
carried out in the presence of FeCl3 (0.05 mmol) in CH3CN (2 mL) at
room temperature for 2 h. b At 60 °C for 1 h. c At 60 °C for 24 h.
in propargylic alcohols did not affect the course of the
construction of carbon-carbon bonds. Variation in the alkyne
substituent from an alkyl to an aryl, trimethylsilyl (1a-c) is
well tolerated. Gratifyingly, 1-phenylprop-2-yn-1-ol (1e) bearing
a terminal alkyne group was successfully allylated in 70%
isolated yield as well under the same reaction conditions, and
no ploymerization was detected (Table 1, entry 5). Tertiary
aliphatic alcohol 1d allows for the construction of a quaternary
carbon by increased the reaction temperature to 60 °C (Table
1, entry 4). However, compared with secondary benzylic alcohol
1b, secondary aliphatic substrate 1f reacted more sluggishly to
give desired 1,5-enynes product in lower yield (Table 1, entry
6 vs entry 2). The primary aliphatic alcohol 3-phenylprop-2-
yn-1-ol (R1, R2 ) H) failed to get allylated product. The
experimental results suggest a mechanism through the formation
of propargylic cation intermediate. Unstability of the propargylic
cation intermediate clearly made the substitution reaction less
favorable. Other Lewis acid-catalyzed nucleophilic propargylic
substitution have been existed,9a-e but the substrate were limited
to propargylic ester. For example, the reaction of propargylic
alcohols with allyltrimethylsilane catalyzed by B(C6F5)3 did not
afford desired 1,5-enynes but corresponding silyl ether; while
propargylic ester instead of propargylic alcohols, substitution
proceeded successfully to give the desired 1,5-enynes in good
yields.9c The result exhibits the superiority of FeCl3 as the
catalyst in the reaction.
We next extended the propargylic substitution by employing
heteroatom-centered and aromatic compound nucleophiles. All
reactions proceeded in the presence of 5 mol % of FeCl3 in
acetonitrile. Typical results are shown in Table 2.
A series of alcohols as the nucleophiles were first treated
with various propargylic alcohols (1a-e), and the corresponding
(9) The significant characteristic feature of this reaction is the direct use
of propargylic alcohols as the substrates. For nucleophilic substitution of
propargylic esters, see: (a) Mahrwald, R.; Quint, S. Tetrahedron Lett. 2001,
42, 1655-1656. (b) Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S. I.
J. Org. Chem. 1994, 59, 2282-2284. (c) Schwier, T.; Rubin, M.; Gevorgyan,
V. Org. Lett. 2004, 6, 1999-2001. (d) Mahrwald, R.; Quint, S.; Scholtis,
S. Tetrahedron 2002, 58, 9847-9851. (e) Bartels, A.; Mahrwald, R.; Quint,
S. Tetrahedron Lett. 1999, 40, 5989-5990. (f) Kondo, T.; Kanda, Y.; Baba,
A.; Fukuda, K.; Nakamura, A.; Wada, K.; Morisaki, Y.; Mitsudo, T. A. J.
Am. Chem. Soc. 2002, 124, 12960-12961. For nucleophilic substitution of
propargylic ethers, see: (g) Yoshimatsu, M.; Shimizu, H.; Kataoka, T. Chem.
Commun. 1995, 149-150.
(10) Liu, J. H.; Muth, E.; Flo¨rke, U.; Henkle, G.; Merz, K.; Sauvageau,
J.; Schwake, E.; Dyker, G. AdV. Synth. Catal. 2006, 348, 456-462.
(11) Hegedus, L. L.; McCabe, R. W. Catalyst Poisoning; Marcel
Dekker: New York, 1984.
J. Org. Chem, Vol. 71, No. 21, 2006 8299

TABLE 2. FeCl3-Catalyzed Substitution of Various Propargylic Alcohols 1 with Various Nucleophiles 2a
a The reactions of 1 (1 mmol) with 2 (3 mmol) were carried out in the presence of FeCl3 (0.05 mmol) in CH3CN (2 mL) at room temperature. b The
reaction was carried out at 60 °C.
8300 J. Org. Chem., Vol. 71, No. 21, 2006

of the propargylic ethers. Hydroxyl, ethoxycarbonyl, and phenyl
moieties contained in the propargylic sulfides provide a handle
for transformation into a variety of other functional groups.
However, the propargylic alcohol bearing terminal alkyne group
participated in the substitution reaction to give propargylic
adduct in lower yields (Table 2, entries 22 and 25).
and commercial availability, broad scope, and mild reaction
conditions of this transformation. Further development on this
methodology is currently underway in our laboratory.
Experimental Section
A typical experimental procedure for the reaction of 1-phenyl-
hept-2-yn-1-ol (1a) with allyl trimethylsilane catalyzed by 5 mol
% of FeCl3 is described below: to a 5-mL flask were successively
added 1-phenylhept-2-yn-1-ol (1a) (188 mg, 1 mmol), allyl tri-
methylsilane (343 mg, 3.0 mmol), CH3CN (2 mL), and anhydrous
FeCl3 (8 mg, 0.05 mmol), and then the mixture was magnetically
stirred at room temperature for 2 h. The solvent was concentrated
under reduced pressure by an aspirator, and then the residue was
purified by silica gel column chromatography (EtOAc/hexane) to
afford 1-(dec-1-en-5-yn-4-yl)benzene (3aa) as a clear colorless oil
(191 mg, 90% yield): 1H NMR (CDCl3, 400 MHz) δ 0.91 (t, 3H,
J ) 7.2 Hz), 1.37-1.55 (m, 4H), 2.23 (td, 2H, J ) 7.2 and 2.4
Hz), 2.45 (dd, apparent t, 2H, J ) 7.2 and 7.2 Hz), 3.65 (tt, 1H, J
) 7.2 and 2.4 Hz), 4.98-5.06 (m, 2H), 5.82 (ddt, 1H, J ) 17.2,
10.4 and 7.2 Hz), 7.16-7.23 (m, 1H), 7.26-7.36 (m, 4H) ppm;
13C NMR (CDCl3, 100 MHz) δ 14.1, 18.9, 22.3, 31.5, 38.3, 43.3,
81.0, 83.7, 116.3, 126.2, 127.1, 127.9, 135.4, 141.6 ppm; IR (film)
3062, 3029, 2204, 1644, 1599, 1581, 1494 cm-1; MS (FAB) m/z
213 (M + H+).
Finally, selected amides also acted as efficient nucleophiles
to give the corresponding propargylic amides in moderate to
good yields. The employment of benzamide, p-chlorobenzamide,
and p-toluenesulfonamide effectively led to the formation of
C-N bonds. Unfortunately, no propargylation occurred under
these conditions when acetamide, aniline, and piperidine were
used as the nucleophiles, even using propargyl esters as the
substrate. However, amination of propargyl esters can be
achieved in the presence of CuCl as the catalyst.12
In summary, we have developed a general and efficient FeCl3-
catalyzed substitution reaction of propargylic alcohols with
carbon- and heteroatom-centered nucleophiles such as allyltri-
methylsilane, alcohols, aromatic compounds, thiols, and amides,
leading to the construction of C-C, C-O, C-S, and C-N
bonds. Propargylic alcohols bearing a terminal alkyne group or
internal alkyne group are readily available.9 The corresponding
propargylic products were obtained in high yields with complete
regioselectivity. In comparison with cobalt, rhenium, ruthenium,
and gold complexes, which are usually used to catalyze the
nucleophilic substitution of propargylic alcohols, FeCl3 as the
catalyst offers several relevant advantages including cheapness
Acknowledgment. The research was supported by the
National Natural Science Foundation of China (No. 30572250).
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.
(12) Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi, S. I. J. Org. Chem.
1994, 59, 2282-2284.
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