FeCl3-catalyzed coupling of propargylic acetates with alcohols

Article abstract of DOI:10.1055/s-2006-949645

A new method for the synthesis of propargylic ethers by FeCl ₃-catalyzed alcoholysis of propargylic acetates was developed. The reaction was carried out at room temperature in acetonitrile without exclusion of moisture or air. High product yiel

Full text of DOI:10.1055/s-2006-949645

2278
LETTER
FeCl3-Catalyzed Coupling of Propargylic Acetates with Alcohols
F
eCl -Catalyzed
h
Coupling
o
u
f
Propargylic
a
A
cetates
w
n
ithAlcoholsg-Ping Zhan,* Hui-Juan Liu
3
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical Enginee-
ring, Xiamen University, Xiamen 361005, P. R. of China
Fax +86(592)2185780; E-mail: zpzhan@xmu.edu.cn
Received 10 May 2006
OR4
R1
R2
OAc
Abstract: A new method for the synthesis of propargylic ethers by
R1
R2
5 mol% FeCl3
MeCN, r.t.
FeCl3-catalyzed alcoholysis of propargylic acetates was developed.
The reaction was carried out at room temperature in acetonitrile
without exclusion of moisture or air. High product yields were ob-
tained with excellent reaction regioselectivity.
R4OH
+
R3
R3
1
2
Scheme 1
Key words: propargylic ethers, propargylic esters, alcohols, ether-
ification
the reaction proceeded smoothly without exclusion of
moisture or air (Scheme 1).11
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. The Nicholas reaction has been
widely accepted as a powerful tool for propargylic substi-
tution reactions2 but has some drawbacks, for example, a
stoichiometric amount of [Co2(CO)8] is required and sev-
eral steps are necessary to obtain the required propargylic
substances from propargylic alcohols via cationic propar-
gylic complexes [Co2(CO)6(propargyl)]+.2,3 Recently,
several transition-metal-catalyzed propargylic substitu-
tion reactions have been reported. Among them, a ruthe-
nium-catalyzed process is a direct and versatile method.4
Nevertheless, with this method, the substrate is limited to
propargylic alcohols bearing terminal alkyne groups.5 Re-
cently, Toste6 and Campagne7 described efficient rhenium
[(dppm)ReOCl3] and gold [NaAuCl4·2H2O]-catalyzed
nucleophilic substitution of propargylic alcohols, respec-
tively, but the high cost of such catalysts is a barrier to
their large-scale use. Remarkably, Mahrwald et al. found
that propargylic etherification was an attractive method
for the preparation of propargylic ethers in the presence of
In order to determine the scope and limitation of this reac-
tion, various propargylic acetates and various alcohols
were investigated (Table 1).12 We found that during ether-
ification propargylic acetates bearing an internal alkyne
group proceeded rapidly at room temperature to give the
corresponding ethers in excellent yields (Table 1, entries
1–11). Variations in the alkyne substituent from alkyl to
aryl or to trimethylsilyl (1a–c) were well tolerated, with-
out noticeable differences observed in the reaction tem-
perature, time, or yields. In the case of 1-phenylhept-2-
ynyl acetate (1b) with ethanol and isopropanol as the nu-
cleophile, the corresponding ethers were obtained in 89%
and 91% yields, respectively (Table 1, entries 5 and 6). In
the TiCl4-catalyzed reaction, only 68% and 42% of the de-
sired products were obtained.8 Therefore, our procedure
was more efficient for the propargylic substitution. Grati-
fyingly, non-benzylic propargylic acetate 1d also partici-
pated in the substitution reaction, and the etherification
proceeded rapidly as well to give the corresponding prod-
ucts in high yields (Table 1, entries 10 and 11). In con-
trast, reactions of propargylic acetate bearing a terminal
alkyne group 1e were sluggish under identical conditions;
a prolonged reaction time and higher temperature (60 °C)
were required to produce the corresponding ether in good
yield (Table 1, entry 12).
8
TiCl4 or Ti(i-PrO)4.9 However, the catalyst loading was
relatively high (10 mol%) and the reaction scope was
somewhat narrow. Furthermore, the catalysts were mois-
ture sensitive, less environmentally friendly, and difficult
to handle. Therefore, the development of a general, effi-
cient, inexpensive, and commercially available catalyst
for propargylic substitution reactions is highly desirable.10
Different alcohols were also tested and the corresponding
propargylic ethers were obtained in good yields with com-
plete regioselectivity. Not only primary alkyl alcohols re-
acted with propargylic esters rapidly, secondary alkyl
alcohols also underwent propargylic etherification to af-
ford the propargyl adducts in excellent yields (Table 1,
entries 2 and 6). Primary as well as secondary alcohols
participated in the reaction without noticeable differences.
Alcohols with other functional groups such as alkenyl,
phenyl, and chloro substituents were also readily reacted
(Table 1, entries 3, 4, 7–9, and 11), allowing the subse-
quent elaboration of the products after propargylic etheri-
fication.
Herein, we described an efficient FeCl3-catalyzed nucleo-
philic substitution reaction of propargylic acetates with al-
cohols, giving an sp3 C–O bond after etherification. The
reaction was carried out at room temperature in the pres-
ence of a catalytic amount of FeCl3 in acetonitrile. High
yields were obtained with excellent regioselectivity and
SYNLETT 2006, No. 14, pp 2278–2280
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Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-949645; Art ID: W09706ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
FeCl3-Catalyzed Coupling of Propargylic Acetates with Alcohols
2279
Table 1 FeCl3-Catalyzed Coupling of Propargylic Acetates with Alcoholsa
Entry
Acetate
1a
R1
Ph
Ph
R2
H
R3
Ph
Ph
R4OH
Time (h)
2.5
Product
2a
Yields of 2 (%)c
1
2
n-BuOH
92
93
1a
H
1.0
2b6b
OH
3
1a
Ph
H
Ph
0.5
2c8a
92
OH
OH
4
5
6
1a
1b
1b
Ph
Ph
Ph
H
H
H
Ph
1.5
1.0
1.0
2d6b
2e8a
2f8a
95
89
91
n-Bu
n-Bu
EtOH
OH
7
8
1b
1c
1c
1d
1d
1e
Ph
Ph
Ph
Me
Me
Ph
H
n-Bu
TMS
TMS
Ph
0.5
0.5
1.5
1.0
0.5
5.0
2g6b
2h6b
2i2b
2j14
2k6b
2l4a
90
95
90
94
90
80b
Cl
Cl
OH
OH
OH
H
9
H
10
11
12
Me
Me
H
EtOH
Ph
Cl
OH
H
EtOH
a The reactions of 1 (1 mmol) with R4OH (3 mmol) were carried out in the presence of FeCl3 (0.05 mmol) in MeCN (2 mL) at r.t.
b The reaction was carried out at 60 °C.
c Isolated yields.
Similarly, reactions of propargylic esters with phenols and b-methoxynaphthalene were also investigated, and
were also investigated.12 Surprisingly, contrary to previ- the corresponding propargyl adducts 2p and 2q were ob-
ous reports, the corresponding ethers were not detected.13 tained in good yields. In all cases, propargylation occurred
Instead the Friedel–Crafts C-arylated products 2m and 2n selectively at the most electron rich position of the aro-
were obtained in excellent yields with excellent regiose- matic compounds. The results indicated that the reaction
lectivity (Scheme 2). b-Naphthol also reacted smoothly proceeded via an electrophilic aromatic substitution
with 1,3-diphenylprop-2-ynyl acetate 1a to afford the mechanism.
corresponding C–C coupling product 2o in good yield.
Other electron-rich aromatics such as methoxybenzene
In conclusion, we have developed a general and efficient
FeCl3-catalyzed substitution reaction of propargylic esters
OH
Ar =
2m (R = Ph, 95%, 0.5 h)
2n (R = n-Bu, 93%, 0.5 h)
OAc
Ar
ArH
OH
5 mol% FeCl3
MeCN, r.t.
Ph
Ph
R
R
2o (R = Ph, 85%, 1.5 h)
1a (R = Ph)
1b (R = n-Bu)
OMe
2p (R = Ph, 92%, 0.5 h)
OMe
2q (R = Ph, 87%, 0.5 h)
Scheme 2
Synlett 2006, No. 14, 2278–2280 © Thieme Stuttgart · New York

2280
Z.-P. Zhan, H.-J. Liu
LETTER
(6) (a) Luzung, M. R.; Toste, F. D. J. Am. Chem. Soc. 2003, 125,
15760. (b) Sherry, B. D.; Radosevich, A. T.; Toste, F. D. J.
Am. Chem. Soc. 2003, 125, 6076. (c) Kennedy-Smith, J. J.;
Young, L. A.; Toste, F. D. Org. Lett. 2004, 6, 1325.
(7) Georgy, M.; Boucard, V.; Campagne, J. M. J. Am. Chem.
Soc. 2005, 127, 14180.
(8) (a) Mahrwald, R.; Quint, S. Tetrahedron 2000, 56, 7463.
(b) Bartels, A.; Mahrwald, R.; Quint, S. Tetrahedron Lett.
1999, 40, 5989.
with alcohols, leading to the construction of C–O bonds.
However, phenolic compounds such as phenol, b-naph-
thol, methoxybenzene, and b-methoxynaphthalene react-
ed with propargylic esters to form C–C bonds under
similar reaction conditions. In comparison to cobalt, rhe-
nium, ruthenium, titanium, and gold complexes, our re-
ported catalyst FeCl3 offers several advantages such as
cheaper cost, commercial availability, and milder reaction
conditions. Further investigations on the elucidation of the
detailed reaction mechanism and broadening the scope of
this methodology are currently ongoing in our laboratory.
(9) Mahrwald, R.; Quint, S.; Scholtis, S. Tetrahedron 2002, 58,
9847.
(10) Very recently new methodologies employing Brønsted acids
as the catalysts have been developed although a higher
temperature was needed or the reaction scope is somewhat
narrow, see: (a) Sanz, R.; Martínez, A.; Álvarez-Gutiérrez,
J. M.; Rodríguez, F. Eur. J. Org. Chem. 2006, 1383.
(b) Liu, J. H.; Muth, E.; Flörke, U.; Henkel, G.; Merz, K.
Adv. Synth. Catal. 2006, 348, 456.
Acknowledgment
The project was supported by the National Natural Science Found-
ation of China (NO. 30572250).
(11) We suppose that HCl (from the reaction of water with FeCl3)
might be the actual catalyst, therefore a control experiment
was done but no reaction occurred in a model reaction
between 1a and 1-butanol in the presence of 10% HCl.
(12) (a) Preparation of propargylic acetates: Bartels, A.;
Mahrwald, R.; Müller, K. Adv. Synth. Catal. 2004, 346, 483.
(b) Propargylic Ethers; Typical Procedure
References and Notes
(1) (a) Hudrlik, P. F.; Hudrlik, A. M. In The Chemistry of the
Carbon-Carbon Triple Bond; Patai, S., Ed.; John Wiley &
Sons: Chichester, 1978, Chap. 7, 199. (b) Trost, B. M.
Comprehensive Organic Synthesis, Vol. 4; Fleming, I., Ed.;
Pergamon Press: Oxford, 1991.
(2) Review articles: (a) Nicholas, K. M. Acc. Chem. Res. 1987,
20, 207. (b) Caffyn, A. J. M.; Nicholas, K. M. In
Comprehensive Organometallic Chemistry II, Vol. 12; Abel,
E. W.; Stone, F. G. A.; Wilkinson, J., Eds.; Pergamon Press:
Oxford, 1995, Chap. 7.1, 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.
1,3-Diphenylprop-2-ynyl acetate (1a) (0.250 g, 1 mmol),
n-BuOH (0.222 g, 3.0 mmol), MeCN (2 mL), and anhyd
FeCl3 (0.008 g, 0.05 mmol) were successively added to a
5-mL flask, and then the mixture was stirred magnetically at
r.t. for 2.5 h. The solution was concentrated under reduced
pressure by an aspirator and then the residue was purified by
silica gel column chromatography to afford 3-butoxy-1,3-
diphenylprop-1-yne (2a) as a clear colorless oil (0.243 g,
92%).
The 1H NMR and 13C NMR spectra of known compounds
2b, 2d, 2g, 2h, 2i, 2k,6b 2c, 2e, 2f,8a 2j,14 2l,4a 2m, 2o, 2p,6c
and 2q5a are in accordance with those previously reported.
Compound 2a: Pale yellow oil. IR (film): 3063, 3032, 2229,
1597, 1493, 1452 cm–1. 1H NMR (400 MHz, CDCl3):
d = 0.94 (t, 3 H, J = 7.2 Hz), 1.39–1.50 (m, 2 H), 1.62–1.71
(m, 2 H), 3.55–3.62 (m, 1 H), 3.72–3.80 (m, 1 H), 5.39 (s, 1
H), 7.24–7.63 (m, 10 H). 13C NMR (100 MHz, CDCl3):
d = 14.3, 19.8, 32.0, 68.3, 72.0, 87.1, 87.2, 122.3, 127.0,
127.8, 128.0, 128.1, 131.3, 138.5. Anal. Calcd for C19H20O
(264.36): C, 86.32; H, 7.63. Found: C, 86.03; H, 7.42.
Compound 2n: Yellow oil. IR (film): 3387, 1598, 1510,
1452cm–1. 1H NMR (400 MHz, CDCl3): d = 0.92 (t, 3 H,
J = 7.2 Hz), 1.38–1.59 (m, 4 H), 2.27 (td, 2 H, J = 7.2, 2.0
Hz), 4.66–4.76 (br s, 1 H), 4.91 (s, 1 H), 6.72–6.77 (m, 2 H),
7.16–7.25 (m, 3 H), 7.29 (t, 2 H, J = 7.6 Hz), 7.32–7.37 (m,
2 H). 13C NMR (100 MHz, CDCl3): d = 13.7, 18.7, 22.1,
31.1, 42.5, 80.8, 85.0, 115.3, 126.6, 127.8, 128.5, 129.1,
135.0, 142.8, 154.2. Anal. Calcd for C19H20O (264.36): C,
86.32; H, 7.63. Found: C, 86.51; H, 7.35.
(3) Nicholas, K. M.; Mulvaney, M.; Bayer, M. J. Am. Chem.
Soc. 1980, 102, 2508.
(4) (a) Nishibayashi, Y.; Wakiji, I.; Hidai, M. J. Am. Chem. Soc.
2000, 122, 11019. (b) Nishibayashi, Y.; Wakiji, I.; Ishii, Y.;
Uemura, S.; Hidai, M. J. Am. Chem. Soc. 2001, 123, 3393.
(c) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.;
Uemura, S. J. Am. Chem. Soc. 2002, 124, 11846.
(d) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton, M.
D.; Hidai, M.; Uemura, S. Angew. Chem. Int. Ed. 2003, 42,
2681. (e) Milton, M. D.; Inada, Y.; Nishibayashi, Y.;
Uemura, S. Chem. Commun. 2004, 2712. (f) Nishibayashi,
Y.; Milton, M. D.; Inada, Y.; Yoshikawa, M.; Wakiji, I.;
Hidai, M.; Uemura, S. Chem. Eur. J. 2005, 11, 1433.
(g) Nishibayashi, Y.; Inada, Y.; Hidai, M.; Uemura, S. J. Am.
Chem. Soc. 2002, 124, 7900.
(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 an 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.
(b) Inada, Y.; Nishibayashi, Y.; Hidai, M.; Uemura, S. J. Am.
Chem. Soc. 2002, 124, 15172.
(13) In TiCl4-catalyzed nucleophilic substitution of 1-phenyl-
hept-2-ynyl acetate(1b) with phenol the ether was obtained
in moderate yield, see: (a) Mahrwald, R.; Quint, S.
Tetrahedron 2000, 56, 7463. (b) Bartels, A.; Mahrwald, R.;
Quint, S. Tetrahedron Lett. 1999, 40, 5989.
(14) Henseling, K.-O. Chem. Ber. 1977, 110, 1027.
Synlett 2006, No. 14, 2278–2280 © Thieme Stuttgart · New York