Improved synthesis of tertiary propargyl alcohols by the Favorskii reaction of alkyl aryl (hetaryl) ketones with acetylene

Article abstract of DOI:10.1134/S1070428013010028

Alkyl aryl (hetaryl) ketones react with acetylene under atmospheric pressure in the superbasic system KOH-EtOH-H₂O-DMSO at 10-15 C (2 h) to give the corresponding tertiary propargyl alcohols in up to 91% yield. The procedure requires no large excess of KOH and low-boiling inflammable solvents, produces few wastes, and is safe and convenient on the laboratory scale; there are no limitations for its large-scale application.

Full text of DOI:10.1134/S1070428013010028

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 1, pp. 8–11. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © E.Yu. Shmidt, I.A. Bidusenko, N.I. Protsuk, A.I. Mikhaleva, B.A. Trofimov, 2013, published in Zhurnal Organicheskoi Khimii, 2013,
Vol. 49, No. 1, pp. 18–21.
Dedicated to Full Member of the Russian Academy of Sciences
G.A. Tolstikov on his 80th anniversary
Improved Synthesis of Tertiary Propargyl Alcohols
by the Favorskii Reaction of Alkyl Aryl (Hetaryl) Ketones
with Acetylene
E. Yu. Shmidt, I. A. Bidusenko, N. I. Protsuk, A. I. Mikhaleva, and B. A. Trofimov
Favorskii Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: boris_trofimov@irioch.irk.ru
Received November 23, 2012
Abstract—Alkyl aryl (hetaryl) ketones react with acetylene under atmospheric pressure in the superbasic
system KOH–EtOH–H2O–DMSO at 10–15°C (2 h) to give the corresponding tertiary propargyl alcohols in up
to 91% yield. The procedure requires no large excess of KOH and low-boiling inflammable solvents, produces
few wastes, and is safe and convenient on the laboratory scale; there are no limitations for its large-scale
application.
DOI: 10.1134/S1070428013010028
Propargyl alcohols are widely used in fine and
large-scale organic synthesis as starting compounds for
the preparation of acetylenic ethers [1, 2], unsaturated
ketones [3, 4], and heterocycles [5, 6]. They are also
used in the synthesis of isoprenoids (including large-
scale manufacture of isoprene) [7], carotenoids [8],
vitamins A and E [9], fragrant compositions [10],
acaricides, herbicides, corrosion inhibitors, non-ionic
surfactants (surfynols) [8, 11], and substituted indenes
[12, 13].
ethylenediamine complex [21] were used as ethynylat-
ing agents.
Blumental [22] described the synthesis of tertiary
propargyl alcohol from acetophenone and acetylene in
the presence of powdered potassium hydroxide with
a rigorously defined grain size (100 mesh) in DMSO
or ethylenediamine (yield 39 and 57%, respectively).
When the reaction was carried out in DMSO, the
product was not isolated as individual substance but as
a mixture of propargyl alcohol and the corresponding
diol (20%). Poor yield of the target product, low
selectivity, and the necessity of using rigorously
defined grain size fraction of KOH and highly toxic
ethylenediamine as solvent did not allow wide applica-
tion of this procedure in preparative practice.
Up to now, the most efficient is the procedure for
the synthesis of tertiary propargyl alcohols (~90%
yield) from alkyl aryl ketones and acetylene according
to the Nazarov version of the Favorskii reaction [23].
The reactions were carried out under an acetylene
pressure of 8–10 atm in anhydrous diethyl ether at 15–
20°C in the presence of KOH (4–6 equiv with respect
to the initial ketone) with addition of ethanol (1 vol %
with respect to the solvent). The reactions were slow
(5–6 h), the conversion of the initial ketone was not
always complete, and the selectivity was not suffi-
The synthesis of propargyl alcohols from acetylene
and ketones of the aliphatic and cycloaliphatic series
according to the Favorskii reaction [14] generally in-
volves no experimental difficulties and ensures almost
quantitative yields, whereas more readily enolizable
alkyl aryl (hetaryl) ketones difficultly react with acety-
lene under analogous conditions, and the yields of their
ethynylation products are usually poor [15]. In order to
enhance the reaction efficiency, it is necessary to
increase pressure, which reduces the safety of the proc-
ess and requires considerably complicated equipment.
In some cases, more complex versions of the Favorskii
reaction were applied. For instance, Iotsitch complexes
[16], alkali metal acetylides in liquid ammonia [17],
tetrahydrofuran [18], or diethyl ether [19], sodium
ethynyl(trimethyl)aluminate [20], or lithium acetylide–
8

IMPROVED SYNTHESIS OF TERTIARY PROPARGYL ALCOHOLS
9
ciently high (up to 5% of the corresponding acetylenic
diol was formed). Furthermore, the necessity of con-
tinuous supply of acetylene and ketone under pressure
and the use of flammable solvent and large excess of
alkali hamper laboratory application of this procedure
and considerably complicate its large-scale implemen-
tation.
concentration of ethanol (as compared to [23]). These
conditions give rise to an equilibrium homogeneous
catalytic system including potassium cations and hy-
droxide, ethoxide, and acetylenide anions (Scheme 2).
Owing to complete dissolution of potassium hy-
droxide in the reaction medium, not only the concen-
tration of base in solution but also its nature change:
the activity of anions, including acetylide ions, sharply
increases due to their weak solvation in DMSO (super-
basic effect [24]). The reactivity of undissociated
potassium hydroxide molecules also increases as a re-
sult of loosening of KOH ion pairs (according to quan-
tum-chemical calculations, the K–O bond becomes
longer [25]).
While performing systematic studies on ethynyla-
tion of alkyl aryl (hetaryl) ketones with acetylene in
superbasic medium we found conditions that allowed
us to radically improve the efficiency of synthesis of
tertiary propargyl alcohols.
Ketones Ia–Ig readily reacted with acetylene under
atmospheric pressure in the superbasic catalytic system
KOH–EtOH–H2O–DMSO at 10–15°C over a period of
2 h to give propargyl alcohols IIa–IIg in 64–91% yield
(Scheme 1). The reaction was highly selective, and
only in a few cases traces of acetylenic diols were de-
tected in the crude products by 1H NMR spectroscopy.
The Favorskii reaction is generally carried out
using a large excess of powdered KOH in an anhy-
drous solvent. Initially, the corresponding acetylenic
alcoholate is formed, for the liberated water is bound
with alkali in the solid phase; i.e., the reaction is non-
catalytic.
Scheme 1.
If only 1 equiv of KOH and 0.5 equiv of water and
ethanol are used per equivalent of ketone I (see above),
alcoholate A is converted into propargyl alcohol II by
the action of water and ethanol (Scheme 3), and the
reactions becomes catalytic.
R2
O
KOH–EtOH–H2O–DMSO
R1
HO
+
HC CH
R1
R2
CH
Ia–Ig
IIa–IIg
R1 = Ph, R2 = Me (a); R1 = Ph, R2 = Pr (b); R1 = 3-MeO-
C6H4, R2 = Me (c); R1 = naphthalen-2-yl, R2 = Me (d); R1 =
pyridin-4-yl, R2 = Me (e); R1 = furan-2-yl, R2 = Me (f); R1 =
thiophen-2-yl, R2 = Me (g).
Scheme 3.
R2
KOH (excess)
R1
RO
+
+
H2O·KOH
I
HC CH
CH
The optimal molar ratio of the components (I–
A
KOH–EtOH–H2O) determined from the results of
a number of experiments was 1:1:0.5:0.5, and the op-
timal concentration of ketones I in DMSO was 2–3 M.
Commercial DMSO containing 0.1–0.5% of water was
used without preliminary purification. A homogeneous
reaction mixture was saturated with acetylene, and the
concentration of the latter was maintained constant
throughout the process by continuously bubbling it
through the solution (flow setup).
H2O–EtOH
A
II
+
KOH + KOEt
This is confirmed by the fact that ethynylation of
ketone Ia with acetylene in the presence of 0.5 equiv
of KOH takes 4.5 h and gives propargyl alcohol IIa in
78% yield (isolated product), the conversion of Ia
being 84%. Furthermore, superbasic medium accel-
erates prototropic processes such as enolization, so that
nucleophilic addition of acetylide ion to the carbonyl
Obviously, the efficiency of the proposed procedure
is determined by enhanced catalytic activity of the
superbasic system and change of physicochemical
parameters of the medium due to the use of potassium
hydroxide hemihydrate (KOH·0.5H2O) and increased
Scheme 4.
R1
HC
HC CH
R3
R1
O–
R3
R3
HO–
Scheme 2.
O
R1
R1
R3
+
+
+
HC CH
EtOH
OH–
OH–
HC C–
H2O
H2O
O
O–
EtO–
+
R = H, Alk.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

SHMIDT et al.
10
group (ethynylation) should not be limited by the
reversible enolization (Scheme 4).
7.22 m (1H, 4′-H), 7.28 m (2H, 3′-H, 5′-H), 7.58 m
(2H, 2′-H, 6′-H). 13C NMR spectrum (CDCl3), δC,
ppm: 32.8 (C1), 69.5 (C2), 72.7 (C4), 86.7 (C3), 124.3
(C2′, C6′), 127.3 (C4′), 124.3 (C3′, C5′), 144.3 (C1′).
Found, %: C 81.93; H 6.56. C10H10O. Calculated, %:
C 82.16; H 6.89.
Significant preparative advantages of the proposed
procedure are experimental simplicity (atmospheric
pressure), replacement of diethyl ether by fire- and
explosion-safe dimethyl sulfoxide, and considerable
reduction of the amount of KOH. Therefore, the proce-
dure is promising for use not only in research labora-
tory but also for enlarged syntheses, and tertiary
propargyl alcohols containing aryl and hetaryl sub-
stituents become really accessible from alkyl aryl
(hetaryl) ketones and acetylene.
3-Phenylhex-1-yn-3-ol (IIb). Yield 18.20 g (68%),
yellow oily substance. IR spectrum, ν, cm–1: 3410,
3303, 3062, 2961, 2873, 2113, 1954, 1888, 1812,
1680, 1600, 1489, 1449, 1379, 1317, 1203, 1139, 1110,
1030, 948, 609, 169, 700, 657, 584. 1H NMR spectrum
(CDCl3), δ, ppm: 0.84–0.88 m (3H, CH3), 1.28–1.52 m
(2H, 5-H), 1.79–1.95 m (2H, 4-H), 2.53 s (1H, OH),
2.64 s (1H, 1-H), 7.26–7.25 m (1H, 4′-H), 7.32–7.30 m
(2H, 3′-H, 5′-H), 7.59–7.58 m (2H, 2′-H, 6′-H).
13C NMR spectrum (CDCl3), δC, ppm: 13.9 (C6), 17.9
(C5), 47.4 (C4), 73.2 (C3), 74.0 (C1), 86.4 (C2), 125.4
(C2′, C6′), 127.7 (C4′), 128.1 (C3′, C5′), 144.2 (C1′).
Found, %: C 82.53; H 8.14. C12H14O. Calculated, %:
C 82.72; H 8.10.
EXPERIMENTAL
The IR spectra were recorded on a Bruker Vertex
70 spectrometer from samples prepared as films or
1
KBr pellets. The H and 13C NMR spectra were
recorded on a Bruker DPX 400 instrument (400.13 and
100.61 MHz, respectively) at room temperature using
hexamethyldisiloxane as internal standard (δ 0.05 ppm).
The elemental compositions were determined on
a Flash EA 1112 analyzer. The melting points were
measured on a Kofler hot stage.
2-(3-Methoxyphenyl)but-3-yn-2-ol (IIc). Yield
24.36 g (90%), yellow oily substance. IR spectrum, ν,
cm–1: 3419, 3290, 2987, 2936, 2837, 2113, 1675, 1600,
1486, 1452, 1363, 1289, 1152, 1078, 1043, 936, 879,
1
817, 786, 702, 651, 546. H NMR spectrum (CDCl3),
Tertiary propargyl alcohols IIa–IIg (general
procedure). A 100-ml round-bottom flask equipped
with a magnetic stirrer and a gas-inlet tube was
charged with a mixture of 10.0 g (0.15 mol) of KOH·
0.5H2O and 5 ml (0.09 mol) of ethanol in 50 ml of
DMSO. The mixture was heated to 110°C under
stirring over a period of 30 min until it turned homo-
geneous. The mixture was then cooled to 15°C and
saturated with acetylene by passing it therethrough
over a period of 30 min. A solution of 0.15 mol of
ketone Ia–Ig in 10 ml of DMSO was added dropwise
over a period of 1 h while continuously bubbling
acetylene, and the mixture was stirred for 1 h under
a stream of acetylene. The mixture was then diluted
with a cold (7–10°C) solution of 16.5 g of ammonium
chloride in 100 ml of water and extracted with diethyl
ether (3×20 ml), the extracts were washed with water
(3×10 ml), dried over MgSO4, and evaporated, and the
crude product was purified by column chromatography
on neutral alumina using hexane as eluent.
δ, ppm: 1.65 s (3H, CH3), 2.21 s (1H, 4-H), 2.61 s (1H,
OH), 3.31 s (3H, OCH3), 6.66–6.64 m (1H, 4′-H),
7.04–7.02 m (1H, 6′-H), 7.25–7.23 m (1H, 2′-H), 7.32–
7.31 m (1H, 5′-H). 13C NMR spectrum (CDCl3), δC,
ppm: 33.4 (C1), 54.7 (OCH3), 69.6 (C2), 72.7 (C4), 87.8
(C3), 111.1 (C2′), 113.2 (C4′), 117.6 (C6′), 129.3 (C5′),
147.5 (C1′), 160.0 (C3′). Found, %: C 74.69; H 6.70.
C11H12O2. Calculated, %: C 74.98; H 6.86.
2-(Naphthalen-2-yl)but-3-yn-2-ol (IId). Yield
26.22 g (87%), yellow oily substance. IR spectrum, ν,
cm–1: 3537, 3394, 3293, 3057, 2986, 2930, 2113, 1923,
1670, 1629, 1600, 1570, 1445, 1368, 1272, 1220,
1187, 1128, 1080, 1051, 953, 934, 860, 820, 749, 669,
1
566, 478. H NMR spectrum (CDCl3), δ ppm: 1.69 s
(3H, CH3), 2.22 s (1H, 4-H), 2.48 s (1H, OH), 7.19–
7.17 m (2H, 6′-H, 7′-H), 7.55–7.54 m (1H, 3′-H), 7.60–
7.57 m (2H, 5′-H, 8′-H), 7.66–7.64 m (1H, 4′-H),
8.10 s (1H, 1′-H). 13C NMR spectrum (CDCl3), δC,
ppm: 33.4 (C1), 69.1 (C2), 73.2 (C4), 87.9 (C3), 133.6–
123.9 (9C, Carom), 143.2 (C2′). Found, %: C 85.60;
H 6.19. C14H12O. Calculated, %: C 85.68; H 6.16.
2-Phenylbut-3-yn-2-ol (IIa). Yield 20.52 g (91%),
colorless crystals, mp 43–47°C; published data [23]:
mp 49°C. IR spectrum, ν, cm–1: 3288, 2983, 2929,
1489, 1448, 1366, 1225, 1151, 1091, 1054, 933, 766,
2-(Pyridin-4-yl)but-3-yn-2-ol (IIe). Yield 18.08 g
(80%), colorless crystals, mp 181–182°C. IR spectrum,
ν, cm–1: 3232, 3086, 2976, 2924, 2821, 2112, 1695,
1605, 1479, 1434, 1368, 1229, 1163, 1084, 1007, 942,
1
701, 660, 586. H NMR spectrum (CDCl3), δ, ppm:
1.70 s (3H, CH3), 2.58 s (1H, 4-H), 2.74 s (1H, OH),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 1 2013

IMPROVED SYNTHESIS OF TERTIARY PROPARGYL ALCOHOLS
11
821, 709, 615, 587. 1H NMR spectrum (acetone-d6), δ,
3. Egi, M., Yamaguchi, Y., Fujiwara, N., and Akai, S., Org.
Lett., 2008, vol. 10, p. 1867.
4. Ye, L. and Zhang, L., Org. Lett., 2009, vol. 11, p. 3646.
5. Zhang, X., Teo, W.T., Sally, and Chan, P.W.H., J. Org.
Chem., 2010, vol. 75, p. 6290.
6. Jo, K.A., Maheswara, M., Yoon, E., Lee, Y.Y., Yun, H.,
and Kang, E.J., J. Org. Chem., 2012, vol. 77, p. 2924.
7. Tedeschi, R.J., Encyclopedia of Physical Science and
Technology, San Diego: Academic, 1992, vol. 1, p. 27.
8. Tedeschi, R.J., Acetylene-Based Chemicals from Coal
and Other Natural Resources, New York: Marcel
Dekker, 1982.
ppm: 1.69 s (3H, CH3), 3.14 s (1H, 4-H), 5.45 s (1H,
3
OH), 7.57 d (2H, 3′-H, 5′-H, J = 5.6 Hz), 8.54 d
3
(2H, 2′-H, 6′-H, J = 5.6 Hz). 13C NMR spectrum
(acetone-d6), δC, ppm: 33.3 (C1), 67.7 (C2), 75.4 (C4),
88.0 (C3), 120.5 (C3′, C5′), 150.1 (C2′, C6′), 155.4 (C4′).
Found, %: C 73.91; H 5.61; N 9.61. C9H9NO. Cal-
culated, %: C 73.45; H 6.16; N 9.52.
2-(Furan-2-yl)but-3-yn-2-ol (IIf). Yield 13.38 g
(64%), yellow oily substance. IR spectrum, ν, cm–1:
3541, 3402, 3295, 3125, 2994, 2938, 1571, 1502,
1468, 1396, 1362, 1292, 1243, 1227, 1160, 1099,
9. Mercer, C. and Chabardes, P., Pure Appl. Chem., 1994,
1
1011, 928, 884, 849, 816, 742, 656, 598. H NMR
vol. 66, p. 1509.
spectrum (CDCl3), δ, ppm: 1.80 m (3H, CH3), 2.58 s
(1H, 4-H), 3.54 s (1H, OH), 6.28–6.27 m (1H, 4′-H),
6.37–6.35 m (1H, 3′-H), 7.34–7.33 m (1H, 5′-H).
13C NMR spectrum (CDCl3), δC, ppm: 28.8 (C1), 64.7
(C2), 72.3 (C4), 85.5 (C3), 106.0 (C3′), 110.5 (C4′),
142.5 (C5′), 156.0 (C2′). Found, %: C 70.45; H 5.81.
C8H8O2. Calculated, %: C 70.57; H 5.92.
10. Nowicki, J., Molecules, 2000, vol. 5, p. 1033.
11. Trofimov, B.A., Curr. Org. Chem., 2002, p. 1121.
12. Shchukin, A.O. and Vasil’ev, A.V., Russ. J. Org. Chem.,
2007, vol. 43, p. 784.
13. Shchukin, A.O., Vasil’ev, A.V., and Grinenko, E.V.,
Russ. J. Org. Chem., 2010, vol. 46, p. 82.
14. Favorskii, A.E. and Skosarevskii, M.P., Zh. Russ. Khim.
Ob–va., 1900, vol. 32, p. 652.
15. Kotlyarevskii, I.L., Shvartsberg, M.S., and Fisher, L.B.,
Reaktsii atsetilenovykh soedinenii (Reactions of Acety-
lenic Compounds), Novosibirsk: Nauka, 1967, p. 5.
2-(Thiophen-2-yl)but-3-yn-2-ol (IIg). Yield
17.53 g (75%), yellow oily substance. IR spectrum, ν,
cm–1: 3400, 3292, 2987, 2932, 1652, 1517, 1414, 1366,
1281, 1236, 1136, 1086, 1073, 1020, 972, 861, 841,
1
16. Iotsich, Zh.I., Zh. Russ. Khim. Ob–va., 1902, vol. 34,
705, 659. H NMR spectrum (C6D6), δ, ppm: 1.86 m
p. 100.
(3H, CH3), 2.27 s (1H, 4-H), 2.33 s (1H, OH), 6.76–
6.75 m (1H, 3′-H), 6.96–6.95 m (1H, 4′-H), 7.15–
7.14 m (1H, 5′-H). 13C NMR spectrum (C6D6), δC,
ppm: 33.2 (C1), 67.1 (C2), 72.6 (C4), 86.7 (C3), 124.2
(C3′), 125.2 (C4′), 126.7 (C5′), 150.0 (C2′). Found, %:
C 63.38; H 5.22; S 20.94. C8H8OS. Calculated, %:
C 63.13; H 5.30; S 21.07.
17. Gmitter, G.T. and Benton, F.L., J. Am. Chem. Soc., 1950,
vol. 72, p. 4586.
18. Midland, M.M., J. Org. Chem., 1975, vol. 40, p. 2250.
19. Guillarme, S., Ple, K., Banchet, A., Liard, A., and
Haudrechy, A., Chem. Rev., 2006, vol. 106, p. 2355.
20. Joung, M.J., Ahn, J.H., and Yoon, N.M., J. Org. Chem.,
1996, vol. 61, p. 4472.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 11-03-00270).
21. Beumel, O.F., Harris, F., Jr., and Harris, R.F., J. Org.
Chem., 1963, vol. 28, p. 2775.
22. Blumental, J.H., US Patent no. 2996552, 1958; Chem.
Abstr., 1962, vol. 56, p. 52804.
REFERENCES
23. Nazarov, N.I. and Ryabchenko, V.F., Izv. Akad. Nauk
SSSR, Otd. Khim. Nauk, 1956, p. 1370.
1. Ammal, S.Ch., Yoshikai, N., Inada, Y., Nishibayashi, Y.,
and Nakamura, E., J. Am. Chem. Soc., 2005, vol. 127,
p. 9428.
24. Trofimov, B.A. and Gusarova, N.K., Usp. Khim., 2007,
vol. 76, p. 550.
25. Larionova, E.Yu., Vitkovskaya, N.M., Kobychev, V.B.,
and Trofimov, B.A., Zh. Strukt. Khim., 2010, vol. 51,
p. 451.
2. Yoshimatsu, M., Otani, T., Matsuda, S., Yamamoto, T.,
and Sawa, A., Org. Lett., 2008, vol. 10, p. 4251.
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