Synthesis of secondary propargyl alcohols from aromatic and heteroaromatic aldehydes and acetylene in the system KOH-H2O-DMSO

Article abstract of DOI:10.1134/S107042801303007X

Ethynylation of aromatic and heteroaromatic aldehydes with acetylene under atmospheric pressure in the catalytic system KOH-H₂O-DMSO (aldehyde-KOH molar ratio 1: 2, -5 to -7 C, 3 h) gave secondary propargyl alcohols in 46-67% yield.

Full text of DOI:10.1134/S107042801303007X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 3, pp. 356–359. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © L.N. Sobenina, D.N. Tomilin, O.V. Petrova, A.I. Mikhaleva, B.A. Trofimov, 2013, published in Zhurnal Organicheskoi Khimii,
2013, Vol. 49, No. 3, pp. 369–372.
Dedicated to Full Member of the Russian Academy of Sciences
I.P. Beletskaya on her jubilee
Synthesis of Secondary Propargyl Alcohols
from Aromatic and Heteroaromatic Aldehydes and Acetylene
in the System KOH–H2O–DMSO
L. N. Sobenina, D. N. Tomilin, O. V. Petrova, 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 21, 2012
Abstract—Ethynylation of aromatic and heteroaromatic aldehydes with acetylene under atmospheric pressure
in the catalytic system KOH–H2O–DMSO (aldehyde–KOH molar ratio 1:2, –5 to –7°C, 3 h) gave secondary
propargyl alcohols in 46–67% yield.
DOI: 10.1134/S107042801303007X
Secondary propargyl alcohols are widely used in
both fine- and large-scale organic syntheses, e.g., as
intermediate products in the preparation of biologically
active compounds [1–3]; they are starting compounds
in the synthesis of unsaturated (including acetylenic)
ketones [4–6] and heterocycles [7–12], components of
photographic compositions [13], and cross-linking
agents [14]. Recent developments in enantioselective
syntheses of secondary propargyl alcohols [15–25]
have stimulated increased interest in this class of
acetylenic compounds.
preliminary preparation of metal acetylides from
terminal acetylenes and organometallic compounds
such as Grignard compounds, butyllithium, or metal
amides. These reactions generally include a number of
steps, and the reactants are sensitive to atmospheric
oxygen and moisture.
A few known versions of the reaction of aliphatic
aldehydes with acetylene in the presence of potassium
hydroxide (classical Favorskii reaction) [30–32] can-
not be applied to the preparation of secondary pro-
pargyl alcohols containing aromatic substituents. For
example, the reaction of benzaldehyde with acetylene
under pressure in diethyl ether in the presence of
a small amount of an aliphatic alcohol gave no expect-
Secondary propargyl alcohols are generally syn-
thesized by addition of acetylide ion to aldehyde
carbonyl group [17, 26–29]. This procedure implies
Scheme 1.
OH
O
HC CH
CHO
CH2OH
KOH–H2O–DMSO
OH
+
+
+
CH
Ia
IIa
IIIa
IVa
OH
HC CH
O
KOH–H2O–DMSO
ArCHO
ArCH2OH
+
Ar
Ar
OH
CH
Ib–Id
IIb–IId
IIIb–IIId
IVb–IVd
Ar = furan-2-yl (b, 59%), thiophen-2-yl (c, 46%), 9-methyl-9H-carbazol-3-yl (d, 51%).
356

SYNTHESIS OF SECONDARY PROPARGYL ALCOHOLS
357
Scheme 2.
OH
OH
O
HC CH
KOH–H2O–DMSO
HO–
CH2
PyCHO
Oligomer
Py
Py
·
Py
CH
CH2
Ie–Ig
IIe–IIg
Py = pyridin-2-yl (e), pyridin-3-yl (f), pyridin-4-yl (g).
ed secondary acetylenic alcohol [32], though analo-
gous conditions were effective in reactions with
aliphatic aldehydes.
were formed in trace amounts (no more than 3%
according to the H NMR and GLC data). In all cases,
the main by-product was a mixture of oligomers and
co-oligomers derived from intermediate allenyl alco-
hols, aryl vinyl ketones, and aldehydes (colorless
water-insoluble solid).
1
The use of the superbasic system KOH–DMSO in
base-catalyzed reactions, including ethynylation of
ketones, considerably improves their preparative value
[33, 34]. However, even under these conditions secon-
dary propargyl alcohols were synthesized only from
aliphatic aldehydes, whereas attempts to obtain phe-
nylpropargyl alcohol were unsuccessful [31] because
of its facile prototropic isomerization into the corre-
sponding allenyl alcohol and then into phenyl vinyl
ketone which underwent anionic polymerization.
Analogous isomerization was observed in the reaction
of 1-vinyl-4,5-dihydrobenzo[g]indole-2-carbaldehyde
with phenylacetylene in the system KOH–DMSO [35].
The role of water as important component of the
catalytic system KOH–H2O–DMSO consists of (1) re-
duction of the basicity of the medium, which inhibits
isomerization of secondary propargyl alcohol into the
corresponding allenyl alcohol, and (2) homogenization
of the reaction mixture and hence increase of the
reactant concentration. In addition, the presence of
water in the system KOH–DMSO reduces the reaction
temperature, which inhibits side processes. On the
other hand, increase of the concentration of water to
40% in the reaction of benzaldehyde with acetylene
makes disproportionation of the aldehyde according to
Cannizzaro the major reaction path (ratio IIa–IIIa
We presumed that acetylene–allene isomerization
occurring in the system KOH–DMSO at high rate at
room temperature [36] could be suppressed by reduc-
ing the basicity of the reaction medium. For this
purpose, we tried the ternary system KOH–H2O–
DMSO. In fact, ethynylation of benzaldehyde Ia in
KOH–H2O–DMSO (10 vol % of water with respect to
DMSO) at –5 to –7°C gave 1-phenylprop-2-yn-1-ol
(IIa) in 67% yield, the conversion of benzaldehyde
being complete. These conditions also ensured prepa-
ration of secondary propargyl alcohols from hetero-
aromatic aldehydes Ib–Id (Scheme 1).
1
1:1.6, according to the H NMR data), and the result-
ing benzoic acid neutralizes potassium hydroxide.
Secondary propargyl alcohols IIe–IIg derived from
pyridinecarbaldehydes Ie–Ig are likely to be unstable
under the given conditions, and they undergo proto-
tropic isomerization into the corresponding pyridyl
vinyl ketones, followed by polymerization (Scheme 2).
Facile isomerization of alcohols IIe–IIg is determined
by their higher CH acidity due to stronger acceptor
effect of pyridyl substituent as compared to phenyl.
No expected acetylenic diols were detected. Prob-
able Cannizzaro disproportionation products, primary
alcohols IIIb–IIId and carboxylic acids IVb–IVd,
It is known [37] that acceptor substituents acceler-
ate redox disproportionation of aromatic and hetero-
Scheme 3.
OH
O2N
CH
HC CH
CHO
KOH–H2O–DMSO
O2N
IIh, IIi
O
CH2OH
OH
Ih, Ii
O2N
+ O2N
IIIh, IIIi
IVh, IVi
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

SOBENINA et al.
358
aromatic aldehydes in the presence of aqueous or alco-
holic alkali, where the key step is hydride ion transfer.
Therefore, the Cannizzaro reaction was the major path
of the transformation of m- and p-nitrobenzaldehydes
Ih and Ii; their conversion was fairly low (35–45%),
and even traces of expected secondary propargyl alco-
hols IIh and IIi were not detected (Scheme 3).
reduced pressure. Yield 7.61 g (67%), bp 93–94°C
(4 mm). The spectral parameters of alcohol IIa coin-
cided with those reported in [27].
1-(Furan-2-yl)prop-2-yn-1-ol (IIb) was synthe-
sized in a similar way from 8.26 g (86 mmol) of
furfural. Yield 6.20 g (59%), bp 79–80°C (4 mm). Its
spectral parameters coincided with those given in [38].
Thus, ethynylation of aromatic and heteroaromatic
aldehydes with acetylene under atmospheric pressure
in the system KOH–H2O–DMSO may be regarded as
a new version of the Favorskii reaction, which
provides a simple and safe synthetic route to difficultly
accessible secondary propargyl alcohols of the aromat-
ic and heteroaromatic series. The proposed procedure
requires neither increased acetylene pressure nor the
use of organometallic compounds or alkali metals in
liquid ammonia and flammable or explosive solvents.
Our results are very important for the chemistry of
acetylene, for they demonstrated for the first time
efficient implementation of the Favorskii reaction with
aromatic and heteroaromatic aldehydes in the presence
of alkali metal hydroxide in aqueous–organic medium
and extended the scope of preparative chemistry of
secondary acetylenic alcohols as valuable building
blocks for organic synthesis.
1-(Thiophen-2-yl)prop-2-yn-1-ol (IIc) was syn-
thesized in a similar way from 9.64 g (86 mmol) of
thiophene-2-carbaldehyde. Yield 5.46 g (46%), bp 96–
98°C (4 mm). IR spectrum, ν, cm–1: 3350, 3291, 3107,
2120, 1656, 1435, 1291, 1230, 1018, 935, 919, 853,
840, 757, 707, 652. 1H NMR spectrum, δ, ppm: 2.64 d
(1H, ≡CH, J = 2.2 Hz), 3.07 br.s (1H, OH), 5.59 d (1H,
CHOH, J = 2.0 Hz), 6.94 d.d (1H, 4-H, J = 3.6,
5.0 Hz), 7.14 d.d (1H, 3-H, J = 1.2, 3.6 Hz), 7.26 d.d
(1H, 5-H, J = 1.2, 5.0 Hz). 13C NMR spectrum, δC,
ppm: 143.7, 126.6, 126.0, 125.7, 82.8, 74.3, 59.5.
Found, %: C 60.56; H 4.43; S 23.36. C7H6OS. Cal-
culated, %: C 60.84; H 4.38; S 23.20.
1-(9-Methyl-9H-carbazol-3-yl)prop-2-yn-1-ol
(IId) was synthesized in a similar way from 1.0 g
(4.8 mmol) of 9-methyl-9H-carbazole-3-carbaldehyde
(Id). The residue was subjected to column chromatog-
raphy on silica gel using hexane–diethyl ether (2:1) as
eluent. Yield 0.57 g (51%), light yellow crystals,
mp 92°C. IR spectrum, ν, cm–1: 3368, 3280, 1628,
1601, 1490, 1473, 1329, 1249, 1019, 891, 812, 748,
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
1
730, 628. H NMR spectrum, δ, ppm: 2.27 br.s (1H,
a Bruker DPX-400 spectrometer at 400.13 and
100.6 MHz, respectively, using CDCl3 as solvent and
hexamethyldisiloxane as internal reference. The IR
spectra were measured on a Bruker IFS25 spectrom-
eters from thin films or KBr pellets. Aldehydes Ia–Ii
were commercial products.
OH), 2.73 s (1H, ≡CH), 3.83 s (3H, NMe), 5.65 s (1H,
CHOH), 7.25 m (1H, 6-H), 7.40 m (2H, 1-H, 8-H),
7.48 m (1H, 7-H), 7.66 m (1H, 2-H), 8.10 m (1H, 5-H),
8.27 s (1H, 4-H). 13C NMR spectrum, δC, ppm: 141.3,
140.9, 130.7, 125.8, 124.5, 122.6, 122.5, 120.3, 119.0,
118.7, 108.5, 108.4, 84.1, 74.6, 64.9, 29.0. Found, %:
C 81.42; H 5.54; N 5.99. C16H13NO. Calculated, %:
C 81.68; H 5.57; N 5.95.
1-Phenylprop-2-yn-1-ol (IIa). A mixture of 50 ml
of DMSO, 11.20 g (172 mmol) of KOH, and 5 ml
(10 vol % with respect to DMSO) of water was cooled
to –5 to –7°C, and acetylene was passed therethrough
under stirring over a period of ~20–30 min. A solution
of 9.13 g (86 mmol) of benzaldehyde in 20 ml of
DMSO was then added dropwise over a period of 1.5 h
at that temperature while continuously passing acety-
lene. When the entire amount of benzaldehyde was
added, acetylene was passed through the mixture for
1.5 h more, the mixture was allowed to warm up to
12–14°C and poured into a solution of ammonium
chloride (18.4 g, 344 mmol) in 200 ml of water, and
the products were extracted into diethyl ether (6×
70 ml). The combined extracts were washed with
water (3×80 ml) and dried over MgSO4, the solvent
was removed, and the residue was distilled under
REFERENCES
1. Liu, J.-J., Konzelmann, F., and Luk, K.-Ch., Tetrahedron
Lett., 2003, vol. 44, p. 3901.
2. Raminelli, C., da Silva, N.C., Dos Santos, A.A.,
Porto, A.L.M., Andrade, L.H., and Comasseto, J.V.,
Tetrahedron, 2005, vol. 61, p. 409.
3. Ying, M., Smentek, M.G., Ma, R., Day, C.S., Torti, S.V.,
and Welker, M.E., Lett. Org.Chem., 2009, vol. 6, p. 242.
4. Vaitekunas, A., Miller, R.E., and Nord, F.F., J. Org.
Chem., 1951, vol. 16, p. 1603.
5. Dinerstein, R.J., Sabol, J.S., and Diekema, K.A., US
Patent no. 5223518, 1992; Chem. Abstr., 1992, vol. 117,
no. 150894.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013

SYNTHESIS OF SECONDARY PROPARGYL ALCOHOLS
359
6. Liu, J., Xie, X., and Ma, S., Synthesis, 2012, vol. 44,
22. Qiu, L., Wang, Q., Lin, L., Liu, X., Jiang, X., Zhao, Q.,
p. 1569.
Hu, G., and Wang, R., Chirality, 2009, vol. 21, p. 316.
7. Braun, R.U., Zeitler, K., and Müller, T.J.J., Org. Lett.,
23. Tyrrell, E., Curr. Org. Chem., 2009, vol. 13, p. 1540.
2001, vol. 3, p. 3297.
24. Chen, Y., Lie, F., and Li, Z., Adv. Synth. Catal., 2009,
8. Bagley, M.C., Brace, C., Dale, J.W., Ohnesorge, M.,
Phillips, N.G., Xiong, X., and Bower, J., J. Chem. Soc.
Perkin Trans. 1, 2002, p. 1663.
vol. 351, p. 2107.
25. Watson, D.G., Ritter, S., and Toste, F.D., J. Am. Chem.
Soc., 2009, vol. 131, p. 2056.
9. Milton, M.D., Inada, Y., Nishibayashi, Y., and
26. Joung, M.J., Ahn, J.H., and Yoon, N.M., J. Org. Chem.,
Uemura, S., Chem. Commun., 2004, p. 2712.
1996, vol. 61, p. 4472.
10. Yada, Y., Miyake, Y., and Nishibayashi, Y., Organo-
metallics, 2008, vol. 27, p. 3614.
27. Mortier, J., Vaultier, M., Carreaux, F., and Douin, J.-M.,
J. Org. Chem., 1998, vol. 63, p. 3515.
11. Sathyamoorthy, B., Axelrod, A., Farwell, V., Ben-
nett, S.M., Calitree, B.D., Benedict, J.B., Sukuma-
ran, D.K., and Detty, M.R., Organometallics, 2010,
vol. 29, p. 3431.
28. Nielsen, T.E., Le Quement, S., and Tanner, D.,
Synthesis, 2004, p. 1381.
29. Kazmaier, U., Lucas, S., and Klein, M., J. Org. Chem.,
2006, vol. 71, p. 2429.
30. Favorskaya, I.A., Shevchenko, Z.A., and Koshki-
12. Bagley, M.C. and Glover, C., Molecules, 2010, vol. 15,
p. 3211.
na, I.M., Zh. Org. Khim., 1967, vol. 3, p. 2075.
13. Oguchi, M., Kuwabara, Y., Iwai, I., and Yura, Y., US
Patent no. 3212900, 1965; Chem. Abstr., 1966, vol. 64,
p. 16.
14. Pedersen, U.R. and Ponmekal, D.D., Russian Patent
no. 2171264, 2001; Byull. Izobret., 2001, no. 21.
15. Frantz, D.E., Fassler, R., Tomooka, C.S., and Car-
reira, E.M., Acc. Chem. Res., 2000, vol. 33, p. 373.
16. Frantz, D.E., Fassler, R., and Carreira, E.M., J. Am.
Chem. Soc., 2000, vol. 122, p. 1806.
31. Tarasova, O.A., Trofimov, B.A., Afonin, A.V., Sinegov-
skaya, L.M., Kalinina, N.A., and Amosova, S.V.,
Zh. Org. Khim., 1991, vol. 27, p. 1172.
32. Nazarov, I.N., Kotlyarevskii, I.L., and Ryabchen-
ko, V.F., Zh. Obshch. Khim., 1953, vol. 23, p. 1900.
33. Trofimov, B.A., Sobenina, L.N., Korostova, S.E., Mi-
khaleva, A.I., Shishov, N.I., Fel’dman, V.D., Shev-
chenko, S.G., and Vasil’ev, A.N., Zh. Prikl. Khim., 1987,
vol. 60, p. 1366.
17. Sasaki, H., Boyall, D., and Carreira, E.M., Helv. Chim.
Acta, 2001, vol. 84, p. 964.
18. Nakamura, S., Kusuda, S., Kawamura, K., and Toru, T.,
34. Trofimov, B.A., Mikhaleva, A.I., Vasil’tsov, A.M.,
Nesterenko, R.N., Stankevich, V.K., Belozerov, L.E.,
and Khamataev, V.A., Russian Patent no. 2059597,
1996; Byull. Izobret., 1996, no. 13.
J. Org. Chem., 2002, vol. 67, p. 640.
35. Shmidt, E.Yu., Bidusenko, I.A., Protsuk, N.I., Usha-
kov, I.A., Ivanov, A.V., Mikhaleva, A.I., and Trofi-
mov, B.A., Khim. Geterotsikl. Soedin., 2012, p. 883.
36. Trofimov, B.A., Curr. Org. Chem., 2002, vol. 6, p. 1121.
37. Geissman, T.A., Org. React., 1944, vol. 2, p. 94.
19. Chun, J., Byun, H.-S., and Bittman, R., Tetrahedron
Lett., 2002, vol. 43, p. 8043.
20. Raminelli, C., Comasseto, J.V., Andrade, L.H., and
Porto, A.L.M., Tetrahedron: Asymmetry, 2004, vol. 15,
p. 3117.
38. Singh, V. and Singh, V., Synth. Commun., 2010, vol. 40,
21. Ariza, X., Garcia, J., Georges, Y., and Vicente, M., Org.
Lett., 2006, vol. 8, p. 4501.
p. 1280.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 49 No. 3 2013