Reaction of Grignard compounds with 4-chloro-2-methyl-3-butyn-2-ol in Diethyl Ether equivalents

Article abstract of DOI:10.1023/A:1012348627878

Reactions of RMgX · THF complexes with 4-chloro-2-methyl-3-butyn-2-ol in aromatic hydrocarbons were studied. The complexes formed by arylmagnesium halides require the presence of anisole for the reaction to occur. 4-Chloro-2-methyl-3-butyn-2-ol can be synthesized by reaction of 2-methyl-3-butyn-2-ol with sodium hypochloride in the two-phase system water-benzene.

Full text of DOI:10.1023/A:1012348627878

Russian Journal of Organic Chemistry, Vol. 37, No. 1, 2001, pp. 5 8. Translated from Zhurnal Organicheskoi Khimii, Vol. 37, No. 1, 2001,
pp. 17 20.
Original Russian Text Copyright
2001 by Shchelkunov, Sivolobova, Mataeva, Minbaev, Muldakhmetov.
Reaction of Grignard Compounds with 4-Chloro-2-methyl-
3-butyn-2-ol in Diethyl Ether Equivalents
S. A. Shchelkunov, O. A. Sivolobova, S. O. Mataeva,
D. B. Minbaev, and Z. M. Muldakhmetov
Institute of Organic Synthesis and Coal Chemistry, Ministry of Science and Academy of Sciences
of Kazakhstan, ul. 40 let Kazakhstana 1, Karaganda, 470061 Kazakhstan
Received February 1, 1999
Abstract Reactions of RMgX THF complexes with 4-chloro-2-methyl-3-butyn-2-ol in aromatic hydro-
carbons were studied. The complexes formed by arylmagnesium halides require the presence of anisole for
the reaction to occur. 4-Chloro-2-methyl-3-butyn-2-ol can be synthesized by reaction of 2-methyl-3-butyn-2-ol
with sodium hypochloride in the two-phase system water benzene.
Reactions of Grignard compounds with 4-chloro-
2-methyl-3-butyn-2-ol provide a convenient method
for preparation of tertiary acetylenic alcohols which
are used in the synthesis of monosubstituted ace-
tylenes [1], herbicide stabilizers [2], and antitumor
compounds [3]. However, from the viewpoint of
safety, the use of diethyl ether as solvent [4] involves
some difficulties due to risk of fire and explosion.
Therefore, we examined the possibility for replacing
diethyl ether by more safe solvents. Specifically, the
reactions of alkylmagnesium halides with 4-chloro-2-
methyl-3-butyn-2-ol were carried out in benzene con-
taining an equimolar (with respect to the Grignard
compound) amount of tetrahydrofuran (THF).
As a rule, the reaction followed pathway a shown
in Scheme 1, but in some cases the resulting mixture
of target acetylenic alcohols and Wurtz condensation
products was subjected to alkaline fission to isolate
monosubstituted acetylenes (pathway b in Scheme 1).
Scheme 1.
In keeping with published data, negative factors are
the heterogeneity of the process and the possibility
for alkylation of the aromatic solvent with alkyl halide
activated by the liberated Lewis acid (Scheme 2) [5].
Scheme 2.
Our experiments showed that, regardless of the
structure of the Grignard compound, no benzene
alkylation occurred. Presumably, originally weak
acceptor properties of MgBr2 are weakened even more
strongly by solvation in THF.
The formation of Grignard compounds and replace-
ment of chlorine in 4-chloro-2-methyl-3-butyn-2-ol
were considerably hindered since the reaction mixture
was heterogeneous (by contrast to the reaction in
diethyl ether). It is known that, as the length of the
carbon chain in the initial bromide increases, the
I, Alk = i-Pr; II, Alk = i-Bu; III, Alk = Bu; IV, Alk = iso-
C5H11; V, Alk = C5H11; VI, Alk = C6H11; VII, Alk = C6H13;
VIII, Alk = C7H15; IX, Alk = C8H17; X, Alk = C9H19;
XI, Alk = C10H21; XII, Alk = C12H25.
1070-4280/01/3701-0005$25.00 2001 MAIK Nauka/Interperiodica

6
SHCHELKUNOV et al.
Reactions of 4-chloro-2-methyl-3-butyn-2-ol with Grignard
compounds
structure of the Grignard compound becomes less
significant: alkyl derivatives with both normal and
iso structure react with equal efficiency. The yields of
the target products are 55 72%. However, we failed
to obtain the corresponding alcohol from tert-butyl-
magnesium chloride. This fact gives one more
evidence in favor of the commonly accepted concerted
reaction mechanism involving formation of a four-
membered transition state [6].
The Wurtz reaction was the main process in the
reactions of 4-chloro-2-methyl-3-butyn-2-ol with aryl-
magnesium halides, which were carried out in hydro-
carbons containing THF. Obviously, the reason is that
the process is heterogeneous. In the reaction with
phenylmagnesium bromide the yield of the corre-
sponding acetylenic alcohol was 18% in benzene and
35% in toluene (according to the GLC data). When
these reactions were performed in the presence of
anisole and equimolar amount of THF (with respect
to ArMgBr), the mixture became homogeneous, and
the yield of the target products attained 60 67%
(Scheme 3).
AlkX
Mg/AlkX
Method
Yield, %
iso-C3H7Br
iso-C4H9Br
C4H9Br
C4H9Br
C4H9Cl
iso-C5H11Br
C5H11Br
C5H11Br
cyclo-C6H11Br
C6H13Br
C6H11Br
C7H15Br
C8H17Br
C8H17Br
C9H19Br
C10H21Br
C12H25Br
1.5
1.1
1.1
2
1.1
1.1
1.1
2
1.1
1.1
2
1.1
1.1
1.1
1.1
1.1
1.1
A
A
B
B
A
A
B
B
B
B
B
B
A
B
B
B
B
60.3
55.7
45.7
64.3
71.4
72.0
55.2
63.2
47.2a
55.4
70.2
58.0a
40.1a
57.5a
73.5
52.3a
56.0a
Scheme 3.
a
Yield of terminal alkyne obtained by alkaline fission of the
primary product, acetylenic alcohol.
Barbier Grignard procedure in diethyl ether gives
much better results than the two-step Grignard process
[4]. A different and more complex pattern is observed
in a hydrocarbon medium: increase in the length of
the alkyl radical, on the one hand, favors the Wurtz
reactions and, on the other, increases the solubility
of magnesium halide alkoxide, thus reducing the
contribution of side processes.
The contribution of the Wurtz reaction can be
minimized by slow addition of alkyl bromide, and
application of the two-step procedure is justified only
for short radicals (up to C6), since the Barbier
Grignard method does not favor formation of organo-
magnesium compound because of the low solubility
of magnesium halide alkoxide. This obstacle can be
circumvented by using twofold excess of magnesium:
the results become comparable with those obtained by
the two-step procedure.
XIV, Ar = C6H5; XV, Ar = o-CH3C6H4; XVI, Ar = m-CH3-
C6H4; XVII, Ar = p-CH3C6H4; XVIII, Ar = o-CH3OC6H4.
The structure of products I III and V XVIII was
proved by comparing their properties with published
data [1, 4, 7, 8]. The IR spectra of compounds I V,
VII, X, and XIII XVIII contained absorption bands
1
typical of C C bond (2220 2230 cm ) and OH
1
group (3350 3400 cm ). Compounds XIV XVIII
also showed in the IR spectra a band at 1600 cm 1 due
to aromatic ring vibrations. The terminal acetylenic
bond in VI, VIII, XI, and XII gives rise to character-
istic absorption bands at 2100 2110 (C C) and
In going to longer hydrocarbon radicals (beginning
with C7), there is no need of applying excess magne-
sium, the second factor (solubilization of magnesium
halide alkoxide; see above) becomes predominating,
and the Barbier Grignard procedure is preferrable (see
table). Unlike diethyl ether, the process in benzene
allows higher temperature to be applied, and the
1
3300 cm ( C H).
Protons of the isopropyl group in I give a doublet
at 1.00 ppm and a septet at 2.63 ppm (J = 6 Hz)
1
in the H NMR spectrum; the methyl group protons
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 1 2001

REACTION OF GRIGNARD COMPOUNDS WITH 4-CHLORO-2-METHYL-3-BUTYN-2-OL
7
appear as a singlet at 1.50 ppm, and the singlet at
4.31 ppm belongs to the hydroxy proton. In the
1H NMR spectrum of XVI we observed signals from
4.0 g (0.166 mol) of metallic magnesium, 1.5 ml of
THF, and 30 ml of benzene. When a reaction started,
5.5 ml (5.9 g, 0.05 mol) of 4-chloro-2-methyl-3-
butyn-2-ol, 16.9 ml (20.40 g, 0.135 mol) of pentyl
bromide, and 11 ml of THF in 60 ml of benzene were
simultaneously added dropwise at 50 65 C over
a period of 3 h. The mixture was heated for 4 h at that
temperature and decomposed with 3% hydrochloric
acid on cooling. The organic phase was separated
and dried over magnesium sulfate, and volatile com-
pounds were distilled off. Vacuum distillation of
the residue at 93 95 C (12 mm) gave 4.25 g (55.2%)
of 2-methyl-3-nonyn-2-ol, n2D0 1.4465; published data
[4]: bp 94 96 C (10 mm), n2D2 1.4489.
aromatic protons at
6.95 7.20 ppm and hydroxy
group at 4.53 ppm. Protons of the methyl groups
attached to the carbinol moiety appear at 1.59 ppm,
and the aromatic methyl group protons give a singlet
at 2.38 ppm. According to the GLC data, the purity
of XVI was 94.3% after single distillation.
EXPERIMENTAL
The IR spectra were obtained from thin films or
1
KBr discs using a UR-20 spectrometer. The H NMR
spectra were recorded on a Tesla BS-587A instrument
operating at 80 MHz; cyclohexane-d12 was used as
solvent, and TMS, as internal reference. GLC was
performed on a Khrom-5 chromatograph; flame-
ionization detector; 3.5-m glass column; stationary
phase 3% of SP2100 on Chromaton N-AW-DMCS;
carrier gas helium.
Initial 4-chloro-2-methyl-3-butyn-2-ol was syn-
thesized by treatment of 2-methyl-3-butyn-2-ol with
sodium hypochlorite at room temperature. Unlike the
procedure reported in [9] which employs diethyl ether,
we used benzene as solvent. As a result, the process
was simplified, and the target product was isolated
in 90% yield.
2,5-Dimethyl-3-hexyn-2-ol (I). 4-Chloro-2-methyl-
3-butyn-2-ol, 5.9 g (0.05 mol), was added dropwise
with stirring to the Grignard compound obtained from
7.2 g (0.23 mol) of metallic magnesium and 18.5 g
(0.15 mol) of isopropyl bromide in benzene containing
10.8 g (0.15 mol) of THF. The mixture was heated
for 5 h at 60 C and decomposed with 3% hydro-
chloric acid on cooling. The organic phase was dried
over magnesium sulfate and evaporated, and the
residue was distilled at 145 147 C to isolate 3.8 g
(60.3%) of 2,5-dimethyl-3-hexyn-2-ol, n2D0 1.4425;
Compounds III, VII, and X were synthesized in
a similar way. Products III, V, and VII were also
obtained by the same procedure but with a twofold
excess of magnesium. The yields are given in table.
2-Methyl-4-(3-tolyl)-3-butyn-2-ol
(XVI).
3-Bromotoluene, 1.8 ml (2.56 g, 0.015 mol), was
added to a mixture of 4 g (0.16 mol) of metallic
magnesium, 30 ml of anisole, and 1.2 ml of THF.
When a reaction started, 5.5 ml (5.9 g, 0.05 mol) of
4-chloro-2-methyl3-butyn-2-ol, 15.9 ml (23.1 g,
0.135 mol) of 3-bromotoluene, and 11 ml of THF in
40 ml of anisole were simultaneously added in
a dropwise manner at 40 45 C over a period of 3 h.
The mixture was heated for 4 h at that temperature
and decomposed with 3% hydrochloric acid on
cooling. The organic phase was separated and dried
over magnesium sulfate, and volatile fractions were
distilled off. Vacuum distillation of the residue at
105 108 C (3 mm) gave 5.5 g (63.2%) of 2-methyl-4-
(3-tolyl)-3-butyn-2-ol, n2D0 1.5498; published data [4]:
bp 92 93.5 C (1.5 mm), n1D6.5 1.5485.
Compounds XIV, XV, XVII, and XVIII were
synthesized by a similar procedure and with similar
yields. In the reaction of phenylmagnesium bromide
with 4-chloro-2-methyl-3-butyn-2-ol in toluene we
isolated a fraction containing 41.8% (GLC) of the
corresponding arylacetylenic alcohol and 58.2% of
biphenyl (overall yield 83.8%, calculated on the
expected 2-methyl-4-phenyl-3-butyn-2-ol).
1-Decyne (IX). Octyl bromide, 5.2 ml (5.80 g,
0.03 mol), was added to a mixture of 6.0 g (0.25 mol)
of metallic magnesium, 60 ml of benzene, and 1.5 ml
of THF. When a reaction started, 8.3 ml (8.9 g,
0.075 mol) of 4-chloro-2-methyl-3-butyn-2-ol, 34.4 ml
(38.60 g, 0.20 mol) of octyl bromide, and 16 ml of
THF in 80 ml of benzene were simultaneously added
dropwise at 50 65 C over a period of 3 h. The mix-
ture was heated for 4 h at that temperature and was
published data [4]: bp 48 50 (12 mm) n2D0 1.4411.
Compounds II IV were synthesized in a similar way;
their yields are given in table.
2,7-Dimethyl-3-octyn-2-ol (IV). bp 71 73 C
(4 mm), n2D0 1.4460, d240 0.8451. Found, %: C 77.84;
H 11.72. C10H18O. Calculated, %: C 77.92; H 11.69.
Reaction of tert-butylmagnesium chloride with
4-chloro-2-methyl-3-butyn-2-ol. The reaction was
carried out as described above for isopropyl bromide.
As a result, 1.9 g (33.3%) of the initial alcohol was
recovered from the reaction mixture.
2-Methyl-3-nonyn-2-ol (V). Pentyl bromide,
3.8 ml (2.25 g, 0.015 mol), was added to a mixture of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 1 2001

8
SHCHELKUNOV et al.
decomposed with 3% hydrochloric acid on cooling.
The organic phase was separated and dried over
magnesium sulfate, and volatile fractions boiling up to
83 C (3 mm) were distilled off. Potassium hydroxide,
1.0 g, was added to the residue, 18.35 g, and the
mixture was heated at a bath temperature of 160
200 C. A fraction distilled in the temperature range
from 56 to 180 C was dried over magnesium sulfate
and distilled again. Yield of 1-decyne 5.95 g (57.5%),
bp 165 166 C, n2D0 1.4376; published data [8]:
REFERENCES
1. Vasil’eva, R.L., Ashirbekova, A.K., Belyakova, V.A.,
Alimova, N.A., and Shchelkunov, A.V., Available
from VINITI, 1987, no. 1192 77.
2. Jeasure, I.K. and Josephs, M.I., Weeds, 1961, vol. 9,
p. 103.
3. US Patent 3028438, 1962; Ref. Zh., Khim., 1964,
no. 1N337P.
4. Vasil’eva, R.L., Ashirbekova, A.K., and Shchelku-
nov, A.V., Available from VINITI, 1975, no. 295 75.
bp 162 165 C, n2D0 1.4320.
Compounds VI, VIII, XI, and XII were obtained
in a similar way. 1-Decyne (IX) was also synthesized
by the two-step procedure (see above). The yields of
the products are given in table.
5. Bryce-Smith, D. and Owen, W., J. Chem. Soc., 1960,
p. 3319.
6. Pal’m, V.A., Vvedenie v teoreticheskuyu organiche-
skuyu khimiyu (Introduction to Theoretical Organic
Chemistry), Moscow: Vysshaya Shkola, 1974, p. 316.
4-Chloro-2-methyl-3-butyn-2-ol (XIII). Sodium
hydroxide, 440 g, was dissolved in 1250 ml of water,
the solution was cooled to room temperature, and
gaseous chlorine prepared from 316 g KMnO4 and
1600 ml of hydrochloric acid was passed through the
solution. A solution of 97.5 ml (84.1 g, 1.0 mol) of
4-chloro-2-methyl-3-butyn-2-ol in 200 ml of benzene
was added at 25 35 C, the mixture was stirred for
1 h, and the organic phase was separated, dried over
magnesium sulfate, and distilled. Yield 107.2 g
(90.5%), bp 134 136 C, n2D0 1.4554; published data
7. Yasnopol’skii, V.D., Fiziko-khimicheskie konstanty
organicheskikh soedinenii s atsetilenovoi svyaz’yu
(Physicochemical Constants of Organic Compounds
Containinf an Acetylenic Bond), Baku: Akad. Nauk
Azerb. SSR, 1966., pp. 18 27.
8. Shchelkunov, A.V. and Ivanova, N.N., Fiziko-khimi-
cheskie konstanty atsetilenovykh soedinenii (Physico-
chemical Constants of Acetylenic Compounds), Alma-
Ata: Nauka Kazakh. SSR, 1988, pp. 128 163.
9. US Patent 298568, 1961; Ref. Zh., Khim., 1962,
[9]: bp 70 C (50 mm), n2D0 1.4571.
no. 13L 47P.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 37 No. 1 2001