K3PO4-KOH mixture as efficient reagent for the deprotection of 4-aryl-2-methyl-3-butyn-2-ols to terminal acetylenes

Article abstract of DOI:10.1080/00397911.2012.744841

A mixture of potassium hydroxide and potassium phosphate was found to be an active reagent mixture for the cleavage of 2-hydroxypropyl-protected acetylenes. The reaction was performed in toluene at reflux temperature and gave terminal acetylenes in good to excellent yields within very short periods of time. Numerous other functional groups are tolerated. Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for full experimental and spectral details.

Full text of DOI:10.1080/00397911.2012.744841

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K3PO4-KOH Mixture as Efficient Reagent
for the Deprotection of 4-Aryl-2-
methyl-3-butyn-2-ols to Terminal
Acetylenes
Alexey Smeyanov a & Andreas Schmidt a
a Clausthal University of Technology, Institute of Organic Chemistry ,
Clausthal-Zellerfeld , Germany
Published online: 08 Jul 2013.
To cite this article: Alexey Smeyanov & Andreas Schmidt (2013) K3PO4-KOH Mixture as Efficient
Reagent for the Deprotection of 4-Aryl-2-methyl-3-butyn-2-ols to Terminal Acetylenes, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:20, 2809-2816, DOI: 10.1080/00397911.2012.744841
To link to this article: http://dx.doi.org/10.1080/00397911.2012.744841
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Synthetic Communications1, 43: 2809–2816, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.744841
K3PO4–KOH MIXTURE AS EFFICIENT REAGENT FOR
THE DEPROTECTION OF 4-ARYL-2-METHYL-
3-BUTYN-2-OLS TO TERMINAL ACETYLENES
Alexey Smeyanov and Andreas Schmidt
Clausthal University of Technology, Institute of Organic Chemistry,
Clausthal-Zellerfeld, Germany
GRAPHICAL ABSTRACT
Abstract A mixture of potassium hydroxide and potassium phosphate was found to be an
active reagent mixture for the cleavage of 2-hydroxypropyl-protected acetylenes. The
reaction was performed in toluene at reflux temperature and gave terminal acetylenes in
good to excellent yields within very short periods of time. Numerous other functional groups
are tolerated.
Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for full experimental and spectral details.
Keywords Acetylenes; deprotection; synthesis
INTRODUCTION
Terminal arylacetylenes are key building blocks for the construction of a
variety of organic compounds including natural products,[1] materials for organic
light-emitting diodes (OLEDs),[2] and organic photovoltaic cells (OPVCs).[3] They
are also interesting starting materials for the synthesis of pharmacologically active
heterocycles.[4]
The palladium-catalyzed Sonogashira–Hagihara cross-coupling of aryl halides
with mono-protected acetylenes followed by removal of the protecting group is an
important synthetic approach to terminal acetylenes and their derivatives. The most
commonly used mono-protected acetylenes are trimethylsilylacetylenes (TMSA),
triisopropylsilylacetylenes (TIPSA), and 2-methyl-3-butyn-2-ols (MEBYNOL). An
Received October 15, 2012.
Address correspondence to Andreas Schmidt, Clausthal University of Technology, Institute of
Organic Chemistry, Leibnizstrasse 6, D-38678 Clausthal-Zellerfeld, Germany. E-mail: schmidt@
ioc.tu-clausthal.de
2809

2810
A. SMEYANOV AND A. SCHMIDT
advantage of the trialkylsilylacetylenes is simple deprotection by treatment with
bases or fluoride at ambient temperature.[5] A disadvantage of TMSA and TIPSA,
however, is the higher price in comparison to 2-methyl-3-butyn-2-ol. MEBYNOLs
usually undergo smooth coupling reactions with aromatic systems in excellent
yields,[6] and the purification of the reaction products is very simple and efficient
because of the considerably different polarities of starting materials and products.[1,7]
Nevertheless, the removal of the 2-hydroxyisopropyl group of the protected acety-
lenes requires harsh conditions. Usually, strong bases (KOH, NaOH, NaH, etc.)
in combination with high temperatures (such as reflux temperature in n-BuOH[8])
and long reactions times (up to 5 h, vide infra) are applied. These factors often lead
to undesired side reactions and decreased yields of the products.
In continuation of our interest in cross-coupling reactions catalyzed by
N-heterocyclic carbene complexed transition metals,[9] heterocyclic synthesis,[10]
and metal-organic frameworks,[11] we required a variety of terminal acetylenes and
therefore tried to improve known deprotection procedures. Here we describe a very
efficient and simple method for the deprotection of 4-aryl-2-methyl-3-butyn-2-ols to
terminal acetylenes. The desired products are obtained in good to excellent yields,
most of them within a few minutes.
DISCUSSION
4-Aryl-2-methyl-3-butyn-2-ols were prepared by Sonogashira–Hagihara cross-
coupling from aryl=heteroaryl halides, MEBYNOL, and a Pd(PPh3)2Cl2–CuI
mixture as catalyst as described before.[1,6,7] The reaction was monitored by thin-
layer chromatography (TLC; Scheme 1).
We choose methyl 4-(3-hydroxy-3-methylbut-1-yn-1-yl)benzoate as the model
compound for screening different bases for the deprotection (Scheme 2). Potassium
phosphate[6d] and potassium carbonate[7a] proved to be totally ineffective (Table 1,
entries 1 and 2). Sodium hydride,[12a] sodium hydroxide, potassium hydroxide, pot-
assium tert-butanolate,[7d] and a tetrabutylammonium bromide (NaOH=TBAB)[7e]
mixture in refluxing toluene, respectively, gave only moderate yields (45–55%) due
to the formation of unidentified by-products under these conditions (Table 1, entries
3–7). We then found that a mixture of KOH and K3PO4 gave 4-(3-hydroxy-3-
Scheme 1. General procedure for Sonogashira–Hagihara couplings to obtain 4-aryl-2-methyl-3-butyn-2-ols.
Scheme 2. Deprotection to furnish a terminal acetylene.

DEPROTECTION TO TERMINAL ACETYLENES
2811
Scheme 3. Simple deprotectionleading to terminal acetylenes.
methylbut-1-yn-1-yl)benzoate in quantitative yields after 5 min, when 1 equiv of the
starting material, 1 equiv of KOH, and 1 equiv of K3PO4 were heated in toluene at
reflux temperature (Table 1, entry 8).
We then tested scope and limitations of this method. As shown in Table 2,
deprotection by a KOH=K3PO4 mixture in toluene can be applied to a broad range
of protected arylacetylenes. With one exception (vide infra) all reactions were
completed within 5–15 min (TLC control) and required no column chromatography
for purification.
As shown, the deprotection is very effective for substrates possessing electron-
withdrawing (Table 2, entries 1, 5–8, 11, 12) as well as electron-donating groups
attached to the aromatic ring (Table 2, entries 4, 13–15, 17, 18). Methyl esters
(entries 1, 5–8), ethyl esters (entries 11, 12, 15), benzyl esters (entry 6), MOM protect-
ing groups (entries 13, 14), carbamates (entry 15), 1,3-dioxane groups (entry 17), and
TIPS (entry 16) and tert-butyldiphenylsilyl (TBDPS) protecting groups (entry 18)
remain intact under these conditions and give terminal acetylenes in good to
quantitative yields.
It is worth mentioning that for 4-aryl-2-methyl-3-butyn-2-ols containing more
than one butynol moiety (entries 9 and 12), deprotection of both groups was
accomplished within 5–10 min and in good yield. We also compared the method
described here with known procedures. As presented in Table 2, the KOH=K3PO4
mixture gives better yields in all cases tested. With one exception (vide infra), the
reaction timeswere shortened from 1 h,[13c] 2 h,[13a] 4 h, and[12d] 5 h[13d] to 5–15 min.
All products were isolated after filtration and evaporation of the solvent in vacuo
without application of column chromatography as reported.[1a,8,12,13]
Only for the case of methyl 4-(3-hydroxy-3-methylbut-1-yn-1-yl)thiophene-2-
carboxylate did the reaction require 120 min (TLC control) to give methyl
4-ethynylthiophene-2-carboxylate in 78% yield (entry 7). As a comparison, we
Table 1. Deprotection of methyl 4-(3-hydroxy-3-methylbut-1-yn-1-yl)
benzoate in the presence of different bases
Entry
Base
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
K3PO4
K2CO3
12
12
1
0
0
NaH
NaOH
55
45
49
45
50
>99
2
KOH
KOtBu
4
3
NaOH=TBAB
KOH=K3PO4
12
<0.1
aYields refer to isolated products characterized by spectroscopic
data (1H and 13C NMR, MS, and IR analyses).

2812
A. SMEYANOV AND A. SCHMIDT
Table 2. Preparation of terminal acetylenes by removal of the
2-hydroxypropyl group
Entry
1
Product
Yield (%)
100 (69)[12a]
2
3
4
93
96 (87)[12d]
100 (95)[13a]
5
6
80 (65)[13b]
91
7
8
78
81
(Continued )

DEPROTECTION TO TERMINAL ACETYLENES
2813
Table 2. Continued
Entry
Product
Yield (%)
9
100
10
84 (75)[13c]
11
70
12
76
13
14
87
96
89
15
16
93 (80)[13d]
(Continued )

2814
A. SMEYANOV AND A. SCHMIDT
Table 2. Continued
Entry
17
Product
Yield (%)
86
18
100
performed the deprotection with KOH without K3PO4 in toluene at reflux tempera-
ture, which resulted in the formation of the target compound in only 26% yield.
In summary, we present an efficient and fast method for the synthesis of
terminal acetylenes by the deprotection of 4-aryl-2-methyl-3-butyn-2-ols. This
method shows good tolerance to a wide range of other functional and protecting
groups present in the substrate.
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded on Bruker Avance 400 (400-MHz)
and Avance III (600-MHz) spectrometers and were taken in dimethylsulfoxide
(DMSO-d6) or CDCl3 at 400 MHz and 600 MHz, respectively. The chemical shifts
are reported in parts per million (ppm) relative to internal tetramethylsilane
(d ¼ 0.00 ppm). Multiplicities are described by using the following abbreviations:
s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, sep ¼ septet, m ¼ multiplet, and
br ¼ broad. Peak assignments were accomplished by results of heteronuclear multiple
bond correlation (HMBC), HSQC NMR, and nuclear Overhauser effect spec-
troscopy (HH-NOESY) measurements. Fourier transform–infrared (FT-IR) spectra
were obtained on a Bruker Vektor 22 in the range of 400 to 4000 cmꢀ1 (2.5% pellets in
KBr). The gas chromatography–mass spectrometry (GC-MS) spectra (EI) were
recorded either on a Varian 320 GC-MS or on a Varian GC3900 with SAT2100 T
mass spectrometer. The electrospray ionization (ESI) mass spectra were measured
with an Agilent LCMSD Series HP1100 with APIES. Samples were sprayed from
methanol at 0-V fragmentor voltage unless otherwise noted. The high-resolution
(HR)-MS were measured on a Bruker Daltonik Tesla-FT-ion cyclotron resonance
mass spectrometer with ESI. Yields are not optimized.
General Procedure for Sonogashira–Hagihara Coupling
The reactions were carried under nitrogen atmosphere. The aryl=heteroaryl
bromide, Pd2(PPh3)2Cl2 (1 mol%), and CuI (1 mol%) were suspended in dry Et3N
(20 mL) with stirring. Then 2-methyl-3-butyn-2-ol (1.1 eq.) was added dropwise at
ambient temperature. The resulting solutions were then stirred at reflux temperature
until complete conversion, as monitored by TLC. Then the mixtures were allowed to
cool to room temperature, treated with dichloromethane (50 mL), and filtered

DEPROTECTION TO TERMINAL ACETYLENES
2815
through celite. The organic phases were then dried over MgSO4 and filtered, and the
solvents were removed in vacuo. The resulting residues were finally purified by col-
umn chromatography (EtOAc–petroleum ether) to afford the products.
Methyl 4-(3-Hydroxy-3-methylbut-1-yn-1-yl)benzoate (2a)
A sample of 30 mmol (6.45 g) of methyl 4-bromobenzoate 1a gave 29.2 mmol
1
(6.36 g, 97%) of 2a as light yellow solid: mp 84–85 ꢁC (lit.[12a] 83.5–84 ꢁC); H NMR
(400 MHz, CDCl3): d ¼ 7.97 (ddd, J ¼ 1.5, J ¼ 2.0, J ¼ 8.2 Hz, 2H; 2-H), 7.46 (ddd,
J ¼ 1.5, J ¼ 2.1, J ¼ 8.2 Hz, 2H; 3-H), 3.91 (s, 3H; Me), 2.29 (s, 1H; CH), 1.63 (s,
6H; Me) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 166.6, 131.6, 129.5, 129.4, 127.5,
96.8, 81.4, 65.6, 52.3, 31.4 ppm. IR (ATR, cmꢀ1) 3432, 2993, 2983, 2950, 1711,
1602, 1434, 1404, 1273, 1174, 1166, 1106, 1097, 959, 906, 857, 836; MS (GC-MS)
[C13H14O3] 218.2 (calc. 218.1); HRMS (ESI) [C13H14O3] 219.1018 (calc. 219.1021).
General Procedure for the Deprotection Reaction
The reactions were carried under a nitrogen atmosphere. A flask was charged
with the protected acetylenes (1 mmol), KOH (1 mmol), K3PO4 (1 mmol), and anhy-
drous toluene (40 mL). Then the flask was immersed into a preheated oil bath. The
suspensions were stirred vigorously at reflux temperature until complete conversion,
as monitored by TLC. The mixtures were then allowed to cool to rt and filtered
through a plug of celite, which was washed several times with toluene. After evapor-
ation of the organic phase to dryness the desired products were obtained.
Methyl 4-Ethynylbenzoate (3a)
A sample of 1 mmol (218 mg) of methyl 4-(3-hydroxy-3-methylbut-1-yn-
1-yl)benzoate (2a) gave 1 mmol (159 mg, 100%) of the yellowish product 3a: mp
[12a]
1
93–94 ꢁC (lit.
91–93 ꢁC). H NMR (400 MHz, CDCl3): d ¼ 7.99 (ddd, J ¼ 1.5=
1.8=8.5 Hz, 2H; 3-H), 7.55 (ddd, J ¼ 1.5=1.8=8.2 Hz, 2H; 2-H), 3.92 (s, 3H; Me),
3.23 (s, 1H; ꢂCH) ppm. 13C NMR (100 MHz, CDCl3): d ¼ 166.5, 132.1, 130.1,
129.5, 126.8, 82.8, 80.1, 52.3 ppm. IR (ATR, cmꢀ1) 3242, 1701, 1434, 1310, 1277,
1192, 1174, 1108, 1017, 958, 859, 771, 719, 677, 528, 460. MS (GS-MS) [C10H8O2]
160.0 (calc. 160.0); HRMS (ESI) [C10H8O2 þ Naþ] 183.0429 (calc. 183.0422).
SUPPORTING INFORMATION
Full experimental details can be found via the ‘‘Supplementary Content’’
section of this article’s webpage.
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