Practical synthesis of functionalized terminal alkynes, 3,3,3-triethoxypropyne and ketal protected prop-2-ynones

Article abstract of DOI:10.1080/00397911.2017.1376334

Practical and economical synthesis of synthetically valuable 3,3,3-triethoxypropyne, ketal protected phenyl and methyl substituents prop-2-ynones is described. Bromination and subsequent 18-crown-6 catalyzed elimination of triethylorthoacrylate and ketal

Full text of DOI:10.1080/00397911.2017.1376334

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Practical Synthesis of Functionalized Terminal
Alkynes, 3,3,3-Triethoxypropyne and Ketal
Protected Prop-2-ynones
Abdullah Karanfil & Mustafa Eskici
To cite this article: Abdullah Karanfil & Mustafa Eskici (2017): Practical Synthesis of
Functionalized Terminal Alkynes, 3,3,3-Triethoxypropyne and Ketal Protected Prop-2-ynones,
Synthetic Communications, DOI: 10.1080/00397911.2017.1376334
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1376334
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Date: 16 September 2017, At: 06:03

Practical synthesis of functionalized terminal alkynes, 3,3,3-
triethoxypropyne and ketal protected prop-2-ynones
Abdullah Karanfil
Department of Chemistry, Faculty of Arts and Science, Ordu University, Ordu, Turkey
Mustafa Eskici*
Department of Chemistry, Faculty of Arts and Science, Manisa Celal Bayar University, Manisa,
Turkey
*Address correspondence to Mustafa Eskici, Department of Chemistry, Faculty of Arts and
Science, Manisa Celal Bayar University, Manisa 45140, Turkey. Tele: +90 236 2013163. Fax:
+90 236 2013040. E-mail: mustafa.eskici@cbu.edu.tr
ABSTRACT
Practical and economical synthesis of synthetically valuable 3,3,3-triethoxypropyne, ketal
protected phenyl and methyl substituent prop-2-ynones is described. Bromination and subsequent
18-Crown-6 catalyzed elimination of triethylorthoacrylate and ketal protected terminal alkenes
with methyl and phenyl substituent which are inturn readily available from
triethylorthopropionate, 3-chlorobutan-2-one and propiophenone afforded multigram quantities
(>10 grams) of corresponding functionalized terminal alkynes. Exploration of the synthetic utility
of these alkynes is also demonstrated by the acetylenic substitution of the phenylalaninol derived
1,2-cyclic sulfamidate to deliver chiral alkynylated amines.
1

GRAPHICAL ABSTRACT
KEYWORDS: 1,2-cyclic sulfamidates, ketal, orthoester, terminal alkynes
Introduction
During the course of our ongoing investigations focused on the reactivity profile of cyclic
sulfamidates towards acetylides, economical and practical synthesis of functionalized terminal
alkynes, 3,3,3-triethoxypropyne, ketal protected phenyl and methyl substituent prop-2-ynones on
multigram quantities was required in order to scan the scope of the chemistry.[1] Cyclic
sulfamidates[2] 1 readily undergo nucleophilic displacement with acetylides 2 to form N-sulfate
intermediates 3 which could be hydrolyzed under acidic conditions to give alkynylated amines 4
in high yields (Scheme 1).
Introduction of the masked carbonyl functionality to the acetylide unit could enable
synthesis of highly functionalized amines that provides a sound platform to develop further
chemistry. Installation of the carbonyl group (or protected form) into alkynylated amine products
called for the use of alkyl propiolates (or protected propiolates) and protected ynones as acetylide
partners in the substitution reactions. Generation of the propiolate anion directly from
methylpropiolate was found to be problematic. This failure may be attributable to the instability
of the propiolate anion in solution through the inclination of the acetylenic moiety and alkyl
2

carboxylate group to react with each other.[3] Our attention subsequently moved to known
triethylorthopropiolate as a synthetically more stable propiolate anion precursor.
A brief survey of literature on the synthesis of triethylorthopropiolate revealed that this
compound can be prepared by a number of ways. Stetter’s synthesis from triethyl orthopropionate
using bromination and elimination reactions is not efficient due to low yielding
dehydrobromination in the last step.[4a] Another synthesis by Boche involves use of expensive
trimethylsilyl acetylene as starting material and reagents.[5a] Stetter’s low yielding step was
improved by Gassman using powdered KOH in the presence of 18-crown-6 ether as catalyst, but
adequate experimental details were not reported in the letter.[6] Adaptation of this procedure for
economical and practical multi gram synthesis of 3,3,3-triethoxypropyne in our hands led to
several practically useful observations to be reported in this communication.[7] The synthesis and
use of the ketal protected ynones with phenyl[8] and methyl[9,10] substituents have been reported in
several papers. Most of the synthetic procedures rely on the direct protection of the expensive
ynones with methyl and phenyl substituents. In these cases, side reactions hamper the efficiency
of the protection with ethylene glycol resulting in only moderate yields.[8] As a result we needed a
reliable, economical and practical synthesis of these valuable functionalized terminal alkynes on
multigram scale. In this communication multigram synthesis of triethylorthopropiolate, ketal
protected methyl and phenyl substituent alkynes from cheap starting materials
triethylorthopropionate, 3-chlorobutan-2-one and propiophenone respectively is reported.
Exploration of synthetic utility of these functionalized terminal alkynes is also demonstrated by
the acetylenic substitution of phenylalaninol derived 1,2-cyclic sulfamidates to deliver chiral
alkynylated amines.
Results Discussion
3

Synthesis of functionalized terminal alkynes
Triethylorthopropionate 5 was brominated with bromine in pyridine according to Stetter’s
procedure[4a] to yield mono brominated compound 6 which upon treatment with powdered KOH
in DMSO eliminated to furnish triethylorthoacrylate 7 (Scheme 2). These first bromination and
elimination reactions proceed efficiently on large scale without problem. The second bromination
in DCM produced dibromo compound 8. As the dibromide 8 was prone to decomposition on heat
and chromatographic purification on silica (monitoring of the reaction was performed on alumina
TLC), the compound was directly subject to the second elimination reaction. Slight less than
stoichiometric amount of bromine (0.9 equivalent) was sufficient to carry out efficient
bromination. Crude dibromide 8 was eliminated with powdered KOH in heptane in the presence
of the crown ether catalyst to give multigram quantities of synthetically valuable 3,3,3-
triethoxypropyne 9. In addition to the use of bromine and powdered KOH, 4-
(dimethylamino)pyridine tribromide as brominating agent and t-BuOK and LiHMDS as base were
investigated to obtain high yield of 9 without any practical improvements. The use of bromine (0.9
equiv.) in DCM in the bromination step and powdered KOH in heptane in the presence of 18-
crown-6 catalyst in the elimination step is the most practical and efficient combination to produce
3,3,3-triethoxypropyne 9 as clear oil of high purity in 61% yield over two steps. By this way we
prepared 3,3,3-triethoxypropyne 9 several times in multigram quantities (30 g).
Propiophenone 10 was brominated according to the literature procedure[11] to obtain give
α-bromo ketone 11 before protection by the treatment of ethylene glycol with PTSA catalyst. It is
worth noting that since the α-bromo ketone 11 was a highly irritant for skin and eyes, caution
should be taken strictly for multigram synthesis. Elimination reaction of 12 with powdered KOH
in DMSO afforded alkene 13. Similarly, application of the use of bromine (0.9 equiv.) in the
4

bromination step and powdered KOH in heptane in the presence of 18-crown-6 catalyst in the
elimination step on the dibromide 14 allowed the synthesis of 2-ethynyl-2-phenyl-1,3-dioxolane
15 as clear oil of high purity in 70% yield over two steps.
3-Chlorobutan-2-one 16 was protected as ketal derivative on the treatment with ethylene
glycol under acidic condition to obtain the known chloro ketal 17 (Scheme 4).[12] Elimination of
17 on exposure to powdered KOH furnished 18. Bromination of the double bond was achieved
with bromine to yield the dibromide compound 19. Performing second elimination in heptane lead
to difficulties in purification of 2-ethynyl-2-methyl-1,3-dioxolane 20 during distillation. Nonpolar
solvent with higher boiling point was necessary in order to make separation by distillation
efficiently. Thus, the second elimination was conducted in n-dodecane (b.p. 214–218C) with
powdered KOH in the presence of 18-crown-6 catalyst to deliver 2-ethynyl-2-methyl-1,3-
dioxolane 20 as clear oil of high purity in 60% yield over two steps.
Synthetic utility of functionalized terminal alkynes
Exploration of the synthetic utility of the synthesized terminal alkynes was also
demonstrated by the acetylenic substitution of phenylalaninol derived 1,2-cyclic sulfamidates 21
(Scheme 5). Functionalized terminal alkynes 9, 15 and 20 was lithiated with the action of n-
butyllithium in THF at –10C. Nucleophilic cleavage of the 1,2- cyclic sulfamidate 21 with the
resulting acetylides 22 and 25 produced N- sulfate 23 and 26 intermediates. Acidic hydrolysis of
23 was performed with the use of 5M HCl condition which is generally considered to be the
standard condition to liberate the nitrogen atom. During hydrolysis the orthoester group was
hydrolyzed concurrently to afford functionalized alkynylated amino ethylester 24 in high yield.[13]
Two equivalent of the acetylide component 22 was required for the complete consumption of 21.
5

Similarly, acetylenic displacement reactions of 21 with ketal protected acetylides 25 also produced
the corresponding N- sulfate 26 intermediates. Due to the instability of the ketal group to 5M HCl
conditions, acidic hydrolysis of 26 was performed with H2SO4 in these cases to be able to obtain
ketal protected alkynylated amines 27 in good yields. Synthetic utility of the alkynylated amino
ethyl ester 24 for asymmetric synthesis of piperidones was already reported.[13] Evaluation of the
functionalized ketal protected alkynylated amines 27 for synthesis of N-heterocycles will be
reported elsewhere.
Conclusion
In summary practical and economical synthesis of 3,3,3-triethoxypropyne 9, ketal
protected prop-2-ynones with phenyl 15 and methyl 20 substituents from cheap starting materials
on multigram quantities is reported. Synthetic utility of these alkynes is also illustrated by the
acetylenic substitution of phenylalaninol derived 1,2-cyclic sulfamidate 21 to deliver chiral
alkynylated amines.
Experimental
1H and 13C NMR spectra were recorded in CDCl3 on a Varian AS 400 MHz NMR
spectrometer with TMS as an internal. Chemical shifts are expressed in δ (parts per million) units
downfield from TMS. Coupling constants (J) are quoted to the nearest 0.5 Hz. IR spectra were
recorded on a Perkin Elmer Spectrum BX spectrometer as thin films on NaCl plates. Mass Spectra
were taken from TUBITAK Marmara Research Centre (MAM), Gebze, Istanbul, and DAYTAM,
Ataturk University, Erzurum, Turkey. Optical rotations were measured with Rudolph Research
Analytical Autopol I Automatic Polarimeter. THF and ether were freshly distilled from LiAlH4
before use. TLC was performed using aluminium plates coated with silica gel (254 nm) and use of
6

the basic permanganate dying system. Flash column chromatography was carried out using silica
gel (0.063–0.2 mm). Removal of solvents in vacuo was achieved using an IKA rotary evaporator
at room temperature unless otherwise stated. Yields refer to isolated material, homogeneous by
TLC and NMR spectroscopy, unless otherwise stated.
Synthesis of 3,3,3-triethoxypropyne 9
2-Bromo-1,1,1-triethoxypropane 6[4a]
To a solution of triethylorthopropionate 5 110 g (0.625 mol) in 50 mL pyridine cooled over
ice-bath was added bromine (32 mL, 102 g, 0.64 mol) dropwise. The resulting reaction mixture
was stirred over the bath for 3 hours. Pyridinium bromide salts began to form as the reaction
progressed. The reaction mixture was diluted with hexane and filtered through Celite®.
Evaporation of the solvents in vacuo gave the crude product. Purification by distillation afforded
2-bromo-1,1,1-triethoxypropane 6 (127.54 g, 80% yield ) as a pale yellow oil; b.p 87C/15 mmHg,
(Lit.[4a], 74–75C/10 mmHg). The compound was directly subjected to elimination step without
characterization.
3,3,3-triethoxyprop-1-ene 7[4a]
A mixture of monobromoorthoester 6 ( 120.6 g, 0.40 mol) and KOH (111.6 g, 1.98 mol)
in 350 mL DMSO was heated gradually to 120°C for 3 hours with stirring. The reaction mixture
was cooled to room temperature and diluted with water to dissolve insoluble material. Extraction
of the resulting solution was performed with Et2O (3  250 mL). Combined organics was dried
over Na2CO3, filtered and evaporated in vacuo to give crude the acrylate product. Purification by
distillation furnished 3,3,3-triethoxyprop-1-ene 7 (54.4 g, 78% yield ) as a clear oil; b.p 54–
7

55°C/15 mmHg, (Lit.[4a], 78–79C/36 mmHg);1H NMR H (400 MHz, CDCl3) (ppm): 1.15 (9H, t,
J=7.2), 3.44 (6H, q, J=7.2), 5.37 (1H, dd, J=2.8 and 10), 5.54 (1H, dd, J=2.8 and 17.2), 5.62 (1H,
dd, J=10 and 17.2).
3,3,3-triethoxypropyne 9[4a]
To a solution of the acrylate (50.1 g, 288 mmol) in 300 mL DCM cooled at –10°C with
ice-salt bath was added a solution of bromine (41.1 g, 258 mmol) in 100 mL DCM dropwise over
1 hour. The resulting pale yellow solution was stirred at this temperature for additional 30 minutes.
Evaporation of volatiles in vacuo produced the crude dibromide compound 8. Since this compound
was prone to decomposition, the crude product was directly subjected to elimination step without
purification or characterization.
To a mixture of powdered KOH (40.5 g, 720 mmol) and 18-crown-6 (800 mg) in 300 mL
heptane was carefully added a solution of the crude dibromide in 75 mL heptane at room
temperature. The resulting reaction mixture began to warm up. It is essential at this point that the
mixture be heated gradually in a controlled manner to the refluxing temperature in order to avoid
uncontrolled heating up (rapid heating may lead to uncontrolled reactions and extensive
decomposition which reduces the reaction yield significantly). The pale yellow mixture was heated
to reflux for 6 hours. The reaction mixture was cooled to room temperature and diluted with 300
mL hexane and 300 mL water to dissolve insoluble material. The organic phase was separated,
washed with brine, dried over Na2CO3, filtered and evaporated in vacuo to give crude
triethylorthopropiolate. Purification by fractional distillation afforded 3,3,3-triethoxypropyne 9 (
30.3 g, 61% over two steps) as a clear oil; b.p 67–68 °C/15 mmHg, (Lit.[4a], 83°C/32 mmHg); IR
8

1
(film) max/cm 3266, 2118, 658 (HC≡C-);1H NMR (400 MHz, CDCl3) H (ppm): 1.24 (9 H, t,
J=7.2), 2.55 (1H, s), 3.7 (6H, q, J=7.2).
Synthesis of 2-ethynyl-2-phenyl-1,3-dioxolane 15
2-bromo-1-phenylpropan-1-one 11[11]
To a solution of propiophenone 10 (64 g, 0.48 mol) in 240 mL acetic acid cooled over ice
bath was added bromine (82.2 g, 0.51 mol) dropwise. The resulting reaction mixture was stirred
at this temperature for 1 h and then allowed to warm up to room temperature with stirring for
additional hour. The reaction mixture was neutralized saturated NaHCO3 solution. Extraction was
carried out with DCM (2  250 mL). Combined organics was dried over Na2SO4 and evaporated
in vacuo to give the crude bromoketone. Purification by distillation afforded 2-bromo-1-
phenylpropan-1-one 11 (93.66 g, 94%) as a clear oil; b.p 112°C/15 mmHg, (Lit.[11]
,
1
135–144°C/19 mmHg); TLC Rf:0.42 [hexane]; H NMR (400 MHz, CDCl3) H (ppm):
1.90 (3H, d, J=6.4), 5.29 (1H, q, J=6.4), 7.46-7.51 (2H, m, Ar-H), 7.56–7.61 (1H, m, Ar-H), 8.01-
8.04 (2H, m, Ar-H). Note that the α-bromo ketone 11 was a highly irritant for skin and eyes, caution
should be taken strictly.
2-(1-bromoethyl)-2-phenyl-1,3-dioxolane 12[11]
A mixture of bromoketone 11 ( 50.15, 235 mmol), ethylene glycol (80.5 g, 1.34 mol) and
p-toluene sulphonic acid (2.15 g, 11 mmol) in 350 mL toluene was stirred under refluxing with
Dean Stark apparatus over night during which period the water produced was distilled off as the
toluene azeotrope. Reaction solvent was removed in vacuo and the residue was dissolved in 250
mL DCM. The solution was then washed with saturated NaHCO3, brine, dried over Na2SO4,
9

evaporated in vacuo to give the crude 2-(1-bromoethyl)-2-phenyl-1,3-dioxolane 12 (53.2 g, 88%).
1
This compound was used as obtained for the next elimination step. TLC Rf:0.40 [hexane]; H
NMR (400 MHz, CDCl3) (ppm) 1.59 (3H, d, J=6.8), 3.82–3.91 (2H,m), 4.13–4.20 (2H,m), 4.38
(1H, q, J=6.8), 7.32–7.38 (3H, m, Ar-H), 7.49–7.52 (2H, m, Ar-H).
2-phenyl-2-vinyl-1,3-dioxolane 13[8]
Application of the elimination procedure for synthesis of 7 to bromo ketal 12 (67.1 g, 0.26
mol) and KOH (88.1 g, 1.57 mol) in 300 mL DMSO at 120°C for 3 hours gave the crude product.
Purification by distillation afforded 2-phenyl-2-vinyl-1,3-dioxolane 13 (41.7 g, 91%) as a clear oil.
b.p 133–135°C/15 mmHg, (Lit.[8] 59–60°C/0.3 mmHg);TLC, Rf: 0,41 [hexane]; 1H NMR H (400
MHz, CDCl3) (ppm) 3.90–3.98 (2H, m), 4.02–4.09 (2H, m), 5.24 (1H, ddd, J=0.4, 1.6 and 10.4),
5.35 (1H, ddd, J=0.4, 1.2 and 17.2), 6.02 (1H, ddd, J=0.4, 10.4 and 17.2), 7.28–7.57 (3H, m, Ar-
H), 7.48-7.52 (2H, m, Ar-H).
2-ethynyl-2-phenyl-1,3-dioxolane 15[8]
Application of the bromination procedure for synthesis of 8 to 2-phenyl-2-vinyl-1,3-
dioxolane 13 (15.1 g, 85.8 mmol) in 100 mL DCM at -10 °C and bromine (12.3 g, 77 mmol) in 25
mL DCM produced the crude dibromide compound 14. TLC, Rf: 0.47 [hexane]. The compound
was directly subjected to elimination step without purification or characterization.
Application of the elimination procedure for synthesis of 9 the crude dibromide 14 in 20
mL heptane, powdered KOH (24 g, 0.43 mol) and 18-crown-6 (250 mg) in 100 mL heptane gave
the crude product. Purification by fractional distillation afforded 2-ethynyl-2-phenyl-1,3-
dioxolane 15 (10.3 g, 70% over two steps) as a clear oil; b.p 110°C/15 mmHg, (Lit.[8], 92–96°C/0.6
1
1
mmHg); TLC, Rf: 0.28 [hexane]; IR (film) max/cm 3281, 2109, 697 (HC≡C-); H NMR (400
10

MHz, CDCl3) (ppm) 2.70 (1H,s), 4.09–4.15 (2H, m), 4.21–4.27 (2H, m), 7.34–7.40 (3H, m, Ar-
H), 7.68–7.73 (2H, m, Ar-H).
Synthesis of 2-ethynyl-2-methyl-1,3-dioxolane 20
2-(1-chloroethyl)-2-methyl-1,3-dioxolane 17[12]
A mixture of 3-choloro-2-butanone 16 ( 30.5 g, 278 mmol), ethylene glycol (16.5 g, 266
mmol) and p-toluene sulphonic acid (210 mg, 1.1 mmol) in 350 mL benzene was stirred under
refluxing with Dean Stark apparatus over night during which period the water produced was
distilled off as the toluene azeotrope. Reaction solvent was removed in vacuo and the residue was
dissolved in 250 mL DCM. The solution was then washed with saturated NaHCO3, brine, dried
over Na2SO4, evaporated in vacuo to give the crude ketal 17. Purification by distillation afforded
2-ethynyl-2-methyl-1,3-dioxolane 15 (36 g, 86%) as a pale yellow oil; b.p 55–58°C/15 mmHg,
(Lit.[12], 58–60°C/ 20 mmHg); TLC, Rf: 0.56 [EtOAc:hexane(1:10)];1H NMR (400 MHz, CDCl3)
(ppm) 1.43 (3H, s), 1.52 (3H, d, J=6.8), 3.95-4.05 (5H,m).
2-methyl-2-vinyl-1,3-dioxolane 18[12]
Application of the elimination procedure for synthesis of 7 to chloro ketal 17 (25 g, 166
mmol) and KOH (60 g, 1.07 mol) in 150 mL DMSO at 100°C for 3 hours gave the crude vinyl-
1,3-dioxolane. Purification by distillation at atmospheric pressure afforded 2-methyl-2-vinyl-1,3-
dioxolane 18 (15.7 g, 83% yield) as a clear oil. b.p 112–114°C, (Lit.[12], 110–112°C); TLC, Rf:
0.54 [EtOAc:hexane (1:6)]; 1H NMR (400 MHz, CDCl3) (ppm) 1.47 (3H, s), 3.86–4.02 (4H, m),
5.14 (1H, dd, J=1.6 and 10.8), 5.37 (1H, dd, J=1.6 and 17.2), 5.79 (1H, dd, J=10.4 and 17.2).
2-ethynyl-2-methyl-1,3-dioxolane 20[10]
11

Application of the bromination procedure for synthesis of 8 to 2-methyl-2-vinyl-1,3-
dioxolane 18 (18.1 g, 159 mmol) in 150 mL DCM at –10°C and bromine (22.9 g, 143 mmol) in
30 mL DCM produced the crude dibromide compound 19. TLC, Rf: 0.44 [EtOAc:hexane
(1:6)].The compound was directly subjected to elimination step.
Application of the elimination procedure for synthesis of 9 to the crude dibromide 19 in 30
mL n-dodecane, powdered KOH (44.5g, 0.8 mol) and 18-crown-6 (0.7 g) in 130 mL n-dodecane,
gave the crude product. Purification by distillation at atmospheric pressure afforded 2-ethynyl-2-
methyl-1,3-dioxolane 20 (10.7 g, 60% over two steps) as a clear oil; b.p 125°C, (Lit[10b], 44°C/38
1
mmHg); TLC, Rf: 0.59 [EtOAc:hexane (1:6)]. IR (film) max/cm ; 3277, 2112, 660 (HC≡C-); 1H
NMR (400 MHz, CDCl3) (ppm) 1.69 (3H, d, J=2), 2.47 (1H, s), 3.97-4.10 (4H, m); 13C NMR (100
MHz, CDCl3) (ppm) 26.10, 64.61 (2xC), 70.94, 82.05, 100.34.
Nucleophilic substitution of 1,2-cyclic sulfamidate 21 with acetylides 22 and 25
Synthesis of (S)-ethyl-5-(benzylamino)-6-phenyl-hex-2-ynoate 24[13]
To a solution of triethylorthopropiolate (1.35 g, 7.85 mmol) in 30 mL freshly distilled dry
THF under argon atmosphere, cooled at –10°C over ice-salt bath was added dropwise n-
butyllithium (5.0 mL, 7.9 mmol, 15% solution in hexane) and the solution was stirred at this
temperature for 1 h. A solution of phenylalaninol 1,2- cyclic sulfamidate 21 (1.2 g, 3.96 mmol) in
3 mL dry THF was then added to the resulting acetylide solution via a syringe. After stirring at –
10ºC for 5–6 h, the reaction mixture was allowed to warm up to room temperature gradually with
stirring overnight (24 h). TLC monitoring showed complete consumption of 21. The resulting
mixture was then treated with 3 mL 5M HCl solution to hydrolyze the N-sulfate intermediate for
3 h before neutralization with saturated NaHCO3 solution. Extraction with ether (3x50 Ml) and
12

drying over anhydrous Na2SO4 followed by evaporation of volatiles in vacuo gave the crude
product. Purification by column chromatography using [EtOAc: Hexane (1:8) to (1:3) gradient]
solvent systems (containing 0.5% triethylamine) afforded (S)-ethyl-5-(benzylamino)-6-phenyl-
hex-2-ynoate 24 as a pale yellow oil (1110 mg, 89% yield). TLC, Rf: 0.53 [(EtOAc:Hexane) 1:3];
[ ] 31 6.4 (c 1.95, CHCl3); IR (film); max/cm-1; 3481,3338 (NH), 2337 (C≡C), 1706 (C=O ester);
α
D
1H NMR H (400 MHz, CDCl3) (ppm) 1.32 (3H, t, J=7.2), 2.40-2.51 (2H, m), 2.81-2.90 (2H, m),
3.02-3.08 8 (1H, m), 3.77 (1H, d, J=13.6), 3.86 (1H, d, J=13.6), 4.23 (2H, q, J=7.2), 7.16-7.31
(10H, m, Ar-H); 13C NMR C (100 MHz, CDCl3) (ppm) 14.27, 23.73, 40.61, 51.27, 56.74, 62.07,
75.52, 85.59, 126.76, 127.24, 128.22, 128.64, 128.77, 129.53, 138.41, 140.08, 153.84; ESI-Tof
(m/z): [M+H]+ found 328.1809, C21H24NO2 requires 328.1807.
Synthesis of (S)-N-benzyl-1-phenyl-5-(2-phenyl-1,3-dioxolan-2-yl)pent-4-yn-2-
amine 27a
To a solution of phenyl ketal alkyne 15 (348 mg, 2 mmol) in 10 mL freshly distilled dry
THF under argon atmosphere, cooled at –10°C over ice-salt bath was added dropwise n-
butyllithium (1.4 mL, 2.2 mmol, 15% solution in hexane) and the solution was stirred at this
temperature for 1 h. A solution of phenylalaninol 1,2- cyclic sulfamidate 21 (303 mg, 1 mmol) in
3 mL dry THF was then added to the resulting acetylide solution via a syringe. After stirring at –
10ºC for 5-6 h, the reaction mixture was allowed to warm up to room temperature gradually with
stirring overnight (24 h). TLC monitoring showed complete consumption of 21. The resulting
mixture was then added one drop conc. H2SO4 and one drop H2O sequentially (total 4 drops H2SO4
and 4 drops H2O) with stirring for 2h to hydrolyze the N-sulfate intermediate before neutralization
with saturated NaHCO3 solution. Extraction with ether (3  20mL) and drying over anhydrous
13

Na2SO4 followed by evaporation of volatiles in vacuo gave the crude product. Purification by
column chromatography using [EtOAc: Hexane (1:7) to (1:4) gradient] solvent systems
(containing 0.5% triethylamine) afforded (S)-N-benzyl-1-phenyl-5-(2-phenyl-1,3-dioxolan-2-
yl)pent-4-yn-2-amine 27a 27a as a pale yellow oil (358mg, 90% yield). TLC, Rf: 0.42
[(EtOAc:hexane) 1:3]; []3D0 +0.36 (c 6.0, CHCl3); IR (film); max/cm ; 3357 (NH), 2234 (C≡C);
1
1H NMR H (400 MHz, CDCl3) (ppm) 2.40 (1H, dd, J=5.6 and 16.8), 2.47 (1H, dd, J=6.0 and
16.8), 2.83 (1H, dd, J=7.2 and 13.6), 2.89 (1H, dd, J=6.0 and 13.6), 3.01–3.07 (1H, m), 3.79 (1H,
d, J=13.2), 3.88 (1H, d, J=13.2), 4.12–4.18 (2H, m), 4.22–4.28 (2H, m), 7.17–7.42 (13H, m, Ar-
H), 7.73–7.77 (2H, m, Ar-H); 13C NMR C (100 MHz, CDCl3) (ppm) 23.50, 40.48, 51.14, 57.14,
65.09, 80.61, 84.20, 102.45, 125.87, 126.37, 126.90, 127.98, 128.22, 129.10, 138.70, 139.50,
140.23; LC/MS Q-TOF (m/z): [M+H]+ found 398.2116, C27H28NO2 requires 398.2120.
Synthesis of (S)-N-benzyl-5-(2-methyl-1,3-dioxolan-2-yl)-1-phenylpent-4-yn-2-
amine 27b
To a solution of methyl ketal alkyne 20 (225 mg, 2 mmol) in 10 mL freshly distilled dry
THF under argon atmosphere, cooled at -10 °C over ice-salt bath was added dropwise n-
butyllithium (1.3 mL, 2.1 mmol, 15% solution in hexane) and the solution was stirred at this
temperature for 1 h. A solution of phenylalaninol 1,2- cyclic sulfamidate 21 (303 mg, 1 mmol) in
3 mL dry THF was then added to the resulting acetylide solution via a syringe. After stirring at –
10ºC for 5–6 h, the reaction mixture was allowed to warm up to room temperature gradually with
stirring overnight (24 h). TLC monitoring showed complete consumption of 21. The resulting
mixture was then added one drop conc. H2SO4 and one drop H2O sequentially (total 4 drops H2SO4
and 4 drops H2O) with stirring for 2h to hydrolyze the N-sulfate intermediate before neutralization
14

with saturated NaHCO3 solution. Extraction with ether (3  20 mL) and drying over anhydrous
Na2SO4 followed by evaporation of volatiles in vacuo gave the crude product. Purification by
column chromatography using [EtOAc: Hexane (1:6) to (1:2) gradient] solvent systems
(containing 0.5% triethylamine) afforded (S)-N-benzyl-5-(2-methyl-1,3-dioxolan-2-yl)-1-
phenylpent-4-yn-2-amine 27b as a pale yellow oil (306mg, 91% yield). TLC, Rf: 0.22
[(EtOAc:Hexane) 1:3]; [ ] 24 5.5 (c 2, CHCl3); IR (film); max/cm ; 3330 (NH), 2241 (C≡C);
1
α
D
1H NMR H (400 MHz, CDCl3) (ppm) 1.72 (3H, s), 2.34 (2H, ddd, J=5.6, 16.8 and 20.6), 2.83
(2H, dd, J=7.2 and 13.6), 2.95–3.01 (1H, m), 3.78 (1H, d, J=13.2), 3.86 (1H, d, J=13.2), 3.96–4.02
13
(2H, m), 4.03–4.10 (2H, m), 7.17–7.32 (10H, m, Ar-H); C NMR C (100 MHz, CDCl3) (ppm)
26.68, 40.38, 51.11, 57.01, 64.59, 80.86, 81.34, 100.86, 126.38, 126.95, 127.99, 128.41, 128.47,
129.34, 138.70, 140.23; LC/MS Q-TOF (m/z): [M+H]+ found 336.1957, C22H26NO2 requires
336.1964.
Acknowledgments
The authors gratefully acknowledge Manisa Celal Bayar University for financial support
through a project (FEF-2011-030).
References
[1] Eskici, M.; Karanfil, A.; Özer M. S.; Sarıkürkcü, C. Tetrahedron Lett. 2011, 52, 6336–6341.
[2] a) Melendez, R. E.; Lubel, W. D. Tetrahedron 2003, 59, 2581–2616; (b) Bower, J. F.;
Rujirawanich, J.; Gallagher, T. Org. Biomol. Chem. 2010, 8, 1505–1519.
[3] For selected examples of generation and use of lithiumalkylpropiolate, see: (a) Shekhar, V.;
Reddy, D. K.; Suresh, V.; Babu, D. C.; Venkateswarlu, Y. Tetrahedron Lett. 2010, 51, 946;
(b) Yaragorla, S.; Muthyala, R. Tetrahedron Lett. 2010, 51, 467; (c) Yadav, J. S.; Rao, M.;
Sanjeevarao, K.; Reddy, B. V. S. Synlett 2008, 1039; (d) Ma, D.; Xie, W.; Zou, B.; Lei, Q.;
Pei, D. Tetrahedron Lett. 2004, 45, 8103; (e) Crimmins, M. T.; Pace, J. M.; Nantermet, P.
G.; Kim-Meade, A. S.; Thomas, J. B.; Watterson, S. H.; Wagman, A. S. J. Am. Chem. Soc.
2000, 122, 8453; (f) Mancini, I.; Guella, G.; Guerriero, A.; Boldrin, A.; Pietra, F. Helv.
15

Chim. Acta 1987, 70, 2011; (g) Hirama, M.; Shigemato, T.; Ito, S. J. Org. Chem. 1987, 52,
3342; (h) Tejedor, D.; Lopez-Tosco, S.; Cruz-Acosta, F.; Mendez-Abt, G.; Garcia-Tellado,
F. Angew. Chem. Int. Ed. 2009, 48, 2090–2098.
[4] (a) Stetter, H.; Uerdingen, W. Synthesis 1973, 4, 207–208; (b) Bates, R. W.; Maiti, T. B. Synth.
Commun. 2003, 33, 633–640.
[5] (a) Boche, G.; Bigalke, J. Tetrahedron Lett. 1984, 25, 955–958; (b) Shattuck, J. C.; Svatog, A.;
Blazey, C. M.; Meinwald, J. Tetrahedron Lett. 1997, 38, 6803–6806; (c) Mames, A.;
Stecko, S.; Mikołajczyk, P.; Soluch, M.; Furman, B.; Chmielewski, M. J. Org. Chem. 2010,
75, 7580–7587.
[6] Gassman, P. G.; Chavan, S. P. Tetrahedron Lett. 1988, 29, 3407–3410.
[7] Armengol, M.; Joule, J. A. J. Chem. Soc. Perkin Trans. 2001, 1, 978–984; The synthesis of
3,3,3-triethoxypropyne 9 using the similar reagents and conditions in comparable yields is
also given in PhD thesis by Montserrat Armengol, “The synthesis of thieno[2,3-
b]quinoxalines and quinoxalines with extended conjugation”, University of Manchester,
UK, 2001. As this material is not published in main stream journals, it is not easily
accessible. Therefore several additional useful observations for practical synthesis of 9 in
large quantities and high purity are presented in this communication.
[8] Frame, R. R.; Faulconer, W. J. Org. Chem. 1971, 36, 2048–2050.
[9] Feugeas, C.; Giusti, G. C. R. Acad. Sci., Ser. C 1967, 264, 1772–1774; (b) Giusti, G. Bull. Soc.
Chim. Fr. 1972, 753.
[10] (a) Henrick, C. A.; Willy, W. E.; Garcia, B. A.; Staal, G. B. J. Agric. Food Chem. 1975, 23,
396–400; (b) Ando, K.; Houk, K. N.; Busch, J.; Menasse, A.; Sequin, U. J. Org. Chem.
1998, 63, 1761–1766.
[11] Uemura, S.; Fukuzawa, S.-I. J. Chem. Soc. Perkin Trans. 1986, 1, 1983–1987.
[12] Knowles, J. P.; Whitting, A. Eur. J. Org. Chem. 2007, 3365–3368.
[13] Karanfil, A.; Balta, B.; Eskici, M. Tetrahedron 2012, 68, 10218–10229.
16

Scheme 1. Nucleophilic substitution of cyclic sulfamidates with acetylides.
17

Scheme 2. Synthesis of 3,3,3-triethoxypropyne 9.
18

Scheme 3. Synthesis of 2-ethynyl-2-phenyl-1,3-dioxolane 15.
19

Scheme 4. Synthesis of 2-ethynyl-2-methyl-1,3-dioxolane 20.
20

Scheme 5. Nucleophilic substitution of 1,2-cyclic sulfamidate 21 with acetylides 22 and 25.
21