J. Org. Chem.

1994,59, 7523-7525 7523

A New Method for the Preparation of

1-Ethynyl Ethers

Jorge A. Cabezasl and Allan C. Oehlschlager*

Department of Chemistry, Simon Fraser University,
Burnaby, B. C. Canada, V5AlS6 1. LDA
2. (EtO)pPOCI, -78OC
Received July 18, 1994
During our study2of the stannylcupration of acetylenic
ethers we required [2J3C]-l for mechanistic studies. OPO(0Et)p
Existing methods3 for the synthesis of acetylenic ethers I
involve dehydrohalogenation of 2-halo,4 1,a-dihalo vinyl
ether^,^ or haloacetals6 using KOH, NaNH2, or n-BuLi.
These procedures are incompatible with labile functional
groups and, if applied to the preparation of 13C-labeled
compounds, would require regiospecific preparation of 1-
or 2-13C-labeledhalo vinyl ethers, which is cumbersome.
We report a new, general and efficient method for the
preparation of acetylenic ethers which we have applied
to the preparation of 13C-labeled and functionalized
acetylenic ethers.

Results and Discussion

The commercial availability of 13C-labeledacetyl chlo- c
ride, encouraged us to consider the possible transforma-
tion of an acetate (2) to an acetylenic ether (1).For this
process, the transformation of an ester to the correspond-
ing enol phosphate 3 followed by trans-elimination
analogous to Negishi's conversion of methyl ketones to
terminal acetylenes7 was an obvious strategy (Scheme
1, path b).
While the conversion of ketones and acetates to the
corresponding enol phosphates are well-known pro-
cesses,8 the presence of a vinyl alkoxy group in the latter
complicates the subsequent elimination. Initial reactions
involving treatment of octyl acetate (2) with 1 equiv of
LDA followed by addition of diethyl chlorophosphate in
the presence of HMPA (1.1equiv), gave the corresponding
enol phosphate 3. "One-pot" reactions in which 2 equiv Table 1. Effect of Base on Efficiency of Conversion of
of LDA was added to 3 at -78 "C gave 70-80% of Enol Phosphate 3 to l-Aurynyl Ethersf
1-octanol (4) and 10-20% of the desired octyl ethynyl
products (%P
ether (1) (Table 1, entry 3). Both products can be
envisioned as arising from 1,2-trans-elimination of 3 entn, base 1 4 6
(Scheme 1, paths a and b). It has been reportedg that 1 NaH - 100 -
elimination of alkoxides from trans-fi-lithio vinyl ethers 2 MeLi - 100 -
is facile even at -100 "C. 3 LDAb 15 80 5
4 LDA/HMPAc 24 d 58
When 2 was treated, at -78 "C, with 3 equiv of LDA, 5 t-BuLi/HMPAC 16 10 74
followed by addition of diethyl chlorophosphate in HMPA 6 K"MP/HMPAC 28 7 55
(8 equiv), the principal product, 5 (58%, Table 1, entry 7 t-BuLi/TMEDA 27 13 e
8 t-BuLVHMPA 35 5 60
(1) Address: Escuela de Quimica, Universidad de Costa Rica, San 9 t-BuLi 40 45 5
JosB, Costa Rica. a Calculated by GC analysis. 1 equiv of HMPA was used in
(2) Cabezas, J. A.; Oehlschlager, A. C. Synthesis 1994,4, 432.
(3) For a review of synthetic procedures see: Brandsma, L.; Bos, this reaction. 8 equiv of HMPA was used. Octyl acetate was
H. J. T.; Arens, J. F. In Chemistry of Acetylenes; Viehe, H. G., Ed.; produced in this reaction (24%).e 60% of octyl acetate was
Marcel Dekker: New York, 1969; Chapter 11. produced. f All reactions were performed in THF at -78 "Cusing
(4) Perichs, M. A.;Serratosa, F.; Valenti, E. Tetrahedron 1987,43, 2 equiv of base per 1 equiv of enol phosphate 3. Reactions in
2311. entries 3-5 were carried out using a "one-pot" procedure. In
( 5 ) Moyano, A.; Charbonnier,F.;Greene, A. E. J . Org. Chem. 1987, entries 1, 2, 6-9 enol phosphate 3 was first isolated and then
52,2919. LBffler, A.; Himbert, G. Synthesis 1992,495. treated with base.
(6) Jones, E. R. H.; Eglinton, G.;Whiting, M. C.;Shaw, B. L. Organic
Syntheses; Wiley: New York, 1963; Coll. Vol. IV.p 404; Jacobs, T. L.; 4), arose from 1,a-phosphate migration (Scheme 1,path
Cramer, R.; Hanson, J. E. J . Am. Chem. SOC.1942, 64,223.
(7) Negishi, E.; King, A. 0.;Klima, W. L. J . O g . Chem. 1980, 45, c). The latter reaction has been extensively studied by
2526. Weimer in cyclic ketones,1° lactones, and a-substituted
(8) (a) Ireland, R. E.; Pfister, G. Tetrahedron Lett. 1969, 26, 2145. esters.ll Reported yields for conversion of a-substituted
(b) Charbonnier, F.;Moyano, A.; Greene, A. E. J. Org. Chem. 1987,
52, 2303. esters to the corresponding a-(diethoxyphosphhyl) esters
(9) Lau, K. S.Y.; Schlosser, M. J . Org. Chem. 1987, 43, 1595. are in the range of 0-26%. The use of KTMP or t-BuLi
0022-3263/9W1959-7523$04.50/0 0 1994 American Chemical Society
7524 J. Org. Chem., Vol. 59, No. 24, 1994 Notes
Table 2. Effect of Solvent and Temperature on Table 3. Transformation of Acetates into Ethynyl
Conversion of Enol Phosphate 3 into Octyl Ethynyl Ethers
Ether 1with t-BuLi
Entry Acetate Acetylenic Ether % Yielda
entry temp ("CY' solvent % yieldb
1 -78 THF 40
2 -100 THF 46 65
3 - 100 pentanec 55
4 -100 pentanec,d 65
Internal temperature. Yield of chromatographically isolated
compound. 10%of THF was used in this case. This sample was 68
LiCl free.
El0 ,OEt
$P.
R'LI-- 0 0 63
LH+OR
H

Figure 1. Coordination of a lithium base RLi with the 64

phosphate group.
A A
in the presence of HMPA appears to offer significant 0 13
advantages for promotion of this process (Table 1, entries
5 and 6). 55
Even with sterically hindered bases such as LDA
preferential abstraction of the hydrogen trans to the
alkoxy group was observed (Table 1, entries 3 and 4).
Superior yields of 1 were obtained if enol phosphate 3 57
was first isolated and then treated with base. Sterically
undemanding bases such as NaH and MeLi afforded only
alkoxide elimination (Table 1, entries 1 and 2). Only in a Yield of chromatographically isolaled compound.
the case of t-BuLi were reasonable yields of 1 obtained
from 3 (Table 1, entries 8 and 9). Lowering the tem-
perature of the elimination from -78 to -100 "C in the to -30 "C and treatment with i-PrOH, resulted in an
t-BuLi-promoted process further increased the yield inseparable mixture (ca. 8:2) of 14 and 7,7-dimethyloctyl
(Table 2, entries 1 and 2). ethynyl ether, from nucleophilic displacement of the
We considered it likely that alkoxide elimination and primary chloride by t-BuLi. Presumably, the later reac-
1,Qphosphate migration might be promoted by coordina-
tion was favoured by the increase in the reaction tem-
tion of the lithium base12and phosphate oxygen favoring
abstraction of the hydrogen trans to the alkoxy group perature from -100 to -30 "C. Treatment of the enol
(Figure 1). phosphate of 9 with 1.8 equiv of t-BuLi at -100 "C
The presence of LiC1, formed in the first step, could followed by treatment with i-PrOH at -85 "C (internal
also promote abstraction of the hydrogen trans to the temperature) resulted in a clean formation of 14 (Table
alkoxy group by formation of a ~he1ate.l~ Yields of 1were 3, entry 5).
marginally improved when LiCl was removed from enol This new method provides easy access to functionalized
phosphate 3 prior to treatment with t-BuLi. This can and 13C-labeled1-ethynyl ethers in acceptable yields.
be executed without chromatography by dissolution of the
crude quenched reaction mixture (from the preparation
Experimental Section
of 3) in pentane and filtration of the LiCl precipitate
before subjecting it to elimination. When this procedure General Methods. All glassware and syringes were dried
was executed prior to treatment of 3 with t-BuLi (2.2 in an oven overnight at 140 "C and flushed with argon im-
equiv) at -100 "C, followed by warming of the reaction mediately prior to use. Transfers of reagents were performed
mixture to -30 "C before quenching, yields of 1increased with syringes equipped with stainless-steel needles. All reac-
from 55 to 65% (Table 2, entries 3 and 4). tions were carried out under a positive pressure of argon. THF
This new method has been applied to the synthesis of was refluxed and freshly distilled from potassiumhenzophenone
13C-labeledacetylenic ethers 1and derivatives containing ketyl under argon atmosphere. Argon was passed through a
labile groups previously unaccessible (Table 3, entry 5). Drierite column (40 cm x 3 cm). HMPA was fractionally
distilled under vacuum (68-70 "CD.1 mmHg) from calcium
Several attempts to obtain acetylenic ether 14, by treat- hydride, collected and stored over activated 4 A molecular sieves.
ment of the corresponding enol phosphate of acetate 9 Diisopropylaminewas freshly distilled from sodium under argon.
with t-BuLi (2.2 equiv) at -100 "C, followed by warming Alkyllithiums were titrated according to Watson and Eastham.14
Diethylchlorophosphate was purchased from Sigma and stored
(10)(a) Hammond, G. B.; Calogeropoulou, T.; Weimer, D. F. over activated 4 A molecular sieves. 'H-NMR spectra were
Tetrahedron Lett. 1986, 27, 4265. (b) Calogeropoulou, T.; Hammond, recorded on a Bruker AMX-400 spectrometer. Mass spectra
G. B.; Weimer, D. F. J. O g . Chem. 1987,52,4185. were obtained on a Hewlett-Packard5985B spectrometerusing
(11)Jackson, J. A.; Hammond, G. B.; Weimer, D. F. J. Org. Chem.
1989, 54, 4750. electron impact at 70 eV. Infrared spectra were obtained on a
(12) Al-Aseer, M.; Beak, P.; Hay, D.; Kempf, D. j.; Mills, S.; Smith, Perkin Elmer series 1600 FT' spectrometer.Acetates not com-
G. J.Am. Chem. SOC.1983,105,2080.(b) Beak, P.; Hunter, J. E.; Jun,
Y.M. J.Am. Chem. SOC.1983,105,6350.
(13)h u p y , A.; Tchoubar, B. Salt Effects in Organic and Organo- (14) Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9,
metallic Chemistry; VCH Verlagsgesellschak Weinheim, 1992; pp168. 165.
Notes J. Org. Chem., Vol. 59, NO.24, 1994 75%

mercially available were prepared from the corresponding al- 730 cm-1; MS (CI) m l e (re1 intensity) 179 (M + 1,loo), 119 (15).
cohols according to Steg1i~h.l~ Anal. Cdcd for CsH1502C1: C, 53.78; H: 8.46. Found: c, 53.77;
Typical Procedure. Preparation of [2JsC1EthynylOctyl H: 8.49.
Ether ([2JSC]-1). A solution of [2-13Cloctylacetate2 (1.73 g, 10 246'-(Acetyloxy)hexyl]-2-methyl-l&dithiane (10 ):I9 lH
mmol) in THF (2 mL) was added to a cold (-78 "C) THF solution NMR(CDC13,400 MHz) 6 1.30-1.42 (m, 4H), 1.43-1.53 (m, 2H),
(6.5 mL) of LDA [prepared from 1.5 mL (10.6 mmol) of diiso- 1.61 (s,3H), 1.63 (m, 2H), 1.85-1.91 (m, 2H), 1.92-2.00 (m, 2H),
propylamine and 4.25 mL (10.4 mmol) of n-BuLi 2.45 M at -40 2.05 (s,3H), 2.80-2.90 (m, 4H), 4.05 (t, 2H, J = 7.0 Hz); l3C
"C] and the mixture stirred for 45 min. at this temperature. A NMR (CDC13, 100.6 MHz) 6 24.3, 25.4, 25.8, 26.5, 27.8, 28.5,
solution of diethyl chlorophosphate (1.7 mL, 12.0 mmol) in 29.4, 41.7, 49.2, 64.4, 171.0; IR (film) 2935, 2858, 1738, 1237,
HMPA (2.5 mL) was then added and the mixture stirred at the 1037 cm-1; MS (EI) m l e (re1 intensity) 276 (M+,201, 133 (loo),
same temperature for 3 h. The reaction mixture was treated
74 (47). Anal. Calcd for C13Hz4Sz02: C, 56.48; H: 8.75.
with 5 mL of a THF:water mixture (l:l),warmed to room
temperature, and extracted with ether (2 x 30 mL). The organic Found: C, 56.66; H: 8.96.
extracts were washed with water (2 X 15 mL) and dried over n-Octyl ethynyl ether (1): lH NMR (CDCl3, 100 MHz) 6
anhyd MgS04. After concentration in uucuo the remaining oil 0.88 (t, 3H), 1.30 (br s, lOH), 1.51 (s, lH), 1.76 (m, 2H), 4.07 (t,
was dissolved in pentane (-40 mL) and the LiCl removed by 2H, J = 7 Hz); 13C NMR (CDC13, 100.6 MHz) 6 14.0, 22.6, 25.3,
filtration through fritted glass.16 26.0,28.6,29.1,31.7, 79.0,91.3; IR(film) 3328,2152, 1467, 1094
The pentane solution thus obtained (-40 mL) was cooled to cm-1; MS (EI), m l e (re1 intensity) 112 (M+ - CzH20, 31, 97 (41,
-100 "C (internal temperature) using a liquid nitrogen-ether 83 (15), 71 (941, 57 (100). Anal. Calcd for CloHisO: C, 77.87;
bath (addition of ca. 5 mL of THF was needed to maintain H: 11.76. Found C, 77.62; H: 11.82.
product in solution) and tert-BuLi (12.4 mL, 21 mmol, 1.7 M in
pentane) was added d r 0 p w i ~ e . lThe
~ internal temperature was 2-0ctyl ethynyl ether (11): 'H NMR (CDC13, 400 MHz) 6
allowed to rise to -30 "C at which point to the mixture was 0.90(t,3H,J=7.0Hz),1.20-1.30(m,6H),1.36(d,3H,J=7.0
added 2-propanol (2-3 mL) and then water (3 mL). The mixture Hz), 1.45-1.58 (m, 2H), 1.54 (s, lH), 1.70-1.80 (m, 2H), 4.10-
was extracted with ether (2 x 20 mL), and the extracts were 4.20 (m, 1H); l3C NMR (CDC13, 100.6 MHz) 6 14.0, 19.1, 22.5,
washed with water (2 x 15 mL) and dried over anhyd MgS04. 25.1, 27.3,29.0,31.7,35.3,85.7,89.8; IR (film) 3331,2145,1105
Evaporation of solvent gave a crude product which was dissolved cm-1; MS (EI) m l e (re1 intensity) 112 (M+ - C2H20,29), 83 (561,
in pentane and filtered through a pad of silica gel (6 x 4 cm) 70 (loo), 55 (67). Anal. Calcd for CloH1sO: C, 77.87; H: 11.76.
(pretreated with EtsN) and eluted with pentane. Evaporation Found: C, 78.12; H: 12.00.
of solvent affored 1.0 g of [2-W]-1(65% yield). For spectroscopic 5-(tert-Butyldimethylsiloxy)pentylethynyl ether (12):
characteristics of this compound and preparation of [2-13Cloctyl 1H NMR (CDC13,400 MHz) 6 0.04 (S, 6H), 0.86 (S, 9H), 1.42 (m,
acetate see ref 2. 2H), 1.50 (s, lH), 1.54 (m, 2H), 1.76 (m, 2H), 3.60 (t, 2H, J = 7
For compound 14,after treatment of the corresponding enol
phosphate with tert-BuLi," the reaction mixture was allowed Hz), 4.05 (t, 2H, J = 7 Hz); 13C NMR (CDC13, 100.6) 6 5.3, 18.3,
to warm from -100 to -85 "C and quenched at the latter 21,7,25.9,26.1,28.4,32.2,62.8,78.9,91.2; IR(fi1m) 3330,2153,
temperature. The crude product was extracted into pentane 1256,1099 cm-1; MS (EI), m l e (re1 intensity) 201 (M+ - C2H20,
which was concentrated by distillation at atmospheric pressure I), 143 (37), 129 (17), 115 (ll),99 (56), 75 (100). Anal. Calcd
through a Vigreaux column. Purification by filtration through for C13H2eSi02: C, 64.41; H, 10.81. Found C: 64.28; H: 10.89.
silica gel followed by concentration of the pentane solution as Menthyl ethynyl ether (13):lH NMR (CDC13,400 MHz) 6
above yielded a residue which was further purified by distillation 0.83 (d, 2H, J = 7.0 Hz), 0.92 (d, 2H, J = 7.0 Hz), 0.96 (4 2H,
under vacuum. J = 7.0 Hz), 1.15-1.30 (m, 3H), 1.40-1.50 (m, 2H), 1.52 (s, 1H),
l-[(Diethoxyphosphinyl)oxy]~inylOctyl ether (3): IH 1.63-1.72 (m, 2H), 2.10-2.18 (m, 1H), 2.27 (dddd, 1H, J = 12,
NMR (CDC13,400 MHz) 6 0.88 (t, 3H, J = 7 Hz), 1.20-1.32 (br 4, 4, 2 Hz), 3.86 (ddd, l H , J = 11, 11,4.5 Hz); l3C NMR (CDC13,
s, lOH), 1.35 (t,6H, J =7 Hz), 1.70 (m, 2H), 3.52 (d, lH, J =3.5 100.6) 6 16.3, 20.5, 21.9, 23.5, 26.0, 27.1, 31.6, 34.0, 39.4, 46.8,
Hz), 3.77 (t, 2H, J = 6.5 Hz), 3.85 (dd, l H , J = 3.5 Hz, 4 J ~ = - ~ 88.3, 89.8; IR (film) 3331, 2145, 1102, cm-'; MS (E11 m l e (re1
2.0 Hz), 4.19 (m, 4H); l3C NMR (CDCl3, 100.6 MHz) 6 14.0, 16.0, intensity) 138 (M+ - C2H20,42), 123 (27), 95 (100),81(81).Anal.
22.6,25.8,28.6,29.1,29.2,31.7,64.5,67.6,69.3,157.0; IR(fi1m)
1669 1242, 1166, 1036; MS (CI) m l e (re1 intensity) 309 (M 1, + Calcd for C12H2oO: C, 79.94; H: 11.18. Found: C: 80.39, H:
11.73.
171, 197 (1001, 155 (83).
Octyl a-(diethoxyphosphhyl)acetate (5): 'H N M R (CDCkj, 6-Chlorohexyl ethynyl ether (14): NMR (CDC4, 400
400 MHz) 6 0.83 (t, 3H, J = 7 Hz), 1.15-1.27 (m, 10 H), 1.30 (t, MHz) 6 1.35-1.50 (m, 4H), 1.53 (s, lH), 1.70-1.83 (m, 4H), 3.53
6H, J = 7 Hz), 1.60 (m, 2H), 2.95 (d, 2H, 2 J ~=-22~ Hz), 4.10 (t, (t, 2H, J = 7.0 Hz), 4.07 (t, 2H, J = 7Hz); 13C NMR (CDC13,
2H, J = 7 Hz), 4.15 (dq, 4H, J = 7.0 Hz, %-H = 7.0 Hz); l3C 100.6 MHz) 6 24.7, 26.2, 26.4, 28.5, 32.4, 44.8, 78.7, 91.1; IR
NMR (CDC13, 100.6 MHz) 6 13.9, 16.3, 22.5, 25.8, 28.5, 29.1, (film) 3321, 2152, 1468, 1120 cm-l; MS (EI) m l e (re1 intensity)
31.7, 33.7, 35.1, 62.6, 65.7, 165.8; IR (film) 2930, 2857, 1737, 118 (M+ - C2H20, 21), 82 (421, 69 (25), 55 (311, 43 (100); h d
1272, 1027 cm-1; MS (CI) m l e (re1 intensity) 309 (M + 1, 100). Calcd. for CsH130C1: C, 59.81; H: 8.16. Found: C, 59.97; H:
5-[(tert-Butyldimethylsilyl)oxy]pentylacetate (7):18 'H 8.33.
NMR (CDC13, 400 MHz) 6 0.04 (s, 6H), 0.87 (s, 9H), 1.40 (m,
2H), 1.54 (m, 2H), 1.63 (m, 2H), 3.60 (t, 2H, J =6.5 Hz), 4.50 (t, 2-[6-(Ethynyloxy)hexyl]-2-methyl-1,3-dithiane (15): 'H
2H, J = 6.7 Hz); 13C NMR (CDCl3, 100.6 MHz) 6 -5.3, 18.3, NMR (CDC13,400 MHz) 6 1.32-1.56 (m, 6H), 1.52 (s, lH), 1.61
20.9,22.3,25.9,28.5,32.4,62.9,64.5,171.0; IR (film) 2930,1743, (s,3H), 1.76 (m, 2H), 1.87-1.98 (m, 4H), 2.83-2.86 (m, 4E0,4.07
1240, 1098, 836, 776 cm-l; MS (CI) m l e (re1 intensity) 261 (M (t, 2H, J = 6.5 Hz); 13CNMR (CDCl3, 100.62 MHz) 6 24.3, 25.2,
+ 1, loo), 201 (211, 117 (6). Anal. Calcd for C13H2803Si: C, 25.4, 26.1, 26.5, 27.8, 28.5, 29.2,41.6, 49.2, 78.9, 91.2; IR (film)
59.95; H: 10.84. Found: C, 60.06; H: 10.66. 3312, 2149, 1093 cm-l; MS (EI) m l e (re1 intensity) 216 (M+ -
5-Chlorohexyl acetate (9): IH NMR (CDC13, 100 MHz) 6 C2H20, 61, 133 (1001, 106 (191, 74 (60). Anal. Calcd for
0.31-0.95 (m, 8H), 2.02 (s, 3H), 3.54 (t, 2H, J = ~ H z )4.05
, (t, C13HzzS20: C, 60.42; H: 8.58. Found: C, 60.74; H: 8.76.
2H, J = 7 Hz); l3C NMR (CDC13, 100.6 MHz) 6 20.9, 25.3, 26.5,
28.5, 32.5, 44.8, 64.3, 171.0; IR (film) 2940, 1740, 1243, 1049,
Acknowledgment. We wish t o thank the Natural
(15) Hofle, G.; Steglich, W.; Vorbriiggen, H Angew. Chem. Int. Ed. Sciences and Engineering Research Council of Canada
Engl. 1978, 17, 569. for a Research Grant to A.C.O. and the University of
(16) It is recommended to perform both steps sequentially. Decom- C o s t a Rica for a stipend to J.A.C.
position of the enol phosphate was observed when this crude was stored
overnight.
(17)For the preparation of 14, the tert-BuLi was added from a
dropping funnel containing an outer jacket filled with dry icelacetone. (19) The corresponding alcohol was prepared by reaction of B-bro-
(18)The corresponding monosilylated diol was prepared according mohexyl tert-butyldimethylsilyl ether, with 2-lithio-2-methyl-l,3-
to McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. J.Org. Chem. dithiane (ref 20), followed by reaction with NH4F.
1986,51 ,3388. (20) Seebach, D.; Corey, E. J. J. Org. Chem. 1975, 40, 231.