Synthesis of alkynyl ethers and low-temperature sigmatropic rearrangement of allyl and benzyl alkynyl ethers

Article abstract of DOI:10.1021/ol802147h

(Chemical Equation Presented) α-Alkoxy ketones 3 can be transformed into 1-alkynyl ethers 5 by a two-step procedure involving formation of the enol triflate or phosphate and base-induced elimination. Performing the same reaction sequence with allylic alcohols (R₂OH, R₂ = allyl) furnishes instead γ,δ-unsaturated carboxylic acid derivatives 6, derived from [3,3]-sigmatropic rearrangement of the intermediate allyl alkynyl ethers at -78 °C and trapping of the subsequently formed ketene with nucleophiles (Nu-H). Benzyl alkynyl ether 5 (R₂ = benzyl) rearranges to indanone 7 upon heating to 60 °C.

Full text of DOI:10.1021/ol802147h

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5091-5094
Synthesis of Alkynyl Ethers and
Low-Temperature Sigmatropic
Rearrangement of Allyl and Benzyl
Alkynyl Ethers
Juan R. Sosa, Armen A. Tudjarian, and Thomas G. Minehan*
Department of Chemistry and Biochemistry, California State UniVersity,
Northridge, Northridge, California 91330
thomas.minehan@csun.edu
Received September 14, 2008
ABSTRACT
r-Alkoxy ketones 3 can be transformed into 1-alkynyl ethers 5 by a two-step procedure involving formation of the enol triflate or phosphate
and base-induced elimination. Performing the same reaction sequence with allylic alcohols (R2OH, R2 ) allyl) furnishes instead γ,δ-unsaturated
carboxylic acid derivatives 6, derived from [3,3]-sigmatropic rearrangement of the intermediate allyl alkynyl ethers at -78 °C and trapping of
the subsequently formed ketene with nucleophiles (Nu-H). Benzyl alkynyl ether 5 (R2 ) benzyl) rearranges to indanone 7 upon heating to 60
°C.
Electron-rich alkynes, such as ynamines and ynol ethers,
are functional groups that possess significant potential in
organic chemistry for the formation of carbon-carbon
bonds.1 The synthetic utility of ynamides has been consider-
ably expanded recently, along with the development of new
methods for their facile preparation from simple building
blocks.2 1-Alkynyl ethers, while possessing many of the
reactivity features of ynamides, have been far less investi-
gated due to the relatively few methods currently available
for their synthesis.3 In this paper, we present a mild and
efficient method for the synthesis of diverse 1-alkynyl ethers
and demonstrate that a facile sigmatropic rearrangement of
allyl and benzyl alkynyl ethers furnishes products containing
new carbon-carbon bonds.
We have previously shown that treatment of allyl 1,1-
dichlorovinyl ethers with 2.2 equiv of n-butyllithium at -78
°C, followed by quenching of the reaction mixture with
excess alcohol, leads to rearranged γ,δ-unsaturated esters in
(1) (a) Shindo, M. Tetrahedron 2007, 63, 10. (b) Brandsma, L.; Bos,
H. J.; Arens, J. F. In The Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel
Dekker: New York, 1969; pp 751. Stang, P. J.; Zhdankin, V. V. In The
Chemistry of Triple-Bonded Functional Groups; Patai, S., Ed.; John Wiley
& Sons: New York, 1994; Chapter 19.
(2) For reviews of the chemistry of ynamines and ynamides, see: (a)
Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.; Wei, L. L
Tetrahedron 2001, 57, 7575. (b) Mulder, J. A.; Kurtz, K. C. M.; Hsung,
R. P. Synlett 2003, 10, 1379. (c) Katritzky, A. R.; Jiang, R.; Singh, S. K.
Heterocycles 2004, 63, 1455. (d) Tetrahedron Symposium-In-Print: Chem-
istry of Electron-Deficient Ynamines and Ynamides. Tetrahedron 2006, 62,
Issue No. 16.
(3) (a) Bruckner, D. Synlett 2000, 10, 1402. (b) Moyano, A.; Charbon-
nier, F.; Greene, A. E. J. Org. Chem. 1987, 52, 2919. (c) Pericas, M. A.;
Serratosa, F.; Valenti, E. Tetrahedron 1987, 2311. (d) Smithers, R. H.
Synthesis 1985, 556. (e) Himbert, G.; Loffler, A. Synthesis 1992, 495.
(4) Christopher, A.; Brandes, D.; Kelly, S.; Minehan, T. G. Org. Lett.
2006, 8, 451.
10.1021/ol802147h CCC: $40.75
Published on Web 10/11/2008
2008 American Chemical Society

high yield.4 The reaction possesses many of the character-
istics of a sigmatropic process, both in terms of its ste-
reospecificity and geometrical requirements. We have pro-
posed that an initially generated allyl alkynyl ether intermediate
undergoes a [3,3]-sigmatropic rearrangement either as a
neutral or as a negatively charged species.
To extend this protocol to the preparation of a diverse
range of substituted alkynyl ethers, we required access to a
variety of R-diazoketones. The procedure of Danheiser et
al.7 allowed the preparation of aryl (1a), alkenyl (Table 1,
Due to its reactivity toward a range of functional groups,
the use of the nucleophilic base n-BuLi to generate the key
intermediate in this reaction may be viewed as a potential
limitation. Furthermore, the preparation of the allyl 1,1-
dichlorovinyl ether substrate via methylenation of an allylic
formate ester requires the use of toxic carbon tetrachloride
in combination with triphenylphosphine. Since terminal and
internal alkynes have been previously prepared from ketones
by treatment of the corresponding enol phosphates or triflates
with a non-nucleophilic base,5 we sought to investigate the
preparation of 1-alkynyl ethers from R-alkoxy ketones via
E2 elimination of the derived enol triflates or phosphates.
Following the procedure of Muthusamy et al.,6 treatment
of a toluene solution of diazoacetophenone 1a and menthol
with a catalytic amount (10 mol %) of indium triflate at room
temperature furnished R-alkoxy ketone 3a in 91% yield
(Scheme 1). Formation of the enol triflate was achieved by
Table 1. Scope of Alkynyl Ether Sythesis via Elimination of
Enol Triflatesa
entry
R1
R2
3 (% yield)
5
5 (% yield)
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
menthyl
CH2CH(CH2)3
t-Bu
91
89
67
78
84
81
69b
87
90
a
b
c
d
e
f
g
h
i
75
82
68
70
90
68
64
Ph
1-cyclohexenyl menthyl
(CH3)2CCH
PhCC
t-Bu
C6H13
CH2CH(CH2)3
menthyl
CH2CH(CH2)3
menthyl
c
-
c
-
a Reaction conditions: (a) R2OH (1.5 equiv), In(OTf)3 (10 mol %),
toluene, rt; (b) LiHMDS, THF, -78 °C, then PhNTf2, DMPU, -78 °C to
rt; (c) KO-t-Bu, THF, -78 °C. b Yield of 3g prepared in three steps from
menthol via an alternative route described in the text. c No alkynyl ethers
were detected in the reaction mixture; see the text for details.
Scheme 1. Preparation of Phenylethynyl Menthyl Ether
1e and 1f), and alkyl (1h, 1i) diazoketones from the
corresponding ketones in high yields. However, the prepara-
tion of alkynyl diazoketone 1g was problematic due to self-
condensation/cycloaddition side reactions.8
The three-step protocol for alkynyl ether synthesis
(diazoketone-alcohol coupling, enol triflate formation, and
elimination) was carried out starting with a number of
different diazoketones and alcohols (Table 1). Primary,
secondary, and tertiary alcohols and phenols all work equally
well, furnishing the expected alkynyl ethers (entries 1-4)
in good yields. Aromatic (R1 ) Ph, entries 1-4), R,ꢀ-
unsaturated (R1 ) 1-cyclohexenyl, (CH3)2CCH, entries 5 and
6), and alkynyl (R ) CCPh, entry 7) ketones 3 were all
effective precursors of alkynyl ethers. Due to the problems
encountered in preparing alkynyl diazoketones (vide supra),
an alternative protocol for the synthesis of R-alkoxy ketone
3g was developed, involving reaction of the sodium alkoxide
of menthol with chloroacetic acid,9 formation of the Weinreb
amide,10 and addition to phenylethynyllithium (2 equiv) at
-78 °C. Enol triflate formation then proceeded uneventfully,
furnishing a ∼1:1 mixture of E and Z geometrical isomers.
Subsequent treatment with KO-t-Bu under standard condi-
tions then allowed the preparation of compound 5g, a 1,3-
diynyl menthyl ether.
stirring 3a with LiHMDS at -78 °C for 1 h, followed by
quenching with PhNTf2 in DMPU/THF (1:2) and warming
to room temperature. The enol triflate obtained (4a) was
sufficiently stable to be purified by silica gel chromatography;
1H NMR spectroscopy of the purified material revealed that
the triflate was formed as a single Z geometric isomer (the
configuration of the double bond was confirmed by NOESY
experiments; see the Supporting Information for details).
Subsequent treatment with 2 equiv of potassium tert-butoxide
at -78 °C in THF smoothly furnished the corresponding
alkynyl ether 5a in 75% overall yield from 3a. Alternatively,
and more expediently, the crude enol triflate can be directly
transformed into 5a in similar overall yield by addition to
an excess (3 equiv) of potassium tert-butoxide in THF at
-78 °C. The presence of the alkynyl ether moiety in 5a was
verified by the chemical shifts of the alkyne carbons in the
13C NMR spectrum (41.8 and 98.5 ppm, respectively) and
also by the sharp spike at 2254 cm-1 in the IR spectrum.
Unlike results for aromatic, alkenyl, and alkynyl ketone
substrates, aliphatic R-alkoxy ketones failed to generate the
corresponding enol triflates upon treatment with LiHMDS/
(7) Danheiser, R. L.; Miller, R. F.; Brisbois, R. G.; Park, S. Z. J. Org.
Chem. 1990, 55, 1959.
(5) (a) Brummond, K. M.; Gesenberg, K. D.; Kent, J. L.; Kerekes, A. D.
Tetrahedron Lett. 1998, 39, 8613. (b) Negishi, E.; King, A. O.; Tour, J. M.
Org. Synth. 1990, 7, 63.
(8) This problem has been previously noted: Boyer, J. H.; Selvarajan,
R. J. Org. Chem. 1971, 36, 1679.
(9) Gibson, H. W.; Berg, M. A.; Clifton Dickson, J.; Lecavalier, P. R.;
Wang, H.; Merola, J. S. J. Org. Chem. 2007, 72, 5759.
(10) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(6) Muthusamy, S.; Babu, S. A.; Gunanathan, C. Tetrahedron Lett. 2002,
43, 3133.
5092
Org. Lett., Vol. 10, No. 21, 2008

PhNTf2 (Table 1, entries 8 and 9). A survey of different
reaction conditions and triflating agents (Tf2O, Comins’
triflimide) yielded no improvement, with high Rf decomposi-
tion products obtained in all cases. We suspect that the enol
triflates derived from aliphatic ketones are unstable, perhaps
decomposing to allenic compounds that undergo side reactions.
To address this important limitation, we investigated the
preparation of putatively more stable enol phosphates from
R-alkoxy ketones.11 Indium triflate catalyzed coupling of tert-
butyl diazoacetate with 4-penten-1-ol provided ketone 3h in
89% yield. Addition of a toluene solution of KHMDS to a
mixture of 3h and diethylphosphoryl chloride in THF at -78
°C furnished enol phosphate 4h (again as a single Z
geometric isomer; see the NOESY data in the Supporting
Information) in 81% yield (Scheme 2). Disappointingly, no
Table 2. Scope of Alkynyl Ether Synthesis via Elimination of
Enol Phosphatesa
% yield
% yield
entry
R1
R2
4
of 4
5
of 5
1
2
3
4
5
t-Bu
C6H13
i-Pr
1-cyclohexenyl t-Bu
Ph t-Bu
CH2CH(CH2)3 hb
81
89
78
72
82
h
i
60
72
85
70
56
menthyl
menthyl
ic
jb
kb
lb
j
k
c
a Reaction conditions: (a) KHMDS, ClPO(OR3)2, THF, 78 °C; (b)
n-BuLi, KO-t-Bu, THF, -78 °C. b The diethyl phosphate derivative was
synthesized. c The diphenyl phosphate derivative was synthesized.
Early investigations by Arens12 and Schmid13 revealed that
substituted and unsubstituted benzyl alkynyl ethers undergo
[3,3]-sigmatropic rearrangement followed by intramolecular
Scheme 2. Preparation of Alkyl-Substituted Alkynyl Ethers
Scheme 3
.
Formation of Allenyl Ether 8 from Methyl Ketone
3m
reaction was observed upon treatment of the enol phosphate
with KO-t-Bu in THF at -78 °C; even after the reaction
mixture was warmed to room temperature and then to reflux,
only starting material was isolated. Use of the stronger bases
LDA or LiTMP also led to no reaction. Finally, it was found
that addition of 2-3 equiv of Schlosser’s base (n-BuLi-KO-
t-Bu) to the enol phosphate at -78 °C led to the rapid
formation of the alkynyl ether in 60% yield.
A variety of alkyl-substituted alkynyl ethers may be
prepared efficiently from the corresponding enol phosphates
(Table 2, entries 1-3). Either the diphenyl phosphate or the
diethylphosphate derivative may be employed for the elimi-
nation step, and the order of addition of base and substrate
appears to have no effect on the reaction yield (addition of
n-BuLi to a mixture of enol phosphate and KO-t-Bu vs
addition of the enol phosphate to preformed BuK). Perform-
ing the two-step sequence on hexyl and isopropyl ketones
3i and 3j furnished enol phosphates 4i and 4j and alkynyl
ethers 5i and 5j, respectively, in good yields. This method
is also an effective means of synthesizing aryl- and alkenyl-
substituted alkynyl ethers (Table 2, entries 4 and 5).
Interestingly, when methyl ketone 3m (Scheme 3) was
treated with KHMDS and ClPO(OEt)2, a 3:1 mixture of enol
phosphates 4n and 4m was obtained in 65% yield. Subjection
of this mixture to n-BuLi/KO-t-Bu at -78 °C cleanly gave
rise to allenyl ether 8 in 85% yield.
ketene trapping to form indanones in high yield. Interestingly,
these processes took place in refluxing CCl4, at temperatures
well below those typical for uncatalyzed aromatic Claisen
rearrangements.14 In(OTf)3-catalyzed coupling of benzyl
alcohol and diazoacetophenone 1a furnished R-benzyloxy
acetophenone 3o in 87% yield (Scheme 4). Enol triflate
Scheme 4
.
Synthesis and Thermal Rearrangement of
Phenylethynyl Benzyl Ether
formation proceeded smoothly to afford 4o, which when
treated with KO-t-Bu in THF at -78 °C gave rise to benzyl
alkynyl ether 5o in 75% yield. This compound proved to be
Finally, we wished to examine the special case of alkynyl
ethers derived from allylic and benzylic alcohols.
(12) Olsman, H.; Graveland, A.; Arens, J. F. Rec. TraV. Chim. Pays-
(11) 1-Ethynyl ethers have been previously prepared by base-induced
elimination of enol phosphates derived from acetate esters: Cabezas, J. A.;
Oehlschlager, A. C. J. Org. Chem. 1994, 59, 7523.
Bas 1964, 83, 301.
(13) Wunderli, A.; Zsindely, J.; Hansen, H. J.; Schmid, H. Chimia 1972,
26, 643.
Org. Lett., Vol. 10, No. 21, 2008
5093

thermally labile, partially rearranging to indanone 7a upon
heating above room temperature for rotary evaporation; it
also readily decomposed on silica gel chromatography. A
solution of 5o in toluene was thus heated to 60 °C for 60
min to effect conversion to indanone 7a in quantitative yield.
The previous studies of Katzenellenbogen,15 as well as our own
investigations,4 have indicated that allyl-1-alkynyl ethers undergo
rapid sigmatropic rearrangement at low temperatures (-33, -78
°C) once formed. Therefore, we wished to assess if sigmatropic
rearrangement would also take place upon t-BuOK treatment of
R-allyloxy ketone-derived vinyl trifates at -78 °C. Reaction of
prenol or allyl alcohol with R-diazoacetophenone in the presence
of indium triflate furnished R-alkoxyketones 3q and 3r in 88%
and 82% yields, respectively (Scheme 5). Enol triflate 4q, derived
THF solution of 4r at -85 °C led to the clean production of 6d in
95% yield.17 Repetition of this reaction with geraniol instead of
methanol gave rise to γ,δ-unsaturated geranyl ester 6e in 77% yield.
A logical mechanistic pathway (Scheme 6) for this process
may involve hindered alkoxide-induced E2 elimination of
triflate ion from A to produce the corresponding allyl alkynyl
Scheme 6. Mechanistic Proposal for the Formation of
γ,δ-Unsaturated Carboxylic Acid Derivatives
Scheme 5. Synthesis of γ,δ-Unsaturated Esters and Amides
ether B, which undergoes [3,3]-sigmatropic rearrangement
to furnish allyl ketene intermediate C. Nucleophilic trap of
the ketene by the excess alkoxide base or other nucleophile
present leads to enolate D, which is protonated by the
conjugate acid of the base (t-BuOH, menthol, etc.) to furnish
the γ,δ-unsaturated carboxylic acid derivative.
In summary, we have developed an efficient procedure for
the synthesis of a diverse range of alkynyl ethers from
R-diazoketones and alcohols. We have also shown that allyl
and benzyl alkynyl ethers undergo sigmatropic rearrangement
and nucleophilic trapping to produce R-substituted ketones,
esters, and amides. Further studies on this useful low-temper-
ature sigmatropic rearrangement are in progress and will be
reported in due course.
from 3q (LHMDS, Tf2NPh, DMPU, -78 °C-rt), was treated with
3 equiv of potassium tert-butoxide in THF at -78 °C; after the
mixture was warmed to room temperature, tert-butyl ester 6a was
obtained in 78% yield. Performing the same reaction with 3 equiv
each of potassium tert-butoxide and morpholine at -78 °C
furnished amide 6b in 69% yield. Enol triflate 4r, derived from
3r (LHMDS, Tf2NPh, DMPU, -78 °C to rt), was similarly
transformed into menthyl ester 6c (54%, as a 1:1 mixture of
diastereomers) by treatment with 2.5 equiv of the potassium
alkoxide of menthol in THF at -78 °C. Surprisingly, however,
attempts to prepare the simple methyl ester 6d met with little initial
success. Addition of 4r to a solution of excess potassium methoxide
in THF at -78 °C led to the exclusive production of 3r,
presumably arising from nucleophilic attack of methoxide at the
triflate sulfur atom. Addition of KO-t-Bu to a solution of 4r and
methanol at -78 °C also gave rise to 3r as major product, as well
as minor amounts of rearranged methyl and tert-butyl ester
products; inclusion of a tertiary amine catalyst (such as triethy-
lamine)16 led to no improvement in the yields of rearranged
products obtained. Finally, it was found that rapid, sequential
addition of 2.5 equiv of KO-t-Bu and 2.5 equiv of MeOH to a
Acknowledgment. We thank the National Institutes of
Health (SC2 GM081064-01), the ACS Petroleum Research
Fund (No. PRF 45277-B1), and the Henry Dreyfus Teacher-
Scholar Award for their generous support of our research
program. We also thank Mr. Shayan Rab (USC), Mr. Nick
Vidar (CSUN), and Ms. Yen-Nhi Do Nguyen (CSUN) for
preparing 5b, 5c, and 7a, respectively.
Supporting Information Available: Detailed experimen-
1
tal procedures, spectroscopic data, and H and 13C NMR
spectra for all compounds in Tables 1 and 2 and Schemes
3-5, as well as NOESY spectra for compounds 4a and 4h.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL802147H
(16) Tertiary amines have been used extensively to catalyze the addition
of alcohols to ketenes; see: (a) Larsen, R. D.; Corley, E. G.; Davis, P.;
Reider, P. J.; Grabowski, E. J. J. J. Am. Chem. Soc. 1989, 111, 7650. (b)
Cannizaro, C. E.; Houk, K. N. J. Am. Chem. Soc. 2004, 126, 10992. (c)
Pracejus, H.; Kohl, G. Justus Liebigs Ann. Chem. 1969, 722. (d) Hodous,
B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem. Soc. 1999, 121, 2637.
(17) At -85 °C, deprotonation of the enol triflate by KO-t-Bu is rapid,
but nucleophilic addition of KO-t-Bu to the intermediate ketene is slow.
Thus, when methanol is added rapidly after the addition of KO-t-Bu, the
remaining alkoxide base (∼1.5 equiv) rapidly deprotonates methanol to form
potassium methoxide, which then adds to the ketene intermediate to form
the corresponding methyl ester enolate; upon protonation, product 6d results.
(14) Typical reaction temperatures for sigmatropic rearrangement of allyl
phenyl ether range from 170°C (neat) to 220 °C (in diphenyl ether). For
mechanistic investigations of the thermal aromatic Claisen rearrangement,
see: (a) Meyer, M. P.; DelMonte, A. J.; Singleton, D. A. J. Am. Chem.
Soc. 1999, 121, 10865. (b) Kupczyk-Subotkowska, L.; Subotkowski, W.;
Saunders, W. H.; Shine, H. J. J. Am. Chem. Soc. 1992, 114, 3441. (c) Gozzo,
F. C.; Fernandes, S. A.; Rodrigues, D. C.; Eberlin, M. N.; Marsaioli, A. J.
J. Org. Chem. 2003, 68, 5493.
(15) Katzenellenbogen, J. A.; Utawanit, T. Tetrahedron Lett. 1975, 16,
3275.
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