One-Pot Synthesis of Allenyl and Alkynyl Esters
TABLE 3. Synthesis of 3-Alkynyl and Allenyl Esters via Enyne
Dianions
NMR (100 MHz, CDCl3) δ 153.8, 89.2, 73.2, 61.7, 21.0, 20.5, 14.0,
13.4; HRMS calcd for C8H12O2 [M + H]+ 141.0910, found
141.0899.
Procedure for the Synthesis of Alkynyl Ester 8. To a round-
bottom flask (50 mL) under argon were added dry THF (7 mL)
and LiHMDS (4 mL, 1.0 M in THF). The solution was then
cooled to -78 °C (acetone/dry ice bath), followed by the addition
of ꢀ-ketoester (2 mmol). After stirring for 45 min, BnBr (2
mmol) was added dropwise followed by warming slowly to room
temperature over the course of 6 h. The reaction mixture was
then cooled to -78 °C and charged with LiHMDS (2 mL, 1.0
M in THF). After for 45 min, Tf2O (2 mmol) was added slowly
over 15 min, and the reaction was stirred overnight, slowly
warming to room temperature, and quenched with saturated
NH4Cl solution. The organic layer was separated, the aqueous
fraction was extracted with ether, and the organic layers were
combined and dried with anhydrous Na2SO4. The product was
purified by silica gel chromatography in the usual manner using
1-2% EtOAc in hexanes.
product
entry
R
R′3Si
(% yield)a
1
2
3
Et
Et
H
TMS
TIPS
TMS
9c (25)
19 (87)
18a (55)
18b (78)
Ethyl 5-Phenylpent-2-ynoate (8): 1H NMR (400 MHz, CDCl3)
δ 7.40-7.22 (m, 5H), 4.21 (q, J ) 7.2 Hz, 2H), 2.89 (t, J ) 7.6
Hz, 2H), 2.61 (t, J ) 7.6 Hz, 2H), 1.30 (t, J ) 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 154.0, 139.9, 128.8, 128.6, 126.9, 88.5,
73.9, 62.1, 34.1, 21.1, 14.3; HRMS calcd for C13H14O2 [M + H]+
203.1067, found 203.1059.
a Isolated yields.
The same reaction sequence with 15 (R ) Et) using TIPSCl
led to the exclusive formation of allenyl ester 18b. This finding
with the much larger TIPS group in the R-position parallels the
trend of substrates with R-substitution from the monoanion
reactions (Table 2 and Figure 2). The synthesis of product 18b
from 6 is also significant since no other substrate with
γ-substitution discussed thus far has been converted exclusively
to an allenyl ester product. Deprotonation of 6, where R ) H,
led to intermediate 16, which upon silylation gave deconjugated
product 19.
General Procedure for Deconjugated Alkyne/Conjugated
Allene Isomers via Monoanionic Enyne Enolate with ZnCl2
Additive. To a round-bottom flask (50 mL) under argon were
added dry THF (7 mL) and LiHMDS (4 mL, 1.0 M in THF).
The solution was then cooled to -78 °C (acetone/dry ice bath)
followed by the addition of ꢀ-ketoester (2 mmol). After stirring
for 45 min, triflic anhydride (2 mmol) was added slowly over
15 min. The reaction was maintained at -78 °C with stirring
for an additional 1 h followed by the addition of LiHMDS (2
mmol). The mixture was stirred at -78 °C for an additional 30
min followed by the addition of HMPA (7 mmol). After stirring
at -78 °C for an additional 30 min, ZnCl2 (2.4 mmol) was added
as an ether solution. The reaction was quenched after an
additional 30 min by pouring into an ice-cold stirring biphasic
mixture of ether and saturated aqueous NH4Cl. NMR spectra
were recorded after workup for each reaction, confirming the
formation of only conjugated allene which were compared with
literature references (except for 10h).
Conclusion
Conditions have been developed to selectively convert a
series of ꢀ-ketoesters to conjugated allenyl, alkynyl, or
ꢀ-deconjugated alkynyl esters. Following a neutral, monoan-
ion, or dianion mechanistic rationale, our method involves a
one-pot stepwise addition of LiHMDS, triflic anhydride, and
quenching under varying conditions to bring about dehydra-
tion. Our investigation has also uncovered an efficient
synthesis of ketene acetal intermediate 17 that preferentially
adds proton at the γ-position to form allene product. We are
currently exploring the reactivity of these types of intermedi-
ates with other electrophiles for the potential development
of an asymmetric allene synthesis method.
tert-Butyl-2-n-butylallenylester (10h): 1H NMR (400 MHz,
CDCl3) δ 5.05 (t, J ) 3.03 Hz, 2H), 2.18 (m, 2H), 1.47 (s, 9H),
1.45-1.30 (m, 4H), 0.91 (t, J ) 7.19 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 213.6, 166.6, 101.7, 80.7, 30.2, 28.0, 27.7, 22.3,
13.9; HRMS calcd for C12H20O2 [M + H]+ 197.1542, found
197.1543.
General Procedures for Silylated Deconjugated Alkyne/
Conjugated Allene Isomers via Dianionic Enolate. To a round-
bottom flask (50 mL) under argon were added dry THF (7 mL)
and LiHMDS (4 mL, 1.0 M in THF). The solution was then cooled
to -95 °C (methanol/liquid N2 bath) followed by addition of
ꢀ-ketoester (2 mmol). After stirring for 1 h, triflic anhydride (2
mmol) was added slowly over 15 min. Since Tf2O is a solid at this
reaction temperature, the slow addition should be accompanied by
vigorous stirring. Alternatively, Tf2O can be added as ether solution
(not in THF since this solvent reacts to form polymer at room
temperature). The reaction mixture was stirred for an additional
1 h at -95 °C followed by the addition of LiHMDS (4 mL, 1.0 M
in THF). After an additional 1 h at -95 °C, R3SiCl (6 mmol) was
added dropwise followed by warming to room temperature over
1 h and quenching with saturated NH4Cl solution. The organic layer
was separated, the aqueous fraction was extracted with ether, and
the organic layers were combined and dried with anhydrous Na2SO4.
The product was purified by silica gel chromatography in the usual
manner using 1-2% EtOAc in hexanes.
Experimental Section
General Procedure for the Synthesis of Conjugate Alkynes
2. To a round-bottom flask (50 mL) under argon were added dry
THF (7 mL) and LiHMDS (4 mL, 1.0 M in THF). The solution
was then cooled to -78 °C (acetone/dry ice bath) followed by the
addition of ꢀ-ketoester (2 mmol). After stirring for 45 min, triflic
anhydride (2 mmol) was added slowly over 15 min. The reaction
was then stirred overnight, slowly warming to room temperature,
and quenched with saturated NH4Cl solution. The organic layer
was separated, the aqueous fraction was extracted with ether, and
the organic layers were combined and dried with anhydrous Na2SO4.
The product was purified by silica gel chromatography in the usual
manner using 1-2% EtOAc in hexanes.
1
Ethyl Hex-2-ynoate (2d): H NMR (400 MHz, CDCl3) δ 4.22
(q, J ) 7.14 Hz, 2H), 2.31 (t, J ) 7.1 Hz, 2H), 1.66-1.57 (m,
2H), 1.31 (t, J ) 7.14 Hz, 3H), 1.02 (t, J ) 7.38 Hz, 3H); 13C
J. Org. Chem. Vol. 74, No. 1, 2009 161