Facile one-pot synthesis of functionalized acetylenes from aryl and heteroaryl aldehydes using lithium trimethylsilyldiazomethane

Article abstract of DOI:10.3987/com-07-s(w)32

The reaction of aryl and heteroaryl aldehydes with lithium trimethylsilyldiazomethane followed by treatment with n-BuLi and then electrophiles in one-pot efficiently afforded functionalized acetylenes.

Full text of DOI:10.3987/com-07-s(w)32

HETEROCYCLES, Vol. 74, 2007
545
HETEROCYCLES, Vol. 74, 2007, pp. 545 - 552. © The Japan Institute of Heterocyclic Chemistry
Received, 17th August, 2007, Accepted, 20th September, 2007, Published online, 21st September, 2007. COM-07-S(W)32
FACILE ONE-POT SYNTHESIS OF FUNCTIONALIZED ACETYLENES
FROM ARYL AND HETEROARYL ALDEHYDES USING LITHIUM
TRIMETHYLSILYLDIAZOMETHANE
Yoshiyuki Hari, Koji Date, and Toyohiko Aoyama*
Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1
Tanabe-dori,
Mizuho,
Nagoya
467-8603,
Japan.
E-mail:
aoyama@phar.nagoya-cu.ac.jp
Abstract – The reaction of aryl and heteroaryl aldehydes with lithium
trimethylsilyldiazomethane followed by treatment with n-BuLi and then
electrophiles in one-pot efficiently afforded functionalized acetylenes.
Functionalized acetylenes are well-known to be useful building blocks in organic synthesis.1 We have
already reported that lithium trimethylsilyldiazomethane (TMSC(Li)N2) smoothly reacted with aldehydes
to give terminal acetylenes via alkylidene carbene intermediates.2 We thought that if the resulting
terminal acetylenes could be converted to functionalized ones in one-pot, the process would provide a
simple and efficient method for the synthesis of functionalized acetylenes from aldehydes. Thus, we
investigated a one-pot synthesis of functionalized acetylenes from aryl and heteroaryl aldehydes. In this
paper, the results are described.
The reaction conditions were examined using 4-methoxybenzaldehyde 1a as an aldehyde and ethyl
chloroformate (ClCO2Et) or ethyl cyanoformate (NCCO2Et) as an electrophile (Table 1). After the
reaction of 1a with TMSC(Li)N2 in THF,3 treatment of the reaction mixture with n-BuLi (1.2 eq.) at
Table 1. Examination of reaction conditions
TMSC(Li)N2 (1.2 eq.)
i) n-BuLi, –78 °C, 0.5 h
MeO
CO2Et
MeO
H
MeO
CHO
ii) XCO2Et, –78 °C, 0.5 h
solvent
–78 °C, 1 h to rt, 0.5 h
1a
2a
Entry
Solvent
Eq. of n-BuLi
XCO2Et
Yield
1
2
3
4
5
THF
THF
THF
THF
Et2O
1.2 eq.
2.0 eq.
3.0 eq.
3.0 eq.
3.0 eq.
ClCO2Et (3.0 eq.)
ClCO2Et (4.0 eq.)
ClCO2Et (5.0 eq.)
NCCO2Et (5.0 eq.)
ClCO2Et (3.0 eq.)
11 %
32 %
74 %
79 %
13 %
This paper is dedicated to Professor Dr. Ekkehard Winterfeldt on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 74, 2007
Table 2. Synthesis of ethyl aryl- and heteroarylpropiolates
i) TMSC(Li)N2 (1.2 eq.), THF
–78 °C, 1 h to rt, 0.5 h
Ar
CO2Et
2b-h
Ar CHO
ii) n-BuLi (3.0 eq.), –78 °C, 0.5 h
iii) XCO2Et (5.0 eq.), –78 °C, 0.5 h
(X = Cl or CN)
1b-h
Entry
1a
Substrate
Yield
(1b)
CHO
69 % (2b)
72 % (2c)
44 % (2d)
52 % (2e)
55 % (2f)
71 % (2g)
60 % (2h)
Me
CHO
OMe
2b
3b
4a
5b
6b
7a
(1c)
(1d)
(1e)
(1f)
(1g)
(1h)
CHO
N
CHO
N
O
CHO
CHO
N
Me
CHO
S
a, NCCO2Et was used as an electrophile. b, ClCO2Et was used as an electrophile.
i) TMSC(Li)N2 (1.2 eq.), THF
–78 °C, 1 h to rt, 0.5 h
CO2Et
CHO
(Eq. 1)
ii) n-BuLi (1.2 eq.), –78 °C, 0.5 h
iii) NCCO2Et (3.0 eq.), –78 °C, 0.5 h
1i
2i (64 %)
–78 °C followed by with ClCO2Et (3.0 eq.) in one-pot afforded the desired arylpropiolate 2a, but the yield
was very low (entry 1). However, an increase in the amount of n-BuLi and ClCO2Et significantly
improved the yield and the use of n-BuLi (3.0 eq.) and ClCO2Et (5.0 eq.) gave the best result affording 2a
(74 % yield) (entries 2 and 3). NCCO2Et, in place of ClCO2Et, could also be efficiently used (79 % yield)
(entry 4). Et2O as a solvent was found to be less effective in this reaction (entry 5).
Under the optimized reaction conditions as shown in entries 3 and 4 of Table 1, the one-pot synthesis of
aryl- and heteroarylpropiolates was examined and the results were summarized in Table 2. Other aryl
aldehdyes 1b and 1c afforded the desired arylpropiolates 2b and 2c in 69 % and 72 % yield, respectively
(entries 1 and 2). Various heteroaryl aldehydes such as pyridyl, furyl, indolyl and benzo[b]thienyl ones
1d-h also successfully underwent this one-pot reaction and the corresponding heteroarylpropiolates 2d-h
were obtained in good to moderate yields (entries 3–7). In addition, this reaction is applicable to aliphatic
aldehydes. For instance, 3-phenylpropanal 1i smoothly gave ethyl 5-phenylpent-2-ynoate 2i in 64 %
yield (Eq. 1).
Finally, the one-pot synthesis of functionalized acetylenes using other electrophiles was examined and the
results were summarized in Table 3. By using N-methoxy-N-methylbenzamide, a Weinreb amide, the
keto acetylene 3 was obtained in 73 % yield (entry 1). Aldehydes, like benzaldehyde and n-hexanal, also

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547
Table 3. Synthesis of other functionalized acetylenes
i) TMSC(Li)N2 (1.2 eq.), THF
–78 °C, 1 h to rt, 0.5 h
MeO
R
1a
ii) n-BuLi (3.0 eq.), –78 °C, 0.5 h
iii) electrophile (5.0 eq.), conditions
3-6
Entry
Electrophile
Conditions
rt, 1 h
–78 °C, 0.5 h
–78 °C, 1 h
0 °C, 2 h
R
COPh
CH(OH)Ph
CH(OH)C5H11
Me
Yield
1
2
3
4
PhCON(Me)OMe
PhCHO
Me(CH2)4CHO
MeI
73 % (3)
80 % (4)
59 % (5)
75 % (6)
underwent the reaction to afford the corresponding hydroxy acetylenes 4 and 5 though the yield of 5 was
somewhat low. The low yield of 5 might be considered to be due to the partial abstraction of the
α-hydrogen of n-hexanal by the remaining acetylide. Furthermore, alkylation with iodomethane smoothly
proceeded to give 6 in good yield (entry 4).
In conclusion, the present method using TMSC(Li)N2 makes possible the easy conversion of aryl and
heteroaryl aldehydes to functionalized acetylenes in a one-pot procedure and will provide an added
flexibility in the synthesis of functionalized acetylenes.
EXPERIMENTAL
All melting points were measured on a Yanagimoto micro melting points apparatus and are uncorrected.
1 13
IR spectra were recorded on a SHIMADZU FTIR-8400S spectrophotometer. H and C NMR spectra
were recorded on a JEOL JNM-EX-270 spectrometer (1H, 270 MHz; C, 67.8 MHz). Mass spectra were
13
recorded on a JEOL JMS-SX-102A spectrometer. The distillation was performed using a Kugelrohr
distillation apparatus.
General procedure for ethyl aryl- or heteroarylpropiolates. Under an argon atmosphere, n-BuLi (1.58
M in hexane, 0.38 mL, 0.6 mmol) was added dropwise to a solution of TMSCHN2 (1.6 M in hexane, 0.38
mL, 0.6 mmol) in THF (4.0 mL) at -78 °C and the mixture was stirred at -78 °C for 0.5 h. A solution of
aryl or heteroaryl aldehyde 1 (0.5 mmol) in THF (1.0 mL) was added dropwise at -78 °C and the mixture
was stirred at -78 °C for 1 h, then at rt for 0.5 h. After addition of n-BuLi (1.58 M in hexane, 0.95 mL, 1.5
mmol) at -78 °C again, the mixture was further stirred at -78 °C for 0.5 h. An electrophile (2.5 mmol) was
added dropwise at -78 °C and the mixture was stirred at -78 °C for 0.5 h. After being quenched with sat.
aqueous NH4Cl at -78 °C, the mixture was extracted with EtOAc (3 times). The organic extracts were
washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (BW-820 MH or BW-200) to give 2.
Ethyl 3-(4-methoxyphenyl)prop-2-ynoate (2a). Prepared from 4-methoxybenzaldehyde 1a (68.3 mg,

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HETEROCYCLES, Vol. 74, 2007
0.5 mmol) and NCCO2Et. The residue was purified by column chromatography on silica gel (BW-200, 8
g, hexane : EtOAc = 20 : 1) to give 2a (80.8 mg, 79 %). Light yellow oil, bp 120 °C / 1.5 mmHg (lit.,4
140 °C / 5 mmHg). IR (neat): 2204, 1701 cm-1. 1H-NMR (CDCl3) δ: 1.35 (t, J = 7.1 Hz, 3H), 3.83 (s, 3H),
13
4.29 (q, J = 7.1 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 8.9 Hz, 2H). C-NMR (CDCl3) δ: 14.2,
55.4, 62.0, 80.1, 86.9, 111.3, 114.2, 134.8, 154.2, 161.3. EI-MS m/z: 204 (M+), 132 (bp).
Ethyl 3-(4-methylphenyl)prop-2-ynoate (2b). Prepared from 4-methylbenzaldehyde 1b (59.3 mg, 0.5
mmol) and NCCO2Et. The residue was purified by column chromatography on silica gel (BW-820 MH,
10 g, hexane : EtOAc = 60 : 1 to 25 : 1) to give 2b (64.5 mg, 69 %). Yellow oil, bp 108 °C / 1.0 mmHg
(lit.,4 120 °C / 2 mmHg). IR (neat): 2208, 1707 cm-1. 1H-NMR (CDCl3) δ: 1.36 (t, J = 7.2 Hz, 3H), 2.38 (s,
13
3H), 4.29 (q, J = 7.2 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H). C-NMR (CDCl3) δ:
14.2, 21.7, 61.9, 80.3, 86.5, 116.4, 129.2, 132.8, 141.1, 154.0. EI-MS m/z: 188 (M+), 116 (bp).
Ethyl 3-(2-methoxyphenyl)prop-2-ynoate (2c). Prepared from 2-methoxybenzaldehyde 1c (65.9 mg, 0.5
mmol) and ClCO2Et. The residue was purified by column chromatography on silica gel (BW-820 MH, 10
g, hexane : EtOAc = 20 : 1) to give 2c (70.9 mg, 72 %). Colorless oil, bp 95 °C / 1.2 mmHg. IR (neat):
1
2212, 1703 cm-1. H-NMR (CDCl3) δ: 1.36 (t, J = 7.2 Hz, 3H), 3.90 (s, 3H), 4.30 (q, J = 7.2 Hz, 2H),
13
6.88-6.98 (m, 2H), 7.37-7.45 (m, 1H), 7.52 (dd, J = 1.6, 7.6 Hz, 1H). C-NMR (CDCl3) δ: 14.2, 55.8,
62.0, 83.1, 84.5, 108.7, 110.7, 120.4, 132.2, 134.8, 154.1, 161.3. EI-MS m/z: 204 (M+), 132 (bp). HR-MS
calcd for C12H12O3: 204.0787, found: 204.0795.
Ethyl 3-(pyridin-2-yl)prop-2-ynoate (2d). Prepared from pyridine-2-carbaldehyde 1d (53.7 mg, 0.5
mmol) and ClCO2Et. The residue was purified by column chromatography on silica gel (BW-820 MH, 8
g, hexane : EtOAc = 10 : 1 to 3 : 1) to give 2d (38.6 mg, 44 %). Light brown crystals, mp 33-34 °C
1
(hexane) and bp 115 °C / 1 mmHg (lit.,5 131 °C / 2.6 mmHg). IR (Nujol): 2216, 1705 cm-1. H-NMR
(CDCl3) δ: 1.35 (t, J = 7.1 Hz, 3H), 4.31 (q, J = 7.1 Hz, 2H), 7.36 (ddd J = 1.2, 4.8, 7.7 Hz, 1H), 7.59 (td,
13
J = 1.2, 7.7 Hz, 1H), 7.73 (dt, J = 1.8, 7.7 Hz, 1H), 8.66 (ddd, J = 1.2, 1.8, 4.8 Hz, 1H). C-NMR
(CDCl3) δ: 14.1, 62.4, 79.1, 83.7, 124.5, 128.4, 136.2, 140.4, 150.4, 153.3. EI-MS m/z: 175 (M+), 130
(bp).
Ethyl 3-(pyridin-3-yl)prop-2-ynoate (2e). Prepared from pyridine-3-carbaldehyde 1e (53.8 mg, 0.5
mmol) and NCCO2Et. The residue was purified by column chromatography on silica gel (BW-820 MH,
10 g, hexane : EtOAc = 10 : 1 to 3 : 1) to give 2e (46.0 mg, 52 %). Yellow oil, bp 105 °C / 2 mmHg (lit.,4
140 °C / 3 mmHg). IR (neat): 2216, 1713 cm-1. 1H-NMR (CDCl3) δ: 1.37 (t, J = 7.2 Hz, 3H), 4.32 (q, J =
7.2 Hz, 2H), 7.33 (dd, J = 4.9, 7.9 Hz, 1H), 7.88 (td, J = 1.7, 7.9 Hz, 1H), 8.66 (dd, J = 1.7, 4.9 Hz, 1H),
13
8.81 (d, J = 1.7 Hz, 1H). C-NMR (CDCl3) δ: 14.1, 62.4, 82.3, 83.5, 116.9, 123.1, 139.7, 150.5, 153.2,
153.4. EI-MS m/z: 175 (M+), 130 (bp).
Ethyl 3-(furan-2-yl)prop-2-ynoate (2f). Prepared from furan-2-carbaldehyde 1f (48.6 mg, 0.5 mmol)

HETEROCYCLES, Vol. 74, 2007
549
and ClCO2Et. The residue was purified by column chromatography on silica gel (BW-820 MH, 8 g,
hexane : EtOAc = 20 : 1) to give 2f (45.6 mg, 55 %). Colorless crystals, mp 37-38 °C (hexane) (lit.,6
39.5-39.8 °C (hexane)) and bp 55 °C / 1.2 mmHg. IR (Nujol): 2210, 1703 cm-1. 1H-NMR (CDCl3) δ: 1.35
(t, J = 7.1 Hz, 3H), 4.30 (q, J = 7.1 Hz, 2H), 6.46 (dd, J = 1.7, 3.5 Hz, 1H), 6.93 (dd, J = 0.5, 3.5 Hz, 1H),
13
7.51 (dd, J = 0.5, 1.7 Hz, 1H). C-NMR (CDCl3) δ: 14.2, 62.2, 76.4, 85.8, 111.5, 120.9, 134.5, 146.1,
153.5. EI-MS m/z: 164 (M+), 92 (bp).
Ethyl 3-(1-methyl-1H-indol-2-yl)prop-2-ynoate (2g). Prepared from 1-methyl-1H-indole-2-
carbaldehyde 1g (79.9 mg, 0.5 mmol) and ClCO2Et. The residue was purified by column chromatography
on silica gel (BW-820 MH, 10 g, hexane : EtOAc = 50 : 1) to give 2g (80.6 mg, 71 %). Colorless crystals,
mp 76 ºC (hexane). IR (Nujol): 2203, 2190, 1698 cm-1. 1H-NMR (CDCl3) δ: 1.38 (t, J = 7.1 Hz, 3H), 3.86
(s, 3H), 4.33 (q, J = 7.1 Hz, 2H), 7.05 (s, 1H), 7.11-7.18 (m, 1H), 7.28-7.38 (m, 2H), 7.62 (d, J = 8.1 Hz,
13
1H). C-NMR (CDCl3) δ: 14.2, 31.0, 62.2, 78.7, 87.4, 109.7, 112.4, 118.3, 120.6, 121.7, 124.7, 126.6,
138.0, 153.8. EI-MS m/z: 227 (M+), 155 (bp). HR-MS calcd for C14H13O2N: 227.0946, found: 227.0943.
Ethyl 3-(benzo[b]thiophen-2-yl)prop-2-ynoate (2h). Prepared from benzo[b]thiophen-2-carbaldehyde
1h (80.7 mg, 0.5 mmol) and NCCO2Et. The residue was purified by column chromatography on silica gel
(BW-820 MH, 10 g, hexane : EtOAc = 100 : 1) to give 2h (68.2 mg, 60 %). Yellow solid, mp 48-49 °C.
1
IR (Nujol): 2210, 1694 cm-1. H-NMR (CDCl3) δ: 1.38 (t, J = 7.1 Hz, 3H), 4.33 (q, J = 7.1 Hz, 2H),
13
7.36-7.49 (m, 2H), 7.73 (s, 1H), 7.77-7.84 (m, 2H). C-NMR (CDCl3) δ: 14.2, 62.3, 79.9, 85.7, 119.2,
122.1, 124.5, 125.0, 126.7, 133.5, 138.3, 141.3, 153.6. EI-MS m/z: 230 (M+), 158 (bp). HR-MS calcd for
C13H10O2S: 230.0402, found: 230.0401.
Ethyl 5-phenylpent-2-ynoate (2i). Under an argon atmosphere, n-BuLi (1.58 M in hexane, 0.38 mL, 0.6
mmol) was added dropwise to a solution of TMSCHN2 (1.6 M in hexane, 0.38 mL, 0.6 mmol) in THF
(4.0 mL) at -78 °C and the mixture was stirred at -78 °C for 0.5 h. A solution of 3-phenylpropanal 1i
(68.3 mg, 0.5 mmol) in THF (1.0 mL) was added dropwise at -78 °C and the mixture was stirred at -78 °C
for 1 h, then at rt for 0.5 h. After addition of n-BuLi (1.58 M in hexane, 0.38 mL, 0.6 mmol) at -78 °C
again, the mixture was further stirred at -78 °C for 0.5 h. NCCO2Et (0.15 mL, 1.5 mmol) was added
dropwise at -78 °C and the mixture was stirred at -78 °C for 0.5 h. After being quenched with sat.
aqueous NH4Cl at -78 °C, the mixture was extracted with EtOAc (3 times). The organic extracts were
washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (BW-820 MH, 10 g, hexane : EtOAc = 100 : 1 to 20 : 1) to give 2i
1
(65.4 mg, 64 %). Colorless oil, bp 60 °C / 0.4 mmHg. IR (neat): 2235, 1711 cm-1. H-NMR (CDCl3) δ:
1.29 (t, J = 7.1 Hz, 3H), 2.61 (t, J = 7.6 Hz, 2H), 2.89 (t, J = 7.6 Hz, 2H), 4.20 (q, J = 7.1 Hz, 2H),
13
7.16-7.34 (m, 5H). C-NMR (CDCl3) δ: 14.1, 20.9, 33.9, 61.8, 73.7, 88.2, 126.5, 128.2, 128.4, 139.5,
153.5. MS m/z: 202 (M+), 91(bp). Anal. Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C, 77.06; H, 7.23.

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HETEROCYCLES, Vol. 74, 2007
3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-one (3). Under an argon atmosphere, n-BuLi (1.58 M in
hexane, 0.38 mL, 0.6 mmol) was added dropwise to a solution of TMSCHN2 (1.6 M in hexane, 0.38 mL,
0.6 mmol) in THF (4.0 mL) at -78 °C and the mixture was stirred at -78 °C for 0.5 h. A solution of 1a
(68.4 mg, 0.5 mmol) in THF (1.0 mL) was added dropwise at -78 °C and the mixture was stirred at -78 °C
for 1 h, then at rt for 0.5 h. After addition of n-BuLi (1.58 M in hexane, 0.95 mL, 1.5 mmol) at -78 °C
again, the mixture was further stirred at -78 °C for 0.5 h. N-Methoxy-N-methylbeznamide (0.38 mL, 2.5
mmol) was added dropwise at -78 °C and the mixture was stirred at rt for 1 h. After being quenched with
sat. aqueous NH4Cl at rt, the mixture was extracted with EtOAc (3 times). The organic extracts were
washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (BW-200, 13 g, hexane : ethyl acetate = 30 : 1) to give 3 (86.3 mg,
73 %). Colorless crystals, mp 81-82 °C (hexane-EtOAc) (lit.,7 81 °C). IR (Nujol): 2188, 1626 cm-1.
1H-NMR (CDCl3) δ: 3.86 (s, 3H), 6.94 (d, J = 8.7 Hz, 2H), 7.51 (t, J = 7.2 Hz, 2H), 7.62 (t, J = 7.2 Hz,
13
1H), 7.65 (d, J = 8.7 Hz, 2H), 8.21 (d, J = 7.2 Hz, 2H). C-NMR (CDCl3) δ: 55.5, 86.8, 94.3, 111.8,
114.3, 128.4, 129.4, 133.8, 135.0, 136.9, 161.5, 177.9. EI-MS m/z: 236 (M+, bp).
3-(4-Methoxyphenyl)-1-phenylprop-2-yn-1-ol (4). Under an argon atmosphere, n-BuLi (1.58 M in
hexane, 0.38 mL, 0.6 mmol) was added dropwise to a solution of TMSCHN2 (1.6 M in hexane, 0.38 mL,
0.6 mmol) in THF (4.0 mL) at -78 °C and the mixture was stirred at -78 °C for 0.5 h. A solution of 1a
(68.4 mg, 0.5 mmol) in THF (1.0 mL) was added dropwise at -78 °C and the mixture was stirred at -78 °C
for 1 h, then at rt for 0.5 h. After addition of n-BuLi (1.58 M in hexane, 0.95 mL, 1.5 mmol) at -78 °C
again, the mixture was further stirred at -78 °C for 0.5 h. Benzaldehyde (255 µL, 2.5 mmol) was added
dropwise at -78 °C and the mixture was stirred at -78 °C for 0.5 h. After being quenched with sat.
aqueous NH4Cl at -78 °C, the mixture was extracted with EtOAc (3 times). The organic extracts were
washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (BW-200, 15 g, hexane : EtOAc = 20 : 1 to 5 : 1) to give 4 (96.1 mg,
80 %). Yellow oil, bp 140 °C / 2 mmHg. IR (neat): 3404, 2226 cm-1. 1H-NMR (CDCl3) δ: 2.23 (d, J = 5.9
Hz, 1H → disappeared with D2O), 3.81 (s, 3H), 5.68 (d, J = 5.9 Hz, 1H → s, 1H with D2O), 6.84 (d, J =
13
8.9 Hz, 2H), 7.33-7.44 (m, 5H), 7.59-7.65 (m, 2H). C-NMR (CDCl3) δ: 55.3, 65.2, 86.6, 87.3, 113.8,
114.3, 126.6, 128.3, 128.5, 133.1, 140.7, 159.6. EI-MS m/z: 238 (M+, bp). HR-MS calcd for C16H14O2:
238.0994, found: 238.0990.
3-(4-Methoxyphenyl)-oct-2-yn-3-ol (5). Under an argon atmosphere, n-BuLi (1.58 M in hexane, 0.38
mL, 0.6 mmol) was added dropwise to a solution of TMSCHN2 (1.6 M in hexane, 0.38 mL, 0.6 mmol) in
THF (4.0 mL) at -78 °C and the mixture was stirred at -78 °C for 0.5 h. A solution of 1a (69.2 mg, 0.5
mmol) in THF (1.0 mL) was added dropwise at -78 °C and the mixture was stirred at -78 °C for 1 h, then
at rt for 0.5 h. After addition of n-BuLi (1.58 M in hexane, 0.95 mL, 1.5 mmol) at -78 °C again, the

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mixture was further stirred at -78 °C for 0.5 h. n-Hexanal (0.3 mL, 2.5 mmol) was added dropwise at
-78 °C and the mixture was stirred at -78 °C for 1 h. After being quenched with sat. aqueous NH4Cl at
-78 °C, the mixture was extracted with EtOAc (3 times). The organic extracts were washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (BW-200, 10 g, hexane : EtOAc = 30 : 1 to 10 : 1) to give 5 (69.1 mg,
1
59 %). Yellow oil, bp 110 °C / 2.5 mmHg. IR (neat): 3354, 2227 cm-1. H-NMR (CDCl3) δ: 0.91 (t, J =
6.8 Hz, 3H), 1.30-1.40 (m, 4H), 1.45-1.58 (m, 2H), 1.72-1.93 (m, 3H → m, 2H with D2O), 3.81 (s, 3H),
13
4.58 (t, J = 6.6 Hz, 1H), 6.83 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H). C-NMR (CDCl3) δ: 14.1,
22.7, 25.0, 31.6, 38.0, 55.3, 63.1, 84.7, 88.8, 113.8, 114.6, 133.0, 159.4. EI-MS m/z: 232 (M+), 161 (bp).
HR-MS calcd for C15H20O2: 232.1463, found: 232.1463.
1-Methoxy-4-(prop-1-ynyl)benzene (6). Under an argon atmosphere, n-BuLi (1.58 M in hexane, 0.38
mL, 0.6 mmol) was added dropwise to a solution of TMSCHN2 (1.6 M in hexane, 0.38 mL, 0.6 mmol) in
THF (4.0 mL) at -78 °C and the mixture was stirred at -78 °C for 0.5 h. A solution of 1a (67.7 mg, 0.5
mmol) in THF (1.0 mL) was added dropwise at -78 °C and the mixture was stirred at -78 °C for 1 h, then
at rt for 0.5 h. After addition of n-BuLi (1.58 M in hexane, 0.95 mL, 1.5 mmol) at -78 °C again, the
mixture was further stirred at -78 °C for 0.5 h. Iodomethane (0.16 mL, 2.5 mmol) was added dropwise at
-78 °C and the mixture was stirred at -78 °C for 1 h. After being quenched with sat. aqueous NH4Cl at
-78 °C, the mixture was extracted with EtOAc (3 times). The organic extracts were washed with water
and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (BW-200, 10 g, hexane : EtOAc = 30 : 1) to give 6 (56.0, mg, 75 %).
Colorless oil, bp 75 °C / 1.2 mmHg (lit.,8 115-117 °C / 9 mmHg). IR (neat): 2042 cm-1. 1H-NMR (CDCl3)
δ: 2.03 (s, 3H), 3.79 (s, 3H), 6.81 (d, J = 8.9 Hz, 2H), 7.32 (d, J = 8.9 Hz, 2H). 13C-NMR (CDCl3) δ: 4.4,
55.3, 79.4, 84.1, 113.7, 116.0, 132.7, 158.8. EI-MS m/z: 146 (M+, bp).
ACKNOWLEDGEMENTS
This work was financially supported by a Grant-in-Aid for Scientific Research (KAKENHI).
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