Novel One-Pot Synthetic Method for Propargyl Alcohol Derivatives from Allyl Alcohol Derivatives

Article abstract of DOI:10.1055/s-0034-1380499

An efficient one-pot procedure for the synthesis of propargyl alcohol derivatives from allyl alcohol derivatives has been developed. The key to this transformation from a C-C double bond to a C-C triple bond is that hydrogen bromide elimination from 1,2-dibromoalkanes that contain a neighboring oxygen functional group is promoted by the inductive electron-withdrawing effect of the oxygen functional group. In the one-pot reaction, tetrabutylammonium hydroxide was the best base, and the addition of molecular sieves 13X also promoted the reaction.

Full text of DOI:10.1055/s-0034-1380499

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1844–1850
paper
1844
N. Kutsumura et al.
Paper
Synthesis
Novel One-Pot Synthetic Method for Propargyl Alcohol Deriva-
tives from Allyl Alcohol Derivatives
Noriki Kutsumura*a,b
one-pot method A
Mai Inagakia
Akito Kirisekoa
Takao Saito*a
R3
i) Py·HBr3, MS13X, MeCN, r.t.
R4
R2
R3
ii) TBAOH, DMSO, 60 °C
one-pot method B
R2
OR1 R4
OR1
i) Py·HBr3, MS 13X, MeCN, r.t.
allyl alcohol
derivatives
a Department of Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka,
Shinjuku-ku, Tokyo 162-8601, Japan
propargyl alcohol
derivatives
ii) TBAOH, Et3N, DMSO, 60 °C
tsaito@rs.kagu.tus.ac.jp
b International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba,
1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan
kutsumura.noriki.gn@u.tsukuba.ac.jp
The paper is dedicated to Professor Amos B. Smith, III, on the occasion of his 70th birthday.
Received: 02.02.2015
Accepted after revision: 02.03.2015
Published online: 08.04.2015
possible to produce the alkynes or their intermediates, the
vinyl bromides, under milder conditions than previously
reported.5 Against this research background, that is, unique
hydrogen bromide elimination effected by the electronega-
tivity of the neighboring oxygen atom, we initiated the de-
velopment of a novel one-pot transformation of allyl alco-
hol derivatives to the corresponding propargyl alcohol de-
rivatives (Scheme 1, equation 3). In this paper, we disclose
the intriguing results and full details.
DOI: 10.1055/s-0034-1380499; Art ID: ss-2015-f0081-op
Abstract An efficient one-pot procedure for the synthesis of propargyl
alcohol derivatives from allyl alcohol derivatives has been developed.
The key to this transformation from a C–C double bond to a C–C triple
bond is that hydrogen bromide elimination from 1,2-dibromoalkanes
that contain a neighboring oxygen functional group is promoted by the
inductive electron-withdrawing effect of the oxygen functional group.
In the one-pot reaction, tetrabutylammonium hydroxide was the best
base, and the addition of molecular sieves 13X also promoted the reac-
tion.
previous work 1 (one-pot synthesis)
Py·HBr3
K2CO3
Br
R3
R3
R4
R2
OR1
R4
R2
Key words elimination, one-pot synthesis, propargyl alcohol deriva-
tives, allyl alcohol derivatives, neighboring-group effects
DCE
or MeCN
Br
OR1
R5
Br
C–C bond
formation
R3
R3
Propargyl alcohols are key synthetic intermediates for
many biologically natural products, their effective ana-
logues, and agricultural and pharmaceutical chemicals, be-
cause of the transformational versatility of both the C–C tri-
ple bond and the oxygen functional group.1 The general
synthetic method for both chiral and achiral propargyl alco-
hols is the addition of acetylenes to carbonyl compounds.2
We recently reported a one-pot synthetic procedure for
vinyl bromides and di- or trisubstituted alkenes from ter-
minal or internal disubstituted alkenes having an oxygen
functional group at the adjacent position (Scheme 1, equa-
tion 1).3 Notably, these sequential reactions proceed in high
yield and selectivity in the same vessel, and the key factor is
DBU
R2
OR1
R2
OR1
(1)
(2)
trans HBr
elimination
R4
R4
previous work 2 (TBAF-promoted alkyne synthesis)
Br
Br
R3
R3
R3
TBAF (5.0 equiv)
DMF, 60 °C
R2
OR1
R2
OR1
R2
Br
OR1
use of TBAF (1.1 equiv) gave the vinyl bromide
this work (one-pot alkyne synthesis)
Br
Py·HBr3
R3
R3
R2
K2CO3
Br
R2
OR1
1,8-diazabicyclo[5.4.0]undec-7-ene-promoted
hydrogen
R4
OR1
R4
Br
bromide elimination utilizing the inductive electron-with-
drawing effects of the neighboring oxygen functional group
in the second reaction. Aside from this one-pot synthesis,
we also reported a novel synthesis of alkynes from 1,2-di-
bromoalkanes having a neighboring oxygen functional
group, by a tetrabutylammonium fluoride mediated trans-
formation (Scheme 1, equation 2).4 This elimination made it
Z-alkene
or R4 = H
R4
R3
R3
base
R4
R2
R2
OR1
(3)
OR1
Scheme 1
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1844–1850

1845
N. Kutsumura et al.
Paper
Synthesis
Based on our previous research results,3,4 the study
started with the benzyl-protected allyl alcohol 1a as a sub-
strate, which was treated with pyridinium bromide perbro-
mide (pyridinium tribromide, py·HBr3) and the subsequent
tetrabutylammonium fluoride (5.0 equiv) promoted hydro-
gen bromide elimination in one pot. Screening of the sol-
vents is shown in Table 1. After the bromine addition in 1,2-
dichloroethane or acetonitrile at room temperature, tetra-
butylammonium fluoride (5 equiv; 1.0 M THF solution) was
added to the same pot and then the reaction system was
stirred at 60 °C for six hours (entries 1 and 2). However,
elimination did not provide the desired benzyl-protected
propargyl alcohol 4a, and dibromoalkane 2a or vinyl bro-
mide 3a was still present. On the other hand, when the
aprotic polar solvent N,N-dimethylformamide or dimethyl
sulfoxide was used, the bromine addition was not complet-
ed, and thus the subsequent elimination was not carried
out (entries 3 and 4). Therefore, after the bromine addition
in acetonitrile, tetrabutylammonium fluoride and N,N-di-
methylformamide or dimethyl sulfoxide of seven times the
volume of acetonitrile was added (entries 5 and 6). As a re-
sult, the mixed solvent system (MeCN–DMSO, 1:7) was the
most effective for the second tetrabutylammonium fluoride
promoted elimination process (entry 6).
Table 2 Screening of Counteranions of Quaternary Ammonium Bases
Br
.
i) Py HBr3 (1.1 equiv)
BnO
BnO
MeCN, r.t., 12 h
Br
Br
BnO
2a
3a
ii) base (5.0 equiv)
DMSO, 60 °C, 6 h
1a
BnO
4a
Entry
Base
Yield (%)
1a
2a
3a
38
4a
1
2
3
4
5
TBAF
0
0
0
0
0
0
50
0
TBACl
97
92
91
0
0
0
0
0
TBAB
0
TBAOAca
TBAOHb
0
83
a TBAOAc = tetrabutylammonium acetate.6
b TBAOH = tetrabutylammonium hydroxide (40% in water).
To accelerate the reaction effectively under milder con-
ditions, the consecutive bromine addition–tetrabutylam-
monium hydroxide promoted hydrogen bromide elimina-
tion was further examined in the presence of an additive
(Table 3). Initially, tetrabutylammonium hydroxide (4.0
equiv) was used without any additive; however, the elimi-
nation was not complete and the intermediate, vinyl bro-
mide 3a, was still present (entry 2). Previous studies of one-
pot methods3 showed that when potassium carbonate (1.1
equiv) was added as a hydrogen bromide scavenger at the
first reaction stage, the elimination proceeded successfully
despite the presence of tetrabutylammonium hydroxide
(4.0 equiv; entry 3). A variety of molecular sieves were also
examined instead of potassium carbonate on the basis of
reports that the appropriate molecular sieve can be an ef-
fective hydrogen bromide trapping agent (entries 4–7).7 Al-
though activated molecular sieves MS 3A and MS 4A did not
affect the efficacy, MS 5A and MS 13X, whose pore diame-
ters are larger, acted in a manner similar to that of potassi-
um carbonate (entries 6 and 7). With the most effective ad-
ditive, MS 13X, the required amount of tetrabutylammoni-
um hydroxide could be successfully reduced to 3.5
equivalents (entry 8, for reference entries 9 and 10). In ad-
dition, the use of 1.1 equivalents of triethylamine and 3.1
equivalents of tetrabutylammonium hydroxide for the hy-
drogen bromide elimination also afforded the desired ben-
zyl-protected propargyl alcohol 4a in almost quantitative
yield (entry 11).
Table 1 Screening of Solvents
Br
i) Py·HBr3 (1.1 equiv)
solvent 1, r.t., 12 h
BnO
2a
BnO
Br
Br
BnO
3a
ii) TBAF (5.0 equiv)
solvent 2, 60 °C, 6 h
1a
BnO
4a
Entry
Solvent 1
Solvent 2a
Yield (%)
1a
2a
12
3a
73
4a
1
DCE
−
0
0
0
0
2
MeCN
DMF
−
0
74
61
0
98
−
3b
4b
5
−
11
28
0
−
DMSO
MeCN
MeCN
−
−
−
DMF
DMSO
80
38
16
50
6
0
0
a Before the addition of TBAF, solvent 2 (7 times the volume of solvent 1)
was added at the second elimination step.
b The elimination process was not carried out, because the first bromine
addition was not completed.
Next, we examined a variety of counteranions (chloride,
bromide, acetate,6 and hydroxide) of the quaternary ammo-
nium salt as a base for the hydrogen bromide elimination,
instead of tetrabutylammonium fluoride (Table 2). Howev-
er, most of the bases did not give the desired compound 4a
(entries 2–4). Significantly, a solution of 40% tetrabutylam-
monium hydroxide in water gave 4a in 83% yield (entry 5).
To confirm the generality of the one-pot synthesis of
propargyl alcohol derivatives 4, we examined a variety of
allyl alcohol derivatives 1 using optimized method A (Table
3, entry 8) and/or B (entry 11). The reactions of the allyl al-
cohols protected with substituted benzyl (1a–c) and phenyl
(1d) groups generally afforded the desired propargyl alco-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1844–1850

1846
N. Kutsumura et al.
Paper
Synthesis
Table 3 Screening of Additives
ide used. As reported in our previous research,9 neighboring
oxygen functional group participation is an important fac-
tor in this synthetic procedure.
i) Py.HBr3 (1.1 equiv)
additive (x equiv)
MeCN, r.t., 12 h
BnO
BnO
BnO
Table 4 Synthesis of Propargyl Alcohol Derivatives 4 from Allyl Alcohol
Derivatives 1 in a One-Pot Procedure
Br
ii) TBAOH (y equiv)
DMSO, 60 °C, 6 h
1a
4a
3a
method A
Entry
Additive (x equiv)
TBAOH
(y equiv)
Yield (%)
3a
.
i) Py HBr3 (1.1 equiv)
4a
MS 13X, MeCN, r.t., 12 h
R4
ii) TBAOH (3.5 equiv)
DMSO, 60 °C, time
1
2
−
5.0
4.0
4.0
4.0
4.0
4.0
4.0
3.5
3.5
3.1
3.1
0
83
R3
R3
R2
R2
−
16
0
70
82
72
76
83
93
96
27
75
95
method B
OR1 R4
OR1
.
i) Py HBr3 (1.1 equiv)
3
K2CO3 (1.1)
MS 3A
MS 13X, MeCN, r.t., 12 h
4a
10
11
0
1
4
ii) TBAOH (3.1 equiv), Et3N (1.1 equiv)
DMSO, 60 °C, time
5a
MS 4A
6a
MS 5A
Entry Product
Method Time Yield
7a,b
8a
MS 13X
MS 13X
−
0
(h)
(%)
0
1
2
A
B
2
2
95
96
BnO
9c
50
11
0
4a
4b
10a
11a,b,d
MS 13X
MS 13X, Et3N (1.1)
3
4
A
B
2
2
82
91
PMBO
a All molecular sieves (MS) were powdered (< 10 μm) and activated. MS of
10 times the mass of 1a was used.
O
5
6
A
B
2
2
67
96
4c
b The second HBr elimination reaction time was 2 h.
c The second HBr elimination reaction time was 9 h.
d Et3N (1.1 equiv) was added together with DMSO and TBAOH.
Cl
Br
O
7
8
A
B
3
3
80
74
4d
hol derivatives 4a–d in good yields by both methods (Table
4, entries 1–8). However, the reaction of 1e, containing a 4-
nitrophenyl group, gave 4e with unsatisfactory yield be-
cause overreaction gave the undesired corresponding al-
lenes (entries 9 and 10).8 The reactions of the benzoyl-pro-
tected 1f and silyl-protected 1g also gave 4f in low yield
and 4g in moderate yield, respectively, because the bromine
addition of 1f was not completed and the triisopropylsilyl
group of 1g was only partly removed (entries 11 and 12).
Next, we examined more complicated substrates. For sec-
ondary alcohol derivatives 1h, 1i, 1j, and 1k, the reaction
yields were sufficient (entries 13–20), although p-meth-
oxybenzyl-protected tertiary alcohol 4l was also produced
in low yield (entries 21 and 22). In addition, compounds
4m–r, with an internal C–C triple bond, were produced in
good yields from the corresponding Z-allyl alcohol deriva-
tives 1m–r through double trans hydrogen bromide elimi-
nations.
In summary, we have established a novel one-pot syn-
thesis of propargyl alcohol derivatives 4 from allyl alcohol
derivatives 1 through double trans hydrogen bromide elim-
inations promoted by tetrabutylammonium hydroxide.
Both the one-pot methods should be applicable to the total
synthesis of natural products and for use in modern drug-
discovery research. In addition, method B might be more
suitable for base-sensitive substrates than method A, be-
cause of the small amount of tetrabutylammonium hydrox-
O2N
9
10
A
B
1
1
41a
42b
4e
4f
O
O
11
B
7
8
12c
49
O
MeO
12
TIPSO
4g
4h
Bd
13
14
A
B
4
4
74
70
PMBO
HO
9
15
16
A
B
6
7
83
72
4i
PMBO
Br
17
18
A
B
2
2
83
87
4j
O
BnO
9
19
20
A
B
6
6
74
75
4k
PMBO
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1844–1850

1847
N. Kutsumura et al.
Paper
Synthesis
Table (continued)
Entry Product
One-Pot Synthesis of 4 by Method B; General Procedure
A mixture of allyl alcohol derivative 1 (x g, 1.0 equiv), py·HBr3 (1.1
equiv), and MS 13X (ca. 10x g) in MeCN (y mL, 0.1 M) was stirred at
r.t. for 12–14 h. Then, DMSO (7y mL), TBAOH (3.1 equiv, 40% in H2O),
and Et3N (1.1 equiv) were added to the reaction mixture at 0 °C and
the system was heated to 60 °C. The reaction was quenched with sat.
aq NH4Cl at 0 °C. After the removal of MS 13X through a cotton filter,
the resulting filtrate was extracted with hexane–EtOAc (2:1, 3 × 30
mL) and dried (MgSO4). The combined extracts were concentrated
under reduced pressure, and the residue was purified by column
chromatography (silica gel) to afford the propargyl alcohol derivative
4.
Method Time Yield
(h)
(%)
n-Bu
n-Bu
21
A
B
4
4
26e
4l
22
31f
PMBO
23
24
A
B
1
1
89
87
4-NO2C6H4O
4m
n-Pr
25
26
A
B
2
3
77
82
4-MeOC6H4O
4-ClC6H4CH2O
PMBO
4n
n-Pr
1-{[(4-Ethyloct-1-en-3-yl)oxy]methyl}-4-methoxybenzene (1h)
Yield: 1.44 g (54%); colorless oil.12
27
28
A
B
4
6
85
80
4o
n-Pr
IR (neat): 3074, 2958, 2870 cm–1
.
29
30
A
0.3
82
85
1H NMR (500 MHz, CDCl3): δ = 0.83–0.87 (m, 6 H), 1.12–1.53 (m, 9 H),
3.63 (dd, J = 13.4, 5.8 Hz, 1 H), 3.80 (s, 3 H), 4.25 (d, J = 10.0 Hz, 1 H),
4.52 (d, J = 10.0 Hz, 1 H), 5.18 (dd, J = 18.0, 1.8 Hz, 1 H), 5.26 (dd,
J = 10.5, 1.8 Hz, 1 H), 5.73 (ddd, J = 18.0, 10.5, 5.8 Hz, 1 H), 6.86 (d,
J = 8.5 Hz, 2 H), 7.25 (d, J = 8.5 Hz, 2 H).
4p
B
0.3
Ph
31
32
PMBO
A
B
8
8
76
79
4q
OBn
13C NMR (126 MHz, CDCl3): δ = 11.1 (CH3), 14.0 (CH3), 21.9 (CH2), 23.0
(CH2), 28.6 (CH2), 29.1 (CH2), 43.9 (CH), 55.0 (CH3), 69.7 (CH2), 82.1
(CH), 113.6 (CH × 2), 117.4 (CH2), 129.1 (CH × 2), 131.1 (C), 137.7
(CH), 158.9 (C); δ (diastereomer) = 11.4 (CH3), 14.0 (CH3), 22.2 (CH2),
23.1 (CH2), 28.7 (CH2), 29.3 (CH2), 44.0 (CH), 55.0 (CH3), 69.7 (CH2),
82.2 (CH), 113.6 (CH × 2), 117.4, (CH2), 129.1 (CH × 2), 131.1 (C), 137.7
(CH), 158.9 (C).
33
34
Ag
6
6
72
75
PMBO
4r
Bh
OH
a The corresponding allene was obtained (42%).
b The corresponding allene was obtained (38%).
c Starting material 1f was recovered (40%).
d TBAOH (10% in MeOH) was used.
e Starting material 1l was recovered (42%).
f Starting material 1l was recovered (43%).
g TBAOH (40% in H2O, 5.5 equiv) was used.
h TBAOH (40% in H2O, 5.1 equiv) was used.
ESI-HRMS: m/z [M + Na]+ calcd for C18H28O2Na: 299.1982; found:
299.1985.
10-[(4-Methoxybenzyl)oxy]dodec-11-en-1-ol (1i)
Yield: 299 mg (89%); colorless oil.12
IR spectra were recorded with a Horiba FT-710 model spectropho-
tometer. 1H and 13C NMR spectral data were obtained with a JEOL
JNM-LA 500 or a JEOL JNM-AL 300 instrument. Chemical shifts are
quoted in ppm using TMS (δ = 0 ppm) as the reference for 1H NMR
spectroscopy, and CDCl3 (δ = 77.0 ppm) for 13C NMR spectroscopy.
Mass spectra were measured with a Bruker Daltonics microTOF or a
Hitachi double-focusing M-80B spectrometer. Column chromatogra-
phy was carried out on silica gel (Kanto Chemical Co. or Merck Co.,
Ltd). All reactions were performed under an argon atmosphere. Allyl
alcohol derivatives 1a–g, 1j, 1m, 1n, and 1r are known and their ana-
lytical data have been reported.10 Propargyl alcohol derivatives 4a–g,
4j, 4m, 4n, and 4r are known and their analytical data have been re-
ported.11
IR (neat): 3398, 3005 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.23–1.66 (m, 17 H), 3.63 (t, J = 6.4 Hz,
2 H), 3.69 (td, J = 14.2, 7.0 Hz, 1 H), 3.80 (s, 3 H), 4.28 (d, J = 11.0 Hz, 1
H), 4.52 (d, J = 11.0 Hz, 1 H), 5.18 (d, J = 17.4 Hz, 1 H), 5.21 (d, J = 10.1
Hz, 1 H), 5.72 (ddd, J = 17.4, 10.1, 7.0 Hz, 1 H), 6.87 (d, J = 8.8 Hz, 2 H),
7.25 (d, J = 8.8 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 25.2 (CH2), 25.6 (CH2), 29.3 (CH2),
29.38 (CH2 × 2), 29.41 (CH2), 32.6 (CH2), 35.4 (CH2), 55.1 (CH3), 62.8
(CH2), 69.6 (CH2), 80.2 (CH), 113.6 (CH × 2), 116.7 (CH2), 129.2
(CH × 2), 130.8 (C), 139.2 (CH), 158.9 (C).
ESI-HRMS: m/z [M + Na]+ calcd for C20H32O3Na: 343.2244; found:
343.2246.
One-Pot Synthesis of 4 by Method A; General Procedure
1-({[12-(Benzyloxy)dodec-1-en-3-yl]oxy}methyl)-4-methoxyben-
zene (1k)
Yield: 1.59 g (63%); colorless oil.12
A mixture of allyl alcohol derivative 1 (x g, 1.0 equiv), py·HBr3 (1.1
equiv), and MS 13X (ca. 10x g) in MeCN (y mL, 0.1 M) was stirred at
r.t. for 12–14 h. Then, DMSO (7y mL) and TBAOH (3.5 equiv, 40% in
H2O) were added to the reaction mixture at 0 °C and the system was
heated to 60 °C. The reaction was quenched with sat. aq NH4Cl at 0 °C.
After the removal of MS 13X through a cotton filter, the resulting fil-
trate was extracted with hexane–EtOAc (2:1, 3 × 30 mL) and dried
(MgSO4). The combined extracts were concentrated under reduced
pressure, and the residue was purified by column chromatography
(silica gel) to afford propargyl alcohol derivative 4.
IR (neat): 3005, 2931 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.21–1.69 (m, 16 H), 3.46 (t, J = 6.5 Hz,
2 H), 3.68 (td, J = 14.2, 7.0 Hz, 1 H), 3.80 (s, 3 H), 4.27 (d, J = 11.0 Hz, 1
H), 4.50 (s, 2 H), 4.52 (d, J = 11.0 Hz, 1 H), 5.18 (d, J = 16.6 Hz, 1 H),
5.21 (d, J = 10.9 Hz, 1 H), 5.72 (ddd, J = 16.6, 10.9, 7.0 Hz, 1 H), 6.86 (d,
J = 8.7 Hz, 2 H), 7.24–7.36 (m, 7 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1844–1850

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N. Kutsumura et al.
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Synthesis
13C NMR (126 MHz, CDCl3): δ = 25.3 (CH2), 26.1 (CH2), 29.4 (CH2 × 2),
29.5 (CH2 × 2), 29.7 (CH2), 35.5 (CH2), 55.1 (CH3), 69.6 (CH2), 70.4
(CH2), 72.8 (CH2), 80.2 (CH), 113.6 (CH × 2), 116.7 (CH2), 127.4 (CH2),
127.5 (CH × 2), 128.2 (CH × 2), 129.2 (CH × 2), 130.9 (C), 138.7 (C),
139.3 (CH), 159.0 (C).
(CH × 2), 128.2 (CH), 128.3 (CH × 2), 129.4 (CH × 2), 129.5 (CH), 130.4
(C), 138.4 (C), 159.2 (C).
ESI-HRMS: m/z [M + Na]+ calcd for C20H24O3Na: 335.1618; found:
335.1616.
ESI-HRMS: m/z [M + Na]+ calcd for C27H38O3Na: 433.2713; found:
433.2716.
1-{[(4-Ethyloct-1-yn-3-yl)oxy]methyl}-4-methoxybenzene (4h)
Yield: 36.7 mg (74%); yellow oil (Method A).
IR (neat): 3302, 2962, 2866, 1612 cm–1
.
1-Methoxy-4-{[(5-vinylnonan-5-yl)oxy]methyl}benzene (1l)
Yield: 771 mg (69%); colorless oil.12
1H NMR (500 MHz, CDCl3): δ = 0.84–0.89 (m, 6 H), 1.21–1.65 (m, 9 H),
2.43 (d, J = 2.4 Hz, 1 H), 3.80 (s, 3 H), 4.03–4.05 (m, 1 H), 4.42 (d,
J = 11.8 Hz, 1 H), 4.74 (d, J = 11.8 Hz, 1 H), 6.88 (d, J = 8.7 Hz, 2 H), 7.28
(d, J = 8.7 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 11.4 (CH3), 14.0 (CH3), 22.5 (CH2), 23.0
(CH2), 29.0 (CH2), 29.3 (CH2), 44.2 (CH), 55.3 (CH3), 70.2 (CH2), 70.6
(CH), 74.3 (CH), 82.3 (C), 113.7 (CH × 2), 129.5 (CH × 2), 130.2 (C),
159.2 (C); δ (diastereomer) = 11.6 (CH3), 14.1 (CH3), 22.6 (CH2), 23.0
(CH2), 29.2 (CH2), 29.3 (CH2), 44.3 (CH), 55.3 (CH3), 70.3 (CH2), 70.8
(CH), 74.3 (CH), 82.3 (C), 113.7 (CH × 2), 129.5 (CH × 2), 130.2 (C),
159.2 (C).
IR (neat): 3086, 2947 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 6.9 Hz, 6 H), 1.30 (m, 8 H),
1.50–1.65 (m, 4 H), 3.79 (s, 3 H), 4.25 (s, 2 H), 5.17 (dd, J = 17.6, 1.5 Hz,
1 H), 5.22 (dd, J = 11.1, 1.5 Hz, 1 H), 5.78 (dd, J = 17.6, 11.1 Hz, 1 H),
6.86 (d, J = 8.7 Hz, 2 H), 7.26 (d, J = 8.7 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 14.1 (CH3 × 2), 23.2 (CH2 × 2), 25.3
(CH2 × 2), 35.0 (CH2 × 2), 55.2 (CH3), 63.3 (CH2), 79.5 (C), 113.7
(CH × 2), 114.9 (CH2), 128.7 (CH × 2), 131.9 (C), 143.0 (CH), 158.8 (C).
ESI-HRMS: m/z [M + Na]+ calcd for C19H30O2Na: 313.2138; found:
313.2136.
ESI-HRMS: m/z [M + Na]+ calcd for C18H26O2Na: 297.1825; found:
297.1821.
(Z)-1-Chloro-4-[(hex-2-en-1-yloxy)methyl]benzene (1o)
Yield: 1.00 g (88%); colorless oil.12
10-[(4-Methoxybenzyl)oxy]dodec-11-yn-1-ol (4i)
Yield: 40.1 mg (83%); colorless oil (Method A).
IR (neat): 3016, 2962, 2861 cm–1
.
IR (neat): 3433, 3290 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 0.90 (t, J = 7.4 Hz, 3 H), 1.39 (tq, J = 7.4,
7.4 Hz, 2 H), 2.02 (td, J = 7.4, 7.1 Hz, 2 H), 4.07 (d, J = 5.4 Hz, 2 H), 4.47
(s, 2 H), 5.60 (m, 2 H), 7.24–7.33 (m, 4 H).
13C NMR (126 MHz, CDCl3): δ = 13.7 (CH3), 22.7 (CH2), 29.6 (CH2), 65.8
(CH2), 71.2 (CH2), 125.9 (CH), 128.5 (CH × 2), 129.0 (CH × 2), 133.3
(CH), 133.9 (C), 137.0 (C).
1H NMR (300 MHz, CDCl3): δ = 1.25–1.77 (m, 17 H), 2.46 (d, J = 2.0 Hz,
1 H), 3.63 (t, J = 6.6 Hz, 2 H), 3.80 (s, 3 H), 4.03 (td, J = 6.6, 2.0 Hz, 1 H),
4.44 (d, J = 11.3 Hz, 1 H), 4.73 (d, J = 11.3 Hz, 1 H), 6.87 (d, J = 8.7 Hz, 2
H), 7.28 (d, J = 8.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 25.2 (CH2), 25.7 (CH2), 29.2 (CH2), 29.35
(CH2), 29.38 (CH2), 29.5 (CH2), 32.8 (CH2), 35.6 (CH2), 55.3 (CH3), 63.1
(CH2), 68.0 (CH), 70.1 (CH2), 73.6 (CH), 83.1 (C), 113.7 (CH × 2), 129.7
(CH × 2), 129.9 (C), 159.2 (C).
ESI-HRMS: m/z [M + Na]+ calcd for C13H17ClONa: 247.0860; found:
247.0855.
ESI-HRMS: m/z [M + Na]+ calcd for C20H30O3Na: 341.2087; found:
341.2088.
(Z)-1-Methoxy-4-{[(3-phenylallyl)oxy]methyl}benzene (1p)
Yield: 209 mg (79%); colorless oil.12
IR (neat): 3062 cm–1
.
1-({[12-(Benzyloxy)dodec-1-yn-3-yl]oxy}methyl)-4-methoxyben-
zene (4k)
1H NMR (500 MHz, CDCl3): δ = 3.78 (s, 3 H), 4.27 (d, J = 6.1 Hz, 2 H),
4.45 (s, 2 H), 5.89 (dt, J = 12.1, 6.1 Hz, 1 H), 6.61 (d, J = 12.1 Hz, 1 H),
6.85 (d, J = 8.6 Hz, 2 H), 7.19 (d, J = 7.7 Hz, 2 H), 7.22–7.26 (m, 2 H),
7.30–7.33 (m, 3 H).
Yield: 35.9 mg (74%); pale yellow oil (Method A).
IR (neat): 3294 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 1.21–1.77 (m, 16 H), 2.45 (d, J = 2.1 Hz,
1 H), 3.46 (t, J = 6.6 Hz, 2 H), 3.80 (s, 3 H), 4.03 (td, J = 6.3, 2.1 Hz, 1 H),
4.44 (d, J = 11.0 Hz, 1 H), 4.50 (s, 2 H), 4.73 (d, J = 11.0 Hz, 1 H), 6.88 (d,
J = 8.3 Hz, 2 H), 7.23–7.37 (m, 7 H).
13C NMR (126 MHz, CDCl3): δ = 25.2 (CH2), 26.2 (CH2), 29.2 (CH2), 29.4
(CH2 × 2), 29.5 (CH2), 29.8 (CH2), 35.6 (CH2), 55.3 (CH3), 68.1 (CH), 70.1
(CH2), 70.5 (CH2), 72.9 (CH2), 73.6 (CH), 83.2 (C), 113.8 (CH × 2), 127.4
(CH), 127.6 (CH × 2), 128.3 (CH × 2), 129.6 (CH × 2), 131.5 (C), 138.7
(C), 159.3 (C).
13C NMR (126 MHz, CDCl3): δ = 55.2 (CH3), 66.6 (CH2), 72.1 (CH2),
113.7 (CH × 2), 127.1 (CH), 128.2 (CH × 2), 128.7 (CH × 2), 129.0 (CH),
129.5 (CH × 2), 130.2 (C), 131.7 (CH), 136.6 (C), 159.2 (C).
ESI-HRMS: m/z [M + Na]+ calcd for C17H18O2Na: 277.1199; found:
277.1201.
(Z)-1-({[5-(Benzyloxy)pent-2-en-1-yl]oxy}methyl)-4-methoxy-
benzene (1q)
Yield: 123 mg (83%); pale yellow oil.12
ESI-HRMS: m/z [M + Na]+ calcd for C27H36O3Na: 431.2557; found:
431.2554.
IR (neat): 3016, 2854, 1095, 818 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 2.38 (td, J = 13.4, 7.0 Hz, 2 H), 3.49 (t,
J = 7.0 Hz, 2 H), 3.80 (s, 3 H), 4.06 (d, J = 6.3 Hz, 2 H), 4.43 (s, 2 H), 4.50
(s, 2 H), 5.66 (m, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.25–7.35 (m, 7 H).
13C NMR (126 MHz, CDCl3): δ = 28.4 (CH2), 55.3 (CH3), 65.5 (CH2), 69.6
(CH2), 71.8 (CH2), 72.9 (CH2), 113.8 (CH × 2), 127.5 (CH), 127.6
1-{[(5-Ethynylnonan-5-yl)oxy]methyl}-4-methoxybenzene (4l)
Yield: 14.7 mg (26%); pale yellow oil (Method A).
IR (neat): 3302, 2946 cm–1
.
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1H NMR (300 MHz, CDCl3): δ = 0.92 (t, J = 7.2 Hz, 6 H), 1.25–1.76 (m,
12 H), 2.49 (s, 1 H), 3.80 (s, 3 H), 4.53 (s, 2 H), 6.87 (d, J = 8.7 Hz, 2 H),
7.26 (d, J = 8.7 Hz, 2 H).
13C NMR (126 MHz, CDCl3): δ = 14.1 (CH3 × 2), 22.9 (CH2 × 2), 26.0
(CH2 × 2), 38.2 (CH2 × 2), 55.3 (CH3), 65.7 (CH2), 73.9 (C), 76.5 (CH),
79.6 (C), 113.8 (CH × 2), 129.1 (CH × 2), 131.9 (C), 159.0 (C).
Supporting Information
for this article is available online at http://dx.doi.org/10.1055/s-0034-
1380499.
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References
ESI-HRMS: m/z [M + Na]+ calcd for C19H28O2Na: 311.1982; found:
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311.1980.
1-Chloro-4-[(hex-2-yn-1-yloxy)methyl]benzene (4o)
Yield: 38.7 mg (85%); colorless oil (Method A).
IR (neat): 2962, 2854, 2283, 2225 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 1.00 (t, J = 7.3 Hz, 3 H), 1.51–1.59 (m, 2
H), 2.21 (tt, J = 7.0, 2.2 Hz, 2 H), 4.16 (t, J = 2.2 Hz, 2 H), 4.55 (s, 2 H),
7.16–7.31 (m, 4 H).
13C NMR (126 MHz, CDCl3): δ = 13.5 (CH3), 20.8 (CH2), 22.1 (CH2), 57.9
(CH2), 70.5 (CH2), 75.7 (C), 87.4 (C), 128.5 (CH × 2), 129.3 (CH × 2),
133.5 (C), 136.3 (C).
ESI-HRMS: m/z [M + Na]+ calcd for C13H15ClONa: 245.0704; found:
245.0705.
1-Methoxy-4-{[(3-phenylprop-2-yn-1-yl)oxy]methyl}benzene (4p)
Yield: 40.6 mg (82%); colorless oil (Method A).
IR (neat): 2839, 2237 cm–1
1H NMR (500 MHz, CDCl3): δ = 3.81 (s, 3 H), 4.36 (s, 2 H), 4.61 (s, 2 H),
6.89 (d, J = 8.5 Hz, 2 H), 7.30–7.33 (m, 5 H), 7.46 (dd, J = 6.6, 2.6 Hz, 2
.
H).
13C NMR (126 MHz, CDCl3): δ = 55.3 (CH3), 57.5 (CH2), 71.3 (CH2), 85.2
(C), 86.4 (C), 113.9 (CH × 2), 122.7 (C), 128.3 (CH × 2), 128.4 (CH),
129.6 (C), 129.8 (CH × 2), 131.8 (CH × 2), 159.4 (C).
ESI-HRMS: m/z [M + Na]+ calcd for C17H16O2Na: 275.1043; found:
275.1042.
1-({[5-(Benzyloxy)pent-2-yn-1-yl]oxy}methyl)-4-methoxyben-
zene (4q)
(8) (a) Matloubi Moghaddam, F.; Emami, R. Synth. Commun. 1997,
27, 4073. (b) Feng, L.; Kumar, D.; Birney, D. M.; Kerwin, S. M.
Org. Lett. 2004, 6, 2059.
Yield: 32.8 mg (76%); pale yellow oil (Method A).
IR (neat): 3433, 1097 cm–1
.
(9) (a) Kutsumura, N.; Iijima, M.; Toguchi, S.; Saito, T. Chem. Lett.
2011, 40, 1231. (b) Kutsumura, N.; Toguchi, S.; Iijima, M.;
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F.; Adams, R. J. Am. Chem. Soc. 1935, 57, 371. For 1d, see:
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G. R. Eur. J. Org. Chem. 2008, 196. For 1e, see: (e) White, W. N.;
Gwynn, D.; Schlitt, R.; Girard, C.; Fife, W. J. Am. Chem. Soc. 1958,
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69, 6894. For 1f, see: (g) Wu, X.-F.; Darcel, C. Eur. J. Org. Chem.
2009, 1144. For 1g, see: ref. 3. For 1j, see: ref. 5b. For 1m and 1n,
see: (h) Goux, C.; Massacret, M.; Lhoste, P.; Sinou, D. Organome-
tallics 1995, 14, 4585. For 1r, see: (i) Sreedhar, E.; Venkanna, A.;
Chandramouli, N.; Babu, K. S.; Rao, J. M. Eur. J. Org. Chem. 2011,
1078.
1H NMR (500 MHz, CDCl3): δ = 2.57 (tt, J = 7.3, 2.4 Hz, 2 H), 3.61 (t,
J = 7.3 Hz, 2 H), 3.79 (s, 3 H), 4.12 (t, J = 2.4 Hz, 2 H), 4.51 (s, 2 H), 4.56
(s, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.24–7.36 (m, 7 H).
13C NMR (126 MHz, CDCl3): δ = 20.2 (CH2), 55.2 (CH3), 57.3 (CH2), 68.4
(CH2), 71.0 (CH2), 72.9 (CH2), 77.1 (C), 83.7 (C), 113.8 (CH × 2), 127.7
(CH × 2), 128.3 (CH), 128.4 (CH × 2), 129.6 (C), 129.7 (CH × 2), 138.0
(C), 159.3 (C).
ESI-HRMS: m/z [M + Na]+ calcd for C20H22O3Na: 333.1461; found:
333.1461.
Acknowledgment
This work was partly supported by the Sasakawa Scientific Research
Grant from The Japan Science Society, the Central Glass Co. Ltd. Award
in Synthetic Organic Chemistry, Japan, and the Tokyo Ohka Founda-
tion for The Promotion of Science and Technology.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1844–1850

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Guanti, G.; Basso, A. Eur. J. Org. Chem. 2000, 939.
(12) For the synthesis, see the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1844–1850