Facile and convenient synthesis of functionalized propargylic alcohols and amines: An InBr3-Et3N reagent system promotes the alkynylation of aldehydes and N,O- or N,S-acetals

Article abstract of DOI:10.1016/j.tet.2005.07.059

The use of a novel InBr₃-Et₃N reagent system to promote the alkynylation of not only a variety of aromatic/heterocyclic or bulky aliphatic aldehydes but also N,O- or N,S-acetals is described. The use of N-silyl-N,O-acetals and 1-alkynes could lead to the direct production of primary propargylic amines in good yields.

Full text of DOI:10.1016/j.tet.2005.07.059

Tetrahedron 61 (2005) 9298–9304
Facile and convenient synthesis of functionalized propargylic
alcohols and amines: an InBr3–Et3N reagent system promotes the
alkynylation of aldehydes and N,O- or N,S-acetals
*
Norio Sakai, Reiko Kanada, Maki Hirasawa and Takeo Konakahara
*
Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan
Received 24 June 2005; revised 19 July 2005; accepted 19 July 2005
Available online 9 August 2005
Abstract—The use of a novel InBr3–Et3N reagent system to promote the alkynylation of not only a variety of aromatic/heterocyclic or bulky
aliphatic aldehydes but also N,O- or N,S-acetals is described. The use of N-silyl-N,O-acetals and 1-alkynes could lead to the direct production
of primary propargylic amines in good yields.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
propargylic alcohols. We also report herein that, unlike
conventional alkynylations using enamines,13 aminals,14
and imines,8,15 by employing N,O-acetals, this reagent
system can be used to directly produce propargylic amines,
especially, with N-silyl-N,O-acetal, to afford primary
propargylic amines in good yields.
The synthesis of functionalized propargylic alcohols and
amines has been widely studied because a number of such
derivatives constitute some of the basic units in natural
products and related biologically active substances.1 The
nucleophilic addition of alkynylmetals containing Ce,2 B,3
and V4 to carbonyl compounds, and the addition of
alknylalminium5 to aminals has been typically used for
this purpose in the past. A practical procedure, in which the
combined use of a Lewis acid, such as Sn(OTf)2,6 GaI3,7
Zn(OTf)2,8 and ZnCl29 and a Lewis base, such as an amine
promotes or catalyzes the alkynylation of not only carbonyl
compounds but also enamines and imine, was recently
developed. On the other hand, because of the interesting
chemical properties of indium halides, such as their high
stability under aqueous conditions, and strong tolerance to
oxygen- and nitrogen containing functional groups, a
number of groups have developed synthetic methodologies
that involve high regio- or chemoselectivity,10 and we
previously reported that a system comprised of indium
halide and an amine effectively promotes the alkynylation
of aldehydes under relatively mild conditions, leading to the
corresponding propargylic alcohols.11,12 Herein, we report
on a reinvestigation of the reaction conditions and some
additional details of the scope and limitations of the
alkynylation of carbonyl compounds by the indium(III)
salt–amine reagent system leading to the corresponding
2. Results and discussion
We initially examined the reaction of phenylacetylene (1a)
with benzaldehyde (2a) in the presence of indium halide and
triethylamine as a model system. Thus, when the acetylene
(2 equiv) was treated with Et3N (2 equiv) and InCl3
(2 equiv) at room temperature in dichloromethane for 1 h,
followed by the addition of benzaldehyde, the correspond-
ing propargylic alcohol 3a was produced in 33% yield (run
1). To optimize the alkynylation, we then ran the reaction
using several different solvents and other indium trihalides.
The results are summarized in Table 1. Consequently, we
found that, when the reaction was conducted in Et2O instead
of CH2Cl2, the product yield was improved to 50% (run 2).
In contrast, in the cases of THF, and PhMe, the yields were
decreased (runs 3 and 4). It is particularly noteworthy that,
when InBr3 was used as a promoter, the reaction was
completed within 2 h and 3a was produced in a near
quantitative yield (run 5). On the other hand, InI3 was not
effective for this reaction (run 6). It was also found that
decreasing of amount of InBr3 to 1.5 equiv reduced the
product yield and it was necessary to prolong the reaction
time (run 7). As expected, in the absence of indium halide,
no alkynylation took place (run 8).
Keywords: Alkynylation; Propargylic alcohols; Propargylic amines; Indium
bromide; Acetal.
Corresponding authors. Tel.: C81 4 7124 1501; fax: C81 4 7123 9890;
e-mail: sakachem@rs.noda.tus.ac.jp
*
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.059

N. Sakai et al. / Tetrahedron 61 (2005) 9298–9304
9299
Table 1. Optimization of the alkynylation of benzaldehyde (2a) with
phenylacetylene (1a)a
underwent the expected alkynylation in good yields (runs 5
and 6). In the case of p-methoxybenzaldehyde, however,
refluxing was required to obtain a satisfactory yield (run 5).
Steric effects of substituent groups at the position did not
affect the product yield (run 7). When aliphatic aldehydes
were used, the alkynylation of bulky aldehydes such as
pival- and isobutyraldehyde gave the corresponding
alcohols in good to moderate yields (runs 8 and 9).
However, an easily enolizable aldehyde, such as butyr-
aldehyde produced only a small amount of the alkynylated
product 3k along with a 22% yield of the side-reaction
product, formed by aldol condensation of the aldehyde (run
10). This result shows that the abstraction of an a-hydrogen
on the aldehyde by the in-situ formed anionic intermediate
proceeds faster than the nucleophilic addition of the
resulting intermediate to the aldehyde, thus leading to
enolization of the aldehyde. Interestingly, the present
method could be applied to alkynylation reactions using
heteroaromatic aldehydes containing pyridine, thiophene,
and furan skeletons (runs 13–15, and 17). For example,
when phenylacetylene or 1-octyne was treated with the
heteroaromatic aldehyde, 3-pyridinecarboxaldehyde, the
corresponding heterocyclic propargyl alcohols 3n and 3r
were produced in satisfactory yields (runs 13 and 17). In
contrast, the alkynylation of ketones, for example, cyclo-
hexanone was somewhat sluggish (O50 h), and the yield of
product 3u (!40%) was low. Furthermore, a reaction using
acetic anhydride, benzoic anhydride, and esters was not
successful.
Run
InX3
Solvent
Time (h)
Yield (%)b
1
2
3
4
5
6
7d
8
InCl3
InCl3
InCl3
InCl3
InBr3
InI3
CH2Cl2
Et2O
THF
PhMe
Et2O
Et2O
Et2O
Et2O
24
24
24
24
2
24
6
10
33
50
4
Trace
95c
26
61
NDe
InBr3
None
a Phenylacetylene (2 equiv), indium halide (2 equiv), Et3N (2 equiv), and
benzaldehyde (0.4 mmol) in 2 mL of solvent.
b NMR yields based on benzaldehyde.
c Isolated yield.
d Phenylacetylene (1.5 equiv), InBr3, and Et3N was used.
e ND, Not detected.
To clarify the general applicability of this alkynylation, the
reaction of various benzaldehyde derivatives and aliphatic/
aromatic aldehydes with four types of 1-alkynes was carried
out under the optimized conditions and the results are listed
in Table 2. The use of benzaldehyde derivatives containing
an electron-withdrawing substituent, such as halogens,
cyano, and nitro groups required only a short time for a
complete reaction, and the corresponding propargylic
alcohols were produced in excellent yields ranging from
83 to 99% (runs 1–4, 7, 16, and 19). Similarly,
benzaldehydes containing an electron-donating group also
We then applied the reaction to the preparation of
propargylic amine derivatives with N,O-acetals. Thus, the
reaction of four types of 1-alkynes 1 with appropriate N,O-
acetals 4 was carried out under the conditions described
above, and the results are shown in Table 3. Generally,
when alkynes and N,O-acetal containing a phenyl group 4a
were used, the reaction proceeded faster than that of
aldehydes to give the corresponding propargylic amine 5a
and 5b in good yields (runs 1 and 2). In the case of
heterocyclic N,O-acetal 4b, the reaction also proceeded,
producing the corresponding products in mild to good yields
(runs 4–7). On the other hand, when the reaction was carried
out with N,O-acetals involving furan and thiophene rings 4c
and 4d, the yields were rather low (runs 8 and 9). However,
the employment of N,S-acetals 4e and 4f instead of the N,O-
acetal solved the problem and the desired product was
produced in moderate yields, as the result of the higher
activity of thiolate anion as a leaving group than methoxy
anion.
Table 2. Reaction of terminal alkynes with various aldehydes leading to
propargyl alcoholsa
Run
Alkyne
R1
Aldehyde
R2
Time (h)
Yield of 3 (%)b
1
2
3
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-Cl–C6H4
p-F–C6H4
p-CN–C6H4
p-NO2–C6H4
p-MeO–C6H4
p-Me–C6H4
o-Br–C6H4
t-Bu
5
5
3b 90
3c 92
3d 97
3e 87
3f 70
3g 80
3h 83
3i 88
3j 44
3k 11
3l 46
3m 61
3n 99
3o 57
3p 93
3q 99
3r 40
3s 67
3t 93
1.5
0.5
24
15
3
24
24
24
20
24
1
24
12
18
12
24
24
4
5c
6
7
8c
9
i-Pr
n-Pr
Finally, on the basis of our previous work,16 we attempted
the preparation of primary propargylic amine derivatives,
since a simple and direct preparation of primary propargylic
amine is lacking.17 Thus, the reaction of three types of
1-alkynes with N-silyl-N,O-acetal 6 was carried out under
optimized conditions, the results of which are listed in
Table 4. All three reactions proceeded smoothly to afford
the corresponding primary amines in satisfactory yields. We
isolated the latter two products, the amide product of which
could be achieved by a one-pot synthesis using benzyl
chloride to prevent the loss of product during the work-up
(runs 2 and 3).
10
11
12
13
14
15
16
17
18
19c
PhCH]CH
2-Naphthyl
3-Pyridyl
2-Thienyl
2-Furyl
p-CN–C6H4
3-Pyridyl
Ph
C6H13
C6H13
t-Bu
Me3Si
p-CN–C6H4
a General procedure: alkyne (0.8 mmol), aldehyde (0.4 mmol), InBr3
(0.8 mmol), Et3N (0.8 mmol) in Et2O (2 mL).
b Isolated yield based on aldehyde 2.
c Reaction was carried out at 40 8C.

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N. Sakai et al. / Tetrahedron 61 (2005) 9298–9304
Table 3. Reaction of terminal alkynes with N,O- or N,S-acetals leading to propargylic aminesa
Run
Alkyne 1
R1
Acetal 4
Time (h)
Yield of 5 (%)b
X
R2
1
2
3
Ph
MeO
MeO
MeO
MeO
MeO
MeO
MeO
PhS
Ph
Ph
Ph
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
2-Furyl
2-Thienyl
0.2
0.2
10
0.2
3
24
24
3
5a 94
5b 78
5c 54
5d 65
5e 42
5f 69
5g 81
5h 24 (12)d
5i 56 (ND)e
C6H13
Me3Si
Ph
C6H13
t-Bu
Me3Si
Ph
4c
5c
6c
7c
8
9
Ph
PhS
24
a General procedure: alkyne (1 mmol), N,O- or N,S-acetal (0.5 mmol), InBr3 (1 mmol), Et3N (1 mmol) in Et2O (3 mL).
b Isolated yields based on acetal 4.
c Reaction was carried out at 40 8C.
d Reaction was carried out with N,O-acetal 4c.
e Reaction was carried out with N,O-acetal 4d.
presence of a catalytic amount of indium salt, the product
yield was decreased significantly, probably due to the
difficulty of regenerating the indium(III) salt.18e
Table 4. Reaction of terminal alkynes with N-silyl-N,O-acetal 6
3. Conclusion
Run
Alkyne 1
R1
Time (h)
Yield (%) of 7a
In summary, we demonstrated that the InBr3–Et3N reagent
system promotes the facile reaction of 1-alkynes with a
variety of aldehydes under mild conditions leading to the
production of functionalized propargylic alcohols in good to
excellent yields. We also found that this reagent system can
be used in alkynylation reactions of heteroaromatic
aldehydes producing the corresponding heterocyclic pro-
pargylic alcohols in excellent yields, and can be widely
applied to the one-pot preparation of primary or tertiary
propargylic amine derivatives and amide derivatives with N,
O- or N,S-acetals. Further investigations of the mechanism
of this reaction are currently in progress.
1
Ph
C6H13
t-Bu
1
5
5
7a 66 (RZH)
7b 54 (RZPhCO)
7c 52 (RZ PhCO)
2b
3b
a Isolated yields.
b Products 7b and 7c were isolated as amide products by using benzoyl
chloride. See Section 4.4.
A plausible mechanism for the alkynylation of an aldehyde
is shown in Scheme 1. InBr3 initially coordinate with an
alkyne p-bond, which increases the acidity of the terminal
hydrogen, followed by the facile abstraction of a proton by a
mild base, such as triethylamine, to form an intermediate
such as an indium acetylide. The intermediate then attacks
the aldehyde, which was activated by the Lewis acidic
InBr3, subsequently leading to the final propargylic alcohol
by the usual work-up. In cases of N,O- or N,S-acetals, the
reaction path also would proceeds similarly and, in such
systems, the indium plays a dual role, first to coordinate with
the alkyne p-bond to facilitate the abstraction of a terminal
hydrogen, and also to activate the aldehydes and acetals.18
Unfortunately, when the reaction was conducted in the
4. Experimental
4.1. General methods
Column chromatography was performed using Silica gel 60
(Merck). Diethyl ether was distilled from sodium–benzo-
phenone before use. Dichloromethane was distilled from
P2O5 and dried over MS4A. The other organic solvents and
materials were dried and distilled prior to use. Commercially
available InCl3, InBr3, and InI3 were used without further
purification. N,N-diethyl-a-(methoxy-3-pyridyl)-methan-
amine (4a), N,N-diethyl-a-methoxy-benzenemethanamine
(4b), N,N-diethyl-a-(methoxy-2-furyl)-methanamine (4c),
N,N-diethyl-a-(methoxy-2-thienyl)-methanamine (4d), N,N-
diethyl-a-(thiophenyl-2-furyl)-methanamine (4e), and N,N-
diethyl-a-(thiophenyl-2-thienyl)-methanamine (4f) were pre-
pared according to previously reported procedures.19,20 All
reactions were carried out under an argon atmosphere, unless
otherwise noted. 1H NMR spectra were measured at 500 MHz
using tetramethylsilane as an internal standard. 13C NMR
Scheme 1.

N. Sakai et al. / Tetrahedron 61 (2005) 9298–9304
9301
spectra were measured at 125 MHz using the chloroform peak
(77.0 ppm) as an internal standard. High-resolution mass
spectra were measured on a JEOL JMS-700 MStation using
NBA (3-nitrobenzylalcohol) as a matrix.
(s, 3H), 5.62 (s, 1H), 6.91 (d, 2H, JZ8.0 Hz), 7.29–7.31 (m,
3H), 7.45 (d, 2H, JZ8.0 Hz), 7.52 (d, 2H, JZ8.0 Hz); 13C
NMR (125 MHz, CDCl3) d 55.3, 64.6, 86.4, 88.9, 113.9,
122.4, 128.1, 128.2, 128.5, 131.7, 133.0, 159.7; MS (EI) m/z
238 (MC), 207.
4.2. General procedure for the alkynylation of aldehydes
or a ketone
4.2.7. 4-Methyl-a-(phenylethynyl)-benzenemethanol
(3g).9 1H NMR (500 MHz, CDCl3) d 2.36 (s, 4H (including
OH)), 5.64 (s, 1H), 7.20 (d, 2H, JZ7.5 Hz), 7.30–7.32 (m,
3H), 7.48–7.49 (m, 2H), 7.50 (d, 2H, JZ7.5 Hz); 13C NMR
(125 MHz, CDCl3) d 21.1, 64.9, 86.4, 88.8, 122.4, 126.6,
128.2, 128.4, 129.3, 131.7, 137.7, 138.2; MS (EI) m/z 222
(MC), 207.
To a Et2O (2 mL) solution of phenylacetylene (1a, 81.7 mg,
0.800 mmol) and Et3N (81.0 mg, 0.800 mmol) were added a
Et2O solution of InBr3 (284 mg, 0.800 mmol) and the
reaction mixture was stirred at room temperature under
argon. After 1 h, benzaldehyde (or a ketone) (2a, 42.5 mg,
0.400 mmol) was added to the solution via a syringe. The
mixture was stirred at the same temperature until the
reaction was complete, as shown by TLC (hexane–AcOEtZ
95/5) or GC. After the reaction, a mixture of CH2Cl2
(10 mL) and 1 N HCl (5 mL) was added to the reaction
mixture, and the organic layer was separated, dried
(Na2SO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography (SiO2/
hexane–AcOEtZ95/5) to give afford propargylic alcohol
3a (79 mg, 95% yield) and, if necessary, further purified by
a Recycling Preparative HPLC equipped with a GPC
column (chloroform as the eluent).
4.2.8. 2-Bromo-a-(phenylethynyl)-benzenemethanol
(3h).22 1H NMR (CDCl3, 500 MHz) d 2.61 (br s, 1H), 5.9
(s, 1H), 7.15 (t, 1H, JZ7.5 Hz), 7.25 (s, 3H), 7.30 (t, 1H,
JZ7.5 Hz), 7.40 (dd, 2H, JZ2.0, 7.5 Hz), 7.51 (d, 1H, JZ
7.5 Hz), 7.77 (dd, 1H, JZ2.0, 7.5 Hz); 13C NMR (CDCl3,
125 MHz) d 64.7, 86.8, 87.6, 122.3, 122.8, 127.9, 128.3,
128.6, 129.9, 130.0, 131.7, 133.0, 139.5.
4.2.9. 4,4-Dimethyl-1-phenyl-1-pentyn-3-ol (3i).7 1H
NMR (500 MHz, CDCl3) d 1.00 (s, 9H), 2.27 (br s, 1H),
4.17 (s, 1H), 7.22–7.24 (m, 3H), 7.34–7.36 (m, 2H); 13C
NMR (125 MHz, CDCl3) d 25.3, 36.1, 71.8, 85.6, 88.9,
122.7, 128.2, 128.3, 131.6; MS (EI) m/z 188 (MC), 131.
4.2.1. 1,3-Diphenyl-2-propyn-1-ol (3a).21 1H NMR
(500 MHz, CDCl3) d 2.44 (br s, 1H), 5.64 (s, 1H), 7.22–
7.24 (m, 4H), 7.28–7.30 (m, 2H), 7.36–7.37 (m, 2H), 7.53–
7.55 (m, 2H); 13C NMR (125 MHz, CDCl3) d 64.5, 86.0,
89.1, 122.3, 126.6, 126.7, 128.1, 128.4, 131.5, 137.5, 140.6;
MS (EI) m/z 208 (MC).
4.2.10. 4-Methyl-1-phenyl-1-pentyn-3-ol (3j).23 1H NMR
(500 MHz, CDCl3) d 1.01 (d, 6H, JZ6.5 Hz), 1.84 (br s,
1H), 1.91 (m, 1H), 4.32 (s, 1H), 7.23–7.25 (m, 3H), 7.36–
7.38 (m, 2H); 13C NMR (125 MHz, CDCl3) d 17.5, 18.1,
34.7, 68.4, 85.5, 88.8, 122.7, 128.2, 128.3, 131.6; MS (EI)
m/z 174 (MC), 131.
4.2.2. 4-Chloro-a-(phenylethynyl)-benzenemethanol
(3b).7 1H NMR (500 MHz, CDCl3) d 2.74 (br s, 1H), 5.64
(s, 1H), 7.29–7.35 (m, 5H), 7.45 (d, 2H, JZ7.5 Hz), 7.52 (d,
2H, JZ7.5 Hz); 13C NMR (125 MHz, CDCl3) d 64.2, 86.8,
88.2, 122.1, 128.0, 128.3, 128.4, 128.7, 131.7, 134.1, 139.0;
MS (EI) m/z 242 (MC), 207.
4.2.11. 1-Phenyl-1-hexyn-3-ol (3k).24 1H NMR (500 MHz,
CDCl3) d 0.95 (t, 3H, JZ7.5 Hz), 1.51 (br s, 1H), 1.52–1.53
(m, 2H), 1.74–1.80 (m, 2H), 4.58 (t, 1H, JZ7.5 Hz), 7.28–
7.29 (m, 3H), 7.39–7.41 (m, 2H); 13C NMR (125 MHz,
CDCl3) d 13.7, 18.5, 40.0, 62.8, 84.8, 90.1, 122.6, 128.2,
128.3, 131.6; MS (EI) m/z 174 (MC), 131.
4.2.3. 4-Fluoro-a-(phenylethynyl)-benzenemethanol
(3c).9 1H NMR (500 MHz, CDCl3) d 2.63 (br s, 1H), 5.65 (s,
1H), 7.00 (t, 2H, JZ7.5 Hz), 7.30–7.31 (m, 3H), 7.45 (d, 2H,
JZ5.5 Hz), 7.57 (d, 2H, JZ7.5 Hz); 13C NMR (125 MHz,
CDCl3) d 64.3, 86.8, 88.4, 115.3, 115.5, 128.3, 128.5, 128.6,
131.7,136.4, 162.6(d, JC–FZ245 Hz); MS(EI) m/z226(MC).
4.2.12. 1,5-Diphenyl-4-penten-1-yn-3-ol (3l).9 1H NMR
(500 MHz, CDCl3) d 2.25 (br s, 1H), 5.30 (d, 1H, JZ
0.6 Hz), 6.40 (dd, 1H, JZ15.0, 0.6 Hz), 6.84 (d, 1H, JZ
15.0 Hz), 7.27–7.34 (m, 6H), 7.43 (d, 2H, JZ7.0 Hz), 7.48
(d, 2H, JZ7.0 Hz); 13C NMR (125 MHz, CDCl3) d 63.4,
86.4, 87.9, 122.3, 126.8, 128.0, 128.1, 128.2, 128.3, 128.5,
131.7, 132.0, 136.0; MS (EI) m/z 234 (MC), 105.
4.2.4. 4-Cyano-a-(phenylethynyl)-benzenemethanol
(3d).9 1H NMR (500 MHz, CDCl3) d 3.19 (br s, 1H), 5.71
(s, 1H), 7.27–7.32 (m, 3H), 7.41–7.42 (m, 2H), 7.61 (d, 2H,
JZ8.0 Hz), 7.68 (d, 2H, JZ8.0 Hz); 13C NMR (125 MHz,
CDCl3) d 64.0, 87.2, 87.5, 111.7, 118.5, 121.7, 127.1, 128.3,
128.8, 131.6, 132.3, 145.6.
4.2.13. a-(Phenylethynyl)-2-naphthalenemethanol (3m).9
1H NMR (500 MHz, CDCl3) d 2.61 (br s, 1H), 6.33 (s, 1H),
7.30–7.32 (m, 3H), 7.47–7.57 (m, 5H), 7.84–7.93 (m, 3H),
8.38 (d, 1H, JZ7.5 Hz); 13C NMR (125 MHz, CDCl3) d
63.3, 87.2, 88.5, 122.4, 123.9, 124.6, 125.2, 125.8, 126.4,
128.2, 128.5, 128.6, 129.3, 130.5, 131.7, 134.0, 135.6; MS
(EI) m/z 258 (MC).
4.2.5. 4-Nitro-a-(phenylethynyl)-benzenemethanol (3e).7
1H NMR (500 MHz, CDCl3) d 3.13 (br s, 1H), 5.77 (s, 1H),
7.29–7.32 (m, 3H), 7.41 (d, 2H, JZ7.5 Hz), 7.74 (d, 2H, JZ
7.5 Hz), 8.18 (d, 2H, JZ7.5 Hz); 13C NMR (125 MHz,
CDCl3) d 63.8, 87.4, 87.5, 121.6, 123.7, 127.3, 128.3, 128.9,
131.6, 147.4, 147.6; MS (EI) m/z 253 (MC).
4.2.14. a-(Phenylethynyl)-3-pyridinemethanol (3n).9 1
H
NMR (500 MHz, CDCl3) d 3.43 (br s, 1H), 5.74 (s, 1H),
7.24–7.31 (m, 4H), 7.41–7.42 (m, 2H), 7.99 (d, 1H, JZ
8.0 Hz), 8.55 (d, 1H, JZ8.0 Hz), 8.83 (d, 1H, JZ8.0 Hz);
13C NMR (125 MHz, CDCl3) d 62.3, 86.7, 88.2, 122.2,
4.2.6. 4-Methoxy-a-(phenylethynyl)-benzenemethanol
(3f).9 1H NMR (500 MHz, CDCl3) d 2.37 (br s, 1H), 3.80

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N. Sakai et al. / Tetrahedron 61 (2005) 9298–9304
123.6, 128.2, 128.6, 131.6, 134.9, 137.2, 147.7, 148.6; MS
(EI) m/z 209 (MC), 180.
was stirred at room temperature for 1 h, followed by the
addition of N,O- or N,S-acetal 4 (0.5 mmol) via a syringe.
The reaction mixture was stirred until the reaction reached
completion, as evidenced by TLC (hexane–AcOEtZ9/1) or
GC. After the reaction, a saturated NaHCO3 aqueous
solution was added to the mixture, and the organic layer
was extracted with Et2O. The combined organic layer was
dried over Na2CO3, filtered, and concentrated in vacuum.
The crude product was purified by flash silica gel
chromatography (hexane–AcOEtZ9/1) to give the corre-
sponding propargylic amine 5.
4.2.15. 3-Phenyl-1-(2-thienyl)-2-propyn-1-ol (3o).11 1H
NMR (500 MHz, CDCl3) d 2.56 (br s, 1H), 5.87 (s, 1H),
6.98 (d, 1H, JZ5.0 Hz), 7.24 (d, 1H, JZ5.0 Hz), 7.30–7.32
(m, 4H), 7.47 (d, 2H, JZ5.0 Hz); 13C NMR (125 MHz,
CDCl3) d 60.7, 86.0, 88.0, 122.1, 125.6, 126.1, 126.7, 128.3,
128.7, 131.7, 144.6; MS (EI) m/z 214 (MC), 184.
4.2.16. a-(Phenylethynyl)-2-furanmethanol (3p).23 1H
NMR (500 MHz, CDCl3) d 2.50 (br s, 1H), 5.62 (s, 1H),
6.31 (s, 1H), 6.45 (s 1H), 7.25–7.27 (m, 3H), 7.40 (s, 1H),
7.42 (d, 2H, JZ7.5 Hz); 13C NMR (125 MHz, CDCl3) d
58.6, 85.7, 86.1, 107.8, 110.3, 122.0, 128.2, 128.7, 131.7,
143.0, 152.9; MS (EI) m/z 198 (MC), 141.
4.3.1. N,N-Diethyl-a-(phenylethynyl)-benzenemethan-
amine (5a).11 1H NMR (500 MHz, CDCl3) d 1.06 (t, 6H,
JZ7.5 Hz), 2.52 (q, 2H, JZ7.5 Hz), 2.61 (q, 2H, JZ
7.5 Hz), 5.03 (s, 1H), 7.30–7.33 (m, 6H), 7.48 (dd, 2H, JZ
7.5, 1.5 Hz), 7.66 (d, 2H, JZ7.5 Hz); 13C NMR (125 MHz,
CDCl3) d 13.5, 44.5, 57.0, 86.1, 87.4, 123.4, 127.2, 128.0,
128.1, 128.2, 128.3, 131.7, 139.9; MS (EI) m/z 263 (MC).
4.2.17. 4-(4-Cyanophenyl)-1-hydroxy-non-2-yne (3q).
Yellow oil; IR (neat) 3325 (br), 2185 cmK1 1H NMR
;
(500 MHz, CDCl3) d 0.91 (t, 3H, JZ7.5 Hz), 1.27–1.30 (m,
3H including OH), 1.34–1.36 (m, 2H), 1.49–1.52 (m, 2H),
2.20–2.25 (m, 4H), 5.48 (m, 1H), 7.64 (d, 4H, JZ1.0 Hz);
13C NMR (125 MHz, CDCl3) d 14.0, 18.7, 22.5, 28.4, 28.5,
31.2, 63.9, 78.9, 88.8, 111.8, 118.7, 127.2, 132.3, 146.2; MS
(EI) m/z 241 (MC); HRMS (FAB): Calcd for C16H19NO:
241.1467, Found 241.1468.
4.3.2. N,N-Diethyl-a-1-octynyl-benzenemethanamine
(5b).11 1H NMR (500 MHz, CDCl3) d 0.89 (t, 3H, JZ
7.0 Hz), 1.03 (t, 6H, JZ7.5 Hz), 1.30–1.32 (m, 4H), 1.44–
1.45 (m, 2H), 1.55–1.57 (m, 2H), 2.29–2.30 (m, 2H), 2.44
(q, 2H, JZ7.5 Hz), 2.53 (q, 2H, JZ7.5 Hz), 4.80 (s, 1H),
7.24–7.25 (m, 1H), 7.30–7.31 (m, 2H), 7.62 (d, 2H, JZ
7.5 Hz); 13C NMR (125 MHz, CDCl3) d 13.5, 14.0, 18.7,
21.1, 22.5, 28.5, 29.0, 31.3, 44.4, 56.5, 75.9, 87.5, 126.8,
127.8, 128.3, 137.6, 140.5.
4.2.18. 1-Hydroxy-1-(3-pyridinyl)-non-2-yne (3r).
Yellow oil; IR (neat) 3495 (br), 2248 cmK1 1H NMR
;
(500 MHz, CDCl3) d 0.80 (t, 3H, JZ7.0 Hz), 1.20–1.24 (m,
4H), 1.29–1.35 (m, 2H), 1.44–1.50 (m, 2H), 2.21 (q, 2H, JZ
7.0 Hz), 3.85 (br s, 1H), 5.45 (s, 1H), 7.24 (m, 1H), 7.84 (d,
1H, JZ7.5 Hz), 8.44 (d, 1H, JZ0.4 Hz), 8.64 (s, 1H); 13C
NMR (125 MHz, CDCl3) d 14.0, 18.7, 22.4, 28.4, 28.5,
31.2, 62.3, 79.2, 88.2, 123.3, 134.5, 137.2, 148.1, 148.9; MS
(EI) m/z 217 (MC); HRMS (FAB): Calcd for C14H19NO:
217.1467, Found: 217.1465.
4.3.3. N,N-Diethyl-a-[(trimethylsilyl)ethynyl]-benzene-
methanamine (5c).11 1H NMR (500 MHz, CDCl3) d 0.19
(s, 9H), 1.02 (t, 6H, JZ7.5 Hz), 2.43 (q, 2H, JZ7.5 Hz),
2.53 (q, 2H, JZ7.5 Hz), 4.80 (s, 1H), 7.25 (d, 1H, JZ
7.5 Hz), 7.29–7.31 (m, 3H), 7.60 (d, 2H, JZ7.5 Hz); 13C
NMR (125 MHz, CDCl3) d 0.32, 13.2, 44.1, 91.8, 101.9,
126.6, 126.9, 127.7, 128.0, 137.4.
4.2.19. 4,4-Dimethyl-1-phenyl-2-pentyn-1-ol (3s).9 1H
NMR (500 MHz, CDCl3) d 1.25 (s, 9H), 2.09 (br s, 1H),
5.42 (s, 1H), 7.29 (d, 2H, JZ7.5 Hz), 7.31–7.37 (m, 2H),
7.53 (d, 1H, JZ7.5 Hz); 13C NMR (125 MHz, CDCl3) d
27.4, 30.8, 64.6, 78.3, 95.8, 126.9, 128.1, 128.4, 141.3; MS
(EI) m/z 188 (MC), 131.
4.3.4. N,N-Diethyl-a-(phenylethynyl-3-pyridyl)-methan-
1
amine (5d). Yellow oil; IR (neat) 3049, 2202 cmK1; H
NMR (500 MHz, CDCl3) d 1.04 (t, 6H, JZ7.1 Hz), 2.48–2.61
(m, 4H), 2.40–2.53 (m, 4H), 5.02 (s, 1H), 7.18–7.25 (m, 2H),
7.29 (t, 2H, JZ3.2 Hz), 7.47 (t, 2H, JZ3.2 Hz), 7.94 (d, 1H,
JZ7.8 Hz), 8.49 (d, 1H, JZ3.7 Hz), 8.89 (s, 1H); 13C NMR
(125 MHz, CDCl3) d 13.6, 44.6, 55.1, 84.5, 88.2, 122.91,
122.94, 127.1, 127.5, 128.2, 128.3, 129.0, 131.8, 135.6, 135.9,
148.5, 149.9; MS (EI): m/z 264; HRMS (FAB): Calcd for
C18H20N2: 264.1626, Found: 264.1621.
4.2.20. 4-[1-Hydroxy-3-(trimethylsilyl)-2-propynyl]-
benzonitrile (3t).11 1H NMR (500 MHz, CDCl3) d 0.15
(s, 9H), 2.22 (br s, 1H), 5.46 (s, 1H), 7.42 (d, 1H, JZ
7.5 Hz), 7.58 (d, 1H, JZ7.5 Hz), 7.75 (d, 1H, JZ7.5 Hz),
8.18 (d, 1H, JZ7.5 Hz); 13C NMR (125 MHz, CDCl3) d
0.34, 64.2, 92.8, 104.8, 127.3, 127.5, 130.1, 132.6, 145.7.
4.3.5. N,N-Diethyl-a-(1-octynyl-3-pyridyl)-methanamine
(5e). Yellow oil; IR (neat) 2977, 2213 cmK1 1H NMR
;
(500 MHz, CDCl3) d 0.89 (t, 3H, JZ6.6 Hz), 1.03 (t, 6H,
JZ7.1 Hz), 1.31 (d, 4H, JZ6.6 Hz), 1.44 (s, 2H), 1.56 (q,
2H, JZ6.4 Hz), 2.30 (t, 2H, JZ6.4 Hz), 2.53–2.42 (m, 4H),
4.81 (s, 1H), 7.27 (d, 1H, JZ7.8 Hz), 7.91 (d, 1H, JZ
7.8 Hz), 8.49 (d, 1H, JZ7.8 Hz), 8.84 (s, 1H); 13C NMR
(125 MHz, CDCl3) d 13.5, 13.9, 18.7, 22.5, 28.5, 28.9, 31.2,
40.4, 54.5, 74.5, 88.5, 122.7, 135.8, 135.9, 148.3, 150.0; MS
(EI): m/z 272; HRMS (FAB): Calcd for C18H28N2:
272.2252, Found: 272.2245.
4.2.21. 1-(Phenylethynyl)-cyclohexanol (3u).21 1H NMR
(500 MHz, CDCl3) d 1.54–1.67 (m, 8H), 1.90–1.93 (m, 2H),
7.23–7.25 (m, 3H), 7.36–7.37 (m, 2H); 13C NMR
(125 MHz, CDCl3) d 23.4, 25.2, 40.0, 69.1, 84.3, 92.7,
122.8, 128.1, 128.2, 131.6.
4.3. General procedure for the alkynylation of N,O- or N,
S-acetal
A Et2O solution (3 mL) of Et3N (101.2 mg, 1.000 mmol),
1-alkyne (1.00 mmol), and InBr3 (354.5 mg, 1.000 mmol)
4.3.6. N,N-Diethyl-a-(t-butylethynyl-3-pyridyl)-methan-
amine (5f). Pale yellow oil; IR (neat) 2912, 2207 cmK1; 1H

N. Sakai et al. / Tetrahedron 61 (2005) 9298–9304
9303
NMR (500 MHz, CDCl3) d 1.03 (t, 6H, JZ7.1 Hz), 1.30 (t,
9H, JZ13.7 Hz), 2.40–2.53 (m, 4H), 4.79 (s, 1H), 7.27 (d, 1H,
JZ7.8 Hz), 7.90 (d, 1H, JZ7.8 Hz), 8.49 (d, 1H, JZ7.8 Hz),
8.85 (s, 1H); 13C NMR (125 MHz, CDCl3) d 13.5, 27.6, 31.3,
44.4, 54.4, 72.8, 97.2, 122.7, 135.9, 148.3, 150.1; MS (EI): m/z
244; HRMS (FAB): Calcd for C16H24N2 (MCH): 245.2018,
Found: 245.2021.
The crude product was purified by flash column chroma-
tography (SiO2/hexane–AcOEtZ9/1) to give the corre-
sponding amide 7.
4.4.1. N-(2-Nonynyl)-benzamide (7b). Colorless oil; IR
1
(neat) 3465, 2931, 2199, 1675 cmK1; H NMR (500 MHz,
CDCl3) d 0.85 (t, 2H, JZ6.4 Hz), 1.44 (m, 9H), 2.16 (s, 2H),
4.20 (s, 2H), 7.41 (t, 2H, JZ7.8 Hz), 7.48 (d, 1H, JZ
7.8 Hz), 7.77 (d, 2H, JZ7.8 Hz); 13C NMR (125 MHz,
CDCl3) d 14.0, 18.7, 22.5, 28.5, 30.3, 30.9, 31.3, 75.3, 84.5,
126.9, 128.5, 131.6, 134.1, 166.9; MS (EI): m/z 243 (MC);
HRMS (FAB): Calcd for C16H21NO (MCH): 244.1701,
Found: 244.1722.
4.3.7. N,N-Diethyl-a-[(trimethylsilyl)ethynyl-3-pyridyl]-
1
methanamine (5g). Yellow oil; IR (neat) 2215 cmK1; H
NMR (500 MHz, CDCl3) d 0.20 (d, 9H, JZ14.7 Hz), 1.02
(t, 6H, JZ7.1 Hz), 2.43–2.51 (m, 4H), 4.82 (s, 1H), 7.22–
7.25 (m, 1H), 7.89 (d, 1H, JZ7.9 Hz), 8.49 (s, 1H), 8.83 (s,
1H); 13C NMR (125 MHz, CDCl3) d 0.30, 13.4, 44.3, 55.1,
92.8, 100.5, 122.8, 135.1, 135.7, 148.4, 149.9; MS (EI): m/z
260; HRMS (FAB): Calcd for C15H24N2Si (MCH):
261.1787, Found: 261.1773.
4.4.2. N-(4,4-Dimethyl-2-pentynyl)-benzamide (7c).
1
Colorless oil; IR (neat) 2977, 2218, 1670 cmK1; H NMR
(500 MHz, CDCl3) d 1.19 (t, 9H, JZ14.2 Hz), 4.21 (d, 2H,
JZ5.0 Hz), 7.42 (d, 2H, JZ7.3 Hz), 7.48 (d, 1H, JZ
7.3 Hz), 7.76 (d, 2H, JZ7.3 Hz); 13C NMR (125 MHz,
CDCl3) d 27.3, 30.3, 30.4, 73.7, 92.7, 126.9, 128.6, 131.6,
134.1, 166.9; MS (EI): m/z 215 (MC); HRMS (FAB): Calcd
for C14H17NO (MCH): 216.1388, Found: 216.1404.
4.3.8. N,N-Diethyl-a-(phenylethynyl-2-furyl)-methan-
1
amine (5h). Brown oil; IR (neat) 3066, 2281 cmK1; H
NMR (500 MHz, CDCl3) d 1.09 (t, 6H, JZ7.3 Hz), 2.59
(dd, 2H, JZ7.0, 6.5 Hz), 2.70 (dd, 2H, JZ7.3, 7.0 Hz), 5.07
(s, 1H), 6.33 (s, 1H), 6.47 (s, 1H), 7.30 (d, 3H, JZ3.0 Hz),
7.40 (s, 1H), 7.46 (s, 1H); 13C NMR (125 MHz, CDCl3) d
13.2, 22.7, 29.7, 44.9, 51.9, 85.8, 109.0, 110.1, 122.9, 129.3,
131.8, 142.4, 152.4; MS (EI): m/z 253; HRMS (FAB): Calcd
for C17H19NO: 253.1467, Found: 253.1471.
Acknowledgements
This work was partially supported by a grant from the Japan
Private School Promotion Foundation and a fund for ‘High-
Tech Research Center’ Project for Private Universities: a
matching fund subsidy from MEXT, 2000-2004.
4.3.9. N,N-Diethyl-a-(phenylethynyl-2-thienyl)-methan-
amine (5i). Brown oil; IR (neat) 3071, 2289 cmK1 1H
;
NMR (500 MHz, CDCl3) d 1.11 (t, 6H, JZ7.3 Hz), 2.55 (dd,
2H, JZ6.9, 6.9 Hz), 2.71 (dd, 2H, JZ7.3, 7.3 Hz), 5.17 (s,
1H), 6.95 (t, 1H, JZ3.7, 4.6 Hz), 7.25 (s, 2H), 7.32 (d, 3H, JZ
3.2 Hz), 7.49 (d, 2H, JZ3.7 Hz); 13C NMR (125 MHz,
CDCl3) d 13.5, 19.2, 44.7, 53.4, 85.7, 86.1, 123.1, 125.1,
125.6, 126.2, 128.1, 128.3, 131.8, 139.9, 145.7; MS (EI): m/z
269; HRMS (FAB): Calcd for C17H19NS: 269.1238, Found:
269.1245.
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