A microwave-enhanced, solventless Mannich condensation of terminal alkynes and secondary amines with para-formaldehyde on cuprous iodide doped alumina

Article abstract of DOI:10.1016/j.tet.2005.10.049

A microwave-enhanced, solventless Mannich condensation of terminal alkynes and secondary amines with para-formaldehyde on cuprous iodide doped alumina has been developed. β-Aminoalkynes are generated in good yields. The reaction can be extended to include a cyclization, which affords 2-substituted benzo[b]furans. The chemoselectivity of the reaction indicates that terminal alkynes are much more reactive than enolizable ketones under the reaction conditions.

Full text of DOI:10.1016/j.tet.2005.10.049

Tetrahedron 62 (2006) 857–867
A microwave-enhanced, solventless Mannich condensation of
terminal alkynes and secondary amines with para-formaldehyde
on cuprous iodide doped alumina
*
George W. Kabalka, Li-Li Zhou, Lei Wang and Richard M. Pagni
Departments of Chemistry and Radiology, The University of Tennessee, Knoxville, TN 37996-1600, USA
Received 17 October 2005; accepted 19 October 2005
Available online 18 November 2005
Abstract—A microwave-enhanced, solventless Mannich condensation of terminal alkynes and secondary amines with para-formaldehyde
on cuprous iodide doped alumina has been developed. b-Aminoalkynes are generated in good yields. The reaction can be extended to include
a cyclization, which affords 2-substituted benzo[b]furans. The chemoselectivity of the reaction indicates that terminal alkynes are much more
reactive than enolizable ketones under the reaction conditions.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Microwave irradiation of organic reactions has gained in
popularity in recent years since it was found to accelerate a
wide variety of transformations.7 Early experiments utilized
solvents with high dielectric constants, which permitted
rapid heating of the reaction solution. In recent years, a
number of reports have appeared in which reactants are
coated on to surfaces, which themselves absorb little or no
microwave energy; in these instances, the reactive species
absorb the microwave energy but the temperature of the
reaction mixture tends to rise only modestly. This results in
relatively large energy saving as well as making it possible
to carry out reactions in relatively simple glassware such as
open beakers and flasks.8
The Mannich reaction is a classic example of a three-
component condensation reaction.1 In general, formal-
dehyde (or para-formaldehyde), an amine, and an
‘active-hydrogen’ component such as an enolizable ketone
or terminal alkyne are allowed to react to afford the
corresponding b-aminoketone or b-aminoalkyne. The latter
Mannich adduct contains at least two potential sites for
further modification: the amine and the alkyne.2 In addition,
b-aminoalkynes and their derivatives have a wide range of
applications including use as pharmaceutical intermediates3
and as general synthetic building blocks.4 Moreover, the
alkyne moieties may be functionalized in various ways.
We now wish to report the details of a microwave-enhanced
Mannich condensation of terminal alkynes with amines and
para-formaldehyde on CuI-doped alumina in the absence of
solvents that produces the corresponding aminomethylated
adducts in good yields. The reaction can be extended to a
Mannich condensation cyclization sequence that generates
2-substituted benzo[b]furans in one-pot and in good yields.
The process is highly efficient, does not require pre-forming
the iminium species, and is not hampered by the
heterogeneity of the reaction medium (Scheme 1).
The traditional Mannich method for synthesizing b-amino-
alkynes often requires drastic reaction conditions and
generally is run in dioxane, a toxic solvent. The organic
solvent and the metal catalyst can be difficult to handle and
often difficult to dispose of safely.
We have found alumina to be a particularly useful reagent in
organic synthesis because it can be modified in a variety of
ways that enhance its reactivity. It also obviates a number of
environmental problems.5 For example, using a com-
mercially available alumina/potassium fluoride mixture to
which palladium powder was added, we were able to carry
out Suzuki and Sonogashira coupling reactions on a wide
variety of aromatic moieties without the use of solvents.6
Keywords: Cuprous salts; Mannich reaction; Solventles; Microwave.
*
Corresponding author. Tel.: C1 865 974 3260; fax: C1 865 974 2997;
e-mail: kabalka@utk.edu
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.10.049

858
G. W. Kabalka et al. / Tetrahedron 62 (2006) 857–867
Table 1. A Effect of cuprous salts on the Mannich condensationa
tested, cuprous iodide was most effective and was chosen
for further study.
Entry
Cuprous salt
Yield (%)b
a
b
c
d
Cu2Cl2
CuBr
CuI
28
26
82
0
2.2. Mannich condensation of terminal alkynes with
secondary amines and para-formaldehyde
None
a Reaction conditions: dibenzylamine (1.00 mmol), 1-decyne (1.00 mmol),
para-formaldehyde (3.00 mmol), cuprous salt (3.00 mmol), Al2O3
(1.00 g), irradiated at 300 W for 10 min.
Table 2 contains a summary of the experimental results. A
number of terminal alkynes were successfully condensed
with secondary amines and para-formaldehyde in good
yields. Dibenzylamine, methylbenzylamine, morpholine,
piperidine, 1-phenylpiperazine, N-methyl-1-naphthalene-
methylamine, di(iso-propyl)amine all reacted smoothly
with terminal alkynes and para-formaldehyde to generate
the corresponding Mannich products. It should be noted that
the reaction tolerated many functional groups and that the
sterically hindered 2,2,6,6-tetramethylpiperidine smoothly
produced the corresponding Mannich adduct.
b Isolated yields.
2. Results and discussion
2.1. Effect of cuprous salts on the Mannich condensation
of terminal alkynes with amines and para-formaldehyde
We initially explored the affect of the cuprous salts on the
Mannich condensation of terminal alkynes with amines
and para-formaldehyde. The results are listed in Table 1.
Dibenzylamine, para-formaldehyde and 1-decyne were
chosen as the model reactants for this investigation.
During the investigation, we found that piperazine reacts
with terminal alkynes (2 equiv) and para-formaldehyde
(excess) to afford the diaminomethylation adducts [bis-
(b-aminoalkyne)] (Scheme 2) and 1,9-decadiyne reacted
with secondary amines (2 equiv) and para-formaldehyde
(excess) to generate the bis-Mannich products in moderate
to good yields (Scheme 3).
It is evident that the Mannich reaction requires a cuprous
salt to ‘active’ the terminal alkyne carbon–hydrogen bond to
promote aminomethylation. Among the cuprous salts we
Table 2. Mannich condensation reaction of terminal alkynes with secondary amine and para-formaldehydea
Entry
Alkyne
Amine
Product
Yield (%)b
a
b
c
d
n-C8H17C^CH
n-C8H17C^CH
n-C6H13C^CH
n-C8H17C^CH
(n-C4H9)2NH
n-C8H17C^CCH2N(n-C4H9)2
n-C6H13C^CCH2N(CH2CH6H5)2
n-C8H17C^CCH2(CH2C6H5)2
n-C8H17C^CCH2N(CH3)CH2C6H5
88
82
81
89
(C6H5CH2)2NH
(C6H5CH2)2NH
C6H5CH2NHCH3
e
n-C8H17C^CH
82
f
n-C8H17C^CH
71
g
h
C6H5C^CH
C6H5C^CH
(C6H5CH2)2NH
C6H5C^CCH2N(CH2C6H5)2
79
88
i
p-CH3C6H4C^CH
p-CH3C6H4C^CH
p-CH3C6H4C^CH
80
83
92
j
(C6H5CH2)2NH
p-CH3C6H4C^CCH2N(CH2C6H5)2
k
l
p-CH3C6H4C^CH
74
m
n
p-FC6H4C^CH
p-FC6H4C^CH
o-FC6H4C^CH
p-BrC6H4C^CH
90
85
72
89
(C6H5CH2)2NH
p-FC6H4C^CCH2N(CH2C6H5)2
p-BrC6H4C^CCH2N(n-C4H9)2
o
p
(n-C4H9)2NH
a Reaction conditions: secondary amine (1.00 mmol), terminal alkyne (1.00 mmol), para-formaldehyde (3.00 mmol), cuprous iodide (3.00 mmol), Al2O3
(1.00 g).
b Isolated yields.

G. W. Kabalka et al. / Tetrahedron 62 (2006) 857–867
859
Scheme 2.
CuI/Al2O3
HC C(CH2)6C CH + (CH2O)n + 2R1R2NH
R1R2NCH2C
56%
C(CH2)6C CCH2NR1R2
MW
R1 = R2 = CH3(CH2)3
51%
R1 R2 = C6H5
N
N
Scheme 3.
2.3. Mannich condensation of terminal alkynes with
primary amines and para-formaldehyde
provides an alternative route to N-methyl-b-aminoalkynes
in a convenient and straightforward fashion.9
As anticipated, benzylamine (1 equiv), a primary amine,
reacted with 1-decyne (2 equiv) and para-formaldehyde
(6 equiv) to produce the bis-Mannich condensation because
there are two nitrogen–hydrogen bonds in the primary
amine (Scheme 4). Interestingly, when the ratio of reactants
is changed alternative reations occur. For example,
benzylamine (1 equiv) reacted with 1-decyne (1 equiv)
and para-formaldehyde (5 equiv) to generate the Mannich
condensation product followed reductive methylation
(Scheme 4) phenylacetylene derivatives also afforded
methylation products in fair yields (Scheme 4). The reaction
2.4. The chemoselectivity of the Mannich condensation
of terminal alkynes with secondary amines and
para-formaldehyde
The chemoselectivity of the reaction was investigated.
When a mixture of acetophenone and 4-ethynyltoluene (or a
mixture of 1-decyne and 2-heptanone) served as competi-
tive acidic substrates for the Mannich reaction, only the
b-aminoalkynes were formed (Scheme 5). As anticipated,
the Mannich reaction of 4-acetyl-1-ethynylbenzene with
dibenzylamine and para-formaldehyde (or 11-dodecyn-2-one
Scheme 4.

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G. W. Kabalka et al. / Tetrahedron 62 (2006) 857–867
Scheme 5.
with 1-phenylpiperazine and para-formaldehyde) generated
b-aminoalkyne products exclusively (Scheme 5).
The Mannich condensation–cyclization of o-ethnylphenol
with secondary amines and para-formaldehyde on cuprous
iodide doped alumina under solvent free and microwave
irradiation conditions generates 2-(dialkylaminomethyl)-
benzo[b]furans in good yields (Scheme 6 and Table 3).
2.5. 2-Subsitituted benzo[b]furans from the Mannich
condensation of o-ethynylphenol with secondary amines
and para-formaldehyde
Table 3 contains a summary of the results. Under
microwave irradiation and solvent free conditions, o-ethynyl-
phenol (as well as p-acetyl-o-ethynylphenol) reacts
smoothly with para-formaldehyde and a variety of
secondary amines, such as 1-phenylpiperizine, piperdine,
morpholine, dibutylamine, di(iso-propyl)amine, and
N-methylaniline, methylbenzylamine, 1,2,3,4-tetrahydro-
isoquioine, and N-methylnaphthylmethylamine to afford the
desired 2-substituted benzo[b]furans in one-pot. It should be
noted that the highly sterically encumbered 2,2,6,
6-tetramethylpiperidine also smoothly undergoes the reaction
to generate the corresponding 2-substituted-benzo[b]furan,
which was characterized by 1H, 13C NMR, MS and
microanalysis, and confirmed by X-ray crystal diffraction.
Interestingly, when o-ethynylphenol (2 equiv) was allowed
Benzo[b]furans and their derivatives have received much
attention in recent years because of their occurrence in
natural products and their physiological activity.10 They are
widely used as antitumor agents,11 as ligands of the
adenosine A1 receptor,12 and as calcium entry blockers.13
General routes to benzo[b]furans involve reductive cycliza-
tion of ketoesters by low-valent titanium,14 photochemically
induced rearrangement of phosphate esters,15 palladium
catalyzed Suzuki coupling of boronic acids with organic
halides or triflates,16 and palladium catalyzed Sonogashira
coupling (followed by cyclization) of o-iodophenol and
terminal alkynes.17 No report has appeared describing the
synthesis of 2-substituted benzo[b]furans using a Mannich
condensation reaction.
Scheme 6.

G. W. Kabalka et al. / Tetrahedron 62 (2006) 857–867
Table 3. Mannich condensation–cyclization reaction of o-ethnylphenol and Table 4. Successive trials for Mannich condensation using CuI/Al2O3
its deriatives with secondary amines and para-formaldehyde (see Scheme
861
a
6)a
Trial
Yield (%)b
1
2
3
4
5
6
7
8
82
80
81
79
80
82
80
79
Entry
a
R
H
Amine
Yield (%)b
65
(n-C4H9)2NH
b
c
d
e
H
H
H
H
68
65
62
55
a Experiment were carried out as described in the Section 4 by using 1-
decyne (1 mmol), dibenzylamine (1.00 mmol), para-formaldehyde
(3.00 mmol), cuprous iodide (3.00 mmol), Al2O3 (1.00 g), microwave
irradiation at 300 W for 10 min.
CH5CH2NHCH3
b Isolated yields.
3. Conclusion
f
H
70
A reliable, rapid, practical, and environmentally benign
method for the synthesizing b-aminoalkynes and 2-sub-
stituted benzo[b]furans has been developed, which involves
the use of a solvent-free mixture of cuprous iodide and
alumina under microwave irradiation conditions. The
process is highly efficient, does not require pre-forming
the iminium species, and is not hampered by the
heterogeneity of the reaction.
g
h
H
H
59
56
(i-C3H7)2NH
i
H
52
4. Experimental
C6H5NHCH3
j
H
H
36
65
Melting points were recorded on a MEL-TEMP melting
point apparatus and are uncorrected. IR were recorded on
k
1
a Bomem MB 100 FT-IR. All H and 13C NMR spectra
were recorded on a 250 MHz Bruker AC 250 or Avance
400 MHz spectrometer. Chemical shift are given as d
value with reference to tetramethylsilane (TMS) as
internal standard. GC/MS data were obtained by using
a Hewlett-Packard 6890 series GC equipped with a 5973
mass selective detector. Microanalyses were performed
by Atlantic Microlabs, Norcross, GA. A commercially
available Ethos E Touch Control microwave unit (Mile-
stone) was utilized.
a Reaction condition: secondary amine (1.00 mmol), o-ethynylphenol
(1.00 mmol), para-formaldehyde (3.00 mmol), cuprous iodide
(3.00 mmol), Al2O3 (1.00 g), irradiated at 300 W for 10 min.
b Isolated yields.
to react with para-formaldehyde (excess) and piperazine
(1 equiv), a bis-Mannich condensation cyclization product
was formed (Scheme 7).
Al2O3 and cuprous iodide were purchased from Aldrich
Chemical Co. The organic reagents were analytical grade
and used as received (Aldrich Chemical Co.).
2.6. Surface recyclability
We utilized a surface containing 3 mmol of cuprous
iodide per gram of alumina for 1 mmol scale reactions. In
an effort to enhance the efficiency of the new solid-state
Mannich condensation reaction and reduce waste,
recycling was investigated. Table 4 contains a summary
of the results. It can be seen that the catalyst and alumina
remain active through at least eight cycles. After the
product was removed from the surface using an organic
solvent, the surface was used directly for the next trial
without further treatment.
Products were purified, if applicable, by flash chromato-
˚
graphy on 230–400 mesh ASTM 60 A silica gel, SiO2.
4.1. General procedure for Mannich condensation of
terminal alkynes with amines and para-formaldehyde
Secondary amine (1.00 mmol) and terminal alkyne
(1.00 mmol) were added to a mixture of cuprous iodide
(0.572 g, 3.00 mmol), para-formaldehyde (0.09 g, 3.00 mmol)
Scheme 7.

862
G. W. Kabalka et al. / Tetrahedron 62 (2006) 857–867
and alumina (1.00 g) contained in a clean, dry, 10 mL
round-bottomed flask. The mixture was stirred at room
temperature to ensure efficient mixing. The flask was then
fitted with a septum (punctured by an 18 gauge needle to
serve as a pressure release valve), placed in the microwave
oven and irradiated at 300 W for 10 min [caution: heating
volatile materials in commercial microwave ovens for
extended periods can be hazardous]. After cooling, ether
(4 mL) was added and the slurry stirred at room temperature
to ensure product removal from the surface. The mixture
was vacuum filtered using a sintered glass funnel and the
product was purified by flash chromatography to yield the
desired b-aminoalkyne.
4.1.6. Methyl-1-(naphthalenemethyl)(undec-2-ynyl)-
amine. Oil; IR (film, CHCl3) 2259 cmK1 (C^C); 1H
NMR (250 MHz, CDCl3): d 8.29 (d, JZ8.1 Hz, 1H), 7.82–
7.73 (m, 2H), 7.52–7.34 (m, 4H), 3.96 (s, 2H), 3.30 (s, 2H),
2.34 (s, 3H), 2.26 (t, JZ6.7 Hz, 2H), 1.62–1.28 (m, 12H),
0.87 (t, JZ6.6 Hz, 3H); 13C NMR (62.5 MHz, CDCl3): d
134.5, 133.8, 132.6, 128.3, 128.0, 127.5, 125.8, 125.5,
125.0, 124.6, 85.9, 74.7, 58.1, 45.6, 41.9, 31.8, 29.2, 29.0,
28.9, 22.6, 18.8, 14.1; MS m/z (relative intensity) 321 (MC,
5), 306 (1), 208 (17), 180 (50), 141 (100), 115 (19). Anal.
Calcd for C23H31N: C, 85.92; H, 9.72; N, 4.36. Found: C,
85.84; H, 9.90; N, 4.44.
4.1.7. Dibenzyl(3-phenylprop-2-ynyl)amine.19 Oil; 1H
NMR (250 MHz, CDCl3): d 7.45–7.18 (m, 15H), 3.72 (s,
4H), 3.43 (s, 2H); 13C NMR (62.5 MHz, CDCl3): d 138.8,
131.7, 129.0, 128.3, 127.9, 127.1, 123.4, 85.9, 84.4, 57.9,
42.0.
4.1.1. Dibutyl(undec-2-ynyl)amine.18 Oil; 1H NMR
(250 MHz, CDCl3): d 3.35 (s, 2H), 2.38–2.49 (t, 4H),
2.12–2.21 (t, 3H), 1.19–1.60 (m, 20H), 0.88–0.94 (m, 9H);
13C NMR (62.5 MHz, CDCl3): d 84.9, 74.7, 53.5, 42.3, 31.7,
29.7, 29.2, 29.1, 29.0, 28.8, 22.7, 20.7, 18.7, 14.1.
4.1.8. 1-(3-phenylprop-2-ynyl)piperidine.20 Oil; IR (film,
CHCl3) 2188 cmK1 (C^C); 1H NMR (250 MHz, CDCl3): d
7.45–7.41 (m, 2H), 7.27–7.25 (m, 3H), 3.46 (s, 2H), 2.55 (s,
br, 2!2H), 1.67–1.59 (m, 2!2H), 1.45 (t, JZ5.5 Hz, 2H);
13C NMR (62.5 MHz, CDCl3): d 131.4, 127.9, 127.7, 123.1,
84.8, 84.7, 53.2, 48.2, 25.7, 23.7; MS m/z (relative intensity)
199 (MC, 42), 170 (11), 157 (25), 130 (7), 122 (13), 115
(100).
4.1.2. Dibenzyl(undec-2-ynyl)amine. Oil; IR (film, CHCl3)
1
2261 cmK1 (C^C); H NMR (250 MHz, CDCl3) d 7.40–
7.16 (m, 10H), 3.65 (s, 2!2H), 3.22 (s, 2H), 2.24 (t, JZ
6.6 Hz, 2H), 1.55–1.30 (m, 12H), 0.88 (t, JZ6.8 Hz, 3H);
13C NMR (62.5 MHz, CDCl3): d 139.1, 128.9, 128.1, 126.9,
85.7, 74.4, 57.5, 41.6, 31.8, 29.3, 29.1, 28.9, 22.6, 18.7,
14.1; MS m/z (relative intensity) 347 (MC, 3), 270 (6), 256
(10), 194 (7), 91 (100). Anal. Calcd for C25H33N: C, 86.40;
H, 9.57; N, 4.03. Found: C, 86.34; H, 9.68; N, 4.09.
4.1.9. 1-[3-(p-Tolyl)prop-2-ynyl]piperidine.21 Oil; 1H
NMR (250 MHz, CDCl3): d 7.34–7.30 (d, 2H), 7.11–7.07
(d, 2H), 3.46 (s, 2H), 2.50–2.61 (t, 3H), 2.32 (s, 3H), 1.59–
1.70 (t, 4H), 1.36–1.48 (m, 2H); 13C NMR (62.5 MHz,
CDCl3): d 137.7, 131.5, 128.8, 120.2, 85.0, 84.2, 53.4, 48.4,
25.9, 23.7, 21.3.
4.1.3. Dibenzyl(non-2-ynyl)amine. Oil; IR (film, CHCl3)
1
2260 cmK1 (C^C); H NMR (250 MHz, CDCl3): d 7.40–
7.18 (m, 10H), 3.65 (s, 2!2H), 3.22 (s, 2H), 2.25 (t, JZ
6.7 Hz, 2H), 1.59–1.31 (m, 8H), 0.91 (t, JZ6.7 Hz, 3H); 13C
NMR (62.5 MHz, CDCl3): d 139.1, 129.0, 128.2, 126.9,
85.8, 74.4, 57.5, 41.6, 31.4, 29.1, 28.6, 22.6, 18.7, 14.1; MS
m/z (relative intensity) 319 (MC, 3), 242 (7), 228 (9), 194
(6), 91 (100). Anal. Calcd for C23H29N: C, 86.47; H, 9.15;
N, 4.38. Found: C, 86.24; H, 9.22; N, 4.41.
4.1.10. Dibenzyl[3-(p-tolyl)prop-2-ynyl]amine. Oil; IR
(film, CHCl3) 2229 cmK1 (C^C); 1H NMR (250 MHz,
CDCl3): d 7.44–7.20 (m, 12H), 7.11 (d, JZ7.9 Hz, 2H),
3.74 (s, 2!2H), 3.45 (s, 2H), 2.33 (s, 3H); 13C NMR
(62.5 MHz, CDCl3): d 138.9, 138.0, 131.6, 129.0, 128.2,
127.0, 120.3, 86.0, 83.6, 57.7, 42.0, 21.4; MS m/z (relative
intensity) 325 (MC, 6), 234 (11), 194 (9), 129 (45), 91
(100). Anal. Calcd for C24H23N: C, 88.57; H, 7.12; N, 4.30.
Found: C, 88.45; H, 7.21; N, 4.27.
4.1.4. Benzylmethyl(undec-2-ynyl)amine. Oil; IR (film,
CHCl3) 2261 cmK1 (C^C); 1H NMR (250 MHz, CDCl3): d
7.34–7.21 (m, 5H), 3.55 (s, 2H), 3.25 (s, 2H), 2.30 (s, 3H),
2.23 (t, JZ6.8 Hz, 2H), 1.56–1.28 (m, 12H), 0.88 (t, JZ
6.0 Hz, 3H); 13C NMR (62.5 MHz, CDCl3): d 138.6, 129.1,
128.1, 127.0, 85.7, 74.5, 60.1, 45.4, 41.7, 31.8, 29.2, 29.0,
28.9, 28.8, 22.6, 18.7, 14.0; MS m/z (relative intensity) 271
(MC, 7), 194 (26), 158 (21), 120 (19), 91 (100). Anal. Calcd
for C19H29N: C, 84.07; H, 10.77; N, 5.16. Found: C, 84.21;
H, 10.88; N, 5.23.
4.1.11. 4-[(3-p-Tolyl)prop-2-ynyl]morpholine. Oil; IR
(film, CHCl3) 2204 cmK1 (C^C); 1H NMR (250 MHz,
CDCl3): d 7.32 (d, JZ8.1 Hz, 2H), 7.09 (d, JZ8.0 Hz, 2H),
3.75 (t, JZ4.7 Hz, 2!2H), 3.48 (s, 2H), 2.62 (t, JZ4.6 Hz,
2!2H), 2.32 (s, 3H); 13C NMR (62.5 MHz, CDCl3): d
138.0, 131.4, 128.9, 119.8, 85.5, 83.2, 66.7, 52.3, 47.9, 21.3;
MS m/z (relative intensity) 215 (MC, 29), 184 (32), 170
(26), 157 (40), 129 (100). HRMS Calcd for C14H17NO:
215.1310, found: 215.1310.
4.1.5. 1-(Undec-2-ynyl)piperidine. Oil; IR (film, CHCl3)
2188 cmK1 (C^C); 1H NMR (250 MHz, CDCl3): d 3.20 (t,
JZ1.8 Hz, 2H), 2.47 (s, br, 2!2H), 2.18 (t, JZ6.8 Hz, 2H),
1.66–1.28 (m, 18H), 0.88 (t, JZ6.5 Hz, 3H); 13C NMR
(62.5 MHz, CDCl3): d 84.9, 75.0, 53.1, 47.9, 31.6, 29.0,
28.9, 28.7, 25.7, 23.8, 22.4, 18.5, 13.8; MS m/z (relative
intensity) 235 (MC, 22), 234 (MCK1, 74), 150 (30), 136
(59), 122 (58), 98 (23), 84 (100). Anal. Calcd for C16H29N:
C, 81.63; H, 12.42; N, 5.95. Found: C, 81.45; H, 12.55; N,
6.02.
4.1.12. 2,2,6,6-Tetramethyl-1-[3-(p-tolyl)prop-2-ynyl]-
piperdine. Mp 178–180 8C; IR (KBr, CHCl3) 2401 cmK1
(C^C); 1H NMR (250 MHz, CDCl3): d 7.27 (d, JZ7.9 Hz,
2H), 7.06 (d, JZ7.8 Hz, 2H), 3.55 (s, 2H), 2.31 (s, 3H),
1.54–1.44 (m, 6H), 1.17 (s, 12H); 13C NMR (62.5 MHz,
CDCl3): d 137.3, 131.3, 128.8, 121.2, 92.2, 81.0, 54.9, 41.2,
33.8, 27.5, 21.4, 17.8; MSm/z (relative intensity) 269 (MC, 2),

G. W. Kabalka et al. / Tetrahedron 62 (2006) 857–867
863
254 (7), 129 (100). Anal. Calcd for C19H27N: C, 84.70; H,
10.10; N, 5.20. Found: C, 84.56; H, 10.23; N, 5.11.
4.2.2. 1,4-Di[3-(p-tolyl)prop-2-ynyl]piperazine. Mp 119–
1
121 8C; IR (film, CHCl3) 2199 cmK1 (C^C); H NMR
(250 MHz, CDCl3) 7.32 (d, JZ8.0 Hz, 2!2H), 7.08 (d, JZ
8.1 Hz, 2!2H), 3.52 (s, 2!2H), 2.74 (s, br, 2!4H), 2.32
(s, 2!3H); 13C NMR (62.5 MHz, CDCl3): d 138.0, 131.5,
128.9, 120.0, 85.4, 83.5, 51.9, 47.6, 21.3; MS m/z (relative
intensity) 342 (MC, 2), 341 (MCK1, 5), 272 (3), 223 (5),
213 (11), 129 (100), 115 (8). Anal. Calcd for C24H26N2: C,
84.17; H, 7.65; N, 8.18. Found: C, 83.96; H, 7.85; N, 8.03.
4.1.13. 1-[3-(4-Fluorophenyl)prop-2-ynyl]-4-phenyl-
piperazine. Mp 80.5–81.5 8C; IR (KBr) 2253 cmK1
(C^C); 1H NMR (250 MHz, CDCl3): d 7.44–7.38 (m,
2H), 7.29–7.23 (m, 2H), 7.01–6.83 (m, 5H), 3.55 (s, 2H),
3.25 (t, JZ4.8 Hz, 2!2H), 2.78 (t, JZ4.8 Hz, 2!2H);
13C NMR (62.5 MHz, CDCl3): d 164.3, 160.3, 151.1, 133.6,
133.4, 129.0, 119.7, 119.0 (d, JZ3.3 Hz), 116.1, 115.6,
115.2, 84.4, 83.9, 52.0, 49.0, 47.6; MS m/z (relative
intensity) 294 (MC, 12), 252 (6), 188 (11), 176 (14), 159
(100), 133 (84), 106 (60). Anal. Calcd for C19H19N2F: C,
77.52; H, 6.51; N, 9.52. Found: C, 77.60; H, 6.66; N, 9.55.
4.3. General procedure for the Mannich condensation
of a,u-dialkyne with secondary amine and
para-formaldehyde
a,u-Dialkyne (1.00 mmol), para-formaldehyde (6.00 mmol)
and secondary amine (2.00 mmol) were mixed well with
Al2O3 (2.00 g) and cuprous iodide (1.16 g, 6.00 mmol) and
placed in the microwave oven and irradiated at 300 W for
10 min.
4.1.14. Dibenzyl[(3-p-fluorophenyl)prop-2-ynyl]amine.22
1
Oil; H NMR (250 MHz, CDCl3): d 7.44–7.01 (m, 14H),
3.74 (S, 2!2H), 3.46 (s, 2H); 13C NMR (62.5 MHz,
CDCl3): d 164.3, 160.4, 138.8, 129.9, 129.8, 129.0, 128.3,
127.6, 127.2, 125.2, 118.7, 118.4, 115.5, 115.2, 85.6, 84.7,
57.8, 41.9.
4.3.1. N,N,N,N-Tetrabutyl-2,10-dodecadiynyl-1,12-
diamine. Oil; IR (film, CHCl3) 2189 cmK1 (C^C); 1H NMR
(250 MHz, CDCl3) 3.34 (t, JZ1.9 Hz, 2!2H), 2.43 (t, JZ
7.3 Hz, 4!2H), 2.19 (t, JZ6.5 Hz, 2!2H), 1.53–1.25 (m,
24H), 0.92 (t, JZ7.1 Hz, 4!3H); 13C NMR (62.5 MHz,
CDCl3): d 84.5, 74.7, 53.3, 42.0, 29.5, 28.7, 28.1, 20.6, 18.5,
13.9; MS m/z (relative intensity) 246 (MCK170, 21), 112
(12), 84 (100), 70 (29), 57 (66). Anal. Calcd for C28H52N2:
C, 80.70; H, 12.58; N, 6.72. Found: C, 80.50; H, 12.62; N,
6.69.
4.1.15. 4-[3-(2-Fluorophenyl)prop-2-ynyl)]morpholine.
Oil; IR (film, CHCl3) 2205 cmK1 (C^C); 1H NMR
(250 MHz, CDCl3): d 7.46–7.39 (m, 1H), 7.33–7.24 (m,
1H), 7.10–7.02 (m, 2H), 3.77 (t, JZ4.6 Hz, 2!2H), 3.56 (s,
2H), 2.66 (s, br, 2!2H); 13C NMR (62.5 MHz, CDCl3): d
162.8 (d, JZ250.3 Hz), 133.4, 129.8 (d, JZ7.6 Hz), 123.8
(d, JZ3.4 Hz), 115.3 (d, JZ20.8 Hz), 111.4 (d, JZ
15.4 Hz), 89.3, 78.9, 66.8, 52.2, 48.0; MS m/z (relative
intensity) 219 (MC, 16), 188 (17), 161 (16), 133 (100), 86
(26). Anal. Calcd for C13H14NFO: C, 71.21; H, 6.44; N,
6.39. Found: C, 70.93; H, 6.50; N, 6.28.
4.3.2. 1,12-Di(4-phenylpiperazino)-2,10-dodecadiyne.
1
Mp 81–82 8C; IR (film, CHCl3) 2204 cmK1 (C^C); H
NMR (250 MHz, CDCl3) 7.28–7.21 (m, 2!2H), 6.93–6.81
(m, 2!3H), 3.29 (s, 2!2H), 3.22 (t, JZ7.7 Hz, 4!2H),
2.69 (t, JZ4.6 Hz, 4!2H), 2.20 (t, JZ6.8 Hz, 2!2H),
1.53–1.39 (m, 8H); 13C NMR (62.5 MHz, CDCl3): d 151.1,
128.9, 119.5, 85.4, 74.5, 51.9, 48.9, 47.2, 28.5, 28.1, 18.5;
MS m/z (relative intensity) 322 (MCK160, 17), 216 (10),
159 (94), 120 (66), 106 (100), 77 (70). Anal. Calcd for
C32H42N4: C, 79.62; H, 8.77; N, 11.61. Found: C, 79.60; H,
8.76; N, 11.55.
4.1.16. [3-(4-Bromophenyl)prop-2-ynyl]dibutylamine.
Oil; IR (film, CHCl3) 2190 cmK1 (C^C); 1H NMR
(250 MHz, CDCl3): d 7.41 (d, JZ8.5 Hz, 2H), 7.27 (d,
JZ8.5 Hz, 2H), 3.58 (s, 2H), 2.51 (t, JZ7.3 Hz, 2!2H),
1.51–1.27 (m, 8H), 0.93 (t, JZ7.1 Hz, 2!3H); 13C NMR
(62.5 MHz, CDCl3): d 133.0, 131.3, 122.3, 121.9, 86.2,
83.8, 53.6, 42.6, 29.6, 20.6, 14.0; MS m/z (relative intensity)
323, 321 (MC, 4, 4), 280, 278 (97, 100), 195, 193 (78, 79),
114 (26), 84 (20). Anal. Calcd for C17H24NBr: C, 63.36; H,
7.51; N, 4.35. Found: C, 63.31; H, 7.53; N, 4.37.
4.4. Mannich condensation reaction of terminal alkyne
with primayl amine and para-formaldehyde
4.2. General procedure for the Mannich condensation of
terminal alkyne with piperazine and para-formaldehyde
(a) 1-Decyne (2.00 mmol), para-formaldehyde (6.00 mmol)
and benzylamine (2.00 mmol) were mixed well with Al2O3
(2.00 g) and cuprous iodide (1.16 g, 6.00 mmol) and placed
in the microwave oven and irradiated at 300 W for 10 min,
worked up the same as the general procedure. (b) Terminal
alkyne (1.00 mmol), para-formaldehyde (5.00 mmol) and
benzylamine (1.00 mmol) were mixed well with Al2O3
(1.00 g) and cuprous iodide (0.58 g, 3.00 mmol) and placed
in the microwave oven and irradiated at 30% power for
10 min.
Terminal alkyne (2.00 mmol), para-formaldehyde (6.00 mmol)
and piperazine (1.00 mmol) were mixed well with Al2O3
(2.00 g) and cuprous iodide (1.16 g, 6.00 mmol) and placed
in the microwave oven and irradiated at 30% power for
10 min.
4.2.1. 1,4-Di(non-2-ynyl)piperazine. Oil; IR (film, CHCl3)
1
2196 cmK1 (C^C); H NMR (250 MHz, CDCl3): 3.25 (s,
2!2H), 2.62 (s, br, 4!2H), 2.17 (t, JZ6.9 Hz, 2!2H),
1.52–1.26 (m, 16H), 0.89 (t, JZ6.7 Hz, 2!3H); 13C NMR
(62.5 MHz, CDCl3): d 85.3, 74.5, 51.7, 47.1, 31.1, 28.6,
28.4, 22.3, 18.5, 13.8; MS m/z (relative intensity) 330 (MC,
3), 287 (10), 260 (9), 231 (10), 207 (100), 178 (26), 108
(20). Anal. Calcd for C22H38N2: C, 79.94; H, 11.59; N, 8.47.
Found: C, 76.69; H, 11.68; N, 8.43.
4.4.1. Benzyldi(undec-2-ynyl)amine. Oil; IR (film, CHCl3)
2232 cmK1 (C^C); 1H NMR (250 MHz, CDCl3) 7.38–7.20
(m, 5H), 3.66 (s, 2H), 3.35 (s, 2!2H), 2.21 (t, JZ6.7 Hz,
2!2H), 1.55–1.28 (m, 2!12H), 0.88 (t, JZ6.6 Hz, 2!
3H); 13C NMR (62.5 MHz, CDCl3): d 138.3, 129.3, 128.1,
127.1, 85.3, 75.0, 56.9, 42.3, 31.8, 29.2, 29.1, 28.9, 22.6,

864
G. W. Kabalka et al. / Tetrahedron 62 (2006) 857–867
18.7, 14.0; MS m/z (relative intensity) 322 (MCK85, 6),
294 (7), 184 (5), 156 (8), 91 (100). Anal. Calcd for
C29H45N: C, 85.44; H, 11.13; N, 3.44. Found: C, 85.37; H,
11.24; N, 3.52.
temperature to ensure product removal from the surface.
The product was purified by chromatography to afford
0.415 g (97% yield) of 4-acetyl-1-ethynylbenzene. Mp 68–
70 8C (lit.23 69–70 8C); 1H NMR (250 MHz, CDCl3): d 7.90
(d, JZ8.3 Hz, 2H), 7.57 (d, JZ8.4 Hz, 2H), 3.27 (s, 1H),
2.59 (s, 3H); 13C NMR (62.5 MHz, CDCl3): d 197.1, 136.7,
132.2, 128.1, 126.8, 82.7, 80.3, 26.5; MS m/z (relative
intensity) 144 (MC, 31), 129 (100), 101 (54), 75 (21).
4.4.2. Benzylmethyl(undec-2-ynyl)amine. Oil; IR (film,
CHCl3) 2260 cmK1 (C^C); 1H NMR (250 MHz, CDCl3): d
7.35–7.22 (m, 5H), 3.55 (s, 2H), 3.26 (t, JZ2.0 Hz, 2H),
2.30 (s, 3H), 2.26–2.20 (m, 2H), 1.59–1.28 (m, 12H), 0.88
(t, JZ6.5 Hz, 3H); 13C NMR (62.5 MHz, CDCl3): d 138.6,
129.2, 128.2, 127.1, 85.8, 74.6, 60.2, 45.5, 41.8, 31.8, 29.2,
29.1, 29.0, 28.9, 22.6, 18.7, 14.0; MS m/z (relative intensity)
271 (MC, 7), 194 (25), 158 (22), 120 (18), 91 (100). Anal.
Calcd for C19H29N: C, 84.07; H, 10.77; N, 5.16. Found: C,
83.96; H, 10.85; N, 5.19.
4.4.6. Preparation of 11-dodecyn-2-one.24 To a suspen-
sion of dry pyridinium chlorochromate (4.85 g, 22.5 mmol)
in dry CH2Cl2 (20 mL), 10-undecyn-1-ol (2.50 g, 15 mmol)
and dry CH2Cl2 (5 mL) were added dropwise. The reaction
mixture was stirred at room temperature for 3 h and
the solution was then extracted with ether (3!20 mL).
The combined organic layer was dried with Na2SO4 and the
solvent removed under reduced pressure. The product was
purified by column chromatography (hexane/ethyl acetate
9:1) to afford 2.00 g (80% yield) of 10-undecyn-1-al.
4.4.3. Benzylmethyl[3-(phenyl)prop-2-ynyl]amine. Oil;
IR (film, CHCl3) 2235 cmK1 (C^C); 1H NMR
(250 MHz, CDCl3): d 7.48–7.44 (m, 2H), 7.38–7.23 (m,
8H), 3.62 (s, 2H), 3.49 (s, 2H), 2.38 (s, 3H); 13C NMR
(62.5 MHz, CDCl3): d 138.3, 131.6, 129.1, 128.1, 127.9,
127.1, 123.2, 85.6, 84.3, 60.1, 45.6, 41.8; MS m/z (relative
intensity) 235 (MC, 18), 158 (41), 144 (27), 115 (100), 91
(64). Anal. Calcd for C17H17N: C, 86.77; H, 7.28; N, 5.95.
Found: C, 86.66; H, 7.43; N, 6.01.
To a solution of 10-undecyn-1-al (1.50 g, 9.04 mmol) in dry
Et2O (15 mL), CH3MgBr in ether (3 M, 3.67 mL, 11 mmol)
was added at 0 8C over a 1 h period. The reaction mixture
was then refluxed for 3 h. Aqueous ammonium chloride was
then added to quench the reaction and the mixture was
extracted with ether (3!20 mL). The combined organic
layer was washed with water and dried with Na2SO4 and
then the solvent removed under reduced pressure (2 mmHg
for 2 h). The crude product was used without purification.
4.4.4. Benzylmethyl[3-(p-tolyl)prop-2-ynyl]amine. Oil;
IR (film, CHCl3) 2247 cmK1 (C^C); 1H NMR
(250 MHz, CDCl3): d 7.37–7.24 (m, 7H), 7.09 (d, JZ
7.94 Hz, 2H), 3.62 (s, 2H), 3.49 (s, 2H), 2.38 (s, 3H), 2.32 (s,
3H); 13C NMR (62.5 MHz, CDCl3): d 138.4, 137.9, 131.5,
129.1, 128.9, 128.2, 127.1, 120.2, 85.7, 83.6, 60.2, 45.7,
41.9, 21.3; MS m/z (relative intensity) 249 (MC, 17), 172
(32), 158 (36), 129 (100), 91 (73). Anal. Calcd for C18H19N:
C, 86.70; H, 7.68; N, 5.62. Found: C, 86.42; H, 7.60; N,
5.57.
11-Dodecyn-2-ol (crude, 1.4 g) in dry CH2Cl2 (5 mL) was
added dropwise to a suspension of pyridinium chlorochro-
mate (2.26 g, 10.5 mmol) in dry CH2Cl2 (10 mL) dropwise
at room temperature. The reaction mixture was stirred at
room temperature for 2 days and then extracted with ether
(3!20 mL). The combined organic layer was dried with
Na2SO4 and then the solvent removed under reduced
pressure. The product was purified by column chromato-
graphy (hexane/ethyl acetate 85:15) to afford 1.20 g
4.4.5. Preparation of 4-acetyl-1-ethynylbenzene.23 To a
stirred solution of p-bromoacetophone (1.00 g, 5.00 mmol)
and Et3N–dioxane (4 mL/4 mL), PdCl2(PPh3)2 (0.035 g,
0.05 mmol) and CuI (0.019 g, 0.100 mmol) were added in
one portion. Then (trimethylsilyl)acetylene (0.85 mL,
6.00 mmol) was added dropwise at room temperature
under nitrogen. The reaction mixture was stirred overnight.
Et3N, dioxane and unreacted (trimethylsilyl)acetylene were
removed under reduced pressure. The product extracted
with Et2O (3!20 mL). The combined organic phase was
washed with H2O, dried (Na2SO4) and concentrated under
vacuum. The residue was purified by column chromato-
graphy to generate 0.820 g (85% yield) of 4-acetyl-1-
1
(combined yield 74%) of 11-dodecyn-2-one. Oil; H NMR
(250 MHz, CDCl3): d 2.41 (t, JZ7.4 Hz, 2H), 2.18–2.12 (m,
5H), 1.93 (t, JZ2.4 Hz, 1H), 1.55–1.28 (m, 12H); 13C NMR
(62.5 MHz, CDCl3): d 208.5, 84.2, 67.9, 43.4, 29.5, 28.9,
28.8, 28.6, 28.3, 28.1, 23.5, 18.0; MS m/z (relative intensity)
165 (MCKC2H5, 2), 147 (2), 122 (6), 107 (9), 95 (15), 81
(23), 58 (100).
4.5. Chemoselectivity of Mannich Condensation
(a) Intermolecular chemoselectivity. A secondary amine
(morpholine or piperazine, 1.00 mmol), terminal alkyne
(4-ethynyltoluene or 1-decyne, 1.00 mmol) and an enolizable
ketone (acetophone or 2-heptone, 1.00 mmol) were mixed
with a mixture of cuprous iodide (0.572 g, 3.00 mmol),
para-formaldehyde (0.09 g, 3.00 mmol) and alumina
(1.00 g) in a clean, dry, 10 mL round-bottomed flask at
room temperature. The flask was then fitted with a septum
(punctured by an 18 gauge needle), placed in the microwave
oven and irradiated at 30% power for 10 min.
1
((trimethylsilyl)ethynyl)benzene. Oil; H NMR (250 MHz,
CDCl3): d 7.87 (d, JZ7.9 Hz, 2H), 7.52 (d, JZ8.4 Hz, 2H),
2.57 (s, 3H), 0.27 (s, 9H); 13C NMR (62.5 MHz, CDCl3): d
196.9, 136.3, 131.9, 128.0, 127.8, 103.9, 97.9, 26.4, -0.29;
MS m/z (relative intensity) 216 (MC, 15), 201 (100), 158
(10), 143 (8), 93 (9).
4-Acetyl-1-((trimethylsilyl)ethynyl)benzene (0.648 g,
3.00 mmol) was added to KF/Al2O3 (2.00 g, 40% by
weight) and stirred at room temperature to ensure efficient
mixing. The result mixture was placed in the microwave
oven and irradiated at 30% power for 3 min. After cooling,
hexane (10 mL) was added and the slurry stirred at room
(b) Intramolecular chemoselectivity. Dibenzylamine or
1-phenylpiperazine (1.00 mmol) and 4-acetyl-1-ethynyl-
benzene or 11-dodecyn-2-one (1.00 mmol) were added to

G. W. Kabalka et al. / Tetrahedron 62 (2006) 857–867
865
a mixture of cuprous iodide (0.572 g, 3.00 mmol), para-
formaldehyde (0.09 g, 3.00 mmol) and alumina (1.00 g)
contained in a clean, dry, 10 mL round-bottomed flask. The
mixture was stirred at room temperature to ensure efficient
mixing. The flask was then fitted with a septum (punctured
by an 18 gauge needle), placed in the microwave oven and
irradiated at 30% power for 10 min.
combined organic phase washed with H2O, dried (Na2SO4)
and concentrated under vacuum. The residue was purified
by column chromatography to afford 0.87 g (86% yield) of
o-((trimethylsilyl)ethynyl)phenol. Mp 46–48 8C (lit.26
1
46–47 8C); H NMR (250 MHz, CDCl3): d 7.32 (dd, JZ
6.3 Hz, JZ1.4 Hz, 1H), 7.20 (dt, JZ7.0 Hz, JZ1.5 Hz,
1H), 6.93 (d, JZ8.2 Hz, 1H), 6.82 (t, JZ7.6 Hz, 1H),
5.90 (s, 1H), 0.26 (s, 9H); 13C NMR (62.5 MHz, CDCl3):
d 157.0, 131.6, 130.6, 120.1, 114.5, 109.5, 102.2, 99.0,
K0.1; MS m/z (relative intensity) 190 (MC, 18), 175 (100),
159 (19), 135 (13), 115 (16), 77 (14).
4.5.1. [3-(4-Acetylphenyl)prop-2-ynyl]dibenzylamine.
Oil; IR (film, CHCl3) 2230 cmK1 (C^C), 1683 cmK1
(C]O); 1H NMR (250 MHz, CDCl3): d 7.92 (d, JZ8.3 Hz,
2H), 7.56 (d, JZ8.2 Hz, 2H), 7.45–7.23 (m, 10H), 3.76 (s,
2!2H), 3.50 (s, 2H), 2.60 (s, 3H); 13C NMR (62.5 MHz,
CDCl3): d 197.2, 138.7, 136.1, 131.9, 129.0, 128.3, 128.2,
127.2, 88.3, 85.2, 57.8, 42.1, 26.6; MS m/z (relative
intensity) 194 (MCK159, 11), 158 (15), 143 (25), 115
(20), 91 (100). Anal. Calcd for C25H23NO: C, 84.95; H,
6.56; N, 3.96. Found: C, 85.11; H, 6.66; N, 3.94.
o-[(Trimethylsilyl)ethynyl]phenol (0.61 g, 3.00 mmol) was
added to KF/Al2O3 (2.00 g, 40% by weight) and stirred at
room temperature to ensure efficient mixing. The resultant
mixture was placed in the microwave oven and irradiated at
30% power for 3 min. After cooling, hexane (10 mL) was
added and the slurry stirred at room temperature to ensure
product removal from the surface. The product was purified
by chromatography to afford 0.365 g (92% yield) of
o-ethynylphenol. Oil;27 1H NMR (250 MHz, CDCl3): d
7.38 (d, JZ7.5 Hz, 1H), 7.27 (dt, JZ7.7 Hz, JZ1.0 Hz,
1H), 6.95 (d, JZ8.2 Hz, 1H), 6.87 (t, JZ7.5 Hz, 1H), 5.80
(s, br, 1H), 3.46 (s, 1H); 13C NMR (62.5 MHz, CDCl3): d
157.4, 132.0, 130.9, 120.3, 114.8, 108.3, 84.3, 78.3; MS m/z
(relative intensity) 118 (MC, 100), 89 (44), 63 (21).
4.5.2. 1-Phenyl-4-(tridec-12-oxo-2-ynyl)piperazine. Mp
33–34 8C; IR (film, CHCl3) 2208 cmK1 (C^C),
1
1711 cmK1 (C]O); H NMR (250 MHz, CDCl3): d 7.29–
7.22 (m, 2H), 6.95–6.82 (m, 3H), 3.31 (s, 2H), 3.23 (t, JZ
4.9 Hz, 2!2H), 2.71 (t, JZ4.9 Hz, 2!2H), 2.39 (t, JZ
7.4 Hz, 2H), 2.19 (t, JZ6.7 Hz, 2H), 2.11 (s, 3H), 1.58–1.28
(m, 12H); 13C NMR (100 MHz, CDCl3): d 209.2, 151.1,
129.0, 119.6, 116.0, 85.6, 74.5, 51.9, 48.9, 47.3, 43.6, 29.7,
29.2, 29.0, 28.8, 28.7, 28.6, 23.7, 18.6; MS m/z (relative
intensity) 354 (MC, 18), 248 (35), 160 (53), 159 (94), 130
(38), 120 (71), 105 (100). Anal. Calcd for C23H34N2O: C,
77.92; H, 9.67; N, 7.90. Found: C, 77.98; H, 9.61; N, 8.02.
4.5.5. p-Acetyl-o-[(trimethylsilyl)ethynyl]phenol. Mp
1
127–129 8C; H NMR (250 MHz, CDCl3): d 8.00 (d, JZ
1.4 Hz, 1H), 7.87 (d, JZ8.7 Hz, 1H), 7.00 (d, JZ8.7 Hz,
1H), 6.63 (s, br, 1H), 2.55 (s, 3H), 0.29 (s, 9H); 13C NMR
(62.5 MHz, CDCl3): d 196.2, 160.9, 133.0, 131.1, 129.9,
114.8, 109.9, 103.2, 97.8, 26.2, K0.2; MS m/z (relative
intensity) 232 (MC, 24), 217 (100), 174 (8), 115 (10), 101
(19). Anal. Calcd for C13H16O2Si: C, 67.20; H, 6.94. Found:
C, 67.40; H, 6.84.
4.5.3. Iodination of phenols: preparation of 4-hydroxy-3-
iodoacetophenone (representative procedure). 4-Hydro-
xyacetophenone (1.36 g, 10 mmol) was dissolved in 10 mL
of THF–H2O (50/50, V/V) and I2 (2.80 g, 11 mmol) and
NaHCO3 (0.92 g, 11 mmol) were crushed together and
added to the solution. After the mixture was stirred for 3 h at
room temperature, residual I2 was destroyed by addition of a
5% aqueous solution of Na2S2O3 until the brown color
disappeared. The mixture was extracted with ether (3!
50 mL). The organic phase was dried with Na2SO4 and the
solvent was removed under pressure. 4-Hydroxy-3-iodo-
acetophenone (1.23 g, 47% yield) was isolated by column
chromatography (silica gel, hexane/ethyl acetate 95:5). Mp
152–154 8C (lit.25 153–155 8C); 1H NMR (250 MHz,
CD3OD): d 8.29 (s, 1H), 7.82 (d, JZ8.5 Hz, 1H), 6.86 (d,
JZ8.4 Hz, 1H), 4.91 (s, br, 1H), 2.51 (s, 3H); MS m/z
(relative intensity) 262 (MC, 36), 247 (100), 219 (16), 127
(7), 120 (23), 92 (40).
4.5.6. p-Acetyl-o-ethynylphenol. Mp 100–102 8C; 1H
NMR (250 MHz, CDCl3): d 8.05 (d, JZ1.5 Hz, 1H), 7.91
(d, JZ8.7 Hz, 1H), 7.37 (s, 1H), 7.03 (d, JZ8.6 Hz, 1H),
3.50 (s, 1H), 2.57 (s, 3H); 13C NMR (62.5 MHz, CDCl3): d
196.7, 161.6, 133.8, 131.3, 129.6, 115.2, 108.8, 84.4, 77.5,
26.1; MS m/z (relative intensity) 160 (MC, 40), 145 (100),
117 (48), 89 (31). HRMS Calcd for C10H8O2 160.0524,
found 160.0520.
4.6. One-pot synthesis of 2-substitutited benzo[b]furans
via the Mannich condensation cyclization sequence
reaction of o-ethynylphenol with secondary amines
and para-formaldehyde: general procedure
4.5.4. Preparation of o-ethynylphenol and p-acetyl-o-
ethynylphenol via a Sonogashira coupling followed by
desilylation: synthesis of o-ethynylphenol as represen-
tative. To a stirred solution of 2-iodophenol (1.10 g,
5.00 mmol) and Et3N–dioxane (4 mL/4 mL), PdCl2(PPh3)2
(0.035 g, 0.05 mmol) and CuI (0.019 g, 0.10 mmol) were
added in one portion. Then (trimethylsilyl)acetylene
(0.85 mL, 6.00 mmol) was added dropwise at room
temperature under nitrogen. The reaction mixture was
stirred overnight. Et3N, dioxane and unreacted (trimethylsilyl)-
acetylene were removed under reduced pressure. The
product was extracted with Et2O (3!20 mL) and the
o-Ethynylphenol (0.18 g, 1.00 mmol) and the secondary
amine (1.00 mmol) were added to a mixture of cuprous
iodide (0.57 g, 3.00 mmol), para-formaldehyde (0.09 g,
3.00 mmol) and alumina (1.00 g) contained in a clean,
dry, 10 mL round-bottomed flask. The mixture was stirred at
room temperature to ensure efficient mixing. The flask was
then fitted with a septum (punctured by an 18 gauge needle),
placed in the microwave oven and irradiated at 30% power
for 10 min. After cooling, ether (4 mL) was added and the
slurry stirred at room temperature to ensure product removal
from the surface. The mixture was vacuum filtered using a
sintered glass funnel and the product purified by flash

866
G. W. Kabalka et al. / Tetrahedron 62 (2006) 857–867
chromatography (hexane/EtOAc as eluting agent) to afford
the desired 2-substituted-benzo[b]furan.
(s, 2H), 3.71 (s, 2H), 2.90 (t, JZ5.3 Hz, 2H), 2.82 (t, JZ
5.4 Hz, 2H); 13C NMR (62.5 MHz, CDCl3): d 155.0, 154.6,
134.3, 133.9, 128.5, 128.2, 126.5, 126.1, 125.5, 123.8,
122.5, 120.6, 111.2, 105.4, 55.6, 54.9, 50.5, 28.8; MS m/z
(relative intensity) 263 (MC, 5), 145 (19), 131 (100), 104
(23), 77 (21). Anal. Calcd for C18H17NO: C, 82.10; H, 6.51;
N, 5.32. Found: C, 81.96; H, 6.57; N, 5.30.
4.6.1. 1-(Benzofuran-2-ylmethyl)-4-phenylpiperazine.
Mp 75–76 8C; H NMR (250 MHz, CDCl3): d 7.53–7.46
1
(m, 2H), 7.26–7.18 (m, 4H), 6.90–6.80 (m, 3H), 6.59 (s,
1H), 3.70 (s, 2H), 3.20 (t, JZ4.8 Hz, 2!2H), 2.67 (t, JZ
4.8 Hz, 2!2H); 13C NMR (62.5 MHz, CDCl3): d 155.0,
154.2, 151.1, 129.0, 128.1, 123.9, 122.6, 120.6, 119.6,
116.0, 111.2, 105.7, 55.3, 52.9, 48.9; MS m/z (relative
intensity) 292 (MC, 33), 186 (12), 173 (22), 159 (98), 131
(100), 106 (54), 77 (56). Anal. Calcd for C19H20N2O: C,
78.05; H, 6.89; N, 9.58. Found: C, 78.04; H, 6.89; N, 9.47.
4.6.8. (Benzofuran-2-ylmethyl)di(isopropyl)amine. Oil;
1H NMR (250 MHz, CDCl3): d 7.50–7.41 (m, 2H), 7.20–
7.16 (m, 2H), 6.57 (s, 1H), 3.77 (d, JZ0.59 Hz, 2H), 3.18–
3.08 (m, 2H), 1.06 (d, JZ6.6 Hz, 4!3H); 13C NMR
(62.5 MHz, CDCl3): d 160.2, 154.8, 128.9, 123.0, 122.3,
120.3, 110.9, 103.2, 49.0, 42.9, 20.7; MS m/z (relative
intensity) 231 (MC, 3), 216 (9), 131 (100). Anal. Calcd for
C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C, 78.16; H,
9.36; N, 5.97.
4.6.2. (Benzofuran-2-ylmethyl)dibutylamine.28 Oil; 1H
NMR (250 MHz, CDCl3): d 7.50–7.43 (m, 2H), 7.22–7.17
(m, 2H), 6.54 (s, 1H), 3.77 (s, 2H), 2.50 (t, JZ7.5 Hz, 2!
2H), 1.53–1.46 (m, 2!2H), 1.35–1.27 (m, 2!2H), 0.90
(t, JZ7.2 Hz, 2!3H); 13C NMR (62.5 MHz, CDCl3):
d 156.2, 154.9, 128.5, 123.5, 122.4, 120.5, 111.1, 104.8,
53.7, 50.7, 29.2, 20.6, 14.0; MS m/z (relative intensity) 259
(MC, 2), 216 (10), 131 (100), 77 (9).
4.6.9. 1-(Benzofuran-2-ylmethyl)-2,2,6,6-tetramethyl-
piperidine. Mp 88–89 8C; H NMR (250 MHz, CDCl3): d
1
7.48–7.36 (m, 2H), 7.17–7.14 (m, 2H), 6.63 (s, 1H), 3.81 (s,
2H), 1.60–1.51 (m, 6H), 1.06 (s, 4!3H); 13C NMR
(62.5 MHz, CDCl3): d 163.5, 154.5, 129.1, 122.7, 122.2,
120.2, 110.7, 102.9, 54.9, 42.4, 41.2, 27.4, 17.8; MS m/z
(relative intensity) 271 (MC, 2), 256 (15), 131 (100), 77 (7).
Anal. Calcd for C18H25NO: C, 79.66; H, 9.28; N, 5.16.
Found: C, 79.40; H, 9.36; N, 4.91.
4.6.3. 1-(Benzofuran-2-ylmethyl)piperidine.29 Oil; 1H
NMR (250 MHz, CDCl3): d 7.53–7.45 (m, 2H), 7.27–7.15
(m, 2H), 6.56 (s, 1H), 3.64 (s, 2H), 2.46 (s, br, 2!2H),
1.63–1.57 (m, 2!2H), 1.44–1.42 (m, 2H); 13C NMR
(62.5 MHz, CDCl3): d 155.0, 128.3, 123.7, 122.5, 120.5,
111.2, 105.3, 56.1, 54.3, 25.8, 24.1; MS m/z (relative
intensity) 251 (MC, 10), 131 (100), 84 (26), 77 (15).
4.6.10. (Benzofuran-2-ylmethyl)methylaniline. Oil; 1H
NMR (250 MHz, CDCl3): d 7.48–7.41 (m, 2H), 7.28–7.15
(m, 4H), 6.86–6.72 (m, 3H), 6.49 (s, 1H), 4.61 (s, 2H), 3.08
(s, 3H); 13C NMR (62.5 MHz, CDCl3): d 155.2, 154.9,
149.1, 129.2, 128.4, 123.7, 122.6, 120.6, 117.3, 112.9,
111.0, 103.9, 50.5, 38.6; MS m/z (relative intensity) 237
(MC, 13), 207 (26), 131 (100), 96 (9), 77 (23). Anal. Calcd
for C16H15NO: C, 80.98; H, 6.37; N, 5.90. Found: C, 81.17;
H, 6.61; N, 5.63.
4.6.4. (Benzofuran-2-ylmethyl)benzylmethylamine. Oil;
1H NMR (250 MHz, CDCl3): d 7.52–7.18 (m, 9H), 6.57 (s,
1H), 3.70 (s, 2H), 3.60 (s, 2H), 2.29 (s, 3H); 13C NMR
(62.5 MHz, CDCl3): d 155.4, 155.0, 138.4, 129.0, 128.3,
128.2, 127.1, 123.7, 122.5, 120.6, 111.2, 105.2, 61.3, 53.7,
42.1; MS m/z (relative intensity) 251 (MC, 10), 160 (13),
131 (100), 91 (27), 77 (13). Anal. Calcd for C17H17NO: C,
81.24; H, 6.82; N, 5.57. Found: C, 81.25; H, 6.82; N, 5.56.
4.6.11. 1-(5-Acetylbenzofuran-2-ylmethyl)-4-phenyl-
piperazine. Mp 111–113 8C; H NMR (250 MHz, CDCl3):
1
4.6.5. 4-(Benzofuran-2-ylmethyl)morpholine. Mp 50–
51 8C (lit.30 51–52 8C); 1H NMR (250 MHz, CDCl3): d
7.54–7.46 (m, 2H), 7.28–7.17 (m, 2H), 6.60 (s, 1H), 3.74 (t,
JZ4.6 Hz, 2!2H), 3.67 (s, 2H), 2.54 (t, JZ4.5 Hz, 2!
2H); 13C NMR (62.5 MHz, CDCl3): d 155.1, 154.0, 128.1,
123.9, 122.6, 120.6, 111.2, 105.8, 66.7, 55.8, 53.4; MS m/z
(relative intensity) 217 (MC, 14), 144 (9), 131 (100), 86
(26), 77 (17).
d 8.19 (s, 1H), 7.93 (d, JZ8.6 Hz, 1H), 7.52 (d, JZ8.7 Hz,
1H), 7.25 (t, JZ7.7 Hz, 2H), 6.93–6.82 (m, 3H), 6.17 (s,
1H), 3.76 (s, 2H), 3.24 (t, JZ4.7 Hz, 2!2H), 2.72 (t, JZ
4.7 Hz, 2!2H), 2.65 (s, 3H); 13C NMR (62.5 MHz,
CDCl3): d 197.5, 157.6, 156.1, 151.1, 132.6, 129.0, 128.3,
124.7, 122.0, 119.7, 116.1, 111.2, 106.2, 55.3, 53.0, 49.0,
26.7; MS m/z (relative intensity) 334 (MC, 25), 228 (11),
201 (55), 173 (64), 130 (36), 106 (87), 56 (100). HRMS
Calcd for C21H22N2O2 334.1681, found 334.1690.
4.6.6. (Benzofuran-2-ylmethyl)methyl(1-naphthalene-
methyl)amine. Oil; H NMR (250 MHz, CDCl3): d 8.20–
1
4.6.12. 1,4-Bis(benzofuran-2-ylmethyl)piperazine. Mp
143–144 8C; 1H NMR (250 MHz, CDCl3): d 7.52–7.44
(m, 4H), 7.29–7.15 (m, 4H), 6.58 (s, 2!1H), 3.69 (s, 2!
2H), 2.62 (s, br, 4!2H); 13C NMR (62.5 MHz, CDCl3): d
155.0, 154.3, 128.2, 123.8, 122.6, 120.6, 111.2, 105.6, 55.3,
52.7; MS m/z (relative intensity) 346 (MC, 2), 215 (46), 131
(100), 77 (15). Anal. Calcd for C22H22N2O2: C, 76.28; H,
6.40; N, 8.09. Found: C, 76.05; H, 6.51; N, 7.99.
8.17 (m, 1H), 7.80–7.70 (m, 2H), 7.50–7.32 (m, 6H), 7.26–
7.14 (m, 2H), 6.57 (s, 1H), 3.94 (s, 2H), 3.76 (s, 2H), 2.30 (s,
3H); 13C NMR (62.5 MHz, CDCl3): d 155.5, 155.0, 134.3,
133.8, 132.4, 128.3, 128.0, 127.4, 125.9, 125.5, 125.0, 124.5,
123.8, 122.5, 120.6, 111.1, 105.4, 59.4, 54.2, 42.3; MS m/z
(relative intensity) 301 (MC, 9), 207 (8), 160 (42), 141 (61),
131 (100), 115 (19), 77 (13). Anal. Calcd for C21H19NO: C,
83.69; H, 6.35; N, 4.65. Found: C, 83.71; H, 6.53; N, 4.68.
4.7. General procedure for recycling
4.6.7. 2-(Benzofuran-2-ylmethyl)-1,2,3,4-tetrahydro-
isoquinoline. Mp 58–59 8C; H NMR (250 MHz, CDCl3):
d 7.53–7.45 (m, 2H), 7.25–6.95 (m, 6H), 6.62 (s, 1H), 3.83
1
After carried out a Mannich condensation, ether was added
to remove the product from the cuprous iodide and alumina

G. W. Kabalka et al. / Tetrahedron 62 (2006) 857–867
867
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Acknowledgements
We wish to thank the US Department of Energy and the
Robert H. Cole Foundation for support of this research. We
are grateful to Mr. Tianniu Chen and Dr. Zhongzhi Wu for
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