An expedient three-component synthesis of tertiary benzylamines

Article abstract of DOI:10.1055/s-0029-1217108

A Mannich-like zinc-mediated three-component reaction of aromatic halides, amines, and paraformaldehyde is described. This procedure, which involves the in situ formation of arylzinc reagents, allows the straightforward synthesis of a range of functionalized tertiary benzylamines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217108

PAPER
249
An Expedient Three-Component Synthesis of Tertiary Benzylamines
M
ulticomponen
r
t
Synthe
w
sis of
T
ertiary
B
en
a
z
ylamines n Le Gall,* Alexandre Decompte, Thierry Martens, Michel Troupel
Électrochimie et Synthèse Organique, Institut de Chimie et des Matériaux Paris-Est, UMR 7182 CNRS - Université Paris Est,
2–8 rue Henri Dunant, 94320 Thiais, France
Fax +33(1)49781148; E-mail: legall@glvt-cnrs.fr
Received 9 July 2009; revised 25 September 2009
omatic halide (3 equiv14), amine (1 equiv), and paraform-
aldehyde (2 equiv) allowed to react at 60 °C; under these
conditions, reactions generally appeared to be complete in
one hour.15,16 Results are reported in Table 1.
Abstract: A Mannich-like zinc-mediated three-component reac-
tion of aromatic halides, amines, and paraformaldehyde is de-
scribed. This procedure, which involves the in situ formation of
arylzinc reagents, allows the straightforward synthesis of a range of
functionalized tertiary benzylamines.
Table 1 Coupling between Aryl Halides, Paraformaldehyde, and
Key words: multicomponent reactions, amines, catalysis, zinc,
organometallic reagents
Piperidinea
FG
FG
Zn, CoBr2
N
X
(CH2O)n
+
+
MeCN, 60 °C
Benzylamines are compounds of high interest that have
potential application both as reliable precursors of fine
chemical derivatives1 and as pharmacologically active
compounds.2 These attractive properties have made them
prominent synthetic targets for organic chemists. Several
general strategies can be envisaged for the preparation of
the benzylamine moiety, including reductive amination of
aldehydes,3 hydroamination of alkenes,4 nitrile reduc-
tion,5 amination of alcohols,6 nucleophilic substitution of
halides by amines,7 Suzuki–Miyaura coupling with tri-
fluoroborates,8 and proton shift of triazenes.9
N
H
1a–i
Entry
1
X
FG
Time (h) Product
Yield (%)
Cl
Br
I
H
1
1a
1a
1a
1b
1c
1d
1e
1f
–
2
H
1
96
70b
87
87
80
70
91
87
83
3
H
0.5
1
4
Br
Br
Br
Br
Br
Br
Br
Br
I
4-i-Pr
4-OMe
3-CF3
4-CO2Et
3-CO2Et
3-F
5
1
Curiously, despite their high synthetic interest, multicom-
ponent procedures related to the Mannich reaction have
not been employed so far in a systematic study dedicated
to the formation of functionalized tertiary benzylamines.10
Such strategies, however, would appear to be very reliable
due to cost-effective starting compounds and the opportu-
nity to prepare easily libraries of compounds.
6
1
7
1
8
1
9
1
1g
1h
1i
Over the last few years, our group has developed a
Mannich-type three-component reaction between organo-
zinc reagents, amines, and aldehyde derivatives.11 In a
very recent study, we disclosed the possibility of operat-
ing under Barbier-like conditions, starting from organic
halides as organozinc precursors.12 Herein, we confirm
the possible in situ metalation of aryl bromides with zinc
dust by applying this strategy to the preparation of a range
of functionalized tertiary benzylamines.
10
11
12
3-Cl
2-Cl
2-Cl
1
c
1
–
2.5
1i
76b
a Reagents: Zn dust (6 g), CoBr2 (0.66 g), ArBr (30 mmol), paraform-
aldehyde (20 mmol), piperidine (10 mmol), MeCN (40 mL).
b Caution, vigorous reaction: conducted at r.t.
c Principally observed as a transient species.
In the first series of experiments we investigated the scope
of the aryl halide in three-component couplings with pip-
eridine as model amine and paraformaldehyde as a form-
aldehyde synthetic equivalent. The most general and
convenient reaction conditions were defined as follows:
acetonitrile was used as solvent, zinc dust as the reductive
metal, and cobalt(II) bromide as the catalyst13 with the ar-
The first point to note is that while chlorobenzene is inac-
tive in the reaction (Table 1, entry 1), bromobenzene is a
very reliable halide, providing the corresponding three-
component coupling product 1a in almost quantitative
yield after one hour at 60 °C (Table 1, entry 2). Iodoben-
zene also undergoes the reaction (Table 1, entry 3). In this
case, heating is not necessary and actually not recom-
mended because a sudden exothermic process tends to de-
velop upon addition of cobalt(II) bromide in the reaction
medium. Accordingly, in most reactions, functionalized
bromobenzenes possess a more appropriate reactivity and
SYNTHESIS 2010, No. 2, pp 0249–0254
x
x
.
x
x
.2
0
0
9
Advanced online publication: 06.11.2009
DOI: 10.1055/s-0029-1217108; Art ID: T15009SS
© Georg Thieme Verlag Stuttgart · New York

250
E. Le Gall et al.
PAPER
also constitute more cost-effective starting compounds mobenzenes (Table 3, entries 1–4), an aromatic bromide
(Table 1, entries 4–10). However, the use of a functional- derived from naphthalene was efficient in the process
ized iodobenzene might constitute a suitable alternative to (Table 3, entry 5). Halopyridines did not undergo the
the corresponding bromobenzene for reactions in which three-component reaction (Table 3, entries 6–8) whereas
the latter would not undergo the coupling. This assertion halothiophenes were very efficient in the process, as at-
is exemplified by the comparison of Table 1, entries 11 tested by the successful coupling of 2- and 3-bromo-
and 12. Indeed, if 1-bromo-2-chlorobenzene is used as the thiophene with amines and paraformaldehyde (Table 3,
starting aryl bromide, a mixture of products is observed entries 9 and 10).
(Table 1, entry 11), whereas a very satisfactory result is
In conclusion, the results reported in this study highlight
obtained by using 1-chloro-2-iodobenzene as the orga-
the versatility and the reliability of this novel three-
nozinc precursor (Table 1, entry 12).
component reaction between aryl halides, amines, and
In a second series of experiments we examined the scope paraformaldehyde for the synthesis of benzylamines. In-
of the secondary amine. To this end, bromobenzene was deed, we show that a large range of halobenzenes and
chosen as the model halide. The experimental conditions amines can be employed in the process to furnish func-
were typically identical to those already described above. tionalized tertiary benzylamines and analogues with short
Results are displayed in Table 2.
reaction times and high yields. Further extensions of this
process, in particular the generalization of the use of
Barbier-like conditions starting from aryl bromides, are
currently in progress.
Table 2 Coupling between Bromobenzene, Paraformaldehyde, and
Secondary Aminesa
R1
Zn,
R1
R2
R2
CoBr2
N
MeCN (analytical grade) and reagents were purchased from com-
mercial suppliers and used without further purification. All reac-
tions were monitored by gas chromatography (GC) using a Varian
3400 chromatograph equipped with a 5 m SGE BP1 column. Melt-
ing points were determined on an Electrothermal IA 9100 capillary
melting apparatus and are uncorrected. IR spectra were performed
on a Bruker Tensor 27 ATR-FTIR spectrophotometer. NMR spectra
were recorded at 400 MHz (1H), 100 MHz (13C), and 376 MHz (19F)
on a Bruker Avance II 400 spectrometer in CDCl3 relative to the re-
sidual CHCl3 signal. Mass spectra were measured on a Finnigan
GC/MS GCQ Thermoquest spectrometer. Elemental analyses were
performed at the ‘Service de Microanalyse’, CNRS, Gif-sur-Yvette
(France).
Br
(CH2O)n
N
H
+
+
MeCN,
60 °C
2a–g
Entry Amine R1R2NH
Time (h) Product
Yield (%)
1
2
3
4
5
6
7
pyrrolidine
2
2a
2b
2c
2d
2e
2f
97
84
70
89
71
97
64
tetrahydroisoquinoline
morpholine
2
2
N-phenylpiperazine
indoline
1.5
0.5
1
Tertiary Benzylamines 1–3; General Procedure
A dried 100-mL round-bottomed flask was flushed with argon and
charged with MeCN (40 mL). Zn dust (6 g, 92 mmol), TFA (306
mg, 200 mL, 2.68 mmol), and 1,2-dibromoethane (872 mg, 400 mL,
4.64 mmol) were added to the soln which was heated with stirring
until production of gas. Heating was then stopped and the soln
stirred at r.t. for an additional 10 min. The aryl bromide (30 mmol),
paraformaldehyde (0.6 g, ~20 mmol), amine (10 mmol), and CoBr2
(0.66 g, 3 mmol) were added to the soln, which was heated at 60 °C
until completion of the reaction (typically 1–2 h). The mixture was
poured into sat. aq NH4Cl soln (150 mL) and extracted with CH2Cl2
(2 × 100 mL). The combined organic fractions were concentrated to
dryness and the crude oil was taken up with Et2O (150 mL). After
complete dissolution, concd H2SO4 (0.5–0.75 mL) was added care-
fully to the vigorously stirred soln. After stirring for 5 min, the re-
sulting ammonium salt was filtered and washed with Et2O (2 × 50
mL). The solid was then poured under stirring into 5% aq NaOH
soln (100 mL) and extracted with CH2Cl2 (2 × 100 mL). The com-
bined organic fractions were dried (Na2SO4) and concentrated to
dryness to yield the analytically pure (>97% GC) benzylamine.
N-methylaniline
diethylamine
2
2g
a Reagents: Zn dust (6 g), CoBr2 (0.66 g), PhBr (30 mmol), paraform-
aldehyde (20 mmol), amine (10 mmol), MeCN (40 mL).
A large range of secondary amines are usable in the pro-
cess. However, it should be noted that diethylamine led to
the corresponding coupling product in only moderate
yield (Table 2, entry 7). This limited yield might be sim-
ply attributed to a partial loss of the starting amine upon
heating, due to its high volatility.
In a third set of experiments we attempted to verify the
versatility of the reaction by realizing ‘cross-couplings’
between paraformaldehyde and a range of bromobenzenes
and amines. We additionally tried to expand further the
scope of the procedure by checking the behavior of other
organic halides and particularly heteroaromatic halides in
the reaction. This could lead to the straightforward forma-
tion of some benzylamines analogues. Miscellaneous re-
sults are reported in Table 3.
1-Benzylpiperidine (1a)8
Light yellow oil; yield: 1.69 g (96%).
1H NMR: d = 7.32–7.11 (m, 5 H), 3.42 (s, 2 H), 2.32 (br s, 4 H),
1.59–1.44 (m, 4 H), 1.41–1.28 (m, 2 H).
13C NMR: d = 138.2, 129.3, 128.1, 127.0, 63.8, 54.4, 25.9, 24.3.
The first point to note is that, apart from the possibility to
operate starting from miscellaneous amines and bro-
MS: m/z (%) = 177 (24), 176 (43), 175 (45), 174 (100), 98 (26), 92
(8), 91 (76), 84 (32), 70 (6), 65 (9).
Synthesis 2010, No. 2, 249–254 © Thieme Stuttgart · New York

PAPER
Multicomponent Synthesis of Tertiary Benzylamines
251
Table 3 Coupling between Aryl Halides, Paraformaldehyde, and Aminesa
R1
R1
R2
Zn, CoBr2
N
R2
ArX
+
(CH2O)n
+
N
H
MeCN, 60 °C
Ar
3a–g
Entry
1
ArX
Amine R1R2NH
Time (h)
1
Product
Yield (%)
75
F3C
morpholine
3a
Br
2
3
4
diethylamine
morpholine
2
1
1
3b
3c
3d
83
75
55
EtO2C
MeO
Br
Br
N-phenylpiperazine
MeO
Br
Br
5
piperidine
1.5
2
3e
66
–
MeO
N
6b
tetrahydroisoquinoline
–
Br
7b
piperidine
1.5
–
–
Br
I
N
8b
9
piperidine
2
1
1
–
–
c
N
piperidine
3f
3g
72
85
Br
S
10
tetrahydroisoquinoline
Br
S
a Reagents: Zn dust (6 g), CoBr2 (0.66 g), ArX (30 mmol), paraformaldehyde (20 mmol), amine (10 mmol), MeCN (40 mL).
b Conducted on a 5 mmol scale using half of the amounts stated above.
c 2,2¢-Bipyridine was the major product of the reaction.
1-(4-Isopropylbenzyl)piperidine (1b)
Colorless oil; yield: 1.89 g (87%).
13C NMR: d = 157.2, 129.1, 128.9, 112.1, 61.8, 53.9, 52.9, 24.5,
23.0.
1H NMR: d = 7.16 (d, J = 8.1 Hz, 2 H), 7.09 (d, J = 8.1 Hz, 2 H),
3.37 (s, 2 H), 2.81 (hept, J = 6.9 Hz, 1 H), 2.30 (br s, 4 H), 1.54–1.44
(m, 4 H), 1.40–1.29 (m, 2 H), 1.17 (d, J = 6.9 Hz, 6 H).
13C NMR: d = 147.5, 135.8, 129.3, 126.1, 63.6, 54.5, 33.8, 25.9,
24.4, 24.1.
MS: m/z (%) = 206 (13), 205 (51), 204 (61), 123 (5), 122 (32), 121
(100), 98 (7), 91 (10), 85 (7), 84 (29), 78 (5), 77 (9).
1-[3-(Trifluoromethyl)benzyl]piperidine (1d)15
Light-yellow oil; yield: 1.95 g (80%).
1H NMR: d = 7.49–7.43 (m, 1 H), 7.34–7.30 (m, 2 H), 7.28 (t, J =
7.7 Hz, 1 H), 3.38 (s, 2 H), 2.25 (br s, 4 H), 1.55–1.40 (m, 4 H),
1.38–1.25 (m, 2 H).
13C NMR: d = 140.0, 132.3, 130.5 (q, J = 32.0 Hz), 128.5, 125.6 (q,
J = 3.8 Hz), 124.3 (q, J = 272.2 Hz), 123.6 (q, J = 3.8 Hz), 63.3,
54.5, 25.9, 24.3.
MS: m/z (%) = 218 (20), 217 (56), 216 (100), 174 (11), 134 (8), 133
(66), 118 (5), 117 (17), 115 (10), 105 (24), 98 (14), 92 (9), 91 (19),
84 (55), 56 (7).
Anal. Calcd for C15H23N: C, 82.89; H, 10.67; N, 6.44. Found: C,
82.54; H, 10.63; N, 6.35.
1-(4-Methoxybenzyl)piperidine (1c)8
Yellow oil; yield: 1.79 g (87%).
1H NMR: d = 7.24 (d, J = 8.7 Hz, 2 H), 6.86 (d, J = 8.7 Hz, 2 H),
3.81 (s, 3 H), 3.44 (s, 2 H), 2.38 (br s, 4 H), 1.64–1.52 (m, 4 H),
1.49–1.35 (m, 2 H).
19F NMR: d = –62.48.
MS: m/z (%) = 244 (5), 243 (32), 242 (100), 200 (5), 159 (42), 109
(8), 98 (13).
Ethyl 4-[(Piperidin-1-yl)methyl]benzoate (1e)
Light-orange oil; yield: 1.73 g (70%).
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252
E. Le Gall et al.
PAPER
1H NMR: d = 7.92 (d, J = 8.3 Hz, 2 H), 7.35 (d, J = 8.3 Hz, 2 H),
4.30 (q, J = 7.1 Hz, 2 H), 3.50 (s, 2 H), 2.35 (br s, 4 H), 1.61–1.49
(m, 4 H), 1.44–1.23 (m, 5 H).
13C NMR: d = 166.6, 129.5, 129.4, 129.2, 63.1, 60.9, 54.4, 25.5,
24.0, 14.3.
MS: m/z (%) = 162 (16), 161 (29), 160 (84), 132 (8), 118 (6), 92
(10), 91 (100), 84 (24), 70 (70), 65 (17).
2-Benzyl-1,2,3,4-tetrahydroisoquinoline (2b)17
Light-brown oil; yield: 1.88 g (84%).
1H NMR: d = 7.48–7.25 (m, 5 H), 7.19–7.09 (m, 3 H), 7.05–6.94 (m,
1 H), 3.73 (s, 2 H), 3.67 (s, 2 H), 2.93 (t, J = 5.9 Hz, 2 H), 2.79 (t,
J = 5.9 Hz, 2 H).
13C NMR: d = 138.2, 134.8, 134.3, 129.2, 128.7, 128.3, 127.2,
126.6, 126.1, 125.6, 62.7, 56.0, 50.6, 29.1.
MS: m/z (%) = 248 (7), 247 (47), 246 (100), 218 (21), 202 (10), 163
(46), 135 (13), 107 (8), 98 (15), 91 (6), 84 (24).
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C,
72.76; H, 8.39; N, 5.59.
Ethyl 3-[(Piperidin-1-yl)methyl]benzoate (1f)
Yellow oil; yield: 2.25 g (91%).
MS: m/z (%) = 224 (5), 223 (44), 222 (100), 146 (5), 133 (5), 132
(34), 130 (7), 104 (6), 92 (5), 91 (46), 78 (6).
1H NMR: d = 7.95–7.81 (m, 2 H), 7.53 (d, J = 7.5 Hz, 1 H), 7.33 (t,
J = 7.6 Hz, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 3.49 (s, 2 H), 2.35 (br s,
4 H), 1.62–1.48 (m, 4 H), 1.43–1.27 (m, 5 H).
13C NMR: d = 166.7, 133.9, 130.4, 130.4, 128.4, 128.3, 63.2, 61.0,
54.3, 25.7, 24.1, 14.4.
4-Benzylmorpholine (2c)6e
Yellow oil; yield: 1.24 g (70%).
1H NMR: d = 7.40–7.19 (m, 5 H), 3.79–3.66 (m, 4 H), 3.52 (s, 2 H),
2.54–2.36 (m, 4 H).
13C NMR: d = 137.6, 129.2, 128.3, 127.2, 67.0, 63.5, 53.6.
MS: m/z (%) = 248 (7), 247 (43), 246 (100), 218 (18), 163 (33), 135
(5), 119 (19), 98 (13), 91 (8), 84 (22).
MS: m/z (%) = 178 (19), 177 (58), 176 (26), 147 (7), 146 (59), 118
(7), 105 (7), 104 (9), 100 (6), 92 (11), 91 (100), 86 (75), 65 (14), 56
(6).
Anal. Calcd for C15H21NO2: C, 72.84; H, 8.56; N, 5.66. Found: C,
72.77; H, 8.68; N, 5.71.
1-Benzyl-4-phenylpiperazine (2d)18
Light-brown solid; yield: 2.25 g (89%); mp 52–54 °C.
1H NMR: d = 7.54–7.29 (m, 7 H), 7.03 (d, J = 7.9 Hz, 2 H), 6.96 (t,
J = 7.3 Hz, 1 H), 3.67 (s, 2 H), 3.37–3.22 (m, 4 H), 2.78–2.63 (m, 4
1-(3-Fluorobenzyl)piperidine (1g)16
Light-yellow oil; yield: 1.68 g (87%).
1H NMR: d = 7.23–7.14 (m, 1 H), 7.05–6.96 (m, 2 H), 6.90–6.81 (m,
1 H), 3.41 (s, 2 H), 2.32 (br s, 4 H), 1.61–1.46 (m, 4 H), 1.42–1.26
(m, 2 H).
13C NMR: d = 162.9 (d, J = 245.2 Hz), 141.1, 129.5 (d, J = 8.2 Hz),
124.7 (d, J = 2.8 Hz), 115.9 (d, J = 21.2 Hz), 113.8 (d, J = 21.1 Hz),
63.1 (d, J = 1.8 Hz), 54.4, 25.8, 24.2.
H).
13C NMR: d = 151.5, 138.1, 129.3, 129.2, 128.4, 127.3, 119.7,
116.1, 63.2, 53.2, 49.2.
MS: m/z (%) = 253 (19), 252 (100), 251 (12), 146 (14), 145 (9), 119
(35), 118 (27), 104 (16), 103 (8), 102 (11), 91 (50).
19F NMR: d = –113.92.
1-Benzyl-2,3-dihydro-1H-indole (2e)19
Brown oil; yield: 1.49 g (71%).
MS: m/z (%) = 194 (5), 193 (40), 192 (100), 109 (10), 98 (15), 84
(58).
1H NMR: d = 7.65–7.43 (m, 5 H), 7.37–7.22 (m, 2 H), 6.91 (t, J =
7.4 Hz, 1 H), 6.73 (d, J = 7.8 Hz, 1 H), 4.45 (s, 2 H), 3.51 (t, J = 8.3
Hz, 2 H), 3.17 (t, J = 8.3 Hz, 2 H).
13C NMR: d = 152.8, 138.7, 130.2, 128.7, 128.1, 127.6, 127.3,
124.7, 118.0, 107.3, 53.9, 53.8, 28.8.
1-(3-Chlorobenzyl)piperidine (1h)16
Yellow oil; yield: 1.74 g (83%).
1H NMR: d = 7.26 (s, 1 H), 7.21–7.06 (m, 3 H), 3.36 (s, 2 H), 2.29
(br s, 4 H), 1.60–1.43 (m, 4 H), 1.41–1.23 (m, 2 H).
13C NMR: d = 140.9, 134.0, 129.4, 129.1, 127.2, 127.0, 63.2, 54.5,
25.9, 24.3.
MS: m/z (%) = 210 (18), 209 (100), 208 (22), 132 (24), 118 (37),
117 (10), 92 (7), 91 (47), 65 (8).
MS: m/z (%) = 212 (14), 211 (20), 210 (80), 209 (43), 208 (100),
127 (17), 126 (9), 125 (45), 99 (6), 98 (23), 91 (8), 89 (14), 84 (60),
70 (7), 56 (8).
N-Benzyl-N-methylaniline (2f)20
Orange oil; yield: 1.92 g (97%).
1H NMR: d = 7.65–7.46 (m, 7 H), 7.11–6.95 (m, 3 H), 4.79 (s, 2 H),
1-(2-Chlorobenzyl)piperidine (1i)16
Light-yellow oil; yield: 1.59 g (76%).
1H NMR: d = 7.42 (dd, J = 7.7, 1.6 Hz, 1 H), 7.25 (dd, J = 7.9, 1.4
Hz, 1 H), 7.20–7.03 (m, 2 H), 3.50 (s, 2 H), 2.37 (m, 4 H), 1.58–1.26
(m, 6 H).
3.27 (s, 3 H).
13C NMR: d = 150.0, 139.3, 129.5, 128.9, 127.2, 127.1, 116.9,
112.7, 56.9, 38.8.
MS: m/z (%) = 198 (14), 197 (100), 196 (44), 180 (5), 120 (44), 118
(5), 106 (9), 104 (6), 91 (44), 77 (10), 65 (9).
13C NMR: d = 136.5, 134.2, 130.6, 129.3, 127.8, 126.5, 59.9, 54.7,
26.1, 24.3.
N-Benzyldiethylamine (2g)6e
Light-yellow oil; yield: 1.05 g (64%).
1H NMR: d = 7.34–7.11 (m, 5 H), 3.50 (s, 2 H), 2.46 (q, J = 7.1 Hz,
4 H), 0.98 (t, J = 7.1 Hz, 6 H).
13C NMR: d = 139.6, 129.0, 128.1, 126.7, 57.5, 46.7, 11.6.
MS: m/z (%) = 212 (5), 211 (14), 210 (53), 209 (40), 208 (100), 174
(6), 127 (10), 125 (34), 98 (14), 89 (6).
1-Benzylpyrrolidine (2a)6e
Light-yellow oil; yield: 1.57 g (97%).
1H NMR: d = 7.32–7.11 (m, 5 H), 3.55 (s, 2 H), 2.49–2.38 (m, 4 H),
1.78–1.62 (m, 4 H).
MS: m/z (%) = 163 (10), 162 (6), 149 (6), 148 (59), 92 (8), 91 (100),
65 (7).
13C NMR: d = 139.2, 128.9, 128.2, 126.9, 60.7, 54.2, 23.4.
Synthesis 2010, No. 2, 249–254 © Thieme Stuttgart · New York

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Multicomponent Synthesis of Tertiary Benzylamines
253
4-[3-(Trifluoromethyl)benzyl]morpholine (3a)15
Light-yellow oil; yield: 1.84 g (75%).
1H NMR: d = 7.53 (br s, 1 H), 7.49–7.31 (m, 3 H), 3.70–3.58 (m, 4
H), 3.47 (s, 2 H), 2.45–2.28 (m, 4 H).
1H NMR: d = 7.31–7.22 (m, 1 H), 7.14–7.09 (m, 1 H), 7.06 (d, J =
5.9 Hz, 1 H), 3.52 (s, 2 H), 2.39 (br s, 4 H), 1.67–1.52 (m, 4 H),
1.49–1.34 (m, 2 H).
13C NMR: d = 139.3, 128.8, 125.1, 122.7, 58.3, 54.4, 25.9, 24.3.
13C NMR: d = 138.9, 132.4 (d, J = 1.0 Hz), 130.6 (q, J = 32.1 Hz),
128.7, 124.2 (q, J = 272.3 Hz), 125.7 (q, J = 3.8 Hz), 124.1 (q, J =
3.8 Hz), 66.9, 62.8, 53.6.
19F NMR: d = –62.61.
MS: m/z (%) = 182 (37), 181 (14), 180 (44), 98 (15), 97 (80), 85 (6),
84 (100), 56 (9), 53 (6).
Anal. Calcd for C10H15NS: C, 66.25; H, 8.34; N, 7.73. Found: C,
65.91; H, 8.17; N, 7.68.
MS: m/z (%) = 246 (30), 245 (99), 244 (63), 215 (13), 214 (100),
200 (5), 186 (9), 172 (11), 160 (19), 159 (92), 141 (12), 110 (6), 109
(18), 100 (12), 86 (45).
2-[(Thiophen-2-yl)methyl]-1,2,3,4-tetrahydroisoquinoline
(3g)3c
Orange semi-solid oil; yield: 1.96 g (85%).
Ethyl 4-[(Diethylamino)methyl]benzoate (3b)
Orange oil; yield: 1.96 g (83%).
1H NMR: d = 7.99 (d, J = 8.5 Hz, 2 H), 7.42 (d, J = 8.5 Hz, 2 H),
4.37 (q, J = 7.1 Hz, 2 H), 3.61 (s, 2 H), 2.52 (q, J = 7.1 Hz, 4 H),
1.39 (t, J = 7.1 Hz, 3 H), 1.04 (t, J = 7.1 Hz, 6 H).
1H NMR: d = 7.35 (dd, J = 4.7, 1.6 Hz, 1 H), 7.29–7.17 (m, 3 H),
7.13–7.02 (m, 3 H), 4.00 (s, 2 H), 3.81 (s, 2 H), 3.02 (t, J = 5.9 Hz,
2 H), 2.89 (t, J = 5.9 Hz, 2 H).
13C NMR: d = 142.0, 134.8, 134.4, 128.8, 126.8, 126.6, 126.3,
126.1, 125.8, 125.2, 57.0, 55.9, 50.4, 29.3.
13C NMR: d = 166.7, 145.5, 129.4, 129.0, 128.6, 60.8, 57.4, 46.9,
14.3, 11.7.
MS: m/z (%) = 229 (8), 228 (27), 145 (18), 133 (9), 132 (100), 117
(9), 105 (6), 104 (8), 103 (5), 97 (47), 78 (6).
MS: m/z (%) = 235 (9), 221 (12), 220 (100), 164 (8), 163 (76), 135
(12), 107 (7).
References
Anal. Calcd for C14H21NO2: C, 71.46; H, 8.99; N, 5.95. Found: C,
71.15; H, 8.83; N, 5.67.
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4-(4-Methoxybenzyl)morpholine (3c)8
Yellow oil; yield: 1.56 g (75%).
(2) (a) Miyazaki, Y.; Kato, Y.; Manabe, T.; Shimada, H.;
Mizuno, M.; Egusa, T.; Ohkouchi, M.; Shiromizu, I.;
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1H NMR: d = 7.15 (d, J = 8.2 Hz, 2 H), 6.78 (d, J = 8.2 Hz, 2 H),
3.72 (s, 3 H), 3.67–3.55 (m, 4 H), 3.36 (s, 2 H), 2.34 (br s, 4 H).
13C NMR: d = 158.8, 130.4, 129.7, 113.6, 67.0, 62.8, 55.2, 53.5.
MS: m/z (%) = 208 (7), 207 (51), 206 (17), 176 (19), 135 (5), 134
(10), 122 (20), 121 (100), 91 (10), 86 (33), 77 (11).
1-(4-Methoxybenzyl)-4-phenylpiperazine (3d)3b
Light-brown solid; yield: 1.57 g (55%); mp 105–107 °C.
1H NMR: d = 7.35–7.20 (m, 4 H), 7.00–6.81 (m, 5 H), 3.82 (s, 3 H),
3.55 (s, 2 H), 3.30–3.13 (s, 4 H) 2.71–2.55 (s, 4 H).
13C NMR: d = 158.8, 151.3, 130.5, 129.1, 119.7, 116.0, 113.7, 62.4,
55.3, 52.9, 49.1.
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(9), 162 (7), 161 (12), 150 (5), 149 (68), 148 (44), 134 (15), 133 (7),
132 (10), 121 (45), 118 (6), 106 (10), 104 (8), 91 (9), 77 (9), 56 (9).
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1-[(6-Methoxynaphthalen-2-yl)methyl]piperidine (3e)
Light-brown solid; yield: 1.68 g (66%); mp 64–66 °C.
1H NMR: d = 7.69–7.54 (m, 3 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.09–
7.01 (m, 2 H), 3.84 (s, 3 H), 3.55 (s, 2 H), 2.36 (br s, 4 H), 1.60–1.47
(m, 4 H), 1.42–1.29 (m, 2 H).
13C NMR: d = 157.5, 133.8, 129.2, 128.7, 128.3, 127.8, 126.6,
118.7, 105.6, 63.8, 55.3, 54.5, 25.8, 24.3.
MS: m/z (%) = 256 (6), 255 (28), 254 (22), 173 (9), 172 (77), 171
(100), 157 (12), 156(8), 129 (11), 128 (34), 84 (51).
Anal. Calcd for C17H21NO: C, 79.96; H, 8.29; N, 5.49. Found: C,
79.78; H, 8.31; N, 5.39.
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1441.
1-[(Thiophen-3-yl)methyl]piperidine (3f)
Yellow oil; yield: 1.31 g (72%).
Synthesis 2010, No. 2, 249–254 © Thieme Stuttgart · New York

254
E. Le Gall et al.
PAPER
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Synthesis 2010, No. 2, 249–254 © Thieme Stuttgart · New York