An efficient method for the preparation of versatile building blocks: 1-substituted 2,2-dimethoxyethylamine hydrochlorides1

Article abstract of DOI:10.1055/s-0029-1216943

A novel method for the preparation of 1-substituted 2,2-dimethoxyethylamine hydrochlorides was developed. The method includes three highly efficient steps: (1) direct use of aqueous (MeO)2CHCHO for the preparation of N,O-acetal by condensation with Betti

Full text of DOI:10.1055/s-0029-1216943

PAPER
3227
An Efficient Method for the Preparation of Versatile Building Blocks:
1-Substituted 2,2-Dimethoxyethylamine Hydrochlorides
1
-Substituted 2,2
o
L
ine
H
ydrochlo
i
r
ides u, Deyong Su, Guolin Cheng, Hui Liu, Xinyan Wang,* Yuefei Hu*
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62771149; E-mail: wangxinyan@mail.tsinghua.edu.cn; E-mail: yfh@mail.tsinghua.edu.cn
Received 30 April 2009; revised 25 May 2009
It is noteworthy that 2,2-dimethoxyethylamine (4a,
R = Me) and 2,2-diethoxyethylamine (4b, R = Et) were
most often used for this purpose for two reasons: (a) they
are commercially available products; and (b) their
Abstract: A novel method for the preparation of 1-substituted 2,2-
dimethoxyethylamine hydrochlorides was developed. The method
includes three highly efficient steps: (1) direct use of aqueous
(MeO)2CHCHO for the preparation of N,O-acetal by condensation
with Betti base without acidic catalyst; (2) regioselective alkyla- deacetylations are much easier than most others. Thus, we
tions of the N,O-acetal with Grignard reagents; and (3) Pd/C cata-
lytic hydrogenolyses of benzylamines in the presence of
may expect that the structural diversity in heterocycle syn-
thesis can be achieved conveniently by replacement of
ClCH2CHCl2 to directly give the target products as crystalline
4a,b with 1-substituted 2,2-dialkoxyethylamines 3, which
amine hydrochlorides. The method reported is extremely conve-
would practically benefit our current projects on chemical
nient and highly efficient with wide substrate scopes.
biology and drug discovery (Scheme 1).
Key words: heterocycles, alkylation, N-debenzylation, Betti base,
2,2-dimethoxyethylamines
NH
N
HN
NH
R
R
N
a-Amino aldehydes 1 (Figure 1) are important precursors
in organic synthesis1 because they hold both the highly re-
active amino and formyl groups. Since they are not chem-
ically stable, one of the functional groups needs to be
protected for storage and reactions. 2-Amidoacetalde-
hydes 2 and 2,2-dialkoxyethylamines 3 are two major
forms depending on the purpose of the application. In lit-
erature, numerous biologically important N-containing
heterocycles, such as isoquinolines,2 imidazoles,3 pyra-
zines,4 azepines,5 and indoles6 etc., were prepared effi-
ciently by using the derivatives of 3 as versatile building
blocks. In these preparations, substrates 3 usually were in-
troduced into the target molecules by N-alkylation or N-
acylation. Then, its formyl group was released by an in
situ deprotection of the acetal group under acidic condi-
tions to undergo an intramolecular cyclization.
H
R
R
R
3
N
N
H
Scheme 1
Unfortunately, a literature survey indicated that the prep-
aration of 3 remains a challenge. For example, some chiral
3 were prepared from natural a-amino acids by multi-step
synthesis,7 but the method suffered from tedious opera-
tions with poor total yields. In practice, the chirality for 3
is not necessary in most of its heterocycles syntheses
(Scheme 1). Although the reductive amination of a,a-di-
alkoxy ketones offered a fast protocol,8 its application was
seriously limited because the substrates themselves are
not easy to synthesize. In fact, there were only two proce-
dures that deal with the methodology for the preparation
of 3 to date. As shown in Figure 2, benzotriazolyl-substi-
tuted Mannich base 59 and benzyl substituted N,O-acetal
610 were employed as key intermediates in those two pro-
cedures, in which the substituents were introduced by
treatment of 5 and 6 with Grignard reagents.
R
R
OHC
RO
NHCOR1
OHC
R1O
NH2
1
2
R
NH2
NH2
OR1
OR
Ph
3
4
N
Ph
HN
N
HN
Figure 1
N
O
O
MeO
EtO
O
NR1R2
O
OMe
OEt
5
6
7
SYNTHESIS 2009, No. 19, pp 3227–3232
x
x.
x
x
.
2
0
0
9
Advanced online publication: 21.08.2009
DOI: 10.1055/s-0029-1216943; Art ID: F09209SS
Figure 2
© Georg Thieme Verlag Stuttgart · New York

3228
B. Liu et al.
PAPER
However, when we repeated the former procedure, we Unfortunately, no alkylated products were obtained when
found that it was only suitable for N,N-disubstituted or N- 9 was treated with a variety of Grignard reagents, even un-
aryl products because Mannich base 5 with NH2 or N- der reflux in THF for 1 hour. Since N,N-disubstituted Bet-
alkyl groups did not react with Grignard reagents at all. ti base derivatives were alkylated smoothly by Grignard
While, according to the latter procedure, we did not obtain reagents,13b,c this problem must be caused by the NH
the corresponding N,O-acetal 7 by the condensation of group in 9. This result was in full agreement with that ob-
(MeO)2CHCHO and (R)-(–)-2-amino-2-phenylethanol. served in the reaction of N-alkylated 5 (with NHR) and
This result must arise from the fact that (MeO)2CHCHO Grignard reagents.9 But in contrast to 9, the alkylation of
is available as an aqueous product (60 wt%), which is not 10 by MeMgBr (11a) was accomplished quickly at room
suitable for direct use in the preparation of N,O-acetals. temperature within 30 minutes to give the desired product
Herein, we report a novel and general procedure for the 12a in 85% isolated yield. This result strongly implied
preparation of 1-substituted 2,2-dialkoxyethylamine hy- that the C–O bond of N,O-acetal group in 10 may be acti-
drochlorides (3·HCl), which is convenient and efficient vated by the a-substituted O,O-acetal group. As shown in
with wide substrate scope.
Table 1, a series of products 12b–o were obtained by us-
ing the corresponding Grignard reagents 11b–o under the
similar conditions. Since the structural assignments of
Betti base 8 is an 1,3-aminohydroxy compound and easily
prepared in kilogram scale.11 Its enantiomers have been
employed as excellent chiral ligands12 and auxiliaries13 in
asymmetric syntheses. In our previous work,14 we found
that the condensation of Betti base 8 and aliphatic alde-
hydes proceeded very efficiently under mild conditions
without acidic catalyst. As shown in Scheme 1, when the
mixtures of Betti base 8 and 1-butanal in MeOH was
stirred at room temperature for 30 minutes, the corre-
1
12a–o suffered from their ambiguous H NMR and 13C
NMR spectra (they were caused by unusual coalescence
phenomenon), they were usually used in the next step
without characterization. However, they were purified by
simple chromatography to remove the homo-coupling by-
products of Grignard reagents, which significantly benefit
the product separation in the next step.
sponding N,O-acetal 9 was obtained in almost quantitative It is well known that the hydrogenolyses of the benzyl-
yield. At the strong encouragement of this result, we tried amines substituted by triaryl or diaryl on benzyl carbon
to explore the condensation between Betti base 8 and are much easier than the regular benzylamine.15 Thus, the
(MeO)2CHCHO. To our great surprise, when the mixture diaryl benzylamine 12a was N-debenzylated quantitative-
of Betti base 8 and aqueous (MeO)2CHCHO (60 wt%) in ly under mild Pd/C catalytic hydrogenolysis conditions
MeOH was stirred at room temperature for one hour, the (Scheme 3). Unfortunately, the oily product 3a was ob-
desired N,O-acetal 10 was obtained in 98% yield even tained in only 69% isolated yield after it was purified by
without the use of an acidic catalyst (Scheme 2). The con- chromatography to remove the by-product 13.
trol experiments proved that this success mainly arose
from the low solubility of the product 10 in aqueous
Recently, we reported a novel procedure for Pd/C catalyt-
ic hydrogenolyses of benzylamines in the presence of
MeOH. A modest additional rate acceleration was ob-
CH2Cl213b or ClCH2CHCl2,16 by which the N-debenzyla-
served by the addition of an extra 10% of water to the re-
tion was accelerated significantly and the debenzylated
action.
products were directly converted into the corresponding
amine hydrochlorides. As shown in Scheme 4, when 12a
was hydrogenolyzed in the presence of ClCH2CHCl2, the
Ph
Me(CH2)2CHO
MeOH, r.t., 30 min
NH
O
N-debenzylation was accomplished within six hours. Af-
ter filtration of the catalyst and evaporation of MeOH, the
crystalline product 3·HCl was formed by addition of small
amount of Et2O. Since the by-product 13 had a good sol-
ubility in Et2O, the separation procedure for 3·HCl was as
simple as a filtration.
n-Pr
99%
Ph
9
NH2
OH
Ph
NH
O
OMe
OMe
aq (MeO)2CHCHO
MeOH, r.t., 1 h
As shown in Table 2, by using the similar procedure, the
desired products 3a–o·HCl were obtained in excellent
yields, which usually were pure enough for most uses
without further purification.
Betti base 8
98%
10
Scheme 2
Ph
Me
10% Pd/C (10 wt%), H2, MeOH
r.t., atmospheric pressure, 12 h
OH
MeO
NH2
+
12a
100% conversion
OMe
3a, 69%
isolated yield
13
Scheme 3
Synthesis 2009, No. 19, 3227–3232 © Thieme Stuttgart · New York

PAPER
1-Substituted 2,2-Dimethoxyethylamine Hydrochlorides
3229
Table 2 Final Products 3a–o·HCl Prepared
Table 1 Alkylated Products 12a–o Prepared
R
OMe
OMe
Entry
3·HCl
Yield (%)
92
Ph
NH
OH
OMe
RMgBr 11a–o, THF, r.t., 30 min
10
NH2⋅HCl
NH2⋅HCl
a
MeO
85–96% after chromatography
3a·HCl
12a–o
OMe
11,12
R
Yield of 12 (%)
b
c
MeO
94
90
a
b
c
d
e
f
Me
85
89
86
85
90
87
93
93
91
93
96
95
94
92
92
Me(CH2)2
3b·HCl
OMe
Me(CH2)4
NH2⋅HCl
MeO
3-[(1,3)-dioxan-2-yl]-1-propyl
cyclopropyl
cyclopentyl
Ph
3
3c·HCl
OMe
NH2⋅HCl
g
h
i
MeO
d
e
91
91
O
2-MeC6H4
3-MeC6H4
4-MeC6H4
3,4-Me2C6H3
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
O
3d·HCl
OMe
j
NH2⋅HCl
MeO
k
l
3e·HCl
OMe
m
n
o
NH2⋅HCl
NH2⋅HCl
MeO
f
90
3f·HCl
OMe
R
10% Pd/C (10 wt%), H2, ClCH2CHCl2
MeOH, r.t., atmospheric pressure, 2–6 h
MeO
g
h
i
MeO
93
98
96
99
96
NH2⋅HCl
12a–o
90–99% after recrystalization
C6H5
OMe
3g·HCl
3a–o⋅HCl
OMe
Scheme 4
NH2⋅HCl
MeO
C6H4-2-Me
In summary, a novel and general procedure for the prepa-
ration of 1-substituted 2,2-dimethoxyethylamine hydro-
chlorides was developed. The benefits of this method are
threefold. First, the commercially available aqueous
(MeO)2CHCHO was directly used for the condensation
with Betti base 8, by which the important N,O-acetal in-
termediate 10 was obtained efficiently in 98% yield with-
in one hour. Second, by activation of O,O-acetal group,
the N,O-acetal 10 was alkylated smoothly with a variety
of Grignard reagents within 30 minutes to give the alky-
lated products 12a–o in high yields. Third, in the presence
of ClCH2CHCl2, the Pd/C catalyzed hydrogenolyses of
12a–o directly gave the products as crystalline amine hy-
drochlorides. The method is extremely convenient and
highly efficient with wide substrate scopes.
3h·HCl
OMe
NH2⋅HCl
MeO
C6H4-3-Me
3i·HCl
OMe
NH2⋅HCl
j
MeO
C6H4-4-Me
3j·HCl
OMe
NH2⋅HCl
k
MeO
C6H3-3,5-Me2
3k·HCl
Synthesis 2009, No. 19, 3227–3232 © Thieme Stuttgart · New York

3230
B. Liu et al.
PAPER
Table 2 Final Products 3a–o·HCl Prepared (continued)
and dried (Na2SO4). Removal of the solvent gave the crude product,
which was purified by chromatography (silica gel, PE–
EtOAc, 10:1) to give the pure compound 12 (85–96%). A suspen-
sion of product 12 (2 mmol), 10% Pd/C (10 wt%) and ClCH2CHCl2
(320 mg, 2.4 mmol) in MeOH (30 mL) was hydrogenated at r.t. and
atmospheric pressure until the absorption of H2 had ceased (2–6 h).
After the Pd/C catalyst was filtered off, the solvent was removed on
a rotavapor. The residue was diluted with Et2O (10 mL) and the
white crystals of 3·HCl (90–99%) were collected by filtration. Usu-
ally, the product was pure enough for any analytical purposes.
Entry
3·HCl
Yield (%)
98
OMe
NH2⋅HCl
l
MeO
C6H4-2-OMe
3l·HCl
OMe
NH2⋅HCl
m
n
94
92
MeO
1-Methyl-2,2-dimethoxyethylamine Hydrochloride (3a·HCl)
Mp 102–103 °C (MeOH–Et2O).
IR (KBr): 3422, 2941, 1455, 1395 cm–1.
1H NMR: d = 4.42 (d, J = 4.47 Hz, 1 H), 3.44 (m, 7 H), 1.21 (d,
J = 6.54 Hz, 3 H).
C6H4-3-OMe
3m·HCl
OMe
NH2⋅HCl
MeO
13C NMR: d = 104.5, 56.9, 55.9, 49.0, 12.9.
C6H4-4-OMe
MS: m/z (%) = 119 (M+ – HCl, 0.5), 75.05 (100).
3n·HCl
OMe
Anal. Calcd for C5H14ClNO2: C, 38.59; H, 9.07; N, 9.00. Found: C,
38.60; H, 9.05; N, 9.01.
NH2⋅HCl
MeO
o
95
C6H3-3,5-(OMe)2
1-Propyl-2,2-dimethoxyethylamine Hydrochloride (3b·HCl)
3o·HCl
Mp 133–135 °C (MeOH–Et2O).
IR (KBr): 3447, 2959, 1453, 1356 cm–1.
1H NMR: d = 4.50 (d, J = 4.47 Hz, 1 H), 3.48 (s, 3 H), 3.47 (s, 3 H),
3.39–3.24 (m, 1 H), 1.65–1.34 (m, 4 H), 0.88 (t, J = 6.87 Hz, 3 H).
13C NMR: d = 103.7, 57.0, 55.9, 52.9, 29.9, 17.9, 13.0.
MS: m/z (%) = 147 (M+ – HCl, 13.2), 73 (100).
All melting points were determined on a Yanaco melting point ap-
paratus and are uncorrected. IR spectra were recorded on a Nicolet
FT-IR 5DX spectrometer. The 1H NMR and 13C NMR spectra were
recorded on a Jeol JNM-ECA 300 spectrometer in D2O. The J val-
ues are given in Hz. MS were recorded on a VG-ZAB-MS spec-
trometer with 70 eV. Elementary analysis data were obtained on a
PerkinElmer-241C apparatus. Petroleum ether (PE) used refers to
the fraction boiling in the range 60–90 °C.
Anal. Calcd for C7H18ClNO2: C, 45.77; H, 9.88; N, 7.63. Found: C,
45.80; H, 9.91; N, 7.59.
1-Pentyl-2,2-dimethoxyethylamine Hydrochloride (3c·HCl)
Mp 109–109.5 °C (MeOH–Et2O).
IR (KBr): 3423, 2962, 2932, 1506 cm–1.
3-(Dimethoxymethyl)-1-phenyl-2,3-dihydro-1H-naph-
tho[1,2-e][1,3]oxazine (10)
To a stirred solution of Betti base 8 (2.49 g, 10 mmol) in MeOH (30
mL) was added an aqueous solution of 2,2-dimethoxyacetaldehyde
(60 wt%, 1.81 g, 12 mmol) at r.t. The resulting mixture was stirred
continuously for another 1 h, the white solid 10 (3.28 g, 98%)
formed was collected by filtration, and purified by chromatography
(silica gel, PE–EtOAc, 5:1). Usually, it was directly used in the next
step without purification; mp 147–149 °C (CH2Cl2–MeOH).
1H NMR: d = 4.50 (d, J = 4.47 Hz, 1 H), 3.47 (s, 3 H), 3.44 (s, 3 H),
3.34–3.28 (m, 1 H), 1.69–1.25 (m, 8 H), 0.81 (t, J = 6.85 Hz, 3 H).
13C NMR: d = 103.7, 57.0, 55.9, 53.2, 30.7, 27.7, 24.1, 21.7, 13.3.
MS: m/z (%) = 175 (M+ – HCl, 1.9), 100 (100).
Anal. Calcd for C9H22ClNO2: C, 51.05; H, 10.47; N, 6.62. Found:
C, 51.11; H, 10.51; N, 6.61.
IR (KBr): 2900, 1620, 1440, 1210, 1230 cm–1.
1H NMR (CDCl3): d = 7.70–7.64 (m, 2 H), 7.28–7.13 (m, 9 H), 5.43
(s, 1 H), 4.74–4.71 (m, 1 H), 4.42–4.41 (m, 1 H), 3.39 (s, 6 H), 2.86–
2.83 (m, 1 H).
1-[3-([1,3]Dioxan-2-yl)-1-propyl]-2,2-dimethoxyethylamine
Hydrochloride (3d·HCl)
Mp 112–114 °C (MeOH–Et2O).
IR (KBr): 3403, 2942, 2902, 1506 cm–1.
13C NMR (CDCl3): d = 151.6, 142.1, 131.2, 129.0 (2 C), 128.8,
128.5, 128.2, 128.0 (2 C), 127.0, 126.3, 123.0, 122.5, 119.0, 114.3,
103.4, 81.3, 55.6, 55.2, 52.7.
1H NMR: d = 4.72–4.71 (m, 1 H), 4.54–4.52 (m, 1 H), 4.09–4.06 (m,
2 H), 3.89–3.86 (m, 2 H), 3.50–3.47 (m, 6 H), 3.46–3.49 (m, 1 H),
2.00–1.42 (m, 6 H).
MS (EI): m/z (%) = 432 (M+, 0.01), 231 (100).
13C NMR: d = 103.5, 101.4, 67.2(2C), 57.1, 56.0, 52.8, 30.1, 25.2,
22.5.
Anal. Calcd for C21H21NO3: C, 75.20; H, 6.31; N, 4.18. Found: C,
75.13; H, 6.41; N, 4.12.
MS: m/z (%) = 219 (M+ – HCl, 2.0), 117 (100).
1-Substituted 2,2- Dimethoxyethylamine Hydrochlorides
3·HCl; General Procedure
Anal. Calcd for C10H22ClNO4: C, 46.96; H, 8.67; N, 5.48. Found: C,
46.90; H, 8.71; N, 5.51.
To a stirred solution of Grignard reagent 11 (15 mmol) in Et2O (30
mL) was added a solution of N,O-acetal 10 (1.01 g, 3 mmol) in THF
(30 mL) at r.t. After stirring the resulting mixture continuously for
another 30 min, it was cooled to 0 °C and quenched by the addition
of sat. aq NH4Cl (30 mL). The organic layer was separated and the
aqueous layer was extracted with Et2O (3 × 30 mL). The combined
organic layers were washed with H2O (30 mL) and brine (30 mL),
1-Cyclopropyl-2,2-dimethoxyethylamine Hydrochloride
(3e·HCl)
Mp 141.5–143 °C (MeOH–Et2O).
IR (KBr): 3352, 3061, 2994, 2932, 1454, 1352 cm–1.
Synthesis 2009, No. 19, 3227–3232 © Thieme Stuttgart · New York

PAPER
1-Substituted 2,2-Dimethoxyethylamine Hydrochlorides
3231
1H NMR: d = 4.58 (d, J = 4.1 Hz, 1 H), 3.53 (s, 3 H), 3.49 (s, 3 H),
2.58–2.54 (dd, J = 3.8, 10.3 Hz, 1 H), 1.04–0.90 (m, 1 H), 0.68–0.62
(m, 2 H), 0.48–0.33 (m, 2 H).
1-(4-Methylphenyl)-2,2-dimethoxyethylamine Hydrochloride
(3j·HCl)
Mp 156–158 °C (MeOH–Et2O).
13C NMR: d = 104.2, 58.6, 57.2, 56.1, 9.0, 3.4, 2.6.
MS: m/z (%) = 145 (M+ – HCl, 0.8), 75 (100).
IR (KBr): 3425, 3176, 2966, 1590, 1521, 1449, 1359 cm–1.
1H NMR: d = 7.33–7.29 (m, 4 H), 4.79 (d, J = 5.64 Hz, 1 H), 4.39
(d, J = 5.89 Hz, 1 H), 3.48 (s, 3 H), 3.33 (s, 3 H), 2.30 (s, 3 H).
13C NMR: d = 140.3, 129.9 (2 C), 129.1, 127.9 (2 C), 104.3, 56.7,
56.2, 56.1, 20.4.
Anal. Calcd for C7H16ClNO2: C, 46.28; H, 8.88; N, 7.71. Found: C,
46.37; H, 8.92; N, 7.66.
1-Cyclopentyl-2,2-dimethoxyethylamine Hydrochloride
(3f·HCl)
Mp 137–138.5 °C (MeOH–Et2O).
IR (KBr): 3423, 2953, 1450 cm–1.
MS: m/z (%) = 195 (M+ – HCl, 1.18), 120 (100).
Anal. Calcd for C11H18ClNO2: C, 57.02; H, 7.83; N, 6.04. Found: C,
57.05; H, 7.79; N, 6.03.
1H NMR: d = 4.59 (d, J = 2.73 Hz, 1 H), 3.54 (s, 3 H), 3.48 (s, 3 H),
3.25–3.21 (dd, J = 3.09, 9.63, 1 H), 2.19–2.05 (m, 1 H), 1.86–1.83
(m, 2 H), 1.67–1.57 (m, 4 H), 1.39–1.19 (m, 2 H).
1-(3,5-Dimethyl)-2,2-dimethoxyethylamine Hydrochloride
(3k·HCl)
Mp 158.5–160.5 °C (MeOH–Et2O).
13C NMR: d = 103.6, 57.9, 57.6, 55.9, 38.9, 29.2, 28.9, 24.5 (2 C).
MS: m/z (%) = 173 (M+ – HCl, 1.8), 98 (100).
IR (KBr): 3415, 3223, 2998, 1608, 1510, 1460, 1361, 1210 cm–1.
1H NMR: d = 7.11 (s, 1 H), 7.03 (s, 2 H), 4.76 (d, J = 5.82 Hz, 1 H),
4.33 (d, J = 5.85 Hz, 1 H), 3.48 (s, 3 H), 3.33 (s, 3 H), 2.26 (s, 6 H).
13C NMR: d = 139.6 (2 C), 132.3, 131.0, 125.4 (2 C), 104.3, 56.7,
56.4, 56.0, 20.4 (2 C).
Anal. Calcd for C9H20ClNO2: C, 51.54; H, 9.61; N, 6.68. Found: C,
51.57; H, 9.62; N, 6.70.
1-Phenyl-2,2-dimethoxyethylamine Hydrochloride (3g·HCl)
Mp 129.5–130.5 °C (MeOH–Et2O).
IR (KBr): 3423, 2962, 2932, 1623, 1506 cm–1.
1H NMR: d = 7.42 (m, 5 H), 4.79 (d, J = 5.49 Hz, 1 H), 4.41 (d,
J = 5.85 Hz, 1 H), 3.49 (s, 3 H), 3.31 (s, 3 H).
MS: m/z (%) = 209 (M+ – HCl, 1.4), 134 (100).
Anal. Calcd for C12H20ClNO2: C, 58.65; H, 8.20; N, 5.70. Found: C,
58.75; H, 8.18; N, 5.73.
1-(2-Methoxyphenyl)-2,2-dimethoxyethylamine Hydrochloride
(3l·HCl)
Mp 142–143 °C (MeOH–Et2O).
IR (KBr): 3423, 2962, 2932, 1623, 1506 cm–1.
1H NMR: d = 7.38–7.33 (m, 1 H), 7.00–6.98 (m, 3 H), 4.75 (d,
J = 5.85 Hz, 1 H), 4.36 (d, J = 5.82 Hz, 1 H), 3.76 (s, 3 H), 3.43 (s,
3 H), 3.31 (s, 3 H).
13C NMR: d = 132.1, 129.8, 129.3 (2 C), 128.0 (2 C), 104.2, 56.7,
56.4, 56.1.
MS: m/z (%) = 181 (M+ – HCl, 4.1), 107 (100).
Anal. Calcd for C10H16ClNO2: C, 55.17; H, 7.41; N, 6.43. Found: C,
55.24; H, 7.37; N, 6.44.
1-(2-Methylphenyl)-2,2-dimethoxyethylamine Hydrochloride
(3h·HCl)
13C NMR: d = 159.3, 133.8, 130.7, 120.5, 115.2, 113.7, 104.2, 56.7,
56.3, 56.1, 55.5.
Mp 153–155 °C (MeOH–Et2O).
IR (KBr): 3437, 3188, 3044, 2934, 1594, 1519, 1377 cm–1.
1H NMR: d= 7.34–7.30 (m, 4 H), 4.80 (d, J = 5.85 Hz, 1 H), 4.7 (d,
J = 5.85 Hz, 1 H, D2O exch.), 3.48 (s, 3 H), 3.32 (s, 3 H), 2.35 (s, 3
MS: m/z (%) = 212 (M+ – HCl + H, 34.7), 136 (100).
Anal. Calcd for C11H18ClNO3: C, 53.33; H, 7.32; N, 5.65. Found: C,
53.30; H, 7.34; N, 5.61.
H).
1-(3-Methoxyphenyl)-2,2-dimethoxyethylamine Hydrochloride
(3m·HCl)
Mp 149–151 °C (MeOH–Et2O).
IR (KBr): 3418, 2965, 2935, 1608, 1517, 1461, 1306, 1276 cm–1.
1H NMR: d = 7.40–7.27 (m, 1 H), 7.27–7.23 (m, 1 H), 7.07–6.98 (m,
2 H), 4.93 (d, J = 6.87 Hz, 1 H), 4.43 (d, J = 6.87 Hz, 1 H), 3.81 (s,
3 H), 3.44 (s, 3 H), 3.19 (s, 3 H).
13C NMR: d = 137.6, 131.2, 130.7, 129.6, 126.9, 126.4, 104.8, 57.1,
56.8, 52.4, 18.7.
MS: m/z (%) = 195 (M+ – HCl, 1.0), 75 (100).
Anal. Calcd for C11H18ClNO2: C, 57.02; H, 7.83; N, 6.04. Found: C,
56.98; H, 7.88; N, 5.99.
1-(3-Methylphenyl)-2,2-dimethoxyethylamine Hydrochloride
(3i·HCl)
13C NMR: d = 157.2, 131.5, 130.3, 121.2, 119.6, 111.8, 102.8, 56.2,
55.5 (2 C), 54.3.
Mp 149.5–152.0 °C (MeOH–Et2O).
IR (KBr): 3430, 2936, 1615, 1590, 1515, 1397 cm–1.
1H NMR: d = 7.35–7.25 (m, 4 H), 4.79 (d, J = 5.85 Hz, 1 H), 4.39
(d, J = 5.85 Hz, 1 H), 3.47 (s, 3 H), 3.34 (s, 3 H), 2.32 (s, 3 H).
MS: m/z (%) = 211 (M+ – HCl, 38.2), 136 (100).
Anal. Calcd for C11H18ClNO3: C, 53.33; H, 7.32; N, 5.65. Found: C,
53.40; H, 7.37; N, 5.65.
1-(4-Methoxyphenyl)-2,2-dimethoxyethylamine Hydrochloride
(3n·HCl)
Mp 148.5–149 °C (MeOH–Et2O).
13C NMR: d = 139.7, 132.2, 130.4, 129.3, 128.5, 124.9, 104.3, 56.8,
56.4, 56.1, 20.6.
MS: m/z (%) = 195 (M+ – HCl, 1.6), 75 (100).
IR (KBr): 3407, 2184, 3036, 2966, 1613, 1517, 1460, 1306, 1255
cm–1.
1H NMR: d = 7.38 (d, J = 8.58 Hz, 2 H), 7.02 (d, J = 8.58 Hz, 2 H),
4.78 (d, J = 6.18 Hz, 1 H), 4.38 (d, J = 5.85 Hz, 1 H), 3.79 (s, 3 H),
3.49 (s, 3 H), 3.34 (s, 3 H).
Anal. Calcd for C11H18ClNO2: C, 57.02; H, 7.83; N, 6.04. Found: C,
57.05; H, 7.79; N, 6.10.
Synthesis 2009, No. 19, 3227–3232 © Thieme Stuttgart · New York

3232
B. Liu et al.
PAPER
Org. Biomol. Chem. 2006, 4, 1768. (c) Su, T.; Yang, H.;
Volkots, D.; Woolfrey, J.; Dam, S.; Wong, P.; Sinha, U.;
Scarborough, R. M.; Zhua, B. Y. Bioorg. Med. Chem. Lett.
2003, 13, 729. (d) Kitamura, S.; Fukushi, H.; Miyawaki, T.;
Kawamura, M.; Konishi, N.; Terashita, Z.-i.; Naka, T.
J. Med. Chem. 2001, 44, 2438.
13C NMR: d = 159.8, 129.6 (2 C), 124.7, 114.8 (2 C), 104.2, 56.7,
56.1, 56.0, 55.5.
MS: m/z (%) = 212 (M+ – HCl + H, 1.7), 136 (100).
Anal. Calcd for C11H18ClNO3: C, 53.33; H, 7.32; N, 5.65. Found: C,
53.29; H, 7.30; N, 5.65.
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Meyer, C.; Cossy, J. Tetrahedron 2006, 62, 3882.
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1-(3,5-Dimethoxy)-2,2-dimethoxyethylamine Hydrochloride
(3o·HCl)
Mp 175–176.5 °C (MeOH–Et2O).
IR (KBr): 3432, 3140, 3029, 2938, 1605, 1515, 1469, 1262, 1234
cm–1.
1H NMR: d = 7.06–7.02 (m, 3 H), 4.77 (d, J = 7.89 Hz, 1 H), 4.37
(d, J = 5.82 Hz, 1 H), 3.81 (s, 6 H), 3.46 (s, 3 H), 3.34 (s, 3 H).
13C NMR: d = 149.1, 148.5, 125.1, 121.3, 112.1, 111.3, 104.3, 56.8,
56.2, 56.1, 55.9, 55.8.
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MS: m/z (%) = 241 (M+ – HCl, 1.4), 166 (100).
Anal. Calcd for C12H20ClNO4: C, 51.89; H, 7.26; N, 5.04. Found: C,
51.82; H, 7.23; N, 5.03.
(10) Muralidharan, K. R.; Mokhallalati, M. K.; Pridgen, L. N.
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Acknowledgment
This work was supported by NNSFC (30600779, 20672066) and
the Cultivation Fund of the Key Scientific and Technical Innovation
Project, Ministry of Education of China (706003).
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Synthesis 2009, No. 19, 3227–3232 © Thieme Stuttgart · New York