A new and convenient synthesis of 1-aryl-2-dimethylaminoethanols

Article abstract of DOI:10.1055/s-2001-16077

An efficient two-step synthesis of 1-aryl-2-dimethylamnoethanols 4 is described, consisting of oxazolidine 3 generation from the cycloaddition of an azomethine ylide to an aldehyde, followed by reductive ring-opening.

Full text of DOI:10.1055/s-2001-16077

PAPER
1479
A New and Convenient Synthesis of 1-Aryl-2-dimethylaminoethanols
A
New and
C
onvenien
i
t
Synth
k
esis of 1-Ary
l
l-2-dim
ó
ethylamino
s
a
Research Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology, Technical University of Buda-
pest, 1521 Budapest P.O.B. 91, Hungary
Fax +36(1)4633648; E-mail: nyerges.oct@chem.bme.hu
b
Institute of Pharmacy and Chemistry, School of Sciences, University of Sunderland, Sunderland SR1 3SD, UK
Received 8 February 2001; revised 24 April 2001
cases either (a) the aldehyde component of the azomethine
ylide, formed in situ, was the same as the dipolarophile,8
or (b) a stable precursor of the azomethine ylide was pre-
pared in advance and this was followed by the cycloaddi-
tion step.8a,9
Abstract: An efficient two-step synthesis of 1-aryl-2-dimethylami-
noethanols 4 is described, consisting of oxazolidine 3 generation
from the cycloaddition of an azomethine ylide to an aldehyde, fol-
lowed by reductive ring-opening.
Key words: aldehydes, amino alcohols, cycloadditions
With our new method it is possible to synthesize a variety
of 5-aryl-3-methyloxazolines 3 by simple mixing of sar-
cosine, paraformaldehyde and an aromatic aldehyde (as
the dipolarophile) in benzene and refluxing under Dean–
Stark conditions (Scheme 2). In all cases only the formal-
dehyde served as a component for the non-stabilised
azomethine ylide generation, and the cycloadduct 3 was
isolated in high yield as the sole product (Table 1).
The importance of -hydroxyamines as -blockers in
medicine is well-known and some of their uses include
nervous system stimulants, bronchodilators, appetite sup-
pressants and, most significantly, combating heart dis-
ease.1 The vicinal amino alcohol moiety is also a
structural component in many naturally occurring and
synthetic molecules.2 Herein, we report a new, conve-
nient, two-step synthesis of 1-aryl-2-dimethylaminoetha-
nols 4, which have a wide range of biological activities.3
Usually the synthesis of these -hydroxyamines consists
of several steps via intermediates such as dimethylamino
ketones,4 vicinal hydroxy halides,3a,5 oxiranes,5 or -ke-
toacetamides.6
Scheme 2
In the course of our studies directed towards the investiga-
tion of substituent effects on the 4 + 2 cycloadditions of
4H-pyran-4-one derivatives7 we observed the formation
of N-methyloxazoline 2, in good yield, in the three com-
ponent reaction of pyranone aldehyde 1, sarcosine and
paraformaldehyde (Scheme 1) and, with a view to prepare
5-aryl-3-methyloxazolidines 3, which are valuable inter-
mediates for further elaboration to 1-aryl-2-dimethylami-
noethanols 4, we initially studied this cycloaddition. It is
known that azomethine ylides can react with C=O double
bonds in 1,3-dipolar cycloadditions, and several oxazoli-
dine-type cycloadducts have been described, but in these
The reaction of these cycloadducts 3 with sodium borohy-
dride in ethanol at room temperature afforded the desired
1-aryl-2-dimethylaminoethanols 4, with only one excep-
tion (3i), (Scheme 3, Table 2).
Table 1 Preparation of 5-Aryl-3-methyloxazolines 3
Entry Starting Aldehyde
Ar
Time (h) Producta Yield
(%)
1
2
2-nitrophenyl
1
1
1
2
3
3
3a
3b
3c
3d
3e
3f
95
98
92
87
91
86
58
72
77
87
3-nitrophenyl
3
4-nitrophenyl
4
4-chlorophenyl
2,4-dichlorophenyl
2-bromophenyl
5
6
7
3,4-methylene-dioxyphenyl 15
3g
3h
3i
8
1-naphthyl
2-pyridyl
5
3
2
Scheme 1
9
Synthesis 2001, No. 10, 30 07 2001. Article Identifier:
1437-210X,E;2001,0,10,1479,1482,ftx,en;E01701SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
10
2-thiophenyl
3j
a Satisfactory microanalyses obtained: C 0.3, H 0.3, N 0.2.

1480
M. Nyerges et al.
PAPER
Table 2 Preparation of 1-Aryl-2-dimethylaminoethanols 4
Entry
Starting
Material
Time (h)
Producta
Yieldb
(%)
87
93
94
91
93
95
88
90
90
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
1
4a
4b
4c
4d
4e
4f
1
Scheme 3
1.5
0.5
1
Column chromatography was performed using Merck Kieselgel 60
70–230 mesh; TLC on aluminum sheets coated with Kieselgel 60
F
254. Plates were stained with anisaldehyde solution (100 mL glacial
AcOH, 2 mL H2SO4 and 1 mL anisaldehyde) and heated at ca. 150
°C. IR spectra were recorded on a NICOLET FT-IR instrument.
Low-resolution electron impact mass spectra were obtained on a
Varian CH5-D spectrometer. NMR measurements were carried out
on a Bruker 250 instrument. Chemical shifts are given relative to
TMS ( = 0.00).
1
3g
3h
3j
1
4g
4h
4j
2
2
5-Aryl-3-methyloxazolidines 3; General Procedure
The corresponding aryl aldehyde 1 (1 mmol), sarcosine (178 mg, 2
mmol) and paraformaldehyde (150 mg, 5 mmol) were suspended in
benzene (50 mL) and the reaction mixture was then heated for the
time given in Table 1 under Dean–Stark conditions. After the reac-
tion was complete, the solvent was removed in vacuo and the resi-
due was dissolved in acetone and filtered through a plug of silica
gel. The filtrate was then evaporated under reduced pressure to give
the product (Table 3).
a Satisfactory microanalyses obtained: C 0.3, H 0.2, N 0.2.
Table 3 Spectral Data for 5-Aryl-3-methyloxazolidines 3a–j
Product IR (film)
(cm–1)
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
3a
2851, 2867, 2799, 8.03 (d, 1 H, J = 8.2), 7.87 (d, 1 H, J = 8.2), 7.65 (t, 1 147.8 (quat), 139.3 (quat), 133.8 (CH), 127.6 (CH),
1524, 1452, 1346, H, J = 8.2), 7.41 (t, 1 H, J = 8.2 Hz), 5.53 (t, 1 H, J = 127.0 (CH), 124.5 (CH), 89.3 (CH2), 73.3 (CH),
1058
6.7 Hz), 4.64 (d, 1 H, J = 5.1), 4.47 (d, 1 H, J = 5.1), 61.1 (CH2), 41.5 (CH3)
3.62 (dd, 1 H, dd, J = 11.6, 6.7), 2.80 (dd, 1 H, J = 11.6,
6.7), 2.49 (s, 3 H)
3b
2941, 2897, 2791, 8.21 (s, 1 H), 8.11 (d, 1 H, J = 7.5), 7.67 (d, 1 H, J = 148.1 (quat), 145.6 (quat), 131.4 (CH), 129.2 (CH),
1522, 1453, 1345, 7.5), 7.52 (t, 1 H, J = 7.5), 5.13 (t, 1 H, J = 6.9), 4.59 122.1 (CH), 120.2 (CH), 89.4 (CH2), 75.3 (CH),
1058
(d, 1 H, J = 4.6), 4.50 (d, 1 H, J = 4.6), 3.40 (dd, 1 H, 62.3 (CH2), 41.0 (CH3)
J = 11.1, 6.9), 2.80 (dd, 1 H, J = 11.1, 6.9), 2.51 (s, 3
H)
3c
3d
3e
3f
2950, 2873, 2801, 8.18 (d, 2 H, J = 8.3), 7.51 (d, 2 H, J = 8.3), 5.13 (t, 1 149.9 (quat), 146.0 (quat), 125.9 (2 CH), 123.5 (2
1601, 1518, 1346, H, J = 7.0), 4.57 (d, 1 H, J = 4.8), 4.51 (d, 1 H, J = 4.8), CH), 89.4 (CH2), 75.3 (CH), 62.3 (CH2), 41.2
(CH3)
1057
3.41 (dd, 1 H, J = 11.2, 7.0), 2.76 (dd, 1 H, J = 11.2,
7.0), 2.50 (s, 3 H)
2949, 2871, 2798, 7.31 (d, 2 H, J = 8.7), 7.25 (d, 2 H, J = 8.7), 5.00 (t, 1 140.6 (quat), 132.9 (quat), 128.5 (2 CH), 126.8 (2
1666, 1489, 1457, H, J = 7.0 Hz), 4.52 (d, 1 H, J = 4.7 Hz), 4.47 (d, 1 H, CH), 89.3 (CH2), 75.8 (CH), 62.6 (CH2), 41.3
1087, 1056, 1011 J = 4.7), 3.30 (dd, 1 H, J = 11.1, 7.0), 2.72 (dd, 1 H, J (CH3)
= 11.1, 7.0), 2.49 (s, 3 H)
2950, 2869, 2797, 7.52 (d, 1 H, J = 8.3), 7.34 (d, 1 H, J = 2.0), 7.24 (dd, 139.2 (quat), 133.2 (quat), 130.0 (quat), 129.0
1587, 1466, 1382, 1 H, J = 8.3, 2.0), 5.23 (t, 1 H, J = 6.9), 4.55 (d, 1 H, J (CH), 127.3 (CH), 127.1 (CH), 89.3 (CH2), 73.5
1053
= 5.1), 4.47 (d, 1 H, J = 5.1), 3.50 (dd, 1 H, J = 11.3, (CH), 61.2 (CH2), 41.7 (CH3)
6.9), 2.69 (dd, 1 H, J = 11.3, 6.9), 2.49 (s, 3 H)
2950, 2869, 2798, 7.57 (d, 1 H, J = 7.7), 7.49 (d, 1 H, J = 7.7), 7.30 (t, 1 141.8 (quat), 132.4 (CH), 128.5 (CH), 127.5 (CH),
1466, 1439, 1159, H, J = 7.7), 7.10 (t, 1 H, J = 7.7), 5.25 (t, 1 H, J = 6.9), 126.3 (CH), 120.9 (quat), 89.3 (CH2), 75.6 (CH),
1058, 1029
4.58 (d, 1 H, J = 5.1), 4.49 (d, 1 H, J = 5.1), 3.56 (dd, 61.3 (CH2), 41.7 (CH3)
1 H, J = 11.5, 7.1), 2.70 (dd, 1 H, J = 11.5, 7.1), 2.48
(s, 3 H)
Synthesis 2001, No. 10, 1479–1482 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
A New and Convenient Synthesis of 1-Aryl-2-dimethylaminoethanols
1481
Table 3 Spectral Data for 5-Aryl-3-methyloxazolidines 3a–j (continued)
Product IR (film)
(cm–1)
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
3g
3h
3i
2880, 2798, 1487, 6.90 (s, 1 H), 6.76 (s, 2 H), 5.92 (s, 2 H), 4.95 (t, 1 H, 147.7 (quat), 146.8 (quat), 135.9 (quat), 118.9
1442, 1245, 1036 J = 6.9), 4.50 (d, 1 H, J = 4.6), 4.44 (d, 1 H, J = 4.6), (CH), 108.0 (CH), 106.1 (CH), 100.9 (CH), 96.9
3.25 (dd. 1 H, J = 11.0, 6.9), 2.73 (dd, 1 H, J = 11.0,
6.9), 2.48 (s, 3 H)
(CH2), 89.2 (CH2), 76.5 (CH), 62.6 (CH2), 41.3
(CH3)
2949, 2870, 2797, 7.89–7.75 (m, 4 H), 7.53–7.46 (m, 3 H), 5.76 (t, 1 H, J 137.9 (quat), 133.5 (quat), 129.9 (quat), 128.7
1674, 1596, 1510, = 7.0), 4.64 (d, 1 H, J = 5.0), 4.59 (d, 1 H, J = 5.0), 3.62 (CH), 127.3 (CH), 125.8 (CH), 125.5 (CH), 125.3
1455, 1329, 1234, (d, 1 H, J = 7.0, 11.1), 2.83 (d, 1 H, J = 7.0, 11.1), 2.54 (CH), 122.7 (CH), 121.2 (CH), 88.7 (CH2), 73.8
1169, 1065, 1015 (s, 3 H)
(CH), 61.8 (CH2), 41.6 (CH3)
2953, 2876, 2791, 8.53 (d, 1 H, J = 3.8), 7.67 (t, 1 H, J = 7.7), 7.50 (d, 1 161.7 (quat), 148.7 (CH), 136.4 (CH), 121.8 (CH),
1666, 1479, 1456, H, J = 7.6), 7.16 (dd, 1 H, J = 7.6, 3.8), 5.13 (t, 1 H, 119.4 (CH), 89.2 (CH2), 76.5 (CH), 60.8 (CH2),
1087, 1052, 1011 6.9), 4.57 (d, 1 H, J = 4.9), 4.49 (d, 1 H, J = 4.9), 3.42 41.3 (CH3)
(dd, 1 H, J = 11.2, 6.9), 3.01 (dd, 1 H, J = 11.2, 6.9),
2.48 (s, 3 H)
3j
2950, 2861, 1588, 7.25 (d, 1 H, J = 8.9), 6.94 (m, 2 H), 5.25 (t, 1 H, J = 145.3 (quat), 126.6 (CH), 124.7 (CH), 124.1 (CH),
1461, 1342, 1053 7.0), 4.49 (d, 1 H, J = 4.9), 4.40 (d, 1 H, J = 4.9), 3.31 88.6 (CH2), 72.5 (CH), 62.4 (CH2), 41.3 (CH3)
(dd, 1 H, J = 11.3, 7.0), 2.93 (dd, 1 H, J = 11.3, 7.0),
2.49 (s, 3 H)
Table 4 Spectral Data for 1-Aryl-2-dimethylaminoethanols 4
Product IR (film)
(cm–1)
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
4a
4b
4c
3420, 2923, 2856, 2830,
1526, 1459, 1345, 1261,
1101, 1030
7.92 (d, 1 H, J = 7.5), 7.89 (d, 1 H, J = 7.5), 7.61 147.6 (quat), 138.0 (quat), 133.6 (CH), 128.4
(t, 1 H, J = 7.5), 7.37 (t, 1 H, J = 7.5), 5.32 (br d, (CH), 128.0 (CH), 124.2 (CH), 65.9 (CH2), 65.3
2 H, J = 9.4), 2.70 (dd, 1 H, J = 9.4, 11.7), 2.39 (CH), 45.0 (2 CH3)
(m, 7 H)
3424, 2919, 2851, 1536,
1452, 1346, 1111, 1039
8.30 (s, 1 H), 8.17 (d, 1 H, J = 7.9), 7.78 (d, 1 H, 148.1 (quat), 144.6 (quat), 131.9 (CH), 129.2
J = 7.9), 7.56 (t, 1 H, J = 7.9), 4.87 (br t, 1 H, J = (CH), 122.2 (CH), 120.7 (CH), 68.5 (CH), 67.0
6.4), 4.15 (br s, 1 H), 2.51 (d, 2 H, J = 6.4 Hz),
(CH2), 45.1 (2 CH3)
2.43 (s, 6 H)
3427, 2921, 2530, 1525,
1453, 1352, 1262, 1037
8.18 (d, 2 H, J = 8.7), 7.56 (d, 2 H, J = 8.7), 4.80 150.0 (quat), 147.0 (quat), 126.4 (2 CH), 123.3
(t, 1 H, J = 7.0), 4.50 (br s, 1 H), 2.43 (d, 2 H, J = (2 CH), 68.6 (CH), 66.9 (CH2), 45.1 (2 CH3)
7.0), 2.36 (s, 6 H)
4d
4e
3421, 3203, 2550, 1588,
1468, 1383, 1084, 1045
7.18 (m, 4 H), 5.59 (br s, 1 H), 4.92 (t, 1 H, J =
6.7), 2.75 (d, 2 H, J = 6.7), 2.59 (s, 6 H)
139.9 (quat), 133.3 (quat), 128.4 (2 CH), 127.3
(2 CH), 67.9 (CH), 65.1 (CH2), 44.3 (2 CH3)
3346, 2869, 2797, 1587,
1466, 1382, 1053
7.65 (d, 1 H, J = 8.2), 7.30 (s, 1 H), 7.27 (d, 1 H, 137.2 (quat), 133.7 (quat), 131.6 (quat), 128.7
J = 8.2), 6.45 (br s, 1 H), 5.28 (br d, 1 H, J = 9.0), (CH), 128.5 (CH), 127.5 (CH), 65.3 (CH), 64.0
2.67 (m, 8 H)
(CH2), 44.5 (2 CH3)
4f
3416, 2981, 2826, 2781,
1466, 1398, 1169, 1118,
1089, 1014
7.65 (d, 1 H, J = 7.6), 7.47 (d, 1 H, J = 7.6), 7.28 141.0 (quat), 132.1 (CH), 128.5 (CH), 127.4
(t, 1 H, J= 7.6), 7.10 (t, 1 H, J = 7.6), 5.03 (br d, (CH), 127.3 (CH), 121.3 (quat), 68.5 (CH2), 65.3
1 H, J = 8.5), 2.58 (m, 2 H), 2.35 (s, 6 H)
(CH), 45.0 (2 CH3)
4g
4h
3428, 2950, 1467, 1389,
1084, 1041
6.94 (s, 1 H), 6.84 (d, 1 H, J = 6.8), 6.69 (d, 1 H, 147.6 (quat), 135.7 (quat), 119.3 (CH), 108.3
J = 6.8), 5.98 (s, 2 H), 4.92 (dd, 1 H, J = 6.8, 2.5), (CH), 108.0 (CH), 100.9 (CH2), 67.1 (CH), 65.9
2.64 (m, 2 H), 2.50 (s, 6 H)
(CH2), 45.0 (2 CH3)
3362, 2528, 1596, 1445,
1375, 1271, 1033
8.00 (d, 1 H, J = 7.8), 7.98–7.70 (m, 3 H), 7.50– 137.5 (quat), 133.3 (quat), 130.0 (quat), 128.7
7.40 (m, 3 H), 5.62 (br t, 1 H, J = 5.6), 5.50 (br s, (CH), 127.6 (CH), 125.8 (CH), 125.4 (CH),
1 H), 2.64 (d, 2 H, J = 5.6), 2.40 (s, 6 H)
125.1 (CH), 123.0 (CH), 122.4 (CH), 66.2 (CH),
65.9 (CH2), 44.9 (2 CH3)
4j
3299, 2950, 1660, 1454,
1400, 1264, 1166, 1034
7.26 (d, 1 H, J = 4.9), 7.00 (m, 2 H), 5.82 (br s, 1 145.3 (quat), 126.6 (CH), 124.4 (CH), 123.8
H), 5.21 (br d, 1 H, J = 9.0), 2.87 (m, 2 H), 2.55 (CH), 66.1 (CH2), 65.4 (CH), 44.8 (2 CH3)
(s, 6 H)
Synthesis 2001, No. 10, 1479–1482 ISSN 0039-7881 © Thieme Stuttgart · New York

1482
M. Nyerges et al.
PAPER
1-Aryl-2-dimethylaminoethanols 4; General Procedure
The 5-aryl-3-methyloxazolidine 3 (1 mmol) was dissolved in EtOH
(15 mL) and NaBH4 (114 mg, 3 mmol) was added in portions at r.t.
After stirring at r.t. for the appropriate time given in Table 2, sat. aq
NH4Cl solution (10 mL) was added, and the EtOH was removed in
vacuo. The residue was extracted with CH2Cl2 (3 10 mL) and the
organic layer was washed with brine (10 mL) and dried (MgSO4).
The solvent was evaporated under reduced pressure to obtain the
crude product, which was purified by flash chromatography (ace-
tone–hexane, 1:1) (Table 4).
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Acknowledgement
This work was financially supported by the National Fund for Sci-
ence and Research, Hungary (OTKA Project No. F 029198 and T
032221). N. M. thanks the Hungarian Academy of Sciences for a
Bolyai J. fellowship.
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Synthesis 2001, No. 10, 1479–1482 ISSN 0039-7881 © Thieme Stuttgart · New York