A simple two-step synthesis of 2-(alkylamino)-1-arylethanols, including racemic adrenaline, from aromatic aldehydes via 5-aryloxazolidines

Article abstract of DOI:10.1016/j.tetlet.2013.08.083

Benzaldehydes react smoothly with nonstabilized azomethine ylides, generated in situ from sarcosine/formaldehyde or N-(methoxymethyl)-N- (trimethylsilylmethyl)benzylamine, to give 5-aryloxazolidines as intermediates. These were converted into 2-(alkylamino)-1-arylethanols in good yields by simple heating in methanol with hydrochloric acid, or by treatment with hydrazine hydrate in ethanol.

Full text of DOI:10.1016/j.tetlet.2013.08.083

Accepted Manuscript
A simple two-step synthesis of 2-(alkylamino)-1-arylethanols, including race‐
mic adrenaline, from aromatic aldehydes via 5-aryloxazolidines
Vladimir S. Moshkin, Vyacheslav Ya. Sosnovskikh
PII:
S0040-4039(13)01469-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.083
TETL 43446
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
18 June 2013
1 August 2013
21 August 2013
Please cite this article as: Moshkin, V.S., Sosnovskikh, V.Y., A simple two-step synthesis of 2-(alkylamino)-1-
arylethanols, including racemic adrenaline, from aromatic aldehydes via 5-aryloxazolidines, Tetrahedron Letters
(2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.083
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Graphical abstract
________________________________________________________________________________
A simple two-step synthesis of 2-(alkylamino)-1-arylethanols, including racemic adrenaline, from aromatic
aldehydes via 5-aryloxazolidines
Vladimir S. Moshkin*, Vyacheslav Ya. Sosnovskikh
________________________________________________________________________________________________________________________
 Corresponding author. Fax: +7 343 261 59 78;
e-mail: mvslc@mail.ru

A simple two-step synthesis of 2-(alkylamino)-1-arylethanols, including racemic
adrenaline, from aromatic aldehydes via 5-aryloxazolidines
Vladimir S. Moshkin*, Vyacheslav Ya. Sosnovskikh
Department of Chemistry, Ural Federal University, prosp. Lenina 51, 620000 Ekaterinburg, Russia
A B S T R A C T
Benzaldehydes react smoothly with nonstabilized azomethine ylides, generated in situ from
sarcosine/formaldehyde or N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, to give 5-
aryloxazolidines as intermediates. These were converted into 2-(alkylamino)-1-arylethanols in good
yields by simple heating in methanol with hydrochloric acid, or by treatment with hydrazine hydrate
in ethanol.
Keywords: Benzaldehydes; Nonstabilized azomethine ylides; [3+2] Cycloaddition; 5-
Aryloxazolidines; Phenethylamines; Epinephrine (Adrenaline)
The chemistry of β-hydroxy-β-phenethylamines has attracted considerable attention from the
synthetic community due to their wide distribution in Nature and various biological activities.1
Examples of such compounds include the alkaloids halostochine (1a), longimammine (1b), and
normacromerine (1c), as well as the drugs phenylephrine (1d) and epinephrine (1e) (Figure 1).2 The
latter, also known as adrenaline, 1-(3,4-dihydroxyphenyl)-2-(methylamino)ethanol, is a naturally
occurring hormone and a neurotransmitter, which has many functions in the body, regulating heart
rate, blood vessel and air passage diameters. It has many clinical uses due to its potent actions on
the heart, and on vascular and other smooth muscle; it also acts as a cardiac stimulant and has
effects on gastrointestinal, uterine, and bronchial muscles.3
2

Figure 1. Examples of valuable 1-aryl-2-(methylamino)ethanols.
Due to the important applications of this class of compounds, their synthesis has been studied
extensively.4 Most pertinent to the present research are the reactions involving the oxazolidine
system as a starting material. To the best of our knowledge, there are only two related examples
reported in the literature. In 1970, Rizzi investigated the reaction of benzaldehyde and m-
benzyloxybenzaldehyde with sarcosine and obtained diaryloxazolidines, which were subsequently
hydrolyzed with hydrochloric acid to form halostochine (1a) and debenzylated into phenylephrine
(1d) in low yields.5 Later, Orsini found that the intermediate unsymmetrical nonstabilized
azomethine ylides generated from sarcosine and aromatic aldehydes reacted with a second molecule
of aldehyde to produce a mixture of regioisomeric diaryloxazolidines, which resulted in low yields
during the Rizzi synthesis.6
In connection with our interest in azomethine ylide chemistry,7 we have developed convenient
methods for the preparation of 1,2,3,4-tetrahydroisoquinolin-4-ols 3, N-benzyl-β-hydroxy-β-
phenethylamines 4, and 4-aryl-1,2,3,4-tetrahydroisoquinolines 5 from aromatic aldehydes and an
azomethine ylide derived from sarcosine and formaldehyde, via intermediate 5-aryloxazolidines 2.8
Taking into account these results, we envisaged that the ring-opening of oxazolidines 2 by
removing the semi-aminal methylene group would produce the corresponding 1-aryl-2-
3

(methylamino)ethanols 1, and may provide a general and simple route for the synthesis of these
important amino alcohols. To the best of our knowledge, no such approach has been reported
previously (Scheme 1).
Scheme 1. One-pot syntheses of phenethylamine derivatives.
To test the feasibility of this idea, the reaction of 3-methyl-5-phenyloxazolidine (2a, R = H),
obtained from benzaldehyde, sarcosine and paraformaldehyde, with methanol was first investigated.
We found that refluxing 2a, methanol and concentrated HCl (1.2 equiv) for 1.5 hours resulted in the
formation of desired halostochine (1a) in 61% overall yield, based on the starting aromatic
aldehyde.9 Using this approach, we were also able to obtain 1-(4-bromophenyl)-2-
(methylamino)ethanol (1f) and 2-(methylamino)-1-(4-nitrophenyl)ethanol (1g) from the
corresponding benzaldehydes in 59% and 63% yields, respectively (Scheme 2, Table 1). It should
be noted that this reaction does not require any chromatographic purification of the intermediate
liquid oxazolidines 2 or the products 1, and thereby greatly facilitates the preparation of the target
arylethanolamines. However, anisaldehyde, under the same conditions, gave a mixture of products,
presumably due to the high nucleophilicity of the benzene ring and the stabilizing effect of the p-
4

methoxy group on the benzylic carbocation intermediate, which facilitate intermolecular side
reactions.
This problem can be overcome by using a previously reported demethylenation protocol on the
oxazolidine ring with hydrazine hydrate in ethanol.10 To our delight, this procedure gave
longimammine (1b) in 70% yield from the starting anisaldehyde; normacromerine (1c) was
obtained from veratraldehyde in a similar way in 59% yield. Analogous reactions with 2,4-
dimethoxybenzaldehyde and 4-benzyloxy-3-methoxybenzaldehyde resulted in the formation of
previously unknown β-hydroxy-β-phenethylamines 1h and 1i.11 Finally, epinephrine (1e) was
synthesized from 3,4-dibenzoyloxybenzaldehyde in 67% yield. In this case, the benzoyl protection
was removed simultaneously by demethylenation of oxazolidine 2e under the action of hydrazine
hydrate (Scheme 2, Table 1).
Scheme 2. Synthesis of β-hydroxy-β-phenethylamines 1.
Reaction conditions: i, MeOH, HCl, reflux, 1.5 h;
ii, EtOH, N2H4·H2O, r.t. (2 d), reflux (3 h).
An alternative method for the generation of a nonstabilized azomethine ylide from N-
(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in the presence of trifluoroacetic acid,12
followed by hydrazinolysis of oxazolidine 2j allowed us to obtain N-benzyl derivative 1j isolated as
the hydrochloride. Application of this reaction to thiophene-2-carbaldehyde led to a two-step
synthesis of 2-(benzylamino)-1-(thien-2-yl)ethanol (1k) in 71% yield (Scheme 3).
5

Scheme 3. Synthesis of compounds 1j,k.
Table 1
Yields and melting points of -hydroxy--phenethylamines 1
Aromatic
aldehyde
-Hydroxy-
-phenethylamine
Yield
(%)a
Mp (C)b
61
59
75–77c
1a
1f
93–95d
115–117e
103–105f
100–103g
79–82
63
70
59
49
1g
1b
1c
1h
6

78
67
107–110
210–213h
1i
1e
68i
193–195i
96–98j
1j
71
1k
a Overall yield of the phenylethylamine based on the starting aromatic aldehyde.
b Melting points are uncorrected.
c Mp 75.5–76.5 C,5 mp 71–74 C.13
d Mp 91.5–93.7 C.14
e Mp 117 C,15 mp 95–98 C.16
f Mp 106–107 C.17
g Mp 105–106 C,19 mp 107–108.5 C.2c
h Mp 211–212 C.18
i Yield and mp of the hydrochloride.
j Mp 84–85 C.20
In conclusion, we have developed a practical, two-step route to N-alkyl--hydroxy--
phenethylamines from aromatic aldehydes via a 5-aryloxazolidine intermediate, followed by its
demethylenation. This one-pot synthesis can be considered as a formal C-nucleophilic addition of
the methyl(benzyl)aminomethyl anion21 from sarcosine/formaldehyde or N-(methoxymethyl)-N-
(trimethylsilylmethyl)benzylamine to the aldehyde carbonyl group. The proposed method allows
easy access to biologically important phenethylamine derivatives. Further studies on this reaction
are underway in our laboratory and the results will be reported in due course.
Acknowledgment
The research was carried out under the terms of the Ural Federal University development
program with the financial support of young scientists, and was supported financially by RFBR
(Grant 12-03-31036).
7

Supplementary data
Supplementary data associated with this article can be found in the online version.
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corresponding aromatic aldehyde (1.0 mmol), finely ground sarcosine (0.13 g, 1.5 mmol), and
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additional purification.
8

For the preparation of amino alcohols 1a,f,g: the corresponding oily oxazolidine 2 was dissolved in
MeOH (1 mL) and treated with concentrated HCl (0.10 mL, 1.2 mmol). The resulting mixture was
refluxed in a fume hood with partial evaporation of the solvent for 1.5 h (for the removing of
dimethoxymethane). The MeOH was evaporated in vacuo and H2O (0.5 mL) was added. The mixture
was extracted with Et2O (2 × 1 mL) followed by basification with an excess of a cold concentrated
solution of NaOH. Extraction with CH2Cl2 (2 × 2 mL), drying over Na2SO4, and evaporation gave the
crude 1-aryl-2-(methylamino)ethanol, which was recrystallized from CH2Cl2–heptane mixture.
For the preparation of amino alcohols 1b,c,h,i: the corresponding oily oxazolidine 2 was dissolved in
EtOH (1 mL) and treated with hydrazine hydrate (0.4 mL). The resulting mixture was left at room
temperature for 2 d and then refluxed for 3 h. The solvents were evaporated in vacuo and a concentrated
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CH2Cl2–heptane mixture.
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CHH), 2.54 (dd, J = 11.9, 3.1 Hz, 1H, CHH), 3.74 (s, 3H, MeO), 3.75 (s, 3H, MeO), 4.88 (dd, J = 8.5,
3.1 Hz, 1H, CH), 6.47–6.52 (m, 2H, ArH), 7.26–7.30 (m, 1H, ArH); 13C NMR (101 MHz, DMSO-d6) 
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62.54; H, 8.11; N, 6.63. Found: C, 62.76; H, 7.88; N, 6.67.
1-[4-(Benzyloxy)-3-methoxyphenyl]-2-(methylamino)ethanol (1i). Colourless crystals, yield 78%, mp
107–110 C (heptane–CH2Cl2). 1H NMR (400 MHz, DMSO-d6)  2.31 (s, 3H, MeN), 2.56 (dd, J = 12.0,
4.8 Hz, 1H, CHH), 2.61 (dd, J = 12.0, 7.6 Hz, 1H, CHH), 3.77 (s, 3H, MeO), 4.59 (dd, J = 7.6, 4.8 Hz,
1H, CH), 5.05 (s, 2H, CH2O), 6.83 (dd, J = 8.2, 1.5 Hz, 1H, H-6), 6.96 (d, J = 8.2 Hz, 1H, H-5), 6.98 (d,
J = 1.5 Hz, 1H, H-2), 7.32 (t, J = 7.1 Hz, 1H, Ph), 7.39 (t, J = 7.1 Hz, 2H, Ph), 7.44 (d, J = 7.1 Hz, 2H,
Ph); 13C NMR (101 MHz, DMSO-d6)  35.8, 55.5, 59.7, 70.0, 70.8, 110.1, 113.4, 117.9, 127.68, 127.74,
128.4, 137.4, 137.7, 146.7, 148.9. Anal. Calcd for C17H21NO3: C, 71.06; H, 7.37; N, 4.87. Found: C,
70.67; H, 7.43; N, 4.99.
2-Benzylamino-1-(3,4,5-trimethoxyphenyl)ethanol hydrochloride (1j). Colourless crystals, yield 68%,
mp 193–195 C (i-PrOH). 1H NMR (400 MHz, D2O)  3.30 (dd, J = 13.0, 8.8 Hz, 1H, CHH), 3.36 (dd,
J = 13.0, 3.7 Hz, 1H, CHH), 3.81 (s, 3H, MeO), 3.89 (s, 6H, 2MeO), 4.35 (s, 2H, CH2N), 5.06 (dd, J =
8.8, 3.7 Hz, 1H, CH), 6.78 (s, 2H, H-2, H-6), 7.49–7.55 (m, 5H, Ph); 13C NMR (101 MHz, D2O)  53.5,
54.7, 58.6, 63.4, 71.3, 105.7, 131.8, 132.3, 132.4, 132.8, 138.9, 139.0, 155.2. Anal. Calcd for
C18H24ClNO4: C, 61.10; H, 6.84; N, 3.96. Found: C, 61.18; H, 7.09; N, 3.99.
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10