Nonstabilized azomethine ylides as reagents for alkylaminomethylation of aromatic ketones via 5-aryloxazolidines

Article abstract of DOI:10.1016/j.tetlet.2015.07.068

Abstract Aromatic ketones were found to react smoothly with nonstabilized azomethine ylides, generated in situ from sarcosine/formaldehyde or N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, to give 5-aryloxazolidines which were converted into 2-alkylaminoethanols in moderate to good yields by heating in n-butanol with hydrochloric acid.

Full text of DOI:10.1016/j.tetlet.2015.07.068

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nonstabilized azomethine ylides as reagents for
alkylaminomethylation of aromatic ketones via 5-aryloxazolidines
⇑
Vladimir S. Moshkin , Evgeny M. Buev, Vyacheslav Y. Sosnovskikh
Department of Chemistry, Institute of Natural Sciences, Ural Federal University, 620000 Ekaterinburg, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Aromatic ketones were found to react smoothly with nonstabilized azomethine ylides, generated in situ
from sarcosine/formaldehyde or N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, to give
5-aryloxazolidines which were converted into 2-alkylaminoethanols in moderate to good yields by
heating in n-butanol with hydrochloric acid.
Received 1 June 2015
Revised 15 July 2015
Accepted 22 July 2015
Available online xxxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Carbonyl compounds
Nonstabilized azomethine ylides
[3+2] Cycloaddition
5-Aryloxazolidines
2-Amino-1-arylethanols
The 2-amino-1-arylethanol functional group is a structural unit
found in a large number of natural products and bioactive
compounds such as peptide enzyme inhibitors, amino sugar
antibiotics, alkaloids, and sympathomimetic amines.1 Examples
of such compounds include the alkaloids halostachine, longimam-
mine, and normacromerine,2 as well as the drugs phenylephrine
and epinephrine.3 Diarylaminoethanols and their desoxy
derivatives have also drawn considerable attention because of
their unique biological and physiological activities.4,5 Moreover,
2-amino-1-arylethanols are also employed for the preparation of
chiral auxiliaries,6 and are important precursors in several
synthetic drugs and natural products.7
The introduction of the aminomethyl fragments to electrophilic
compounds such as aromatic aldehydes and ketones is widespread
in synthetic organic chemistry. Typically, this is achieved by
cyanohydrin synthesis6,8 or the Henry reaction of nitromethane,
followed by hydrogenation to the desired 2-amino-1-
arylethanols.9 The insertion of a more complex alkylaminomethyl
anion synthon I based on the above strategies requires multiple
steps, including N-alkylation of the primary amines.10 Finally,
2-aryloxiranes can be synthesized from the corresponding
carbonyls and ring-opened with nitrogen nucleophiles.11
proton and secondly stabilization of the negative charge on the car-
bon atom. Among the more common methylaminomethyl anion
precursors are O-tert-butyl-N-(chloromethyl)-N-methyl carba-
mate12 and N,N-dimethylthiopivalamide.13 These compounds are
lithiated at the Me group in an
a-position to the nitrogen atom
using an excess of lithium powder or s-BuLi to generate the methy-
laminomethyl anion equivalents II and III which are then reacted
with an electrophile, followed by removal of the Li-coordinating
moiety attached to nitrogen. Such reactions are limited by the
complex conditions required for the initial deprotonation and final
hydrolysis steps. Therefore, these precursors have not found
widespread application due to the difficulties in their preparation
and utilization. On the other hand, synthetic equivalents of such
types are 2-azaallyl anion IV which can be generated from
N-(trimethylsilylmethyl)imines,14 and nonstabilized azomethine
ylide V. The latter example is highly reactive and easily accessible,
which makes it very attractive (Scheme 1).
A novel azomethine ylide strategy for the introduction of the
alkylaminomethyl group to aromatic aldehydes has been recently
developed by our research group.15 This approach, based on the
1,3-dipolar cycloaddition of nonstabilized azomethine ylides with
a carbonyl functional group, represents one of the simplest conver-
sions of carbonyl compounds into 2-amino-1-arylethanols and it
was felt that further investigations in order to expand the scope
of its possible applications were required. Taking into account the
broad utility of 2-amino alcohols in medicinal chemistry and con-
tinuing our research in the field of 5-aryloxazolidine chemistry,16
we herein report our extension of this methodology to a number
From another point of view, synthetic equivalents of the alky-
laminomethyl anion I would possess certain advantages if they
could be directly introduced to keto compounds. The requirements
for such molecules would firstly be an absence of an acidic NH
⇑
Corresponding author.
http://dx.doi.org/10.1016/j.tetlet.2015.07.068
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Moshkin, V. S.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.07.068

2
V. S. Moshkin et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Indeed, we found that the reaction with fluorenone led to pre-
H2C
Alk
C
N
NO2
viously unknown oxazolidine 3a in 96% NMR yield, which could
be readily purified by recrystallization in 61% yield. Utilization of
the typical ring-opening procedure (HCl/H2O/MeOH)15 on this oxa-
zolidine did not proceed to completion, however use of the higher
boiling n-BuOH at 90 °C for 1.5 h gave hydrochloride 4a in 83%
yield. Attempts to demethylenate oxazolidine 3a by refluxing with
dry HCl (from SOCl2) in MeOH gave only the hydrochloride of the
starting compound 30a. The latter observation can be accounted
for by the fact that such aminoalcohols are only formed in the
presence of water (Scheme 3, Table 1, entry 1).
Li
S
Li
O
H
N
N
t-Bu
N
Ot-Bu
I
Me
Me
III
II
R
N
N
IV
V
OH
O
H
V
N
Ar
Ar
R'
R
R'
As expected, (trifluoromethyl)phenylketone reacted readily
with the azomethine ylide derived from sarcosine and formalde-
hyde to give liquid oxazolidine 3b, which, without isolation, was
hydrolyzed to give the hydrochloride salt of 2-amino alcohol 4b
in 70% yield (Table 1, entry 2). Thus, the described one-pot
synthesis of 2-methylamino-1-arylethanols from aromatic ketones
Scheme 1. Synthetic equivalents for the alkylaminomethyl anion.
of aromatic ketones and 1,2-diketones for the preparation of new
1,1-disubstituted 2-alkylaminoethanols.
Nonstabilized azomethine ylides have high nucleophilicity
and can be readily generated from N-alkyl-a-amino acids or N-
Me
N
(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (Scheme 2).
However, in contrast to the well documented reactivity of the
C@C double bond, to date little attention has been paid to the
[3+2] cycloaddition reaction of carbonyl compounds with nonsta-
bilized azomethine ylides. The pioneering studies of Rizzi,17
Padwa,18 Orsini,19 and Nyerges20 established that nonstabilized
azomethine ylide [3+2] cycloadditions with carbonyl compounds
enable a one-step synthesis of 5-aryloxazolidines. Although several
papers regarding their preparation have been published,21 the syn-
thetic utility of these intermediates has not been extensively
explored. Only three papers describing intra- and intermolecular
reactions of 5-aryloxazolidines with nucleophilic reagents have
been reported.16a–c In view of the fact that the aminoacetal
methylene group of 5-aryloxazolidines 1, the former azomethine
ylide cationic center, retains electrophilic character after the
cycloaddition step due to the presence of the two geminal
acceptor atoms, we envisaged that the ring-opening of the
oxazolidines by removing the methylene group would produce
the corresponding 2-amino-1-arylethanols 2, providing a general
and simple route for the synthesis of these valuable compounds
(Scheme 2). It is noteworthy that a similar introduction of more
complex amino acid fragments to aldehydes has been previously
achieved using stabilized azomethine ylides.22
O
O
CH2O
MeNHCH2CO2H
3a
(61%)
SOCl2
MeOH
aq. HCl
BuOH, Δ
Me
N·HCl
Me
HO
NH·HCl
O
4a
3'a
(83%)
(74%)
Scheme 3. Synthesis of compounds 3a and 4a.
Table 1
Yields of hydrochlorides 4
Entry Aromatic ketone
NMR
2-Aminoethanol
Isolated
yield of
yield of
oxazolidine
3a (%)
4ꢀHCl
4ꢀHClb (%)
Me
NH
O
HO
Initially, we investigated the reaction of sarcosine and
paraformaldehyde with aromatic ketones. In previous publications
using coumarins and chromones we observed that nonstabilized
azomethine ylides reacted poorly with weak electron-
withdrawing or sterically hindered dipolarophiles.16e,23 We
envisaged that the reactions with more active fluorenone and
(trifluoromethyl)phenylketone may produce the corresponding
oxazolidines in good yield.
1
96 (61)c
83
4a
F3C OH
H
N
O
Me
CF3
CH3
2
3
Quant.
64%d
70
—
4b
O
O
e
—
Bn
CO2H
NH
N
SiMe3
OMe
Bn
NH
Me
O
CH2O
CF3CO2H or LiF
HO
R2 = Me
R2 = Bn
4
5
72
34
86
O
R2
N
R1
+
[3+2]
4c
R1
N
R
R2
R
1
O
aq. HCl
OH
Me
BuOH, Δ
O
N
H
OH
Quant.
H
N
R2
R
R1
O
2
4d
Scheme 2. Synthesis of b-hydroxy-b-phenethylamines 2.
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V. S. Moshkin et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
As expected, 1,2-diketo compounds, such as benzil and ace-
naphthoquinone, were very reactive and gave the corresponding
oxazolidines in almost quantitative yield without appreciable for-
mation of by-products (1H NMR). These intermediate compounds
were demethylenated using aq HCl in n-BuOH at 90 °C to give pre-
viously unknown 4d and 4e in 86% and 47% yields, respectively
(Table 1, entries 5 and 6).
Phenylglyoxylic acid ethyl ester gave the expected ethyl 3-me
thyl-5-phenyloxazolidine-5-carboxylate, however, removal of the
aminoacetal methylene group was associated with partial hydrol-
ysis of the ester moiety. In view of this, the residue was hydrolyzed
in 6 M HCl to give amino acid hydrochloride 4f in 75% yield
(Table 1, entry 8).
Lastly, the scope of this methodology was further expanded
using three N-alkylated isatin derivatives. Treatment of these hete-
rocycles with sarcosine and formaldehyde followed by acidic
hydrolysis, under the above conditions, produced the correspond-
ing aminoethanols 4g–i in high yields (Table 1, entries 9–11).
The structures of hydrochlorides 4 were determined by elemen-
tal analysis and their IR, 1H, and 13C NMR spectra. A characteristic
feature of their 1H NMR spectra was the appearance of an
AB-system at d 3.49–3.82 ppm (J = 13.1–13.4 Hz) for the CH2
protons.
In summary we have developed a practical, two-step route to
2-alkylamino-1-arylethanols from aromatic aldehydes15 and
ketones proceeding via demethylenation of a 1,3-oxazolidine inter-
mediate. We report that the acid hydrolysis of oxazolidines,
obtained from suitably substituted carbonyl compounds and non-
stabilized azomethine ylides, is a new and convenient synthetic
route leading to aminoalcohols. This one-pot synthesis can be
considered as a formal C-nucleophilic addition of the methyl
(benzyl)aminomethyl anion from sarcosine/formaldehyde or
N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine to the
carbonyl group. The proposed method allows easy access to biolog-
ically important phenethylamine derivatives, which are versatile
and useful building blocks for the construction of more complex
compounds.
Table 1 (continued)
Entry Aromatic ketone
NMR
2-Aminoethanol
4ꢀHCl
Isolated
yield of
yield of
oxazolidine
3a (%)
4ꢀHClb (%)
OH
O
Me
O
O
O
N
H
6
7
8
Quant.
47
—
4e
f
96
—
O
O
O
OH
H
HO
N
O
94
75
Me
Me
O
4f
HN
HO
O
9
Quant.
Quant.
nd
69
78
68
O
O
O
N
N
Me
Me
4g
Me
HN
HO
O
10
11
O
N
N
C5H11
C5H11
4h
Me
HN
HO
O
O
O
N
N
Bn
Bn
4i
Acknowledgment
Ylide formation method for synthesis of 5-aryloxazolidines. Entries 1–2, 5–11:
sarcosine/CH2O; entries 3 and 4: (MeOCH2)(Me3SiCH2)NBn, LiF, DMF.
Based on the 1H NMR spectrum of the crude mixture.
a
This work was financially supported by the Russian Science
Foundation (Grant 14-13-00388).
b
Overall yield based on the starting aromatic ketone.
c
Isolated yield of oxazolidine 3a.
d
Acetophenone did not react with sarcosine/CH2O, conversion is given for the
Supplementary data
reaction with (MeOCH2)(Me3SiCH2)NBn (2.5 equiv), LiF, DMF,
D
, 8 h.
Isolation of the hydrochloride was unsuccessful due to complex mixture
formation.
e
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.07.
068.
f
Starting anthraquinone was isolated as a result of the demethylenation.
does not require chromatographic purification at any stage and is
scalable.
References and notes
Due to the lower activity of the diaryl ketone carbonyl group
when compared to fluorenone, the reaction with benzophenone
did not provide the corresponding oxazolidine in good yield. As
determined by 1H NMR spectroscopy, conversion under typical con-
ditions was low (23%). This result forced us to examine another
method for the generation of the azomethine ylide from
N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine in apro-
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72%). Subsequent hydrolysis of the intermediate oxazolidine with
aq HCl in n-BuOH gave the required 2-(benzylamino)-1,1-diphenyle
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