Synthesis of 3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro-9h-imidazo[1,2-a]- indol-2-ones by reaction of 2,3,3-trimethyl-3h-indole with 2-bromopropionamides

Article abstract of DOI:10.1007/s10593-005-0066-y

Alkylation of 2,3,3-trimethyl-3H-indole with 2-bromopropionamide and the subsequent treatment of the formed 1-(1-carbamoylethyl)-2,3,3-trimethyl-3H- indolium bromide with a base afforded 3,9,9,9a-tetramethyl-1,2,3,9a-tetrahydro- 9H-imidazo[1,2-a]indol-2-o

Full text of DOI:10.1007/s10593-005-0066-y

Chemistry of Heterocyclic Compounds, Vol. 40, No. 10, 2004
REGIOSELECTIVITY OF THE
INTERACTION OF (1S,2S)-2-AMINO-
1-(4-NITROPHENYL)-1,3-PROPANEDIOL
WITH SOME SYMMETRICAL KETONES
M. Madesclaire1, P. Coudert1, V. P. Zaitsev2, and Yu. V. Zaitseva2
The interaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol with a series of symmetrical
ketones has been studied. As a result isomeric oxazolidines are formed in a ratio of 85:15. These
oxazolidines were shown to decompose readily under the action of hydrazine.
Keywords: (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol, acetone, oxazolidine, cyclohexanone,
cyclopentanone, symmetrical ketones, regioselectivity.
Study of the regioselectivity of organic reactions is of considerable interest. We showed previously that
(1S,2S)-2-arylmethylamino-1-(4-nitrophenyl)-1,3-propanediols interact regioselectively with paraformaldehyde
[1]. The first step of the method proposed for using the side product of the manufacture of the levomycetin
analog thiamphenicol is based on the regioselectivity of the interaction of (1S,2S)-2-amino-1-(4-nitrophenyl)-
1,3-propanediol with acetone [2].
On interacting (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (1) with the symmetrical ketones
2a-d it is possible to form two isomeric oxazolidines 3 and 4.
O
NO2
NO2
NO2
R
R
2a−d
–H2O
+
CH2
OH
CH
CH
CH CH CH2
CH CH CH2
OH
NH2
O
R
NH
R
OH
OH HN
R
O
R
1
3a−d
4a−d
2–4 a R+R = (CH2)5, b R+R = (CH2)4, c R+R = (CH2)6, d R = Me
The use of this reaction [2] assumes a high degree of regioselectivity for it with the preferential
formation of isomer 3, but there are no data in this work on the regioselectivity of the reaction. Meanwhile it is
known that secondary alcoholic groups of 1,2-diols are more inclined than primary to form cyclic acetals [3].
__________________________________________________________________________________________
1
Universite d'Auvergne, Faculte de Farmacie, Clermont-Ferrand, France; e-mail:
2
michel.madesclaire@u-clermont1.fr.
Samara State University, Samara 443011, Russia; e-mail:
vzaitsev@ssu.samara.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1518-1523,
October, 2004. Original article submitted June 18, 2002; revision submitted December 20, 2003.
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0009-3122/04/4010-1310©2004 Springer Science+Business Media, Inc.

Symmetrical ketones are frequently used to form O-alkylidene protection, possessing various stability
depending on the structure of the ketone used [3]. In the present work we have investigated the conditions of
interaction of a series of symmetrical ketones 2a-d with 2-amino-1,3-propanediol 1, the regioselectivity of this
reaction, and the stability of oxazolidines obtained towards hydrazinolysis [4].
The interaction of compound 1 with ketones was carried out in boiling benzene with azeotropic
distillation of water. The criterion for completion of the reaction is the dissolution of the solid and cessation of
water distillation, after which the reaction mixture was boiled for a further 30 min. Benzene was then distilled
off on a rotary evaporator and the excess of ketone on vacuum equipment to constant weight, which
corresponded to quantitative conversion of 2-amino-1,3-propanediol. The compounds obtained were spectrally
pure and were not subjected to additional purification before assessing regioselectivity. As is evident from Table
1, the reactivity of ketones falls in the series, cyclohexanone > cyclopentanone >> cycloheptanone. In the
reaction cyclic ketones were taken in 30% excess in the case of cyclohexanone and cyclopentanone and in 80%
excess in the case of cycloheptanone. Since the boiling point of acetone is less than the boiling point of benzene
and it accumulates in the Dean–Stark stillhead, acetone is introduced into the reaction in a large excess. Under
the conditions indicated it displays a greater reactivity than cycloheptanone but less than cyclopentanone.
Recently, semiempirical quantum-mechanical methods of calculation, particularly AM1 and PM3, have
been widely used to predict the results of reactions and the structure of the resulting products [5,6]. We selected
isomers 3a and 4a, the products of the interaction of compound 1 with cyclohexanone, as model compounds.
Four optimal conformers were considered for each of the isomers, two with R and S configuration of the nitrogen
atom, and the following energy values (kcal/mol) were obtained for the conformers being considered:
AM1 (3a): -4144.1; -4146.2; -4146.5; -4147.8; PM3 (3a): -4152.5; -4153.8; -4155.1; -4158.2.
AM1 (4a): -4146.7; -4147.7; -4147.7; -4147.8; PM3 (4a): -4155.6; -4156.5; -4157.2; -4157.4.
It is evident that the difference in energy values will be of the same order for other pairs of compounds 3
and 4.
In spite of the fact that the energy values obtained indicate some preference for isomer 4a, it is
impossible from these data to draw a conclusion on the preference of forming one of the isomers, since the
difference in the obtained values is less than the admissible error of the calculation, which may reach 5 kcal/mol
[7]. However it is possible to conclude from these data that the regioselectivity of this reaction may not be high [8].
1
The H NMR spectra of the reaction products were taken for an experimental assessment of the
regioselectivity of the reaction. It turned out that the spectra taken in CDCl3 and DMSO-d6 differed strongly
(Fig. 1). The signals of the Ar–CH and N–CH methine protons of isomers 3 and 4 have different chemical shifts
only in deuterochloroform, so it is possible to assess the regioselectivity of the reaction investigated by the
1H NMR spectrum of the reaction mixtures in deuterochloroform. Independent on the nature of ketone taken the
ratio of isomers was approximately 85:15 (Fig. 1, Table 1) and did not change with time or after purification on a
chromatographic column.
TABLE 1. Data on the Interaction of Compound 1 (2.1 g, 0.01 mol) with
Ketones 2a-d
Amount of ketone,
g (mol)
Ratio of isomers 3 and 4,
Ketone 2
Reaction time, min*
as % (data of 1H NMR)
Cyclohexanone (a)
Cyclopentanone (b)
Cycloheptanone (c)
Acetone (d)
1.3 g (0.013)
1.1 g (0.013)
2.1 g (0.018)
10 ml (0.14)
15/45
45/75
180/210
60/90
84 : 16
85 : 15
83 : 17
83 : 17
_______
* The time required for complete solution of 1 is given in the numerator, the
total reaction time is given in the denominator.
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Fig. 1. Region of the 1H NMR spectrum of the interaction products of compound 1 with cyclohexanone
used for assessment of the regioselectivity of the reaction, a) in CDCl3 and b) in DMSO-d6.
1
The H NMR spectra of the reaction mixture formed on interacting compound 1 with cyclohexanone
were taken in the presence of Eu(fod)3 to confirm the structure of the main reaction product. This reaction
product was selected because of its better solubility in deuterochloroform. The signals of the methine proton
close to the aromatic ring are readily discernible in both cases (Fig. 1a). The proton being considered in isomer
4a is closer to the shift reagent and under its influence correspondingly must have a larger shift of signal in the
1H NMR spectrum, which is in fact observed (Fig. 2).
Fig. 2. Signals of the Ar–CH methine proton of isomers 3a and 4a in the presence of Eu(fod)3.
The molar ratio of Eu(fod)3/substrate is a) 0.03; b) 0.04; c) 0.07; d) 0.09.
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This enables structure 3a to be assigned unequivocally to the main reaction product.
NO2
NO2
CH–CH–CH2
CH–CH–CH2
OH
O
NH
HO
NH O
Eu3+
+
Eu 3
3a
4a
Acetal protection is widely used for the protection of neighboring hydroxyl groups. It is known that
acetals formed with 1,2-diols possess differing stability depending on the nature of ketone used. Methylene
acetals are the most stable to acid hydrolysis, which also causes their infrequent use [3]. We showed previously
that oxazolidines formed on interacting 1,2-amino alcohols with paraformaldehyde are decomposed on treatment
with alcoholic solution of hydrazine [4].
In the present work the stability of the various oxazolidine systems has been studied. For this purpose
the mixture of oxazolidines formed on interacting compound 1 with cyclohexanone, cyclopentanone,
cycloheptanone, and acetone was dissolved in ethyl alcohol and hydrazine hydrate was added. Even after
15-20 min precipitation of the solid initial compound 1 from the reaction mixture had begun, which indicates the
low stability of these oxazolidines under hydrazinolysis conditions. In all the experiments the yield of compound
1 was ~80%. The described oxazolidines began to decompose straight away under the action of hydrazine,
consequently a quantitative assessment of their relative stability was not carried out.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker Avance DRX 200 (200 MHz) spectrometer in CDCl3,
internal standard was TMS. Spectra were processed with the MESTREC computer program. Melting points were
determined on a Kofler block. (1S,2S)-2-Amino-1-(4-nitrophenyl)-1,3-propanediol (1) (Akrikhin works
(Kupavna, Moscow region)) recrystallized from alcohol was used in the work. Ketones 2a-c were commercial
preparations of Aldrich, silica gel type SDS was from France. Column chromatography was carried out on
column (3 × 40 cm) packed with silica gel 35-70 µm. Eluent was ethyl acetate–cyclohexane, 1:1.
Interaction of Compound 1 with Ketones 2a-d. Compound 1 (2.1 g, 0.01 mol), cyclohexanone 2a
(1.3 g, 0.013 mol), and benzene (50 ml) were placed in a round-bottomed flask fitted with a Dean–Stark
stillhead. The reaction mixture was boiled for 15 min until complete dissolution of compound 1 and then for a
further 30 min. Benzene was distilled off on a rotary evaporator, and the excess of cyclohexane on vacuum
equipment. Crude product (2.9 g, 100%) was obtained. The 1H NMR spectrum was determined in
deuterochloroform to determine the ratio of isomers 3a and 4a.
Reactions with cyclopentanone 2b, cycloheptanone 2c, and acetone 2d were carried out by an analogous
procedure. The yields of crude product 3b-d were 98-100%. The crude product was purified by
chromatography.
(1S,2S)-2-Amino-1,2-O,N-cyclohexylidene-1-(4-nitrophenyl)-1,3-propanediol (3a). Oil. 1H NMR
spectrum, δ, ppm (J, Hz): 7.53, 8.21 (4H, two d, J = 8, Harom); 4.80 (1H, d, J = 8, CHAr); 3.66-3.92 (2H, two dd,
J = 4, J = 12, diastereotopic CH2); 3.14-3.20 (1H, m, CHN); 2.90 (2H, br. s, OH, NH); 1.49-1.87 (10H, m,
(CH2)5). Found, %: C 61.87; H 7.12. C15H20N2O4. Calculated, %: C 61.61; H 6.90.
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1
(1S,2S)-2-Amino-1,2-O,N-cyclopentylidene-1-(4-nitrophenyl)-1,3-propanediol (3b). Oil. H NMR
spectrum, δ, ppm (J, Hz): 7.57, 8.24 (4H, two d, J = 8, Harom); 4.78 (1H, d, J = 8, CHAr); 3.70-3.90 (2H, two dd,
J = 4, J = 12, diastereotopic CH2); 3.16-3.22 (1H, m, CHN); 2.78 (2H, br. s, OH, NH); 1.70-1.93 (8H, m,
(CH2)4). Found, %: C 60.63; H 6.71. C14H18N2O4. Calculated, %: C 60.40; H 6.52.
(1S,2S)-2-Amino-1,2-O,N-cycloheptylidene-1-(4-nitrophenyl)-1,3-propanediol (3c). Mp 63-65°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.53, 8.23 (4H, two d, J = 8, Harom); 4.74 (1H, d, J = 8, CHAr); 3.66-3.92
(2H, two dd, J = 4, J = 12, diastereotopic CH2); 3.03-3.09 (1H, m, CHN); 2.90 (2H, br. s, OH, NH); 1.49-1.89
(12H, m, (CH2)6). Found, %: C 62.92; H 7.39. C16H22N2O4. Calculated, %: C 62.71; H 7.24.
(1S,2S)-2-Amino-1,2-O,N-isopropylidene-1-(4-nitrophenyl)-1,3-propanediol (3d). Mp 41-43°C.
1H NMR spectrum, δ, ppm (J, Hz): 7.53-8.23 (4H, two d, J = 8, Harom); 4.82 (1H, d, J = 8, CHAr); 3.69-3.94
(2H, two dd, J = 4, J = 12, diastereotopic CH2); 3.16-3.21 (1H, m, CHN); 2.90 (2H, br. s, OH, NH); 1.56 [6H, s,
C(CH3)2]. Found, %: C 56.91; H 7.23. C12H16N2O4. Calculated, %: C 56.66; H 7.14.
Hydrazinolysis of the Products of Interaction of Compound 1 with Ketones 2a-d. Mixtures obtained
by reacting compound 1 (5 g) with the appropriate quantity of ketones 2a-d were dissolved in alcohol (10 ml)
and hydrazine hydrate (5 ml) was added. The mixtures were left overnight, the precipitated crystals 1 were
filtered off, washed with a small amount of alcohol, and dried. Yield for 2a was 4.05 g (81%), and for 2b-d (80-
82%). In all cases mp 164-166°C (163-164°C [4]).
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