N-Substituted tetrahydro-1,3-oxazines and oxazolidines 1. A new version of the Mannich reaction involving amino alcohols

Article abstract of DOI:10.1023/A:1009537504497

A new version of the Mannich reaction involving amino alcohols (3-aminopropan-1-ol and aminoethanol) was developed. These compounds react with formaldehyde and CH or NH acids to give N-substituted tetrahydro-1,3-oxazines or oxazolidines.

Full text of DOI:10.1023/A:1009537504497

1
04
Russian Chemical Bulletin, International Edition, Vol. 50, No. 1, pp. 104—109, January, 2001
N-Substituted tetrahydro-1,3-oxazines and oxazolidines
. A new version of the Mannich reaction involving amino alcohols
1
«
A. G. Korepin, P. V. Galkin, N. M. Glushakova, G. V. Lagodzinskaya, M. V. Loginova,
V. P. Lodygina, and L. T. Eremenko
Institute of Problems of Chemical Physics, Russian Academy of Sciences,
8 Institutskii prosp., 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (096) 576 4009. E-mail: elt@icp.ac.ru
1
A new version of the Mannich reaction involving amino alcohols (3-aminopropan-1-ol
and aminoethanol) was developed. These compounds react with formaldehyde and CH or NH
acids to give N-substituted tetrahydro-1,3-oxazines or oxazolidines.
Key words: C-, N-, and O-aminomethylation, amino alcohols, tetrahydro-1,3-oxazines
and oxazolidines, amides, imides, nitrogen heterocycles, 1,1-dinitroalkanes.
The Mannich reactions (C- and N-aminomethylation)
hydes, and ketones, they obtained numerous tetrahydro-
oxazoles (oxazolidines), tetrahydro-1,3-oxazines, and
1,3-oxazepanes, depending on the mutual arrangement
of the amino and hydroxy groups in the starting amino
alcohol.7
In the present work, a new version of aminomethyla-
tion of CH and NH acids with the use of amino alcohols
is described. The reaction involves a molecule of a CH
or NH acid, a molecule of an amino alcohol, and two
molecules of a carbonyl compound (formaldehyde). In
this case, the NH2 group of the amino alcohol is used
twice for aminomethylation to give N-substituted
tetrahydro-1,3-oxazine or oxazolidine as a final product
with the use of amino alcohols are described in a
comparatively small number of papers, all of them being
concerned with C-aminomethylation, e.g., of dinitro-
1
2
3
methane, fluorodinitromethane, trinitromethane, and
1
,1-dinitroethane4,5 according to Scheme 1.
Scheme 1
O N
H
O N
2
CH O
2
2
OH
NO2
Me
NO2
Me
(
Scheme 3).
O N
OH
H N(CH ) OH
2
2
2
2
NH
NO2
–
H O
Scheme 3
2
Me
RH + H N(CH ) OH + 2 CH O
In this version, amino alcohol functions only as an
2
2 n
2
amino component, its second reaction center (the OH
group) remaining inactive.
N
O
R
–
2 H O
A much greater number of papers are devoted to
reactions of amino alcohols with carbonyl compounds
2
(CH2)n
6
such as aldehydes or ketones (Scheme 2).
RH = CH- or NH-acid, n = 2, 3
Scheme 2
Results and Discussion
Initially, 1,1-dinitroethane, bromodinitromethane,
and dinitromethane were used as CH acids in the new
version of the reaction. Aminomethylation of the last
two compounds was carried out in two steps. First, they
reacted with formaldehyde to give 2-bromo-2,2-
dinitroethanol and 2,2-dinitropropane-1,3-diol, respec-
tively. These dinitroalkanols, which are more convenient
in use than the starting nitroalkanes, then were mixed
with amino alcohols and additional amounts of form-
Me
Me
OH
Me
Me
R
O
R
R
+
O
–H O
2
NH2
R
N
H
This process is similar to the Mannich reaction and
can be treated as intramolecular O-aminoalkylation that
involves both reaction centers of amino alcohol, i.e., the
NH2 and OH groups. Varying amino alcohols, alde-
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 101—106, January, 2001.
066-5285/00/5001-0104 $25.00 © 2001 Plenum Publishing Corporation
1

A new version of the Mannich reaction
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
105
Scheme 4
O N
H
O N
2
2
N
O
O
+
2 CH O
+
+
2
H N
OH
OH
2
–2 H O
2
Me
NO2
Me
NO2
1
O N
O N
2
2
OH
NO2
N
+
CH O
2
H N
2
–2 H O
Br
2
Br
NO2
2
O N
HO
O N
2
2
OH
NO2
N
O
+
2
CH O
+
2 H N
OH
2
2
–
4 H O
O
N
2
NO2
3
Scheme 5
CH O
N
N
O
O
2
R
R
RH
+
CH O
+
(a)
2
H N
OH
–H O
R
N
H
OH
–H O
2
2
2
HN
O
RH, CH O
2
CH O
+
(b)
2
H N
OH
–H O
–H O
2
2
2
aldehyde. Reactions with 3-aminopropan-1-ol gave, in
all three cases, tetrahydro-1,3-oxazines 1—3 in high
yields (Scheme 4).
The reactions proceeded smoothly in an aqueous
medium at room temperature, being completed within a
short time. Crystalline products 1—3 were filtered off
and recrystallized from organic solvents.
then reacted with formaldehyde to give tetrahydro-1,3-
oxazine 3 (Scheme 6).
In the case of 1,3-oxazacyclic derivatives, the prob-
lem of competing C- and O-aminomethylation reactions
is interesting only theoretically. However, if C-amino-
methylation alone is desired (see Scheme 1), such a
competition is of practical importance, because the oc-
currence of O-aminomethylation is always possible.
The proposed version of the reaction can also involve
NH acids, namely, dicarboxamides (oxamide and
succinamide), dicarboximides (succinimide and phthal-
imide), cyclic anhydrides of α-amino acids (piperazine-
2,5-dione), and nitrogen-containing heterocycles (benz-
imidazole, benzotriazole, and isatin).
Presumably, these reactions can follow pathway a
or b (Scheme 5).
When all reagents are mixed simultaneously, the
reaction route is determined by the ratio between the
rates of C- and O-aminomethylation. However, the
reaction can be directed to each pathway by changing
the order of mixing the reagents according to equations
a or b. For example, we managed to separate C- and
O-aminomethylation of 2,2-dinitropropane-1,3-diol, i.e.,
the C-aminomethylated product 4 was first isolated and
The reactions of all these compounds with 3-amino-
propanol and formaldehyde afford the corresponding
N-substituted tetrahydro-1,3-oxazines 5—12 (Scheme 7).
The reactions were mostly carried out in a water-
i
alcohol (Pr OH) medium at 50—70 °C for 0.5—2.5 h.
Scheme 6
The product yields were 24—85%.
O N
2
HO
Worse results were obtained in the reactions of
aminoethanol with the above CH and NH acids and
formaldehyde. Only two tetrahydrooxazoles 13 and 14
OH
+ 2
H N
OH
2
–2 H O
2
NO2
(
derived from piperazine-2,5-dione and benzotriazole,
respectively) were isolated in a rather pure state
O N
2
NH
NO2
OH
(
Scheme 8).
HO
NH
The compounds synthesized were identified by
elemental analysis and NMR and IR spectroscopy
Table 1).
Singlets from different methylene groups in nitro
compounds 1 and 3 are close in chemical shifts and thus
4
(
2
–
CH O
2
3
2 H O
2

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06
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
Korepin et al.
Scheme 7
O
N
XH2
+
4 CH O
2
+
2
H N
OH
X
2
N
O
–
4 H O
2
5
—7
O
O
O
N
NH
O
NH
X =
(5);
(6);
(7)
NH
NH
N
O
O
R
N
O
RH
+
2 CH O
+
2
H N
OH
2
–2 H O
2
8
—12
O
O
N
O
O
N
N
N
N
R =
N
(8);
(9);
(10);
N
(11);
O
(12)
N
O
Scheme 8
O
O
OH
O
N
N
HN
H N
+
4 CH O
+
2
2
2
–
4 H O
2
N
N
O
NH
O
O
1
3
N
N
N
OH
N
N
H N
2
+
2 CH O
+
2
–
2 H O
2
N
H
N
O
1
4
difficult to assign. The problem was solved by taking into
account a broadened singlet from a group attached to
the dinitromethylene fragment and the influence of its
electronegativity and magnetic anisotropy.8 For com-
pounds 2, 7, and 13, assignment remains ambiguous.
Chemical Physics, Russian Academy of Sciences. IR spectra
were recorded on a Specord M-82 spectrophotometer.
The starting CH acids and the products of their reactions
with formaldehyde were prepared as described in Refs. 1 and 10.
The starting NH acids and amino alcohols were commercial
chemicals and used without additional purification. Formalde-
hyde was taken in the form of formalin (34%).
The COC and CN(C ) stretching vibrations in the
2
tetrahydrooxazine and tetrahydrooxazole rings are close
in frequency to those in cyclic ethers and tertiary amines.9
In conclusion, it should be noted that the proposed
version of the reaction opens the way to the synthesis of
new N-substituted 1,3-oxazacyclic compounds.
3-(2,2-Dinitropropyl)tetrahydro-1,3-oxazine (1). A solu-
tion of 3-aminopropanol (1.5 g, 20 mmol) in 4 mL water was
added dropwise with stirring at room temperature to a mixture
of 1,1-dinitroethane (2.4 g, 20 mmol) and 12 mL of water.
Then formalin (4 mL, 45 mmol of CH O) was added, and the
2
reaction mixture was kept for 2 h. An oily product crystallized
upon trituration with a glass rod. The crystals were filtered off,
washed with water, and dried. Yield 4.2 g (96%), m.p. 63—65 °C.
Experimental
Recrystallization from a mixture CCl —heptane gave the prod-
4
uct with m.p. 63—65 °C.
1
H NMR spectra were recorded on an NMR spectrometer
3-(2-Bromo-2,2-dinitroethyl)tetrahydro-1,3-oxazine (2) was
obtained as described for compound 1 from 2-bromo-2,2-
dinitroethanol (4.3 g, 20 mmol), 3-aminopropanol (1.5 g,
with a superconducting magnet (294 MHz). This instrument
was designed and manufactured at the Institute of Problems of

A new version of the Mannich reaction
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
107
Table 1. Physicochemical characteristics of N-substituted tetrahydro-1,3-oxazines and oxazolidines
Com- Molecular
Found
Calculated
T /°C
1H
(solvent)
NMRIR
(KBr),
(
%)
m
pound
formula
(
Me Si, δ, J/Hz)
ν/cm–1
4
C
H
N
1
Ñ Í N O
38.03 5.64 19.19
8.36 5.98 19.17
63—65
88—89
87—88
(CD Cl ) 1.64 (br.m, 2 H,
CH CH CH ); 2.11 (s, 3 H, CH );
2 2 2 3
2966, 2946, 2921, 2851,
1458, 1452, 1440, 1346
(CH , CH ); 1561, 1320
3 2
7
13
3
5
2
2
3
2
3
3
4
.94 (t, 2 H, NCH CH , J = 5.0);
2
2
.80 (s, 2 H, CH N);
(NO ); 1221, 1200, 1046,
2
2
.82 (t, 2 H, OCH , J = 4.0);
966, 888 (oxazacycle)
2
.21 (s, 2 H, NCH O)
2
2
3
Ñ Í BrN O 25.47 3.60 14.54
(CDCl ) 1.67 (quint, 2 H,
2970, 2936, 2876, 1475,
1426, 1376, 1367,
6
10
3
5
3
2
5.37 3.55 14.79
CH CH CH , J = 5.7 );
2 2 2
3
3
4
.04 (t, 2 H,NCH CH , J = 5.7 );
1341 (CH ); 1227,
2
2
2
.87 (t, 2 H, OCH CH , J = 5.7);
1199, 1051, 974,
888 (oxazacycle);
775 (C—Br)
2
2
.17, 4.33 (both s, each 2 H,
Br(NO ) CCH N; NCH O)
2
2
2
2
Ñ11Í20N O
43.51 6.58 18.22
(CD Cl ) 1.63 (br.m, 4 H,
2963, 2918, 2861, 1451,
4
6
2
2
4
3.42 6.62 18.41 (decomp.) CH CH CH ); 2.90 (t, 4 H,
1439, 1427 (CH ); 1556,
2
2
2
2
NCH CH , J = 5.0);
1346 (NO ); 1199, 1076,
2
2
2
3
3
4
.80 (t, 4 H, CH CH O, J = 5.0);
1049, 992, 977,
878 (oxazacycle)
2
2
.82 (s, 4 H, C(NO ) CH N);
2
2
2
.15 (s, 4 H, NCH O)
2
4
5
*
Ñ Í N O
38.13 7.29 19.62
65—66
(CD Cl ) 1.72 (quint, 4 H,
CH CH CH , J = 6.0, 5.4 ); 2.68 (t,
2 2 2
3316, 1039 (OH); 3252 sh
(NH); 2942, 2873, 1472,
1465, 1442, 1378, 1348
9
20
4
6
2
2
3
8.57 7.19 19.99
4
3
3
3
H, NHCH CH , J = 6.0 ); 3.10,
2 2
.39 (both br.s, each 2 H; OH; NH);
.62 (s, 4 H, C(NO ) CH );
(CH ); 1569, 1560, 1370
2
(NO ); 3617 (OH);
2
2
2
2
.66 (t, 4 H, CH CH OH, J = 5.4)
1580 (NO ), 1325**
2
2
2
Ñ12Í22N O
50.30 7.81 19.78 142—144 (CD Cl ) 1.65 (m, 4 H,
3335, 1505 (NH); 2945,
2927, 2861, 1448,
4
4
4
4
2
2
5
0.34 7.74 19.57
CH CH CH ); 2.94 (t, 4 H,
2 2 2
NCH CH , J = 5.5); 3.80 (t,4 H,
1385, 1370 (CH );
2
2
2
CH CH O, J = 5.5); 4.31 (s, 4 H,
1673 (C=O); 1211,
1040, 1007, 971,
944, 878 (oxazacycle)
2
2
NCH O); 4.33 (d, 4 H, NHCH ,
2
2
JCH—NH = 5.5); 7.94 (br.t,
2
H, C(O)NH)
6
Ñ14Í26N O
52.74 8.69 17.91 122—124 (CD Cl ) 1.65 (m, 4 H,
3248, 3080, 1550 (NH);
2966, 2957, 2927, 2801,
1481, 1463, 1415,
4
2
2
5
3.00 8.34 17.82
CH CH CH ); 2.52 (s, 4 H, CH CO);
2 2 2 2
2
3
4
4
6
.90 (t, 4 H, NCH CH , J = 5.5);
2 2
.78 (t, 4 H, CH CH O, J = 5.2);
1376 (CH ); 1652
2
2
2
.20 (d, 4 H, NHCH , J
= 5.5);
NH—CH
(C=O); 1208, 1187,
1061, 1049, 971,
866 (oxazacycle)
2987, 2960, 2939, 2873,
2843, 1478, 1460, 1431,
2
.28 (s, 4 H, NCH O);
2
.85 (br.t, 2 H, C(O)NH)
7
8
Ñ14Í24N O
53.53 7.63 17.80 168—170 (CD CN) 1.59 (m, 4 H, CH CH CH );
4
3
2
2
2
5
3.83 7.74 17.93
2.90 (t, 4 H, NCH CH , J = 5.3);
2 2
3
3
4
.78 (t, 4 H, OCH CH , J = 5.3);
1388, 1379, 1370 (CH );
2
2
2
.91 (s, 4 H, NCH C(O));
1667 (C=O); 1220, 1205,
1052, 998, 980, 884
(oxazacycle)
2987, 2969, 2954, 2924,
2864, 2810, 2750, 2726,
1442, 1418, 1409,
2
.29; 4.35 (both s,
each 4 H, NCH N; NCH O)
2
2
Ñ Í N O
54.24 6.92 14.40
4.53 7.12 14.13
64—66
85—87
(CD Cl ) 1.11 (quint, 2 H,
9
14
2
3
2
2
5
CH CH CH , J = 5.1; 4.8); 2.68 (s,
2 2 2
4
H, CH C(O)); 2.92 (t, 2 H,
2
NCH CH , J = 5.1); 3.73 (t,
1388, 1367, 1349 (CH );
2
2
2
2
4
4
H, CH CH O, J = 4.8);
1763, 1697 (C=O); 1223,
1058, 983, 899
(oxazacycle)
2
2
.28 (s, 2 H, NCH O);
2
.42 (s, 2 H, NCH N)
2
9
Ñ13Í14N O
63.13 5.91 11.78
3.40 5.73 11.38
(CD Cl ) 1.65 (quint, 2 H,
3098, 3032, 2993, 1613,
2
3
2
2
6
CH CH CH , J = 5.0); 3.00 (t,
1508, 1466, 728, 713 (Ar);
2960, 2924, 2876, 2843,
1451, 1409, 1358,
2
2
2
2
2
2
H, NCH CH , J = 5.0 ); 3.72 (t,
2 2
H, CH CH O, J = 5.0); 4.38 (s,
2
2
H, NCH O); 4.70 (s, 2 H,
1334 (CH ); 1772, 1706
2
2
NCH N); 7.60—7.90 (m,
(C=O); 1208, 1040, 980,
959, 884 (oxazacycle)
2
4
H, CH, system AA´BB´)
(
to be continued)

1
08
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
Korepin et al.
Table 1 (continued)
Com- Molecular
Found
Calculated
T /°C
1H
(solvent)
NMRIR
(KBr),
ν/cm–1
(
%)
m
pound
formula
(
Me Si, δ, J/Hz)
4
C
H
N
1
1
1
0
1
2
Ñ12Í15N O 66.31 6.64 19.38
58—60
(CD Cl ) 1.68 (br.m, 2 H,
CH CH CH ); 3.02 (t, 2 H,
2 2 2
3095, 2984, 1613, 1502,
1454, 791, 749 (Ar); 2963,
2921, 2903, 2867, 1397,
3
2
2
6
6.18 6.99 19.43
NCH CH , J = 4.8); 3.83 (t, 2 H,
2
2
CH CH O, J = 4.8); 4.41 (s, 2 H,
1379, 1349, 1337 (CH );
2
2
2
NCH O); 5.15 (s, 2 H, NCH N);
1652 (C=N); 1202, 1193,
1046, 1019, 986, 950,
2
2
7
7
.30 (m, 2 H, CH(5), CH(6)); 7.51,
.75 (both d, each 1 H, CH(7), J = 7.0; 878 (oxazacycle)
CH(4), J = 7.0); 7.95 (s, H, NCHN)
Ñ11Í14N O 60.32 6.32 26.01 105—107 (CD CN) 1.60 (quint, 2 H,
3062, 3029, 1616, 1496,
1454, 800, 743 (Ar);
2973, 2951, 2930, 2870,
2837, 1382, 1367,
4
3
6
0.54 6.47 25.67
CH CH CH , J = 5.0 ); 2.98 (t, 2 H,
2 2 2
NCH CH , J = 5.0); 3.70 (t, 2 H,
2
2
OCH CH , J = 5.0); 4.41 (s, 2 H,
2
2
NCH O); 5.63 (s, 2 H, NCH N); 7.41,
1340 (CH ); 1205, 1181,
2
2
2
7
.55 (both dd, each 1 H, CH(6), J = 8.0; 1046, 1001,
CH(5), J = 8.0); 7.75, 8.00 (both d, each 977, 950, 884
1
H, CH(7), J = 8.0; CH(4), J = 8.0)
(oxazacycle)
2978, 2954, 2927, 2849,
Ñ13Í14N O
63.53 5.59 11.10 130—131 (CD CN) 1.70 (quint, 2 H,
2
3
3
6
3.40 5.73 11.37
CH CH CH , J = 4.8); 3.10 (t, 2 H,
1352 (CH ); 1733 (C=O);
2
2
2
2
NCH CH , J = 4.8 ); 3.80 (t, 2 H,
1610, 1508, 1475,
764, 755 (Ar);
1205, 1046,
2
2
CH CH O, J = 4.8); 4.38 (s, 2 H,
2
2
NCH O); 4.70 (s, 2 H, NCH N); 7.10,
2
2
7
.55 (both d, each 1 H, CH(7), J = 8.0; 986, 878
CH(4), J = 8.0); 7.14, 7.63 (both t, each (oxazacycle)
H, CH(6), J = 8.0; CH(5), J = 8.0)
50.13 7.19 19.82 157—159 (CDCl ) 3.06 (t, 4 H, NCH CH , 2946, 2884, 1451, 1396,
1
1
1
3
4
Ñ12Í20N O
4
4
3
2
2
5
0.69 7.09 19.71
J = 6.8 ); 3.75 (t, 4 H, CH CH O,
1336 (CH ); 1657 (C=O);
2
2
2
J = 6.8); 4.17 (s, 4 Í, NCH C(O));
1171, 1011, 981, 869
(oxazacycle)
2
4
.26; 4.37 (both s, each 4 H,
NCH N, OCH N)
2
2
Ñ10Í13N O 58.54 6.10 27.23
96—98
—
3070, 3030, 2985, 1615,
4
5
8.81 5.92 27.43
1495, 1455, 750, 720 (Ar);
2
1
1
945, 2885, 1405, 1390,
365 (CH ); 1185, 1155,
2
005, 985, 875 (oxazacycle)
*
*
An intermediate product.
* A solution in CH Cl , C = 1.7 wt %.
2
2
2
5
0 mmol), and formalin (1.94 mL, 22 mmol of CH O). Yield
Formalin (0.48 mL, 5.5 mmol of CH O) was added dropwise
2
2
.3 g, (93%), m.p. 87—89 °C. Recrystallization from
a
with stirring to a solution of compound 4 (0.7 g, 2.5 mmol) in
3 mL of water. The reaction mixture was kept for 2 h. The
precipitate was filtered off, washed with water, and dried. The
yield of compound 3 was 0.62 g (82%), m.p. 87—88 °C
(decomp.). Its spectral parameters are identical with those of
compound 3 described above.
CCl —heptane mixture gave the product with m.p. 88—89 °C.
,2-Dinitro-1,3-bis(tetrahydro-1,3-oxazino)propane (3). A
solution of 2,2-dinitropropane-1,3-diol (3.32 g, 20 mmol) in
6
3
4
2
mL of water was added with stirring at 2—4 °C to a solution of
-aminopropanol (3 g, 40 mmol) in 5 mL of water. The
reaction mixture was kept for 1 h and, after addition of formalin
3.9 mL, 44 mmol of CH O), for additional 2 h. The precipitate
was filtered off, washed with water, dried, and recrystallized
N,N´-Bis(tetrahydro-1,3-oxazinomethyl)oxamide (5). A
mixture of oxamide (8.8 g, 0.1 mol), Pr OH (60 mL), water
(30 mL), 3-aminopropanol (15 g, 0.2 mol), and formalin
i
(
2
from CCl . Yield 4.4 g (72%), m.p. 87—88 °C (decomp.).
(35.3 mL, 0.4 mol of CH O) was stirred at 70 °C for 2.5 h and
then concentrated in vacuo. Organic material was extracted
4
,6-Dinitro-4,8-diazaundecane-1,11-diol (4) and its reac-
2
6
tion with formaldehyde. A solution of 2,2-dinitropropane-1,3-
diol (3.32 g, 20 mmol) in 6 mL of water was added with stirring
at 0—2 °C to a solution of 3-aminopropanol (2.8 g, 37 mmol)
in 5 mL of water. The reaction mixture was kept for 1.5 h. The
product was extracted with CH Cl , and the extract was washed
from the residue with 100 mL of CHCl . The organic layer was
3
separated, washed with water, and dried over MgSO . The
4
chloroform was removed to give compound 5 (19.8 g, 69%),
m.p. 136—140 °C. Recrystallization from CHCl —CCl gave
3
4
the product with m.p. 142—144 °C.
2
2
with water and dried over MgSO . The solvent was removed
in vacuo, and the residue was twice recrystallized from a
N,N´-Bis(tetrahydro-1,3-oxazinomethyl)succindiamide (6).
A mixture of succindiamide (5.8 g, 50 mmol), water (70 mL),
3-aminopropanol (7.5 g, 0.1 mol), and formalin (17.7 mL,
4
CHCl —CCl mixture. The yield of compound 4 was 0.42 g
3
4
(
8%), m.p. 65—66 °C.
0.2 mol of CH O) was stirred at 70 °C for 0.5 h. The water was
2

A new version of the Mannich reaction
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 1, January, 2001
109
removed in vacuo, and the products were extracted from the
dione (11.4 g, 0.1 mol) was stirred at 70 °C for 3 h. After
removal of the solvent in vacuo, CHCl3 (60 mL) and CH Cl
residue with 80 mL of CHCl . The lower layer was separated,
3
2
2
washed with water, and dried over MgSO . After removal of
the chloroform in vacuo, the residue was recrystallized
(90 mL) were added, and the resulting mixture was stirred. The
lower layer was separated and dried over MgSO . The solvents
4
4
from CHCl —CCl4 to give compound
m.p. 122—124 °C.
6
(3.8 g, 24%),
were removed in vacuo. Ethyl acetate (10 mL), CCl (10 mL),
and Pr OH (5 mL) were added with stirring, and the mixture
3
4
i
1
,4-Bis(tetrahydro-1,3-oxazinomethyl)piperazine-2,5-dione
was kept at –15 °C for 18 h. The precipitate that formed was
filtered off and washed with a mixture of Pr OH with MeOH.
i
(
7). A mixture of piperazine-2,5-dione (5.7 g, 50 mmol),
Pr OH (16 mL), 3-aminopropanol (7.5 g, 0.1 mol), and forma-
lin (17.65 mL, 0.2 mol of CH O) was stirred at 70 °C for 1 h.
i
Yield 1.7 g (6%), m.p. 147—151 °C. Recrystallization from
i
Pr OH gave the product with m.p. 157—159 °C.
2
The resulting solution was cooled to –10 °C and kept for 18 h.
1-(Oxazolidinomethyl)benzotriazole (14). A mixture of
2-aminoethanol (3.1 g, 50 mmol), Pr OH (15 mL), formalin
i
The precipitate that formed was filtered off. The yield of 7 was
i
6
.6 g (42%), m.p. 168—170 °C. Recrystallization from Pr OH
(8.82 mL, 0.1 mol of CH O), and benzotriazole (5.95 g,
2
gave the product with m.p. 168—170 °C.
50 mmol) was stirred at 70 °C for 1 h. The solvents were
N-(Tetrahydro-1,3-oxazinomethyl)succinimide (8). A mix-
ture of succinimide (14.85 g, 0.15 mol), Pr OH (45 mL),
removed in vacuo. CHCl3 (20 mL), CH Cl (20 mL), CCl4
(10 mL), and heptane (30 mL) were added with stirring. The
2 2
i
3
0
-aminopropanol (11.25 g, 0.15 mol), and formalin (26.5 mL,
lower layer was separated and dried over MgSO . The solvents
were removed in vacuo. Pr OH (26 mL) and heptane (6.5 mL)
were added with stirring, and the mixture was kept at –15 °C
4
i
.3 mol of CH O) was stirred at 50 °C for 1 h. The solvent was
2
i
removed in vacuo. Pr OH (30 mL) and heptane (30 mL) were
added to the residue, and the resulting mixture was stirred and
cooled to 0 °C. The precipitate that formed was filtered off.
Yield 22.5 g (76%), m.p. 58—60 °C. Recrystallization from
for 24 h. The precipitate that formed was filtered off. Yield 5.6 g
i
(55%), m.p. 94—98 °C. Recrystallization from Pr OH—MeCN
gave the product with m.p. 96—98 °C.
i
Pr OH—heptane gave the product with m.p. 64—66 °C.
N-(Tetrahydro-1,3-oxazinomethyl)phthalimide (9). A mix-
ture of phthalimide (7.35 g, 50 mmol), Pr OH (22 mL),
-aminopropanol (3.75 g, 50 mmol), and formalin (9 mL,
This work was financially supported by the Inter-
national Scientific and Technical Center (Project
No. 123-94).
i
3
0
.1 mol of CH O) was stirred at 50 °C for 1 h. The solvent was
2
i
removed in vacuo. Pr OH (30 mL) was added to the residue,
and the resulting mixture was stirred and cooled to 0 °C. The
precipitate that formed was filtered off. Yield 6.8 g (55%),
References
i
m.p. 84—86 °C. Recrystallization from Pr OH—heptane gave
1
2
. H. Feuer, G. Bachman, and W. May, J. Am. Chem. Soc.,
954, 76, 5124.
. L. T. Eremenko, D. A. Nesterenko, and N. S. Natsibullina,
Izv. Akad. Nauk SSSR, Ser. Khim., 1970, 1335 [Bull. Acad.
Sci. USSR, Div. Chem. Sci., 1970, 19, 1261 (Engl. Transl.)].
the product with m.p. 85—87 °C.
1
1
-(Tetrahydro-1,3-oxazinomethyl)benzimidazole (10). A
i
mixture of benzimidazole (1.18 g, 10 mmol), Pr OH (14 mL),
3
2
-aminopropanol (0.75 g, 10 mmol), and formalin (1.77 mL,
0 mmol of CH O) was stirred at 70 °C for 2.5 h. The solvent
2
3. H. Feuer and W. A. Swarts, J. Org. Chem., 1962, 27, 1455.
was removed in vacuo. The residue was allowed to solidify at
°C. Recrystallization from CCl —heptane and then from hep-
4
. M. H. Gold, C. R. Wanneman, K. Klager, G. B. Linden,
and M. B. Frankel, J. Org. Chem., 1961, 26, 4729.
0
4
i
tane—Pr OH gave compound 10 (0.69 g (32%), m.p. 58—60 °C.
-(Tetrahydro-1,3-oxazinomethyl)benzotriazole (11). A mix-
ture of benzotriazole (11.9 g, 0.1 mol), Pr OH (40 mL),
5
6
. K. Baum and W. Maurice, J. Org. Chem., 1962, 27, 2231.
. K. Lenard, Magyar Kem. Foly. (Ung. Z. Chem.), 1956, 62,
1
i
1
89; 1957, 63, 5059.
3
0
-aminopropanol (7.5 g, 0.1 mol), and formalin (17.65 mL,
.2 mol of CH O) was stirred at 50 °C for 0.5 h, cooled to 0 °C,
7
8
. H. Hellmann and G. Opitz, α-Aminoalkylierung, Verlag
Chemie GMBH, Weinheim, 1960, 336 pp.
. N. G. Yunda, I. Yu. Kozyreva, G. V. Lagodzinskaya, and
G. B. Manelis, Izv. Akad. Nauk SSSR, Ser. Khim., 1983,
2
and kept for 1 h. The precipitate that formed was filtered off.
The yield of 11 was 18.5 g (85%), m.p. 105—107 °C. Recrystal-
lization from water gave the product with m.p. 105—107 °C.
1
1
772 [Bull. Acad. Sci. USSR, Div. Chem. Sci., 1983, 32,
603 (Engl. Transl.)].
1
-(Tetrahydro-1,3-oxazinomethyl)isatin (12). A mixture of
i
isatin (2.94 g, 20 mmol), Pr OH (29 mL), 3-aminopropanol
1.5 g, 20 mmol), and formalin (3.53 g, 40 mmol of CH O) was
9
. N. B. Colthup, L. H. Daly, and S. E. Wiberley, Introduction
to Infrared and Raman Spectroscopy, Academic Press, New
York, 1964.
(
2
stirred at 50 °C for 1 h and cooled to 15 °C. The pre-
cipitate that formed was filtered off. Yield 3.9 (79%),
g
1
0. H. E. Ungnade and L. W. Kissinger, Tetrahedron, 1963,
19, 121.
m.p. 128—130 °C. Recrystallization from CCl gave the product
4
with m.p. 130—131 °C.
1
,4-Bis(oxazolidinomethyl)piperazine-2,5-dione (13). A
i
mixture of 2-aminoethanol (12.2 g, 0.2 mol), Pr OH (24 mL),
formalin (35.5 mL, 0.4 mol of CH O), and piperazine-2,5-
Received December 28, 1999;
in revised form September 22, 2000
2