Synthesis of 2-substituted 1-tosyl-3-(1-tosyliminoalkyl)imidazolidines and-hexahydropyrimidines

Article abstract of DOI:10.1007/s11172-006-0350-8

Reactions of N-tosylimidoyl chlorides with the Schiff bases of the general formula TsNH(CH₂)_nN=CHR (n = 2 or 3; R = Prⁱ, 4-MeOC₆H₄, 4-Me₂NC₆H₄, and 3-O₂NC

Full text of DOI:10.1007/s11172-006-0350-8

Russian Chemical Bulletin, International Edition, Vol. 55, No. 5, pp. 903—906, May, 2006
903
Synthesis of 2ꢀsubstituted 1ꢀtosylꢀ3ꢀ(1ꢀtosyliminoalkyl)imidazolidines
and ꢀhexahydropyrimidines
G. V. Pokhvisnevaꢀ and O. A. Luk´yanov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5328
Reactions of Nꢀtosylimidoyl chlorides with the Schiff bases of the general formula
TsNH(CH2)nN=CHR (n = 2 or 3; R = Pri, 4ꢀMeOC6H4, 4ꢀMe2NC6H4, and 3ꢀO2NC6H4)
afforded 2ꢀsubstituted 1ꢀtosylꢀ3ꢀ(1ꢀtosyliminoalkyl)imidazolidines (n = 2) or ꢀhexahydroꢀ
pyrimidines (n = 3).
Key words: Nꢀtosylimidoyl chlorides, imidazolidines, hexahydropyrimidines, Schiff bases,
heterocyclization, diamines.
Earlier,1 we have proposed a method for the synthesis
Scheme 2
of 2ꢀsubstituted N,N´ꢀdiacylated or ꢀdisulfonylated imidꢀ
azolidines (DI). The method involves baseꢀcatalyzed cyꢀ
clization of the Schiff bases 1 (prepared from Nꢀmonoꢀ
acylated/sulfonylated ethylenediamines) in the presence
of acylating/sulfonylating agents (Scheme 1).
Scheme 1
1
n
R
3
X
R
R1, R3 = AlkCO, ArCO, AlkSO2, ArSO2; R2 = Alk, Ar
a
b
c
d
e
f
2
2
2
2
3
3
Pri
a
b
c
d
e
f
H
Cl
H
Cl
Cl
H
Pri
Pri
4ꢀMeOC6H4
4ꢀMe2NC6H4
3ꢀO2NC6H4
Pri
Variation in any of the three components (acyl/sulfoꢀ
nyl substituent in the starting diamine, aldehyde compoꢀ
nent in imine 1, and especially acylating/sulfonylating
agent) affords a variety of DI. Previously,1 at the final
step of DI synthesis, we have employed carboxylic, sulꢀ
fonic, and carbamic anhydrides and acid chlorides and
chloroformates. Here we used the known2,3 Nꢀtosylꢀ
imidoyl chlorides 2. Since compounds 2 may be regarded
as analogs of acid chlorides, in which the C=O fragꢀ
ment is replaced by the C=N—Ts fragment, we hoped
to use them as cyclization agents. Indeed, imines 1a—d
prepared from Nꢀtosylethylenediamine and aldehydes,
underwent cyclization in reactions with compounds 2
in MeCN in the presence of Et3N to give 2ꢀsubstiꢀ
tuted 1ꢀtosylꢀ3ꢀ(1ꢀtosyliminoalkyl)imidazolidines 3a—g
(Scheme 2).
4ꢀMeOC6H4
4ꢀMeOC6H4
4ꢀMe2NC6H4
3ꢀO2NC6H4
3ꢀO2NC6H4
3ꢀO2NC6H4
g
Cl
n = 2 (3a—g), 3 (4a—c)
2: X = H (a), Cl (b)
4: X = H, R = Pri (a); X = Cl, R = Pri (b); X = H, R = 3ꢀO2NC6H4 (c)
ents in the benzene ring (e.g., 3ꢀnitrobenzaldehyde deꢀ
rivative 1d), which have been reported1 to form no
imidazolidines in reactions with acid chlorides. This proꢀ
cess may involve either preliminary synthesis of imines 1
(procedure A) or their in situ formation (procedure B),
which is convenient with oily and difficultꢀtoꢀcrystallize
compounds 1.
The reaction easily occurred at room temperature,
even with imines 1 prepared from Nꢀtosylethylenediamine
and aldehydes containing electronꢀwithdrawing substituꢀ
Imidoyl chlorides 2a,b also reacted with Nꢀtosylꢀ
trimethylenediamine derivatives 1e,f, yielding hexahydroꢀ
pyrimidines 4a—c (see Scheme 2).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 872—875, May, 2006.
1066ꢀ5285/06/5505ꢀ0903 © 2006 Springer Science+Business Media, Inc.

904
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 5, May, 2006
Pokhvisneva and Luk´yanov
Table 1. Yields, melting points, and elemental analysis data for 2ꢀsubstituted imidazolidines 3a—g and
5a—c and hexahydropyrimidines 4a—c and 6
Comꢀ Yield
pound (%)
M.p.
/°С
Found
Calculated
Molecular
formula
(%)
С
Н
Cl
—
N
S
3a
3b
3c
3d
3e
3f
47
65
78
30
82
59
61
50
49
70
42
60
65
69
150—151
146—148
155—157
164—166
188—190
144—145
164—166
188—190
184—186
214—216
116—118
146—148
175—177
159—161
56.72
57.00
6.39
6.30
9.19
9.06
13.74
13.83
C22H29N3O4S2
C22H28ClN3O4S2
C26H29N3O5S2
C26H28ClN3O5S2
C27H31ClN4O4S2
C25H26N4O6S2
C25H25ClN4O6S2
C23H31N3O4S2
C23H30ClN3O4S2
C26H28N4O6S2
C29H34N4O4S2
C26H36N4O5S2
C31H38N4O5S2
C27H38N4O5S2
53.15
53.05
5.96
5.67
7.03
7.12
8.20
8.44
12.70
12.87
59.30
59.18
5.56
5.54
—
7.90
7.96
12.18
12.15
55.97
55.56
5.15
5.02
6.14
6.31
7.37
7.48
11.10
11.41
56.05
56.39
5.39
5.43
5.98
6.16
9.88
9.74
11.12
11.15
55.27
55.34
4.78
4.83
—
10.35
10.33
11.77
11.82
3g
4a
4b
4c
5a
5b
5c
6
52.06
52.03
4.40
4.37
6.41
6.14
9.96
9.71
10.87
11.11
57.46
57.84
6.54
6.54
—
8.94
8.80
13.22
13.42
53.71
53.95
6.23
5.90
6.68
6.92
8.06
8.21
12.18
12.52
56.27
56.10
5.01
5.07
—
—
—
—
—
10.22
10.06
11.27
11.52
60.88
61.24
6.49
6.38
10.17
9.85
10.97
11.27
56.99
57.43
5.75
5.71
10.11
10.30
11.45
11.79
61.02
60.96
6.60
6.27
9.00
9.17
10.17
10.50
57.36
57.63
6.51
6.81
9.81
9.96
10.99
11.39
Attempted analogous reactions with the Schiff bases
prepared from Nꢀbenzoylethylenediamine gave mixtures
of unidentified compounds.
Earlier,1 DI containing Nꢀchloroacetyl substituents
have been found to react with amines through the reꢀ
placement of the Cl atom. Since products 3 and DI are
similar in structure (and probably in reactivity), we carꢀ
ried out such reactions with compounds 3b,d and 4b
(Scheme 3) and obtained the corresponding amino deꢀ
The structures of compounds 3a—g were proved by
elemental analysis and 1H NMR spectroscopy. The yields
and characteristics of imidazolidines 3a—g are given in
Table 1; their spectroscopic data are presented in Table 2.
We believed that a certain structural analogy between
imidoyl chlorides 2a,b and acetyl/chloroacetyl chlorides
should lead to the structural similarity of the resulting
compounds 3 and cyclic DI amides, respectively. This
Scheme 3
1
was confirmed by the H NMR spectra of compounds 3
and DI with Nꢀacyl substituents.1 In both cases, the signal
for the H(2) proton appears as one or two doublets at
δ 5.0—5.5 (R = Pri) or as one or two singlets at δ 6.3—6.8
(R = Ar). When moving from imidazolidines to hexaꢀ
hydropyrimidines (i.e., with an extension of the heteroꢀ
cycle by a methylene unit), the signal for the H(2) proton
is shifted downfield (δ 5.5—6.5 for 4a,b and δ 7.6 for 4c).
Compound
n
R1
NR2R3
5a
5b
5c
6
2
2
2
3
Pri
Pri
NHCH2Ph
Morpholinꢀ4ꢀyl
Piperidinꢀ1ꢀyl
Morpholinꢀ4ꢀyl
4ꢀMeOC6H4
Pri

3ꢀ(1ꢀTosyliminoalkyl)imidazolidines
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 5, May, 2006
905
Table 2. 1H NMR spectra of 2ꢀsubstituted imidazolidines 3a—g and 5a—c and hexahydropyrimidines 4a—c and 6
Comꢀ
pound
Solvent
δ (J/Hz)
Me
CH2
CH
H arom.
3a
3b
(CD3)2CO
(CD3)2CO
0.85—1.10 (m, 6 H);
2.00, 2.40, 2.45
(all s, 3 H each)
0.95 (m, 6 H);
2.40, 2.50 (both s,
3 H each)
2.85, 3.15 (both m, 1 H);
3.50—3.80 (m, 2 H);
4.05 (m, 1 H)
2.50 (m, 1 H);
5.30, 5.55 (both d, (all d, 2 H each,
1 H, J = 9.3)
2.10 (m, 1 H);
5.55 (d, 1 H,
J = 9.3)
7.30, 7.40, 7.65, 7.85
J = 8.4)
3.25 (m, 1 H); 3.75
(m, 2 H); 4.15 (m, 1 H);
4.40, 4.55 (both d,
1 H each, J = 6.0)
2.65—4.50 (m, 4 H)
7.25, 7.45, 7.65, 7.85
(all d, 2 H each,
J = 8.4)
3c
3d
3e
CDCl3
2.12, 2.32 (both s, 3 H);
2.40—2.50 (m, 6 H);
3.80 (s, 3 H)
6.42, 6.85
(both s, 1 H)
6.80—7.72
(m, 12 H)
(CD3)2CO
CDCl3
2.40 (s, 6 H);
3.75 (s, 3 H)
2.75—3.90 (m, 4 H);
4.45, 4.70 (both d,
1 H each, J = 12.9)
3.20—4.05 (m, 4 H);
4.70, 5.20 (both d,
1 H each, J = 12.7)
3.20—4.20 (m, 4 H)
6.62 (s, 1 H)
6.75 (s, 1 H)
6.80, 7.20, 7.55, 7.70
(all d, 2 H each,
J = 8.4); 7.30 (m, 4 H)
2.40, 2.45, 2.95, 3.00
(all s, 3 H each)
6.55—7.80
(m, 12 H)
3f
(CD3)2CO
(CD3)2CO
2.00, 2.40, 2.45
(all s, 3 H each)
2.40, 2.45
6.65, 6.80
(both s, 1 H)
6.60 (s, 1 H)
7.20—8.25
(m, 12 H)
7.20—8.15
(m, 12 H)
3g
3.55—4.20 (m, 4 H);
4.65, 4.75 (both d,
1 H each, J = 12.7)
1.25—1.40 (m, 2 H);
3.20—3.95 (m, 4 H)
(both s, 3 H each)
4a
4b
CDCl3
0.80, 0.90 (both d, 3 H,
J = 6.8); 1.05 (d, 3 H,
J = 6.8); 2.33, 2.69
(both s, 3 H); 2.42,
2.43 (both s, 3 H each)
0.72, 0.98 (both d, 3 H
each, J = 6.8); 2.40,
2.45 (both s, 3 H)
1.70 (m, 1 H);
5.50, 6.45
(both d, 1 H,
J = 12.5)
7.25—7.35 (m, 4 H);
7.61, 7.78, 7.95
(all d, 4 H, J = 8.4)
(CD3)2CO
1.00—1.35 (m, 2 H);
3.34—3.95 (m, 4 H);
4.70 (s, 2 H)
2.00 (m, 1 H);
6.35 (d, 1 H,
J = 13.5)
7.32, 7.42, 7.75, 7.95
(all d, 2 H each,
J = 8.0)
4с
5a
(CD3)2CO
CDCl3
2.35, 2.73 (both s, 3 H
each); 2.45 (s, 6 H)
0.95 (m, 6 H); 2.45,
2.46 (both s, 3 H each)
1.20—1.35 (m, 2 H);
3.05—4.00 (m, 4 H)
3.12—4.10 (m, 8 H)
7.10, 7.60
7.21—8.25
(m, 12 H)
(both s, 1 H)
2.30 (m, 1 H);
5.55 (d, 1 H,
J = 8.0)
7.12—7.38 (m, 9 H);
7.60, 7.80 (both d,
2 H each, J = 10.0)
7.30—7.45 (m, 4 H);
7.68, 7.85 (both d,
2 H each, J = 10.0)
6.75—7.85
5b
5c
6
(CD3)2CO
CDCl3
0.95 (m, 6 H); 2.45,
2.46 (both s, 3 H each)
2.30 (m, 4 H);
2.70—4.10 (m, 10 H)
2.00 (m, 1 H);
5.60 (d, 1 H,
J = 7.4)
2.42, 2.47, 3.83
(all s, 3 H each)
1.34—1.70 (m, 6 H);
2.20—2.55 (m, 4 H);
2.80—4.05 (m, 6 H)
1.28—1.60 (m, 2 H);
2.25—2.55 (m, 4 H);
3.15—4.20 (m, 10 H)
6.70, 7.50
(both s, 1 H)
(m, 12 H)
(CD3)2CO
0.78, 0.98 (both d, 3 H
each, J = 6.8); 2.39,
2.43 (both s, 3 H each)
2.40 (m, 1 H);
6.30 (d, 1 H,
J = 11.0)
7.20, 7.33, 7.65, 7.90
(all d, 2 H each,
J = 9.0)
rivatives 5a—c and 6. Their structures were proved by
elemental analysis and 1H NMR spectroscopy. The yields,
characteristics, and spectroscopic data for compounds
5a—c and 6 are given in Tables 1 and 2.
Thus, with imidoyl chlorides 2 as cyclization agents,
we obtained a number of previously unknown 2ꢀsubstiꢀ
tuted 1ꢀtosylꢀ3ꢀ(1ꢀtosyliminoalkyl)imidazolidines and
ꢀhexahydropyrimidines.
Experimental
1
H NMR spectra were recorded on a Bruker AMꢀ300 inꢀ
strument. Melting points were determined on a Kofler hot stage.
Commercial chemicals were used freshly distilled or recrystalꢀ
lized. The starting imines 1 1 and imidoyl chlorides 2 2—4 were
prepared according to known procedures. The synthesis of
Nꢀtosylethylenediamine has been described earlier.5

906
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 5, May, 2006
Pokhvisneva and Luk´yanov
NꢀTosyltrimethylenediamine. A solution of tosyl chloride
or 4c (0.44 mmol) in anhydrous MeCN (3 mL). The reaction
mixture was kept at 20 °C for 6 h, diluted with water, and left
for ~24 h. The precipitate that formed was filtered off, dried in
air, and recrystallized from EtOH. This procedure was used to
obtain 3ꢀ(2ꢀbenzylaminoꢀ1ꢀtosylimino)ethylꢀ2ꢀisopropylꢀ1ꢀtosylꢀ
imidazolidine (5a), 2ꢀisopropylꢀ3ꢀ[2ꢀ(morpholinꢀ4ꢀyl)ꢀ1ꢀtosylꢀ
imino]ethylꢀ1ꢀtosylimidazolidine (5b), 2ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀ
[2ꢀ(piperidinꢀ1ꢀyl)ꢀ1ꢀtosylimino]ethylꢀ1ꢀtosylimidazolidine (5c),
and 2ꢀisopropylꢀ3ꢀ[2ꢀ(morpholinꢀ4ꢀyl)ꢀ1ꢀtosylimino]ethylꢀ1ꢀ
tosylhexahydropyrimidine (6).
(6.8 g, 3.5 mmol) in benzene (30 mL) was added dropwise for
1 h to stirred trimethylenediamine (7.9 g, 10.7 mmol, 8.9 mL) in
benzene (20 mL). The reaction mixture was stirred for 3 h. The
precipitate that formed was filtered off, washed with benzene
(10 mL) and cold water (10 mL), and recrystallized from water.
The yield of Nꢀtosyltrimethylenediamine was 4.2 g (52%), m.p.
113—115 °C (cf. Ref. 6: m.p. 112—113 °C). The residue that
was insoluble in hot water was identified as N,N´ꢀditosyltriꢀ
methylenediamine (2 g, 16%), m.p. 147—149 °C.
2ꢀArylꢀ1ꢀtosylꢀ3ꢀ(1ꢀtosyliminoalkyl)imidazolidines 3c—g
and 2ꢀ(3ꢀnitrophenyl)ꢀ1ꢀtosylꢀ3ꢀ(1ꢀtosyliminoethyl)hexahydroꢀ
pyrimidine (4c) (general procedure A). Triethylamine (1 mmol)
and imidoyl chloride 2 (1 mmol) were added to a stirred solution
or suspension of imine 1b—d,f (1 mmol) in anhydrous MeCN
(5 mL). The reaction mixture was stirred at 20 °C for 3—4 h and
then diluted with water. The precipitate that formed was filꢀ
tered off, washed with water, dried in air, and recrystallized
from EtOH.
2ꢀIsopropylꢀ1ꢀtosylꢀ3ꢀ(1ꢀtosyliminoalkyl)imidazolidines 3a,b
and 2ꢀisopropylꢀ1ꢀtosylꢀ3ꢀ(1ꢀtosyliminoalkyl)hexahydropyriꢀ
midines 4a,b (general procedure B). Isobutyraldehyde (1 mmol)
was added to a solution of Nꢀtosylethylenediamine or Nꢀtosylꢀ
trimethylenediamine (1 mmol) in anhydrous MeCN (5 mL).
The reaction mixture was kept at 20 °C for 1 h and Et3N (1 mmol)
and imidoyl chloride 2 (1 mmol) were added. The following
steps in this procedure were the same as described above.
Reactions of chloromethyl derivatives 3b,d and 4c with priꢀ
mary and secondary amines (general procedure). An appropriate
amine (0.9 mmol) was added to a solution of compound 3b,d
References
1. G. V. Pokhvisneva and O. A. Luk´yanov, Izv. Akad. Nauk,
Ser. Khim., 2000, 896 [Russ. Chem. Bull., Int. Ed., 2000,
49, 894].
2. A. E. Kretov and M. M. Kremlev, Ukr. Khim. Zh. [Ukr.
Chem. J.], 1959, 25, 482 (in Russian).
3. V. L. Dubina, L. I. Shebitchenko, and G. I. Belov, Vopr.
Khim. Khim. Tekhnol., 1983, 72, 79 (in Russian).
4. A. E. Kretov, Ukr. Khim. Zh. [Ukr. Chem. J.], 1957, 23, 344
(in Russian).
5. A. V. Kirsanov and N. A. Kirsanova, Zh. Obshch. Khim., 1962,
32, 887 [J. Gen. Chem. USSR, 1962, 32 (Engl. Transl.)].
6. F. Veznik, A. Guggishberg, and M. Hesse, Helv. Chim. Acta,
1991, 74, 654.
Received January 23, 2006;
in revised form April 21, 2006