A practical synthesis of new S,N-disubstituted derivatives of 5-(4-methylpiperidino)methyl-2-thiouracil

Article abstract of DOI:10.1016/j.tetlet.2008.06.079

5-(4-Methylpiperidino)methyl-2-thiouracil (1) has been obtained via the Mannich reaction between 2-thiouracil, paraformaldehyde, and a cyclic secondary amine such as 4-methylpiperidine (4-MP) in ethanol. New S,N(1)-di-o-(m- and p-)bromo-(nitro-) benzyl-substituted derivatives have been synthesized successfully in the reactions of 1 with the corresponding o-(m- and p-)bromobenzyl bromides or o-(m- and p-) nitrobenzyl chlorides in DMF solution in the presence of K₂CO₃. The opposite method of synthesis, that is, the reaction between 2-o-(m- and p-)bromobenzylthio-1-o-(m- and p-)bromobenzyluracils and 2-o-(m- and p-)nitrobenzylthio-1-o-(m- and p-) nitrobenzyluracils (8), with paraformaldehyde and 4-methylpiperidine in ethanol failed, indicating the important role of the enol form of 2-thiouracil for the Mannich reaction to be successful.

Full text of DOI:10.1016/j.tetlet.2008.06.079

Tetrahedron Letters 49 (2008) 5319–5321
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Tetrahedron Letters
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A practical synthesis of new S,N-disubstituted derivatives
of 5-(4-methylpiperidino)methyl-2-thiouracil
*
_
Tomasz Pospieszny , Elzbieta Wyrzykiewicz
Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 October 2007
Revised 5 June 2008
Accepted 17 June 2008
Available online 21 June 2008
5-(4-Methylpiperidino)methyl-2-thiouracil (1) has been obtained via the Mannich reaction between
2-thiouracil, paraformaldehyde, and a cyclic secondary amine such as 4-methylpiperidine (4-MP) in
ethanol. New S,N(1)-di-o-(m- and p-)bromo-(nitro-) benzyl-substituted derivatives have been synthe-
sized successfully in the reactions of 1 with the corresponding o-(m- and p-)bromobenzyl bromides or
o-(m- and p-) nitrobenzyl chlorides in DMF solution in the presence of K2CO3. The opposite method of
synthesis, that is, the reaction between 2-o-(m- and p-)bromobenzylthio-1-o-(m- and p-)bromobenzyl-
uracils and 2-o-(m- and p-)nitrobenzylthio-1-o-(m- and p-) nitrobenzyluracils (8), with paraformalde-
hyde and 4-methylpiperidine in ethanol failed, indicating the important role of the enol form of
2-thiouracil for the Mannich reaction to be successful.
Ó 2008 Elsevier Ltd. All rights reserved.
The thio analogs of pyrimidine bases, including 2-thiouracil, are
minor components of t-RNA. Their S-, N-, or S,N-disubstituted ana-
logs have shown therapeutic properties, especially antiviral, anti-
thyroid, and antitumor activities.1 The prototropic tautomerism
of 2-thiouracil has attracted much attention in the last decade.
The tautomeric equilibrium of 2-thiouracil determines its chemo-
and regioselectivity, and depends on the temperature and on
whether the 2-thiouracil is in solution or in the solid state.2
This Letter reports the synthesis and physicochemical
properties of new, 5-(4-methylpiperidino)methyl-2-thiouracil (1),
2-o-(m- and p-)bromobenzylthio-1-o-(m- and p-)bromobenzyl-5-
(4-methylpiperidino)methyluracils (2–4), and 2-o-(m- and p-)
nitrobenzylthio-1-o-(m- and p-)nitrobenzyl-5-(4-methylpiperidi-
A series of S,N(1)-di-o-(m- and p-)bromo-(nitro-)benzyl-substi-
tuted derivatives were synthesized regioselectively via the reaction
of 1 with o-(m- and p-)bromobenzyl bromides or o-(m- and p-)-
nitrobenzyl chlorides in dry DMF solution in the presence of
K2CO3 at room temperature for 24 h (Scheme 1). These compounds
were not produced from 2-o-(m- and p-)bromobenzylthio-1-o-(m-
and p-)bromobenzyluracils and 2-o-(m- and p-)nitrobenzyl-thio-1-
o-(m- and p-)nitrobenzyluracils (8), when heated with paraformal-
dehyde and 4-methylpiperidine in ethanol (Scheme 2).
The mechanism of the well-known Mannich reaction involves
nucleophilic attack of the free electrons of the nitrogen atom of
4-methylpiperidine on the carbonyl atom of formaldehyde, leading
to formation of an intermediate formaldehyde-amine adduct.5 This
adduct is a very good aminomethylation agent. In the next step, the
adduct reacts with the lactam-thione form of 2-thiouracil to give
C-5-substituted derivatives of 2-thiouracil.6 Compounds 8 cannot
lose an N-hydrogen because the N(1) atom is substituted with an
o-(m- and p-)bromo- or nitrobenzyl group, and this must prevent
the Mannich reaction taking place.
no)methyluracils (5–7). Compound
1 was synthesized via a
Mannich reaction of 2-thiouracil, paraformaldehyde, and 4-meth-
ylpiperidine. The structures of all the compounds obtained were
determined by examining their 1H and 13C NMR, FT-IR, UV/VIS,
EI-MS as well as ESI-MS spectra and elemental analyses.
Previously, Mannich reactions using 2-methylthio-6-methyl-
uracil or 6-methyl-2-thiouracil with 40% formalin, glacial acetic
acid, and piperidine in ethanol had given 2-methylthio-5-meth-
ylpiperidino-6-methyluracil or 6-methyl-5-methylpiperidino-
2-thiouracil, respectively, in low yields.3 An antimetabolite of
thymine, 5-morpholinomethyl-2-thiouracil (MMTU), had been
synthesized via the Mannich reaction of 2-thiouracil, formalde-
hyde, and morpholine in ethanol as a solvent.4 We used this meth-
od, with some modifications, to prepare compound 1.
The reaction of 5-(4-methylpiperidino)methyl-2-thiouracil (1)
with relatively soft o-(m- and p-)bromobenzyl bromide electro-
philes or hard o-(m- and p-)nitrobenzyl chloride electrophiles in
DMF at room temperature led regioselectively to 2-o-(m- and
p-)bromobenzylthio-1-o-(m- and p-)bromobenzyl-5-(4-methylpi-
peridino)methyl uracils (2–4) and 2-o-(m- and p-)nitrobenzyl-
thio-1-o-(m- and p-)nitrobenzyl-5-(4-methylpiperidino)methyl
uracils (5–7).
The 1H NMR spectra of compounds 1–7 in DMSO-d6 showed a
characteristic two-hydrogen singlet in the range 3.11–3.37 ppm,
assigned to the methylene protons C–CH2–N, and a one hydrogen
singlet in the range 7.23–8.59 ppm for C6–H of the 2-thiouracil
* Corresponding author. Tel.: +48 0618291252.
E-mail address: tposp@amu.edu.pl (T. Pospieszny).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.079

5320
T. Pospieszny, E. Wyrzykiewicz / Tetrahedron Letters 49 (2008) 5319–5321
O
CH3
O
8
7
4
H
S
O
H
H
S
5
9
EtOH
reflux
N
3 N
N
+ H
C
+
10
11
6
N
H
N
H
2
N1
H
CH3
(1)
O
N
R2
H2C
N
N
DMF
+
S
CH3
(1)
K2CO3
R1
R1
R1
R1 = o-, m-, p-Br (2-4)
R1 = o-, m-, p-Br; R2=Br
R1 = o-
,
m
-, p
-NO2; R2=Cl
R1 = o-
,
m-,
p
-NO2 (5-7)
Scheme 1.
O
N
O
N
CH3
N
S
O
N
+ H
C
+
H
S
N
CH3
N
H
R1
R1
R1
R1
(8)
Scheme 2.
ring. The 1H NMR spectra of compounds 2–7 in DMSO-d6 showed
characteristic singlets in the range 4.45–4.58 ppm and 4.91–
5.21 ppm, assigned to the S–CH2 and N1–CH2 protons, respectively.
The protons of the o-, m-, and p-bromo- or o-, m-, and p-nitrosub-
stituted benzyl rings gave signals in the range 7.27–8.33 ppm.
The FT-IR spectra of all the compounds in KBr tablets revealed
two strong, characteristic bands in the region 1669–1641 cmꢀ1
Swaney, S. M.; Poppe, S. M.; Morris, J.; Tarpley, W. G.; Thomas, R. C. J. Med. Chem.
1998, 41, 3793–3803.
2. For example: (a) Civcir, P. Ü. J. Mol. Struct. (Theochem) 2000, 532, 157–169; (b)
Moustafa, H.; El-Taher, S.; Shibil, M. F.; Hilal, R. Int. J. Quant. Chem. 2002, 87, 378–
381; (c) Leszczyn´ ski, J. Int. J. Quant. Chem.: Quant. Biol. Symp. 1991, 18, 9–18; (d)
´
Les, A.; Adamowicz, L. J. Am. Chem. Soc. 1990, 112, 1504–1509; (e) Marino, T.;
Russo, N.; Sicilia, E.; Toscano, M. J. Quant. Chem. 2001, 82, 44–52; (f) Civcir, P. U. J.
Phys. Org. Chem. 2001, 14, 171–179; (g) Contreras, J. G.; Alderete, J. B. J. Phys. Org.
Chem. 1995, 8, 395–399; (h) Nowak, M. J.; Rostkowska, H.; Lapinski, L.;
Leszczynski, J.; Kwiatkowski, J. S. Spectrochim. Acta, Part A 1991, 47, 339–353.
3. Snyder, H. R.; Foster, H. M.; Nussberger, G. A. J. Am. Chem. Soc. 1953, 76, 2441–
2444.
and 1587–1541 cmꢀ1, assigned to
m(C4@O) and m(C5@C6), respec-
tively. The most characteristic peaks in the FT-IR spectra of water-
free 2–7 in KBr pellets were the bands at 2871–2863 cmꢀ1, 2951–
4. Kamalakannan, P.; Venkappayya, D.; Balasubramanian, T. J. Chem. Soc., Dalton
Trans. 2002, 3381–3391.
2926 cmꢀ1, and 1448–1427 cmꢀ1, assigned to
m(N–CH2), m(S–CH2),
5. For example: (a) Cordova, A. Acc. Chem. Res. 2004, 37, 102–112; (b) Kobayashi, S.;
Ueno, M. Comprehensive Asymmetric Catalysis, 2004; supplement Vol. 1, pp 143–
150.; (c) Smith, M. B.; March, J. March’s Advanced Organic Chemistry, 5th ed.; John
Wiley and Sons: New York, 2001. p 1189; (d) List, B. J. Am. Chem. Soc. 2000, 122,
9336–9337; (e) Padwa, A.; Bur, S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett
2002, 851–862; (f) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004, 37,
580–591.
6. Huang, Y.; Kenttämaa, H. J. Am. Chem. Soc. 2003, 125, 9878–9889.
7. (a) General procedure for the synthesis of 1: a mixture of 2-thiouracil (12.8 g),
paraformaldehyde (3.0 g), and 4-methylpiperidine (11.8 ml) was suspended in
400 ml of ethanol (99.8%) and refluxed for 48 h. The homogeneous solution
obtained was filtered and concentrated on a rotary evaporator to 200 ml. The
reaction mixture was kept at room temperature for 24 h. The precipitated solid
was isolated by filtration, dried at room temperature, and recrystallized from
methanol. (b) General procedure for the synthesis of 2–7: a mixture of K2CO3
(0.17 g) and 5-(4-methylpiperidino)methyl-2-thiouracil (1) (0.3 g) in 10 ml of
dry DMF was stirred at room temperature for 2 h. Next, to the mixture, o-(m- or
p-)bromobenzyl bromide (0.77 g) or o-(m- or p-)nitrobenzyl chloride (0.53 g)
was added. After stirring at room temperature for 24 h, 10 ml of distilled water
was added. The reaction mixture was kept at room temperature for 24 h. The
oily organic layer was separated, triturated with dry diethyl ether (20 ml), and
left for 24 h in a refrigerator. The precipitate of 2–7 was collected by filtration
and crystallized from methanol. The spectral and elemental data of compounds
1–7 are given below.
and d(S–CH2), respectively.
In conclusion, 5-(4-methylpiperidino)methyl-2-thiouracil (1)
was synthesized via a Mannich reaction of 2-thiouracil, formalde-
hyde, and 4-methylpiperidine. From this, six new compounds
2-o-(m- and p-)bromobenzylthio-1-o-(m- and p-)bromobenzyl-5-
(4-methylpiperidino)methyl uracils (2–4) and 2-o-(m- and p-)
nitrobenzylthio-1-o-(m- and p-)nitrobenzyl-5-(4-methylpiperidi-
no)methyl uracils (5–7) were prepared.7
References and notes
1. For example: (a) De Clercq, E.; Balzarini, J. Il Farmaco 1995, 50, 735–747; (b)
Tanaka, H.; Takashima, H.; Ubasawa, M.; Sekiya, K.; Inouye, N.; Baba, M.;
Shigeta, S.; Walker, R. T.; De Clercq, E. J. Med. Chem. 1995, 38, 2860–2865; (c)
Crooks, J. In Side Effects of Drugs; Meyler, L., Herzheimer, A., Eds.; Expertia
Medica; Elsevier: Amsterdam, 1972; p 573; (d) Barth, R. F.; Soloway, A. H.;
Fairchild, R. G. Cancer Res. 1990, 50, 1061–1070; (e) Tjarks, W.; Gabel, D. J. Med.
Chem. 1991, 34, 315–319; (f) Hawthorne, M. F. Angew. Chem. 1993, 105, 997–
1033; (g) Nugent, R. A.; Schlachter, S. T.; Murphy, M. I.; Cleek, G. J.; Poel, T. J.;
Wishka, D. G.; Graber, D. R.; Yagi, Y.; Kaiser, B. J.; Olmsted, R. A.; Kopta, L. A.;

T. Pospieszny, E. Wyrzykiewicz / Tetrahedron Letters 49 (2008) 5319–5321
5321
Compound 1—(isolated yield 89%, mp 95–96 °C). 1H NMR (300 MHz, DMSO-d6,
ppm): d 3.11 (2H, s, C5–CH2), 7.23 (1H, s, C6–H), 2.50 (4H, t, J = 12.3 Hz,
N(CH2)2), 1.46 (4H, q, J = 12.3 Hz, CH2), 1.35 (1H, m, C10–H), 0.88 (3H, d,
J = 12.0 Hz, CH3). 13C NMR (75 MHz, DMSO-d6, ppm): d 174.15 (C2), 161.15 (C4),
113.90 (C5), 139.41 (C6), 52.97 (C7), 52.67 (C8), 33.96 (C9), 30.12 (C10), 21.87
J = 12.3 Hz, CH3), 4.58 (2H, s, S–CH2), 5.05 (2H, s, N1–CH2), phenyl ring: 8.28 (1H,
d, J = 7.2 Hz, C30–H), 7.99 (1H, t, J = 7.3 Hz, C40–H), 7.84 (1H, t, J = 7.3 Hz, C50–H),
7.77 (1H, d, J = 7.2 Hz, C60–H), 8.16 (1H, d, J = 7.2 Hz, C300–H), 7.96 (1H, t,
J = 7.3 Hz, C400–H), 7.74 (1H, t, J = 7.3 Hz, C500–H), 7.48 (1H, d, J = 7.2 Hz, C600–H).
13C NMR (75 MHz, DMSO-d6, ppm): d 167.95 (C2), 160.92 (C4), 117.90 (C5),
153.04 (C6), 54.09 (C7), 51.90 (C8), 34.27 (C9), 30.35 (C10), 21.27 (C11), 32.08
(S–CH2), 64.09 (N1–CH2), phenyl ring: 132.42 (C-10), 148.62 (C-20), 125.11 (C-30),
130.20 (C-40), 134.08 (C-50), 133.54 (C-60), 132.15 (C-100), 147.99 (C-200), 124.53
(C11). FT-IR (KBr, cmꢀ1):
(m/z, % int.): 239 (M+Å, 26), 98 (100). UV/Vis (CH3OH, nm, log
m
(C4@O) 1652,
m
(C5@C6) 1569,
m
(C2@S) 1246. EI MS
): 213.5 (4.09),
e
273.0 (4.16). Anal. Calcd for C11H17N3OS: C, 55.20; H, 7.16; N, 17.56; S, 13.40.
Found: C, 55.23; H, 7.15; N, 17.63; S, 13.46.
(C-300), 128.53 (C-400), 133.79 (C-500), 132.92 (C-600). FT-IR (KBr, cmꢀ1):
1669, (C5@C6) 1586, (N–CH2) 2863, (S–CH2) 2947, d(S–CH2) 1442. EI MS
(m/z, % int.): 98 (100), 509 (M+Å, 2). UV/Vis (CH3OH, nm, log
): 225.0 (4.38),
m(C4@O)
Compound 2—(isolated yield 62%, mp 185–186 °C). 1H NMR (300 MHz, DMSO-
d6, ppm): d 3.33 (2H, s, C5–CH2), 8.59 (1H, s, C6–H), 2.50 (4H, t, J = 12.3 Hz,
N(CH2)2), 1.72 (4H, q, J = 12.3 Hz, CH2), 1.34 (1H, m, C10–H), 0.91 (3H, d,
J = 12.0 Hz, CH3), 4.52 (2H, s, S–CH2), 5.21 (2H, s, N1–CH2), phenyl ring: 7.68 (H,
d, J = 7.4 Hz, C30–H), 7.32 (H, t, J = 7.6 Hz, C40–H), 7.27(H, t, J = 7.6 Hz, C50–H),
7.46 (H, d, J = 7.4 Hz, C60–H), 7.57 (H, d, J = 7.4 Hz, C300–H), 7.29 (H, t, J = 7.6 Hz,
C400–H), 7.27 (H, t, J = 7.6 Hz, C500–H), 7.44 (H, d, J = 7.4 Hz, C600–H). 13C NMR
(75 MHz, DMSO-d6, ppm): d 165.99 (C2), 161.14 (C4), 116.90 (C5), 152.18 (C6),
55.38 (C7), 51.93 (C8), 34.41 (C9), 30.85 (C10), 20.34 (C11), 34.41 (S–CH2), 64.66
(N1–CH2), phenyl ring: 134.67 (C-10), 123.92 (C-20), 132.78 (C-30), 127.91 (C-40),
130.13 (C-50), 131.45 (C-60), 133.03 (C-100), 121.59 (C-200), 132.49 (C-300), 127.68
m
m
m
e
285.0 (4.14). Anal. Calcd for C25H27N5O5S: C, 58.93; H, 5.34; N, 13.74; S, 6.29.
Found: C, 58.99; H, 5.38; N, 13.79; S, 6.34.
Compound 6—(isolated yield 63%, mp 124–125 °C). 1H NMR (300 MHz, DMSO-
d6, ppm): d 3.64 (2H, s, C5–CH2), 8.30 (1H, s, C6–H), 2.50 (4H, t, J = 12.3 Hz,
N(CH2)2), 1.64 (4H, q, J = 12.2 Hz, CH2), 1.47 (1H, m, C10–H), 0.90 (3H, d,
J = 12.3 Hz, CH3), 4.46 (2H, s, S–CH2), 4.94 (2H, s, N1–CH2), phenyl ring: 8.33 (1H,
s, C20–H), 8.23 (1H, d, J = 7.3 Hz, C40–H), 8.19 (1H, t, J = 7.2 Hz, C50–H), 8.26 (1H,
d, J = 7.3 Hz, C60–H), 8.30 (1H, s, C200–H), 8.22 (1H, d, J = 7.3 Hz, C400–H), 8.15 (1H,
t, J = 7.2 Hz, C500–H), 8.23 (1H, d, J = 7.3 Hz, C600–H). 13C NMR (75 MHz, DMSO-d6,
ppm): d 166.15 (C2), 163.70 (C4), 116.95 (C5), 152.94 (C6), 53.64 (C7), 51.73
(C8), 33.20(C9), 31.92 (C10), 21.48 (C11), 32.55 (S–CH2), 65.82 (N1–CH2), phenyl
ring: 140.83 (C-10), 123.38 (C-20), 147.38 (C-30), 122.86 (C-40), 129.99 (C-50),
135.49 (C-60), 139.99 (C-100), 123.17 (C-200), 147.30 (C-300), 122.00 (C-400), 129.47
(C-400), 129.92 (C-500), 131.27 (C-600). FT-IR (KBr, cmꢀ1):
1541, (N–CH2) 2869, (S–CH2) 2926, d(S–CH2) 1439. EI MS (m/z, % int.): 577
(M+Å, 3), 168 (100). UV/Vis (CH3OH, nm, log
): 218.0 (4.36), 291.0 (4.16). Anal.
m(C4@O) 1645, m(C5@C6)
m
m
e
Calcd for C25H27N3OSBr2: C, 52.01; H, 4.71; N, 7.28; S, 5.55. Found: C, 52.06; H,
4.78; N, 7.33; S, 5.59.
(C-500), 135.34 (C-600). FT-IR (KBr, cmꢀ1):
CH2) 2871,
(S–CH2) 2951, d(S–CH2) 1446. EI MS (m/z, % int.): 98 (100), 509 (M+Å
2). UV/Vis (CH3OH, nm, log ): 221.0 (4.37), 283.0 (4.14). Anal. Calcd for
m(C4@O) 1669, m(C5@C6) 1586, m(N–
Compound 3—(isolated yield 68%, mp 103–104 °C). 1H NMR (300 MHz, DMSO-
d6, ppm): d 3.34 (2H, s, C5–CH2), 8.50 (1H, s, C6–H), 2.50 (4H, t, J = 12.3 Hz,
N(CH2)2), 1.74 (4H, q, J = 12.3 Hz, CH2), 1.39 (1H, m, C10–H), 0.91 (3H, d,
J = 12.0 Hz, CH3), 4.50 (2H, s, S–CH2), 5.21 (2H, s, N1–CH2), phenyl ring: 7.59 (1H,
s, C20–H), 7.41 (1H, d, J = 7.4 Hz, C40–H), 7.28 (1H, t, J = 7.6 Hz, C50–H), 7.33 (1H,
d, J = 7.4 Hz, C60–H), 7.49 (1H, s, C200–H), 7.38 (1H, d, J = 7.4 Hz, C400–H), 7.29 (1H,
t, J = 7.6 Hz, C500–H), 7.31 (1H, d, J = 7.4 Hz, C600–H). 13C NMR (75 MHz, DMSO-d6,
ppm): d 165.30 (C2), 161.27 (C4), 116.80 (C5), 152.10 (C6), 55.26 (C7), 52.73
(C8), 34.14 (C9), 30.64 (C10), 20.24 (C11), 34.14 (S–CH2), 65.32 (N1–CH2),
phenyl ring: 140.87 (C-10), 131.67 (C-20), 121.94 (C-30), 129.84 (C-40), 130.95 (C-
50), 128.09 (C-60), 139.10 (C-100), 131.33 (C-200), 121.40 (C-300), 129.51 (C-400),
m
,
e
C25H27N5O5S: C, 58.93; H, 5.34; N, 13.74; S, 6.29. Found: C, 58.97; H, 5.30; N,
13.76; S, 6.35.
Compound 7—(isolated yield 66%, mp 112–113 °C). 1H NMR (300 MHz, DMSO-
d6, ppm): d 3.45 (2H, s, C5–CH2), 8.18 (1H, s, C6–H), 2.51 (4H, t, J = 12.2 Hz,
N(CH2)2), 1.65 (4H, q, J = 12.2 Hz, CH2), 1.46 (1H, m, C10–H), 0.90 (3H, d,
J = 12.0 Hz, CH3), 4.45 (2H, s, S–CH2), 4.91 (2H, s, N1–CH2), phenyl ring: 8.26 (1H,
d, J = 7.2 Hz, C20–H), 8.15 (1H, d, J = 7.2 Hz, C30–H), 8.15 (1H, d, J = 7.2 Hz, C50–H),
8.26 (1H, d, J = 7.2 Hz, C60–H), 8.18 (1H, d, J = 7.2 Hz, C200–H), 7.65 (1H, d,
J = 7.2 Hz, C300–H), 7.65 (1H, d, J = 7.2 Hz, C500–H), 8.18 (1H, d, J = 7.2 Hz, C600–H).
13C NMR (75 MHz, DMSO-d6, ppm): d 166.21 (C2), 161.72 (C4), 116.81 (C5),
152.82 (C6), 53.82 (C7), 51.79 (C8), 33.20 (C9), 31.96 (C10), 21.19 (C11), 32.74
(S–CH2), 64.75 (N1–CH2), phenyl ring: 145.73 (C-10), 130.28 (C-20), 123.58 (C-30),
146.57 (C-40), 123.58 (C-50), 130.28 (C-60), 145.44 (C-100), 129.89 (C-200), 123.32
130.76 (C-500), 127.07 (C-600). FT-IR (KBr, cmꢀ1):
(N–CH2) 2869,
(S–CH2) 2927, d(S–CH2) 1427. EI MS (m/z, % int.): 577 (M+Å, 3),
168 (100). UV/Vis (CH3OH, nm, log ): 220.0 (4.39), 295.0 (4.15). Anal. Calcd for
25H27N3OSBr2: C, 52.01; H, 4.71; N, 7.28; S, 5.55. Found: C, 52.11; H, 4.68; N,
7.32; S, 5.58.
m(C4@O)1641, m(C5@C6) 1541,
m
m
e
C
(C-300), 146.03 (C-400), 123.32 (C-500), 129.89 (C-600). FT-IR (KBr, cmꢀ1):
1669, (C5@C6) 1587, (N–CH2) 2869, (S–CH2) 2947, d(S–CH2) 1448. EI MS (m/
z, % int.): 509 (M+Å, 10), 98 (100). UV/Vis (CH3OH, nm, log
): 219.0 (4.33), 286.0
m(C4@O)
Compound 4—(isolated yield 64%, mp 98–99 °C). 1H NMR (300 MHz, DMSO-d6,
ppm): d 3.33 (2H, s, C5–CH2), 8.56 (1H, s, C6–H), 2.51 (4H, t, J = 12.3 Hz,
N(CH2)2), 1.74 (4H, J = 12.3 Hz, q, CH2), 1.39 (1H, m, C10–H), 0.91 (3H, d,
J = 12.0 Hz, CH3), 4.46 (2H, s, S–CH2), 5.21 (2H, s, N1–CH2), phenyl ring: 7.58 (1H,
d, J = 7.2 Hz, C20–H), 7.39 (1H, d, J = 7.2 Hz, C30–H), 7.38 (1H, d, J = 7.2 Hz, C50–H),
7.57 (1H, d, J = 7.2 Hz, C60–H), 7.52 (1H, d, J = 7.2 Hz, C200–H), 7.37 (1H, d,
J = 7.2 Hz, C300–H), 7.37 (1H, d, J = 7.2 Hz, C500–H), 7.51 (1H, d, J = 7.2 Hz, C600–H).
13C NMR (75 MHz, DMSO-d6, ppm): d 166.14 (C2), 161.36 (C4), 117.99 (C5),
153.99 (C6), 55.18 (C7), 51.79 (C8), 34.28 (C9), 30.76 (C10), 20.24 (C11), 32.84
(S–CH2), 64.83 (N1–CH2), phenyl ring: 136.17 (C-10), 135.59 (C-20), 131.57 (C-30),
121.26 (C-40), 131.57 (C-50), 135.59 (C-60), 135.78 (C-100), 135.05 (C-200), 131.19
m
m
m
e
(4.12). Anal. Calcd for C25H27N5O5S: C, 58.93; H, 5.34; N, 13.74; S, 6.29. Found: C,
58.96; H, 5.37; N, 13.72; S, 6.33.
Compound 8, for example, the para–nitro isomer (isolated yield 78%, mp 117–
118 °C). 1H NMR (300 MHz, CDCl3-d, ppm): d 6.54 (1H, d, J = 7.5 Hz, C5–H),
8.24 (1H, d, J = 7.3 Hz, C6–H), 4.43 (2H, s, S–CH2), 5.44 (2H, s, N1–CH2),
phenyl ring: 7.35 (1H, d, J = 7.2 Hz, C20–H), 7.90 (1H, d, J = 7.2 Hz, C30–H), 7.90
(1H, d, J = 7.2 Hz, C50–H), 7.35 (1H, d, J = 7.2 Hz, C60–H), 7.50 (1H, d, J = 7.2 Hz,
C200–H), 7.68 (1H, d, J = 7.2 Hz, C300–H), 7.68 (1H, d, J = 7.2 Hz, C500–H), 7.50
(1H, d, J = 7.2 Hz, C600–H). 13C NMR (75 MHz, CDCl3-d, ppm): d 170.02 (C2),
157.57 (C4), 104.49 (C5), 167.88 (C6), 34.50 (S–CH2), 66.69 (N1–CH2), phenyl
ring: 145.520 (C-10), 128.28 (C-20), 123.87 (C-30), 151.87 (C-40), 123.87 (C-50),
129.97 (C-6 ), 142.99 (C-100), 128.09 (C-200), 123.72 (C-300), 151.87 (C-400),
(C-300), 120.54 (C-400), 131.19 (C-500), 135.05 (C-600). FT-IR (KBr, cmꢀ1):
1642, (C5@C6) 1548, (N–CH2) 2869, (S–CH2) 2926, d(S–CH2) 1429. EI MS
(m/z, % int.): 577 (M+Å, 3), 168 (100). UV/Vis (CH3OH, nm, log
): 222.0 (4.38),
m(C4@O)
m
m
m
e
290.0 (4.14). Anal. Calcd for C25H27N3OSBr2: C, 52.01; H, 4.71; N, 7.28; S, 5.55.
Found: C, 52.09; H, 4.80; N, 7.34; S, 5.51.
123.72 (C-500), 129.56 (C-600). FT-IR (KBr, cmꢀ1):
1555, (N–CH2) 2828, (S–CH2) 2884, d(S–CH2) 1425. EI MS (m/z, % int.): 398
(M+Å, 51), 136 (100). UV/Vis (CHCl3, nm, log
): 271.50 (4.34). Anal. Calcd for
18H14N4O5S: C, 54.27; H, 3.54; N, 14.06; S, 8.05. Found: C, 54.11; H, 3.39; N,
14.32; S, 8.33.
m(C4@O) 1673, m(C5@C6)
m
m
Compound 5—(isolated yield 62%, mp 133–134 °C). 1H NMR (300 MHz, DMSO-
d6, ppm): d 3.37 (2H, s, C5–CH2), 7.67 (1H, s, C6–H), 2.51 (4H, t, J = 12.3 Hz,
N(CH2)2), 1.67 (4H, q, J = 12.2 Hz, CH2), 1.41 (1H, m, C10–H), 0.90 (3H, d,
e
C