Synthesis, solid-state fluorescence properties, and computational analysis of novel 2-aminobenzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxides

Article abstract of DOI:10.3762/bjoc.8.28

New fluorescent compounds, benzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxides (3a-g), 2-amino-4-methylsulfanylbenzo[4,5]thieno[3,2-d]pyrimidine (6), and 2-amino-4-methylsulfanyl-7-methoxybenzo[4,5]furo[3,2-d]pyrimidine (7), were synthesized in good yields from heterocyclic ketene dithioacetals (1a-c) and guanidine carbonate (2a) or (S)-methylisothiourea sulfate (2b) in pyridine under reflux. Among the fused pyrimidine derivatives, compound 3c, which has an amino group at the 2-position and a benzylamino group at the 4-position of the pyrimidine ring, showed the strongest solid-state fluorescence. The absorption and emission properties of the compounds were quantitatively reproduced by a series of ab initio quantum-chemical calculations.

Full text of DOI:10.3762/bjoc.8.28

Synthesis, solid-state fluorescence properties,
and computational analysis of novel
2-aminobenzo[4,5]thieno[3,2-d]pyrimidine
5,5-dioxides
Kenichirou Yokota1, Masayori Hagimori*2, Naoko Mizuyama3,
Yasuhisa Nishimura1, Hiroshi Fujito3, Yasuhiro Shigemitsu4
and Yoshinori Tominaga*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 266–274.
1Faculty of Environmental Studies, Nagasaki University, 1-14,
Bunkyo-machi, Nagasaki 852-8521, Japan, 2Faculty of
Pharmaceutical Sciences, Nagasaki International University, 2825-7,
Huis Ten Bosch, Sasebo 859-3298, Japan, 3Department of
Pharmacy, Saga University Hospital, 5-1-1, Nabeshima, Saga
849-8521, Japan and 4Industrial Technology Center of Nagasaki,
Omura, Nagasaki, 856-0026, Japan
doi:10.3762/bjoc.8.28
Received: 09 December 2011
Accepted: 27 January 2012
Published: 16 February 2012
Associate Editor: C. Stephenson
Email:
© 2012 Yokota et al; licensee Beilstein-Institut.
License and terms: see end of document.
Masayori Hagimori* - mhagimori@niu.ac.jp; Yoshinori Tominaga* -
ytomi@nagasaki-u.ac.jp
* Corresponding author
Keywords:
amino group; fluorescence; HOMO/LUMO; pyrimidine; solid-state
Abstract
New fluorescent compounds, benzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxides (3a–g), 2-amino-4-methylsulfanyl-
benzo[4,5]thieno[3,2-d]pyrimidine (6), and 2-amino-4-methylsulfanyl-7-methoxybenzo[4,5]furo[3,2-d]pyrimidine (7), were synthe-
sized in good yields from heterocyclic ketene dithioacetals (1a–c) and guanidine carbonate (2a) or (S)-methylisothiourea sulfate
(2b) in pyridine under reflux. Among the fused pyrimidine derivatives, compound 3c, which has an amino group at the 2-position
and a benzylamino group at the 4-position of the pyrimidine ring, showed the strongest solid-state fluorescence. The absorption and
emission properties of the compounds were quantitatively reproduced by a series of ab initio quantum-chemical calculations.
Introduction
Solid-state fluorescent compounds are currently attracting which have solid-state blue fluorescence, by means of a one-pot
considerable interest from both theoretical and practical stand- synthesis, involving the reaction of ketene dithioacetals, amines,
points [1-4]. Recently, we prepared new pyrimidine derivatives, and guanidine carbonate in pyridine [5]. We have also reported
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Beilstein J. Org. Chem. 2012, 8, 266–274.
Results and Discussion
the one-pot synthesis of a new, fluorescent, fused pyrimidine
derivative 2,4-diaminoindeno[1,2-d]pyrimidin-5-one; this Synthesis
pyrimidine derivative, which was synthesized by heating a Heterocyclic ketene dithioacetals (1a–c) were easily prepared
ketene dithioacetal, 2-[bis(methylsulfanyl)methylidene]indan- by the condensation of the corresponding heterocyclic active
1,3-dione, under reflux with amine and amidine derivatives in methylene compounds with carbon disulfide in sodium
pyridine solution, showed blue-green fluorescence in the solid hydroxide solution as a base, followed by methylation with
state [6]. These one-pot synthetic methods are also promising dimethyl sulfate [8-10]. The reaction of 1a with guanidine
for the preparation of other new solid-state fluorescent pyrimi- carbonate (2a) in pyridine under reflux gave the expected prod-
dine derivatives containing polycyclic heterocycles. In this uct, 2-amino-4-(methylsulfanyl)benzo[4,5]thieno[3,2-d]pyrimi-
paper, we report the synthesis of new fluorescent dine 5,5-dioxide (3a) in 89% yield (Scheme 1). Based on our
2-aminobenzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxides and findings that diaminopyrimidine derivatives show blue fluores-
related fused pyrimidine derivatives. It is thought that these cence in the solid state [5], we attempted to synthesize
derivatives show strong fluorescence as a result of the presence diaminopyrimidine derivatives (3b–e), expecting them to
of a hetero-π-electron conjugated system [7]. The electronic and show intense solid-state fluorescence. 2,4-Diamino-
emission spectra of these new compounds were analyzed benzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxide (3b) was easily
computationally by using a series of ab initio quantum-chem- obtained, in 47% yield, by the displacement reaction of 3a with
ical calculations.
28% ammonia solution at 200 °C for 3 h in a mini-autoclave.
Scheme 1: Syntheses of benzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxides (3a–f).
267

Beilstein J. Org. Chem. 2012, 8, 266–274.
Compound 3b was also synthesized by the reaction of 2a with characteristics. The TDDFT calculations consistently employed
2-(diaminomethylene)benzo[b]thiophene-3(2H)-one 1,1-dioxide the B3LYP functional and 6-31+G(d,p) basis set [13]. Solvent
(4), which was easily obtained from 1a by using 28% ammonia effects were evaluated by using the linear-response polarized-
in methanol under reflux. The reactions of 1a, 2a, and amines continuum model for ethanol (PCM(ethanol)-TDDFT(B3LYP)/
5a–c (benzylamine, piperidine, and aniline) in pyridine under 6-31G+(d,p)) [14]. MS-CASPT2 used ten active electrons
reflux gave diaminopyrimidine derivatives 3c–e in good yields, distributed within eight active spaces combined with an ANO-S
i.e., 92%, 51%, and 86%, respectively. The reaction of 1a and basis set (MS-CASPT2(10,8)/ANO-S). The DFT, CIS, and
2a under reflux in methanol instead of pyridine gave the TDDFT computations were performed by using Gaussian 09
methoxy pyrimidine derivative 3f in 55% yield.
software [15], and CASSCF and MS-CASPT2 were performed
by using the MOLCAS 7.4 suite of programs [16].
In the presence of sulfuric acid solution, 2,4-dimethylsulfanyl
Comparison of predicted and experimental
derivative 3g was obtained from 1a with (S)-methylisothiourea
sulfate (2b) in 87% yield (Scheme 2). Fused pyrimidine deriva- absorption spectra
tives 6 and 7 containing the electron-rich heterocycles benzo- The UV–vis spectra of the compounds exhibited peaks (λmax) at
thiophene or benzofuran were prepared by the reaction of 280–360 nm. The spectra possessed multiple subpeaks around
ketene dithioacetal 1b or 1c with guanidine carbonate (2a) in λmax. The experimental and computational λmax values are
74% and 65% yield, respectively.
given in Table 1. The theoretical and experimental λmax values
are in fairly good agreement, within 50 nm deviation. The red-
shifts observed for 3d, 3e, and 6 relative to 3b were well repro-
Computational methods
The ground-state (S0) geometries were optimized by means of duced by the TDDFT computations. The sidebands around λmax
density functional theory (DFT) with the B3LYP hybrid func- were not reproduced by our TDDFT computations, which
tional and 6-311G(d,p) [11] basis set (DFT(B3LYP)/6- predicted single-peak maxima for all the compounds. The
311G(d,p)). The first excited-state (S1) geometries were opti- subpeaks are considered to be vibronically assisted absorptions,
mized with configuration interaction singles CIS/6-311G(d,p) because the extended π-systems of the molecules have large
and the complete active space SCF CASSCF(10,10)/ANO-S- degrees of vibrational freedom effectively coupled with their
MB [12] level of theory. Time-dependent TDF (TDDFT), electronic states. As a representative example of the electronic
CASSCF, and multistate complete active-space second-order structures, the HOMO and LUMO of 3a are depicted in
perturbation theory (MS-CASPT2) calculations were subse- Figure 1. The λmax was assigned as the HOMO–LUMO π–π*
quently performed for the optimized geometries to evaluate the excitation (configuration weight = 0.697) with an oscillator
vertical transition energies along with the associated transition strength of 0.096 at 335 nm. The next theoretical peak appeared
Scheme 2: Syntheses of 3g, 6, and 7.
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Beilstein J. Org. Chem. 2012, 8, 266–274.
at 290 nm, derived from (HOMO − 1) to LUMO excitations, directed along the long molecular axis. The electron density
considerably separated from the first peak. The HOMO and difference between HOMO and LUMO is shown in Figure 2;
LUMO delocalize on the whole system, indicating that modest this reflects the balanced electron redistribution between the
intramolecular electron transfer from the methylthio and amino pyrimidine and phenyl moieties.
groups on the pyrimidine ring (HOMO) to the phenyl moiety
(LUMO) is expected upon S0→S1 transition. The transition
character is also rationalized with the transition dipole moment
Table 1: Experimental and computed absorption maxima (λmax) for
3a–g, 6, and 7.
No.
λmax (exp.)a
λmax (calc.)b
3a
3b
3c
3d
3e
3f
341
282
341
343
344
322
322
361
342
335
329
339
350
371
322
347
351
328
Figure 2: The distribution of the HOMO minus LUMO density for 3a,
computed with TD-DFT(B3LYP)/6-31+G(d,p). The pink (blue) lobes
indicate a positive (negative) isocontour value of 0.003, respectively.
3g
6
7
Solid-state fluorescence
ameasured in dichloromethane, excluding 3b (in ethanol).
Tris(8-hydroxyquinolinato)aluminium (Alq3) was used as the
standard for fluorescence spectrum measurements [17]. We
analyzed the solid-state fluorescence emission spectra of 3a–g,
6 and 7 at room temperature. The fluorescence maxima
(λem,max) and relative fluorescence intensities (RI) of these
compounds are listed in Table 2. The λem,max values of 3a and
3c–g were in the range 430–462 nm. The fluorescence of the
N-unsubstituted diamino compound 3b exhibited a large
bathochromic shift, and green fluorescence was observed
(λem,max = 529 nm). Compound 3a, which has an amino group
at the 2-position in the pyrimidine ring, showed stronger fluo-
rescence than did compound 3g, which has a methylsulfanyl
group. This result was in agreement with the previous findings
that an amino group at the 2-position of an indenopyrimidine
influences the fluorescence intensity [6]. 2,4-Diaminopyrimi-
dine derivatives (3b–e) also showed stronger fluorescence than
did 3g. Compound 3c, which has an amino group at the 2-pos-
ition and a benzylamino group at the 4-position of the pyrimi-
dine ring, showed the strongest fluorescence (RI = 1.95). This
value was larger than those of indenopyrimidine derivatives
(RI = 0.01–0.73). We speculated that the effect of the π–π-elec-
tron conjugated system in the sulfonyl group of benzothieno-
pyrimidine 5,5-dioxide is stronger than that of the carbonyl
group of the indeno pyrimidines.
bTD-DFT(B3LYP)/6-31+G(d,p)//DFT(B3LYP)/6-311G(d,p).
Benzo[4,5]thieno[3,2-d]pyrimidine derivative 6 and
benzo[4,5]furo[3,2-d]pyrimidine derivative 7 showed different
emission properties from those of 3a–g. Compound 6 exhibited
a large bathochromic shift compared with that of the
benzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxides 3a and 3c–g,
Figure 1: (a) HOMO and (b) LUMO for 3a, computed with
TD-DFT(B3LYP)/6-31+G(d,p). The pink (blue) lobes indicate a posi-
tive (negative) isocontour value of 0.03.
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Beilstein J. Org. Chem. 2012, 8, 266–274.
bond lengths. These disagreements could be resolved by
geometric optimizations using MS-CASPT2 including dynamic
correlation, but this is not feasible in the present study owing to
the huge computational burden.
Table 2: Solid-state-fluorescence data for 3a–g, 6, and 7.
No.
λmax
λ em,max
SSa
Rlb
(nm)
(nm)
3a
3b
3c
3d
3e
3f
341
282
341
343
344
322
322
361
342
462
529
435
448
444
430
430
555
425
118
180
90
1.16
0.23
1.95
0.99
0.58
0.42
0.07
0.84
0.16
102
95
80
3g
6
80
218
76
7
aStokes shift; emission - excitation in solid state. bRelative intensity of
fluorescence in solid states, using Alq3 as the standard compound.
and relatively strong fluorescence. In contrast, the weakly fluo-
rescent compound 7 exhibited a hypsochromic shift relative to
3a–g. These results presumably indicate that hetero atoms
incorporated in the ring moieties strongly influence the solid-
state-fluorescent properties.
Figure 3: Schematic diagram of 3a.
Solid-state fluorescence is strongly influenced by intermolec-
ular steric hindrance. In general, the fluorescence intensity can
be enhanced by minimizing intermolecular interactions through
the introduction of bulky substituents. Compound 3c, which has
a bulky benzylamino moiety shows the strongest fluorescence
of these molecules (Figure 2). The emission from 3e with a
bulky phenylamino moiety, however, is relatively weak. This
contradiction reflects the complex emission mechanism, which
is driven not only by intermolecular stacking effects but also by
the electronic structures. The weak fluorescence of 7 is assumed
to be dominated by the inductive effect of the methoxy group,
rather than by stacking effects.
Table 3: Key bond lengths of 3a in the S0 and S1 states.
No.
S0
S1
DFTa [Å]
CASb [Å]
CISc [Å]
CASb [Å]
C4–C5
S1–C4
S1–C7
N2–C8
C5–C8
C7–C8
C7–C9
C9–N1
N3–C10
S2–C9
S2–C11
1.399
1.806
1.790
1.331
1.476
1.399
1.404
1.335
1.353
1.763
1.824
1.439
1.891
1.886
1.416
1.528
1.461
1.461
1.433
1.471
1.917
1.946
1.444
1.745
1.755
1.345
1.395
1.433
1.423
1.295
1.336
1.747
1.807
1.437
1.885
1.874
1.430
1.516
1.414
1.496
1.383
1.442
1.905
1.956
To elucidate the S1 nature of the compounds in question, we
carried out ab initio molecular-orbital calculations, focused on
3a (Figure 3). The computed key bond lengths are shown in
Table 3. Comparison of the S0 (DFT) and S1 (CIS) bond lengths
shows that the S0→S1 (dominant HOMO→LUMO) transition is
aDFT(B3LYP)/6-311G(d,p). bCASSCF(10, 10)/ANO-S-MB.
cCIS/6-311G(d,p).
reflected in the bond-length variations. The C4–C5 bond, with a The theoretical fluorescence λmax values of 3a, obtained using
bonding lobe in S0 but an antibonding one in S1, is signifi- several quantum-chemical methods, are summarized in Table 4.
cantly lengthened, by 0.045 Å, as a result of the S0→S1 tran- The CIS-predicted peak shows a significant blue-shift relative
sition. In contrast, the C5–C8 bond, with an antibonding lobe in to the experimental value; this is well known, and is a result of
S0 but a bonding one in S1, is considerably shortened, by 0.081 the lack of multi-excitation character. The TDDFT peaks
Å, on S0→S1 excitation. No significant deviation from planarity partially improve the gap, with the CIS optimized geometry for
was observed in the fused-ring structure associated with the the S1 state not being of trustworthy quality. The CASSCF
S0→S1 excitation. The geometrical discrepancies between DFT peak, in contrast, overshoots the experimental peak. The best
and CAS for S0 and CIS and CAS for S1 indicate that the prediction was obtained by using the most elaborate method,
significant roles of dynamic electron correlations are inade- MS-CASPT2, which can take the majority of the electronic
quate in the CAS method, which consistently predicted longer correlations into account. The MS-CASPT2 result indicates that
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Beilstein J. Org. Chem. 2012, 8, 266–274.
Table 4: The computed first intense fluorescence maxima for 3a.
CISa
TDb
CASc
MS-CASPT2d
Exp. (in solid)
462
λmax (oscillator strength)
291 (0.294)
391 (0.081)
530 (0.12 × 10−3)
(H)2 →(L)2 (0.66)
498 (0.12 × 10−3)
(H)2 →(L)2 (0.58)
excitation
H→L (0.66)
H→L (0.70)
aTD(B3LYP)/6-31G+(d,p)//CIS/6-311G(d,p). bTD(B3LYP)/6-31G+(d,p)//CIS/6-311G(d,p). cCAS(10,8)/ANO-S//CAS(10,10)ANO-S-MB.
dMS-CASPT2(10,8)/ANO-S//CAS(10,10)/ANO-S-MB.
the excitation character includes significant contributions from (500 MHz) spectrometers with tetramethylsilane as an internal
the HOMO→LUMO double excitation. This implies that the standard. Mass spectra (MS) were recorded on a JOEL DX-303
predictive abilities of CIS and other single-configuration-refer- mass spectrometer. Microanalyses were performed by
enced methods, which cannot handle multi-excitation features, H. Mazume on a Yanaco M-5 at Nagasaki University. All
are limited.
chemicals were reagent grade and used without further purifica-
tion unless otherwise specified.
Conclusion
New solid-state fluorescent compounds, benzo[4,5]thieno[3,2- Method of measurement of fluorescence
d]pyrimidine 5,5-dioxides (3a–g), were synthesized in good A powder sample of the subject compound was heaped in the
yields by a convenient one-pot reaction of 2-[bis(methylsul- tray. After the sample was covered with a quartz plate, this part
fanyl)methylene]benzo[b]thiophene-3(2H)-one 1,1-dioxide (1a) was fixed in the fluorescence spectrometer. After fixing the
with guanidine carbonate (2a) or (S)-methylisothiourea sulfate fluorescence wavelength, the excitation spectrum was deter-
(2b) under reflux in pyridine. Benzo[4,5]thieno[3,2-d]pyrimi- mined by scanning with the fluorescence wavelength. Similarly,
dine derivative 6 and benzo[4,5]furo[3,2-d]pyrimidine deriva- the fluorescence spectrum was obtained after scanning with the
tive 7 were also synthesized by one-pot reactions between 2a excitation wavelength. After obtaining these results, the excita-
and 1b or 1c, under the same conditions. The products 6 and 7 tion wavelength was decided and the fluorescence spectrum was
showed solid-state fluorescence. Compound 3c, which has an measured. The relative intensity of fluorescence was deter-
amino group at the 2-position and a benzylamino group at the mined by using Alq3 as the standard sample. The fluorescence
4-position of the pyrimidine ring, showed the strongest solid- of the standard sample and all subject compounds was
state fluorescence. These results indicated that heteroatoms in measured at 272 nm excitation.
the ring moieties have a strong influence on the solid-state
emissions. The absorption and emission spectra of the com- Synthesis
pounds were computationally analyzed by means of a series of 2-Amino-4-(methylsulfanyl)benzo[4,5]thieno[3,2-d]pyrimi-
ab initio quantum-chemical calculations. The theoretical dine 5,5-dioxide (3a): A mixture of 2-[bis(methyl-
analyses quantitatively reproduced the S0→S1 and S1→S0 tran- sulfanyl)methylene]benzo[b]thiophene-3(2H)-one 1,1-dioxide
sitions. The associated HOMO/LUMO distributions and the (1a; 1.43 g, 5.0 mmol), guanidine carbonate (2a; 0.90 g,
transition characters were also elucidated theoretically.
5.0 mmol) and pyridine (10 mL) was stirred for 5 h under
reflux. The reaction mixture was poured into ice water
(100 mL). The colorless crystals that appeared were collected
by filtration and washed with methanol (30 mL) to give 3a
Experimental
General
Identifications of compounds and measurements of properties (1.28 g, 89%) as colorless needles. An analytical sample was re-
were carried out by general procedures employing the following crystallized from a mixture of toluene and methanol to give
equipment: All melting points were determined with a Mita- colorless needles. Mp 294–296 °C; IR (KBr, cm−1) ν: 3409,
mura Riken Kogyo Mel-Temp apparatus or a Laboratory 3332, 3219, 1650, 1546, 1520, 1145; UV (CH2Cl2) λmax, nm
Devices Mel-Temp II apparatus and were uncorrected. Infrared (log ε): 341 (4.15), 396 (3.99), 461 (3.77); UV (EtOH) λmax, nm
(IR) spectra were recorded in potassium bromide pellets on a (log ε): 252 (4.43), 297 (3.91), 307 (4.04), 366 (3.92), 376
JASCO 810 or Shimazu IR-460 spectrometer. Ultraviolet (UV) (3.93); 1H NMR (300 MHz, DMSO-d6) δ 2.64 (s, 3H, SMe),
absorption spectra were determined in 95% ethanol on a Hitachi 7.86 (m, 2H, 7-H, 8-H), 7.95–8.04 (m, 4H, NH2, 6-H, 9-H); 13C
323 spectrometer. Fluorescence spectra were determined on a NMR (100 MHz, DMSO-d6) δ 11.0, 114.4, 121.5, 122.9, 129.6,
Shimazu RF-1500. Nuclear-magnetic-resonance (NMR) spectra 134.3, 134.4, 140.3, 158.5, 164.1, 165.2; MS m/z (% relative
were obtained on Gemini 300NMR (300 MHz) and 500NMR intensity): 280 (M+ + 1, 17), 279 (M+, 100), 262 (29), 215 (36),
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Beilstein J. Org. Chem. 2012, 8, 266–274.
188 (30), 114 (21); HRMS: [M+] calcd for C11H9N3O2S2, 341 (4.08), 397 (3.99), 463 (3.77); 1H NMR (300 MHz, CDCl3)
279.0136; found, 279.0121; Anal. calcd for C11H9N3O2S2: C, δ 4.66 (d, J = 5.6 Hz, 2H, N-CH2-), 5.31 (br s, 2H, NH2), 5.64
47.31; H, 3.23; N, 15.05; found: C, 47.46; H, 3.25; N, 15.08.
(br s, 1H, NH), 7.28–7.38 (m, 5H, phenyl-H), 7.68 (m, 2H, 7-H,
8-H), 7.82 (m, 1H, 9-H), 7.99 (m, 1H, 5-H); 13C NMR (100
2-(Diaminomethylene)benzo[b]thiophene-3(2H)-one 1,1- MHz, DMSO-d6) δ 42.9, 101.2, 120.9, 122.3, 126.7, 127.5,
dioxide (4): A mixture of 1a (1.43 g, 5.0 mmol), ammonia solu- 128.2, 130.7, 133.3, 133.8, 139.5, 140.3, 155.5, 159.3 165.3;
tion (28%, 5 mL) and methanol (10 mL) was heated under MS m/z (% relative intensity): 339 (M+ + 1, 21), 338 (M+, 100),
reflux for 30 min. After cooling, water and methanol were evap- 321 (62), 304 (25), 303 (44), 201 (23), 91 (47); Anal. calcd for
orated. The residue was collected, washed with water and C17H14N4O2S: C, 60.34; H, 4.17; N, 16.56; found: C, 60.35; H,
methanol, and crystallized from methanol to give 0.98 g 4.18; N, 16.51.
(4.4 mmol, 88%) of colorless needles. Mp 312–314 °C; MS m/z
(% relative intensity): 225 (M+ + 1, 18), 224 (M+, 100), 159 2-Amino-4-piperidinylbenzo[4,5]thieno[3,2-d]pyrimidine
(11), 153 (24), 104 (11), 76 (13); Anal. calcd for C9H8N2O3S: 5,5-dioxide (3d): This compound (0.32 g, 1.0 mmol) was
C, 48.21; H, 3.60; N, 12.49; found: C, 48.27; H 3.42; N, 12.51. prepared in 51% yield from 1a (0.57 g, 2.0 mmol), piperidine
(5b; 0.34 g, 4.0 mmol), and 2a (0.30 g, 1.7 mmol) in a similar
2,4-Diaminobenzo[4,5]thieno[3,2-d]pyrimidine 5,5-dioxide procedure to that described for the synthesis of 3c. An analyt-
(3b): Method A: A mixture of 0.30 g (1.2 mmol) of 3a and am- ical sample was recrystallized from a mixture of toluene and
monium hydroxide (28%, 20 mL) in a mini-autoclave (50 mL) methanol to give colorless needles. Mp 224–226 °C; IR (KBr,
was heated at 200 °C for 3 h. After cooling, the precipitate that cm−1) ν: 3480, 3447, 3329, 3213, 2942, 1633, 1558, 1282, 993,
appeared was collected by filtration and washed with water to 551; UV (CH2Cl2) λmax, nm (log ε): 343 (4.16), 397 (4.03); 1H
give pale yellow needles (0.14 g, 0.6 mmol, 47%). Mp NMR (300 MHz, CDCl3) δ 1.74 (m, 6H, -(CH2)3-), 3.91 (m,
315–318 °C (dec.). Method B: A mixture of 4 (0.30 g, 4H, N-CH2-), 5.11 (br s, 2H, NH2), 7.66 (m, 2H, 7-H, 8-H),
1.2 mmol), 2a (0.50 g, 3.0 mmol) and pyridine (10 mL) was re- 7.81 (m, 1H, 9-H), 8.00 (m, 1H, 6-H); 13C NMR (100 MHz,
fluxed for 7 h. After cooling, the reaction mixture was poured DMSO-d6): 24.1, 25.7, 25.7, 46.8, 46.8, 102.2, 120.8, 122.3,
into water (50 mL). The precipitate that appeared was collected 130.6, 13.5, 133.9, 138.6, 156.1, 160.9, 164.08; MS m/z (%
by filtration to give pale yellow needles (0.12 g, 0.5 mmol, relative intensity): 317 (M+ + 1, 10), 316 (M+, 53), 299 (100),
41%). Mp 320–322 °C (dec.). An analytical sample was re- 282 (23), 127 (12), 84 (11); Anal. calcd for C15H16N4O2S: C,
crystallized from methanol to give pale yellow needles. Mp 56.94; H, 5.10; N, 17.71; found: C, 56.79; H, 5.11; N, 17.56.
320–322 °C (dec.); IR (KBr, cm−1) ν: 3418 (NH), 3319 (NH),
3138 (br NH), 1666 (CO), 1563, 1501, 1402, 1232; UV (EtOH) 2-Amino-4-phenylaminobenzo[4,5]thieno[3,2-d]pyrimidine
λmax, nm (log ε): 274 (3.64), 282 (3.68); 1H NMR (300 MHz, 5,5-dioxide (3e): This compound (0.56 g, 1.7 mmol) was
DMSO-d6) δ 7.30 (br s, 2H, NH2), 7.81 (m, 2H, 7-H, 8-H), prepared in 86% yield from 1a (0.57 g, 2.0 mmol), aniline (5c;
7.92–7.98 (m, 2H, 5-H, 6-H); 13C NMR (100 MHz, DMSO-d6) 0.33 g, 3.5 mmol), and 2a (0.30 g, 1.7 mmol) in a similar proce-
δ 100.8, 120.9, 122.3, 130.8, 133.3, 133.8, 140.5, 156.8, 159.7, dure to that described for the synthesis of 3c. An analytical
165.5; MS m/z (% relative intensity): 249 (M+ + 1, 17), 248 sample was recrystallized from a mixture of toluene and
(M+, 100), 203 (20), 200 (33), 136 (33); HRMS: [M+] calcd for methanol to give colorless needles. Mp 252–255 °C; IR (KBr,
C10H8N4O2S, 248.0368; found, 248.0359; Anal. calcd for cm−1) ν: 3346 (NH), 3192 (NH), 1651, 1602, 1551, 1292, 1143;
C10H8N4O2S: C, 48.38; H, 3.25; N, 22.57; found: C, 48.27; H UV (CH2Cl2) λmax, nm (log ε): 271 (4.65), 344 (4.15), 396
3.22; N 22.51.
(3.99), 461 (3.77); 1H NMR (500 MHz, CDCl3) δ 7.15 (m, 2H,
phenyl-H), 7.34 (m, 2H, phenyl-H), 7.40 (br s, 1H, NH), 7.49
2-Amino-4-benzylaminobenzo[4,5]thieno[3,2-d]pyrimidine (br s, 1H, NH), 7.69 (d, J = 7.3 Hz, 2H, phenyl-H), 7.83–7.86
5,5-dioxide (3c): A mixture of 1a (0.57 g, 2.0 mmol), benzyl- (m, 2H, 7-H, 8-H), 7.97–8.03 (m, 2H, 6-H, 9-H); 13C NMR
amine (5a; 0.25 g, 2.3 mmol), 2a (0.27 g, 1.5 mmol) and pyri- (100 MHz, DMSO-d6) δ 102.2, 121.0, 122.3, 123.9, 124.0,
dine (10 mL) was stirred for 5 h under reflux. The reaction mix- 124.3, 128.2, 128.3, 130.5, 133.6, 134.0, 138.2, 140.4, 154.3,
ture was poured into ice water (100 mL). The colorless crystals 160.1, 165.1; MS m/z (% relative intensity): 326 (M+ + 2, 11),
that appeared were collected by filtration and washed with 325 (M+ + 1, 35), 324 (M+, 100), 323 (79), 260 (14), 259 (62),
methanol (10 mL) to give colorless needles (0.62 g, 92%). An 91 (15); Anal. calcd for C16H12N4O2S: C, 59.25; H, 3.73; N,
analytical sample was recrystallized with a mixture of toluene 17.27; found: C, 59.58; H, 3.95; N, 17.25.
and methanol to give colorless needles. Mp 221–222 °C; IR
(KBr, cm−1) ν: 3406, 3347, 3233, 1654, 1558, 1462, 1283, 2-Amino-4-methoxybenzo[4,5]thieno[3,2-d]pyrimidine 5,5-
1142; UV (CH2Cl2) λmax, nm (log ε): 258 (4.62), 332 (4.06), dioxide (3f): A mixture of 1a (0.57 g, 2.0 mmol), 2a (0.36 g,
272

Beilstein J. Org. Chem. 2012, 8, 266–274.
2.0 mmol), and methanol (10 mL) was refluxed for 1 h. After C11H9N3S2: C, 53.42; H, 3.67; N, 16.99; found: C, 53.56; H,
cooling, the precipitate that appeared was collected by filtration 3.64; N, 16.93.
to give colorless crystals (0.29 g, 1.1 mmol) in 55% yield. An
analytical sample was recrystallized from toluene to give color- 2-Amino-4-methylsulfanyl-7-methoxybenzo[4,5]furo[3,2-
less needles. Mp 298–302 °C; IR (KBr, cm−1) ν: 3476, 3399, d]pyrimidine (7): This compound (0.41 g, 1.6 mmol) was
3343, 3222, 1654, 1551, 1374, 1301, 1158; UV (CH2Cl2) λmax, prepared in 65% yield from 1c (0.64 g, 2.4 mmol) and 2a
nm (log ε): 253 (4.75), 322 (4.10), 397 (4.00), 462 (3.79); 1H (0.33 g, 1.8 mmol) in a manner similar to that described for the
NMR (300 MHz, CDCl3) δ 4.04 (s, 3H, OMe), 7.83–7.88 (m, synthesis of 3a. An analytical sample was recrystallized from a
2H, 7-H, 8-H), 7.94 (br s, 1H, NH), 7.95–8.03 (m, 2H, 6-H, mixture of toluene and methanol to give colorless needles: Mp
9-H), 8.04 (br s, 1H, NH); 13C NMR (100 MHz, DMSO-d6) δ 203–204 °C; IR (KBr, cm−1) ν: 3470 (NH), 3179 (NH), 1627,
54.2, 103.4, 121.4, 122.6, 129.8, 134.1, 134.4, 140.7, 161.5, 1572, 1432, 1366, 1255; UV (CH2Cl2) λmax, nm (log ε): 306
164.2, 166.1; MS m/z (% relative intensity): 264 (M+ + 1, 15), (4.37), 342 (4.40), 397 (3.99), 462 (3.77); 1H NMR (300 MHz,
263 (M+, 100), 262 (12), 246 (12), 220 (18), 152 (16), 136 (15); CDCl3) δ 2.66 (s, 3H, SMe), 3.90 (s, 3H, OMe), 4.97 (br s, 2H,
Anal. calcd for C11H9N3O3S, C, 50.16; H, 3.45; N, 15.96; NH2), 6.97 (dd, J = 2.0, 8.8 Hz, 1H, 8-H), 7.05 (d, J = 2.0 Hz,
found: C, 50.18; H, 3.41; N, 15.91.
1H, 6-H), 7.90 (1H, d, J = 8.8 Hz, 9-H); 13C NMR (100 MHz,
CDCl3) 11.4, 55.8, 96.5, 112.8, 114.8, 122.4, 140.9, 148.1,
2,4-Bis(methylsulfanyl)benzo[4,5]thieno[3,2-d]pyrimidine 152.2, 159.4, 159.5, 162.7; MS m/z (% relative intensity): 263
5,5-dioxide (3g): This compound (0.54 g, 1.8 mmol) was (M+ + 2, 15), 262 (M+ + 1, 43), 261 (M+, 100), 260 (79), 246
obtained in 87% yield from 1a (0.57 g, 2.0 mmol), (18), 216 (15), 215 (22), 214 (12), 201 (19); Anal. calcd for
S-methylisothiourea sulfate (2b; 0.56 g, 2.0 mmol), and pyri- C12H11N3O2S: C, 55.16; H, 4.24; N, 16.08; found: C, 55.08; H,
dine (10 mL) in a manner similar to that described for the syn- 4.32; N, 16.11.
thesis of 3a. An analytical sample was recrystallized from
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