2,4-Bis(methylsulfanyl)pyrimidine o-quinodimethane: a versatile building block for functionalized fused pyrimidines

Article abstract of DOI:10.1016/j.tet.2008.12.016

Two alternative methods for the preparation of new pyrimidine Diels-Alder cycloadducts from the readily available 2,4-bis(methylsulfanyl)-5,6-dihydrocyclobuta[d]pyrimidine are presented. In the first method, the in situ generated pyrimidine ortho-quinodim

Full text of DOI:10.1016/j.tet.2008.12.016

Tetrahedron 65 (2009) 1697–1703
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2,4-Bis(methylsulfanyl)pyrimidine o-quinodimethane: a versatile building block
for functionalized fused pyrimidines
a
a
,
a
a
,
,
z
Antonio Herrera , Roberto Martınez-Alvarez , Nazario Martın , Mourad Chioua y, Rachid Chioua a
,
´
*
´
´
b
b
c
´
´
´
Angel Sanchez-Vazquez , Dolores Molero , John Almy
a
´
´
´
Departamento de Quımica Organica, Facultad de Ciencias Quımicas, Universidad Complutense, E-28040 Madrid, Spain
b CAI de RMN, Facultad de Ciencias Qu´ımicas, Universidad Complutense, E-28040 Madrid, Spain
c Department of Chemistry, California State University Stanislaus, Turlock, CA 95382, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Two alternative methods for the preparation of new pyrimidine Diels–Alder cycloadducts from the
readily available 2,4-bis(methylsulfanyl)-5,6-dihydrocyclobuta[d]pyrimidine are presented. In the first
method, the in situ generated pyrimidine ortho-quinodimethane reacts with various dienophiles to form
the respective cycloadducts bearing two methylthio groups, which can be easily replaced by other
functional groups. In the second method, one or both of the methylsulfanyl groups of the starting py-
rimidine are replaced first and the resulting functionalized pyrimidines are able to undergo Diels–Alder
cyclization with different dienophiles to form pyrimidine cycloadducts. These alternative synthetic
strategies provide access to a wide variety of pyrimidine cycloadducts with a different substitution
pattern on the pyrimidine ring. Yield data indicate that the electronic nature of the functional groups
strongly influence the efficiency of the cycloaddition reaction.
Received 5 November 2008
Received in revised form 26 November 2008
Accepted 5 December 2008
Available online 9 December 2008
Keywords:
Pyrimidines
Quinodimethanes
Cycloaddition
Pyrimidine cycloadducts
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
pyrimidinones13 or from 2,4-disubstituted cyclobutapyrimidines14
(6) can be trapped with different dienophiles (Chart 1). The use of
Fused pyrimidine derivatives are an important class of com-
pounds with remarkable pharmaceutical applications. Thus,
pyrrolopyrimidine derivatives inhibit the receptor tyrosine kinase
enzymes.1 Substituted thienopyrimidines are reported as insulin
secretion enhancers2 and for the treatment of inflammatory and
immunoregulatory conditions.3 Spiropyrimidines show a strong
antibacterial and fungicidal activity.4 On the other hand, ortho-
quinodimethanes5 (o-QDMs) (1), their heteroaromatic analogues6
(2) and aza-ortho-quinodimethanes7 (3) have been of interest as
Diels–Alder dienes for the synthesis of various heterocyclic and
organometallic compounds with potential pharmacological ap-
plications.8 Homo and hetero Diels–Alder reactions of o-QDMs are
employed as traceless linkers for solid-phase synthesis.9 Normally,
heteroaromatic o-QDMs (2) are generated in situ either ther-
mally10 or under microwave irradiation11 from heterocyclic pre-
cursors that include sulfolene-fused heterocyclic compounds (4).12
A variety of pyrimidine o-QDMs (5) formed either from sulfolene
2,4-bis(methylsulfanyl)cyclobuta[d]pyrimidine15 allows to exploit
the different reactivity at positions 2 and 4 to carry out the in-
dependent chemical modification of each substituent. As a result,
products having different substituents at these positions became
readily available.16
In this paper we identify 2,4-bis(methylsulfanyl)-5,6-dihy-
drocyclobuta[d]pyrimidine (7) as a key versatile reagent for the
generation of new 2,4-functionalized pyrimidine o-quinodi-
methanes. New functionalities (F1 and F2) can be introduced before
or after the cycloaddition process to afford in an efficient way new
Diels–Alder pyrimidine cycloadducts (Scheme 1).
NH
Het
1
2
3
R
N
R
N
Het
SO2
* Corresponding author. Tel.: þ34913944325; fax: þ34913944103.
N
N
´
´
E-mail address: rma@quim.ucm.es (R. Martınez-Alvarez).
y
´
´
Permanent address: Instituto de Quımica Organica General, CSIC, E-28006
R'
5
R'
6
Madrid, Spain.
z
4
Permanent address: De´partement de Chimie, Faculte´ des Sciences, Universite´
Chart 1. Homo-, hetero- and aza-quinodimethanes and precursors.
ˆ
´
Abdelmalek Essaadi, Tetouan, Morocco.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.016

1698
A. Herrera et al. / Tetrahedron 65 (2009) 1697–1703
MeS
N
Cycloaddition
Functionalization
N
SMe
MeS
N
F1
N
Pyrimidine Cycloadducts
N
N
F1
N
SMe
7
F2
N
Functionalization
Cycloaddition
Functionalized
Pyrimidine Cycloadducts
F2
Functionalized
Pyrimidines
Scheme 1. Synthetic alternatives to functionalized pyrimidine cycloadducts.
2. Results and discussion
2,4-Bis(methylsulfonyl)cyclobutapyrimidine (17) was found to
be a highly versatile synthetic intermediate. As shown in Scheme
4, treatment with ammonia at atmospheric pressure yields 4-
amino-2-methylsulfonyl-5,6-dihydrocyclobuta[d]pyrimidine (18)
in a very good yield. Under harsher reaction conditions (120 ꢀC),
a double substitution takes place to give 2,4-diamino-5,6-dihy-
drocyclobuta[d]pyrimidine (19) in moderate yield. Treatment of 17
with sodium methoxide in methanol results in a double sub-
stitution of the methylsulfonyl groups to give 2,4-dimethoxy-5,6-
dihydrocyclobuta[d]pyrimidine (20) in good yield.
Following the replacement of the functional groups, cycloaddi-
tion with different dienophiles can be carried out (Scheme 5).
Thus, thermal opening of the cyclobutane ring of disubstituted
cyclobutapyrimidines (21) leads to the highly reactive pyrimidine
o-quinodimethanes (22), further reaction of which with dieno-
philes (8–10) affords different doubly functionalized cycloadducts.
Interestingly, the electronic nature of substituents F1 and F2 plays
a decisive role in the yield and stereochemistry of the DA reaction.
Theoretical calculations at the semiempirical level (PM3 and AM1)
(Hyperchem v. 7.51) were used to predict the nature and geometry
of cycloadducts. Table 1 indicates that energy differences HOMO-
(diene)ꢁLUMO(dienophile) below 7.8 eV are sufficient to allow DA
cyclization. Most of these adducts were formed in very good yields.
However, 2,4-diamino-5,6-dihydrocyclobuta[d]pyrimidine (19)
(having the most favourable energy difference) gave very poor
yields. This can be explained by the thermal sensitivity of the amino
groups to the harsh conditions (48 h, 180 ꢀC). Bis(methylsulfo-
nyl)pyrimidine 17 does not undergo Diels–Alder cyclization under
the employed conditions due to the unfavourable HOMO orbital
energy as well as on the thermolability induced by some
Following our general method,15,17 2,4-bis(methylsulfanyl)-5,6-
dihydrocyclobuta[d]pyrimidine (7) was obtained in 40% yield in
one step from a 1:2:1 molar ratio of cyclobutanone, methyl-
thiocyanate and Tf2O (triflic anhydride) in dichloromethane as
solvent. In this reaction, the relatively low yield in which 7 is
formed is due to the formation of side-products derived from the
aldol condensation of cyclobutanone, as it has previously been
observed either with aliphatic or aromatic nitriles.18 Cycloadducts
(11–14) were directly obtained by heating compound (7) with
either N-phenylmaleimide (8), naphthoquinone (9) or diethyl
fumarate (10) in ortho-dichlorobenzene (o-DCB) as solvent under
reflux conditions (Scheme 2).
A strategic step in the synthesis of functionalized pyrimidines is
the oxidation of both methylsulfanyl groups to methylsulfonyl to
allow a further facile substitution by various nucleophiles.16 Thus,
oxidation of the pyrimidine adduct 12 with m-CPBA under mild
conditions affords 2,4-bis(methylsulfonyl)pyrimidine adduct (15).
Both methylsulfonyl groups are in turn easily substituted as it is
exemplified by the reaction of 15 with sodium methoxide to give
the expected dimethoxy product (16) in 50% yield (Scheme 3).
The alternative synthetic approach consists in an initial chem-
ical modification of 2 and 4 positions at the pyrimidine ring, fol-
lowed by the Diels–Alder reaction with formation of the respective
adduct. Following a similar strategy, 2,4-bis(methylsulfanyl)-5,6-
dihydrocyclobuta[d]pyrimidine (7) undergoes mild oxidation with
m-CPBA (Scheme 4) thus transforming both methylsulfanyl groups
to the corresponding methylsulfonyl groups. The methylsulfonyl
groups can in turn be substituted by a different nucleophile.
O
O
NPh
NPh
MeS
O
NPh
MeS
N
N
8
O
+
N
N
O
(21%)
O
SMe
SMe
N
O
O
12
(42%)
O
11
MeS
N
MeS
MeS
9
N
N
N
SMe
7
O
(55%)
SMe
N
13
EtOOC
COOEt
10
COOEt
COOEt
SMe
14 (68%)
(racemate)
Scheme 2. Cycloadducts from 7 and N-phenylmaleimide (8), naphthoquinone (9) and diethyl fumarate (10).

A. Herrera et al. / Tetrahedron 65 (2009) 1697–1703
1699
O
O
O
MeS
N
MeO2S
N
MeO
N
m-CPBA
r.t. 4h
NaOMe
MeOH
NPh
NPh
NPh
N
N
N
O
O
O
SMe
SO2Me
15 (60%)
OMe
16 (50%)
12
Scheme 3. Oxidation of adduct 12 and subsequent reaction of 15 to form adduct 16.
MeO2S
N
confirm the proposed structure for the rearranged cycloadduct 31
(see Supplementary data).
Some cycloadducts were obtained only in very low yield, pos-
sibly due to the drastic reaction conditions needed to compensate
NH3
N
N
rt, CH2Cl2
NH2
18
(90%)
the unfavourable
D
E(HOMOꢁLUMO) or to the thermal instability of
the starting materials (Table 1). Nevertheless, the chemical versa-
tility of the substituents F1 and F2 permits the straightforward and
efficient preparation of these compounds by using simple reactions
from readily available adducts. Thus, oxidation of 11 with m-CPBA
leads to the formation of 34 in 87% yield. Compound 24 is obtained
in 90% yield by oxidation of 14, while uracil 35 is formed by acid
hydrolysis of 32 in 90% yield (Scheme 7).
H2N
N
MeS
N
MeO2S
N
NH4OH
120 °C
m-CPBA
r.t. 4h
N
N
NH2
SMe
7
SO2Me
(93%)
(35%)
19
17
MeO
N
NaOMe
With regard to the stereochemistry observed for the Diels–Alder
cycloadducts, homoaromatic o-QDMs are known to react with
dienophiles by following the endo-addition,19 pyridinone o-QDMs
furnished cis-fused pyridinone cycloadducts corresponding to
endo-addition,20 and pyrazino o-QDMs cycloadd forming also the
expected cis-adducts as a result of an endo-cycloaddition.21 In our
60 °C, MeOH
N
OMe
20
(81%)
Scheme 4. Oxidation of (7) to 2,4-bis(methylsulfonyl)-5,6-dihydrocyclobuta[d]pyr-
imidine (17) and some functionalization possibilities.
O
O
F1
N
F1
N
NPh
NPh
N
N
F2
F2
O
O
12:F1=F2=SMe
11:F1=F2=SMe
16:F1=F2=OMe
F
N
F1
N
25:F1=SO2Me;F2=NH2
28:F1=F2=NH2
1
Dienophiles
D
N
N
8-10
O
F2
21
F2
22
F1
N
F1
N
COOEt
COOEt
N
N
F2
O
F2
13:F1=F2=SMe
23:F1=F2=SO2Me
29:F1=F2=NH2
32:F1=F2=OMe
14:F1=F2=SMe
24:F1=F2=SO2Me
27:F1=SO2Me;F2=NH2
30:F1=F2=NH2
33:F1=F2=OMe
Scheme 5. Cycloadducts formed from variously substituted cyclobutapyrimidines (21) and dienophiles (8–10).
substituents (see Supplementary data). In contrast, bis(me-
thylsulfanyl) and dimethoxy pyrimidines (7 and 20) react easily
with all the dienophiles forming the corresponding cycloadducts in
very good yields. Although there are differences between the LUMO
orbital energies of the dienophiles (8–10) (see Supplementary
data), these differences do not seem to play any role in the obtained
results. The choice of synthetic strategy (cycloaddition before
functionalization or vice versa) will depend on this energy differ-
ence as well as on the thermolability of the substituents.
The reaction of pyrimidine 20 with dienophile 8 affords a mix-
ture of the expected cycloadduct 16 together with a new and un-
expected adduct 31 (Scheme 6). This compound results from the
migration of the methyl group attached at the oxygen atom on
position 2 to the N atom at position 1, presumably due to the harsh
reaction conditions used. NMR experiments, including NOE,
case, the stereochemistry of the cycloadducts obtained from N-
phenylmaleimide (8) and the substituted dienes 36–38 derived
from the corresponding cyclobutapyrimidines (Scheme 8) has been
calculated using the semiempirical software described above. The
results are summarized in Table 2 and indicate that the endo ap-
proach requires a lower energy path, as expected.
As a representative example, cycloadduct 16 exists as two con-
formers (16A and 16B) with axial and equatorial orientation of the
maleimide ring, respectively (Scheme 9). In order to distinguish
between both conformers, NMR experiments were carried out on
cycloadduct 16. The proximity of the N atom of the pyrimidine ring
causes the protons H9 to be less shielded than protons H5. More-
over, this proximity produces a decrease in the coupling constants
for H9 protons. Irradiation of H5a and H8a at
d 3.54 ppm simplifies
the spectrum allowing the total assignment and measurements of

1700
A. Herrera et al. / Tetrahedron 65 (2009) 1697–1703
Table 1
O
MeS
N
MeO2S
N
MeO
N
Molecular orbital energies of dienes and dienophiles and yields of cycloadducts
obtained in the direct Diels–Alder reaction (Scheme 5)
NPh
N
N
N
D
EHomoꢁLumo Yieldb
a
a
Adduct Cyclobutapyrimidine Dienophile EHomo ELumo
(eV) (eV)
O
SMe
36
NH2
37
OMe
38
(eV)
(%)
8
F1, F2¼SMe
Scheme 8. Dienes 36–38 and dienophile 8 used to predict the stereochemistry of
adducts 12, 25 and 16.
11þ12
13
7
7
7
8
9
10
ꢁ8.237 ꢁ1.267 6.960
ꢁ8.237 ꢁ1.146 7.081
ꢁ8.237 ꢁ0.907 7.330
63
67
65
14
F1, F2¼SO2Me
c
c
c
Table 2
15
23
24
17
17
17
8
9
10
ꢁ9.735 ꢁ1.267 8.468
ꢁ9.735 ꢁ1.146 8.589
ꢁ9.735 ꢁ0.907 8.828
Calculated energy values (eV) for HOMO–LUMO interactions leading to the forma-
tion of cycloadducts
F1¼SO2Me, F2¼NH2
Pyrimidine
o-QDM
Dienophile
Adduct
endo
exo
25
26
27
18
18
18
8
9
10
ꢁ9.095 ꢁ1.267 7.828
ꢁ9.095 ꢁ1.146 7.949
ꢁ9.095 ꢁ0.907 8.188
45
AM1
PM3
AM1
PM3
c
36
37
38
8
8
8
12
25
16
4.648
ꢁ13.762
ꢁ96.812
ꢁ81.456
13.636
ꢁ9.260
c
ꢁ61.444
ꢁ60.633
ꢁ94.570
ꢁ80.259
F1, F2¼NH2
ꢁ49.725
ꢁ48.739
c
c
c
28
29
30
19
19
19
8
9
10
ꢁ8.048 ꢁ1.267 6.781
ꢁ8.048 ꢁ1.146 6.902
ꢁ8.048 ꢁ0.907 7.131
F1, F2¼OMe
H9eq
N
H9ax
16
32
33
20
20
20
8
9
10
ꢁ8.661 ꢁ1.267 7.394
ꢁ8.661 ꢁ1.146 7.515
ꢁ8.661 ꢁ0.907 7.754
40þ18d
66
H
8aO
MeO
59
NPh
N
a
b
c
AM1.
O
Percent yield of isolated product.
Below 5%.
H5a
H5eq
MeO
H5ax
d
Under the strong reaction conditions, 40% of adduct 16 and 18% of 31 were
16
isolated (Scheme 6).
H9ax
H5ax
MeO
N
MeO
H8a
H5a
O
N
H8a
H5a
N
H9eq
H5eq
N
O
O
N
MeO
MeO
N
Ph
O
H
5ax H9ax
NPh
O
Ph
Me
N
O
16A
16B
O
O
8
O
MeO
N
MeO
N
Scheme 9. Cycloadduct 16 and the two possible conformers for the endo-addition.
NPh
NPh
+
N
N
N
o-DCB,
180 °C
O
O
OMe
OMe
OMe
20
3. Conclusion
31 (18%)
16 (40%)
Scheme 6. Normal (16) and rearranged cycloadduct (31) obtained in the Diels–Alder
reaction of 20 with N-phenylmaleimide (8).
In summary, we report two new alternative and complementary
synthetic paths to the preparation of new functionalized pyrimi-
dine cycloadducts. This method allows the access to a large variety
of pyrimidine-fused cycloadducts, which are otherwise unavailable.
The electronic nature of the functional groups on the pyrimidine
ring has a strong impact on the HOMO–LUMO energy levels and,
therefore, on the course of the reaction and will determine the
choice of the synthetic route to follow. As expected, experimental
findings as well as theoretical calculations reveal that the stereo-
chemistry of the obtained cycloadducts follows the endo rule.
O
O
MeS
MeS
N
MeO2S
MeO2S
N
m-CPBA
m-CPBA
NPh
NPh
N
N
N
N
O
O
SMe
SO2Me
11
34 (87%)
N
COOEt
N
COOEt
COOEt
4. Experimental
4.1. General
COOEt
SO2Me
SMe
14
24 (90%)
O
O
O
H
N
Dichloromethane was purified by distillation over P2O5. Triflic
anhydride was prepared from TfOH25 and distilled twice over P2O5
before use. 1H NMR and 13C NMR were recorded in CDCl3 and
DMSO-d6 at 300 and 500 MHz and 57 and 125 MHz and referenced
to 7.26 and 77.00 ppm for chloroform and 2.50 and 39.5 ppm for
DMSO, respectively. Due to the insolubility of compound 19, the 13C
NMR spectrum was recorded in a mixture of DMSO-d6 and meth-
anol-d4. Homonuclear J couplings were confirmed by single-fre-
quency experiments. Multiplicity assignments of 13C NMR signals
were made from DEPT spectra. Homonuclear irradiation was used
to simplify some complex nuclei systems and NOE spectra were
used to confirm proposed structures.
MeO
N
O
HCl 6M
N
HN
Δ
OMe
O
O
32
35 (90%)
Scheme 7. Synthetic alternatives to the preparation of cycloadducts 34, 24 and 35.
coupling constants. The measured values are in agreement with the
expected values indicating a preferred axial orientation of the
maleimide ring as in conformer 16A (see Supplementary data).

A. Herrera et al. / Tetrahedron 65 (2009) 1697–1703
1701
4.2. 2,4-Bis(methylsulfanyl)-5,6-dihydrocyclo-
buta[d]pyrimidine (7)
189 [MþNa]þ, 166 [MþH]þ. Anal. Calcd for C8H10N2O2: C, 57.82; H,
6.07; N, 16.86. Found: C, 57.57; H, 5.88; N, 16.58.
Compound 7 was prepared from cyclobutanone, methythio-
4.4. Synthesis of cycloadducts. General procedure
cyanate and triflic anhydride following reported synthetic
methods15,18 in 40% yield, mp 102–103 ꢀC (MeOH); IR (KBr)
n
¼1546,
¼2.51 (s, 3H,
SMe), 2.53 (s, 3H, SMe), 3.10 (t, J¼3.9 Hz, 2H, CH2), 3.30 (t, J¼3.9 Hz,
A solution of the appropriate cyclobutapyrimidine (1 mmol) and
the corresponding dienophile (8–10) (1.1 mmol) in o-dichloro-
benzene (20 mL) was heated under reflux (180 ꢀC) for a variable
period of time. The progress of the reaction was monitored by TLC.
The solvent was removed under reduced pressure and the residue
purified by column chromatography (eluent EtOAc/hexanes¼5:95,
20:80 and 40:60). Further purification of the solid obtained was
accomplished by recrystallization in the appropriate solvent.
1427, 1334 cmꢁ1 1H NMR (300 MHz, CDCl3, 25 ꢀC):
; d
13
2H, CH2); C NMR (57 MHz, CDCl3, 25 ꢀC):
d
¼11.5 (SMe), 14.2
(SMe), 27.1 (CH2), 35.0 (CH2), 129.5, 136.5, 161.6, 170.2 (arom); MS
ꢂ
(EI) m/z 198 (Mþ , 198), 183 (MꢁCH3, 72), 137 (183ꢁSCH2, 19), 78
(21). Anal. Calcd for C8H10N2S2: C, 48.45; H, 5.08; N, 14.13; S, 32.34.
Found: C, 48.31; H, 4.89; N, 13.98; S, 32.14.
4.4.1. 2,4-Bis(methylsulfanyl)-7-phenyl-5H-pyrrolo[3,4-
g]quinazoline-6,8(7H,9H)dione (11)
Following the general procedure, the reaction of 7 with 8 affords
the compound in 42% yield, reaction time 48 h, mp 208–209 ꢀC
4.3. General procedures for the functionalization of
cyclobutapyrimidines
4.3.1. 2,4-Bis(methylsulfonyl)-5,6-dihydrocyclobuta[d]pyr-
imidine (17)
(EtOH); IR (KBr)
CDCl3, 25 ꢀC):
n
¼1704,1596,1504,1392 cmꢁ1; 1H NMR (300 MHz,
d
¼2.71 (s, 3H, SMe), 2.73 (s, 3H, SMe), 2.78 (t,
Compound 17 was prepared by oxidation from 7 according to
J¼7.4 Hz, 2H, CH2), 3.49 (t, J¼7.4 Hz, CH2), 7.42 (m, 5H, Ar–H); 13C
the previously reported method22 in 90% yield, mp 185–186 ꢀC
NMR (57 MHz, CDCl3, 25 ꢀC):
d
¼12.5 (CH2), 14.1 (CH2), 16.1 (SMe),
(EtOH); IR (KBr)
CDCl3, 25 ꢀC):
n
¼1620, 1427, 1176, 1072 cmꢁ1; 1H NMR (300 MHz,
22.3 (SMe), 118.3, 123.2, 126.4, 128.0, 128.3, 129.1, 131.1, 157.3, 165.2,
ꢂ
d¼3.21 (s, 3H, OMe), 3.27 (s, 3H, OMe), 3.56 (t,
166.2, 167.3 (arom); MS (EI) m/z (%B) 369 (Mþ , 100), 354 (MꢁCH3,
J¼5 Hz, 2H, CH2), 3.72 (t, J¼5 Hz, 2H, CH2); 13C NMR (57 MHz, CDCl3,
30), 336 (MꢁSH, 53), 329 (63), 77 (C6Hþ5 , 15), Anal. Calcd for
C18H15N3O2S2: C, 58.52; H, 4.09; N, 11.37; S, 17.36. Found: C, 58.37;
H, 3.88; N, 11.11; S, 16.99.
25 ꢀC):
d
¼29.1 (CH2), 38.3 (SO2Me), 39.4 (CH2), 39.6 (SO2Me), 139.3,
156.2, 160.2, 181.3 (arom); MS (ESI) m/z 263 [MþH]þ. Anal. Calcd for
C8H10N2O4S2: C, 36.63; H, 3.84; N, 10.68; S, 24.45. Found: C, 36.50;
H, 3.90; N, 10.53; S, 24.11.
4.4.2. 2,4-Bis(methylsulfanyl)-7-phenyl-8a,9-dihydro-5H-
pyrrolo[3,4-g]quinazoline-6,8(5aH,7H)-dione (12)
4.3.2. 4-Amino-2-(methylsulfonyl)-5,6-dihydrocyclo-
buta[d]pyrimidine (18)
Following the general procedure, the reaction of 7 with 8 affords
the compound in 21% yield, reaction time 48 h, mp 189–190 ꢀC
Compound 18 was prepared from 17 according to the previously
(MeOH); IR (KBr)
n
¼1708, 1542, 1510, 1388 cmꢁ1
;
1H NMR
d 2.57 (s, 6H, SMe), 2.87–3.50 (two ABX
reported methods23 in 90% yield, mp 183–184 ꢀC (EtOH); IR (KBr)
(300 MHz, CDCl3, 25 ꢀC)
n
¼3495, 3300, 3120, 1404, 1190, 1010 cmꢁ1
;
1H NMR (300 MHz,
systems, CH2, CH), 7.14–7.40 (m, 5H, Ar–H); 13C NMR (57 MHz,
CDCl3, 25 ꢀC):
DMSO-d6, 25 ꢀC):
d
¼2.95 (t, J¼3.9 Hz, 2H, CH2), 3.09 (s, 3H, SO2Me),
d
¼12.7 (SMe), 14.2 (SMe), 23.5 (CH2), 31.4 (CH2), 39.0
3.19 (t, J¼3.9 Hz, 2H, CH2), 3.23 (s, 3H, SO2Me), 3.87 (br s, 2H, NH2);
(CH), 39.2 (CH), 119.5, 126.2, 128.7, 129.1, 131.5, 161.0, 177.1, 177.3
ꢂ
13C NMR (57 MHz, DMSO-d6, 25 ꢀC):
d¼26.5 (CH2), 34.0 (CH2), 38.8
(arom); MS (EI) m/z (%B) 371 (Mþ , 100), 356 (MꢁCH3, 14), 338
ꢂ
(SO2Me), 121.0, 156.6, 157.4, 170.1; MS (EI) m/z (%B) 199 (Mþ , 27),
184 (MꢁCH3, 65), 120 (MꢁSO2Me, 56), 42 (100). Anal. Calcd for
C7H9N3O2S: C, 42.20; H, 4.55; N, 21.09; S, 16.09. Found: C, 41.90; H,
4.33; N, 20.89; S, 15.87.
(MꢁSH, 48), 223 (16), 191 (18), 77 (C6Hþ5 , 25). Anal. Calcd for
C18H17N3O2S2: C, 58.20; H, 4.61; N, 11.31; S, 17.26. Found: C, 58.05;
H, 4.55; N, 11.11; S, 17.09.
4.4.3. 2,4-Bis(methylsulfanyl)naphtho[2,3-g]quinazoline-6,11-
dione (13)
4.3.3. 2,4-Diamino-5,6-dihydrocyclobuta[d]pyrimidine (19)
A solution of 17 (0.20 g, 0.76 mmol) in ammonium hydroxide
(20 mL) was heated at 100 ꢀC in a pressure reactor (1.5 atm) for
24 h. The reaction mixture was extracted with dichloromethane
(3ꢃ20 mL), washed with water (2ꢃ20 mL) and dried over sodium
sulfate. The elimination of solvent affords a residue, which was
purified by column chromatography (eluent EtOAc/hexanes¼4:6).
The target compound was obtained in 35% as undistillable oil; IR
According to the general procedure, the reaction of 7 with 9
affords the compound in 55% yield, reaction time 48 h, mp 237–
238 ꢀC (MeOH); IR (KBr)
n
;
¼1674, 1591 cmꢁ1 1H NMR (300 MHz,
CDCl3, 25 ꢀC)¼
n 2.71 (s, 3H, SMe), 2.74 (s, 3H, SMe), 7.85 (m, 2H,
Ar–H), 8.39 (m, 2H, Ar–H), 8.64 (s, 1H, Ar–H), 8.98 (s, 1H, Ar–H); 13C
NMR (57 MHz, CDCl3, 25 ꢀC):
d
¼13.0 (SMe), 14.4 (SMe), 123.6, 125.8,
127.5,127.7,129.3, 134.0, 134.1,137.0,151.0,170.8,173.7 (arom),181.6
ꢂ
(film)
n
¼3500, 3400, 3300, 3200 cmꢁ1; 1H NMR (300 MHz, DMSO-
(CO), 182.2 (CO); MS (EI) m/z (%B) 352 (Mþ , 58), 337 (MꢁCH3, 57),
d6þCD3OD, 25 ꢀC):
d
¼2.07, 2.21, 2.33, 2.39 (4H, AA0XX0system), 2.52
83 (36), 72 (67), 59 (100). Anal. Calcd for C18H12N2O2S2: C, 61.34; H,
3.43; N, 7.95; S, 18.20. Found: C, 61.19; H, 3.19; N, 7.57; S, 17.99.
(s, 2H, NH2), 3.19 (s, 2H, NH2); 13C NMR (57 MHz, DMSO-d6þMeOD-
d4, 25 ꢀC):
d
¼20.3 (CH2), 33.5 (CH2), 105.0, 129.7, 174.0, 184.4
ꢂ
(arom); MS (EI) m/z (%B) 136 (Mþ , 37), 85 (33), 59 (47), 43 (100).
Anal. Calcd for C6H8N4: C, 52.93; H, 5.92; N, 41.15. Found: C, 52.70;
H, 5.80; N, 40.92.
4.4.4. Diethyl(6R,6S,7R,7S)-2,4-bis(methylsulfanyl)-5,6,7,8-
tetrahydroquinazoline-6,7-dicarboxylate (14)
According to the general procedure, the reaction of 7 and 10
affords the compound in 68% yield, reaction time 48 h, mp 93–
4.3.4. 2,4-Dimethoxy-5,6-dihydrocyclobuta[d]pyrimidine (20)
Compound 20 was prepared according to the previously
reported methods24 in 81% yield, mp 46–47 ꢀC (MeOH); IR (KBr)
94 ꢀC (hexanes); IR (KBr)
(300 MHz, CDCl3, 25 ꢀC):
CH2CH3), 2.51 (s, 3H, SMe), 2.53 (s, 3H, SMe), 2.62 (m, 1H, CH), 2.87
n
¼1733, 1527, 1313, 1184 cmꢁ1
;
1H NMR
¼1.23 (overlapped t, J¼6 Hz, 6H,
d
n
¼1211, 1085 cmꢁ1
;
1H NMR (300 MHz, CDCl3, 25 ꢀC):
d
¼3.03 (t,
(m, 2H, CH2), 3.04 (m, 3H, CH, CH2), 4.16 (overlapped q, J¼6 Hz, 4H,
J¼4 Hz, 2H, CH2), 3.24 (t, J¼4 Hz, 2H, CH2), 3.93 (s, 6H, OMe); 13C
CH2CH3); C NMR (57 MHz, CDCl3, 25 ꢀC):
d
¼12.9 (CH3CH2), 14.1
13
NMR (57 MHz, CDCl3, 25 ꢀC):
(OMe), 54.7 (OMe), 113.9, 163.5, 166.0, 175.2 (arom); MS (ESI) m/z
d
¼25.5 (CH2), 34.6 (CH2), 53.80
(SMe), 25.7 (CH2), 33.1 (CH2), 40.7 (CH), 40.8 (CH), 118.8, 160.2,
168.2, 168.6 (arom), 169.9 (CO), 173.2 (CO); MS (EI) m/z (%B) 370

1702
A. Herrera et al. / Tetrahedron 65 (2009) 1697–1703
ꢂ
(Mþ , 51), 325 (MꢁOEt, 21), 297 (MꢁCOOEt, 100), 223 (10). Anal.
Calcd for C16H22N2O4S2: C, 51.87; H, 5.99; N, 7.56; S, 17.31. Found: C,
51.61; H, 5.59; N, 7.40; S, 17.17.
4.5.5. 4-Methoxy-1-methyl-7-phenyl-5,5a,8a,9-tetrahydro-1H-
pyrrolo[3,4-g]quinazoline-2,6,8(7H)-trione (31)
Following the general procedure, the reaction of 20 with 8 af-
fords the compound in 18% yield, reaction time 48 h, mp 115–116 ꢀC
4.5. General procedure for the functionalization of
cycloadducts
(MeOH); IR (KBr)
n
¼1705, 1662, 1552, 1342 cmꢁ1
;
1H NMR
¼2.61 (AB system, J¼10 Hz, 2H, CH2),
(300 MHz, CDCl3, 25 ꢀC):
d
2.83 (AB system, J¼10 Hz, 2H, CH2), 3.40 (m, 2H, CH), 3.59 (s, 3H,
The different procedures employed for the functionalization of
cycloadducts are the same as reported above for the functionali-
zation of cyclobutapyrimidines.
NMe), 3.98 (s, 3H, OMe), 7.13 (m, 2H, Ar–H), 7.40 (m, 1H, Ar–H), 7.46
(m, 2H, Ar–H); 13C NMR (57 MHz, CDCl3, 25 ꢀC):
d
¼20.9 (CH2), 25.4
(CH2), 32.0 (NMe), 38.4 (CH), 39.2 (CH), 54.4 (OMe), 100.7, 126.0,
128.8, 129.0, 131.1, 153.1, 156.6, 167.8 (arom), 177.0 (CO), 177.2 (CO);
ꢂ
4.5.1. 2,4-Bis(methylsulfonyl)-7-phenyl-8a,9-dihydro-5H-
pyrrolo[3,4-g]quinazoline-6,8(5aH,7H)-dione (15)
MS (EI) m/z (%B) 339 (Mþ , 100), 309 (MꢁOMe, 25), 191 (97), 177
(20), 119 (36), 77 (C7H7þ, 18). Anal. Calcd for C18H17N3O4: C, 63.71; H,
5.05; N, 12.38. Found: C, 63.50; H, 4.96; N, 12.12.
According to reported methods,22 the oxidation of cycloadduct
12 affords 15 in 60% yield, mp 250 ꢀC (decomp.) (EtOH); IR (KBr)
n
¼1716, 1398, 1315, 1211 cmꢁ1
;
1H NMR (300 MHz, CDCl3, 25 ꢀC):
4.5.6. 2,4-Dimethoxynaphtho[2,3-g]quinazoline-6,11-dione (32)
According to the general procedure, the reaction of 20 with 9
affords the compound in 66% yield, reaction time 48 h, mp 251–
d
¼3.52 (s, 3H, SO2Me), 3.57 (s, 3H, SO2Me), 3.67 (m, 6H, CH2, CH),
7.24 (m, 2H, Ar–H), 7.46 (m, 3H, Ar–H); 13C NMR (57 MHz, CDCl3,
25 ꢀC):
d¼12.7 (CH), 14.1 (CH), 23.5 (CH2), 31.3 (CH2), 38.9 (SO2Me),
252 ꢀC (MeOH); IR (KBr)
n
¼1682, 1589, 1508, 1394, 1309 cmꢁ1
;
13C
39.2 (SO2Me), 119.5, 126.1, 128.6, 128.9, 131.4, 160.9, 167.5, 169.8
NMR (57 MHz, CDCl3, 25 ꢀC):
d
¼4.18 (s, 3H, OMe), 4.26 (s, 3H, OMe),
ꢂ
(arom), 177.1 (CO), 177.2 (CO); MS (EI) m/z (%B) 435 (Mþ , 100), 403
7.84 (m, 2H, Ar–H), 8.38 (m, 2H, Ar–H), 8.60 (s, 1H, Ar–H), 9.08 (s,
13
(MꢁS, 11), 311 (97), 163 (44). Anal. Calcd for C18H17N3O6S2: C, 49.65;
1H, Ar–H); C NMR (57 MHz, CDCl3, 25 ꢀC):
d
¼55.2 (OMe), 55.4
H, 3.93; N, 9.65; S, 14.73. Found: C, 49.55; H, 3.69; N, 9.50; S, 14.44.
(OMe), 116.7, 126.0, 126.1, 127.6, 134.0, 134.1, 134.3, 134.5, 136.7,
ꢂ
158.3, 170.3, 175.1 (arom), 178.9 (CO); MS (EI) m/z (%B) 320 (Mþ
,
4.5.2. 2,4-Dimethoxy-7-phenyl-8a,9-dihydro-5H-pyrrolo[3,4-
g]quinazoline-6,8(5aH,7H)-dione (16)
100), 305 (MꢁCH3, 19), 290 (MꢁOMe, 43), 249 (23). Anal. Calcd for
C18H12N2O4: C, 67.50; H, 3.78; N, 8.75. Found: C, 67.33; H, 3.59; N,
8.61.
Following the general procedure, the reaction of 20 with 8 af-
fords the compound in 40% yield, reaction time 48 h, mp 165–166
(EtOH); IR (KBr)
CDCl3, 25 ꢀC):
n
¼1705, 1541, 1375, 1203 cmꢁ1; 1H NMR (300 MHz,
4.5.7. Diethyl(6R,6S,7R,7S)-2,4-dimethoxy-5,6,7,8-
tetrahydroquinazoline-6,7-dicarboxylate (33)
According to the general procedure, the reaction of 20 with 10
affords the compound in 59% yield, reaction time 48 h, mp 175–
d
¼2.85, 3.33 (ABX system, 3H, CH2, CH), 3.11, 3.44
(ABX system, 3H, CH2, CH), 4.01 (s, 6H, OMe), 7.15 (m, 2H, Ar–H), 7.37
(m, 1H, Ar–H), 7.43 (m, 2H, Ar–H); 13C NMR (57 MHz, CDCl3, 25 ꢀC):
d
¼20.6 (CH2), 31.2 (CH2), 39.3 (CH), 54.1 (OMe), 54.8 (OMe), 106.9,
177 ꢀC (MeOH); IR (KBr)
n
¼1724, 1587, 1377, 1186 cmꢁ1
;
1H NMR
¼1.27 (overlapped t, J¼7 Hz, 6H,
126.9, 128.6, 129.0, 131.6, 169.9, 165.4, 168.0 (Ar–H), 177.6 (CO), 177.8
(300 MHz, CDCl3, 25 ꢀC):
d
ꢂ
(CO); MS (EI) m/z (%B) 339 (Mþ , 100), 324 (MꢁCH3, 8), 309
CH3CH2), 2.60 (m, 2H, CH), 3.10 (m, 4H, CH2), 3.93 (s, 3H, OMe), 3.97
(s, 3H, OMe), 4.20 (overlapped q, J¼7 Hz, 4H, CH2CH3); 13C NMR
(MꢁOMe, 10), 191 (97), 77 (C7Hþ7, 18). Anal. Calcd for C18H17N3O4: C,
63.71; H, 5.05; N, 12.38. Found: C, 63.59; H, 4.91; N, 12.21.
(57 MHz, CDCl3, 25 ꢀC):
d
¼23.7 (CH3CH2), 25.5 (CH3CH2), 33.2
(CH2), 34.6 (CH2), 41.0 (CH), 41.2 (CH), 54.0 (OMe), 54.7 (OMe), 61.0
(OCH2), 61.7 (OCH2), 107.4, 133.3, 134.7, 167.9 (arom), 173.5 (CO),
4.5.3. Diethyl (6R,6S,7R,7S)-2,4-bis(methylsulfonyl)-5,6,7,8-
tetrahydroquinazoline-6,7-dicarboxylate (24)
ꢂ
173.7 (CO); MS (EI) m/z (%B) 338 (Mþ , 10), 293 (MꢁOCH2CH3, 15),
According to reported methods,22 the oxidation of 14 leads to
the formation of 24 in 90% yield, mp 139–140 ꢀC (MeOH); IR (KBr)
265 (MꢁCOOEt, 100), 191 (55). Anal. Calcd for C16H22N2O6: C, 56.80;
H, 6.55; N, 8.28. Found: C, 56.55; H, 6.39; N, 8.09.
n
¼1733, 1371, 1134 cmꢁ1; 1H NMR (300 MHz, CDCl3, 25 ꢀC):
¼1.26
d
(overlapped t, J¼6.5 Hz, 6H, CH3CH2), 3.29 (m, 2H, CH2), 3.35 (s, 3H,
SO2Me), 3.45 (s, 3H, SO2Me), 3.51 (m, 2H, CH2), 3.58 (m, 1H, CH),
3.64 (m, 1H, CH), 4.19 (overlapped qt, J¼6.5 Hz, 4H, CH3CH2); 13C
4.5.8. 2,4-Bis(methylsulfonyl)-7-phenyl-5H-pyrrolo[3,4-
g]quinazoline-6,8-(7H,9H)-dione (34)
Following reported methods,22 the oxidation of compound 11
affords cycloadduct 34 in 87% yield, mp 205–206 ꢀC (MeOH); IR
NMR (57 MHz, CDCl3, 25 ꢀC):
d¼14.0 (CH3CH2), 14.1 (CH3CH2), 24.4
(CH2), 33.0 (CH2), 39.0 (SO2Me), 39.3 (SO2Me), 39.5 (CH), 39.7 (CH),
(KBr)
n
¼1718, 1388, 1307, 1143 cmꢁ1
;
1H NMR (300 MHz, CDCl3,
61.8 (CH2CH3), 128.5, 136.9, 162.2, 163.7 (arom), 172.0 (CO); MS (EI)
25 ꢀC):
d
¼3.03 (t, 5J¼7.2 Hz, 2H, CH2), 3.52 (s, 3H, SO2Me), 3.56 (s,
ꢂ
m/z (%B) 434 (Mþ , 22), 388 (MꢁEtOH, 87), 361 (MꢁCOOEt, 100),
3H, SO2Me), 4.09 (t, 5J¼7.2 Hz, 2H, CH2), 7.45 (m, 5H, Ar–H); 13C
313 (81), 225 (44). Anal. Calcd for C16H22N2O8S2: C, 44.23; H, 5.10;
N, 6.45; S, 14.76. Found: C, 43.98; H, 4.90; N, 6.39; S, 14.60.
NMR (57 MHz, CDCl3, 25 ꢀC):
d
¼22.6 (SO2Me), 25.4 (SO2Me), 36.0
(CH2), 40.8 (CH2), 126.0, 126.4, 128.2, 129.1, 129.5, 129.8, 130.2, 131.1,
ꢂ
133.6, 134.2 (arom),169.5 (CO); MS (EI) m/z (%B) 433 (Mþ , 100), 354
4.5.4. 4-Amino-2-(methylsulfonyl)-7-phenyl-8a,9-dihydro-5H-
pyrrolo[3,4-g]quinazoline-6,8(5aH,7H)-dione (25)
(MꢁSO2Me, 88), 273 (5), 77 (C6Hþ5 , 10). Anal. Calcd for
C18H15N3O6S2: C, 49.88; H, 3.49; N, 9.69; S, 14.80. Found: C, 49.65;
H, 3.39; N, 9.48; S, 14.53.
According to the general procedure, the reaction of 18 with 8
affords the compound in 45% yield, reaction time 48 h, mp 272–
273 ꢀC (MeOH); IR (KBr)
n
¼3492, 1722, 1498, 1390, 1321 cmꢁ1
;
1H
4.5.9. Naphtho[2,3-g]quinazoline-2,4,6,11(1H,3H)-tetrone (35)
Cycloadduct 32 (0.20 g, 1.0 mmol) is suspended in aqueous HCl
6 M and heated for 6 h. The solvent was removed at reduced
pressure and the residue washed with water and recrystallized.
Uracil 35 was obtained in 90% yield, mp 260 ꢀC (decomp.) (MeOH);
NMR (300 MHz, DMSO-d6, 25 ꢀC):
d
¼2.89–3.10 (m, 4H, CH2, CH),
3.23 (s, 3H, SO2Me), 3.55 (m, 2H, CH2), 7.09 (m, 2H, Ar–H), 7.46 (m,
3H, Ar–H), 7.58 (br s, 2H, NH2); 13C NMR (57 MHz, DMSO-d6, 25 ꢀC):
d
¼26.5 (CH2), 36.2 (CH2), 44.0 (SO2Me), 44.1 (CH), 44.2 (CH), 118.0,
132.0, 133.7, 134.1, 137.3, 166.5, 167.8, 168.2 (arom), 183.2 (CO), 183.3
IR (KBr)
n
¼3419, 3197, 1728, 1683, 1616 cmꢁ1
;
1H NMR (300 MHz,
¼7.96 (m, 2H, Ar–H), 8.24 (m, 2H, Ar–H), 8.56 (s,
ꢂ
(CO); MS (EI) m/z (%B) 372 (Mþ , 34), 293 (21), 224 (40), 173 (100),
DMSO-d6, 25 ꢀC):
d
77 (C7Hþ7, 72). Anal. Calcd for C17H16N4O4S: C, 54.83; H, 4.33; N,
15.04; S, 8.61. Found: C, 54.61; H, 4.23; N, 14.90; S, 8.59.
2H, Ar–H), 11.75 (br s, 1H, NH), 11.79 (br s, 1H, NH); 13C NMR
(57 MHz, DMSO-d6, 25 ꢀC):
¼114.4, 119.0, 127.7, 127.8, 128.0, 134.1,
d

A. Herrera et al. / Tetrahedron 65 (2009) 1697–1703
1703
Yoshida, H.; Nakano, S.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Org. Lett. 2006, 8,
4157–4159; Goli, M.; Johnston, M. R.; Margeti, D.; Schultz, A. C.; Warrener, R. N.
Aust. J. Chem. 2006, 59, 899–914.
134.2, 135.4, 135.8, 138.3, 145.7, 150.9 (arom), 162.8 (CONH), 181.6
ꢂ
(CO), 182.7 (CO); MS (EI) m/z (%B) 292 (Mþ , 91), 249 (MꢁCONH,
100), 222 (23),162 (19). Anal. Calcd for C16H8N2O4: C, 65.76; H, 2.76;
N, 9.59. Found: C, 65.59; H, 2.67; N, 9.39.
9. Craig, D.; Robson, M. J.; Shaw, S. J. Synlett 1998, 1381–1383.
´n, N.; Seoane, C. Tet-
10. Herrera, A.; Martı´nez, R.; Gonza´lez, B.; Illescas, B.; Martı
rahedron Lett. 1997, 38, 4873–4876; Ko, C. W.; Chou, T. S. Tetrahedron Lett. 1997,
30, 5315–5318; Carly, P. R.; Cappelle, S. L.; Compernolle, F.; Hoornaert, G. J.
Tetrahedron 1996, 52, 11889–11904.
Acknowledgements
11. Diaz-Ortiz, A.; Herrero, M. A.; de la Hoz, A.; Moreno, A.; Carrillo, J. R. Synlett
2006, 579–582.
We thank the DGESIC (Spain, Grant CTQ2006-0444) for financial
support and the CAIs of the UCM (Madrid, Spain) for determining
spectra and CHN analyses.
12. Tome´, J. P. C.; Tome´, A. C.; Neves, M.; Cavaleiro, J. A. S. Tetrahedron Lett. 1997, 38,
2753–2756; Tome´, J. P. C.; Tome´, A. C.; Neves, M.; Almeida, P. F. A.; Gates, P. J.;
Klinowski, J.; Cavaleiro, J. A. S. Tetrahedron 2003, 59, 7907–7913; Capelle, S. L.;
Vogels, I.; Compernolle, F.; Hoornaert, G. Tetrahedron Lett. 2001, 42, 3759–3762;
Carly, P. R.; Govaerst, T. C.; Capelle, S. L.; Hoornaert, G. J. Tetrahedron 2001, 57,
4203–4212.
Supplementary data
13. Govaerts, T. C.; Vogels, I.; Compernolle, F.; Hoornaert, G. Tetrahedron 2004, 60,
429–439.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.12.016.
´
´
´
14. Herrera, A.; Martınez-Alvarez, R.; Chioua, M.; Chioua, R.; Almy, J.; Sanchez, A.
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´
´
15. Garcıa Martınez, A.; Herrera, A.; Moreno, F.; Luengo, M. J.; Subramanian, L. R.
Synlett 1994, 559–560.
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