6-Carbohydrazonamidepurines: Convenient precursors for 4,8-disubstituted pyrimido[5,4-d]pyrimidines

Article abstract of DOI:10.1055/s-0033-1340344

A series of 4-arylamino-8-(alkyl or aryl)hydrazidepyr?imido[5,4-d] pyrimidines was obtained efficiently from 6-carbo?hydrazonamidepurines by reaction with piperidine. The 6-carbo-?hydrazonamidepurines were generated selectively by the reaction of 6-imidatopurine with hydrazides under acidic conditions. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340344

LETTER
▌343
letter
6-Carbohydrazonamidepurines: Convenient Precursors for 4,8-Disubstituted
Pyrimido[5,4-d]pyrimidines
Synthesis of 4,8-Disubstituted Pyrimido[5,4-d]pyrimidines
Ashly Rocha, Ana H. Bacelar, Joana Fernandes, M. Fernanda Proenca, M. Alice Carvalho*
Centro de Química, Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Fax +351(253)604382; E-mail: mac@quimica.uminho.pt
Received: 25.09.2013; Accepted after revision: 09.11.2013
chlorine atoms by amines.6 The 6-cyanopurines have also
Abstract: A series of 4-arylamino-8-(alkyl or aryl)hydrazidepyr-
been used as precursors of substituted pyrimido[5,4-d]py-
imido[5,4-d]pyrimidines was obtained efficiently from 6-carbo-
rimidines, as the reaction with amines leads to the desired
hydrazonamidepurines by reaction with piperidine. The 6-carbo-
hydrazonamidepurines were generated selectively by the reaction of
structure by an ANRORC-type mechanism.7 This ap-
6-imidatopurine with hydrazides under acidic conditions.
proach has been used in our group for the efficient synthe-
sis of compounds 2 (Scheme 1).4,8–10 According to the
literature, structure 2 can be used to generate the aromatic
analogue 3 by Dimroth rearrangement, in the presence of
acid or base catalysis.11 Furthermore, our studies on the
reactivity of the pyrimidopyrimidine derivatives 2 (R2 =
OBn) have proved that the conversion of 2 (R2 = OBn)
into 3 (R2 = OBn) occurs efficiently under acid conditions
although other products may also be formed (Scheme 1).10
In the present work, compounds 2 were considered to be
convenient precursors of the aromatic pyrimido[5,4-d]py-
rimidines 3 (R2 = NHCOR3).
Key words: rearrangement, ring opening, ring closure, substituent
effects, fused-ring systems, heterocycles
Tuberculosis affects much of the world population and it
is estimated that 9.2 million new cases appear each year,
from which many lead to death.1 The emergence of multi-
drug resistant tuberculosis (MDR-TB) and extensively
drug resistant tuberculosis (XDR-TB) has added urgency
to the search for new antitubercular agents2 and, since the
last decade of the 20th century, the scientific community
has undertaken intensive research in this area.3 Recently,
in our research group, the pyrimido[5,4-d]pyrimidines
(Figure 1) were identified as a promising new class of an-
titubercular agents.4 The new compounds showed high
potency that depends on the substituents R1 and R2. Fur-
thermore, the new compounds have no structural similar-
ity to any other compounds active against Mycobacterium
tuberculosis and may have a different mechanism of ac-
tion in relation to drugs currently on the market. Therefore
a research program was started in order to develop new
methods for the efficient synthesis of new pyrimido[5,4-
d]pyrimidines derivatives 3 (Scheme 1) for structure–
activity relationship studies.
R1
R1
HN
R1
N
N
HN
N
N
H+, Δ
R2NH2
complex
mixture
N
+
N
N
N
N
or
N
HO–, Δ
CN
N
R2
NH
N
NHR2
1
3
2
R
1 = 4-NCC6H4
R2 = NHCOPh
EtOH, H+, Δ
3
R
1 = Ar
R2 = OBn
Scheme 1 Synthesis of 2, its conversion into 3 (R2 = OBn) and at-
tempts to generate new derivatives 3 (R1 = 4-NCC6H4, R2
=
R1
NHCOR3).
N
HN
R1 = Ar
N
R2 = Alk, Ar, HetAr
N
Herein we report our attempts to convert pyrimido[5,4-
d]pyrimidine 2 (R2 = NHCOR3) into 3 (R2 = NHCOR3)
and the new synthetic strategy designed to generate deriv-
atives 3 starting from 6-carbohydrazonamidepurines 4
that have proved to be valuable precursors for the target
compounds 3.
N
NH
3.5 μg/mL < IC90 < 10 μg/mL
NHCOR2
Figure 1 A new class of antitubercular agents
In the literature, the pyrimido[5,4-d]pyrimidine core
structure has been prepared from a substituted pyrimidine,
upon reaction with an appropriate electrophile or nucleo-
phile.5 Amino substituents are usually incorporated into
the heteroaromatic ring by nucleophilic substitution of
Compound 2 (R1 = 4-NCC6H4, R2 = NHCOPh) was pre-
pared by reaction of the 6-cyanopurine 1 (R1 = 4-NCC6H4)
with benzoic hydrazide according to a previously de-
scribed procedure.4 Attempts to perform the Dimroth re-
arrangement of 2 (R1 = 4-NCC6H4, R2 = NHCOPh) under
reflux conditions using ethanol and hydrochloric acid led
to a complex mixture (evidence by TLC) and the product
was isolated as a yellow solid when the starting material
SYNLETT 2014, 25, 0343–0348
Advanced online publication: 19.12.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
1
DOI: 10.1055/s-0033-1340344; Art ID: ST-2013-D0911-L
© Georg Thieme Verlag Stuttgart · New York
was no longer present. The H NMR of the solid con-

344
A. Rocha et al.
LETTER
firmed the formation of a complex mixture, where the sig- of the purine ring 4 readily leading to the substituted py-
nals for the desired product 3 could be identified as the rimidine 5. The bulkiness of the piperidine group presum-
major component (Scheme 1). A similar result was ob- ably prevents nucleophilic attack at the starred carbon by
tained when sulfuric acid or trifluoroacetic acid were used the sterically congested amidrazone nitrogen (blue nitro-
as catalysts. The conversion of 2 (R2 = NHCOR3) into 3 gen atom) in intermediate 5 (Scheme 2). Cyclization oc-
(Scheme 1) was also attempted under basic conditions us- curred preferentially through the primary amine (red
ing ethanol as solvent and aqueous sodium hydroxide. nitrogen atom), leading to 3. The reactions were per-
Again, complex mixtures resulted from these reactions formed under reflux conditions, and the products were
and the desired product 3 was only identified by 1H NMR isolated in good to excellent yield after 17–30 hours (Ta-
analysis of the isolated solids as a minor component. The ble 1, entries 11–20),14 following removal of solvent by
reactivity of compound 2 was clearly affected by the na- rotary evaporator and addition of water. The structures of
ture of the substituent R2 as the presence of the amide all new compounds were supported by analytical and
group resulted in complex reaction mixtures under the ex- spectroscopic data.15
perimental conditions normally used for the Dimroth rear-
In conclusion, we have described a new and efficient
rangement. Thus, efficient formation of pyrimido[5,4-
method to generate 4,8-disubstituted pyrimido[5,4-
d]pyrimidines 3 required an alternative approach and a
d]yrimidines 3 (R2 = NHCOR3) starting from novel 6-car-
new synthetic strategy was designed (Scheme 2).
bohydrazonamidepurines 4. Purines 4 were obtained from
6-Cyanopurines 1 had been previously used to generate 6- 6-imidatopurines 6 by reaction with hydrazides under
imidatopurines 6,12 and reaction of these compounds with acidic conditions. The reaction proceeds smoothly when
hydrazides was carried out in the presence of acid cataly- R1 is an aryl group while amidrazone substituent R3 can be
sis, aiming to prepare the 6-amidinopurines 4. Previous alkyl, aryl or heteroaryl groups. We have also demonstrat-
results on the reactivity of the purine ring, under basic ed that pyrimido[5,4-d]pyrimidines 2 (R2 = NHCOR3) are
conditions and in the presence of nucleophiles, indicated not convenient precursors of the new derivatives 3 as
that attack on C8 was the major pathway,8–10 leading to compounds 2 (R2 = NHCOR3) generated complex mix-
pyrimidopyrimidines 2. The use of a catalytic amount of tures when submitted to reaction conditions normally
sulfuric acid, when a suspension of compound 6a in di- leading to Dimroth rearrangement.
methylsulfoxide was combined with acetic hydrazide 7a,
prevented the competitive formation of product 2.
Acknowledgment
The mixture was stirred at room temperature and, when
Thanks are due to the University of Minho and Fundação para a
TLC showed the absence of starting material, addition of
Ciência e Tecnologia (FCT) for financial support [project nºF-
COMP-01-0124-FEDER-022716
UI0686/2011) FEDER-COMPETE, FCT-Portugal, a PhD grant
awarded to Ana Bacelar (SRFH/BD/24959/2005)]. The NMR spec-
trometer (Bruker 400 Avance III) is part of the National NMR Net-
work supported with funds from FCT.
water led to the isolation of a solid product identified as
(ref.
FCT
PEst-/QUI/
4a, in 51% yield13 (Table 1, entry 1). Similar reaction con-
ditions were applied to the reactions of 6a–c with other
alkyl (7b), aryl (7c,e) and heteroaryl hydrazides (7d). The
products 4a–j were isolated in excellent yields by simple
filtration of the reaction mixture (Table 1, entries 2–10).
References and Notes
The conversion of 6-amidinopurines 4 into the pyrimi-
do[5,4-d]pyrimidines 3 was performed in the presence of
piperidine using ethanol or ethanol–DMF, when the re-
agents were observed to be poorly soluble in ethanol
alone. Piperidine is a powerful nucleophile that attacks C8
(1) (a) Dye, C. Nat. Rev. Microbiol. 2009, 7, 81. (b) Tomioka,
H.; Tatano, Y.; Yasumoto, K.; Shimizu, T. Expert Rev.
Respir. Med. 2008, 2, 455.
R1
R1
R1
N
N
HN
HN
N
HN
Nu
N
N
N
N
N
N
N
*
N
NHR2
R2
N
R2
NH
H2N
3
5
2
R1
N
R1
N
R1
N
N
N
N
8
N
N
N
N
N
N
N
R2
CN
H2N
HN
OMe
1
6
4
Scheme 2 Disconnection of pyrimido[5,4-d]pyrimidine 3 (R2 = NHCOR3)
Synlett 2014, 25, 343–348
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 4,8-Disubstituted Pyrimido[5,4-d]pyrimidines
345
Table 1 Synthesis of 6-Carbohydrazonamidepurines 4 and 4,8-Disubstituted Pyrimido[5,4-d]pyrimidines 3
R1
N
R1
N
R1
HN
i) H2NNHCOR3 (1.5 equiv)
DMSO, H+ (cat.), r.t.
N
N
N
ii) EtOH, piperidine
reflux
N
N
N
N
N
N
7
HN
OMe
H2N
NNHCOR3
N
NHNHCOR3
a R3 = Me
6
b R3 = heptyl
c R3 = Ph
4
a R1 = Ph
b R1 = 4-ClC6H4
c R1 = 4-Me-3-ClC6H3
3
d R3 = 3'-pyridinyl
e R3 = 4'-O2NC6H4
Entry
Reagent
R1
R3
Reaction conditions
Product Yield (%)
1
2
6a (0.75 mmol)
6a (1.59 mmol)
6a (0.60 mmol)
6a (0.99 mmol)
6b (0.92 mmol)
6b (0.86 mmol)
6b (1.01 mmol)
6c (1.27 mmol)
6c (1.20 mmol)
6c (0.82 mmol)
4a (1.20 mmol)
4b (0.49 mmol)
4c (0.28 mmol)
4d (0.60 mmol)
4e (0.61mmol)
4f (0.51 mmol)
4g (1.22 mmol)
4h (1.35 mmol)
4i (0.92 mmol)
4j (0.48 mmol)
Ph
7a
7b
7c
7d
7b
7e
7d
7b
7e
7d
Me
i) DMSO (1.2 mL), 1 h
i) DMSO (2.5 mL), 10 min
i) DMSO (2.0 mL), 1 h
i) DMSO (2.0 mL), 10 min
i) DMSO (2.2 mL), 15 min
i) DMSO (2.0 mL), 15 min
i) DMSO (2.0 mL), 10 min
i) DMSO (2.2 mL), 10 min
i) DMSO (2.0 mL), 18 min
i) DMSO (2.4 mL), 20 min
ii)a 24 h
4a
4b
4c
4d
4e
4f
51
97
85
83
99
98
94
99
83
79
63
76
51
54
75
81
72
86
82
99
Ph
heptyl
Ph
3
Ph
4
Ph
3′-pyridinyl
heptyl
5
4-ClC6H4
4-ClC6H4
4-ClC6H4
6
4′-O2NC6H4
3′-pyridinyl
heptyl
7
4g
4h
4i
8
4-Me-3-ClC6H3
4-Me-3-ClC6H3
4-Me-3-ClC6H3
Ph
9
4′-O2NC6H4
3′-pyridinyl
Me
10
11
12
13
14
15
16
17
18
19
20
4j
3a
3b
3c
3d
3e
3f
Ph
heptyl
ii)b 24 h
Ph
Ph
ii)c 30 h
Ph
3′-pyridinyl
heptyl
ii)c 24 h
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-Me-3-ClC6H3
4-Me-3-ClC6H3
4-Me-3-ClC6H3
ii)b 18 h
4′-O2NC6H4
3′-pyridinyl
heptyl
ii)b 23 h
ii)b 22 h
3g
3h
3i
ii)b 20 h
4′-O2NC6H4
3′-pyridinyl
ii)b 17 h
ii)b 24 h
3j
a EtOH (10 mL), piperidine (0.6 mL).
b EtOH (10 mL), piperidine (0.5 mL).
c EtOH (10 mL), DMF (0.4 mL), piperidine (0.5 mL).
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 343–348

346
A. Rocha et al.
LETTER
Player, M. R. Comb. Chem. High Throughput Screening
2004, 7, 413.
Compound 3b: yield: 76%; crème solid; mp 142–144 °C. IR
(nujol mull): 3365, 3237, 1678, 1597, 1576, 1524 cm–1. 1H
NMR (300 MHz, DMSO-d6–TFA): δ = 10.11 (s, 1 H, NH,
D2O exch.), 10.08 (s, 1 H, NH, D2O exch.), 8.64 (s, 1 H,
CH), 8.58 (s, 1 H, CH), 7.99 (d, J = 7.5 Hz, 2 H, Ar), 7.38 (t,
J = 7.5 Hz, 2 H, Ar), 7.13 (t, J = 7.5 Hz, 1 H, Ar), 2.21 (t,
J = 7.2 Hz, 2 H), 1.55–1.58 (m, 2 H), 1.28 (m, 8 H), 0.84–
0.86 (m, 3 H). 13C NMR (75 MHz, DMSO-d6–TFA): δ =
171.4, 158.3, 156.4, 154.1 (2 ×), 138.4, 131.9, 131.0, 128.6,
124.0, 121.9, 33.3, 31.3, 28.6, 28.5, 25.1, 22.1, 14.0. Anal.
Calcd for C20H25N7O: C, 63.30; H, 6.64; N, 25.84. Found: C,
63.33; H, 6.86; N, 25.85.
Compound 3c: yield: 51%; yellow solid; mp >300 °C. IR
(nujol mull): 3315, 3169, 1670, 1680, 1539, 1530 cm–1. 1H
NMR (300 MHz, DMSO-d6): δ = 10.69 (br s, 1 H, NH, D2O
exch.), 10.41 (br s, 1 H, NH, D2O exch.), 10.06 (s, 1 H, NH,
D2O exch.), 8.67 (s, 1 H, CH), 8.59 (s, 1 H, CH), 8.01 (d,
J = 7.8 Hz, 2 H, Ar), 7.96 (d, J = 7.2 Hz, 2 H, Ar), 7.60 (t,
J = 7.2 Hz, 1 H, Ar), 7.52 (t, J = 7.2 Hz, 2 H, Ar), 7.39 (t, J
= 7.8 Hz, 2 H, Ar), 7.13 (t, J = 7.8 Hz, 1 H, Ar). 13C NMR
(75 MHz, DMSO-d6): δ = 165.4, 158.7, 156.3, 154.4, 154.1,
132.5, 132.1, 131.8, 131.1, 128.6, 128.5, 127.5, 123.3,
121.6. Anal. Calcd for C19H15N7O: C, 63.86; H, 4.23; N,
27.44. Found: C, 63.58; H, 4.32; N, 27.53.
Compound 3d: yield: 54%; yellow solid; mp 255–257 °C.
IR (nujol mull): 3315, 3248, 3105, 1640, 1601, 1591, 1568,
1527 cm–1. 1H NMR (300 MHz, DMSO-d6–TFA): δ = 10.95
(s, 1 H, NH, D2O exch.), 10.10 (s, 1 H, NH, D2O exch.), 9.14
(d, J = 1.6 Hz, 1 H), 8.81 (dd, J = 1.6, 5.2 Hz, 1 H, HetAr),
8.69 (s, 1 H, CH), 8.63 (s, 1 H, CH), 8.35 (dd, J = 1.6, 6.0
Hz, 1 H, HetAr), 8.01 (d, J = 7.6 Hz, 2 H, Ar), 7.64 (dd, J =
5.2, 6.0 Hz, 1 H, HetAr), 7.39 (t, J = 7.6 Hz, 2 H, Ar), 7.14
(t, J = 7.6 Hz, 1 H, Ar). 13C NMR (75 MHz, DMSO-d6–
TFA): δ = 164.4, 158.8, 156.5, 154.5, 154.3, 152.1, 148.1,
138.4, 136.0, 132.2, 131.1, 128.6, 128.4, 124.0 (2 ×), 121.7.
Anal. Calcd for C18H14N8O: C, 60.33; H, 3.94; N, 31.27.
Found: C, 60.09; H, 4.00; N, 31.13.
Compound 3e: yield: 75%; off-white solid; mp 165–167 °C.
IR (nujol mull): 3357, 3251, 1679, 1654, 1615, 1603, 1595,
1569, 1547 cm–1. 1H NMR (300 MHz, DMSO-d6–TFA): δ =
10.23 (s, 1 H, NH, D2O exch.), 10.05 (s, 1 H, NH, D2O
exch.), 8.65 (s, 1 H, CH), 8.58 (s, 1 H, CH), 8.07 (d, J = 8.9
Hz, 2 H, Ar), 7.42 (d, J = 8.9 Hz, 2 H, Ar), 2.21 (t, J = 7.5
Hz, 2 H), 1.54–1.59 (m, 2 H), 1.26–1.29 (m, 8 H), 0.84–0.86
(m, 3 H). 13C NMR (75 MHz, DMSO-d6–TFA): δ = 171.4,
158.6, 156.4, 154.4, 153.9, 137.5, 132.0, 131.1, 128.4,
127.5, 123.2, 33.3, 31.2, 28.6, 28.5, 25.0, 22.1, 14.0. Anal.
Calcd for C20H24ClN7O: C, 58.04; H, 5.84; N, 23.69. Found:
C, 58.15; H, 5.95; N, 23.43.
(7) (a) Srivastava, P. C.; Revankar, G. R.; Robins, R. K.;
Rousseau, R. J. J. Med. Chem. 1981, 24, 393. (b) Cook, P.
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S.; Colacino, J. M.; Grindey, G. B.; Worzalla, J. F.; Pearce,
H. L. Nucleosides Nucleotides 1994, 13, 1125. (d) Berman,
H. M.; Rousseau, R. J.; Mancuso, R. W.; Kreishman, G. P.;
Robins, R. K. Tetrahedron Lett. 1973, 3099. (e) Westover, J.
D.; Revankar, G. R.; Robins, R. K.; Madsen, R. D.; Ogden,
J. R.; North, J. A.; Mancuso, R. W.; Rousseau, R. J.;
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A.; Marrelec, E.; Pritchard, R. G.; Proença, M. F. J. Chem.
Soc., Perkin Trans. 1 2001, 2532.
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Eur. J. Org. Chem. 2007, 1324.
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(13) Experimental Procedure for the Synthesis of 6-Carbo-
hydrazonamidepurine 4a: The 6-imidatopurines 6a (0.19
g, 0.75 mmol) and hydrazide 7a (0.08g, 1.3 mmol, 1.5 equiv)
were combined in a round-bottom flask using DMSO (1.2
mL) as solvent and sulfuric acid (25 μL) as catalyst. The
reaction was stirred at r.t. until TLC analysis showed the
absence of starting material (1 h) and H2O (10 mL) was
added to the reaction mixture. The yellow suspension was
filtered, washed with H2O, EtOH and Et2O and identified as
6-carbohydrazonamidepurine 4a (0.12 g, 0.38 mmol, 51%);
mp 235–237 °C. IR (nujol mull): 3459, 3363, 3203, 3057,
1680, 1655, 1590, 1576, 1567 cm–1. 1H NMR (300 MHz,
DMSO-d6–TFA): δ = 10.27 (s, 2 H, NH2, D2O exch.), 9.44
(s, 1 H, CH), 9.29 (s, 1 H, CH), 7.93 (d, J = 7.8 Hz, 2 H, Ar),
7.68 (t, J = 7.8 Hz, 2 H, Ar), 7.57 (t, J = 7.8 Hz, 1 H, Ar),
2.03 (s, 3 H, Me). 13C NMR (75 MHz, DMSO-d6): δ = 168.7,
158.6, 153.4, 152.3, 149.4, 139.6, 133.6, 131.9, 129.8,
128.9, 124.0, 21.0. Anal. Calcd for C14H13N7O: C, 56.94; H,
4.44; N, 33.20. Found: C, 56.77; H, 4.55; N, 33.02.
(14) Experimental Procedure for the Synthesis of
Pyrimido[5,4,-d]pyrimidine 3a: A solution of 6-carbo-
hydrazonamidepurine 4a (0.35 g, 1.2 mmol) in EtOH (10
mL) and piperidine (0.6 mL) was heated to reflux for 24 h,
when TLC showed the absence of starting material. The
suspension was concentrated to dryness and H2O was added
to the residue. The resulting off-white solid was filtered,
washed with H2O and EtOH and identified as the
Compound 3f: yield: 81%; orange solid; mp >300 °C. IR
(nujol mull): 3310, 3218, 1693, 1666, 1604, 1594, 1570,
1537 cm–1. 1H NMR (300 MHz, DMSO-d6–TFA): δ = 10.08
(s, 1 H, NH, D2O exch.), 10.29 (s, 1 H, NH, D2O exch.), 8.71
(s, 1 H, CH), 8.63 (s, 1 H, CH), 8.38 (d, J = 8.9 Hz, 2 H, Ar),
8.18 (d, J = 8.9 Hz, 2 H, Ar), 8.08 (d, J = 8.9 Hz, 2 H, Ar),
7.43 (d, J = 8.9 Hz, 2 H, Ar). 13C NMR (75 MHz, DMSO-
d6–TFA): δ = 164.1, 158.7, 156.5, 154.5, 154.2, 149.5,
138.1, 137.5, 132.2, 131.2, 129.1, 128.4, 127.6, 123.8,
123.3. Anal. Calcd for C19H13ClN8O3: C, 52.24; H, 3.00; N,
25.65. Found: C, 51.99; H, 3.27; N, 25.42.
Compound 3g: yield 72%; light yellow solid; mp 282–284
°C. IR (nujol mull): 3347, 3209, 1684, 1642, 1614, 1580,
1544, 1505 cm–1. 1H NMR (400 MHz, DMSO-d6–TFA): δ =
10.99 (br s, 1 H, NH, D2O exch.), 10.27 (s, 1 H, NH, D2O
exch.), 9.14 (d, J = 1.6 Hz, 1 H, HetAr), 8.83 (s, 1 H, CH),
8.71 (s, 1 H, CH), 8.82 (dd, J = 2.0, 4.8 Hz, 1 H, HetAr), 8.37
(dt, J = 2.0, 8.0 Hz, 1 H, HetAr), 8.08 (d, J = 8.8 Hz, 2 H,
pyrimido[5,4-d]pyrimidine 3a (0.22 g, 0.76 mmol, 63%);
mp 181–182 °C. IR (nujol mull): 3360, 3225, 3048, 1610,
1590, 1551, 1528 cm–1. 1H NMR (300 MHz, DMSO-d6–
TFA): δ = 10.19 (br s, 1 H, NH, D2O exch.), 10.16 (br s, 1 H,
NH, D2O exch.), 8.65 (s, 1 H, CH), 8.61 (s, 1 H, CH) 7.97 (d,
J = 7.5 Hz, 2 H, Ar), 7.38 (t, J = 7.5 Hz, 2 H, Ar), 7.14 (t,
J = 7.5 Hz, 1 H, Ar), 1.96 (s, 3 H, Me). 13C NMR (75 MHz,
DMSO-d6–TFA): δ = 168.4, 157.9, 156.5, 154.2, 153.5,
138.3, 131.8, 131.0, 128.6, 124.2, 121.9, 20.7. Anal. Calcd
for C14H13N7O: C, 56.94; H, 4.44; N, 33.20. Found: C,
56.77; H, 4.55; N, 33.57.
(15) Analytical and spectroscopic data for compounds 3b–j and
4b–j:
Synlett 2014, 25, 343–348
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 4,8-Disubstituted Pyrimido[5,4-d]pyrimidines
347
Ar), 7.66 (dd, J = 4.8, 8.0 Hz, 1 H, HetAr), 7.43 (d, J = 8.8
63.86; H, 4.23; N, 27.44. Found: C, 63.55; H, 4.45; N, 27.17.
Compound 4d: yield: 83%; orange solid; mp >300 °C. IR
(nujol mull): δ = 3352, 3180, 1682, 1631, 1583, 1509 cm–1.
1H NMR (400 MHz, DMSO-d6–TFA): δ = 9.77 (s, 2 H, NH2,
D2O exch.), 9.43 (s, 1 H, CH), 9.28 (s, 1 H, CH), 9.24 (d,
J = 1.2 Hz, 1 H, HetAr), 8.63 (dd, J = 1.2, 4.8 Hz, 1 H,
HetAr), 8.46 (d, J = 8.0 Hz, 1 H, HetAr), 7.95 (d, J = 7.6 Hz,
2 H, Ar), 7.65–7.70 (m, 3 H, Ar + HetAr), 7.57 (t, J = 7.6 Hz,
1 H, Ar). 13C NMR (75 MHz, DMSO-d6–TFA): δ = 151.0,
163.8, 154.7, 153.1, 151.9, 148.0, 147.3, 145.1, 136.8,
133.7, 131.5, 129.7, 129.6, 128.8, 123.9, 123.8. Anal. Calcd
for C18H14N8O: C, 60.33; H, 3.94; N, 31.27. Found: C,
60.49; H, 4.11; N, 30.98.
Compound 4e: yield: 99%; off-white solid; mp 209–211 °C.
IR (nujol mull): δ = 3420, 3345, 3283, 3225, 1668, 1646,
1603, 1575, 1553, 1518 cm–1. 1H NMR (400 MHz, DMSO-
d6–TFA): δ = 10.81 (s, 1 H, NH, D2O exch.), 10.22 (s, 2 H,
NH2, D2O exch.), 9.45 (s, 1 H, CH), 9.31 (s, 1 H, CH), 8.00
(d, J = 8.0 Hz, 2 H, Ar), 7.74 (d, J = 8.0 Hz, 2 H, Ar), 2.31
(t, J = 7.8 Hz, 2 H), 1.57–1.61 (m, 2 H), 1.24–1.30 (m, 8 H),
0.83–0.88 (m, 3 H). 13C NMR (75 MHz, DMSO-d6–TFA): δ
= 171.7, 158.4, 153.3, 152.3, 149.1, 139.6, 133.3, 132.5,
131.9, 129.8, 125.6, 33.3, 31.2, 28.6, 28.5, 24.3, 22.1, 13.9.
Anal. Calcd for C20H24ClN7O: C, 58.04; H, 5.84; N, 23.69.
Found: C, 57.95; H, 5.93; N, 23.44.
Compound 4f: yield: 98%; orange solid; mp >300 °C. IR
(nujol mull): 3405, 3355, 3298, 3258, 3241, 3210, 3040,
1686, 1671, 1650, 1620, 1590, 1573, 1547, 1509 cm–1. 1H
NMR (300 MHz, DMSO-d6–TFA): δ = 10.27 (s, 2 H, NH2,
D2O exch.), 9.48 (s, 1 H, CH), 9.34 (s, 1 H, CH), 8.41 (d,
J = 8.9 Hz, 2 H, Ar), 8.25 (d, J = 8.9 Hz, 2 H, Ar), 8.02 (d,
J = 8.7 Hz, 2 H, Ar), 7.79 (d, J = 8.7 Hz, 2 H, Ar). 13C NMR
(75 MHz, DMSO-d6–TFA): δ = 157.2, 154.2, 153.3, 152.4,
149.6, 149.2, 139.7, 137.9, 133.3, 132.6, 131.8, 129.8,
129.6, 125.7, 123.6. Anal. Calcd for C19H13ClN8O3: C,
52.24; H, 3.00; N, 25.65. Found: C, 52.38; H, 3.28; N, 25.80.
Compound 4g: yield: 94%; orange solid; mp >300 °C. IR
(nujol mull): 3430, 1680, 1653, 1580 cm–1. 1H NMR (300
MHz, DMSO-d6–TFA): δ = 9.77 (s, 2 H, NH2, D2O exch.),
9.47 (s, 1 H, CH), 9.34 (s, 1 H, CH), 9.24 (d, J = 1.5 Hz, 1 H,
HetAr), 8.86 (dd, J = 1.5, 5.4 Hz, 1 H, HetAr), 8.63 (d, J =
8.1 Hz, 1 H, HetAr), 8.02 (d, J = 6.9 Hz, 2 H, Ar), 7.73–7.80
(m, 3 H, Ar + HetAr). 13C NMR (75 MHz, DMSO-d6–TFA):
δ = 163.7, 156.9, 153.3, 152.4, 150.8, 149.2, 147.5, 139.6,
137.7, 133.3, 132.6, 131.8, 129.8, 129.2, 125.7, 124.4.
HRMS (ESI): m/z [M+ + 1] calcd for C18H14ClN8O:
393.80976; found: 393.80975.
Hz, 2 H, Ar). 13C NMR (100 MHz, DMSO-d6–TFA): δ =
163.9, 158.8, 156.5, 154.8, 154.1, 151.8, 147.8, 137.5,
136.3, 132.2, 131.2, 128.5, 128.4, 127.6, 124.2, 123.2. Anal.
Calcd for C18H13ClN8O: C, 55.04; H, 3.34; N, 28.53. Found:
C, 55.14; H, 3.54; N, 28.74.
Compound 3h: yield: 86%; yellow solid; mp 165–167 °C.
IR (nujol mull): 3360, 3225, 1674, 1599, 1525 cm–1. 1H
NMR (400 MHz, DMSO-d6–TFA): δ = 10.10 (s, 1 H, NH,
D2O exch.), 10.07 (s, 1 H, NH, D2O exch.), 8.68 (s, 1 H,
CH), 8.58 (s, 1 H, CH), 8.24 (d, J = 1.5 Hz, 1 H, Ar), 7.84
(dd, J = 1.5, 8.1 Hz, 1 H, Ar), 7.31 (d, J = 8.1 Hz, 1 H, Ar),
2.30 (s, 3 H, Me), 2.26 (t, J = 7.2 Hz, 2 H), 1.54–1.58 (m, 2
H), 1.26–1.29 (m, 8 H), 0.84–0.86 (m, 3 H). 13C NMR (100
MHz, DMSO-d6–TFA): δ = 171.4, 158.4, 156.4, 154.1,
154.0, 137.7, 132.8, 131.9, 131.0, 130.9, 130.6, 121.4,
120.3, 33.3, 31.1, 28.6, 28.5, 25.1, 22.1, 14.0. HRMS (ESI):
m/z [M+ + 1] calcd for C21H27ClN7O: 428.93838; found:
428.93840.
Compound 3i: yield: 82%; orange solid; mp >300 °C. IR
(nujol mull): 3311, 3215, 1665, 1591, 1533, 1522 cm–1. 1H
NMR (300 MHz, DMSO-d6–TFA): δ = 11.06 (s, 1 H, NH,
D2O exch.), 10.22 (s, 1 H, NH, D2O exch.), 8.74 (s, 1 H,
CH), 8.63 (s, 1 H, CH), 8.39 (d, J = 8.8 Hz, 2 H, Ar), 8.27 (d,
J = 2.0 Hz, 1 H, Ar), 8.18 (d, J = 8.8 Hz, 2 H, Ar), 7.87 (dd,
J = 2.0, 8.4 Hz, 1 H, Ar), 7.34 (d, J = 8.4 Hz, 1 H, Ar), 2.31
(s, 3 H, Me). 13C NMR (100 MHz, DMSO-d6–TFA): δ =
164.0, 158.8, 156.4, 154.6, 154.2, 149.5, 138.1, 137.7, 132.8
(2 ×), 131.1, 130.9, 130.4, 129.1, 123.8, 121.4, 120.3, 19.0.
HRMS (ESI): m/z [M+ + 1] calcd for C20H16ClN8O3:
451.84584; found: 451.84583.
Compound 3j: yield: 99%; yellow solid; mp 300–302 °C.
IR (nujol mull): 3438, 3358, 3199, 1683, 1652, 1604, 1584,
1540 cm–1. 1H NMR (400 MHz, DMSO-d6–TFA): δ = 11.05
(s, 1 H, NH, D2O exch.), 10.23 (s, 1 H, NH, D2O exch.), 9.18
(d, J = 1.6 Hz, 1 H, HetAr), 8.88 (dd, J = 1.6, 5.2 Hz, 1 H,
HetAr), 8.74 (s, 1 H, CH), 8.62 (s, 1 H, CH), 8.48 (dd, J =
1.6, 8.0 Hz, 1 H, HetAr), 8.26 (d, J = 2.0 Hz, 1 H, Ar), 7.86
(dd, J = 2.0, 8.6 Hz, 1 H, Ar), 7.75 (dd, J = 5.2, 8.0 Hz, 1 H,
HetAr), 7.34 (d, J = 8.6 Hz, 1 H, Ar), 2.31 (s, 3 H, Me). 13
C
NMR (100 MHz, DMSO-d6): δ = 163.5, 159.0, 156.5, 154.4,
154.2, 150.8, 146.9, 137.6 (2 ×), 132.8, 132.2, 131.2, 130.9,
130.6, 128.9, 124.7, 121.5, 120.3, 19.0. Anal. Calcd for
C19H15ClN8O: C, 56.09; H, 3.72; N, 27.54. Found: C, 56.22;
H, 3.82; N, 27.88.
Compound 4b: yield: 97%; crème solid; mp 208–210 °C. IR
(nujol mull): 3430, 3351, 3291, 3224, 3108, 3066, 3048,
1666, 1647, 1581, 1556, 1506 cm–1. 1H NMR (400 MHz,
DMSO-d6–TFA): δ = 10.80 (s, 1 H, NH, D2O exch.), 10.24
(s, 2 H, NH2, D2O exch.), 9.46 (s, 1 H, CH), 9.31 (s, 1 H,
CH), 7.94 (d, J = 7.6 Hz, 2 H, Ar), 7.69 (t, J = 7.6 Hz, 2 H,
Ar), 7.58 (t, J = 7.6 Hz, 1 H, Ar), 2.30 (t, J = 7.2 Hz, 2 H),
1.58–1.60 (m, 2 H), 1.28–1.30 (m, 8 H), 0.86 (t, J = 6.8 Hz,
3 H). 13C NMR (75 MHz, DMSO-d6–TFA): δ = 171.5,
158.7, 153.3, 152.3, 149.3, 139.6, 133.6, 131.9, 129.8,
128.9, 124.0, 33.3, 31.2, 28.6, 28.5, 24.3, 22.1, 13.9. Anal.
Calcd for C20H25N7O: C, 63.30; H, 6.64; N, 25.84. Found: C,
63.27; H, 6.56; N, 25.74.
Compound 4c: yield: 85%; yellow solid; mp 236–240 °C.
IR (nujol mull): 3378, 3316, 3181, 3097, 1650, 1600, 1590,
1573, 1532, 1509 cm–1. 1H NMR (300 MHz, DMSO-d6–
TFA): δ = 9.63 (br s, 2 H, NH2, D2O exch.), 9.39 (s, 1 H,
CH), 9.27 (s, 1 H, CH), 8.01 (d, J = 7.2 Hz, 2 H, Ar), 7.95 (d,
J = 7.8 Hz, 2 H, Ar), 7.69 (t, J = 7.8 Hz, 2 H, Ar), 7.57 (m, 4
H, Ar). 13C NMR (75 MHz, DMSO-d6–TFA): δ = 165.3,
157.3, 153.1, 152.2, 148.7, 141.5, 132.5, 132.1, 131.7,
128.4, 128.8, 128.0, 124.0. Anal. Calcd for C19H15N7O: C,
Compound 4h: yield: 99%; white solid; mp 234–236 °C.
IR (nujol mull): 3425, 3350, 3288, 3224, 3110, 3048, 1667,
1646, 1602, 1579, 1553, 1506 cm–1. 1H NMR (300 MHz,
DMSO-d6–TFA): δ = 10.81 (s, 1 H, NH, D2O exch.), 10.20
(s, 2 H, NH2, D2O exch.), 9.46 (s, 1 H, CH), 9.32 (s, 1 H,
CH), 8.12 (d, J = 2.1 Hz, 1 H, Ar), 7.87 (dd, J = 2.1, 8.4 Hz,
1 H, Ar), 7.67 (d, J = 8.4 Hz, 1 H, Ar), 2.25 (m, 5 H), 1.50–
1.61 (m, 2 H), 1.24–1.29 (m, 8 H), 0.82–0.87 (m, 3 H). 13
C
NMR (75 MHz, DMSO-d6–TFA): δ = 171.7, 158.3, 153.3,
152.4, 149.1, 139.7, 136.3, 133.9, 132.6, 132.1, 131.8,
123.9, 122.4, 33.4, 31.2, 28.6, 28.5, 24.3, 22.1, 19.3, 13.9.
Anal. Calcd for C21H26ClN7O: C, 58.94; H, 6.12; N, 22.91.
Found: C, 59.00; H, 5.98; N, 22.72.
Compound 4i: yield: 83%; orange solid; mp >300 °C. IR
(nujol mull): 3389, 3188, 1672, 1657, 1649, 1580, 1521,
1509 cm–1. 1H NMR (400 MHz, DMSO-d6–TFA): δ = 9.59
(s, 2 H, NH2, D2O exch.), 9.38 (s, 1 H, CH), 9.28 (s, 1 H,
CH), 8.35 (d, J = 8.4 Hz, 2 H, Ar), 8.28 (d, J = 8.4 Hz, 2 H,
Ar), 8.11 (d, J = 2.0 Hz, 1 H, Ar), 7.87 (dd, J = 2.0, 8.4 Hz,
1 H, Ar), 7.65 (d, J = 8.4 Hz, 1 H, Ar), 2.45 (s, 3 H, Me). 13
C
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 343–348

348
A. Rocha et al.
LETTER
NMR (75 MHz, DMSO-d6–TFA): δ = 163.2, 156.3, 152.0,
149.4, 149.1, 140.3, 138.1, 136.0, 133.7, 132.4, 131.8,
131.3, 128.7, 124.5, 123.1, 122.1, 18.9. HRMS (ESI): m/z
[M+ + 1] calcd for C20H16ClN8O3: 451.84584; found:
451.84583.
Compound 4j: yield: 79%; orange solid; mp >300 °C. IR
(nujol mull): 3438, 3358, 3199, 3041, 1683, 1652, 1604,
1584, 1540, 1510 cm–1. 1H NMR (300 MHz, DMSO-d6–
TFA): δ = 10.07 (s, 2 H, NH2, D2O exch.), 9.34 (s, 1 H, CH),
9.47 (s, 1 H, CH), 9.23 (d, J = 1.5 Hz, 1 H, HetAr), 8.85 (dd,
J = 1.5, 4.8 Hz, 1 H, HetAr), 8.48 (d, J = 7.8 Hz, 1 H, HetAr),
8.13 (d, J = 2.1 Hz, 1 H, Ar), 7.89 (dd, J = 2.1, 2.4 Hz, 1 H,
Ar), 7.66–7.73 (m, 2 H, Ar + HetAr), 2.49 (s, 3 H, Me). 13
C
NMR (75 MHz, DMSO-d6–TFA): δ = 163.8, 156.1, 153.2,
152.4, 151.0, 147.8, 139.9, 137.2, 136.3, 133.9, 132.6,
132.1, 131.6, 129.4, 124.2, 124.0, 122.4, 19.3. Anal. Calcd
for C19H15ClN8O: C, 56.09; H, 3.72; N, 27.54. Found: C,
56.31; H, 4.00; N, 27.72.
Synlett 2014, 25, 343–348
© Georg Thieme Verlag Stuttgart · New York

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