Diversity oriented synthesis: Substitution at C5 in unreactive pyrimidines by Claisen rearrangement and reactivity in nucleophilic substitution at C2 and C4 in pteridines and pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1016/j.tet.2011.03.011

Diversity oriented synthesis of fused pyrimidines leads to scaffolds with many biological activities. In the case of the preparation of pyrido[2,3-d]pyrimidines from 2-alkylthiopyrimidines, the formation of a new carbon-carbon bond at C5 is required, a reaction, that is, very limited in scope. However Claisen type rearrangement of simple 4-allylic ethers affords C5 substituted pyrimidines readily; in cases with an ester substituent, rearrangement occurs at room temperature. Subsequent cyclisation to afford 6-methylpyrido[2,3-d]pyrimidin-7(8H)-ones was achieved in high yield. Using allylic ethers derived from 3-chloromethyl-4-arylbut-3-en-2-ones as substrates, a new titanium[IV]chloride catalysed reaction affording 6-arylmethyl-7- methylpyrido[2,3-d]pyrimidines was discovered. In contrast, 2- alkylthiopteridines are readily available. In both cases, substitution at C2 and C4 to generate diversity has been carried out and the reactivity compared; yields of substitution products were generally higher with pteridine substrates. In biological assays unexpected hits were found for activity against the Gram positive bacterium, Nocardia farcinia, and against the parasite Trypanosoma brucei brucei, illustrating the value of diversity oriented synthesis in the discovery of biologically active compounds.

Full text of DOI:10.1016/j.tet.2011.03.011

Tetrahedron 67 (2011) 3226e3237
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Diversity oriented synthesis: substitution at C5 in unreactive pyrimidines by
Claisen rearrangement and reactivity in nucleophilic substitution at C2 and C4
in pteridines and pyrido[2,3-d]pyrimidines
*
Jonathan Adcock, Colin L. Gibson, Judith K. Huggan, Colin J. Suckling
WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, Scotland, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Diversity oriented synthesis of fused pyrimidines leads to scaffolds with many biological activities. In the
case of the preparation of pyrido[2,3-d]pyrimidines from 2-alkylthiopyrimidines, the formation of a new
carbonecarbon bond at C5 is required, a reaction, that is, very limited in scope. However Claisen type
rearrangement of simple 4-allylic ethers affords C5 substituted pyrimidines readily; in cases with an
ester substituent, rearrangement occurs at room temperature. Subsequent cyclisation to afford
6-methylpyrido[2,3-d]pyrimidin-7(8H)-ones was achieved in high yield. Using allylic ethers derived from
3-chloromethyl-4-arylbut-3-en-2-ones as substrates, a new titanium[IV]chloride catalysed reaction af-
fording 6-arylmethyl-7-methylpyrido[2,3-d]pyrimidines was discovered. In contrast, 2-alkylthiopter-
idines are readily available. In both cases, substitution at C2 and C4 to generate diversity has been carried
out and the reactivity compared; yields of substitution products were generally higher with pteridine
substrates. In biological assays unexpected hits were found for activity against the Gram positive bac-
terium, Nocardia farcinia, and against the parasite Trypanosoma brucei brucei, illustrating the value of
diversity oriented synthesis in the discovery of biologically active compounds.
Received 20 September 2010
Received in revised form 18 February 2011
Accepted 7 March 2011
Available online 12 March 2011
Keywords:
Pyrimidines
Claisen allyl rearrangement
Pyridopyrimidines
Pteridines
Diversity oriented synthesis
Antiparasitic activity
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
developments has been the alkylthio substituent, either at C2 or C4
of a pyrimidine and we have established a prototype solid phase
Whilst the synthesis of pteridines and related bicyclic nitrogen
heterocycles is established,1 the synthesis of their deaza analogues
requires further development because most methods for the syn-
thesis of such compounds have not been designed with the in-
tention of creating highly diverse libraries of compounds as is
required for modern medicinal chemistry in which multiple bi-
ological targets may be relevant. With emphasis on diversity ori-
ented synthesis in our own studies, we have identified active
compounds with respect to GTP cyclohydrolase 1,2 dihydropterin
diphosphokinase,3 dihydrofolate reductase,4 pteridine reductase 15
and nitric oxide synthase.6 Several of these targets are significant
clinically and the optimisation of activity requires the availability of
more diverse libraries within the same basic structural skeleton.
Our recent work, therefore, has emphasised maximising the
number of easily variable sites, so that at least three variations are
readily available from one synthetic stream. At the centre of these
synthesis of pteridines using this linker, which proceeds through C5
nitrosation of the alkylthiopyrimidine.7 Extension of this chemistry
to pyrido[2,3-d]pyrimidines and pyrrolo[2,3-d]pyrimidines re-
quires carbon substitution to take place at C5 of the pyrimidine.
Although a 2- or 4-alkylthio substituent gives access to diversity,
via oxidation and nucleophilic displacement, the presence of the
alkylthio substituent significantly reduces the reactivity of C5 to
electrophiles compared with the more common 2-amino sub-
stituent such that carbon electrophiles, do not react. A significant
exception is that when certain Michael acceptors are used, C5
substitution occurs in reduced yield8 and this chemistry has been
developed to provide compounds with significant activity against
Trypanosoma brucei.5 A further example of a successful C5 sub-
stitution of a 2-alkylthiopyrimidine is found in nucleoside analogue
synthesis and involves Vilsmeier formylation.9 In contrast, halogen
electrophiles substitute 2-alkylthiopyrimidines in high yield and
provide suitable precursors for C5 carbon substitution.10 In view of
the low reactivity of these intermolecular substitution reactions,
we hypothesised that intramolecular C5 substitution might be
successful and that suitable precursors for the Claisen allyl rear-
rangement would be available from O4 allyl ethers. Allyl rear-
rangements have been used in the synthesis of many natural
Abbreviations: BOP, (1-benzotriazolyl)oxy tris(dimethylamino) phosphonium
hexafluorophosphate; m-CPBA, m-chloroperbenzoic acid; DBU, 1,8-diazabicyclo
[5,4,0]undec-7-ene; TBD, 1,5,7-triazabicyclo[4.4.0]dec-5-ene.
* Corresponding author. Tel.: þ44 141 548 2271; e-mail address: c.j.suckling@
strath.ac.uk (C.J. Suckling).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.011

J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
3227
products.11 The Claisen rearrangement was first described in the
pyrimidine series in 1961 but the reactions lacked functional
groups for further transformations leading to fused pyrimidines.12
Pyrimidine 1 was therefore treated slowly over a period of days with
ethyl bromomethylacrylate at room temperature in the absence of
added base to afford the rearranged C5 alkylated product 6a (46%).
Similar reactions occurred between 1 and bromomethylacrylic acid
to give 6b (30%), as well as on the 2-aminopyrimidine 7a to give 6c
and 6d in 83 and 53% yield, respectively (Scheme 3). A set of 6-N-
alkylpyrimidines (7bed) was also prepared in a similar manner. As
planned, the C5 alkylated products were cyclised with non-nucle-
ophilic base to afford a set of pyrido[2,3-d]pyrimidine-7(8H)-ones
(6feg). Optimisation of the cyclisation conditions of the C5 alkylated
Claisen rearrangement products 6 showed that triazabicyclodecane
(TBD) was more effective than diazabicycloundecane (DBU) and
yields of >80% were reproducibly obtained leading to a series of
2-alkylthiopyrido[2,3-d]-3(4H),7(8H)-diones (Scheme 3) from
which a library of compounds through C2 substitution was gener-
ated (8aee).
2. Results and discussion
2.1. Claisen rearrangement
To investigate further the Claisen rearrangement approach,12
pyrimidine 1 was treated with allyl bromide in DMF in the pres-
ence of solid potassium carbonate to afford a mixture of the O4 and
N3 allyl pyrimidines 2 (62%) and 3 (9%), which were separable by
column chromatography. The O4 allylated pyrimidine 2 underwent
quantitative Claisen rearrangement to afford 4 at 200 ꢀC in the melt
(Scheme 1); in previous work, reactions took place in high boiling
solvents and gave only 20% yield.
Scheme 1. Substitution by Claisen rearrangement. Reagents and conditions: i. DMF, K2CO3, 100 ꢀC, 20 h; ii. 200 ꢀC, 24 h.
Cyclisation of 4 to either a pyrido[2,3-d]- or a pyrrolo[2,3-d]-
pyrimidine proved unsuccessful using palladium catalysis.10 How-
ever, this cyclisation reactionwas nota priority because the products
of cyclisation of 4 would lack substituents in the newly formed ring,
an outcome inappropriate for a diversity oriented synthesis;
substituted allylic groups are necessary for library synthesis. In
electrocyclic reactions, it is often found that the introduction of an
electron withdrawing group to an alkene greatly increases the re-
action rate.11 By using ethyl bromomethylacrylate as the alkylating
agent and pyrimidine 1, twosurprising results were obtained. Firstly,
alkylation of the anion of 1 with ethyl bromomethylacrylate led di-
rectly to the disubstituted pyrimidine, 5 (Scheme 2); such a product
could arise if rearrangement was exceptionally rapid and was fol-
lowed by a subsequent O-alkylation. The structure of 5 was con-
firmed by X-ray crystallography.13
2.2. Lewis acid catalysed rearrangement and cyclisation
In principle, the bromomethylacrylate substitution and Claisen
rearrangement leads to pyrido[2,3-d]pyrimidindiones with di-
versity at two positions and efforts were made to extend the re-
action using more highly substituted acrylates without success.
However the Claisen rearrangement route has further potential
for the synthesis of diverse pyrido[2,3-d]pyrimidines if ketones
are used in place of esters. b-Halomethyl arylidene ketones are
readily available through the BayliseHillman reaction using
methyl vinyl ketone and the appropriately substituted aldehyde.14
Such compounds 9a, 9b were found to react readily with the
benzylthiopyrimidinone 1 in the presence of cesium carbonate to
afford the O-alkyl products 10a,b in 60e70% yield. Unlike the
previous examples, these compounds are stable at room temper-
ature and do not rearrange cleanly on thermolysis. Base catalysis
via an N6 anion formed using sodium hydride or DBU did not
This reaction suggested that both allyl ether formation and
rearrangement surprisingly had taken place at room temperature.
Scheme 2. Preparation of dialkylated pyrimidine 5. Reagents and conditions: i. DMF, K2CO3, 55 ꢀC, 24 h.

3228
J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
Scheme 3. Reagents and conditions: i. DMF, rt, 7 days; ii. TBD or DBU, MW, 100 ꢀC, 30 min.
promote any reaction. Many metal complexes have been used to
accelerate electrocyclic reactions including the Claisen rear-
rangement.11,15 Several Lewis acids were tested for their ability to
promote rearrangement of the arylallyl ethers, 10; boron tri-
fluoride, magnesium dibromide, stannic chloride and zinc chlo-
ride failed but titanium tetrachloride (10 mol)16,17 induced both
a rearrangement and concomitant cyclisation to afford the 6-
arylmethylpyrido[2,3-d]pyrimidines 11a,b in modest yield
(Scheme 4). It is notable that these are not the expected products
of Claisen rearrangement and subsequent cyclisation, which
would be 5-aryl-6,7-dimethylpyrido[2,3-d]pyrimidines. Titanium
tetrachloride catalysis has therefore caused the reaction to follow
another course; the proposed mechanism for the reaction is
shown in Scheme 5.
Increasing the molar proportion of titanium tetrachloride up to
50 mol% also failed to improve yields. Indeed the major product
under conditions of higher concentration of titanium tetrachloride
was the precursor BayliseHillman chloroketone, 9. The occurrence
of these competing reactions can be rationalised by a mechanism in
which titanium tetrachloride generates an electrophile from the
allyl ether, possibly with coordination also of the ketone carbonyl
group to maintain an essentially intramolecular reaction. The initial
coordination of titanium tetrachloride to the pyrimidyl ether would
liberate chloride, which, at the higher concentrations, traps the
intermediate delocalised allylic cation 12 reverting to the starting
material 9. Nevertheless, two new pyrido[2,3-d]pyrimidines 11
were obtained for investigation of the introduction of diversity by
modifications at C2 and C4.
Scheme 4. Regents and conditions: i. Cs2CO3, KI, rt, 24 h; ii. TiCl4$2THF, THF, reflux, 3 days.

J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
3229
Scheme 5. Proposed mechanism for the synthesis of derivatives 11.
2.3. Diversification
Having established ring syntheses of pyrido[2,3-d]pyrimidines
11 from allyl ethers it was necessary to demonstrate diversification
of these compounds at the 2-position. Two reactions were in-
vestigated, firstly oxidation of benzylthio substituents followed by
nucleophilic substitution and secondly conversion of a 4-oxo sub-
stituent into a 4-aminoalkyl substituent using BOP (benzotriazole-
1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate)
and the corresponding amine.18 The oxidation/substitution se-
quence is successful and in high yield (typically 85e95%) with
pteridines and other compounds with electron deficient rings fused
to pyrimidines.19e21 In many cases with pteridines as substrates,
oxidation was not required before nucleophilic substitution of the
alkylthio group. In this study, the range of examples has been ex-
tended to 4-aminoalkyl pteridines as substrates, the latter being
available through BOP chemistry as noted above.18
At the other extreme of reactivity, pyrrolo[2,3-d]pyrimidines
underwent substitution only after oxidation, under vigorous con-
ditions and in much lower yields.5 It would be reasonable to expect
that the reactivity of pyrido[2,3-d]pyrimidines to nucleophilic
substitution after oxidation would lie between these two extremes
and this indeed proved to be the case. The 7-oxopyrido[2,3-d]py-
rimidines 8d and 8e gave 13aed in yields typically of 50e60%,
somewhat greater than those for the pyrido[2,3-d]pyrimidines 11b
lacking the 7-oxo group, which afforded typically 35e55% yields of
14aed under the same conditions.
A further reaction of value in the diversification of oxo-hetero-
cycles has been demonstrated by scientists from Wyeth who
showed that oxo substituents in 4- and 7-positions especially could
be converted into aminoalkyl substituents by treatment with BOP
and the required amine.18 This reaction was successful with 13a as
a representative pyridopyrimidine substrate affording pentasub-
stituted pyrido[2,3-d]pyrimidines 15a and 15b in satisfactory yield
(55e65%, Scheme 6).
Scheme 6. Diversification reactions for pyrrolopyrimdines. Reagents and conditions: i.
DMF, m-CPBA, rt, 3 h; ii, appropriate amine, MW, 110 ꢀC, 1 h; iii, BOP, CHCN, rt, 10 min;
iv, DBU, appropriate amine, rt, 48 h.
was not critical was shown by the successful oxidative substitution
of the new 4-alkylaminopteridines by a variety of amines to give
19aee although yields were poorer for the BOP-mediated sub-
stitution (w30%).
As a third example of a class of compounds for diversification,
two pyrimido-oxazines, 20 and21 were substituted directly with
benzylamine without oxidative alkylation. In addition to sub-
stitution at C2, in the case of 21, the C6 ester substituent underwent
condensation affording the 6-benzylcarboxamide, 23 (Scheme 8).
Direct substitution of methylthio groups in related pterins in
moderate yield has been reported previously.21
In the pteridine series, both oxidative substitution and BOP-
activated substitution were successful; the former gave a series of
2-alkylamino-4-oxopteridines (17aeh) in good yield and the latter,
4-aminoalkyl pteridines (18aef) in acceptable to good yields
(65e80%) (Scheme 7). That the order of substitution at C2 and C4
2.4. Conclusions and biological activity
In summary, we find that of the fused pyrimidines we have
examined in this and in previous work, alkylthiopteridines undergo
nucleophilic substitution most readily.19,22 Thus in pteridines,

3230
J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
Scheme 7. Diversification reactions for pteridines. Reagents and conditions: i, HNO2; ii, Na2S2O4; iii, EtOH, reflux; iv, DMF, m-CPBA, rt, 3 h; v, appropriate amine, MW, 110 ꢀC, 1 h; vi,
BOP, CH3CN, rt, 10 min; vii, DBU, appropriate amine, rt, 48 h.
weak but measurable activity against the Gram positive bacterium,
Nocardia farcinia (MIC¼50 and 100
mM, respectively). On the other
hand, several 4-amino substituted compounds were hits in a cell
based assay against the parasite T. brucei brucei. In the pteridine
series, both 2-alkylamino and 2-thiobenzyl compounds were active
(18a, MIC¼25
mM; 18c, 12.5; 18d, 25; 18e, 12.5; 18f, 12.5; 19c, 3.1;
19d, 3.1; 19e, 6.3); the most active compounds were the 2,4-dia-
lkylamino compounds, 19cee. The pyridopyrimidin-2,4-dione 14d
was also a modest hit with a MIC of 25 mM. All of these compounds
are, however, inferior as antiparasitic compounds to the pyrrolo-
pyrimidines we have already described23 because they have un-
acceptably high values of clog P (6e7). Nevertheless, the results
reported here serve to illustrate the value of diversity oriented
synthesis on heterocyclic templates in the discovery of biologically
active compounds.
Scheme 8. Diversification for pyrimido-oxazines. Reagents and conditions: i, HNO2; ii,
Na2S2O4; iii, aq EtOH, NaOAc, reflux; iv PhCH2NH2, MW, 110 ꢀC, 1 h.
substitution after oxidation of the alkylthio group occurred at room
temperature in 30e60% yield with water, azide, primary and sec-
ondary amines as nucleophiles. Pyrido[2,3-d]pyrimidines, as de-
scribed above, are somewhat less reactive, requiring higher
temperature and concentration of nucleophile to obtain a good
yield. To a small extent, the 7-oxo group, which can assist in the
delocalisation of charge in the intermediate in nucleophilic sub-
stitution, appears to give better yields. Pyrrolo[2,3-d]pyrimidines
were the least reactive substrates requiring the use of neat amine as
nucleophile and temperatures above 130 ꢀC to effect sub-
stitution;5,23 this behaviour is consistent with the more electron
rich pyrrole fused to the pyrimidine ring. In the pteridine series,
substitution at C2 and C4 can be undertaken in either order using
oxidation/substitution or BOP activation/substitution chemistry.
Taken together, all of these methods provide access to a wide range
of fused pyrimidines diversely substituted at a late stage in the
pyrimidine ring.
We have described elsewhere how this approach has led to
compounds with significant biological activity, especially in anti-
parasitic applications.5,23 The biological activity of the compounds
prepared in this study has been assessed in screens for antibacterial
and antiparasitic properties. None of the pyrimido-oxazines was
found to be active in any assay used. There was no significant an-
tibacterial activity observed against Staphylococcus aureus, or
Escherichia coli, but two of the 4-oxopteridines, 17g and 17h had
3. Experimental
3.1. Instrumentation and general methods
NMR spectra were recorded on a Bruker Spectrospin spec-
trometer operating at 400 MHz for 1H spectra and 100 MHz for 13
C
spectra. The following abbreviations were used: s¼singlet,
d¼doublet, t¼triplet, m¼multiplet, br¼broad. Coupling constants
(J) are quoted in hertz. Chemical shifts are reported as parts per
million relative to the residual protio solvent resonance spectra
were determined using a Mattson 1000 FT spectrometer or
a Nicolet Impact 400D FT spectrometer as a KBr disc. Mass spectra
were measured on a JEOL JMS AX505 spectrometer at the Univer-
sity of Strathclyde using electrospray (ES), or chemical ionisation
(CI) methods. Accurate mass was recorded at the University of
Glasgow on Jeol JMS-7 MStation high resolution magnetic sector
using electron impact (EI) or fast atom bombardment (FAB) ion-
isation. Melting points, where measurable, were determined on
a Reichert hot stage apparatus and are uncorrected. Microanalysis is
typically unreliable in polyazabicyclic compounds due to poor
combustion even in the presence of a catalyst (WO3); microana-
lytical data is reported where satisfactory and 400 MHz 1H NMR
spectra are included in the Electronic Supplementary Data. TLC was

J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
3231
carried out on silica (Merck 0.25 mm 60 F254) visualising the plates
with either aqueous potassium permanganate solution or UV;
whilst suitable for monitoring reactions and product purity, with
these highly polar compounds, Rf values vary from run to run and
have therefore not been given. Column chromatography was car-
ried out using silica gel (230e400 mesh; 40e60 mm). All reagents
were bought from Aldrich (Gillingham, Dorset, U.K.). Microwave
reactions were carried out on a Biotage Initiator 2.0. HPLC was
carried out on a Waters machine equipped with a 1525 binary HPLC
C6H5),11.66 (1H, br s, NH); dC (DMSO-d6): 26.4, 33.1, 90.6,114.2,127.1,
128.3,129.1,135.4,137.9. HRMS(EI):Mþ, found273.0939. C14H15N3OS
requires 273.0936.
3.2.4. Ethyl 2-[(4-amino-2-(benzylsulfanyl)-6-{[2-(ethoxycarbonyl)-
2-propenyl]oxy}5-pyrimidinyl)methyl]acrylate 5. 6-Amino-2-(ben-
zylthio)pyrimidin-4(3H)-one 1 (0.690 g, 2.95 mmol) was dissolved
in DMF (12 mL, anhydrous) at room temperature under nitrogen.
Ethyl 2-(bromomethyl)acrylate (610 ml, 4.40 mmol, 1.50 equiv) and
pump, Waters 2487 dual
ware using Vydac protein and peptide C18 column,
Gradient elution was with water/acetonitrile with or without tri-
fluoroacetic acid.
l
absorbance detector, and Breeze soft-
potassium carbonate (0.500 g, 3.62 mmol, 1.23 equiv) were added
and the reaction mixture was stirred at 55 ꢀC for 24 h. Once the
reaction was complete (confirmed by TLC), the mixture was cooled
to room temperature and the solvent evaporated under reduced
pressure. The subsequent yellow oil was dissolved in DCM, the
organics were extracted with brine and dried over MgSO4 and
concentrated under reduced pressure to give a yellow oil. Purifi-
cation of the crude product was achieved using column chroma-
tography using ethyl acetate/hexane (1:1) as eluant. The title
compound 5 was isolated as a white solid (0.114 g, 0.249 mmol, 8%),
mp 110e112 ꢀC. nmax (KBr): 3407, 3323, 3191, 2991, 1707, 1652, 1572,
1493, 1474, 1444, 1401, 1376, 1316, 1264, 1158, 1050, 956, 855, 776,
l¼254 nm.
3.2. Experimental procedures
3.2.1. 6-Amino-2-(benzylthio)pyrimidin-4(3H)-one 119. Compound
1was prepared as previously described.
3.2.2. 6-(Allyloxy)-2-(benzylthio)-pyrimidin-4-amine 2 and 3-allyl-
6-amino-2-(benzylthio) pyrimidin-4(3H)-one 3. To 6-amino-2-
(benzylsulfanyl)pyrimidin-4(3H)-one 1 (1.790 g, 7.67 mmol) in
563 cmꢁ1
;
dH (DMSO-d6): 1.15e1.26 (6H, m, CH3 ꢂ2), 3.33 (2H, s,
anhydrous DMF (20 mL) was added allyl bromide (700
ml, 0.980 g,
CH2]C(CO2Et)CH2), 4.09e4.20 (4H, m, CH2 ꢂ2), 4.29 (2H, s, CH2S),
4.98 (2H, s, CH2O), 5.14 (1H, s, ]CHH), 5.75 (1H, s, ]CHH), 5.99 (1H,
s, ]CHH), 6.19 (1H, s, ]CHH), 6.19 (2H, br s, NH2), 7.19e7.31 (3H, m,
C6H5), 7.39e7.41 (2H, m, C6H5); dC (DMSO-d6): 13.9, 14.0, 24.4, 33.8,
60.3, 60.5, 63.5, 90.7, 123.1, 126.1, 126.8, 128.3, 128.8, 136.3, 137.0,
138.7, 163.4, 164.8, 165.4, 166.2, 166.2, 166.4. HRMS (ES): MþHþ,
found 458.1650. C23H27N3O5S requires 458.1671.
8.03 mmol,1.05 equiv) and potassium carbonate (1.24 g, 8.98 mmol,
1.17 equiv). The reaction mixture was left stirring at 100 ꢀC for 20 h.
The reaction mixture was cooled to room temperature, filtered un-
der vacuum and the solventevaporated under reduced pressure. The
residue was dissolved in water (20 mL) and extracted with DCM
(50 mL). The organic layers were combined, dried over MgSO4 and
concentrated under reduced pressure to give a pale yellow solid. The
crude product was purified by column chromatography using ethyl
acetate (100%) as eluant to give 6-(allyloxy)-2-(benzylthio)-pyr-
imidin-4-amine 2 as a pale yellow crystalline solid (0.924 g,
3.38 mmol, 62%) and 3-allyl-6-amino-2-(benzylthio)pyrimidin-4
(3H)-one 3 as a white crystalline solid (0.127 g, 0.464 mmol, 9%).
Characterisation of 2: mp 80e82 ꢀC. nmax (KBr): 3477, 3302,
3143, 1642, 1549, 1469, 1430, 1336, 1205, 984, 933, 815, 716, 696,
3.2.5. Ethyl 2-{(4-amino-2-(benzylsulfanyl)-1,6-dihydro-6-oxopyr-
imidin-5-yl)methyl} acrylate 6a. 6-Amino-2-(benzylthio)pyr-
imidin-4(3H)-one 1 (0.520 g, 2.22 mmol) was dissolved in DMF
(10 mL, anhydrous) to which ethyl 2-(bromomethyl)acrylate
(310 ml, 2.24 mmol) was added. The reaction mixture was then
stirred under nitrogen for 7 days at room temperature prior to the
concentration of excess solvent under reduced pressure. The
resulting residue was purified by flash column chromatography
using hexane/ethyl acetate (2:1) as eluant. The title compound 6a
was obtained as a white crystalline solid (0.340 g, 0.998 mmol,
44%), mp 160e162 ꢀC. nmax (KBr): 3483, 3368, 1693, 1614, 1475,
592 cmꢁ1
;
dH (DMSO-d6): 4.30 (2H, s, CH2S), 4.73 (2H, d, J¼5.6 Hz,
CH2O), 5.20 (1H, d, J¼10.8 Hz, CH]CH2), 5.33 (1H, d, J¼16.0 Hz,
CH]CHH), 5.45 (1H, s, H-5), 5.94e6.04 (1H, m, CH]CH2), 6.75 (2H,
br s, NH2), 7.21e7.31 (3H, m, C6H5), 7.39e7.41 (2H, m, C6H5); dC
(DMSO-d6): 33.8, 66.0, 81.9, 117.4, 126.9, 128.3, 128.8, 133.6, 138.6,
165.2, 168.3, 168.8. HRMS (EI): Mþ, found 273.0936. C14H15N3OS
requires 273.0936.
1438, 1333, 11,260, 1187, 1152, 1029, 953, 693 cmꢁ1
; dH (DMSO-d6):
1.27 (3H, t, J¼7.6 Hz, CH3), 3.18 (2H, s, CH2C]), 4.19 (2H, q, J¼7.6 Hz
CH2CH3), 4.34 (2H, s, CH2S), 5.22 (1H, s, C]CH2), 5.97 (1H, s, C]
CH2), 6.34 (2H, br s, NH2), 7.21e7.34 (3H, m, C6H5), 7.43e7.46 (2H,
m, C6H5), 11.70 (1H, br s, NH); dC (DMSO-d6): 14.1, 24.7, 33.1, 60.2,
89.2, 122.7, 127.1, 128.4, 129.2, 137.3, 137.8, 160.4, 163.0, 166.8 (ꢂ2).
HRMS (EI): Mþ, found 345.1149. C17H19N3O3S requires 345.1147.
Similarly prepared were:
Characterisation of 3: mp 167e174 ꢀC (slow decomposition).
nmax (KBr): 3391, 3316, 3186, 1644, 1620, 1508, 1453, 1424, 1289,
1253, 1197, 1127, 1025, 913, 800, 635 cmꢁ1
; dH (DMSO-d6): 4.39 (2H,
s, CH2N), 4.45 (2H, s, CH2S), 4.94 (1H, s, H-5), 5.01 (1H, d, J¼17.6 Hz,
CH]CHH), 5.12 (1H, d, J¼10.4 Hz, CH]CH2), 5.70e5.80 (1H, m,
CH]CH2), 6.57 (2H, br s, NH2), 7.24e7.33 (3H, m, C6H5), 7.44e7.46
(2H, m, C6H5); dC (DMSO-d6): 35.1, 44.3, 80.7, 116.8, 127.4, 128.4,
129.3, 132.1, 137.0, 160.5, 161.2 (ꢂ2). HRMS (EI): Mþ, found
273.0936. C14H15N3OS requires 273.0936.
3.2.6. 2-{[4-Amino-2-(benzylsulfanyl)-6-oxo-1,6-dihydro-5-pyr-
imidinyl]methyl}acrylic acid 6b. From 6-amino-2-(benzylthio)pyr-
imidin-4(3H)-one 1 and 2-(bromomethyl)acrylic acid using 2 equiv
of the latter added over 2 days and a further 5 days reaction in 30%
yield, mp 157e159 ꢀC. nmax (KBr): 3444, 3003, 1705, 1642, 1552,
3.2.3. 5-Allyl-6-amino-2-(benzylthio)-4(3H)-pyrimidinone
4. 6-(Allyloxy)-2-(benzylsulfanyl)-4-pyrimidinylamine 2 (0.310 g,
1.13 mmol) was heated to 200 ꢀC under nitrogen for 24 h using a sand
bath. The resulting brown solid was dissolved in methanol (15 mL)
andfiltered. The excess solventwasremovedunderreducedpressure
and the resulting solid was purified by flash chromatography to yield
the title compound 4 as a white solid (0.290 g, 1.06 mmol, 92%), mp
152e154 ꢀC. nmax (KBr): 3400, 3925, 1625, 1610, 1582, 1470, 1410,
1320, 1207, 1017, 929, 843, 710 cmꢁ1
; dH (DMSO-d6): 3.07 (2H, s,
CH2eC]), 4.31 (2H, s, CH2S), 5.91 (1H, br s, C]CH2), 6.33 (1H, br s,
C]CH2), 6.36 (2H, s, NH2), 7.20e7.40 (3H, m, C6H5), 7.41e7.53 (2H,
m, C6H5), 12.01 (1H, br s, NH); dC (DMSO-d6): 34.0, 79.6, 124.7, 128.1,
128.6, 129.5, 137.5, 138.7, 158.3, 164.6, 166.2, 172.6. HRMS (EI): Mþ,
found 317.0831. C15H15N3O3S requires 317.0834.
1305, 1206, 1046, 934, 815, 717, 637, 593 cmꢁ1
(2H, d, J¼8.0 Hz, CH2CH]), 4.72 (2H, s, CH2S), 4.94 (1H, d, J¼10.4 Hz,
CH]CH2), 5.05 (1H, d, J¼16.0 Hz, CH]CH2), 5.67e5.89 (1H, m, CH]
CH2), 6.26 (2H, br s, NH2), 7.18e7.30 (3H, m, C6H5), 7.37e7.47 (2H, m,
;
dH (DMSO-d6): 2.50
3.2.7. Ethyl 2-[(2,4-diamino-6-oxo-1,6-dihydro-5-pyrimidinyl) methyl]
acrylate 6c. From 2,6-diamino-4(3H)-pyrimidinone 7a and ethyl
2-(bromomethyl)acrylate reacting for 3 days in 83% yield, mp
120e122 ꢀC. nmax (KBr): 3455, 3341, 3176, 1698, 1629, 1500, 1446,

3232
J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
1372, 1260, 1151, 1023, 779, 647 cmꢁ1
;
dH (DMSO-d6): 1.24 (3H, t,
chromatography to yield the title product as a fine white powder
(186 mg, 0.0752 mmol, 38%), mp >230 ꢀC. nmax (KBr): 3214, 3059,
J¼7.1 Hz, CH3), 3.05 (2H, s, CH2eC]), 4.14 (2H, q, J¼7.1 Hz, CH2CH3),
5.26 (1H, d, J¼1.7 Hz, CH2]), 5.67 (2H, s, NH2), 5.94 (1H, d, J¼1.7 Hz,
CH2]), 6.02 (2H, br s, NH2), 9.86 (1H, br s, NH); dC (DMSO-d6): 14.2,
25.1, 60.2, 83.4, 122.6, 137.4, 152.3, 157.7, 161.8, 166.7. HRMS (EI): Mþ,
found 238.1070. C10H14N4O3 requires 238.1066.
1637, 1618, 1421, 1302, 1256, 1207, 1097, 978, 792, 711, 570 cmꢁ1
; dH
(DMSO-d6): 2.77 (3H, s, CH3), 4.35 (2H, s, CH2S), 4.81 (1H, s, H-5),
6.96 (1H, br d, eNHCH3), 7.23e7.44 (5H, m, C6H5), 11.55 (1H, s, NH);
dC (DMSO-d6): 27.8, 33.1, 127.1, 128.4, 129.0, 137.9, 162.8, 164.0.
HRMS (EI): Mþ, found 247.0776. C12H13N3OS requires 247.0779.
Similarly prepared were:
3.2.8. 2-((2,4-Diamino-1,6-dihydro-6-oxopyrimidin-5-yl)methyl)
acrylic acid 6d. From 2,6-diaminopyrimidin-4(3H)-one 7a and 2-
(bromomethyl)acrylic acid using 2 equiv of the latter added over 2
days and a further 5 days reaction in 53% yield, mp >230 ꢀC. nmax
(KBr): 3378, 3199, 2972, 2758,1707,1647,1604,1511,1419,1282,1237,
3.2.13. 6-(Benzylamino)-2-(benzylsulfanyl)-4(3H)-pyrimidinone
7c. Compound 7c as a white solid in 38% yield, mp 230 ꢀC. nmax
(KBr): 3450, 3000, 2906, 2818, 1884, 1807, 1650, 1554, 1466, 1351,
1193, 1116,1091, 958, 808, 617, 550 cmꢁ1
;
dH (DMSO-d6): 2.45 (2H, s,
1222, 1097, 984, 937, 829, 712, 552 cmꢁ1
; dH (DMSO-d6): 4.14 (2H, s,
CH2eC]), 5.28 (1H, s, C]CH2), 5.90 (1H, s, C]CH2), 6.13 (2H, br s,
NH2), 7.08 (2H, br s, NH2),10.94 (1H, br s, NH),11.22 (1H, br s, CO2H);
dC (DMSO-d6): 24.2, 84.3,122.7,138.1,152.0,162.1,162.3,168.5. HRMS
(EI): Mþ, found 211.0832. C8H10N4O3 requires 211.0831.
CH2N), 4.47 (2H, s, CH2S), 4.90 (1H, s, H-5) 7.22e7.45 (11H, m, C6H5
ꢂ2 and NHCH2), 11.54 (1H, s, NH); dC (DMSO-d6): 34.3, 44.5, 126.8,
127.0, 127.1, 127.9, 128.3, 137.6, 138.2, 159.3, 162.4, 163.8. HRMS
(FAB): MþþH, found 324.1174. C18H17N3OS requires 324.1171.
3.2.9. Ethyl 2-{[2-(benzylsulfanyl)-4-(methylamino)-6-oxo-1,6-dihy-
dro-5-pyrimidinyl]methyl}acrylate 6e. From 2-(benzylsulfanyl)-6-
(methylamino)-4(3H)-pyrimidinone 7b and ethyl 2-(bromomethꢀyl)
acrylate with a reaction time of 4 days in 33% yield, mp 171e173 C.
3.2.14. 6-(Allylamino)-2-(benzylsulfanyl)-4(3H)-pyrimidinone
7d. Compound 7d as a white solid in 37% yield, mp >230 ꢀC. nmax
(KBr): 3214, 3059, 1637, 1618, 1421, 1302, 1256, 1207, 1097, 978, 792,
711, 570 cmꢁ1
; dH (DMSO-d6): 3.88 (2H, m, eNHeCH2), 4.34 (2H, s,
nmax (KBr): 3503, 3367, 1670, 1618, 1483, 1452, 1370,1181, 707 cmꢁ1
;
CH2S), 4.89 (1H, s, H-5), 5.10 (1H, d, J¼1.5, eCH2eCH]CH2), 5.17
(1H, d, J¼17.5, eCH2eCH]CH2), 5.80 (1H, m, eCH2eCH]CH2), 7.21
(1H, br s, NH) 7.42e7.23 (5H, m, C6H5), 11.54 (1H, s, eNH); dC
(DMSO-d6): 33.2, 42.4, 115.4, 115.6, 127.1, 128.4, 129.0, 134.4, 137.9,
159.2, 162.2, 163.3.
dH (CDCl3): 1.24 (3H, t, J¼7.1 Hz, CH3), 2.93 (3H, s, NHCH3), 3.26 (2H,
s, CH2C]), 4.14 (2H, q, J¼7.1 Hz, CH2CH3), 4.36 (2H, s, CH2S), 5.85
(1H, d, J¼1.4 Hz, CH2]), 5.95 (1H, d, J¼1.4 Hz, CH2]), 6.12 (1H, m,
NH), 7.18e7.33 (5H, m, C6H5), 12.48 (1H, br s, NH); dC (CDCl3): 14.2,
24.5, 28.7, 34.5, 61.1, 92.7, 127.4, 127.7, 128.6, 128.9, 137.0, 137.6,
158.2, 160.1, 164.2, 169.0. HRMS (EI): Mþ, found 359.1303 requires
C18H21N3O3S 359.1304.
3.2.15. 2-(Benzylsulfanyl)-6-methylpyrido[2,3-d]pyrimidine-4,7
(3H,8H)-dione 8a. Ethyl 2-{[4-amino-2-(benzylsulfanyl)-6-oxo-1,6-
dihydro-5-pyrimidinyl]methyl}acrylate 6a (0.100 g, 0.289 mmol)
was dissolved in DMF (3 mL, anhydrous) to which 1,3,4,6,7,8-hex-
ahydro-2H-pyrimido[1,2-a]pyrimidine (0.089 g, 0.597 mmol,
2.2 equiv) was added. The reaction solution was then irradiated in
the microwave apparatus at 100 ꢀC for 30 min. The excess solvent
was removed under reduced pressure and the resulting residue was
dissolved in de-ionised water (10 mL). The reaction solution was
adjusted to pH 6e7 using dil acetic acid, which caused a white
precipitate to form. The precipitate was filtered off and washed
with ether (2ꢂ10 mL) to yield the title compound 8a as a white solid
(0.085 g, 0.0283 mmol, 98%), mp >230 ꢀC. nmax (KBr): 3450, 3027,
2890, 1953, 1807, 1626, 1590, 1394, 1271, 959, 922, 790, 719,
3.2.10. Ethyl 2-{[4-(benzylamino)-2-(benzylsulfanyl)-6-oxo-1,6-di-
hydro-5-pyrimidinyl]methyl}acrylate 6f. From 2-(benzylsulfanyl)-
6-(benzylamino)-4(3H)-pyrimidinone 7c and ethyl 2-(bromo-
methyl)acrylate with four reaction in 33% yield, mp 168e171 ꢀC.
nmax (KBr): 3478, 3165,1774,1661,1559,1534,1459,1205, 986 cmꢁ1
;
dH (CDCl3): 1.32 (3H, t, J¼7.1 Hz, CH3), 3.35 (2H, s, CH2eC]), 4.11
(2H, q, J¼7.1 Hz, CH2CH3), 4.25 (2H, d, J¼5.5 Hz, CH2NH), 4.45 (3H, s,
CH2S), 5.95 (1H, d, J¼1.5 Hz, CH2]), 6.04 (1H, d, J¼1.5 Hz, CH2]),
6.15 (1H, t, J¼5.5 Hz, NHCH2), 7.47e7.22 (10H, m, 2ꢂ C6H5), 12.96
(1H, br s, NH). HRMS (FAB): MþþH, found 436.1694. C24H25N3O3S
requires 436.1695.
571 cmꢁ1
; dH (DMSO-d6): 2.01 (3H, s, CH3), 4.43 (2H, s, CH2S),
3.2.11. Ethyl 2-{[4-(allylamino)-2-(benzylsulfanyl)-6-oxo-1,6-dihy-
dro-5-pyrimidinyl] methyl} acrylate 6g. Compound 6g as a pale
yellow solid in 33% yield, mp 165e168 ꢀC. nmax (KBr): 3503, 3367,
7.23e7.33 (3H, m, C6H5), 7.53e7.67 (2H, m, C6H5), 7.68 (1H, s, H-5),
12.27 (1H, br s NH), 12.73 (1H, br s, NH); dC (TFA): 14.1, 35.3, 102.9,
127.3, 127.8, 128.4, 128.7, 134.2, 137.6, 151.5, 164.2, 166.5. HRMS
(FAB): MþþH, found 300.0816. C15H14N3O2S requires 300.0807.
Similarly prepared were:
1670, 1618, 1483, 1452, 1370, 1181, 707 cmꢁ1
; dH (CDCl3): 1.31 (3H, t,
J¼7.1 Hz, CH3), 3.37 (2H, s, CH2eC]), 4.08e4.12 (2H, m, CH2NH), 4.22
(2H, q, J¼7.1 Hz, CH2CH3), 4.40 (2H, s, CH2S), 5.12 (1H, d, J¼1.5 Hz,
CH2]), 5.16 (1H, d, J¼1.5 Hz, CH2]), 5.85e5.94 (1H, m, CH]CH2),
6.04 (1H, d, J¼1.6 Hz, CH]CHH), 6.09 (1H, t, J¼5.7 Hz, NHCH2), 6.21
(1H, d, J¼16 Hz, CH]CHH), 7.24e7.42 (5H, m, C6H5), 13.04 (1H, s,
NH); dC (CDCl3): 13.2, 23.4, 33.5, 43.0, 60.1, 91.9, 114.5, 126.4, 126.7,
127.6,127.9,134.4,135.8,136.5,157.3,158.3,163.5,167.9. HRMS(FAB):
MþþH, found 386.1534. C20H23N3O3S requires 386.1538.
3.2.16. 2-Amino-6-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione
8b. Compound 8b as a highly insoluble beige solid in 81% yield, mp
>230 ꢀC. nmax (KBr): 3443, 3413, 3141, 1698, 1673, 1458, 1351, 1112,
841; dH (TFA): 2.32 (3H, s, CH3), 8.12 (1H, s, H-5); dC (TFA): 16.4,
100.2, 130.1, 138.6, 145.5, 153.3, 161.3, 167.8.
3.2.17. 2-(Benzylsulfanyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7
(3H,8H)-dione 8c. Compound 8c as a white solid in 96% yield, mp
>230 ꢀC. nmax (KBr): 2854, 1642, 1537, 1492, 1453, 1281, 1152, 988,
3.2.12. 2-(Benzylsulfanyl)-6-(methylamino)-4(3H)-pyrimidinone
7b. 2-(Benzylsulfanyl)-6-chloro-4(3H)-pyrimidinone (500 mg,
1.98 mmol) was dissolved in 2.0 M methylamine solution in THF
(4.95 mL, 5 equiv). The solution was heated to 80 ꢀC in a sealed tube
and stirred for 48 h. The excess solvent was removed under reduced
pressure and the residue was taken up in ethyl acetate. The solvent
layer was washed with water (2ꢂ15 mL) and then saturated
aqueous sodium bicarbonate solution (15 mL). The organic layer
was then dried over MgSO4. The solvent was removed under
reduced pressure and the residue was purified by flash
789, 701, 570 cmꢁ1
; dH (DMSO-d6): 2.06 (3H, s, CCH3), 3.62 (3H, s,
NCH3), 4.53 (2H, s, CH2S), 7.26e7.48 (5H, m, C6H5), 7.74 (1H, s, H-5),
12.97 (1H, s, NH); dC (DMSO-d6): 14.1, 35.3, 102.9, 127.3, 127.8, 128.4,
128.7, 134.2, 137.6, 151.5, 164.2, 166.5. HRMS (FAB): MþþH, found
314.0962. C16H16N3O2S requires 314.0963.
3.2.18. 8-Benzyl-2-(benzylsulfanyl)-6-methylpyrido[2,3-d]pyrimi-
dine-4,7(3H,8H)-dione 8d. Compound 8d as a white solid in 96%

J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
3233
yield, mp >230 ꢀC. nmax (KBr): 3452, 3183, 1642, 1629, 1588, 1465,
1264, 1098, 964, 951; dH (DMSO-d6): 2.01 (3H, s, CH3), 4.48 (2H, s,
CH2S), 5.35 (2H, s, CH2N), 7.21e7.36 (10H, m, C6H5 ꢂ2), 7.71 (1H, s, H-
5),12.98 (1H, s, NH); dC (DMSO-d6): 16.6, 33.8, 43.9, 99.4,120.6,127.0,
127.3, 127.6, 128.0, 128.1, 128.3, 132.7, 138.1, 152.2, 160.8, 161.1, 165.3.
HRMS (FAB): MþþH, found 390.1276. C22H19N3O2S requires
390.1276.
under nitrogen. The excess solvent was removed under reduced
pressure and the resulting residue was washed with saturated
aqueous NaHCO3 solution (2ꢂ10 mL) and de-ionised water
(2ꢂ10 mL). The organic layer was dried over MgSO4, filtered under
reduced pressure and the solvent was removed under reduced
pressure. The resulting residue was purified by HPLC to yield the
title compound 11a as a white solid (0.042 g, 0.112 mmol, 18%), mp
181e183 ꢀC. nmax (KBr): 3437, 1709, 1662, 1638, 1541, 1186, 797,
3.2.19. 8-Allyl-2-(benzylsulfanyl)-6-methylpyrido[2,3-d]pyrimidine-
4,7(3H,8H)-dione 8e. Compound 8e as a white solid in 96% yield, mp
>230 ꢀC. nmax (KBr): 2854, 1642, 1537, 1492, 1453, 1281, 1152, 988,
700 cmꢁ1
; dH (CDCl3): 2.65 (3H, s, CH3), 4.12 (2H, s, CCH2), 4.68 (2H,
s, SCH2) 7.53e7.12 (10H, m, C6H5 ꢂ2), 8.23 (1H, s, H-5), 10.00 (1H, s,
NH); dC (CDCl3): 19.9, 35.7, 37.7, 114.4, 127.4, 127.9, 128.6, 128.6,
129.3, 129.3, 134.3, 135.1, 136.5, 141.2, 152.8, 160.1, 162.3, 165.5.
HRMS (EI): Mþ, found 374.1330. C22H20N3OS requires 374.1327.
789, 701, 570 cmꢁ1
; dH (DMSO-d6): 2.00 (3H, s, CH3), 4.47 (2H, s,
CH2S), 4.91 (2H, d, J¼2.1 Hz, CH2eCH]), 4.95 (1H, dd, J¼17.2, 1.6 Hz,
CH]CHH), 5.07 (1H, dd, J¼10.3,1.6 Hz, CH]CHH), 5.86e5.93 (1H, m,
CH]CH2), 7.25e7.42 (5H, m, C6H5), 7.75 (1H, s, H-5), 12.99 (1H, s,
NH); dC (DMSO-d6): 16.8, 33.8, 43.4, 99.8, 116.3, 125.1, 127.4, 128.6,
128.8, 131.3, 133.0, 136.8, 151.8, 160.5, 161.3, 162.2. HRMS (FAB):
MþþH, found 340.1119. C18H17N3O2S requires 340.1120.
3.2.23. 2-(Benzylsulfanyl)-7-methyl-6-[4-(trifluoromethyl)benzyl]
pyrido[2,3-d]pyrimidin-4(3H)-one 11b. 3-({[6-Amino-2-(benzylsul-
fanyl)-4-pyrimidinyl]oxy}methyl)-4-[4-(trifluoromethyl)phenyl]-3-
buten-2-one 10b (0.250 g, 0.544 mmol) was dissolved in THF (20 mL,
anhydrous) to which titanium tetrachloride complex 1:2 THF
(0.018g, 0.054mmol)wasadded.Thereactionwasrefluxedfor3 days
under nitrogen. The excess solvent was removed under reduced
pressure and was washed with saturated aqueous NaHCO3 solution.
The reaction mixturewas filtered and partitionedbetweenwaterand
ethyl acetate. The ethyl acetate layer was dried over MgSO4, filtered
under reduced pressure and the solvent was removed under reduced
pressure. The title compound 11b was recrystallised from methanol as
awhite solid (0.055 g, 0.0125 mmol, 23%), mp 195e198 ꢀC. nmax (KBr):
3.2.20. 3-({[6-Amino-2-(benzylsulfanyl)-4-pyrimidinyl]oxy}methyl)-
4-phenyl-3-buten-2-one 10a. 6-Amino-2-(benzylsulfanyl)pyrimidin-
4(3H)-one 1 (0.250 g, 1.07 mmol) was dissolved in DMF (15 mL,
anhydrous) to which cesium carbonate (0.348 g, 1.07 mmol,
1.0 equiv), 3-(chloromethyl)-4-phenyl-3-buten-2-one15 (0.250 g,
1.28 mmol, 1.2 equiv) and potassium iodide (0.035 g, 0.214 mmol,
0.2 equiv) was added. The reaction mixture was stirred at room
temperature for 24 h. The reaction mixture was then filtered and
partitioned between water and ethyl acetate. The ethyl acetate layer
was then dried over MgSO4, the solvent was removed under reduced
pressure and the residue was purified by flash column chromatog-
raphy to yield the title compound 10a as a pale yellow solid (0.273 g,
0.70 mmol, 65%), mp 146e148 ꢀC. nmax (KBr): 3476, 3350, 3230,1964,
1643, 1626, 1514, 1425, 1396, 1300, 1270, 1196, 1035, 803, 759,
3027, 2922, 1682, 1570, 1411, 1325, 1164, 1066, 805, 699 cmꢁ1
; dH
(CDCl3): 2.63 (3H, s, CH3), 4.15 (2H, s, CH2C), 4.68 (2H, s, CH2S),
7.23e7.58 (9H, m, C6H5 and C6H4), 8.26 (1H, s, H-5),11.57 (1H, s, NH);
dC (CDCl3): 23.7, 35.5, 38.4, 113.2, 125.4, 125.8, 127.9, 128.8, 128.9,
129.3, 128.8, 132.1, 136.6, 142.4, 157.2, 159.0, 163.2, 166.0. HRMS (EI):
Mþ, found 441.1126. C23H18F3N3OS requires 441.1123.
700 cmꢁ1
; dH (CDCl3): 2.49 (3H, s, CH3), 4.32 (2H, s, CH2S), 4.67 (2H,
br s, NH2), 5.15 (2H, s, OCH2), 5.53 (1H, s, H-5), 7.17e7.44 (10H, m,
C6H5 ꢂ2), 7.82 (1H, s, C]CH); dC (CDCl3): 27.0, 34.7, 60.4, 82.8, 135.3,
136.0, 139.5, 146.0, 166.1, 169.2, 169.7, 199.4. HRMS (EI): Mþ, found
391.1356. C22H21N3O2S requires 391.1354.
3.2.24. 8-Benzyl-2-(benzylamino)-6-methylpyrido[2,3-d]pyrimidine-
4,7(3H,8H)-dione 13a. 8-Benzyl-2-(benzylsulfanyl)-6-methylpyr-
ido[2,3-d]pyrimidine-4,7(3H,8H)-dione 8d (0.050 g, 0.128 mmol)
was dissolved in DMF (3 mL, anhydrous) to which m-CPBA (0.066 g,
0.39 mmol, 3 equiv) was added and the mixture was stirred under
nitrogen for 3 h at room temperature. The excess solvent was re-
moved under reduced pressure and the residue was dissolved in
benzylamine (2.0 mL, 18.31 mmol) and heated in the microwave at
110 ꢀC for 1 h. The excess solvent was removed under reduced
pressure and the resulting residue was purified by flash chroma-
tography to yield the title compound 13a as a pale yellow solid
(0.033 g, 0.088 mmol, 68%), mp >230 ꢀC. nmax (KBr): 3351, 3316,
3.2.21. 3-({[6-Amino-2-(benzylsulfanyl)-4-pyrimidinyl]oxy}methyl)-
4-[4-(trifluoromethyl)phenyl]-3-buten-2-one 10b. 6-Amino 2-(ben-
zylsulfanyl)pyrimidin-4(3H)-one
1 (250 mg, 1.07 mmol) was
dissolved in DMF (15 mL, anhydrous) to which cesium carbonate
(0.348 g, 1.07 mmol, 1.0 equiv), 3-(chloromethyl)-4-(4-tri-
fluoromethylphenyl)-3-buten-2-one15 (0.267 g, 1.28 mmol,
1.2 equiv) and potassium iodide (0.035 g, 0.214 mmol, 0.2 equiv)
was added. The reaction mixture was stirred at room temperature
for 24 h. The reaction mixture was then filtered and partitioned
between water and ethyl acetate. The ethyl acetate layer was dried
over MgSO4, the solvent was removed under reduced pressure and
the residue was purified by flash column chromatography to yield
the title compound 10b as a white powder (0.340 g, 0.074 mmol,
69%), mp 145e147 ꢀC. nmax (KBr): 3477, 3366,1651,1625, 1578, 1454,
2987, 1677, 1648, 1589, 1176, 1049, 949 cmꢁ1
; dH (DMSO-d6): 2.00
(3H, s, CH3), 4.51 (2H, d, J¼5.5 Hz, NHCH2), 5.37 (2H, s, NCH2),
7.18e7.24 (10H, m, C6H5 ꢂ2), 7.18e7.24 (1H, m, NH), 7.66 (1H, s, H-5),
11.44 (1H, s, NH); dC (DMSO-d6): 14.5, 43.7, 44.0, 95.7, 120.1, 126.7,
126.9, 127.2, 127.6, 128.1, 132.0, 137.8, 138.9, 153.4, 154.6, 161.0, 163.1.
HRMS (FAB): MþþH, found 373.1662. C22H20N4O2 requires 373.1665.
Similarly prepared were:
1424,1325,1300,1195,1123,1069, 704 cmꢁ1
; dH (CDCl3): 2.50 (3H, s,
CH3) 4.31 (2H, s, CH2S), 4.72 (2H, br s, NH2), 5.10 (2H, s, OCH2), 5.51
(1H, s, H-5), 7.18e7.66 (9H, m, C6H5 and C6H4), 7.78 (1H, s, C]CH);
dC (CDCl3): 26.4, 35.0, 60.1, 83.4, 125.7, 125.7 (CF3), 127.0, 128.3,
128.8, 129.7, 137.5, 137.9, 138.0, 142.5, 164.1, 169.0, 170.5, 198.2.
HRMS (EI): Mþ, found 459.1232. C23H20F3N3O2S requires 459.1228.
3.2.25. 8-Benzyl-6-methyl-2-(1-pyrrolidinyl)pyrido[2,3-d]pyrimi-
dine-4,7(3H,8H)-dione 13b. Compound 13b as a beige solid in 59%
yield, mp >230 ꢀC. nmax (KBr): 3342, 2987, 2852, 1668, 1652, 1441,
1216, 1062, 925 cmꢁ1
; dH (DMSO-d6): 1.89 (4H, s, CH2CH2), 2.01 (3H,
s, CH3), 3.46 (4H, s, CH2N ꢂ2), 5.37 (2H, s, CH2N), 7.18e7.33 (5H, m,
C6H5), 7.67 (1H, s, H-5), 11.16 (1H, s, NH); dC (DMSO-d6): 16.6, 24.7,
44.0, 46.2, 94.6, 119.6, 126.8, 127.8, 128.1, 132.2, 138.1, 150.7, 154.3,
161.1, 163.3. HRMS (FAB): MþþH, found 337.1667. C19H20N4O2 re-
quires 367.1659.
3.2.22. 6-Benzyl-2-(benzylsulfanyl)-7-methylpyrido[2,3-d]pyr-
imidin-4(3H)-one trifluoroacetate salt 11a. 3-({[6-Amino-2-(ben-
zylsulfanyl)-4-pyrimidinyl]oxy}methyl)-4-phenyl-3-buten-2-one
10a (0.250 g, 0.639 mmol) was dissolved in THF (20 mL, anhydrous)
to which titanium tetrachloride complex 1:2 THF (0.021 g,
0.0628 mmol) was added. The reaction was refluxed for 3 days
3.2.26. 8-Allyl-2-(benzylamino)-6-methylpyrido[2,3-d]pyrimidine-
4,7(3H,8H)-dione 13c. Compound 13c as a beige solid in 62% yield,

3234
J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
mp >230 ꢀC; dH (DMSO-d6): 1.98 (3H, s, CH3), 4.53 (2H, d, J¼5.9,
CH2NH), 4.75 (2H, d, J¼5.9, CH2eCH]), 4.94 (1H, dd, J¼17.2, 1.5 Hz,
CH]CHH), 4.95 (1H, dd, J¼10.3, 1.5 Hz, CH]CHH), 5.75e5.84 (1H,
m, CH]CH2), 7.24e7.34 (5H, m, C6H5), 7.63 (1H, s, H-5), 11.11 (1H, s,
NH); dC (DMSO-d6): 16.5, 43.1, 43.9, 95.5, 116.6, 120.2, 127.0, 128.3,
131.7, 133.0, 138.8, 152.8, 154.3, 160.3, 162.7. HRMS (FAB): MþþH,
found 323.1510. C18H18N4O2 requires 323.1508.
anhydrous) to which m-CPBA (0.059 g, 0.342 mmol, 3 equiv) was
added. The reaction mixture was stirred at room temperature un-
der nitrogen for 3 h. Aniline (2.0 mL, 21.95 mmol) was then added
to the solution and heated in the microwave at 110 ꢀC for 1 h. The
excess solvent was removed under reduced pressure and the resi-
due was dissolved in ethyl acetate (10 mL) and washed with satu-
rated aqueous NaHCO3 solution (2ꢂ5 mL) and water (2ꢂ5 mL). The
organic layer was then dried over MgSO4 and purified by HPLC to
yield the title compound 14c as a white solid (0.017 g, 0.0414 mmol,
37%), mp 199e201 ꢀC. nmax (KBr): 3288, 3020, 2934, 1643, 1578,
3.2.27. 8-Allyl-6-methyl-2-(1-pyrrolidinyl)pyrido[2,3-d]pyrimidine-
4,7(3H,8H)-dione 13d. Compound 13d as a beige solid 64% yield, mp
>230 ꢀC. nmax (KBr): 3161, 2962, 1683, 1652, 1605, 1547, 1524, 1378,
1462, 1381, 1320, 1215, 990, 739 cmꢁ1
; dH (DMSO-d6): 2.56 (3H, s,
1205, 986 cmꢁ1
;
dH (DMSO-d6): 1.92 (4H, t, J¼6.8 Hz, CH2CH2), 1.99
CH3), 4.22 (2H, s, CH2C), 7.14e7.23 (9H, m, C6H5 and C6H4), 8.37 (1H,
s, H-5), 9.60 (1H, s, NH), 11.54 (1H, s, NH); dC (DMSO-d6): 20.1, 35.9,
100.0, 121.2, 123.4, 124.2, 125.2, 125.5, 127.1, 127.3, 128.9, 129.3,
129.5, 137.6, 143.7, 151.5, 158.3, 158.5. HRMS (FAB): MþþH, found
411.1429. C22H17F3N4O requires 411.1433.
(3H, d, J¼1.1 Hz, CH3), 3.50 (4H, t, J¼6.8 Hz, CH2N ꢂ2), 4.81 (2H, dd,
J¼7.0, 1.4 Hz, CH2eCH]), 5.06 (1H, t, J¼1.5 Hz, CH]CHH), 5.09 (1H,
dd, J¼12.0,1.5 Hz, CH]CHH), 5.85e5.95 (1H, m, CH]CH2), 7.63 (1H,
d, J¼1.1 Hz, H-5), 11.02 (1H, s, NH); dC (DMSO-d6): 16.5, 24.7, 43.0,
46.8, 95.4, 116.8, 119.5, 132.0, 133.1, 150.6, 154.1, 161.1, 162.9. HRMS
(FAB): MþþH, found 287.1505. C15H18N4O2 requires 287.1508.
3.2.31. 7-Methyl-6-[4-(trifluoromethyl)benzyl]pyrido[2,3-d]pyrimi-
dine-2,4(1H,3H)-dione trifluoroacetate salt 14d. 2-(Benzylsulfanyl)-
7-methyl-6-[4-(trifluoromethyl)benzyl]pyrido[2,3-d]pyrimidin-4-
(3H)-one 11b (0.050 g, 0.113 mmol) was dissolved in THF (3 mL,
anhydrous) to which m-CPBA (0.059 g, 0.342 mmol, 3 equiv) was
added. The reaction mixture was stirred under nitrogen for 24 h at
room temperature. The excess solvent was removed under reduced
pressure and the residue was dissolved in ethyl acetate (10 mL) and
washed with saturated aqueous NaHCO3 solution (2ꢂ5 mL) and
water (2ꢂ5 mL). The organic layer was then dried over MgSO4
and purified by HPLC to yield the title compound 14d as a white solid
(0.018 mg, 0.0401 mmol, 35%), mp 210e212 ꢀC. nmax (KBr): 3318,
3.2.28. 2-(Benzylamino)-7-methyl-6-[4-(trifluoromethyl)benzyl]pyr-
ido[2,3-d]pyrimidin-4(3H)-one 14a. 2-(Benzylsulfanyl)-7-methyl-
6-[4-(trifluoromethyl)benzyl]pyrido [2,3-d]pyrimidin-4(3H)-one
11b (0.050 g, 0.113 mmol) was dissolved in THF (3 mL, anhydrous)
to which m-CPBA (0.059 g, 0.342 mmol) was added. The reaction
mixture was stirred at room temperature for 3 h under nitrogen.
The excess solvent was removed and the residue was dissolved in
benzylamine (2 mL, 18.31 mmol) and the solution was heated in
a microwave at 110 ꢀC for 1 h. The excess solvent was removed
under reduced pressure and the residue was dissolved in ethyl
acetate (10 mL) and washed with saturated aqueous NaHCO3 so-
lution (2ꢂ5 mL) and water (2ꢂ5 mL). The organic layer was then
dried over MgSO4 and was purified by HPLC to yield the title
compound 14a as a white solid (0.021 g, 0.0495 mmol, 44%), mp
201e203 ꢀC. nmax (KBr): 3335, 3193, 1672, 1561, 1523, 1493, 1351,
2931, 1661, 1621, 1567, 1506, 1465, 1298, 941, 767 cmꢁ1
; dH (DMSO-
d6): 2.43 (3H, s, CH3), 4.16 (2H, s, CH2C), 7.41 (2H, d, J¼8.1 Hz, 2,6-CH
of Ar), 7.68 (2H, d, J¼8.1 Hz, 3,5-CH of Ar), 7.97 (1H, s, H-5), 11.35
(1H, s, NH), 11.54 (1H, s, NH); dC (DMSO-d6): 22.6, 36.5, 99.5, 107.63,
125.4, 129.0, 129.5, 136.5, 144.3, 150.4, 150.5, 162.4, 163.4. HRMS
(FAB): Mþþ1, found 336.0966. C16H12F3N3O2 requires 336.0960.
1292, 1131, 1039, 964 cmꢁ1
; dH (DMSO-d6): 2.54 (3H, s, CH3), 4.22
(2H, s, CH2C), 4.66 (2H, d, J¼5.8 Hz, CH2NH), 7.26e7.70 (9H, m, C6H5
and C6H4), 8.01 (1H, s, H-5), 8.39 (1H, br s, NH), 11.96 (1H, s, NH); dC
(DMSO-d6): 26.2, 35.6, 43.8, 99.5, 123.4, 125.5, 125.5, 127.2, 127.2,
128.5, 129.5, 130.4, 138.2, 143.7, 154.3, 158.0, 158.2, 158.4, 172.9.
HRMS (FAB): MþþH, 425.1588. C23H19F3N4O requires 425.1589.
3.2.32. 8-Benzyl-2,4-bis(benzylamino)-6-methylpyrido[2,3-d]pyr-
imidin-7(8H)-one 15a. 8-Benzyl-2-(benzylsulfanyl)-6-methylpyr-
ido[2,3-d]pyrimidine-4,7(3H,8H)-dione 13a (0.050 g, 0.134 mmol)
and BOP (77 mg, 0.174 mmol, 1.3 equiv) were suspended in aceto-
nitrile (10 mL, anhydrous) at room temperature. DBU (31
ml,
3.2.29. 7-Methyl-2-(1-pyrrolidinyl)-6-[4-(trifluoromethyl)benzyl] pyr-
ido[2,3-d]pyrimidin-4(3H)-one 14b. 2-(Benzylsulfanyl)-7-methyl-6-
[4-(trifluoromethyl)benzyl]pyrido [2,3-d]pyrimidin-4(3H)-one 11b
(0.050g, 0.113mmol)wasdissolvedinTHF(3mL,anhydrous)towhich
m-CPBA (0.059 g, 0.342 mmol) was added. The reaction mixture was
stirred at room temperature for 3 h under nitrogen. The excesssolvent
was removed and the residue was dissolved in pyrrolidine (2.0 mL,
23.96 mmol) and the solutionwas heated in a microwave at 110 ꢀC for
1 h. The excess solvent was removed under reduced pressure and the
residue was dissolved in ethyl acetate (10 mL) and washed with sat-
urated aqueous NaHCO3 solution (2ꢂ5 mL) and water (2ꢂ5 mL). The
organic layer was then dried over MgSO4 and purifiedby HPLCtoyield
the title compound 14b as a white solid (0.022 g, 0.0574 mmol, 51%),
mp 205e207 ꢀC. nmax (KBr): 3177, 3061, 1720, 1621, 1553, 1414, 1328,
0.201 mmol, 1.5 equiv) was added dropwise and the reaction so-
lution became heterogeneous. After stirring for 10 min at room
temperature, benzylamine (22 ml, 0.201 mmol,1.5 equiv) was added
and the solution was stirred for a further 48 h. The excess solvent
was removed under reduced pressure and the resulting residue was
purified by flash column chromatography to yield the title com-
pound 15a as a pale yellow (0.040 g, 0.0867 mmol, 65%), mp
>230 ꢀC. nmax (KBr): 3348, 3288, 3041, 2992, 1643, 1612, 1591, 1211,
1151, 989, 761 cmꢁ1
;
dH (DMSO-d6): 2.03 (3H, d, J¼0.9 Hz, CH3), 4.64
(2H, d, J¼6.3 Hz, CH2NH), 4.79 (2H, d, J¼4.8 Hz, CH2NH), 5.51 (2H, br
s, NH ꢂ2), 7.16e7.36 (15H, m, C6H5 ꢂ3), 7.85 (1H, s, H-5); dC (DMSO-
d6): 16.2, 44.3, 44.6, 91.1, 126.6, 126.8, 127.4, 127.6, 127.9, 128.2,
128.2, 128.9, 138.6, 139.5, 140.4, 155.3. HRMS (FAB): MþþH, found
462.2290. C29H27N5O requires 462.2294.
1217, 1042, 921 cmꢁ1
;
dH (DMSO-d6): 1.90 (4H, t, J¼6.5 Hz, CH2CH2),
2.41 (3H, s, CH3), 3.50 (4H, t, J¼6.5 Hz, CH2N ꢂ2), 4.12 (2H, s, CH2C),
7.40(2H, d, J¼8.1 Hz, 2,6-CHof Ar), 7.67 (2H, d, J¼8.1 Hz, 3,5-CH2 of Ar),
7.88 (1H, s, H-5),11.20 (1H, s, NH); dC (DMSO-d6): 23.6, 25.4, 38.2, 47.0,
108.9, 125.6, 127.6, 128.8, 129.0, 136.1, 143.1, 150.2, 159.6, 164.3, 165.7.
HRMS (FAB): MþþH, found 389.1584. C20H19F3N4O requires 389.1589.
3.2.33. 8-Benzyl-2-(benzylamino)-6-methyl-4-(1-pyrrolidinyl)
pyrido[2,3-d]pyrimidin-7(8H)-one 15b. 8-Benzyl-2-(benzylsul-
fanyl)-6-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione 13a
(0.150 g, 0.134 mmol) and BOP (77 mg, 0.174 mmol, 1.3 equiv)
were suspended in acetonitrile (10 mL, anhydrous) at room
temperature. DBU (31
dropwise and the reaction solution became heterogeneous. After
stirring for 10 min at room temperature pyrrolidine (17 l,
ml, 0.201 mmol, 1.5 equiv) was added
3.2.30. 2-Anilino-7-methyl-6-[4-(trifluoromethyl)benzyl]pyrido[2,3-
d]pyrimidin-4(3H)-one trifluoroacetate salt 14c. 2-(Benzylsulfanyl)-
7-methyl-6-[4-(trifluoromethyl)benzyl]pyrido[2,3-d]pyrimidin-4-
(3H)-one 11b (0.050 g, 0.113 mmol) was dissolved in THF (3 mL,
m
1.5 equiv) was added and the solution was stirred for a further
48 h at room temperature. The excess solvent was removed

J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
3235
under reduced pressure and the resulting residue was purified by
flash column chromatography to yield the title compound 15b as
an orange solid (0.033 g, 0.0775 mmol, 58%), mp >230 ꢀC. nmax
t, J¼6.1 Hz, CH2CH2), 2.48 (3H, s, CH3), 2.49 (3H, s, CH3), 3.50 (4H, t,
J¼6.1, CH2N ꢂ2), 11.34 (1H, s, NH); dC (DMSO-d6): 21.3, 22.5, 24.8,
46.9, 115.6, 129.0, 147.0, 150.3, 154.7, 162.3. HRMS (FAB): MþþH,
found 246.1351. C12H15N5O requires 246.1355.
(KBr): 3348, 3128, 1682, 1557, 1458, 1435, 1388, 1329, 1213,
ꢁ1
977 cm
; dH (DMSO-d6): dH (DMSO-d6): 2.01e1.85 (4H, m,
CH2CH2), 2.03 (3H, s, CH3), 3.73 (2H, t, J¼6.5, CH2N), 4.24 (2H, t,
J¼6.5, CH2N), 4.80 (2H, d, J¼5.8, C6H5CH2NH), 5.53 (2H, s,
C6H5CH2N8), 7.17e7.27 (10H, m, C6H5 ꢂ2), 7.17e7.27 (1H, br, NH),
7.85 (1H, s, H-5); dC (DMSO-d6): 17.1, 25.5, 44.2, 44.9, 50.6, 93.1,
118.7, 126.8, 126.9, 127.7, 128.2, 128.4, 128.5, 133.1, 138.9, 141.2,
157.0, 160.0, 162.9. HRMS (FAB): MþþH, found 426.2296.
C26H27N5O requires 426.2294.
3.2.38. 2-Anilino-6,7-dimethyl-4(3H)-pteridinone 17c. From 2-(ben-
zylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone and aniline in 54%
yield, mp >230 ꢀC. nmax (KBr): 3318, 3013, 2922, 1663, 1590, 1454,
1405, 1323, 1232, 986, 741 cmꢁ1
; dH (DMSO-d6): 2.53 (3H, s, CH3),
2.55 (3H, s, CH3), 7.06e7.74 (5H, m, C6H5), 8.92 (1H, s, NHC6H5) 11.12
(1H, s, NH); dC (DMSO-d6): 21.4, 22.5, 99.5, 119.9, 123.1, 126.9, 128.8,
138.3,148.5,149.1,154.3,158.7. HRMS (FAB): MþþH, found 268.1201.
C14H13N5O requires 268.1198.
3.2.34. 2-(Benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone 16a. To
a solution of 5,6-diamino-2-(benzylsulfanyl)-4(3H)-pyrimidinone
(500 mg, 2.11 mmol) in ethanol (20 mL) was added biacetyl (353 ml,
3.2.39. 2-(Allylamino)-6,7-dimethyl-4(3H)-pteridinone 17d. From 2-
(benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone and allylamine in
86% yield, mp >230 ꢀC. nmax (KBr): 3278, 2934, 1688, 1621, 1546,
4.02 mmol, 2 equiv) dropwise at room temperature. The reaction
mixture was refluxed at 80 ꢀC for 24 h. The excess solvent was
removed under reduced pressure and the resulting yellow solid
was triturated with diethyl ether to yield the title compound 16a as
a pale yellow solid (511 mg, 1.71 mmol, 85%), mp >230 ꢀC. nmax
(KBr): 2993, 2866, 1675, 1579, 1543, 1445, 1386, 1264, 1163, 959,
1498, 1312, 1225, 1064 cmꢁ1
;
dH (DMSO-d6): 2.50 (6H, s, 2ꢂ CH3),
3.90 (2H, s, CH2CH]), 5.02 (1H, dd, J¼10.3, 1.6 Hz), 5.15 (1H, dd,
J¼17.2, 1.6 Hz), 5.93e5.99 (1H, m, CH2CH]), 12.30 (1H, s, NH).
HRMS (FAB): MþþNa, found 254.1020. C11H13N5ONa requires
254.1018.
821, 717, 639, 516 cmꢁ1
; dH (DMSO-d6): 2.58 (3H, s, CH3), 2.61 (3H, s,
CH3), 4.52 (2H, s, CH2S), 7.26e7.47 (5H, m, C6H5), 12.95 (1H, s, NH);
dC (DMSO-d6): 21.8, 22.6, 33.8, 127.4, 128.5, 128.6, 129.1, 136.8, 152.6,
152.6, 158.8, 159.2, 160.4. HRMS (FAB): MþþH, found 299.0971.
C15H14N4OS requires 299.0967.
3.2.40. 2-(Benzylamino)-6,7-diphenyl-4(3H)-pteridinone 17e. From
2-(benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone and benzyl-
amine in 83% yield, mp >230 ꢀC. nmax (KBr): 3422, 3260, 3019, 1686,
1622, 1560, 1535, 1490, 1451, 1357, 1277, 1036, 727 cmꢁ1
; dH (DMSO-
d6): 4.66 (2H, d, J¼5.8 Hz, CH2), 7.23e7.42 (16H, m, C6H5 ꢂ3 and
NH), 11.46 (1H, s, NH); dC (DMSO-d6): 43.8, 127.0, 127.2, 127.4, 128.0,
128.1, 128.4, 129.0, 129.6, 138.2, 138.4, 138.8, 146.8, 152.8, 155.2,
156.5, 160.7. HRMS (FAB): MþþH, found 406.1665. C25H19N5O re-
quires 406.1668.
3.2.35. 2-(Benzylsulfanyl)-6,7-diphenyl-4(3H)-pteridinone 16b. To
a solution of 5,6-diamino-2-(benzylsulfanyl)-4(3H)-pyrimidinone
(1000 mg, 4.03 mmol) in ethanol (20 mL) was added benzil
(1270 mg, 6.04 mmol, 1.5 equiv) at room temperature. The reaction
mixture was heated at 85 ꢀC for 24 h. The excess solvent was re-
moved under reduced pressure and the resulting yellow solid was
triturated with diethyl ether (10 mL) to yield the title compound 16b
as a pale yellow solid (1.498 g, 3.25 mmol, 88%), mp >230 ꢀC. nmax
3.2.41. 6,7-Diphenyl-2-(1-pyrrolidinyl)-4(3H)-pteridinone 17f. From
2-(benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone and pyrroli-
dine in 83% yield, mp >230 ꢀC. nmax (KBr): 3421, 3201, 2971, 1681,
(KBr): 3165, 2988,1664,1573,1559, 1423, 1378, 1167, 976, 723 cmꢁ1
;
1610,1556,1516,1453,1287, 980, 765 cmꢁ1
; dH (DMSO-d6): 1.95 (4H,
dH (DMSO-d6): 4.59 (2H, s, CH2S), 7.26e7.51 (15H, m, C6H5 ꢂ3),13.17
(1H, s, NH); dC (DMSO-d6): 34.0, 127.4, 128.1, 128.2, 128.6, 128.7,
129.1, 129.4, 129.6, 129.7, 129.8, 136.7, 137.8, 138.0, 150.4, 152.4,
156.8, 160.4, 160.8. HRMS (FAB): MþþH, found 423.1282.
C25H18N4OS requires 423.1280.
t, J¼6.5 Hz, CH2CH2), 3.57 (4H, t, J¼6.5 Hz, CH2N), 7.30e7.43 (10H, m,
C6H5), 11.13 (1H, s, NH); dC (DMSO-d6): 24.8, 47.1, 126.3, 127.9, 128.0,
129.0, 129.4, 129.6, 131.1,138.4, 138.5, 146.1, 151.3, 154.7,156.5, 162.0.
HRMS (FAB): MþþH, found 370.1672. C22H19N5O requires 370.1668.
3.2.42. 2-Anilino-6,7-diphenyl-4(3H)-pteridinone 17g. From 2-(ben-
zylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone and aniline in 61%
yield, mp >230 ꢀC. nmax (KBr): 3423, 3089, 2924, 1729, 1641, 1539,
3.2.36. 2-(Benzylamino)-6,7-dimethyl-4(3H)-pteridinone
17a. 2-
(Benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone 16a (100 mg,
0.335 mmol) was dissolved in dry DMF (3.0 mL). To this solution
was added m-CPBA (3.0 equiv, 1.01 mmol, 174 mg) and was stirred
under nitrogen for 3 h at room temperature. The solvent was then
removed under reduced pressure and the resulting solid was dis-
solved in benzylamine (2.0 mL, 18.31 mmol) and heated in the
microwave at 110 ꢀC for 1 h. The excess solvent was removed under
reduced pressure and the resulting residue was purified by flash
chromatography to yield the title compound 17a as a yellow solid
(89 mg, 0.316 mmol, 94%), mp >230 ꢀC. nmax (KBr): 3413, 2925,
1492, 1313, 1185, 836, 781 cmꢁ1
; dH (DMSO-d6): 7.10e7.81 (15H, m,
C6H5 ꢂ3), 9.29 (1H, br s, NHCH2), 11.29 (1H, s,); dC (DMSO-d6): 120.3,
123.4, 128.0, 128.1, 128.2, 128.3, 128.8, 129.1, 129.5, 129.6, 138.2,
138.3,147.8,150.5,154.5,156.7. HRMS (FAB): MþþH, found 392.1509.
C24H17N5O requires 392.1511.
3.2.43. 2-(Allylamino)-6,7-diphenyl-4(3H)-pteridinone 17h. From 2-
(benzylsulfanyl)-6,7-diphenyl-4(3H)-pteridinone and allylamine in
79% yield, mp >230 ꢀC. nmax (KBr): 3288, 2931, 1685, 1623, 1563,
1666, 1590, 1535, 1447, 1414, 1268, 1036, 727 cmꢁ1
;
dH (DMSO-d6):
1496, 1287, 1095, 765 cmꢁ1
; dH (DMSO-d6): 4.07 (2H, m,
2.47 (3H, s, CH3), 2.48 (3H, s, CH3), 4.59 (2H, d, J¼5.6 Hz, CH2NH),
7.23e7.40 (5H, m, C6H5), 7.60 (1H, br s, CH2NH), 9.59 (1H, s, NH); dC
(DMSO-d6): 21.3, 22.5, 43.6, 126.1, 126.8, 127.1, 128.3, 139.3, 146.8,
153.1, 155.1, 158.0, 162.2. HRMS (FAB): MþþH, found 282.1353.
C15H15N5O requires 282.1355.
NHCH2eCH]), 5.15 (1H, dd, J¼10.3, 1.6 Hz, CH]CHH), 5.25 (1H, dd,
J¼17.2, 1.6 Hz, CH]CHH), 5.94e5.99 (1H, m, CH2eCH]), 6.94 (1H,
s, NH), 7.30e7.43 (10H, m, C6H5 ꢂ2), 11.41 (1H, s, NH); dC (DMSO-
d6): 42.5, 115.6, 127.3, 128.0, 128.0, 129.1, 129.4, 129.6, 134.8, 138.2,
146.7, 152.6, 155.2, 156.5, 160.6. HRMS (FAB): MþþH, found
356.1510. C21H17N5O requires 356.1511.
Similarly prepared were:
3.2.37. 6,7-Dimethyl-2-(1-pyrrolidinyl)-4(3H)-pteridinone
17b. From 2-(benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone and
pyrrolidine in 90% yield, mp >230 ꢀC. nmax (KBr): 3442, 3197, 2964,
3.2.44. 2-(Benzylsulfanyl)-N-butyl-6,7-dimethyl-4-pteridinamine
18a. 2-(Benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone 16a (100 mg,
0.335 mmol) and BOP (196 mg, 0.443 mmol, 1.3 equiv) were sus-
1685,1611,1558,1518, 392,1270, 976 cmꢁ1
;
dH (DMSO-d6): 1.91 (4H,
pended in dry acetonitrile (10 mL). DBU (76 ml, 0.493 mmol, 1.5 equiv)

3236
J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
was then added dropwise and the reaction mixture became homo-
geneous. After stirring for 10 min at room temperature, butylamine
152.0, 156.9, 160.7, 169.2. HRMS (FAB): MþþH, found 402.1756.
C23H23N5S requires 402.1752.
(50 ml, 0.502 mmol, 1.5 equiv) was added dropwise and the solution
was stirred for a further 48 h. The excess solvent was removed under
reduced pressure and the resulting residue was partitioned between
ethyl acetate and water. The organic layer was dried over MgSO4 and
purified by flash chromatography to yield the title compound 18a as
pale yellow solid (92 mg, 78%), mp >230 ꢀC. nmax (KBr): 3423, 3027,
3.2.50. N-Benzyl-6,7-dimethyl-4-(1-pyrrolidinyl)-2-pteridinamine
19a. 2-(Benzylsulfanyl)-6,7-dimethyl-4-(1-pyrrolidinyl)pteridine
18c (100 mg, 0.285 mmol) was dissolved in dry DMF (3.0 mL). To
this was added m-CPBA (147 mg, 0.852 mmol, 3.0 equiv) at room
temperature and the reaction was stirred for 3 h under nitrogen.
The excess solvent was removed and the residue was dissolved in
benzylamine (2.0 mL, 18.31 mmol) and the solution was heated in
a microwave for 1 h at 110 ꢀC. The excess solvent was removed
under reduced pressure and the resulting residue was purified by
flash chromatography to yield the title compound 19a as a yellow
solid (40 mg, 0.120 mmol, 42%), mp >230 ꢀC. nmax (KBr): 3297, 2975,
2928, 1676, 1602, 1495, 1454, 1388, 750 cmꢁ1
; dH (CDCl3): 0.98 (3H, t,
J¼7.2 Hz, CH3), 1.40e1.50 (2H, m, CH2), 1.66e1.73 (2H, m, CH2), 2.64
(3H, s, CH3), 2.71 (3H, s, CH3), 3.63 (2H, t, J¼6.5 Hz), 4.57 (2H, s, CH2S),
6.93 (1H, m, NH) 7.22e7.48 (5H, m, C6H5); dC (CDCl3): 11.8, 20.1, 22.3,
23.3, 31.4, 35.9, 40.7, 122.2, 127.0, 128.4, 128.4, 128.5, 129.2, 137.6, 150.1,
152.2, 159.1, 159.9, 171.6. HRMS (FAB): MþþNa, found 376.1573.
C19H23N5SNa requires 376.1572.
1659, 1542, 1364, 1295, 981 cmꢁ1
; dH (DMSO-d6): 1.93 (4H, s,
Similarly prepared were:
CH2CH2), 2.47 (3H, s, CH3), 2.48 (3H, s, CH3), 3.95 (4H, br s, CH2N),
4.58 (2H, d, J¼4.8, CH2NH), 6.84 (1H, br s, NH), 7.18e7.37 (5H, m,
C6H5); dC (DMSO-d6): 21.8, 22.5, 45.0, 50.2, 122.9, 126.8, 127.7, 128.5,
141.5, 144.0, 156.3, 157.3, 158.9, 161.1. HRMS (FAB): MþþH, found
335.1987. C19H22N6 requires 335.1984.
3.2.45. N-Benzyl-2-(benzylsulfanyl)-6,7-dimethyl-4-pteridinamine
18b. From 2-(benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone and
benzylamine in 87% yield, mp >230 ꢀC. nmax (KBr): 3403, 3084,
2981, 1684, 1621, 1574, 1448, 1223, 909 cmꢁ1
;
dH (DMSO-d6): 2.63
Similarly prepared were:
(6H, s, CH3 ꢂ2), 4.39 (2H, s, CH2S), 4.71 (2H, d, J¼6.2, Hz, CH2NH),
7.19e7.44 (10H, m, C6H5 ꢂ2), 9.10 (1H, t, J¼6.2 Hz, CH2NH); dC
(DMSO-d6): 22.0, 23.0, 34.4, 43.6, 121.6, 126.9, 127.3, 128.3, 128.4,
128.6, 128.7, 138.3, 138.9, 150.8, 151.7, 159.0, 160.3, 169.4. HRMS
(FAB): MþþH, found 388.1593. C22H21N5S requires 388.1596.
3.2.51. 6,7-Dimethyl-2,4-di(1-pyrrolidinyl)pteridine 19b. From 2-
(benzylsulfanyl)-6,7-dimethyl-4-(1-pyrrolidinyl)pteridine 18 c and
pyrrolidine in 86% yield, mp >230 ꢀC. nmax (KBr): 3098, 2975, 1683,
1620, 1467,1346, 1234, 1082, 830 cmꢁ1
; dH (DMSO-d6): 1.90 (8H, s,
CH2CH2 ꢂ2), 2.46 (3H, s, CH3), 2.48 (3H, s, CH3), 3.51 (4H, s, CH2N
ꢂ2), 3.68 (2H, s, CH2N), 4.18 (2H, s, CH2N); dC (DMSO-d6): 21.8, 22.8,
25.4, 46.8, 50.1, 122.3, 143.6, 156.3, 157.2, 158.5, 159.1. HRMS (FAB):
MþþH, found 299.1987. C16H22N6 requires 299.1984.
3.2.46. 2-(Benzylsulfanyl)-6,7-dimethyl-4-(1-pyrrolidinyl)pteridine
18c. From 2-(benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone and
pyrrolidine in 81% yield, mp >230 ꢀC. nmax (KBr): 3368, 3121, 2963,
1644, 1568, 1553, 1450, 1378, 1262, 820, 724 cmꢁ1
;
dH (DMSO-d6):
Prepared by the same method as 15a and 15b were:
2.02e1.86 (4H, m, CH2CH2), 2.56 (3H, s, CH3), 2.59 (3H, s, CH3), 3.67
(2H, t, J¼6.6, Hz, CH2N), 4.21 (2H, t, J¼6.6 Hz, CH2N), 4.44 (2H, s,
CH2S), 7.21e7.45 (5H, m, C6H5); dC (DMSO-d6): 22.1, 22.7, 23.1, 26.4,
34.4, 49.8, 50.9, 123.5, 126.9, 128.4, 128.7, 138.5, 148.8, 153.3, 156.7,
158.4, 168.3. HRMS (FAB): MþþH, found 352.1599. C19H21N5S re-
quires 352.1596.
3.2.52. N2-Allyl-N4-butyl-6,7-diphenyl-2,4-pteridinediamine
19c. From 2-(allylamino)-6,7-diphenyl-4(3H)-pteridinone 17h and
n-butylamine in 70% yield, mp >230 ꢀC. nmax (KBr): 3283, 3080,
2974, 1691, 1616, 1560, 1492, 1220, 903, 735 cmꢁ1
; dH (DMSO-d6):
0.93 (3H, t, J¼7.3 Hz, CH3), 1.31e1.40 (2H, m, CH2), 1.60e1.67 (2H, m,
CH2), 3.63 (2H, q, J¼6.5 Hz, CH2CH2NH), 4.02 (2H, t, J¼5.6 Hz,
CH2CH]), 5.06 (2H, dd, J¼10.2, 1.6 Hz, CH]CHH), 5.18 (2H, dd,
J¼17.2, 1.6 Hz, CH]CHH), 5.95 (1H, m, CH]CH2), 7.29e7.44 (11H,
m, C6H5 and NH) 8.16 (1H, s, NH). HRMS (FAB): MþþH, found
411.2298. C25H26N6 requires 411.2297.
3.2.47. 2-(Benzylsulfanyl)-6,7-dimethyl-N-phenyl-4-pteridinamine
18d. From 2-(benzylsulfanyl)-6,7-dimethyl-4(3H)-pteridinone and
aniline in 65% yield, mp >230 ꢀC. nmax (KBr): 3451, 3096, 1681, 1574,
1541, 1483, 1241, 1090, 828, 741 cmꢁ1
; dH (DMSO-d6): 2.68 (3H, s,
CH3), 2.70 (3H, s, CH3), 4.45 (2H, s, CH2S), 7.45e7.21 (10H, m, C6H5
ꢂ2), 10.09 (1H, s, NH); dC (DMSO-d6): 22.0, 23.0, 34.5, 121.6, 122.0,
124.2,126.9,128.4,128.5,128.8,138.0,151.5,152.0,157.0,160.8,169.2.
HRMS (FAB): MþþH, found 374.1436.C21H19N5S requires 374.1439.
3.2.53. N2-Allyl-N4-benzyl-6,7-diphenyl-2,4-pteridinediamine
19d. From 2-(allylamino)-6,7-diphenyl-4(3H)-pteridinone 17h and
benzylamine in 83% yield, mp >230 ꢀC. nmax (KBr): 3310, 3054, 2986,
1663,1621,1446,1421,1263, 993, 895, 739 cmꢁ1
; dH (DMSO-d6): 4.01
3.2.48. 2-(Benzylsulfanyl)-6,7-dimethyl-N-(4-methylphenyl)-4-pter-
idinamine 18e. From 2-(benzylsulfanyl)-6,7-dimethyl-4(3H)-pter-
idinone and p-toluidine in 71% yield, mp >230 ꢀC. nmax (KBr):
(2H, s, C6H5CH2NH), 4.75 (2H, d, J¼5.2, Hz, CH2CH]) 5.05 (1H, dd,
J¼10.0,1.6 Hz, CH]CHH), 5.18 (1H, dd, J¼17.2,1.6 Hz, CH]CHH), 5.94
(1H, m, CH]CH2), 7.21e7.45 (16H, m, C6H5 ꢂ3 and NH), 8.67 (1H, s,
NH); dC (DMSO-d6): 43.2, 43.3, 114.8, 126.7, 127.4, 127.8, 128.0, 128.2,
128.8, 129.5, 129.6, 136.0, 138.4, 138.9, 139.4, 144.8, 160.0, 161.4.
HRMS (FAB): MþþH, found 445.2136. C28H25N6 requires 445.2141.
3430, 3030, 2845, 1683, 1539, 1478, 1234, 1025, 697 cmꢁ1
; dH
(DMSO-d6): 2.29 (3H, s, C6H4CH3), 2.67 (3H, s, CH3), 2.70 (3H, s,
CH3), 4.44 (2H, s, CH2S), 7.17e7.77 (9H, m, C6H5 and C6H4), 10.03
(1H, s, NH); dC (DMSO-d6): 20.5, 22.0, 23.0, 34.4, 121.6, 122.0, 127.0,
128.4, 128.8, 128.9, 133.3, 135.6, 138.0, 151.4, 152.0, 156.9, 160.6,
169.2. HRMS (FAB): MþþH, found 388.1597. C22H21N5S requires
388.1596.
3.2.54. N-Allyl-6,7-diphenyl-4-(1-pyrrolidinyl)-2-pteridinamine
19e. From 2-(allylamino)-6,7-diphenyl-4(3H)-pteridinone 17h and
pyrrolidine in 80% yield, mp >230 ꢀC. nmax (KBr): 3304, 3063, 2951,
1696, 1612, 1439, 1412, 1249, 998, 755 cmꢁ1
; dH (DMSO-d6):
3.2.49. 2-(Benzylsulfanyl)-N-(4-ethylphenyl)-6,7-dimethyl-4-pter-
idinamine 18f. From 2-(benzylsulfanyl)-6,7-dimethyl-4(3H)-and 4-
ethylaniline in 71% yield, mp >230 ꢀC. nmax (KBr): 3424, 3026, 2942,
1.87e2.02 (4H, m, CH2CH2), 3.74 (2H, t, J¼6.5 Hz, CH2N), 4.02 (2H, d,
J¼5.6 Hz, CH2CH]), 4.26 (2H, t, J¼6.5, Hz, CH2N), 5.06 (1H, dd,
J¼10.3, 1.7 Hz, CH]CHH), 5.19 (1H, dd, J¼17.2, 1.7 Hz, CH]CHH),
5.91e6.00 (1H, m), 7.29e7.45 (11H, m, C6H5 ꢂ2 and NH). HRMS
(FAB): MþþH, found 409.2139. C25H24N6 requires 409.2141.
2853, 1678, 1513, 1495, 1392, 1259, 1012, 744 cmꢁ1
; dH (DMSO-d6):
1.18 (3H, t, J¼7.6 Hz, CH3), 2.59 (2H, q, J¼7.6 Hz, CH2), 2.67 (3H, s,
CH3), 2.70 (3H, s, CH3), 4.44 (2H, s, CH2S), 7.20e7.80 (9H, m, C6H5
and C6H4), 10.03 (1H, s, NH); dC (DMSO-d6): 15.6, 22.0, 23.0, 27.6,
34.5, 121.6, 122.1, 126.9, 127.7, 128.4, 128.8, 135.8, 138.0, 139.8, 151.4,
3.2.55. 2-(Benzylsulfanyl)-6,7,7-trimethyl-3,7-dihydro-4H-pyrimido
[4,5-b][1,4]oxazin-4-one
20. 2-(Benzylthio)-6-hydroxy-5-nitroso

J. Adcock et al. / Tetrahedron 67 (2011) 3226e3237
3237
pyrimidin-4(3H)-one (300 mg, 1.14 mmol) was dissolved in ethanol
(20 mL) to which sodium dithionite (496 mg, 2.85 mmol, 2.5 equiv)
in water (20 mL) was added dropwise at room temperature and
allowed to stir for 4 h. The flask was covered with aluminium foil to
protect from light. A light yellow solid was precipitated, which was
filtered and washed with water (2ꢂ10 mL) and ether (2ꢂ10 mL).
The resulting solid was suspended in a 1:1 water/ethanol mixture
(20 mL). 3-Chloro-3-methylbutan-2-one (206 mg, 1.5 equiv) in
ethanol (10 mL) was then added to the suspension and this mixture
was heated to reflux. After 15 min sodium acetate (112 mg,
1.2 equiv) in water (5 mL) was added dropwise and heating under
reflux was continued for a further 3 h. The resulting mixture was
allowed to cool to room temperature and then stored at 0 ꢀC for
12 h. The resulting precipitate was filtered, washed with water
(2ꢂ10 mL) and dry ether (2ꢂ10 mL) to yield the title compound 20
as a beige solid (126 mg, 0.399 mmol, 35%), mp 222e224 ꢀC. nmax
with saturated sodium bicarbonate solution (2ꢂ5 mL) and water
(2ꢂ5 mL). The organic layer was then dried over MgSO4 and the
title product was recrystallised from methanol as an orange solid
(34 mg, 0.088 mmol, 30%), mp >230 ꢀC. nmax (KBr): 3423, 3005,
2873, 1701, 1669, 1539, 1234, 1025, 697 cmꢁ1
; dH (DMSO-d6): 4.36
(2H, d, J¼6.4 Hz, CH2NH), 4.36 (2H, d, J¼5.9 Hz, CH2NH), 5.00 (2H, s,
CH2O) 7.29 (10H, m, C6H5 ꢂ2), 7.52 (1H, s, NH), 8.69 (1H, s, NH),
10.95 (1H, s, NH); dC (DMSO-d6): 42.1, 43.7, 63.1, 126.7, 127.1, 127.3,
127.4, 128.2, 128.4, 138.4, 139.4, 142.3, 153.8, 159.3, 162.0, 162.3.
HRMS (FAB): MþþH, found 390.1570. C21H19N5O3 requires
390.1566.
Supplementary data
Electronic Supplementary Data (ESD) available: 1H NMR spectra
for most new compounds. Supplementary data related to this ar-
ticle can be found online at doi:10.1016/j.tet.2011.03.011.
(KBr): 3424, 2981, 1658, 1561, 1312, 1239, 1121, 965, 705; cmꢁ1
; dH
(DMSO-d6): 1.44 (6H, s, 7-CH3 ꢂ2), 2.07 (3H, s, 6-CH3), 4.36 (2H, s,
CH2S), 7.41e7.20 (5H, m, C6H5), 12.63 (2H, br s, NH). HRMS (FAB):
MþþH, found 316.1119. C16H17N3O2S requires 316.1120.
Similarly prepared was:
References and notes
1. Gibson, C. L.; Huggan, J. K.; Suckling, C. J. In Comprehensive Heterocyclic Chem-
istry III; Jones, R. A., Ed.; Elsevier: Oxford, 2008; Chapter 10.18, pp 915e975.
2. Gibson, C. L.; La Rosa, S.; Ohta, K.; Boyle, P. H.; Leurquin, F.; Lemac¸ on, A.;
Suckling, C. J. Tetrahedron 2004, 60, 943e959; Gibson, C. L.; Huggan, J. K.;
Suckling, C. J.; Werner, E. R. Unpublished observations, 2006.
3. Al Hassan, S. S.; Cameron, R. J.; Curran, A. W. C.; Lyall, W. J. S.; Nicholson, S. H.;
Robinson, D. R.; Stuart, A.; Stirling, I.; Suckling, C. J.; Wood, H. C. S. J. Chem. Soc.,
Perkin Trans. 1 1985, 1645e1659.
4. Haddow, J.; Suckling, C. J.; Wood, H. C. S. J. Chem. Soc., Perkin Trans. 1 1989,
1297e1304.
5. Gibson, C. L.; Huggan, J. K.; Kennedy, A.; Kiefer, L.; Lee, J.-H.; Suckling, C. J.;
Clements, C.; Harvey, A. L.; Hunter, W. N.; Tulloch, L. B. Org. Biomol. Chem. 2009,
7, 1829e1842.
3.2.56. Ethyl 2-(benzylsulfanyl)-4-oxo-3,7-dihydro-4H-pyrimido[4,5-
b][1,4]oxazine-6-carboxylate 21. From 2-(Benzylthio)-6-hydroxy-5-
nitrosopyrimidin-4(3H)-one reduced with sodium dithionite and
ethyl bromopyruvate in 30% yield, mp 205e207 ꢀC. nmax (KBr):
3413, 3046, 2873, 1700, 1681, 1539, 1234, 1025, 721, 697 cmꢁ1
; dH
(DMSO-d6): 1.28 (3H, t, J¼7.1 Hz, CH3), 4.25 (2H, q, J¼7.1 Hz, CH2),
4.40 (2H, s, CH2S), 5.10 (2H, s, CH2O), 7.42e7.25 (5H, m, C6H5), 13.00
(1H, br s, NH). HRMS (FAB): MþþH, found 346.0863. C16H15N3O4S
requires 346.0862.
6. Suckling, C. J.; Gibson, C. L.; Huggan, J. K.; Morthala, R. R.; Clarke, B.; Kununthur,
S.; Wadsworth, R. M.; Daff, S.; Papale, D. Bioorg. Med. Chem. Lett. 2008, 18,
1552e1555.
7. Gibson, C. L.; La Rosa, S.; Suckling, C. J. Org. Biomol. Chem. 2003, 1, 1909e1918.
8. Melguizo, M.; Nogueras, M.; Sanchez, A. Heterocycles 1991, 32, 1719e1728.
9. Negrillo, J.; Nogueras, M.; Sanchez, A.; Melgarejo, A. Chem. Pharm. Bull. 1988, 36,
386e393.
10. Huggan, J. K., Ph.D. Thesis, University of Strathclyde, 2006.
11. Castro, A. M. M. Chem. Rev. 2004, 104, 2939e3002; Li, C. J. Chem. Rev. 1993, 93,
2023e2035.
12. Minnemeyer, H. J.; Egger, J. A.; Holland, J. F.; Tieckelmann, H. J. Org. Chem. 1961,
26, 4425e4429; Dinan, F. J.; Minkemeyer, H. J.; Tieckelmann, H. J. Org. Chem.
1963, 28, 1015e1018.
3.2.57. 2-(Benzylamino)-6,7,7-trimethyl-3,7-dihydro-4H-pyrimido
[4,5-b][1,4]oxazin-4-one
22. 2-(Benzylsulfanyl)-6,7,7-trimethyl-
3,7-dihydro-4H-pyrimido[4,5-b][1,4]oxazin-4-one 20 (100 mg,
0.32 mmol) was dissolved in benzylamine (2.0 mL,18.31 mmol) and
the solution was heated in a microwave for 1 h at 110 ꢀC. The excess
solvent was removed under reduced pressure and the residue was
dissolved in ethyl acetate (10 mL) and washed with saturated so-
dium bicarbonate solution (2ꢂ5 mL) and water (2ꢂ5 mL). The or-
ganic layer was then dried over MgSO4 and was purified by flash
chromatography to yield the title product as a beige solid (44 mg,
0.148 mmol, 37%), mp >230 ꢀC. nmax (KBr): 3425, 3283, 2992, 1643,
13. Gibson, C. L.; Huggan, J. K.; Kennedy, A. R.; Suckling, C. J. Acta Crystallogr. E 2006,
324e326.
14. Shi, M.; Feng, Y.-S. J. Org. Chem. 2001, 66, 406e411.
15. Corma, A.; Garcia, H. Chem. Rev. 2003, 103, 4307e4365.
16. Jamieson, A. G.; Sutherland, A. Org. Biomol. Chem. 2005, 5, 735e736.
17. Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem. Soc. 1999, 121,
9726e9727.
1551, 1213, 1303, 1239, 1091, 705 cmꢁ1
; dH (DMSO-d6): 1.36 (6H, s,
CH3 ꢂ2), 2.00 (3H, s, CH3), 4.43 (2H, d, J¼6.3 Hz, CH2NH), 7.15 (1H,
br s, NH), 7.25e7.35 (5H, m, C6H5), 10.63 (1H, s, NH). HRMS (FAB):
MþþH, found 299.1506. C16H18N4O2 requires 299.1508.
18. Wan, Z.-K.; Wacharasindhu, S.; Bunnun, E.; Mansour, T. Org. Lett. 2006, 8,
2425e2428.
19. Guiney, D.; Gibson, C. L.; Suckling, C. J. Org. Biomol. Chem. 2003, 1, 664e675.
20. Menichincheri, M.; Angiolini, M.; Bassini, D. F.; Gude, M. Tetrahedron Lett. 2005,
46, 8749e8752.
21. Murata, S.; Yoshikawa, K.; Chen, N. Chem.dEur. J. 2005, 11, 4835e4848.
22. Gibson, C. L.; Huggan, J. K.; Kiefer, L.; Suckling, C. J. In Chemistry and Biology of
Pteridines and Folates; Jansen, G., Peters, G. J., Eds.; SPS Publications: Heilbronn,
2007; pp 269e278.
3.2.58. N-Benzyl-2-(benzylamino)-4-oxo-3,7-dihydro-4H-pyrimido
[4,5-b][1,4]oxazine-6-carboxamide 23. Ethyl 2-(benzylsulfanyl)-4-
oxo-3,7-dihydro-4H-pyrimido[4,5-b][1,4]oxazine-6-carboxylate 21
(100 mg, 0.29 mmol) was dissolved in benzylamine (2.0 mL,
18.31 mmol) and the solution was heated in a microwave for 1 h at
110 ꢀC. The excess solvent was removed under reduced pressure
and the residue was dissolved in ethyl acetate (10 mL) and washed
23. Tulloch, L. B.; Martini, V. P.; Iulek, J.; Huggan, J. K.; Lee, J. H.; Gibson, C. L.; Smith,
T. K.; Suckling, C. J.; Hunter, W. N. J. Med. Chem. 2010, 53, 221e229.