Synthesis and reactivity of 5-polyfluoroalkyl-5-deazaalloxazines

Article abstract of DOI:10.1039/c3ob26837c

Reaction of 6-arylamino-1,3-dialkyluracils with anhydrides of polyfluorocarboxylic acids in the presence of pyridine and subsequent cyclization with concentrated H₂SO₄ gave the corresponding 1,3-dialkyl-5-(polyfluoroalkyl)pyrimido[4,

Full text of DOI:10.1039/c3ob26837c

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Synthesis and reactivity of 5-polyfluoroalkyl-
5-deazaalloxazines†
Cite this: DOI: 10.1039/c3ob26837c
Sergii Dudkin,a Viktor O. Iaroshenko,*a,b Vyacheslav Ya. Sosnovskikh,c
Andrey A. Tolmachev,b,d Alexander Villingera and Peter Langer*a,e
Reaction of 6-arylamino-1,3-dialkyluracils with anhydrides of polyfluorocarboxylic acids in the presence
of pyridine and subsequent cyclization with concentrated H2SO4 gave the corresponding 1,3-dialkyl-
5-(polyfluoroalkyl)pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones (5-polyfluoroalkyl-5-deazaalloxazines). The
reactivity of these compounds towards nucleophilic reagents, such as sodium cyanoborohydride, aceto-
phenone, nitromethane, potassium cyanide, indole and p-thiocresol, as well as Suzuki and Sonogashira
couplings are described. The nucleophilic addition takes place at the 5-position of the 5-deazaalloxazine
system and is in many cases irreversible to give 5,10-dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-dione
derivatives in good to excellent yields.
Received 19th September 2012,
Accepted 13th June 2013
DOI: 10.1039/c3ob26837c
www.rsc.org/obc
5-position of the 5-deazaflavin ring system I is very π-electron
deficient and the reactions of these compounds with nucleo-
Introduction
Heterocyclic scaffolds, containing polar groups capable of philes start predominantly with attack at the unsubstituted C-5
hydrogen bond formation, are of high relevance for drug atom.6
design as basic structural platforms for the development of
Introduction of a trifluoromethyl group into bioactive
tightly binding enzyme ligands, enzyme pitfalls and suicide molecules, especially in the positions responsible for their
substrates.1 To date, several dozens of such compounds have physiological profile, has become an important aspect of
been reported; among them are bioactive molecules and pharmaceutical research owing to the unique physical and bio-
drugs.1–3 Pyrimido[4,5-b]quinoline-2,4(3H,10H)-diones (also logical properties of fluorine.7 Now it is well known that a tri-
known as 5-deazaflavins or 5-deazaisoalloxazines, I), where N-5 fluoromethyl group can have profound and unexpected results
of the naturally occurring flavins (isoalloxazines, II) is replaced on biological activity and reactivity of the derived fluorinated
by CH, have been studied extensively in both enzymatic and compounds.8 Recently, the strong electrophilic feature of the
model systems to provide mechanistic insight into flavin-cata- CF3 group was used to design a set of protease inhibitors.3
lysed reactions.4 In addition, the 5-deazaflavins I can be con- Very recently, we applied the concept illustrated above to
sidered structurally as a model not only of flavin nucleotides, develop several types of 2-RF- and 6-RF-functionalized purines,
but also of nicotinamide nucleotides protected by annelation, purine isosteres as well as their corresponding nucleosides.9
since they oxidize simple alcohols under alkaline conditions to These compounds are potential inhibitors of two biologically
the corresponding carbonyl compounds and they are them- relevant de novo purine bio-synthesis enzymes, namely adeno-
selves hydrogenated to 1,5-dihydro-5-deazaflavins.5 The sine deaminase (ADA)10 and inosine monophosphate dehydro-
genase (IMPHD).11
We envisaged that introduction of such powerful electron-
withdrawing substituents like RF groups into the 5-position of
aInstitut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock,
Germany. E-mail: peter.langer@uni-rostock.de; Fax: +0049 381 498 6412;
Tel: +0049 381 498 6410
bNational Taras Shevchenko University, 62 Volodymyrska Str., 01033 Kyiv, Ukraine
cDepartment of Chemistry, Ural Federal University, 51 Lenina Ave., 620000
Ekaterinburg, Russia
pyrimido[4,5-b]quinoline-2,4(1H,3H)-diones
(5-deazaallox-
azines, III), which are closely related to pyrimido[4,5-b]quino-
line-2,4(3H,10H)-diones (5-deazaisoalloxazines, I), would
increase their reactivity toward nucleophilic reagents and open
up a broad synthetic scope of this important nitrogen-contain-
ing heterocyclic system. Unlike previously known 5-deazaallox-
azines III,12 selectively fluorinated pyrimido[4,5-b]quinolines
IV have not received much attention, despite their potential
interest as highly reactive substrates in organic synthesis for
the construction of a wide range of novel 5-deazaalloxazine
dEnamine Ltd, Alexandra Matrosova Street 23, Kyiv 01103, Ukraine
eLeibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a,
18059 Rostock, Germany
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra of all compounds.
CCDC 895395–895401, 934983. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c3ob26837c
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Results and discussion
The requisite starting materials, 6-anilino-1,3-dialkyluracils 2,
were prepared by nucleophilic displacement of commercially
available 6-chloro-1,3-dimethyluracil with the appropriate aryl-
amines according to the reported procedures (Table 1).15,17,18
6-Chloro-1,3-dipropyluracil 1b, the starting material for 1,3-
dipropyl-5-deazaalloxazines 4s and 4t, was prepared from N,N’-
dipropylurea and malonic acid in two steps and 54% overall
yield.19 Coupling reactions with anilines were carried out
in most cases at 180 °C.15 In the case of tetrahydroquinoline,
5-amino-3-methyl-1-phenylpyrazole and α-naphthylamine, the
use of n-butyllithium as a base was necessary.18
In our initial study we have obtained a series of 6-anilino-
Fig. 1 5-Deazaflavins I, flavins II and 5-deazaalloxazines III and IV.
5-(polyfluoroacyl)-1,3-dialkyluracils
3 starting from easily
accessible 6-anilino-1,3-dialkyluracils 2 by a usual polyfluoro-
acylation procedure.17 It was found that treatment of uracils 2
derivatives with interesting biological activities and useful with the corresponding polyfluorinated carboxylic acid anhy-
physicochemical applications (Fig. 1). Of particular interest is dride (or acid chloride, if RF = n-C3F7), carried out in dioxane
the development on the basis of fluorescent nucleosides that at room temperature in the presence of pyridine (1.2 equiv.),
maintain the hydrogen-bonding properties of natural nucleo- resulted in the formation of 6-anilino-5-(polyfluoroacyl)-1,3-
side bases.13
dimethyluracils 3a–x in excellent yields (79–99%). In most
5-Deazaisoalloxazines I and 5-deazaalloxazines III (R = H) cases, the reaction was complete after 10–12 h and the pro-
have previously been synthesized by cyclization of 6-arylamino- ducts could be isolated by solvent evaporation, followed by
1,3-dimethyluracils with one-carbon reagents (triethyl ortho- trituration with water and simple filtration of the precipitate
formate, dimethylformamide dimethylacetal, carbon disulfide, formed (Scheme 1). The results are summarized in Table 2.
and the Vilsmeier reagent).14 Similarly, treatment of 6-aryl- Derivatives 3k,l,s were not isolated in pure form, because we
amino-1,3-dimethyluracils with aromatic aldehydes provided faced difficulties with crystallization, whereas compound 3x
5-aryl-1,3-dimethylpyrimido[4,5-b]quinoline-2,4(1H,3H,5H,10H)- simultaneously cyclizes immediately after its formation.
diones, which were subsequently dehydrogenated with thionyl As can be seen from Table 2, this reaction has virtually no
chloride to give 5-aryl-1,3-dimethylpyrimido[4,5-b]quinoline- limitations with regard to the nature of the polyfluoroalkyl
2,4(1H,3H)-diones III (R = Me, Ar).15,16 The three-component group or the nature and position of the substituent in
condensation between barbituric acids, anilines and aldehydes the aniline ring. Although the chemistry of uracils has been
is an excellent and convenient approach, provided that the well documented,4–6 compounds 3 have hitherto not been
corresponding aldehyde is readily available.10 At the same reported.
time, examples of the synthesis of 5-RF-5-deazaalloxazines IV
It is important to note that similar reactions of 6-(4-anisi-
are lacking, a fact which prompted us to investigate their dino)-1,3-dipropyluracil 2j, 6-(1-naphthylamino)-1,3-dimethyl-
preparation and reactivity. Derivatives of polyfluorinated acids uracil 2m, 6,6′-[biphenyl-4,4′-diyldi(imino)]bis(1,3-dimethyl-
are commercially available and relatively inexpensive as com- uracil) 2k, and 6,6′-[methylenebis(4,1-phenyleneimino)]bis(1,3-
pared to the corresponding aldehydes, which is the reason dimethyluracil) 2l gave the corresponding compounds 3t–w
why we decided to utilize them in the 5-RF-5-deazaalloxazine (Table 2). These results clearly show that the present reaction
synthesis.
could be applicable to various types of 6-arylamino-1,3-dial-
When the presence of a perfluorinated residue is required kyluracils 2, providing a simple and rapid route to the syn-
in a bioactive target molecule, either the fluoroalkylation thesis of a wide range of the polyfluoroacylated uracil deriva-
reaction of a convenient intermediate or the synthesis from tives 3, which are precursors for the preparation of 5-RF-5-
a perfluoroalkyl substituted precursor may be employed.7 deazaalloxazines 4. The structures of products 3 were estab-
If the latter approach is used, a perfluoroacylated reagent lished from satisfactory analytical and spectroscopic data and,
is often employed as the electrophilic species for the synthesis in particular, by the presence of the characteristic quartet or
of RF-containing building blocks.17 Herein, we report that triplet of the carbonyl carbon atom connected to the RF group
a perfluoroalkyl chain can be introduced at C-5 of 5-deazaallox- in their 13C NMR spectra.
azines III by reaction of 6-arylamino-1,3-dimethyluracils
When the corresponding uracil 3 was dissolved in concen-
with polyfluorocarboxylic acid anhydrides or chlorides trated H2SO4 and allowed to stand at room temperature for
and subsequent cyclization mediated by concentrated sulfuric 3 h, 5-RF-5-deazaalloxazines 4a–x were obtained in good to
acid. This is a general synthesis of novel 5-RF-5-deazaalloxa- excellent yields (49–92%). In the case of a meta-substituted
zines IV which possess interesting chemical and physical aniline residue, regioselective cyclization took place yielding
properties.
mainly the 8-substituted 5-deazaalloxazines 4k–n. Electrophilic
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Table 1 Yields of 6-amino-1,3-dialkyluracils 2a–s
Table 1 (Contd.)
Structurea
Yield 2b (%)
2h (70)
Methodc
A
Structurea
Yield 2b (%)
Methodc
A
2a (79)
2b (71)
A
A
A
A
2i (76)
A
A
B
2c (75)
2d (64)
2e (85)
2j (69)
B
C
2m (69)
2f (84)
A
2n (82)
C
2g (35)
A
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Table 1 (Contd.)
Structurea
Yield 2b (%)
2o (56)
Methodc
A
2p (69)
A
2q (87)
C
Scheme 1 Synthetic route to 5-polyfluoroalkyl-5-deazaalloxazines exemplified
for the synthesis of 4a. Reagents and conditions: i: arylamine (2.2 equiv.), 180 °C,
3 h, under argon; ii: pyridine, dioxane, 20 °C, overnight; iii: concd H2SO4, 20 °C,
3 h.
conditions, which gave compounds 4t–w in 46–81% yields.
Pyrazolopyridopyrimidine 4x was prepared in 75% yield
directly from 2n, which cyclizes immediately during the tri-
fluoroacetylation reaction (3x could not be isolated). The struc-
tures of 4j,m,q were confirmed by X-ray crystal structure
analysis (see ESI, Fig. 1–3†).20
2r (87)
2s (98)
D
E
Products 5a and 5b were prepared by perfluoroacylation of
6-aminouracils 2p and 2q, respectively (Scheme 2). Product
5c–e was prepared by reaction of 2o, 2r and 2s with trifluoro-
acetic anhydride. The reaction of 5a–c with sulfuric acid pro-
vided the 5-hydroxy-5,10-dihydro-5-deazaflavins 6a–c in high
yields (72–94%). The analogous reactions of 5d,e failed, due to
decomposition. Treatment of compounds 6a,b with thionyl
chloride resulted in the formation of 5-deazaalloxazines 7a,b
which possess an ω-chloroalkyl group at the 9-position. The
formation of 7a,b can be explained by aromatization and ring
cleavage by attack of a thionyl chloride derived chloride anion
to the position next to the nitrogen atom (nucleophilic substi-
tution). This reaction is irreversible which is understandable
based on our observation that flavin 4b did not undergo
methylation with methyl iodide or dimethyl sulphate (xylene,
150 °C; no reaction was observed). The structures of 6a and 7a
a These compounds, except examples 2f,j–l,n,p,q, have been previously
described in the literature. b Yields refer to pure isolated products.
c Method A: 6-chloro-1,3-dialkyluracil 1a or 1b (1 equiv.), arylamine
(2.2 equiv.), 180 °C, 3 h, under argon; method B: 1a (1 equiv.),
arylamine (0.8 equiv.), quinoline, 180 °C, 3 h, under argon; method C:
arylamine (2.2 equiv.), n-BuLi, THF, −78 to 20 °C, under argon;
method D: 1a, benzylamine, triethylamine, dioxane, boiling under
reflux, 10 h; method E: 1a, piperidine, dioxane, 100 °C, 2 h.
attack of the less sterically hindered position leads to predomi- were confirmed by X-ray single crystal analysis (see ESI, Fig. 4
nation of the 8-substituted isomer. On the other hand, hydro- and 5†).20
phobic interaction can take place between the substituent
To further study this observation, we followed the reaction
attached to the aniline ring and the polyfluoroalkyl group. of 6a with triflic anhydride by NMR. Addition of triflic
This balance between attraction and repulsion is supposed to anhydride to 6a, dissolved in a mixture of CDCl3 and CD2Cl2,
be decisive for the observed regioisomeric ratio.
resulted in the formation of 5-deazaalloxazine 6′a, which was
The 8-methoxy isomers 4k,l were prepared in low yields by a observed by H and 13C NMR. The CH2-protons appear as two
combined procedure including the reaction of uracil 2e with triplets which prove the equivalence of the protons within
trifluoro- and chlorodifluoroacetic anhydride, respectively, and each methylene group and, consequently, the molecular sym-
subsequent treatment of the crude products with sulfuric acid, metry as the methylene groups are located in the mirror plane.
followed by a proper recrystallization from methanol (Table 2). In the opposite case, it can be expected that the pattern of the
Purification of 4m,n required a recrystallization. A similar signals would be more complicated, namely four doublets of
result was obtained with uracils 3t–w under the same doublets of doublets.
1
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Table 2 Yields of 6-arylamino-5-(polyfluoroacyl)uracils 3a–w and 5-polyfluoro-
alkyl-5-deazaalloxazines 4a–x
Table 2 (Contd.)
Starting
material Yielda (%)
Structure of 4
Starting
material Yielda (%)
Structure of 4
2e
—
4k (12)b 87/13d
2a
3a (93)
3b (96)
3c (90)
3d (88)
3e (87)
3f (88)
3g (97)
3h (94)
3i (90)
3j (92)
4a (89)
4b (73)
4c (84)
4d (84)
4e (92)
4f (50)
4g (57)
4h (81)
4i (49)
4j (67)
—
4l (40)b 92/8d
3m (94) 4m (32) 50/50d
2b
2f
3n (99)
3o (79)
3p (94)
3q (82)
3r (99)
—
4n (51) 86/14d
2g
2h
2i
4o (82)
4p (84)
2c
4q (73)
4r (80)
2j
4s (86)b
4t (81)
2d
3t (86)
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Table 2 (Contd.)
Starting
material Yielda (%)
Structure of 4
2k
3u (93)
4u (46)
2l
3v (98)
4v (51)
2m
2n
3w (86)
3x (0)c
4w (54)
4x (75)c
a Yields refer to pure isolated products. b Yield after 2 steps (the
product of acylation was introduced into the reaction without
purification). c After acylation, product 4x was directly isolated. d Ratio
of 8/6-substituted isomers.
5-RF-5-deazaalloxazines 4 and 7 show an enhanced reactiv-
ity at their 5-position, due to the presence of the perfluoroalkyl
group. Therefore, these molecules are promising starting
materials for reactions with nucleophiles. The reaction of 4c,f
with sodium cyanoborohydride21 gave 5-(trifluoromethyl)-5,10-
dihydropyrimido[4,5-b]quinoline-2,4(1H,3H)-diones 8a,b in
almost quantitative yields (Scheme 3). The structure of 8a was
independently confirmed by X-ray diffraction analysis (see ESI,
Fig. 6†).20 Compound 8a could also be successfully prepared Scheme 2 Synthesis of compounds 5a–e, 6a–c and 7a,b.
from diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxy-
late, albeit under more rigorous conditions and in lower yield
allowed to react with acetophenone, nitromethane and potass-
(41%). The reaction of 8a with benzyl bromide afforded the
trans-configured benzylated derivative 9 (Scheme 3). The struc-
ture of the product was independently confirmed by X-ray
crystal structure analysis (see ESI, Fig. 7†).
The Suzuki reaction of 7-bromo-5-deazaalloxazine 4p with
phenylboronic acid, carried out using K2CO3 and Pd(PPh3)4 in
dioxane and water at 100 °C,22 resulted in the formation of pro-
duct 10. The Sonogashira coupling of 4p with terminal acetyl-
enes, in the presence of Pd(PPh3)2Cl2, CuI and diisopropylamine
in THF,23 gave compounds 11a,b in high yields (Scheme 4).
To demonstrate the ability of compounds 4 to undergo
nucleophilic addition reactions, 5-deazaalloxazine 4f was
ium cyanide (Scheme 5). We found that 4f smoothly reacted
with these reagents under basic conditions to produce the
expected products 12a–c in excellent yields (81–94%). The con-
jugate addition of indole also took place, in the presence of
sodium hydride under mild conditions, to give product 12d.
The reaction proceeded under kinetic reaction control with
very good regioselectivity in favour of the attack of the nitrogen
(rather than the carbon) atom of indole. The addition of a
small amount of acetic acid proved to stabilize the N-substi-
tuted adduct 12d, but it can also be readily cleaved to give the
starting materials upon heating in the presence of trace
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Scheme 4 Suzuki and Sonogashira coupling reactions of 7-bromo-5-deaza-
alloxazine 4p. Reagents and conditions: i: Pd(PPh3)4, K2CO3, dioxane, H2O,
100 °C, 0.5 h, under argon; ii: Pd(PPh3)2Cl2, CuI, HN(iPr)2, THF, 20 °C, 48 h, under
argon.
Scheme 3 Reduction of 5-deazaalloxazines 4c,f and benzylation of 8a.
Reagents and conditions: i: NaBH3CN, THF, AcOH, 4 days; ii: diethyl 1,4-dihydro-
2,6-dimethyl-3,5-pyridinedicarboxylate (6 equiv.), xylene, TsOH, 155 °C, 5 h,
under argon; iii: K2CO3, DMF, 20 °C, overnight, under argon.
towards product 12f, which was observed by TLC. However, 12f
could not be isolated, because of its decomposition during the
isolation. In the case of the reaction of 5f with morpholine, no
product could be detected even when sodium hydride was
added as a catalyst. Therefore, we assume that the equilibrium
is strongly shifted towards the starting materials (Scheme 5).
The reaction of 7a, containing a pendent chloroethyl group,
with acetophenone, nitromethane and potassium cyanide
amounts of a base. The N-substituted adduct 12d underwent a
rearrangement at 80 °C to form the thermodynamically more
stable C-substituted isomer 12e. The latter can be prepared
directly by reaction of 4f with indole under the same con-
ditions in 57% yield.
The reaction of 5-deazaalloxazine 4f with p-thiocresol is
reversible. The equilibrium is shifted almost completely
Scheme 5 Reactions of 5-deazaalloxazine 4f with C- and S-nucleophiles. Reagents and conditions: i: NaH, THF, 20 °C, overnight; ii: NaOMe, THF, MeOH, 20 °C, over-
night; iii: DMSO, 20 °C, overnight; iv: NaH, THF, 20 °C, 5 min; v: NaH, DMF, 80 °C, 5 h, under argon.
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Scheme 7 Synthesis of compound 14.
analysis (see the ESI, Fig. 8†).20 The formation of 1,3-oxazine
14 can be rationalized by a [1,5] hydrogen shift, followed by
nucleophilic addition of the hydroxy group to the imino
function.
Previously, this unexpected redox reaction was observed in
the case of trifluoroacetylated 1-(3,4-dihydro-1-naphthalenyl)-
pyrrolidine and 1-(3,4-dihydro-1-naphthalenyl)piperidine.24
But our example differs from the reactions described in the
literature. To the best of our knowledge, no similar reactions
with secondary amines have been reported to date. In fact,
only reactions involving tertiary amines were reported. This
phenomenon is strongly associated with the so-called tert-
amino effect. Secondly, these reactions proceed mostly either
under acidic catalysis (TFA,25 silica gel,26 Sc(OTf)3 27) or at
high temperature,28 but never in basic media.
Scheme 6 Reactions of 5-deazaalloxazine 7a with C- and S-nucleophiles.
Reagents and conditions: i: NaH, THF, 20 °C, overnight; ii: NaOMe, THF, MeOH,
20 °C, overnight; iii: DMSO, 20 °C, overnight; iv: NaOMe, DMF, 20 °C, overnight.
afforded, under the same conditions, products 13a–c in high
yields (70–93%) (Scheme 6). This transformation can be ration-
alized by initial nucleophilic addition of the nucleophile to
position C-5 of the flavin, accompanied by intramolecular
nucleophilic substitution of chlorine. Thus, flavins 7a and 4f
show the same type of reaction with nucleophiles. This can be
explained by the fact that the electron-withdrawing RF group
enhances the electrophilicity of the C-5 atom and supports a
nucleophilic addition at this position. This effect results in the
fact that position 5 of compound 7a is more reactive towards
nucleophiles as the CH2 carbon atom located next to the chlo-
ride group. In contrast, the reaction of 7a with p-thiocresol (in
the presence of NaOMe in DMF) followed the normal path and
gave deazaalloxazine 13d by simple nucleophilic substitution
in 95% yield. The formation of products 13a–d can be
explained based on the HSAB principle. The soft sulfur nucleo-
phile results in direct attack on the soft alkyl chloride moiety
while the more hard carbon nucleophiles attack at the other
position located next to the polyfluoro group.
Conclusions
Our results related to hitherto unknown 5-RF-5-deazaalloxa-
zines are of current importance for our ongoing research
program related to the design and synthesis of suicide sub-
strates for adenosine deaminase (ADA) and inosine 5-mono-
phosphate dehydrogenase (IMPHD). Their high C-5 reactivity
towards nucleophiles and their structural similarity to several
biologically relevant compounds, for instance their isosterism
to flavins, make the 5-RF-5-deazaalloxazines reported herein
privileged scaffolds for mechanism- and fragment-based drug
design. At the same time, the possibility to reduce the pyridine
fragment of pyrimido[4,5-b]quinoline-2,4(3H,10H)-dione is
a crucial feature important for the development of artificial
analogues of the NADH/NAD+ reductive/oxidative system
with a tunable redox potential. This is relevant for biocatalysis
and structural biochemistry as well as for the design and con-
struction of new FAD-like redox-systems. On the other hand,
the combinatorial aspect of our synthetic strategies can be
used in other fields of biology-oriented syntheses.29 In the
future, we plan to study the synthesis of 5-RF-5-deazaflavins as
well as polyfluorinated analogues of riboflavin (vitamin B2)
containing sugars or sugar mimicking fragments located at
position 10.
The reaction of 6-(benzylamino)-1,3-dimethyl-5-(trifluoro-
acetyl)uracil (5d) with triethylamine in DMF afforded product
14 as a 7 : 1 mixture of diastereomers (while the trans-isomer is
the major one) (Scheme 7). Both isomers crystallize together.
Therefore, it was not possible to separate them by recrystalliza-
tion as even a single crystal contained both isomers. The
stereochemistry was established by X-ray crystallographic
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812 (m), 775 (s), 756 (s), 745 (s), 712 (w), 624 (s), 592 (m),
550 (m), 532 (w).
Experimental
General procedure for the synthesis of 6-anilino-
5-(polyfluoroacyl)-1,3-dialkyluracils (3)
General procedure for the synthesis of 5-hydroxy-1,3-dimethyl-
5-(perfluoroalkyl)-5,10-dihydro-1H-pyrimido[4,5-b]quinoline-2,4-
diones (6)
To a solution of the corresponding 6-amino-1,3-dialkyluracil 2
(0.4 g) in 4 mL of dry dioxane was added pyridine (1.2 equiv.)
and the corresponding anhydride (or chloroanhydride if RF
=
The corresponding uracil 5 (1.0 g) was dissolved in concen-
n-C3F7) of polyfluorocarboxylic acid (2 equiv.). Then the reac- trated H2SO4 (5 mL) and allowed to stand at r.t. for 2 h. Then
tion mixture was allowed to stand at r.t. overnight. The next the solution was poured into ice water and extracted with
day the solvent was evaporated, the residue was dried under chloroform, dried over Na2SO4 and evaporated by rotovap. The
high vacuum at 100 °C and the crude product 2 was triturated crude product was purified via short-part column chromato-
with water, filtered off by suction and dried under a high graphy (silica gel/CHCl3), followed by recrystallization from
vacuum.
6-(4-Ethoxyanilino)-1,3-dimethyl-5-(trifluoroacetyl)uracil (3q).
methanol.
5-Hydroxy-1,3,10-trimethyl-5-(trifluoromethyl)-5,10-dihydro-
1
Yield 82%, brownish solid, mp 142 °C. H NMR (300.1 MHz, pyrimido[4,5-b]quinoline-2,4(1H,3H)-dione (6c). Yield 72%,
3
1
DMSO-d6): δ = 1.36 (t, 3H, J = 7.0 Hz, Me), 3.03 (s, 3H, Me), white solid, mp 216–218 °C. H NMR (300.1 MHz, DMSO-d6):
3
3.22 (s, 3H, Me), 4.07 (q, 2H, J = 7.0 Hz, CH2O), 7.00 (d, 2H, δ = 3.26 (s, 3H, Me), 3.48 (s, 3H, Me), 3.51 (s, 3H, Me), 7.32
3
3J = 8.9 Hz, Ar), 7.29 (d, 2H, J = 8.9 Hz, Ar), 11.34 (br s, 1H, (dd, 1H, 3J = 7.7, 7.2 Hz, H-7), 7.46 (d, 1H, 3J = 8.3 Hz, H-9), 7.6
NH); 13C NMR (125.8 MHz, DMSO-d6): δ = 15.4 (Me), 28.6 (Me), (dd, 1H, J = 8.3, 7.2 Hz, H-8), 7.67 (d, 1H, 3J = 7.7 Hz, H-6),
3
1
36.3 (Me), 64.3 (CH2), 92.7 (C-5), 116.1 (CH), 117.9 (q, JC,F
=
8.45 (br s, 1H, OH); 13C NMR (62.9 MHz, DMSO-d6): δ = 28.5
287.9 Hz, CF3), 126.3 (CH), 131.5, 151.7, 157.9, 159.4, 160.6, (Me), 37.3 (Me), 41.8 (Me), 71.8 (q, 2JC,F = 30.5 Hz), 88.1 (C-4a),
2
1
178.4 (q, JC,F = 35.7 Hz, CO); MS (GC, 70 eV): m/z (%) = 371 119.3 (CH), 125.2 (CH), 126.2 (q, JC,F = 290.5 Hz, CF3), 126.7
([M]+, 11), 353 (10), 276 (21), 275 (100), 274 (19), 247 (10), 246 (CH), 130.8 (CH), 141.7, 152.4, 153.3, 165.0; 19F NMR
(73), 189 (16), 162 (10), 161 (14), 148 (20), 147 (22), 134 (15), (282.4 MHz, DMSO-d6): δ = −83.1 (s, CF3); MS (EI, 70 eV):
133 (15), 132 (17), 82 (24); HRMS (EI): calcd for C16H16F3N3O4 m/z (%) = 273 (41), 272 (100), 257 (10); HRMS (ESI): calcd for
[M]+: 371.10874, found: 371.10840; IR (ATR, cm−1): ν = 2982 (w), C15H15F3N3O3 [M + H]+: 342.10600, found: 342.10635; IR (ATR,
1722 (m), 1668 (s), 1614 (s), 1576 (s), 1504 (s), 1485 (s), 1454 (s), cm−1): ν = 3271 (w), 3190 (w), 2980 (w), 1703 (s), 1687 (m),
1441 (s), 1408 (m), 1389 (m), 1315 (s), 1304 (m), 1281 (m), 1622 (s), 1608 (s), 1574 (m), 1504 (s), 1487 (s), 1470 (s),
1257 (s), 1242 (s), 1211 (s), 1188 (s), 1169 (s), 1151 (s), 1113 (s), 1464 (s), 1456 (s), 1423 (s), 1396 (m), 1381 (m), 1323 (m),
1080 (s), 1045 (s), 995 (s), 957 (m), 932 (m), 922 (m), 874 (m), 1254 (s), 1207 (m), 1161 (s), 1119 (s), 1090 (m), 1070 (s),
833 (s), 824 (m), 795 (s), 758 (s), 737 (s), 721 (m), 689 (s), 1049 (s), 972 (m), 955 (w), 937 (m), 922 (s), 866 (w), 833 (m),
656 (s), 633 (m), 586 (m), 567 (s), 534 (m).
779 (s), 768 (s), 760 (s), 746 (s), 710 (s), 662 (s), 642 (s), 602 (m),
565 (m), 550 (m), 538 (m).
General procedure for the synthesis of 1,3-dialkyl-5-
(polyfluoroalkyl)pyrimido[4,5-b]quinoline-2,4-diones (4)
Addition of acetophenone to 1,3-dimethyl-5-(trifluoromethyl)-
pyrimido[4,5-b]quinoline-2,4-diones 4f and 7a. Synthesis of
compounds 12a and 13a
The corresponding uracil 3 (0.3 g) was dissolved in concen-
trated H2SO4 (1.5 mL) and allowed to stand at r.t. for 3 h. Then
the solution was poured into ice water and the formed precipi- Into a flask were placed compound 4f or 7a (1 equiv.), aceto-
tate was filtered off by suction and recrystallized from metha- phenone (1.5 equiv.), dry THF (20 mL per 1.0 g of starting
nol giving the pure product 4.
material) and sodium hydride (60% in mineral oil, 2 equiv.).
1,3-Dimethyl-5-(trifluoromethyl)pyrimido[4,5-b]quinoline-2,4- The reaction mixture was stirred for half an hour at r.t. and
(1H,3H)-dione (4a). Yield 89%, yellow solid, mp 195 °C. 1H then allowed to stand overnight. Afterwards 2.5 equiv. of acetic
NMR (300.1 MHz, CDCl3): δ = 3.52 (s, 3H, Me-3), 3.83 (s, 3H, acid was added and the mixture was diluted with water. The
Me-1), 7.55–7.62 (m, 1H, H-7), 7.81–7.89 (m, 1H, H-8), formed precipitate was filtered off by suction, washed with
8.01–8.06 (m, 1H, H-9), 8.30–8.36 (m, 1H, H-6); 13C NMR heptane and recrystallized from methanol–water giving the
(62.9 MHz, CDCl3): δ = 29.4 (Me-3), 30.6 (Me-1), 110.4 (C-4a), pure product.
1
4
121.7, 123.3 (q, JC,F = 278.7 Hz, CF3), 126.1 (q, JC,F = 6.1 Hz,
8,10-Dimethyl-6-phenacyl-6-(trifluoromethyl)-1,2-dihydro-6H-
2
C-6), 127.2, 129.1 (CH), 133.4 (CH), 138.7 (q, JC,F = 33.4 Hz, pyrimido[4,5-b]pyrrolo[3,2,1-ij]quinoline-7,9(8H,10H)-dione (13a).
C-5), 148.2, 150.2, 151.1 (CO-2), 159.3 (CO-4); 19F NMR Yield 93%, white solid, mp 304–305 °C. H NMR (250.1 MHz,
1
(282.4 MHz, CDCl3): δ = −52.5 (s, CF3); MS (GC, 70 eV): m/z (%) CDCl3): δ = 3.18 (s, 3H, Me), 3.20–3.44 (m, 2H, CH2-2), 3.64 (s,
2
= 310 ([M + H]+, 13), 309 ([M]+, 77), 197 (100); HRMS (ESI): 3H, Me), 3.85 (d, 1H, J = 18.4 Hz, CHHCO), 4.00–4.14 (m, 1H,
2
calcd for C14H11F3N3O2 [M + H]+: 310.07979, found: 310.07967; CHH-1), 4.54–4.65 (m, 1H, CHH-1), 5.63 (d, 1H, J = 18.4 Hz,
IR (ATR, cm−1): ν = 2956 (w), 1713 (s), 1669 (s), 1614 (w), 1583 (s), CHHCO), 7.00 (dd, 1H, 3J = 7.2, 8.1 Hz, H-4), 7.11–7.19 (m, 2H,
1565 (m), 1494 (m), 1464 (s), 1419 (m), 1378 (s), 1332 (m), Ar), 7.39–7.49 (m, 2H, Ph), 7.54 (t, 1H, 3J = 7.3 Hz, Ph),
1286 (m), 1216 (m), 1194 (m), 1156 (s), 1142 (s), 1124 (s), 7.91–7.98 (m, 2H, Ph); 13C NMR (62.9 MHz, CDCl3): δ = 28.5
2
1100 (s), 1069 (m), 1030 (m), 989 (s), 929 (w), 877 (w), 856 (w), (Me), 28.9 (CH2), 38.4 (CH2), 38.6 (Me), 47.8 (q, JC,F = 26.7 Hz,
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C-5), 53.4 (CH2), 84.7 (C-6a), 117.6, 124.4 (CH), 124.8 (CH),
125.0 (CH), 127.5 (q, JC,F = 286.6 Hz, CF3), 128.2 (CH), 128.8,
2 M. Palmer, J. F. Honek and T. Dieckmann, Biochemical
Pharmacology, John Wiley & Sons, 1st edn, 2012, p. 428,
ISBN-13: 978-0-470-17445-6.
3 J.-P. Begue and D. Bonnet-Delpont, Bioorganic and Medic-
inal Chemistry of Fluorine, John Wiley & Sons, 1st edn, 2008,
p. 366, ISBN-10: 0470278307.
4 (a) A. Ohno, J. Kunitomo, Y. Kawai, T. Kawamoto,
M. Tomishima and F. Yoneda, J. Org. Chem., 1996, 61,
9344–9355; (b) F. Yoneda, K. Mori, Y. Sakuma and
H. Yamaguchi, J. Chem. Soc., Perkin Trans. 1, 1980, 978–
981; (c) T. Nagamatsu, Y. Hashiguchi, M. Higuchi and
F. Yoneda, J. Chem. Soc., Chem. Commun., 1982, 1085–1086;
(d) K. Mori, K. Shinozuka, Y. Sakuma and F. Yoneda,
J. Chem. Soc., Chem. Commun., 1978, 764.
1
128.9 (CH), 133.3, 137.2, 141.8, 152.9, 152.9, 162.0, 195.7; 19F
NMR (235.3 MHz, CDCl3): δ = −76.8 (s, CF3); MS (GC, 70 eV):
m/z (%) = 455 ([M]+, 5.8), 387 (26), 386 (100), 336 (15), 105 (38),
77 (14); HRMS (ESI): calcd for C24H21F3N3O3 [M + H]+:
456.15295, found: 456.15399; IR (ATR, cm−1): ν = 3043 (w),
3016 (w), 2929 (w), 1691 (s), 1633 (s), 1626 (s), 1539 (s),
1498 (s), 1464 (s), 1446 (s), 1435 (s), 1408 (s), 1375 (s), 1360 (s),
1342 (m), 1302 (m), 1242 (s), 1227 (s), 1201 (m), 1186 (m),
1176 (m), 1155 (s), 1120 (s), 1078 (m), 1057 (m), 1041 (m),
1028 (m), 1001 (m), 976 (m), 964 (m), 939 (m), 912 (m),
897 (w), 860 (w), 847 (w), 779 (s), 770 (m), 756 (s), 748 (s), 737 (s),
714 (m), 694 (s), 658 (m), 617 (s), 581 (m), 569 (m), 528 (m).
5 F. Yoneda and Y. Sakuma, J. Chem. Soc., Chem. Commun.,
1977, 825–826.
Addition of hydrogen cyanide to 1,3-dimethyl-5-
(trifluoromethyl)pyrimido[4,5-b]quinoline-2,4-diones 4f and
7a. Synthesis of compounds 12c and 13c
6 (a) H.-J. Duchstein, H. Fenner, P. Frank and W. Bauch,
Arch. Pharm., 1990, 323, 67–72; (b) H.-J. Duchstein,
H. Fenner and W. Bauch, Arch. Pharm., 1989, 322, 271–275.
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and J. Jiang, Tetrahedron, 2000, 56, 3635–3671;
(c) G. Resnati, Tetrahedron, 1993, 49, 9385–9445.
Compound 4f or 7a (1 equiv.) was suspended in DMSO and
KCN (2 equiv.) was added. Then the reaction mixture was
stirred overnight and acetic acid (2 equiv.) was carefully added
under a fume hood. Afterwards the mixture was diluted with
water and the formed precipitate was filtered off by suction
and recrystallized from methanol–water giving the pure
product.
8 T. Hiyama, Organofluorine Compounds: Chemistry and Appli-
cation, Springer, Berlin, 2000.
9 (a) V. O. Iaroshenko, D. V. Sevenard, A. V. Kotljarov,
D. M. Volochnyuk, A. O. Tolmachev and V. Y. Sosnovskikh,
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2009, 3967–3974; (c) V. O. Iaroshenko, D. Ostrovskyi,
A. Petrosyan, S. Mkrtchyan, A. Villinger and P. Langer,
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S. Vittori, R. Volpini and E. Camaioni, Med. Res. Rev., 2001,
21, 105–128; (b) O. Maydanovych and P. A. Beal, Chem. Rev.,
2006, 106, 3397–3411; (c) E. Santaniello, P. Ciuffreda and
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7-Ethyl-1,3-dimethyl-2,4-dioxo-5-(trifluoromethyl)-1,2,3,4,5,10-
hexahydropyrimido[4,5-b]quinoline-5-carbonitrile (12c). Yield
1
94%, white solid, mp 179 °C. H NMR (300.1 MHz, DMSO-d6):
3
3
δ = 1.22 (t, 3H, J = 7.6 Hz, Me), 2.70 (q, 2H, J = 7.6 Hz, CH2),
3.26 (s, 3H, Me), 3.54 (s, 3H, Me), 7.43 (dd, 1H, 3J = 8.4 Hz, 4J =
3
1.8 Hz, H-8), 7.51 (d, 1H, J = 8.4 Hz, H-9), 7.53 (s, 1H, H-6),
9.96 (br s, 1H, NH); 13C NMR (75.5 MHz, DMSO-d6): δ = 16.4
2
(Me), 28.3 (CH2), 28.8 (Me), 31.4 (Me), 46.3 (q, JC,F = 31.9 Hz,
C-5), 74.5 (C-4a), 112.6, 115.9, 118.7 (CH), 124.8 (q, JC,F
1
=
289.3 Hz, CF3), 128.4 (CH), 131.7 (CH), 134.6, 141.0, 148.3,
151.0, 160.4; 19F NMR (282.4 MHz, DMSO-d6): δ = −75.1 (s,
CF3); MS (EI, 70 eV): m/z (%) = 364 ([M]+, 1.03), 338 (17), 337
([M − HCN]+, 97), 322 (27), 309 (11), 296 (10), 295 (53), 280 (11),
268 (19), 265 (23), 239 (10), 238 (16), 237 (11), 226 (12),
225 (100), 224 (13), 210 (17), 196 (11); HRMS (ESI): calcd for
C17H16F3N4O2 [M + H]+: 365.12199, found: 365.12186; IR (ATR,
cm−1): ν = 3526 (w), 3326 (m), 2977 (w), 1688 (m), 1633 (m),
1613 (s), 1601 (m), 1531 (s), 1502 (s), 1472 (s), 1435 (s),
1414 (m), 1392 (w), 1368 (w), 1338 (w), 1300 (w), 1260 (w),
1232 (w), 1218 (m), 1180 (s), 1159 (m), 1145 (m), 1101 (w),
1068 (w), 1035 (m), 1002 (w), 965 (m), 940 (w), 894 (w), 866 (w),
835 (s), 771 (m), 759 (m), 733 (w), 706 (w), 692 (w), 661 (w),
577 (m), 565 (m), 545 (m), 531 (w).
11 (a) G. Cristalli, S. Costanzi, C. Lambertucci, G. Lupidi,
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12 (a) K. Senga, F. Yoneda and S. Nishigaki, J. Org. Chem.,
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