One or two-step Bohlmann-Rahtz heteroannulation of 6-aminouracil derivatives for the synthesis of pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1055/s-2002-32953

The Michael addition-cyclodehydration of a 6-aminouracil and alkynone proceeds to give 5-deazapterin derivatives with total control of regiochemistry. This simple and facile cyclocondensation process is catalyzed by zinc(II) bromide or ytterbium(III) trifluoromethanesulfonate at 110°C, providing the heteroannulated products in up to 94% yield.

Full text of DOI:10.1055/s-2002-32953

1332
LETTER
One or Two-Step Bohlmann–Rahtz Heteroannulation of 6-Aminouracil
Derivatives for the Synthesis of Pyrido[2,3-d]pyrimidines
Bohlmann-Rahtz
H
a
e
teroannul
v
ation of 6-A
i
d
acil
D
erivatives D. Hughes, Mark C. Bagley*
Department of Chemistry, Cardiff University, PO Box 912, Cardiff, CF10 3TB, UK
Fax +44(29)20874030; E-mail: Bagleymc@cf.ac.uk
Received 20 May 2002
Replacing pyrimidinone 1 with a range of different uracil
derivatives will not only increase the scope of this hitherto
poorly understood reaction, but it will expand the synthet-
ic versatility of uracil derivatives and provide diversity in
Abstract: The Michael addition-cyclodehydration of a 6-aminou-
racil and alkynone proceeds to give 5-deazapterin derivatives with
total control of regiochemistry. This simple and facile cycloconden-
sation process is catalyzed by zinc(II) bromide or ytterbium(III) tri-
fluoromethanesulfonate at 110 °C, providing the heteroannulated the nature of the heterocyclic motif in a targeted library of
products in up to 94% yield.
potential folate antagonists that could be elaborated from
these compounds in subsequent studies.
Key words: pyridopyrimidines, uracil derivatives, Bohlmann–
Rahtz heteroannulation, heterocycles, Lewis acids
O
N
R1
N
O
O
R1
HN
R2
HN
The versatility of uracil derivatives for the synthesis of ni-
trogen-containing heteroaromatic species of biological
importance has been well documented in the literature.1
Pyrazolopyridines,2 pyrimidopyrimidines,3 pyridopu-
rines,4 pyrazolopyrimidines5 and xanthine derivatives6
have all been prepared by the functionalization of these
important heterocyclic building blocks, whose structures
are interesting in their own right as biologically-active
pyrimidine nucleosides.7 In recent years, interest in pyri-
do[2,3-d]pyrimidine derivatives has increased drama-ti-
cally as the structural relationship between 5-deazapterins
and the vitamin folic acid,8 with its essential role in the
prevention of disease,9 has been recognised. The diverse
range of biological properties and highly species-specific
tissue responses elicited by compounds containing the 5-
deazapterin motif have been well documented.10 Howev-
er, although pyrido[2,3-d]pyrimidines have been prepared
from uracil derivatives in the past, many of these reactions
suffer from low yields, use expensive or not readily avail-
able starting materials and exhibit limited substrate toler-
ance.11 This paper describes the facile synthesis of a
number of 5-deazapterins from commercially available 6-
aminouracil derivatives using a simple one-pot Bohl-
mann–Rahtz heteroannulation procedure.
H2N
R2
H2N
N
NH2
AcOH or ZnBr2
1
2
Scheme 1
Judging by the poor reactivity exhibited by 6-aminouracil
derivatives in related cyclocondensation reactions,11 it re-
mained to be established whether the Bohlmann–Rahtz
heteroannulation of these substrates would proceed at all.
To this end, a solution of 6-aminouracil 3a and 4-(trime-
thylsilyl)but-3-yn-2-one (4a) in DMSO was stirred at
1
room temperature. However, after 72 hours, H NMR
spectroscopic analysis established that no reaction had oc-
curred. When the procedure was repeated at 110 °C using
3 equivalents of alkynone 4a, Michael addition product 5a
(Figure) was generated in 97% isolated yield after addi-
tion of water and precipitation of the product. The cyclo-
dehydration of 5a failed according to standard conditions
(returning unreacted starting material 5a), even at temper-
atures of 180 °C, but when a solution of this intermediate
in DMSO was stirred at 110 °C overnight in the presence
of zinc(II) bromide or ytterbium(III) triflate, the heteroan-
nulated product pyridine 6a (Figure) was generated in
quantitative yield. This new modified two-step procedure
demonstrated both the advantage of our new Lewis acid
catalysed cyclodehydration conditions and the poor/un-
predictable reactivity of 6-aminouracil derivatives (lack-
ing 1,3-substitution) in heteroannulation reactions.
The two-step Bohlmann–Rahtz reaction,12 which pro-
ceeds by Michael addition-cyclodehydration of an enam-
ine and alkynone, was first reported in 1957 for the
synthesis of simple pyridines but has seen very little use
since that date.13 Following our discovery of a facile one-
pot heteroannulation procedure, catalysed by acetic acid,
amberlyst 15 ion exchange resin14 or a Lewis acid,15 we
developed new conditions for the synthesis of 5-deazap-
terin 2 from 2,4-diaminopyrimidinone 1 (Scheme 1).16
Following the success of our two-step modified Bohl-
mann–Rahtz reaction, it remained to be seen if a one-pot
heteroannulation procedure could be facilitated in the
presence of a Lewis acid catalyst. A solution of 6-aminou-
racil 3a and one equivalent of 4-(trimethylsilyl)but-3-yn-
2-one (4a) in DMSO was stirred at 110 °C for 72 hours in
the presence of either zinc(II) bromide17 or ytterbium(III)
triflate (20 mol%) to give 5-deazapterin 6a as the sole
product in 60% or 52% yield, respectively. Spontaneous
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1332,1334,ftx,en;D10402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Bohlmann–Rahtz Heteroannulation of 6-Aminouracil Derivatives
1333
O
Table 1 Heteroannulation Reactions of Uracil Derivatives 3a–c
O
R3N
Entry 3
R1
R3
Temp. Lewis acid Com- Yielda
Me3Si
°C
pound
%
Me
O
N
NH2
R1
1
3a
H
H
110
110
110
110
110
r.t.
None
5a
97
60
74
94
90
53
54
3a R1 = R3 = H
3b R1 = Me, R3 = H
3c R1 = R3 = Me
4a
2
3a
3b
3b
3b
3c
3c
H
H
ZnBr2
6a
3
Me
Me
Me
Me
Me
H
None
6b
O
O
O
4
H
ZnBr2
6b
HN
HN
Me
5
H
Yb(OTf)3
ZnBr2
6b
O
N
N
Me
O
N
H
NH2
5a
H
6b
7b
Me
Me
5c
6a
r.t.
Yb(OTf)3
5c
Figure
a Isolated yield.
b Reactions were run over 96 hours.
desilylation occurred throughout the course of the reac-
tion. Although the yield in this case was lower than for the
two-step process, the simplicity of the facile one-pot yield (60–75%). Replacing zinc(II) bromide with ytterbi-
Michael addition-cyclodehydration reaction made it an at- um(III) triflate (entries 6 and 10) always caused a small
tractive alternative that warranted further study.
reduction in the efficiency of the cyclocondensation pro-
cess, but offered some improvement over the uncatalysed
reaction (entry 8, 42% yield) which always proceeded in
a low yield. It was apparent that the new Lewis acid catal-
With successful conditions established for the one- and
two-step heteroannulation of 6-aminouracil, it remained
to explore whether these conditions were appropriate for
a range of different uracil derivatives. 6-Amino-1-methyl-
and 6-amino-1,3-dimethyluracil, 3b and 3c respectively,
were stirred for 72 h with one equivalent of 4-(trimethyl-
silyl)but-3-yn-2-one (4a) in DMSO either in the presence
or absence of a Lewis acid. Although uracil 3b gave het-
eroannulation product 6b in excellent yield (Scheme 2)
under Lewis acid catalysed conditions at elevated temper-
atures, 1,3-dimethyluracil 3c yielded the Michael addition
product 5c at room temperature and cyclodehydration
could not be completed under any of the conditions inves-
tigated (Table 1).
R5
O
O
O
R5
4b-d
R3N
R3N
R7
O
N
NH2
O
N
N
R7
DMSO, 110 °C, 72 h, cat.
R1
R1
3a-c
7-12
Scheme 3
Table 2 Reaction of Uracil 3a–c with 4-Substituted Alkynone 4b–d
Entry
3
4
R5
R7
Lewis
acid
Com- Yielda
pound %
O
O
O
4a
R3N
Me
R3N
3a-c
1
2
3a
3b
3b
3b
3b
3b
3b
3c
3c
3c
3c
4b
4b
4b
4b
4c
4c
4d
4c
4c
4c
4d
SiMe3
SiMe3
SiMe3
SiMe3
Et
CO2Et
CO2Et
CO2Et
CO2Et
Me
ZnBr2
None
7
8
60b
43b
39b,c
65b
71
O
N
NH2
5a-c
O
N
N
Me
R1
R1
6a-c
3
ZnBr2
ZnBr2
ZnBr2
Yb(OTf)3
ZnBr2
None
8
Scheme 2
4
8
To examine further the scope of the heteroannulation re-
action, uracils 3a–c were treated with different 4-substi-
tuted alkynones 4b–d in DMSO at 110 °C for 72 hours in
the presence of a Lewis acid catalyst (Scheme 3). When
ethyl propynoate 4b was reacted with uracil 3a,b (entries
1–4, Table 2) spontaneous desilylation accompanied
Michael addition-cyclodehydration to generate pyridopy-
rimidine 7,8 (R5 = H). When these reactions were con-
ducted either in the absence of a Lewis acid (entry 2) or at
room temperature (entry 3) the efficiency of reaction was
reduced. The optimum experimental conditions reacted
uracil 3a–c with alkynone 4b–d at 110 °C in the presence
of zinc(II) bromide for 72 h to give product 7–12 in good
5
9
6
Et
Me
9
68
7
Ph
Me
10
11
11
62
8
Et
Me
42
9
Et
Me
ZnBr2
75
10
11
Et
Me
Yb(OTf)3 11
ZnBr2 12
72
Ph
Me
72
a Isolated yield;
b Spontaneous disilylation accompanied the reaction (R5 = H).
c Reaction was carried out at room temperature.
Synlett 2002, No. 8, 1332–1334 ISSN 0936-5214 © Thieme Stuttgart · New York

1334
D. D. Hughes, M. C. Bagley
LETTER
(9) Scott, J. M.; Weir, D. G.; Kirke, P. In Folate and Neural
ysed cyclocondensation reaction was appropriate for a
number of different alkynones and a range of uracil deriv-
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Tube defects. Folate in Health and Disease; Bailey L. B.,
Marcel Dekker: New York, 1994, Chap. 12, 329–360.
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Nichol, C. A. J. Med. Chem. 1980, 23, 327. (b) Matsumoto,
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In conclusion the zinc(II) bromide catalysed heteroannu-
lation, for the synthesis of pyrido[2,3-d]pyrimidines 6–12
in up to 94% yield, proceeds by cyclocondensation of a 6-
aminouracil 3a–c and alkynone 4a–d in a single prepara-
tive step using a simple and facile experimental proce-
dure. Work is now underway to apply this new general
method to the synthesis of a number of biologically active
heterocycles based upon modified uracil derivatives for
the preparation of diverse 5-deazapterin libraries as inhib-
itors of folate-dependent enzymes.
(11) (a) Majumdar, K. C.; Bhattacharyya, T. Synthesis 2001,
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Acknowledgement
We thank the BBSRC (grant to DDH) and Royal Society for support
of this work and the EPSRC Mass Spectrometry Service, Swansea
for high and low resolution spectra.
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Synlett 2002, No. 8, 1332–1334 ISSN 0936-5214 © Thieme Stuttgart · New York