An unusual Michael addition of 3,3-dimethoxypropanenitrile to 2-aryl acrylates: A convenient route to 4-unsubstituted 5,6-dihydropyrido[2,3-d] pyrimidines

Article abstract of DOI:10.1021/jo902345r

(Chemical Equation Presented) An unusual Michael addition between 2-aryl-substituted acrylates and 3,3-dimethoxypropanenitrile which leads, depending on the reaction temperature (60 or -78 °C, respectively), to a 4-methoxymethylene-substituted 4-cyanobutyric ester or to a 4-dimethoxymethyl 4-cyanobutyric ester is described. These compounds can be subsequently converted to 4-unsubstituted pyrido[2,3-d]-pyrimidines upon treatment with a guanidine system under microwave irradiation.

Full text of DOI:10.1021/jo902345r

pubs.acs.org/joc
Particularly, 6-aryl-substituted 5,6-dihydropyrido[2,3-d]-
An Unusual Michael Addition of
3,3-Dimethoxypropanenitrile to 2-Aryl Acrylates:
A Convenient Route to 4-Unsubstituted
5,6-Dihydropyrido[2,3-d]pyrimidines
pyrimidin-7(8H)-ones (3) are selective inhibitors of the ki-
nase insert domain-containig receptor (KDR) and fibroblast
growth factor receptor (FGFR).4 More recently, several
pyrido[2,3-d]pyrimidines have been identified as antibacterials
in a drug design program targeting eukaryotic tyrosine
protein kinases.5
ꢀ
Xavier Berzosa, Xavier Bellatriu, Jordi Teixido, and
ꢀ
Jose I. Borrell*
´
ꢁ
Grup d’Enginyeria Molecular, Institut Quımic de Sarria
(IQS), Universitat Ramon Llull, Via Augusta 390,
E-08017 Barcelona, Spain
j.i.borrell@iqs.url.edu
Received November 4, 2009
FIGURE 1. Some biologically active pyridopyrimidine scaffolds.
The synthesis of such compounds is usually achieved by
multistep procedures in which the pyridone ring is constructed
onto a preformed pyrimidine ring. Thus, for instance, compounds
3 are prepared with use of uracil as starting material in at
least six steps.4
Our group has broad experience in the synthesis of 5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-ones, with up to five
diversity centers, from R,β-unsaturated esters. The two
straightforward strategies developed construct the pyrimi-
dine ring onto a preformed pyridone6 or, alternatively,
form both rings from an intermediate Michael adduct.7
More recently, we have described an efficient multicompo-
nent reaction providing 4-amino- or 4-oxopyrido[2,3-d]-
pyrimidines in a one-pot microwave-assisted cycloconden-
sation of R,β-unsaturated esters, guanidine systems, and
malononitrile or methyl cyanoacetate in NaOMe/MeOH,
respectively.8
An unusual Michael addition between 2-aryl-substituted
acrylates and 3,3-dimethoxypropanenitrile which leads,
depending on the reaction temperature (60 or -78 °C,
respectively), to a 4-methoxymethylene-substituted 4-cy-
anobutyric ester or to a 4-dimethoxymethyl 4-cyanobu-
tyric ester is described. These compounds can be
subsequently converted to 4-unsubstituted pyrido[2,3-d]-
pyrimidines upon treatment with a guanidine system
under microwave irradiation.
However, in no case were we able to obtain 4-unsubstituted
5,6-dihydropyrido[2,3-d]pyrimidines 4 (Figure 2), being thus
referable to active compounds 2 and 3, by an expeditive
synthetic approach similar to our preceding strategies. Here-
Pyrido[2,3-d]pyrimidines represent a heterocyclic ring system
of considerable interest due to several biological activities
associated with this scaffold. Particularly, this kind of het-
erocycles are able to inhibit the protein kinase catalytic
activity by blocking the ATP binding site and, subsequently,
preventing the phosphorylation of the corresponding natural
substrates.1
Thus, compounds of general structure 1 (Figure 1) inhibit
cyclin-dependent kinase so they can be used for the treatment
of neurodegenerative diseases.2 On the other hand, 6-aryl-
substituted pyrido[2,3-d]pyrimidines (2) are useful in treating
cellular proliferation mediated diseases due to their capability
to inhibit protein kinases.3
(4) Liu, J.-J.; Luk, K.-C. 5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones.
US patent 7098332(B2), August 29, 2006 (CAN 141:71554).
(5) Miller, J. R.; Dunham, S.; Mochalkin, I.; Banotai, C.; Bowman, M.;
Buist, S.; Dunkle, B.; Hanna, D.; Harwood, J.; Hubanda, M. D.; Karnovsky,
A.; Kuhn, M.; Limberakis, C.; Liu, J. Y.; Mehrens, S.; Mueller, W. T.;
Narasimhan, L.; Ogden, A.; Ohren, J.; Vara Prasad, J. V. N.; Shelly, J. A.;
Skerlos, L.; Sulavik, M.; Thomas, V. H.; VanderRoest, S.; Wang, L.; Wang,
Z.; Whitton, A.; Zhu, T.; Stover, C. K. Proc. Natl. Acad. Sci. U.S.A. 2009,
106 (6), 1737–1742.
(6) (a) Victory, P.; Diago, J. Afinidad 1978, 35, 154–158. (b) Victory, P.;
Diago, J. Afinidad 1978, 35, 161–165. (c) Victory, P; Jover, J. M.; Sempere, J.
Afinidad 1981, 38, 491–495. (d) Victory, P.; Borrell, J. I. 6-Alkoxy-5-cyano-3,4-
dihydro-2-pyridones as starting materials for the synthesis of heterocycles. In
Menon, J., Ed. Trends in Heterocyclic Chemistry; Council of Scientific Research
Integration: Trivandrum, India, 1993; Vol. 3, pp 235-247 and references cited
therein. (e) Victory, P.; Jover, J. M.; Nomen, R. Afinidad 1981, 38, 497–500.
(f) Victory, P.; Nomen, R.; Colomina, O.; Garriga, M.; Crespo Heterocycles.
1985, 23, 1135–1141.
(1) Hartmann, J. T.; Haap, M.; Kopp, H. G.; Lipp, H. P. Tyrosine kinase
inhibitors-a review on pharmacology, metabolism and side effects. Curr.
Drug Metab. 2009, 10, 470–481.
(2) Booth, R. J.; Chatterjee, A.; Malone, T. C. Pyridopyrimidinone
derivatives for treatment of neurodegenerative disease. WO0155148, August
02, 2001 (CAN 135:152818).
(3) Boschelli, D. H.; Wu, Z.; Klutchko, S. R.; Showalter, H. D. H.;
Hamby, J. M.; Lu, G. H.; Major, T. C.; Dahring, T. K.; Batley, B.; Panek,
R. L.; Keiser, J.; Hartl, B. G.; Kraker, A. J.; Klohs, W. D.; Roberts, B. J.;
Patmore, S.; Elliott, W. L.; Steinkampf, R.; Bradford, L. A.; Hallak, H.;
Doherty, A. M. J. Med. Chem. 1998, 41, 4365–4377.
ꢀ
(7) (a) Borrell, J. I.; Teixido, J.; Matallana, J. L.; Martı
´
nez-Teipel, B.;
Colominas, C.; Costa, M.; Balcells, M.; Schuler, E.; Castillo, M. J. J. Med.
ꢀ
Chem. 2001, 44, 2366–2369. (b) Borrell, J. I.; Teixido, J.; Martınez-Teipel, B.;
´
Serra, B.; Matallana, J. L.; Costa, M.; Batllori, X. Collect. Czech. Chem.
Commun. 1996, 61, 901–909.
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(8) (a) Mont, N.; Teixido, J.; Borrell, J. I.; Kappe, C. O. Tetrahedron Lett.
2003, 44, 5385–5387. (b) Mont, N.; Teixido, J.; Kappe, C. O.; Borrell, J. I.
ꢀ
Mol. Diversity 2003, 7, 153–159.
DOI: 10.1021/jo902345r
r
Published on Web 12/10/2009
J. Org. Chem. 2010, 75, 487–490 487
2009 American Chemical Society

Berzosa et al.
JOCNote
SCHEME 1. Synthesis of 9a and 10a from 2-Phenylacrylate 7a
FIGURE 2. Retrosynthetic analysis for the preparation of 6-aryl-
substituted 5,6-dihydropyrido[2,3-d]pyrimidines (4).
in we disclose a new method for the synthesis of 4-unsub-
stituted 5,6-dihydropyrido[2,3-d]pyrimidines via a novel type
of intermediates.
A retrosynthetic analysis of compounds 4 (Figure 2) pointed
to a 4-formyl-substituted 4-cyanobutyric ester (5) as the key
intermediate to be cyclized with a guanidine system 6. A further
disconnection of the formyl substituted compound 5 suggested
a Michael addition between a 2-aryl-susbstituted acrylate (7)
and 3,3-dimethoxypropanenitrile (8), a commercially available
formyl protected synthetic equivalent of the unstable 3-formyl-
acetonitrile.
SCHEME 2. Synthesis of 4-Unsubstituted 5,6-Dihydropyrido-
[2,3 d]pyrimidines 12 and 13 from 2-Aryl-Substituted Acrylates 7
Although this design was quite attractive, a major draw-
back was the extremely low acidity of the R-cyano methylene
to be ionized in 8 (calculated pKa = 25.94).9
In fact, there are only a few examples in the literature of a
Michael addition of a so poor active methylene such as the
addtion of acetonitrile to chalcones.10 In the case of 3,3-
dimethoxypropanenitrile (8) there are only examples of a few
condensations with aldehydes catalyzed by NaOMe/
MeOH.11
With this information in mind we tested the Michael
addition of 3,3-dimethoxypropanenitrile (8) to methyl
2-(2,6-dichlorophenyl)acrylate (7a) as a model compound
in the presence of a wide range of strong bases (NaOMe/
MeOH, NaHMDS/THF, LiHMDS/THF, NaOMe/DMF,
t-BuOK/THF). 7a, obtained upon condensation of 2-(2,6-
dichlorophenyl)acetate with paraformaldehyde in CaO/
K2CO3/DMF (94% yield),12 was selected because the 2,6-
dichlorophenyl substituent is present in several biologically
active pyrido[2,3-d]pyrimidines.3,4
The reaction afforded, in most of the cases, a mixture of
the (E)- and (Z)-3-methoxyacrylonitrile as a result of a
MeOH elimination from 3,3-dimethoxypropanenitrile (8).
Only the use of a 0.1 M solution of t-BuOK in THF gave
positive results, the starting R,β-unsaturated ester 7a being
immediately converted to a mixture of compounds (as
revealed by NMR) in which the expected acetal 9a (as a
mixture of diastereomers) was the minor component. The
presence in the 1H NMR spectrum of two singlets at 6.45 and
6.69 ppm pointed to the E/Z mixture of the enol ether 10a,
formed by an E1cB elimination of MeOH from 9a, as the
major component of the mixture (Scheme 1).
mixture of diastereomers of the acetal 9a was obtained as the
major product. On the contrary, when the reaction was
conducted at 60 °C the MeOH elimination proceeds
smoothly giving the E/Z mixture of the enol ether 10a as
the major product (Scheme 1).
In all cases the resulting mixture between the acetal 9a and
the enol ethers 10a represents roughly an 80% yield. The
main difficulty for the isolation of these compounds was the
presence of the unreacted excess of 3,3-dimethoxypropane-
nitrile (8), which could not be separated by column croma-
tography so it was necessary to remove it by concentrating in
vacuo (80 °C, 30 mbar).
Thus, the reaction crude obtained at 60 °C was column
cromatographed (silica gel 60 A C.C 35-70 μm with a 1:3
mixture of AcOEt/Hex as eluent) to afford a 61% yield of the
E/Z mixture of the enol ether 10a (66% E isomer, 34% Z
isomer). This mixture was further column chromatographed
to obtain analytical samples of both isomers. The E/Z isomer
assignment was supported by NOESY-1D spectroscopy.
Similarly, the reaction crude obtained at -78 °C was column
cromatographed (silica gel 60 A C.C 35-70 μm with a 1:3
mixture of AcOEt/Hex as eluent) to afford the diastereo-
meric mixture of the acetal 9a in a 68% yield.
Once the preparation of the Michael adduct 9a and the
MeOH elimination product 10a were achieved, we started
the study of their conversion to the corresponding 5,6-
dihydropyrido[2,3-d]pyrimidines 12a and 13a by cyclization
with guanidine 6 (R2 = H) and phenylguanidine 11 (R2 =
Ph), respectively (Scheme 2).
The reaction was then studied at different temperatures
showing that the MeOH elimination is minimized at lower
ones. Thus, when the reaction was carried out at -78 °C the
(9) Hilal, S. H.; Karickhoff, S. W.; Carreira, L. A. Quant. Struct.-Act.
Relat. 1995, 14, 348.
(10) (a) Shibata, K.; Urano, K.; Matsui, M. Chem. Lett. 1987, 519–20.
(b) Boruah, A.; Baruah, M.; Prajapati, D.; Sandhu, J. S. Chem. Lett. 1996,
965–966.
(11) Elliott, A. J.; Morris, P. E. Jr.; Petty, S. L.; Williams, C. H. J. Org.
Chem. 1997, 62 (23), 8071–8075.
(12) Holan, G.; Walser, R. A. Preparation of alkyl 2-aryl acrylates,
EP0003670(A1), August 22, 1979 (CAN 92:94079).
Initial experiments were carried out with the E/Z mixture
of the enol ether 10a and guanidine carbonate 6 by heating
the mixture under microwaves in the presence of NaOMe/
MeOH, a base previosuly used in our group for referable
cyclizacions with guanidine.8 The desired product 12a was
488 J. Org. Chem. Vol. 75, No. 2, 2010

Berzosa et al.
JOCNote
TABLE 1. Examples of 5,6-Dihydropyrido[2,3-d]pyrimidines 12 and 13
Synthesized
ether 10a and the acetal 9a was used instead of the pure 10a.
As a result, in order to obtain pyridopyrimidines 12 and 13 it
is not necessary to obtain a pure sample of the corresponding
enol ether 10, instead a mixture of the enol ether 10 and the
acetal 9 in any ratio can be used.
At this point we decided to investigate the possibility of
combining these two separate processes into a one-pot
reaction useful to obtain a wide range of pyridopyrimidines
12 and 13. To asses the substrate scope of such a procedure, a
variety of 2-aryl-substituted acrylic esters were tested (Table 1).
The Michael addition of the corresponding 2-aryl-substi-
tuted acrylate 7 and 3,3-dimethoxypropanenitrile (8) gave, in
all cases, an almost pure mixture of the corresponding enol
ether 10 and acetal 9 after neutralization with AcOH, filtra-
tion through a short pad of silica, and elimination of THF
and nitrile 8 under reduced pressure. Then, guanidine
carbonate 6 or phenylguanidine carbonate 11 was added to
the reaction crude and the mixture was heated under the
condittions stated before for each type of guanidine. Sub-
stituted pyridopyrimidines 12 and 13 were obtained in
acceptable overall yields through this two-step procedure
without intermediate isolation, which is clearly shorter than
the 6-7 steps long procedures previously used for such types
of compounds.4
To establish the scope of the procedure, we tested it with
alkyl-susbtituted acrylates (such as methyl methacrylate or
methyl crotonate) and 3-aryl-susbtituted acrylates (such as
methyl cinnamate). Although the reaction proceeded in all
cases the yields were very low (less than 15%). In the case of
the less reactive methyl cinnamate, an increase of the reaction
temperature led to large quantities of potassium cinnamate
as a byproduct caused possibly by the nucleophilic attack of
the tert-butoxide anion onto the ester methyl group.
Consequently, this methodology seems to be restricted to
2-aryl-substituted acrylates 7, which lead to 6-aryl-substi-
tuted 5,6-dihydropyrido[2,3-d]pyrimidines 12 and 13, pre-
cisely the position and type of substituents that have been
claimed as necessary to confer biological activity to struc-
tures 2 and 3.3-5
However, even in the case of 2-aryl-substituted acrylates
7, when the reaction was assayed with methyl atropate
(2-phenyl acrylate, 7f) the reaction led to large quantities
of a polymeric material instead of the corresponding pyr-
idopyrimidine 12f. This observation agrees with the known
instability of 2-aryl acrylates without ortho substituents,
particularly in the presence of strong bases,14 confirmed by
the practical impossibility of buying methyl atropate and
other 2-aryl acrylates from commercial sources.
aOverall yield from the corresponding 2-aryl acrylates 7a-e.
obtained but in a very poor yield (20%), so we tested
different reaction conditions using pyridine as base and
solvent. Pyridine was selected due to its non-nucleophilic
character and high boiling point, which allows heating under
microwave irradiation at high temperatures without reach-
ing high pressures. When a mixture of 1 equiv of 10a and 3
equiv of 6 was heated under microwave irradiation for 1 h at
180 °C in pyridine, the desired pyridopyrimidine 12a was
formed in a 70% yield. 12a was collected by filtration after
the addition of water to the reaction crude.
However, when we tried the aforementioned procedure
but using phenylguanidine carbonate 11 instead of guanidine
carbonate 6, the expected 5,6-dihydropyrido[2,3-
d]pyrimidine 13a was not obtained. In fact, there are many
examples in the literature of the formation of heterocyclic
rings with guanidine 6 but only a few with arylguanidines.13
Finally, using a modification of the reaction conditions
described by Shigekazu and co-workers,13b consisting of
heating a 1:3 molar mixture of 10a and phenylguanidine
carbonate 11 without any solvent at 150 °C overnight with
stirring, the desired 5,6-dihydropyrido[2,3-d]pyrimidine 13a
was obtained in a 44% yield.
To overcome such a limitation, we considered the use of a
2-(ortho-substituted)phenyl acrylate in which the ortho sub-
stituent could be removed after the formation of the corre-
sponding pyrido[2,3-d]pyrimidine. We selected methyl 2-(o-
bromophenyl)acrylate 7e, easily obtainable from methyl
2-(o-bromophenyl)acetate in 84% yield, to prepare the cor-
responding 5,6-dihydropyrido[2,3-d]pyrimidine 12e (Scheme3)
in 40% yield (in this case the condensation with 3,3-dimethox-
ypropanenitrile 8 was carried out for 1 min at 0 °C instead of
To our delight, the cyclizations to form 12a and 13a
proceeded with similar yields when a mixture of the enol
(13) (a) Gueremy, C.; Audiau, F.; Uzan, A.; Le Fur, G.; Leger, J. M.;
Carpy, A. J. Med. Chem. 1982, 25 (12), 1459–65. (b) Shigekazu, I.; Katsumi,
M.; Shoji, K.; Toshihiro, N.; Yoshiyuki, K.; Nobumitsu, S.; Shinichiro, M.
Pyrimidine derivatives and agricultural or horticultural fungicidal composition
contaning the same. EP0270111 (A1), June 08, 1988 (CAN 109:124400).
(14) (a) Yuki, H.; Hatada, K.; Ohshima, J.; Komatsu, T. Polym. J. 1971,
2, 812–814. (b) Jiang, J.; Jia, X.; Pang, Y.; Huang, J. J. Macromol. Sci., Pure
Appl. Chem. 1998, A35, 781–792. (c) Liu, C.; Xu, X.; Huang, J. J. Appl.
Polym. Sci. 2004, 94, 355–360.
J. Org. Chem. Vol. 75, No. 2, 2010 489

Berzosa et al.
JOCNote
SCHEME 3. Synthesis of 12e and Debromination to 12f
1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 7.96 (s, 1H),
7.55 (m, 2H), 7.37 (t, J = 8.1 Hz, 1H), 6.40 (s, 2H), 4.65 (dd, J =
13.8, 7.9 Hz, 1H), 3.14 (m, 1H), 2.88 (dd, J = 15.6, 7.9 Hz,
1H); 13C NMR (100 MHz, DMSO-d6) δ 169.8, 162.5, 157.5,
155.9, 135.2, 134.9, 134.7, 129.8, 128.4, 102.0, 43.5, 24.9;
HRMS (FABþ) m/z calcd for C13H10Cl2N4O 309.0310, found
309.0304.
General Procedure for the Preparation of Pyrido[2,3-d]-
pyrimidines 13a-c. A solution of t-BuOK (0.34 g, 2 mmol) in
THF (20 mL) was added to a mixture of the corresponding
2-aryl acrylate 7a-c (2 mmol) and 3,3-dimethoxypropanenitrile
8 (0.35 mL, 3 mmol). After 5 min of stirring at room temperature
the solution was neutralized with AcOH and filtered through a
short pad of silica with 200 mL of hexanes/AcOEt 1:1 as eluent.
The solvent was removed under reduced pressure, phenylgua-
nidine carbonate 11 (1.07 g, 6 mmol) was added to the residue,
and the mixture was stirred at 150 °C overnight. The reaction
crude was suspended in MeOH. The precipitate formed was
collected by filtration and washed with water and MeOH to
afford the corresponding 13a-c.
6-(2,6-Dichlorophenyl)-2-(phenylamino)-5,6-dihydropyrido-
[2,3-d]pyrimidin-7(8H)-one (13a): 36%, white solid, mp >250 °C;
IR (KBr) νmax 3289, 3204, 3145, 1685, 1602, 1579, 1498, 1446,
1241, 756 cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H),
9.41(s, 1H), 8.19 (s, 1H), 7.82 (d, J = 7.8 Hz, 2H), 7.56 (d, J = 8.2
Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.39(t, J = 8.1Hz, 1H), 7.24 (t,
J = 7.9 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 4.76 (dd, J = 13.8, 8.0
Hz, 1H), 3.23 (m, 1H), 2.99 (dd, J = 15.8, 8.0 Hz); 13C NMR (100
MHz, DMSO-d6) δ 169.8, 158.8, 157.4, 155.6, 140.7, 135.3, 134.9,
134.8, 129.9, 129.8, 128.4 (2C), 121.0, 118.6 (2C), 104.3, 43.3,
25.0; HRMS (FABþ) m/z calcd for C19H14Cl2N4O 385.0623,
found 385.0622.
Procedure for the Preparation of 2-Amino-6-phenyl-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-one (12f). A 0.192 g (0.6 mmol)
sample of 2-amino-6-(2-bromophenyl)-5,6-dihydropyrido[2,3-d]-
pyrimidin-7(8H)-one (12e) was suspended in 20 mL of THF and
3.53 mL of a 1.7 M solution of t-BuLi in pentane (6 mmol) was
added dropwise. The mixture was stirred for 1 h at room tempera-
ture. Ten milliliters of MeOH was added and the mixture was
neutralized with AcOH. The solvent was removed under reduced
pressure and the residue was suspended in water. The precipitate was
collected by filtration and washed with water and cyclohexane to
give 0.19 g (83%) of 12f as a white-brown solid: mp >250 °C; IR
(KBr) νmax 3333, 3153, 3067, 2896, 1682, 1632, 1573, 1496, 1228, 698
cm-1; 1H NMR (400 MHz, DMSO-d6) δ10.62 (s, 1H), 7.93 (s, 1H),
7.34-7.28(m, 2H), 7.27-7.21(m, 3H), 6.34(s, 2H), 3.86(t, J=7.9,
1H), 2.99-2.93 (m, 2H); 13CNMR(100MHz,DMSO-d6) δ172.15,
162.48, 157.88, 155.48, 138.90, 128.29, 128.13, 126.86, 103.41, 46.19,
27.86; HRMS (FABþ) m/z calcd for C13H13N4O (MHþ) 241.1089,
found 241.1091.
-78 °C due to the lower reactivity of 7e and the instability of the
enol ether 10e).
A literature search revealed that t-BuLi in THF could be
the best solution to remove the bromine atom.15 Therefore
12e was suspended in THF and 10 equiv of t-BuLi was
added. After 1 h at room temperature MeOH was added
and the crude was neutralized with AcOH to afford the
desired 6-phenyl-substituted pyridopyrimidine 12f in 83%
yield (33% from 2-(o-bromophenyl)acrylate 7e).
This approach seems to constitute a general solution for
phenyl substituents not containing an ortho substituent
because there are more than 30 commercially available
2-bromophenylacetic acids and esters (the starting products
for 2-aryl acrylates 7) carrying other substituents in the
phenyl ring compatible with the aforementioned debromina-
tion.
Finally, as is shown in Table 1, the yields obtained for
2-phenylamino-substituted pyridopyrimidines 13 (R2 = Ph)
are lower than those obtained for the 2-amino-substituted
ones 12 (R2 = H), a result that agrees with the lower reactivity
of phenylguanidine 11 with respect to guanidine 6.
In conclusion we have developed a new and very simple
methodology for the preparation of 4-unsubstituted 5,6-
dihydropyrido[2,3-d]pyrimidine systems 12 and 13 based
on a novel Michael addition.16 This unusual addition can
be a way to obtain other heterocyclic rings in the future.
Experimental Section
General Procedure for the Preparation of 5,6-Dihydropyrido-
[2,3-d]pyrimidines 12a-e. A solution of t-BuOK (0.34 g, 2 mmol)
in THF (20 mL) was added to a mixture of the corresponding 2-
aryl acrylate 7a-e (2 mmol) and 3,3-dimethoxypropanenitrile 8
(0.35 mL, 3 mmol). After 5 min of stirring at room temperature,
the solution was neutralized with AcOH and filtered through a
short pad of silica with 200 mL of hexanes/AcOEt 1:1 as eluent.
The solvent was removed under reduced pressure and guanidine
carbonate 6 (0.54 g, 6 mmol) and pyridine (4 mL) were added to
the residue and the mixture was heated under microwave
irradiation at 180 °C for 1 h. Water was added to the solution
and the precipitate was collected by filtration and washed with
water and cold MeOH to afford the corresponding 12a-e.
2-Amino-6-(2,6-dichlorophenyl)-5,6-dihydropyrido[2,3-d ]pyri-
midin-7(8H)-one (12a): 53%, white solid, mp >250 °C; IR (KBr)
Acknowledgment. X. Berzosa is grateful for a fellowship
from Generalitat de Catalunya (2006-2009, grant 2006FI
00058).
ν
max 3379, 3199, 2894, 1691, 1627, 1570, 1480, 1435, 783 cm-1
;
Supporting Information Available: General experimental
methods, characterization data for 7a-e, 9a, 10a, 10e, 12a-f,
and 13a-c, and copies of 1H and 13C NMR spectra. This
material is available free of charge via the Internet at http://
pubs.acs.org.
(15) (a) Kolotuchin, S. V.; Meyers, A. I. J. Org. Chem. 1999, 64, 7921–
7928. (b) Klein, C.; Graf, E.; Hosseini, M. W.; De Cian, A.; Kyritsakas-
Gruber, N. Eur. J. Org. Chem. 2002, 802–809.
(16) Berzosa, X.; Borrell, J. I. Sıntesis y usos de 4-cianopentanoatos y
´
4-cianopentenoatos sustituidos. ES200901191, April 29, 2009.
490 J. Org. Chem. Vol. 75, No. 2, 2010