First functionalization by metallation of the pyridine moiety of pyridopyrimidin-4(3H)-ones. Diazines. Part 36

Tetrahedron 60 (2004) 4107–4123

First functionalization by metallation of the pyridine moiety

of pyridopyrimidin-4(3H)-ones. Diazines. Part 36

*

Jerome Audoux, Nelly Ple, Alain Turck and Guy Queguiner

´ ˆ

´

´ ´

Laboratoire de Chimie Organique Fine et Heterocyclique, UMR 6014, IRCOF-INSA, B.P. 08, 76131 Mont St Aignan Cedex, France

Received 14 November 2003; revised 9 February 2004; accepted 12 February 2004

Abstract—Starting from o-aminopyridine carboxylic acids, a general synthetic route leading to various pyridopyrimidin-4(3H)-ones is

described. The ﬁrst metallation and functionalization of the pyridine moiety has been studied and a regioselective metallation at the peri-

position C₅of the pyridine ring has been highlighted.

q 2004 Published by Elsevier Ltd.

1. Introduction

could provide a consistent strategy for the synthesis of new

pyridopyrimidines.

Among the pyridodiazines, the pyridopyrimidines have

received much attention because of their potential biological

activities as isosteres of quinazolines or pteridines. All four

possible pyridopyrimidine systems, pyrido[2,3-d]pyrimi-

dine I, pyrido[3,4-d]pyrimidine II, pyrido[4,3-d]pyrimidine

III and pyrido[3,2-d]pyrimidine IV are known (Scheme 1).

The pyrido[2,3-d]pyrimidine system has been more studied

according to its medicinal applications such as inhibitor

of the adenosine kinase¹(AK) or dihydrofolate reductase²

(DHFR) enzymes.

In previous papers, we have mentioned the lithiation of the

benzene moiety of benzodiazines: cinnolines,³quinazo-

lines,^4,5quinoxalines and phtalazines.⁵As a continuation of

our studies of metallation of ortho-condensed diazines, we

report here the synthesis, the direct lithiation and func-

tionalization of the pyridine moiety of pyridopyrimidin-

4(3H)-ones.

Various syntheses of pyridopyrimidine systems have been

previously described,⁶among them, a general synthetic

route is the cyclization of o-acylaminopyridine carboxylic

acids with acetic anhydride,⁷leading to pyrido[1,3]oxazin-

4-ones intermediates which react with ammonia to give the

expected pyridopyrimidin-4(3H)-ones (Scheme 2).

For the reason given above, the synthesis of pyridopyrimi-

dine derivatives provides an interesting challenge. Con-

struction of functionalized pyridopyrimidines involves

cyclization of appropriately substituted pyrimidines or

pyridines whose synthesis is not always easy. The

functionalization via metallation of the pyridine moiety

This synthetic route could be used with o-aminopyridine

Scheme 1.

Scheme 2.

Keywords: Metallation; Pyridopyrimidin-4(3H)-ones; Functionalization.

*

Corresponding author. Tel.: þ33-2-35-52-29-02; fax: þ33-2-35-52-29-62; e-mail address: nelly.ple@insa-rouen.fr

0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.

doi:10.1016/j.tet.2004.02.040

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J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

carboxylic acids as starting material which could be reacted

with acid chlorides to give the expected o-acylamino-

pyridine carboxylic acids. The 2-aminonicotinic acid was

the sole commercial material, the other o-acylaminopyri-

dine carboxylic acids have been obtained from commercial

aminopyridines which reacted with pivaloyl chloride to give

the expected N-pivaloylaminopyridines. The pivaloylamino

group, a very good ortho-directing group, allowed us to

obtain ortho lithioderivatives which after reaction with

carbon dioxide led to o-N-pivaloylaminopyridine car-

boxylic acids.⁸It could be noticed that, if most are

known, three of them are new (1-3) ones (Scheme 3).

Scheme 5.

if the lactam group of the pyrimidinone moiety could have

any inﬂuence on the peri position C₅(Scheme 5).

The lactam group has been previously used as ortho-

directing group during the regioselective metallation at C₂

of the pyridine moiety of 5- or 6-methoxyquinolin-2(1H)-

ones.¹⁰Otherwise, the lithiation of N₃-acylaminoquinazo-

lin-4(3H)-ones has been described,¹¹in this case, metalla-

tion occurred exclusively at C₂which was inﬂuenced by the

acylamino group on the ring nitrogen N₃. More recently, we

have reported the metallation of quinazolones, these

compounds underwent a regioselective metallation of the

benzene moiety at the C₈position, in peri to the ring

nitrogen atom N₁, only when the benzene ring was

substituted at C₇position by a chlorine atom or a methoxy

group.⁵

Scheme 3.

According to this general synthetic route, we have

synthesized eight pyridopyrimidin-4(3H)-ones (4-11)

among them compounds 6-11 are new ones. Compounds 4

and 5 were described as herbicides⁹(Scheme 4).

We have tested the metallation of 2-tert-butylpyridopyrimi-

din-4-(3H)-ones to appreciate if the presence of the pyridine

nitrogen makes the deprotonation more easy than with

quinazolones and could inﬂuence the regioselectivity. The

presence of a tert-butyl group at the C₂position has been

chosen to avoid a nucleophilic attack of the metallating

agent at this position^12,13and to prevent the deprotonation

on the carbon C_aof the lateral chain.^14–16

We have tested the direct lithiation and functionalization of

the 2-tert-butylpyridopyrimidin-4(3H)-ones 4-11.

During the lithiation of the benzene moiety of various

benzodiazines,^3–5it has been highlighted an exceptional

regioselective metallation at the C₈position, in peri to the

ring nitrogen atom N₁. It has also been highlighted that the

presence on the benzene moiety of a substituent inducing an

ortho-directed metallation favored the lithiation reaction.

First, various attempts to metallate 6 with alkyllithiums

have been performed. n-butyllithium and phenyllithium

have been tested as metallating agent, followed by reaction

with diphenyl disulﬁde as the electrophile. Treatment of 6

with 2 equiv. of n-butyllithium at 278 8C did not allow any

reaction and 95% of starting material were recovered; use of

4 equiv. of butyllithium at this temperature afforded

addition products (91%) besides a small amount of starting

material (8%) (Scheme 6). Compounds 12 and 13 resulted

from an addition at the a positions of the pyridine nitrogen

(C₆and C₈), whereas the main compound 14 resulted from

an addition of n-butyllithium at C₈followed by reaction

In the case of 2-tert-butylpyridopyrimidin-4(3H)-ones 4-11,

several parameters could be taken into account to direct the

regioselectivity of the metallation (Scheme 5): the peri

effect of the nitrogen atom N₁of the pyrimidine moiety, the

a effect of the nitrogen atom N_xof the pyridine moiety

where the a position of the nitrogen atom was free and the

ortho-effect of substituent such as a chlorine atom or a

methoxy group for compounds 5, 7, 8. For all these

compounds except for 11, it could be interesting to observe

Scheme 4.

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

4109

Scheme 6.

Scheme 7.

with electrophile at C₅, peri to the carbonyl of the lactam

function.

which are known to be less nucleophilic than alkyllithiums.

Later, the conditions of metallation have been established

for compound 6, with various amounts of lithium alkyl-

amides as metallating agent, and diphenyl disulﬁde as the

electrophile (Scheme 7, Table 1).

When the reaction was performed with phenyllithium at

210 8C, two compounds 15 and 16 resulting from an

addition reaction at C₈were obtained in 69% total yield

beside starting material (30%). For compound 14 as for

compound 16, we observed that the reaction with the

electrophile has occurred at C₅at the peri position of the

lactam function.

The results given in Table 1 revealed that a ﬁrst attempt with

2 equiv. of LTMP at 278 8C afforded a small amount of 17

beside starting material (entry 1). With 4 equiv. of LTMP at

278 8C, the yield was improved to 55%, nevertheless,

increasing the temperature to 0 8C gave a slightly lower

yield (entries 2 and 3). A large excess of LTMP (6–

8 equiv.) afforded 17 in very good yields (entries 5 and 6).

When LDA, less basic than LTMP, was used even in large

excess, only a few amount of 17 was obtained beside

starting material (entry 7). The structure of compound 17

has been established thanks to its ¹H NMR spectrum which

presented two singlets at 7.68 and 8.67 ppm assigned, to H₆

and H₈, highlighting a total regioselectivity at the C₅

position.

Reactions of addition observed with alkyllithiums as

metallating agent urged us to use lithium alkylamides

such as lithium 2,2,4,4-tetramethylpiperidide (LTMP) or

lithium diisopropylamide (LDA) as metallating agent,

Table 1. Lithiation and functionalization of 6

Entry Metallating agent

n

(equiv.)

Temperature u Compound 17

(8C)

(%)

1

2

3

4

5

6

7

LTMP

LDA

2

4

5

6

8

278

0

278

5

We have also tested if metallation could be performed by a

mixture of bases. In the ﬁrst step, the labile proton of the

lactam function was trapped by 1 equiv. of base (n-BuLi or

LTMP), leading to a lithium salt 6a (Scheme 8) as this

has been observed with its IR spectrum obtained with

ReactIRe spectrometer (Fig. 1). We could observe that the

55

45

75

90

97

5

Scheme 8.

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J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

reaction with (52n) equivalents of n-butyllithium, the

results revealed that a large excess of LTMP improved the

yield of compound 17. The best results have been obtained

with the experimental conditions of entry 3. When LDA was

used as alkylamide under the conditions of the entry 3, only

small amount of 17 was obtained beside starting material

(entry 6).

These results require some comments: when n equivalents

of lithium alkylamides were ﬁrst introduced followed by

addition of (52n) equivalents of n-butyllithium, the

metallation reaction was observed without addition, even

if n-butyllithium was in excess. In this case, it could be

assumed that the ﬁrst equivalent of lithium alkylamide

trapped the labile proton of the lactam function, the other

equivalents were used to give aggregates which then could

favor metallation by LTMP or n-BuLi without occurrence of

competitive addition reaction. We have nevertheless used

the conditions of metallation given in Table 1 (entry 6) to

functionalize the 2-tert-butylpyridopyrimidin-4(3H)-ones

4-11, because the work up of the reaction mixture was

easier.

Figure 1. Spectroscopic analysis FTIR of 6 with n equivalent of

n-butyllithium or LTMP.

introduction of 1 equiv. of metallating agent led to

disappearance of peaks at 1700 and 1600 cm²¹assigned,

respectively, to n(CvO) and d(N–H). The further equiva-

lents of base could be used to induce either the metallation

or additions.

Various attempts have been performed with a total of

5 equiv. of bases at 278 8C in THF for 1 h as total reaction

time and with diphenyl disulﬁde as the electrophile. We

have tested a mixture of lithium alkylamide–alkyllithium in

various ratios. When a mixture of bases was used, the ﬁrst

base was reacted for 30 min, then the second base was

introduced and reacted again for 30 min. The experimental

conditions and results are given in Table 2.

Treatment of 6 with 8 equiv. of LTMP at 278 8C followed

by reaction with various electrophiles afforded ﬁve-substi-

tuted derivatives in very good yields (Scheme 9).

It must be noticed that when tributyltin chloride was used as

the electrophile, a distannyl compound 20 was obtained, the

presence of a lactam group was conﬁrmed by its IR

Table 2. Metallation of 6 with a mixture of bases

spectrum which exhibited a n(CO) at 1688 cm²¹

.

Entry

Bases

Compound 6 (%)

Compound 17 (%)

With iodine as the electrophile we have observed that the

regioselectivity was dependent on the direct or inverse

introduction of iodine. When iodine was introduced in the

reaction mixture, two mono iodo derivatives at C₅and C₆

were obtained, whereas compound 21 was the sole product

isolated when the lithiated derivative was added to a

solution of iodine in THF. The 6-iodo derivative 23 was

obtained as sole product beside starting material (41%) by

use of only 2 equiv. of iodine introduced in the reaction

mixture after a 1 h reaction time (Scheme 10). Such a result

could be explained by a ‘halogen-dance’ mechanism which

has been previously described in the diazine series.¹⁷

1

2

5 equiv. LTMP

25

35

75

65

(1) 1 equiv. n-BuLi

(2) 4 equiv. LTMP

3

4

5

6

(1) 4 equiv. LTMP

(2) 1 equiv. n-BuLi

5

90

75

33

10

(1) 3 equiv. LTMP

(2) 2 equiv. n-BuLi

25

66

90

(1) 2 equiv. LTMP

(2) 3 equiv. n-BuLi

(1) 4 equiv. LDA

(2) 1 equiv. n-BuLi

It should be interesting to observe if the presence of a

substituent such as a chlorine atom or a methoxy group

could improve the reactivity towards lithiation and induce a

particular regioselectivity. We have tested the metallation of

substituted pyridopyrimidin-4(3H)-ones 7-9.

Treatment of 6 with 5 equiv. of LTMP as sole base provided

the ﬁve-substituted compound 17 in 75% yield (entry 1).

With 1 equiv. of n-butyllithium followed by reaction of

4 equiv. of LTMP (entry 2), we observed the formation of

17 in slightly lower yield (65%). For the entries 3–5, we

have ﬁrst used (n) equivalents of LTMP followed by

For all these compounds the C₅position, peri to the

Scheme 9.

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

4111

Scheme 10.

Scheme 11.

Table 3. Lithiation and functionalization of 7-9

Starting material

X

Y

E

u

Compounds (yield, %)

7

Cl

H

PhS

278 8C

24 (86)

25 (97)

26 (97)

27 (84)

28 (87)

MeCH(OH)

PhCH(OH)

Bu₃Sn

I

8

9

OMe

H

PhS

278 to 0 8C

29 (71)

30 (92)

31 (91)

32 (75)

33 (88)

MeCH(OH)

PhCH(OH)

Bu₃Sn

I

H

OMe

PhS

278 to 220 8C

34 (89)

35 (90)

36 (85)

37 (75)

38 (85)

MeCH(OH)

PhCH(OH)

Bu₃Sn

I

carbonyl group, was free as also one a position of the

pyridine nitrogen atom. Various experimental conditions

were tested and as before 8 equiv. of LTMP were necessary

to obtain good yields (Scheme 11, Table 3).

the temperature was raised, respectively, to 0 8C and to

220 8C.

We have then tested the metallation of the 2-tert-butyl-5-

chloropyrido [3,4-d]pyrimidin-4(3H)-one 22, for this

compound the C₅position carried a chlorine atom and

could not undergo lithiation, whereas positions C₆and C₈in

a position to pyridine nitrogen atom were free. Treatment

of 22 with 8 equiv. of LTMP at 220 8C for 1 h followed by

reaction with benzaldehyde as electrophile afforded two

compounds 39 and 40 in equal amounts with a global yield

of 70% beside starting material (17%) (Scheme 12).

Under these experimental conditions, lithiation of 7-9

occurred exclusively at the C₅position and reaction with

various electrophiles led to 2-tert-butyl-5-substituted pyrido-

[3,4-d]pyrimidin-4(3H)-ones 24-38 in good yields. As it

has been previously mentioned, when tributyl tin chloride

was used as the electrophile, the distannyl compounds 27,

32 and 37 were obtained. It can be noticed that the presence

of a methoxy group on the pyridine moiety required

higher metallation temperature. For compounds 8 and 9

the metallating agent was introduced at 278 8C and

Despite the substitution of the C₅position, this result

indicated that metallation could occur at once at the C₆

Scheme 12.

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J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

Scheme 13.

Scheme 14.

Table 4. Metallation of compound 10

Entry

Temperature , u (8C)

Time, t (h)

Compound 46 (%)

Compound 47 (%)

Compound 10 (%)

1

2

3

4

5

6

278

220

0

20

1

2

3

20

92

75

62

9

—

3

18

29

74

76

80

5

7

9

16

17

20

7

position inﬂuenced by the chlorine atom as ortho-directing

group and the pyridine nitrogen atom, or at the C₈position

under inﬂuence of the two ring nitrogen atoms N₁and N₇. It

could be noticed that, if the single effect of the pyridine

nitrogen N₇was not sufﬁcient to allow the metallation, the

reaction became feasible when this effect was associated to

an other effect such as an ortho-directing group or a peri

ring nitrogen atom.

When the reaction was performed at 20 8C with rising

reaction times, the compound 47 became the main product

with 2 or 3 h for reaction time beside starting material

(entries 4–6).

Regioselectivity of the lithiation could be discussed in terms

of kinetic or thermodynamic control. Compound 47 which

was obtained at higher temperatures and with a longer

reaction time could be the thermodynamic compound while

compound 46 obtained in softer conditions could be the

kinetic compound. When deprotonation is thermodynamic-

ally controlled, heats of formation of the lithiated deriva-

tives determined by semi-empirical Li/PM3 method could

be examined as a simple approach to account for the

regioselectivity. Heat of formation of the lithiated deriva-

tives calculated by Li/PM3 method (Scheme 15) indicated

that the C₅lithiated intermediate is the more stable isomer,

which is in agreement with the experimental results.

We have then tested the metallation of compounds 4 and 10

for which the C₅position was kept free. Treatment of 4

with 8 equiv. of LTMP at 0 8C for 1 h, followed by reaction

with various electrophiles led to ﬁve-substituted compounds

41-45 in good yields (Scheme 13).

For compound 10, the metallation reaction was performed

with 8 equiv. of LTMP at various temperatures with

benzaldehyde as the electrophile, under these conditions it

has been observed that the regioselectivity was dependent

on the temperature and the reaction time (Scheme 14,

Table 4).

The results given in Table 4 revealed, that with a 1 h

reaction time, only a few amount of 46 was obtained at

278 8C beside starting material (entry 1). When the

temperature was raised to 220 8C, compound 46 was

observed as the main product with a very good yield (entry

2). Then when temperature was increased from 220 8C to

room temperature, we observed decreasing amounts of 46,

whereas the formation of 47 was growing up (entries 2–4).

Scheme 15.

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

4113

Scheme 16.

Scheme 17.

We have extended these results to other electrophiles and

observed that at low temperature (220 8C) with a reaction

time of 1 h the eight-substituted compounds were obtained

as main products in very good yields. When the reaction was

performed at room temperature with a reaction time of 2 h,

the C₅-substituted compounds were obtained in moderate

yields (Scheme 16).

formation of peri compounds either at C₅or C₈positions.

This general synthetic route associated to palladium cross-

coupling reactions is promising to access to new

compounds.

3. Experimental

At last, we have tested the metallation of compound 11 for

which the pyridine nitrogen atom is at the position 5, peri to

the carbonyl group of the lactam function. It should be

interesting to observe if the lithiation could be obtained and

in the afﬁrmative if a regioselectivity could de observed.

Treatment of 11 with 8 equiv. of LTMP at 278 8C for 1 h

followed by reaction with various electrophiles afforded the

eight-substituted compounds 56-60 (Scheme 17).

Melting points were determined on a Koﬂer hot-stage. The

¹H and ¹³C NMR spectra were recorded in deuteriochloro-

form or deuteriodymethylsulfoxide on Bruker instrument

(Avance 300). Microanalyses were performed on a Carlo

Erba CHNOS 1160 apparatus. The IR spectra were obtained

as potassium bromide pellets with a Perkin Elmer FTIR

1650 spectrophotometer.

All reagents were of commercial quality and were

purchased from Aldrich Chemical Co. or Acros. 2-tert-

Butylpyrido [3,2-d]pyrimidine-4(3H)-one 4 was synthe-

sized according to the procedure described in the literature.⁹

2. Conclusion

Starting from o-aminopyridine carboxylic acids, a general

synthetic route leading to various pyridopyrimidin-4(3H)-

ones has been described. The ﬁrst metallation and

functionalization of the pyridine moiety has been studied.

An original regioselective metallation at the peri position C₅

of the pyridine ring has been observed when an excess of

metallating agent was used, allowing access to a wide range

of new substituted pyridopyrimidin-4(3H)-ones. In some

cases, control of the experimental conditions allowed the

3.1. Procedure A for the metallation of various

N-pivaloylaminopyridines

An oven-dried three-necked round bottom ﬂask was cooled

in a dessicator and then equipped with a thermometer and a

magnetic stirrer, and ﬂushed with a nitrogen inlet. The ﬂask

was charged with N-pivaloylaminopyridine and stoppered

with a rubber septum and anhydrous THF or diethylether

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J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

was introduced. After cooling to 278 8C, metallating agent

and TMEDA were added dropwise via syringe. The mixture

was stirred for 15 min and heated to T (8C). After 3 h of

stirring at T (8C), a precipitate appeared and the suspension

was cooled again to 278 8C and poured onto an excess of

dry ice. After 1 h, the reaction mixture was hydrolyzed with

50 mL of water and was allowed to warm to room

temperature, and the organic layer was removed under

reduced pressure. The residue was partitioned between

water and ethyl ether, and the aqueous phase separated and

again washed with ethyl ether. The aqueous layer was

acidiﬁed with 50% hydrochloric acid to give an off-white

solid that was ﬁltered, thoroughly washed with water. The

solid was triturated with acetone and ﬁltered to leave a white

solid.

of the 2-tert-butylpyridopyrimidin-4(3H)-one in THF

(10 mL). Then, the mixture was stirred for 5 min and

heated to T (8C). After 1 h of stirring at T (8C), the

temperature was decreased to 278 8C and the electrophile

introduced and stirring was continued for t hour(s) at this

temperature. Hydrolysis was then carried out at 278 8C

using a solution of water and ethanol (1:1). When the

electrophile was iodine, the solution was decolorized with

sodium thiosulfate. At room temperature, water (10 mL)

was added to the mixture and THF was removed under

reduced pressure. The aqueous layer was extracted with

dichloromethane or ethyl acetate (3£20 mL), the combined

organic extracts were then dried over magnesium sulfate

and evaporated. The crude product was puriﬁed by column

chromatography on silica gel.

3.2. Procedure B for preparation of 2-tert-butylpyrido-

pyrimidin-4(3H)-ones via 2-tert-butylpyrido[1,3]oxazin-

4-ones

3.5. Procedure E for metallation of 2-tert-butylpyrido-

pyrimidin-4(3H)-ones by lithium 2,2,6,6- tetramethyl-

piperidide

Acetic anhydride (20–100 mL) and o-(N-pivaloylamino)-

pyridinecarboxylic acids (2–8 g) were reﬂuxed together for

2 h. The excess of anhydride was removed by distillation

under reduced pressure to give crude pyrido-oxazinone,

then ammonia 15 N (30–150 mL) was added, and the

mixture was stirred at room temperature for 24 h. Evapor-

ation of the solution or suspension under reduced pressure

yielded the pyridopyrimidinone by precipitation and

ﬁltration. To complete the conversion of pyrido-oxazinone

into pyridopyrimidinone, the mixture could be heated with

5% aqueous sodium hydroxide for 15 min.

The workup of the procedures D and E is similar but differs

only by the order of introduction of the electrophile. For

procedure E, the lithiated product was introduced into the

electrophile solution.

3.5.1. 3-(tert-Butylcarbonylamino)-6-methoxy-isonico-

tinic acid (1). Metallation of N-(6-methoxy-3-pyridyl)-

2,2-dimethylpropanamide (10 g, 48 mmol) according to

the procedure A with n-BuLi 2.5 M (2.5 equiv., 48 mL),

TMEDA (2.5 equiv., 18.13 mL) in anhydrous ethyl ether

(300 mL) at T¼210 8C gave 7.43 g (61%) of 1 as a

1

colorless solid, mp 240–241 8C; H NMR (CDCl₃): d 1.15

3.3. Procedure C for direct metallation of 2-tert-butyl-

pyrido[3,4-d]pyrimidin-4(3H)-one by n-butyl-lithium or

phenyllithium

(s, 9H, tert-butyl); 3.78 (s, 3H, OMe); 7.12 (s, 1H, H₅); 9.00

(s, 1H, H₂); 10.49 (s, 1H, NH); ¹³C NMR (CDCl₃): d 27.5 (3

Me_tert-butyl); 49.0 (CMe₃); 53.9 (OMe); 110.5 (CH); 129.8

(C_py); 130.7 (C_py); 140.6 (CH); 159.8 (C_py); 167.9 (CO);

176.5 (CO). Anal. Calcd for C₁₂H₁₆N₂O₄(252.27): C,

57.13; H, 6.39; N, 11.10. Found: C, 57.39; H, 6.76; N, 10.88.

A solution of 2-tert-butylpyridopyrimidin-4(3H)-one

(50 mg, 0.24 mmol) in anhydrous THF (20 mL) was cooled

to 278 8C, at this temperature a solution of n-butyllithium

or phenyllithium (n equivalents) in hexane was introduced

dropwise under an atmosphere of dry argon. The mixture

was stirred for 15 min and warmed to the temperature T

(8C). After 1 h of stirring at T (8C), the temperature was

decreased again to 278 8C and the diphenyl disulﬁde

(4 equiv., 215 mg) was introduced in solution with THF

(5 mL). After 1 h, hydrolysis was carried out using a

mixture of water and ethanol (1:1), the organic layer was

removed under reduced pressure. The aqueous phase was

extracted with ethyl acetate (3£20 mL), the combined

organic extracts were then dried over magnesium sulfate

and evaporated. The crude product was puriﬁed by column

chromatography on silica gel.

3.5.2. 3-(tert-Butylcarbonylamino)-2-methoxy-isonico-

tinic acid (2). Metallation of N-(2-methoxy-3-pyridyl)-

2,2-dimethylpropanamide (10 g, 48 mmol) according to the

procedure A with n-BuLi 2.5 M (2.5 equiv., 48 mL),

TMEDA (2.5 equiv., 18.13 mL) in anhydrous diethyl ether

(300 mL) at T¼210 8C gave 8.41 g (69%) of 2 as a

colorless solid, mp 39–40 8C; ¹H NMR (CDCl₃): d 1.25 (s,

9H, tert-butyl); 3.96 (s, 3H, OMe); 7.19 (d, J_5–6¼5.6 Hz,

1H, H₅); 7.98 (d, J¼5.6 Hz, 1H, H₆); 7.89 (s, 1H, NH); ¹³

C

NMR (CDCl₃): d 27.5 (3 Me_tert-butyl); 39.8 (CMe₃); 54.8

(OMe); 116.7 (CH); 119.8 (C_py); 133.4 (C_py); 142.9 (CH);

157.4 (C_py); 167.5 (CO); 177.9 (CO). Anal. Calcd for

C₁₂H₁₆N₂O₄(252.27): C, 57.13; H, 6.39; N, 11.10. Found:

C, 56.98; H, 6.09; N, 11.51.

3.4. Procedure D for metallation of 2-tert-butylpyrido-

pyrimidin-4(3H)-ones by lithium 2,2,6,6-tetramethyl-

piperidide

3.5.3. 2-(tert-Butylcarbonylamino)-5-chloronicotinic

acid (3). Metallation of N-(5-chloro-2-pyridyl)-2,2-

dimethylpropanamide (10 g, 47 mmol) according to the

procedure A with tert-BuLi 1.5 M (2.25 equiv., 48 mL) in

anhydrous THF (150 mL) at T¼278 8C gave 11.35 g (94%)

of 3 as a white solid mp 238–239 8C; ¹H NMR (DMSO): d

1.52 (s, 9H, tert-butyl); 8.14 (d, J¼2.8 Hz, 1H, H₄); 8.35 (d,

J¼2.8 Hz, 1H, H₆); 12.41 (s, 1H, NH); ¹³C NMR (DMSO):

d 27.3 (Me_tert-butyl); 39.7 (CMe₃); 67.3 (CCl); 120.6 (C_py);

A solution of n-butyllithium (1.6 or 2.5 M in hexane) was

added to cold (278 8C), stirred and anhydrous mixture of

THF (15 mL) and 2,2,6,6-tetramethylpiperidine (TMPH)

under an atmosphere of dry nitrogen. The mixture was

warmed to 0 8C and after 30 min, the mixture temperature

was cooled to 278 8C and added to a cold (278 8C) solution

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

4115

124.7 (C_py); 138.8 (CH); 148.1 (CH); 150.8 (C_py); 166.8

(CO); 175.7 (CO). Anal. Calcd for C₁₁H₁₃N₂O₃Cl (256.69):

C, 51.47; H, 5.10; N, 10.91. Found: C, 51.38; H, 5.07; N,

11.03.

hydroxyde (100 mL) gave 5.93 g (93%) of 9 as a colorless

1

solid, mp.250 8C; H NMR (CDCl₃): d 1.44 (s, 9H, tert-

butyl), 4.07 (s, 3H, OMe); 7.54 (d, J_5–6¼5.3 Hz, 1H, H₅);

8.08 (d, J¼5.3 Hz, 1H, H₆); 11.15 (s, 1H, NH); ¹³C NMR

(CDCl₃): d 28.6 (3Me_tert-butyl); 38.2 (CMe₃); 55.0 (OMe);

111.7 (CH_py); 127.5 (C_py); 134.8 (C_py); 142.7 (CH_py); 160.4

(C_py); 162.8 (C_py); 163.8 (C_py). Anal. Calcd for C₁₂H₁₅N₃O₂

(233.27): C, 61.79; H, 6.48; N, 18.01. Found: C, 61.82; H,

6.65; N, 18.31.

3.5.4. 2-tert-Butyl-6-chloropyrido[2,3-d]pyrimidin-4(3H)-

one (5). Reaction of 2-(tert-butyl-carbonylamino)-5-chloro-

nicotinic acid (3 g) with acetic anhydride (30 mL) according

to the procedure B, followed by reaction with 15 N

ammonia (100 mL) gave 2.286 g (82%) of 5 as a colorless

1

solid, mp.250 8C; H NMR (DMSO): d 1.39 (s, 9H, tert-

3.5.9. 2-tert-Butylpyrido[4,3-d]pyrimidin-4(3H)-one (10).

Reaction of 4-(tert-butylcarbonyl-amino)nicotinic acid

(6.44 g) with acetic anhydride (100 mL) according to the

procedure B, followed by reaction with 15 N ammonia

(100 mL) gave 5.155 g (87%) of 10 as a colorless solid, mp

butyl); 8.47 (d, J_5–7¼2.6 Hz, 1H, H₅); 8.94 (d, J¼2.6 Hz,

1H, H₇); 12.38 (s, 1H, NH); ¹³C NMR (DMSO): d 27.9

(3Me_tert-butyl); 38.0 (CMe₃); 116.7 (C_py); 128.4 (C_py); 134.2

(CH_py); 154.6 (CH_py); 156.9 (C_py); 162.5 (C_py); 167.0 (C_py).

Anal. Calcd for C₁₁H₁₂N₃OCl (237.69): C, 55.59; H, 5.09;

N, 17.68. Found: C, 55.71; H, 5.04; N, 17.73.

1

248–249 8C; H NMR (DMSO): d 1.13 (s, 9H, tert-butyl);

7.30 (d, J_7–8¼5.65 Hz, 1H, H₈); 8.56 (d, J¼5.65 Hz, 1H,

H₇); 9.02 (s, 1H, H₅); 12.03 (s, 1H, NH); ¹³C NMR

(DMSO): d 27.9 (3Me_tert-butyl); 38.0 (CMe₃); 116.7 (C_py);

120.9 (CH_py); 149.6 (CH_py); 153.6 (CH_py); 161.9 (C_py);

168.2 (C_py). Anal. Calcd for C₁₁H₁₃N₃O (203.24): C, 65.01;

H, 6.45; N, 20.67. Found: C, 65.11; H, 6.43; N, 20.64.

3.5.5. 2-tert-Butylpyrido[3,4-d]pyrimidin-4(3H)-one (6).

Reaction of 3-(tert-butylcarbonyl-amino)isonicotinic acid

(2.8 g) with acetic anhydride (30 mL) according to the

procedure B, followed by reaction with 15 N ammonia

(30 mL) gave 1.61 g (63%) of 6 as a colorless solid, mp

1

208–209 8C; H NMR (CDCl₃): d 1.43 (s, 9H, tert-butyl);

3.5.10. 2-tert-Butylpyrido[3,2-d]pyrimidin-4(3H)-one

(11). A solution of 3-aminopicolinic acid (1.50 g) and

pivaloyl chloride (3.27 mL, 2.5 equiv.) in pyridine (10 mL)

was reﬂuxed for 30 min. The mixture was cooled to 10 8C,

diluted with water and extracted with dichloromethane

(3£25 mL). The combined organic extracts were then dried

over magnesium sulfate and evaporated under reduced

pressure to give crude pyrido-oxazinone. Then, 15 N

ammonia (50 mL) was added and the mixture was stirred

at room temperature for 24 h. Evaporation of the solution or

suspension under reduced pressure yielded 1.71 g (78%) of

11 as a brown solid, mp 250–251 8C; ¹H NMR (DMSO): d

7.96 (dd, J_6–5¼5.3 Hz, J_6–8¼0.76 Hz, 1H, H₆); 8.61 (d,

J¼5.3 Hz, 1H, H₅); 9.10 (d, J¼0.76 Hz, 1H, H₈); 11.10 (s,

1H, NH); ¹³C NMIR (CDCl₃): d 28.5 (3Me_tert-butyl); 38.1

(CMe₃); 118.3 (CH_py); 125.8 (C_py); 144.0 (C_py); 146.3

(CH_py); 152.0 (CH_py); 163.1 (C_py); 164.5 (C_py). Anal. Calcd

for C₁₁H₁₃N₃O (203.24): C, 65.01; H, 6.45; N, 20.67.

Found: C, 64.98; H, 6.44; N, 20.20.

3.5.6. 2-tert-Butyl-6-chloropyrido[3,4-d]pyrimidin-

4(3H)-one (7). Reaction of 3-(tert-butyl-carbonylamino)-

6-chloro-isonicotinic acid (8 g) with acetic anhydride

(80 mL) according to the procedure B, followed by reaction

with 15 N ammonia (150 mL) gave 6.72 g (90%) of 7 as a

brown solid, mp 237–238 8C; ¹H NMR (CDCl₃): d 1.43 (s,

9H, tert-butyl); 7.98 (s, 1H, H₅); 8.87 (s, 1H, H₈); 11.19 (s,

1H, NH); ¹³C NMR (CDCl₃): d 28.5 (3Me_tert-butyl); 38.2

(CMe₃); 118.9 (CH_py); 128.2 (C_py); 143.0 (C_py); 147.8

(C_py); 152.0 (CH_py); 162.2 (C_py); 164.7 (C_py). Anal. Calcd

for C₁₁H₁₂N₃O₂Cl (237.68): C, 55.59; H, 5.09; N, 17.68.

Found: C, 55.53; H, 5.37; N, 17.72.

1.42 (s, 9H, tert-butyl); 7.83 (dd, J_6–7¼4.5 Hz, J_7–8

¼

8.3 Hz, 1H, H₇); 8.09 (dd, J_8–6¼1.5 Hz, J¼8.3 Hz, 1H, H₈);

8.81 (dd, J¼4.5, 1.5 Hz, 1H, H₆); 12.24 (s, 1H, NH); ¹³C

NMR (DMSO): d 28.1 (3Me_tert-butyl); 37.6 (CMe₃); 129.0

(CH_py); 135.9 (CH_py); 137.9 (C_py); 145.3 (C_py); 149.1

(CH_py); 161.1 (C_py); 163.8 (C_py). Anal. Calcd for

C₁₁H₁₃N₃O (203.24): C, 65.01; H, 6.45; N, 20.67. Found:

C, 64.87; H, 6.44; N, 20.82.

3.6. Metallation of 2-tert-butylpyrido[3,4-d]pyrimidin-

4(3H)-one (6)

3.5.7. 2-tert-Butyl-6-methoxypyrido[3,4-d]pyrimidin-

4(3H)-one (8). Reaction of 3-(tert-butyl-carbonylamino)-

6-methoxy-isonicotinic acid (2.42 g) with acetic anhydride

(30 mL) according to the procedure B, followed by reaction

with 15 N ammonia (30 mL) gave 1.43 g (65%) 8 as a

According to the procedure C with n-BuLi 1.6 M (4 equiv.,

0.63 mL), T¼278 8C followed by reaction with diphenyl-

disulﬁde (4 equiv., 215 mg) gave after puriﬁcation by

column chromatography (silicagel, eluent: (1) dichloro-

methane, (2) diethyl ether) 11 mg (18%) of 8-n-butyl-2-tert-

butylpyrido[3,4-d]pyrimidin-4(3H)-one (12), 10 mg (17%)

of 6-n-butyl-2-tert-butylpyrido[3,4-d]pyrimidin-4(3H)-one

(13) and 51 mg (56%) of 8-n-butyl-2-tert-butyl-5-phenyl-

thiopyrido[3,4-d]pyrimidin-4(3H)-one (14).

1

colorless solid, mp 248–249 8C; H NMR (CDCl₃): d 1.39

(s, 9H, tert-butyl); 3.96 (s, 3H, OMe); 7.37 (s, 1H, H₅); 8.70

(s, 1H, H₈); 10.49 (s, 1H, NH); ¹³C NMR (CDCl₃): d 28.5

(3Me_tert-butyl); 37.7 (CMe₃); 54.7 (OMe); 103.3 (CH_py);

129.3 (C_py); 138.8 (C_py); 149.2 (CH_py); 160.7 (C_py); 162.6

(C_py); 162.8 (C_py). Anal. Calcd for C₁₂H₁₅N₃O₂(233.27): C,

61.79; H, 6.48; N, 18.01. Found: C, 61.67; H, 6.72; N, 17.79.

3.6.1. 8-n-Butyl-2-tert-butylpyrido[3,4-d]pyrimidin-

1

4(3H)-one (12). Light brown solid, mp 120–121 8C; H

NMR (CDCl₃): d 0.90 (t, J¼7.3 Hz, 3H, Me); 1.37 (m, 2H,

CH₂); 1.40 (s, 9H, tert-butyl); 1.68 (m, 2H, CH₂); 3.23 (t,

J¼7.6 Hz, 2H, CH₂); 7.80 (d, J_5–6¼5.5 Hz, 1H, H₅); 8.48

(d, J¼5.5 Hz, 1H, H₆); 10.53 (s, 1H, NH); ¹³C NMR

3.5.8. 2-tert-Butyl-8-methoxypyrido[3,4-d]pyrimidin-

4(3H)-one (9). Reaction of 3-(tert-butyl-carbonylamino)-

2-methoxy-isonicotinic acid (6.8 g) with acetic anhydride

(80 mL) according to the procedure B, followed by reaction

with 15 N ammonia (150 mL) and 5% aqueous sodium

4116

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

(CDCl₃): d 14.3 (Me); 23.1 (CH₂); 28.5 (3Me_tert-butyl); 31.9

(CH₂); 33.7 (CH₂); 38.2 (CMe₃); 116.3 (CH_py); 125.6 (C_py);

134.1 (C_py); 145.0 (CH_py); 162.7 (C_py); 163.6 (C_py); 163.9

(C_py). Anal. Calcd for C₁₅H₂₁N₃O (259.35): C, 69.47; H,

8.16; N, 16.20. Found: C, 69.53; H, 8.11; N, 16.28.

142.1 (C_py); 152.1 (C_py); 163.4 (C_py); 164.3 (C_py). Anal.

Calcd for C₂₃H₂₁N₃OS (387.51): C, 71.29; H, 5.46; N,

10.84; S, 8.27. Found: C, 71.34; H, 5.51; N, 10.90; S, 8.21.

3.7.3. 2-tert-Butyl-5-phenylthiopyrido[3,4-d]pyrimidin-

4(3H)-one (17). Metallation of 6 (100 mg, 0.48 mmol)

according to the procedure D with n-BuLi 1.6 M (8 equiv.,

2.46 mL), TMPH (8 equiv., 0.67 mL), T¼278 8C, followed

by reaction with diphenyl disulﬁde (8 equiv., 860 mg) in

solution with anhydrous THF (5 mL), t¼1 h, gave after

puriﬁcation by column chromatography (silicagel, eluent:

petroleum ether/di ethyl ether , 1:1)) 159 mg (97%) of 12 as

3.6.2. 6-n-Butyl-2-tert-butylpyrido[3,4-d]pyrimidin-

1

4(3H)-one (13). Light brown solid, mp 114–115 8C; H

NMR (CDCl₃): d 0.88 (t, J¼7.3 Hz, 3H, Me); 1.33 (m, 2H,

CH₂); 1.39 (s, 9H, tert-butyl); 1.64 (m, 2H, CH₂); 3.08 (t,

J¼7.7 Hz, 2H, CH₂); 8.18 (s, 1H, H₅); 10.12 (s, 1H, NH);

10.22 (s, 1H, H₆); ¹³C NMR (CDCl₃): d 14.3 (Me); 23.0

(CH₂); 28.5 (3Me_tert-butyl); 30.0 (CH₂); 32.0 (CH₂); 32.9

(CH₂); 38.2 (CMe₃); 111.6 (C_py); 113.2 (C_py); 133.2 (CH_py);

136.3 (CH_py); 151.7 (CH_py); 152.9 (C_py); 162.2 (C_py); 167.4

(C_py). Anal. Calcd for C₁₅H₂₁N₃O (259.35): C, 69.47; H,

8.16; N, 16.20. Found: C, 69.36; H, 8.09; N, 15.98.

1

a yellow solid, mp.250 8C; H NMR (CDCl₃): d 1.46 (s,

9H, tert-butyl); 7.43 (m, 3H, Ph); 7.60 (m, 2H, Ph); 7.68 (s,

1H, H₆); 8.67 (s, 1H, H₈); 11.87 (s, 1H, NH); ¹³C NMR

(CDCl₃): d 28.5 (3Me_tert-butyl); 38.2 (CMe₃); 121.4 (C_py);

130.3 (CH_Ph); 130.5 (C_Ph); 130.6 (2CH_Ph); 136.4 (2CH_Ph);

137.3 (C_py); 142.5 (CH_py); 144.7 (C_py); 146.5 (CH_py); 164.0

(C_py); 165.0 (C_py). Anal. Calcd for C₁₇H₁₇N₃OS (311.40):

C, 65.57; H, 5.50; N, 13.49; S, 10.30. Found: C, 65.33; H,

5.51; N, 13.26; S, 9.98.

3.6.3. 8-n-Butyl-2-tert-butyl-5-phenylthiopyrido[3,4-d]-

pyrimidin-4(3H)-one (14). Colorless solid, mp 160–

1

161 8C; H NMR (CDCl₃): d 0.86 (t, J¼7.3 Hz, 3H, Me);

1.32 (m, 2H, CH₂); 1.45 (s, 9H, tert-butyl); 1.64 (m, 2H,

CH₂); 3.08 (t, J¼7.6 Hz, 2H, CH₂); 7.40 (m, 3H, Ph); 7.58

(m, 2H, Ph); 7.59 (s, 1H, H₆); 11.84 (s, 1H, NH); ¹³C NMR

(CDCl₃): d 14.3 (Me); 23.0 (CH₂); 28.5 (3Me_tert-butyl); 31.6

(CH₂); 33.2 (CH₂); 38.3 (CMe₃); 121.3 (C_py); 130.0 (CH_Ph);

130.4 (2CH_Ph); 131.1 (C_Ph); 134.1 (C_py); 136.4 (2CH_Ph);

141.3 (CH_py); 142.6 (C_py); 158.2 (C_py); 163.3 (C_py); 164.5

(C_py). Anal. Calcd for C₂₁H₂₅N₃OS (367.51): C, 68.63; H,

6.86; N, 11.43; S, 8.73. Found: C, 68.67; H, 6.79; N, 12.01;

S, 8.82.

3.7.4. 2-tert-Butyl-5-(1-hydroxyethyl)pyrido[3,4-d]pyri-

(100 mg,

midin-4(3H)-one (18). Metallation of

6

0.48 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 2.46 mL), TMPH (8 equiv., 0.67 mL),

T¼278 8C, followed by reaction with acetaldehyde

(10 equiv., 0.27 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: petroleum ether/

ethyl acetate, 1:1)) 116 mg (96%) of 18 as a white solid, mp

1

244–245 8C; H NMR (DMSO): d 1.24 (s, 9H, tert-butyl);

1.26 (d, J¼6.4 Hz, 3H, Me); 5.32 (d, J¼4.5 Hz, 1H, OH);

5.83 (dq, J¼5.8, 4.5 Hz, 1H, CHOH); 8.70 (s, 1H, H₆); 8.74

(s, 1H, H₈); 12.02 (s, 1H, NH); ¹³C NMR (DMSO): d 26.3

(Me); 27.9 (3Me_tert-butyl); 37.5 (CMe₃); 64.3 (CHOH); 121.7

(C_py); 141.5 (C_py); 143.3 (CH_py); 143.6 (C_py); 149.5 (CH_py);

162.2 (C_py); 164.9 (C_py). Anal. Calcd for C₁₃H₁₇N₃O

(247.29): C, 63.14; H, 6.93; N, 16.96. Found: C, 62.98; H,

7.07; N, 16.53.

3.7. Metallation of 2-tert-butylpyrido[3,4-d]pyrimidin-

4(3H)-one (6)

According to the procedure C with PhLi 1.8 M (4.2 equiv.,

0.57 mL), T¼0 8C, followed by reaction with diphenyl

disulﬁde (4 equiv., 215 mg) gave after puriﬁcation by

column chromatography (silica, eluent: dichloromethane/

diethylether, 7:3)) 27 mg (40%) of 2-tert-butyl-8-phenyl-

pyrido[3,4-d]pyrimidin-4(3H)-one (15) and 28 mg (29%) of

2-tert-butyl-8-phenyl-5-phenylthio-pyrido[3,4-d]pyrimi-

din-4(3H)-one (16).

3.7.5. 2-tert-Butyl-5-(hydroxyphenylmethyl)pyrido[3,4-d]-

pyrimidin-4(3H)-one (19). Metallation of 6 (50 mg,

0.24 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.33 mL), T¼

278 8C, followed by reaction with benzaldehyde (8 equiv.,

0.27 mL), t¼1 h, gave after puriﬁcation by column chroma-

tography (silicagel, eluent: petroleum ether/ethyl acetate,

1:1)) 73 mg (96%) of 19 as a colorless solid, mp 194–

3.7.1. 2-tert-Butyl-8-phenylpyrido[3,4-d]pyrimidin-

1

4(3H)-one (15). Light brown solid, mp 218–219 8C; H

NMR (CDCl₃): d 1.39 (s, 9H, tert-butyl); 7.39 (m, 3H, Ph);

7.96 (d, J_5–6¼4.9 Hz, 1H, H₅); 8.13 (m, 2H, Ph); 8.68 (d,

J¼4.9 Hz, 1H, H₆); 11.29 (s, 1H, NH); ¹³C NMR (CDCl₃): d

28.5 (3Me_tert-butyl); 38.5 (CMe₃); 117.6 (CH_py); 127.0 (C_py);

128.0 (2CH_Ph); 129.2 (CH_Ph); 131.4 (2CH_Ph); 138.0 (C_Ph);

141.6 (C_py); 145.7 (CH_py); 157.9 (C_py); 163.1 (C_py); 163.6

(C_py). Anal. Calcd for C₁₆H₁₆N₃O (266.33): C, 72.16; H,

6.06; N, 15.78. Found: C, 72.19; H, 6.11; N, 15.81.

1

195 8C; H NMR (CDCl₃): d 1.33 (s, 9H, tert-butyl); 5.49

(d, J¼7.5 Hz, 1H, OH); 6.36 (d, J¼7.5 Hz, 1H, CHOH);

7.22 (m, 5H, Ph); 8.42 (s, 1H, H₆); 9.05 (s, 1H, H₈); 10.70 (s,

1H, NH); ¹³C NMR (CDCl₃): d 28.5 (3Me_tert-butyl); 37.8

(CMe₃); 72.9 (CHOH); 123.2 (C_py); 127.0 (2CH_Ph); 127.8

(CH_Ph); 128.6 (2CH_Ph); 136.5 (C_Ph); 142.5 (C_py); 145.5

(C_py); 146.7 (CH_py); 152.5 (CH_py); 164.1 (C_py); 164.3 (C_py).

Anal. Calcd for C₁₈H₁₉N₃O₂(309.36): C, 69.88; H, 6.19; N,

13.58. Found: C, 69.79; H, 6.18; N, 13.68.

3.7.2. 2-tert-Butyl-8-phenyl-5-phenylthiopyrido[3,4-d]-

pyrimidin-4(3H)-one (16). Colorless solid, mp.250 8C;

¹H NMR (CDCl₃): d 1.44 (s, 9H, tert-butyl); 7.38 (m, 6H,

Ph); 7.63 (m, 2H, Ph); 7.80 (s, 1H, H₆); 8.05 (m, 2H, Ph);

11.63 (s, 1H, NH); ¹³C NMR (CDCl₃): d 28.6 (3Me_tert-butyl);

38.6 (CMe₃); 122.4 (C_py); 127.9 (2CH_Ph); 128.8 (CH_Ph);

130.2 (CH_Ph); 130.6 (2CH_Ph); 130.8 (C_Ph); 131.0 (2CH_Ph);

136.2 (C_py); 136.4 (2CH_Ph); 138.0 (C_Ph); 142.0 (CH_py);

3.7.6. 2-tert-Butyl-5,N₃-bis(tributylstannyl)pyrido[3,4-d]-

pyrimidin-4(3H)-one (20). Metallation of 6 (100 mg,

0.48 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 2.46 mL), TMPH (8 equiv., 0.67 mL),

T¼278 8C, followed by reaction with tri-n-butylstannyl

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

4117

chloride (8 equiv., 1.08 mL), t¼1 h, gave after puriﬁcation

by column chromatography (silicagel, eluent: ethyl acetate)

372 mg (97%) of 20 as a colorless solid, mp 108–109 8C;

¹H NMR (CDCl₃): d 0.80 (m, 18H, 6Me); 1.19 (m, 24H,

12CH₂); 1.37 (s, 9H, tert-butyl); 1.69 (m, 12H, 6CH₂); 8.62

(t, J_H6–Sn¼10.7 Hz, 1H, H₆); 8.97 (t, J_H8–Sn¼3.7 Hz, 1H,

H₈); ¹³C NMR (CDCl₃): d 11.5 (CH₂); 13.9 (Me); 14.0

(Me); 17.3 (CH₂); 27.3 (CH₂); 27.7 (CH₂); 28.2 (CH₂); 28.6

(3Me_tert-butyl); 29.5 (CH₂); 37.8 (CMe₃); 131.0 (C_py); 135.1

(C_py); 144.1 (C_py); 151.3 (CH_py); 153.1 (CH_py); 162.9 (C_py);

163.6 (C_py). Anal. Calcd for C₃₅H₆₅N₃OSn₂(781.34): C,

53.80; H, 8.39; N, 5.38. Found: C, 53.72; H, 8.31; N, 5.59.

1.6 M (8 equiv., 1.05 mL), TMPH (8 equiv., 0.29 mL),

T¼278 8C, followed by reaction with diphenyl disulﬁde

(8 equiv., 367 mg) in solution with anhydrous THF (5 mL),

t¼1 h, gave after puriﬁcation by column chromatography

(silicagel, eluent: dichloromethane/ethyl acetate, 9:1))

1

62 mg (86%) of 24 as a yellow solid, mp 211–212 8C; H

NMR (CDCl₃): d 1.34 (s, 9H, tert-butyl); 7.10 (m, 5H, Pb);

8.82 (s, 1H, H₈); 11.41 (s, 1H, NH); ¹³C NMR (CDCl₃): d

28.3 (3Me_tert-butyl); 38.1 (CMe₃); 126.6 (CH_Ph); 127.7 (C_py);

128.4 (2CH_Ph); 129.3 (C_Ph); 129.4 (2CH_Ph); 136.5 (C_py);

144.8 (C_py); 151.4 (CH_py); 153.5 (C_py); 161.6 (C_py); 165.6

(C_py). Anal. Calcd for C₁₇H₁₆N₃OSCl (345.85): C, 59.04; H,

4.66; N, 12.15; S, 9.27. Found: C, 59.07; H, 4.67; N, 11.97;

S, 9.22.

3.7.7. 2-tert-Butyl-5-iodopyrido[34-d]pyrimidin-4(3H)-

one (21). Metallation of 6 (50 mg, 0.24 mmol) according

to the procedure E with n-BuLi 1.6 M (8 equiv., 1.23 mL),

TMPH (8 equiv., 0.33 mL), T¼278 8C, followed by reac-

tion with iodine (8 equiv., 500 mg) in solution with

anhydrous THF (5 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: dichloro-

methane/diethyl ether, 7:3)) 61 mg (75%) of 21 as a

3.7.11. 2-tert-Butyl-6-chloro-5-(1-hydroxyethyl)pyrido-

7

[3,4-d]pyrimidin-4(3H)-one (25). Metallation of

(50 mg, 0.21 mmol) according to the procedure D with

n-BuLi 1.6 M (8 equiv., 1.05 mL), TMPH (8 equiv.,

0.29 mL), T¼278 8C, followed by reaction with acet-

aldehyde (9 equiv., 0.11 mL), t¼1 h, gave after puriﬁcation

by column chromatography (silicagel, eluent: dichloro-

methane/ethyl acetate, 8:2)) 51 mg (87%) of 25 as a

1

colorless solid, mp.250 8C; H NMR (DMSO): d 1.20 (s,

9H, tert-butyl), 8.71 (s, 1H, H₆), 8.78 (s, 1H, H₈), 12.12 (s,

1H, NH); ¹³C NMR (DMSO): d 27.8 (3Me_tert-butyl), 37.8

(CMe₃), 90.1 (C_py), 125.7 (C_py), 144.9 (C_py), 150.7 (CH_py),

155.2 (CH_py), 160.3 (C_py), 165.2 (C_py). Anal. Calcd for

C₁₁H₁₂N₃OI (329.14): C, 40.14; H, 3.67; N, 12.77. Found:

C, 40.07; H, 3.59; N, 12.85.

1

colorless solid, mp 202–203 8C; H NMR (CDCl₃): d 1.42

(s, 9H, tert-butyl); 1.59 (d, J¼6.8 Hz, 3H, Me); 5.58 (dq,

J¼6.2 Hz, 1H, CHOH); 6.13 (d, J¼12.0 Hz, 1H, OH); 8.83

(s, 1H, H₈); 10.50 (s, 1H, NH); ¹³C NMR (CDCl₃): d 22.4

(Me); 28.5 (3Me_tert-butyl); 37.8 (CMe₃); 68.7 (CHOH); 125.4

(C_py); 137.8 (C_py); 145.5 (C_py); 146.9 (C_py); 151.2 (CH_py);

163.9 (C_py); 164.0 (C_py). Anal. Calcd for C₁₃H₁₆N₃O₂Cl

(281.74): C, 55.42; H, 5.72; N, 14.91. Found: C, 55.41; H,

5.95; N, 14.77.

3.7.8. 2-tert-Butyl-5-chloropyrido[3,4-d]pyrimidin-

4(3H)-one (22). Metallation of 6 (500 mg, 2.46 mmol)

according to the procedure E with n-BuLi 1.6 M (9 equiv.,

13.85 mL), TMPH (9 equiv., 3.74 mL), T¼278 8C, fol-

lowed by reaction with hexachloroethane (9 equiv., 5.25 g)

in solution with anhydrous THF (15 mL), t¼1 h, gave after

ﬁltration 476 mg (82%) of 22 as a colorless solid,

3.7.12. 2-tert-Butyl-6-chloro-5-(hydroxyphenylmethyl)-

pyrido[3,4-d]pyrimidin-4(3H)-one (26). Metallation of 7

(50 mg, 0.21 mmol) according the to procedure D with

n-BuLi 1.6 M (8 equiv., 1.05 mL), TMPH (8 equiv.,

0.29 mL), T¼278 8C, followed by reaction with benzalde-

hyde (8 equiv., 0.17 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: petroleum ether/

ethyl acetate, 5:5)) 70 mg (97%) of 26 as a colorless solid,

1

mp.250 8C; H NMR (DMSO): d 1.45 (s, 9H, tert-butyl);

8.67 (s, 1H, H₆); 8.98 (s, 1H, H₈); 12.40 (s, 1H, NH); ¹³C

NMR (DMSO): d 27.9 (3Me_tert-butyl); 37.7 (CMe₃); 122.8

(C_py); 128.0 (C_py); 145.3 (C_py); 145.9 (CH_py); 149.7 (CH_py);

160.0 (C_py); 166.3 (C_py). Anal. Calcd for C₁₁H₁₂N₃OCl

(237.68): C, 55.59; H, 5.09; N, 17.68. Found: C, 55.41; H,

5.18; N, 17.71.

1

mp 227–228 8C; H NMR (CDCl₃): d 1.28 (s, 9H, tert-

butyl); 6.34 (d, J¼12.0 Hz, 1H, CHOH); 6.64 (d, J¼

12.0 Hz, 1H, OH); 7.19 (m, 5H, Ph); 8.91 (s, 1H, H₈); 9.71

(s, 1H, NH); ¹³C NMR (CDCl₃): d 28.4 (3Me_tert-butyl); 37.7

(CMe₃); 72.9 (CHOH); 125.9 (C_py); 126.2 (2CH_Ph); 127.6

(CH_Ph); 128.6 (2CH_Ph); 135.5 (C_py); 142.1 (CH_Ph); 145.6

(C_py); 148.6 (C_py); 151.9 (CH_py); 162.8 (C_py); 164.1 (C_py).

Anal. Calcd for C₁₈H₁₈N₃O₂Cl (343.81): C, 62.88; H, 5.28;

N, 12.22. Found: C, 62.68; H, 5.36; N, 11.92.

3.7.9. 2-tert-Butyl-6-iodopyrido[3,4-d]pyrimidin-4(3H)-

one (23). Metallation of 6 (50 mg, 0.24 mmol) according

to the procedure D with n-BuLi 1.6 M (8 equiv., 1.23 mL),

TMPH (8 equiv., 0.33 mL), T¼278 8C, followed by

reaction with iodine (2 equiv., 125 mg) in solution with

anhydrous THF (5 mL), t¼2 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: dichloro-

methane/ethyl ether, 5:5)) 45 mg of 23 as a colorless solid

3.7.13. 2-tert-Butyl-5,N₃-bis(tributylstannyl)-6-chloro-

pyrido[3,4-d]pyrimidin-4(3H)-one (27). Metallation of 7

(50 mg, 0.21 mmol) according to the procedure E with

n-BuLi 1.6 M (8 equiv., 1.05 mL), TMPH (8 equiv.,

0.29 mL), T¼278 8C, followed by reaction with tri-n-

butylstannyl chloride (8 equiv., 0.47 mL), t¼1 h, gave after

puriﬁcation by column chromatography (silicagel, eluent:

1

(56%), mp 210–211 8C; H NMR (CDCl₃): d 1.42 (s, 9H,

tert-butyl); 8.34 (s, 1H, H₆); 8.83 (s, 1H, H₈); 11.27 (s, 1H,

NH); ¹³C NMR (CDCl₃): d 28.5 (3Me_tert-butyl); 38.3 (CMe₃);

111.6 (C_py); 127.4 (C_py); 129.4 (CH_py); 143.5 (C_py); 152.7

(CH_py); 161.8 (C_py); 165.2 (C_py). Anal. Calcd for

C₁₁H₁₂N₃OI (329.14): C, 40.14; H, 3.67; N, 12.77. Found:

C, 40.26; H, 3.82; N, 12.13.

1

dichloromethane) 92 mg (84%) of 27 as an oil; H NMR

(CDCl₃): d 0.79 (t, J¼7.1 Hz, 9H, Me); 1.18 (m, 12H, CH₂);

3.7.10. 2-tert-Buyl-6-chloro-5-phenylthiopyrido[3,4-d]-

pyrimidin-4(3H)-one (24). Metallation of 7 (50 mg,

0.21 mmol) according to the procedure E with n-BuLi

1.35 (s, 9H, tert-butyl); 1.44 (m, 6H, CH₂); 8.72 (t, J_H8–Sn

¼

3.0 Hz, 1H, H₈); 8.89 (s, 1H, NH); ¹³C NMR (CDCl₃): d

14.1 (Me); 15.2 (CH₂); 27.7 (CH₂); 28.6 (3Me_tert-butyl); 29.5

4118

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

(CH₂); 37.6 (CMe₃); 134.3 (C_py); 138.3 (C_py); 143.1 (C_py);

151.3 (CH_py); 156.6 (C_py); 162.3 (C_py); 162.6 (C_py). Anal.

Calcd for C₂₃H₃₈N₃OClSn (526.73): C, 52.45; H, 7.27; N,

7.98. Found: C, 52.41; H, 7.26; N, 7.79.

column chromatography (silicagel, eluent: dichloro-

methane/ethyl acetate, 7:3)) 67 mg (91%) of 31 as a

colorless solid, mp.250 8C; H NMR (CDCl₃): d 1.41 (s,

1

9H, tert-butyl); 3.95 (s, 3H, OMe); 5.97 (d, J¼12.4 Hz, 1H,

CHOH); 6.84 (d, J¼12.4 Hz, 1H, OH); 7.18 (m, 5H, Ph);

8.72 (s, 1H, H₈); 10.49 (s, 1H, NH); ¹³C NMR (CDCl₃):

d 28.3 (3Me_tert-butyl); 37.3 (CMe₃); 55.0 (OMe); 68.8

(CHOH); 122.6 (C_Ph); 125.9 (C_py); 126.4 (2CH_Ph); 127.2

(CH_Ph); 128.3 (2CH_Ph); 140.5 (C_py); 143.6 (C_py); 148.9

(CH_py); 159.8 (C_py); 160.5 (C_py); 164.5 (C_py). Anal. Calcd

for C₁₉H₂₁N₃O₃(339.39): C, 67.24; H, 6.24; N, 12.38.

Found: C, 67.28; H, 6.34; N, 12.16.

3.7.14. 2-tert-Butyl-6-chloro-5-iodopyrido[3,4-d]pyrimi-

din-4(3H)-one (28). Metallation of 7 (50 mg, 0.21 mmol)

according to the procedure E with n-BuLi 1.6 M (8 equiv.,

1.05 mL), TMPH (8 equiv., 0.29 mL), T¼278 8C, followed

by reaction with iodine (8 equiv., 427 mg) in solution with

anhydrous THF (5 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: ethyl acetate/

dichloromethane, 1:9)) 66 mg (87%) of 28 as a yellow solid,

1

mp 238–239 8C; H NMR (CDCl₃): d 1.45 (s, 9H, tert-

3.7.18. 2-tert-Butyl-5,N₃-bis(tributylstannyl)-6-methoxy-

pyrido[3,4-d]pyrimidin-4(3H)-one (32). Metallation of 8

(50 mg, 0.21 mmol) according to the procedure D with

n-BuLi 1.6 M (8 equiv., 1.07 mL), TMPH (8 equiv.,

0.29 mL), T¼0 8C, followed by reaction with tri-n-butyl-

stannyl chloride (8 equiv., 0.48 mL), t¼1 h, gave after

puriﬁcation by column chromatography (silicagel, eluent:

diethyl ether/petroleum ether, 5:5)) 130 mg (75%) of 32 as

butyl); 8.74 (s, 1H, H₈); 11.52 (s, 1H, NH); ¹³C NMR

(CDCl₃): d 28.5 (3Me_tert-butyl); 38.3 (CMe₃); 90.9 (C_py);

128.9 (C_py); 143.8 (C_py); 151.1 (C_py); 154.2 (C_py); 161.3

(C_py); 165.0 (C_py). Anal. Calcd for C₁₁H₁₁N₃OClI (363.58):

C, 36.34; H, 3.05; N, 11.56. Found: C, 36.42; H, 2.89; N,

11.05.

1

3.7.15. 2-tert-Butyl-6-methoxy-5-phenylthiopyrido[3,4-d]-

pyrimidin-4(3H)-one (29). Metallation of 8 (50 mg,

0.21 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.07 mL), TMPH (8 equiv., 0.29 mL),

T¼0 8C, followed by reaction with dipheny disulﬁde

(8 equiv., 380 mg) in solution with anhydrous THF

(5 mL), t¼1 h, gave after puriﬁcation by column chroma-

tography (silicagel, eluent: dichloromethane) 52 mg (71%)

of 29 as a yellow solid, mp 210–211 8C; ¹H NMR (CDCl₃):

d 1.35 (s, 9H, tert-butyl); 3.72 (s, 3H, OMe); 7.10 (m, 5H,

Ph); 8.61 (s, 1H, H₈); 10.50 (s, 1H, NH); ¹³C NMR (CDCl₃):

d 28.4 (3Me_tert-butyl); 37.6 (CMe₃); 54.8 (OMe); 114.4 (C_py);

126.3 (CH_Ph); 128.8 (C_Ph); 128.9 (2CH_Ph); 128.9 (2CH_Ph);

137.5 (C_py); 140.4 (C_py); 148.0 (CH_py); 161.1 (C_py); 161.5

(C_py); 162.2 (C_py). Anal. Calcd for C₁₈H₁₉N₃O₂S (341.43):

C, 63.32; H, 5.61; N, 12.31; S, 9.39. Found: C, 63.21; H,

5.84; N, 12.35; S, 9.47.

an oil; H NMR (CDCl₃): d 0.79 (m, 18H, Me); 1.13 (m,

24H, CH₂); 1.32 (s, 9H, tert-butyl); 1.42 (m, 12H, CH₂);

3.87 (s, 3H, OMe); 8.56 (t, J_H8–Sn¼3.03–3.39 Hz, 1H, H₈);

¹³C NMR (CDCl₃): d 13.6 (CH₂); 14.2 (Me); 27.8 (CH₂);

28.7 (3Me_tert-butyl); 29.7 (CH₂); 37.3 (CMe₃); 54.2 (OMe);

121.4 (C_py); 135.0 (C_py); 139.4 (C_py); 148.9 (CH_py); 158.7

(C_py); 163.3 (C_py); 167.6 (C_py). Anal. Calcd for

C₄₄H₆₇N₃O₂Sn₂(811.36): C, 53.29; H, 8.32; N, 5.18.

Found: C, 53.61; H, 8.04; N, 5.46.

3.7.19. 2-tert-Butyl-5-iodo-6-methoxypyrido[3,4-d]pyri-

midin-4(3H)-one (33). Metallation of

8

(50 mg,

0.21 mmol) according to the procedure E with n-BuLi

1.6 M (8 equiv., 1.07 mL), TMPH (8 equiv., 0.29 mL),

T¼0 8C, followed by reaction with iodine (8 equiv.,

432 mg) in solution with anhydrous THF (5 mL), t¼1 h,

gave after puriﬁcation by column chromatography (silica-

gel, eluent: dichloromethane/diethyl ether, 9:1)) 67 mg

(88%) of 33 as a yellow solid, mp.250 8C; ¹H NMR

(DMSO): d 1.39 (s, 9H, tert-butyl); 4.02 (s, 3H, OMe); 8.86

(s, 1H, H₈); 12.06 (s, 1H, NH); ¹³C NMR (DMSO): d 27.8

(3Me_tert-butyl); 37.4 (CMe₃); 55.7 (OMe); 75.6 (C_py); 129.1

(C_py); 139.6 (C_py); 147.5 (CH_py); 160.5 (C_py); 160.6 (C_py);

161.7 (C_py). Anal. Calcd for C₁₂H₁₄N₃O₂I (359.16):

C, 40.13; H, 3.93; N, 11.70. Found: C, 40.10; H, 4.02; N,

11.52.

3.7.16. 2-tert-Butyl-5-(1-hydroxyethyl)-6-methoxypyrido-

[3,4-d]pyrimidin-4(3H)-one (30). Metallation of 8 (50 mg,

0.21 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.07 mL), TMPH (8 equiv., 0.29 mL),

T¼0 8C, followed by reaction with acetaldehyde

(10 equiv., 0.10 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: petroleum ether/

diethyl ether, 3:7)) 54 mg (92%) of 30 as a colorless solid,

1

mp 227–228 8C; H NMR (CDCl₃): d 1.41 (s, 9H, tert-

butyl); 1.53 (d, J¼6.4 Hz, 3H, Me); 4.00 (s, 3H, OMe); 5.63

(d, J¼12.4 Hz, 1H, OH); 5.77 (dq, J¼5.9 Hz, 1H, CHOH);

8.66 (s, 1H, H₈); 11.14 (s, 1H, NH); ¹³C NMR (CDCl₃): d

23.4 (Me); 28.5 (3Me_tert-butyl); 37.5 (CMe₃); 54.8 (OMe);

64.5 (CHOH); 125.1 (C_py); 125.3 (C_py); 140.4 (C_py); 148.1

(CH_py); 159.0 (C_py); 160.3 (C_py); 165.3 (C_py). Anal. Calcd

for C₁₄H₁₉N₃O₃(277.32): C, 60.63; H, 6.91; N, 15.15.

Found: C, 60.59; H, 7.12; N, 14.98.

3.7.20. 2-tert-Butyl-8-methoxy-5-phenylthiopyrido[3,4-d]-

pyrimidin-4(3H)-one (34). Metallation of 9 (50 mg,

0.21 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.07 mL), TMPH (8 equiv., 0.29 mL),

T¼220 8C, followed by reaction with diphenyl disulﬁde

(8 equiv., 380 mg) in solution with anhydrous THF (5 mL),

t¼1 h, gave after puriﬁcation by column chromatography

(silicagel, eluent: ethyl acetate/petroleum ether, 5:5)) 65 mg

1

(89%) of 34 as a yellow solid, mp 249–250 8C; H NMR

3.7.17. 2-tert-Butyl-5-(hydroxyphenylmethyl)-6-methoxy-

pyrido[3,4-d]pyrimidin-4(3H)-one (31). Metallation of 8

(50 mg, 0.21 mmol) according to the procedure D with

n-BuLi 1.6 M (8 equiv., 1.07 mL), TMPH (8 equiv.,

0.29 mL), T¼0 8C, followed by reaction with benzaldehyde

(8 equiv., 0.18 mL), t¼1 h, gave after puriﬁcation by

(CDCl₃): d 1.47 (s, 9H, tert-butyl); 3.95 (s, 3H, OMe); 7.25

(s, 1H, H₆); 7.38 (m, 3H, Ph); 7.53 (m, 2H, Ph); 11.98 (s, 1H,

NH); ¹³C NMR (CDCl₃): d 28.5 (3Me_tert-butyl); 38.3 (CMe₃);

54.9 (OMe); 123.8 (C_py); 127.1 (C_Ph); 129.5 (CH_Ph); 128.9

(2CH_Ph); 132.1 (C_py); 135.4 (C_py); 135.6 (2CH_Ph); 139.4

(CH_py); 157.8 (C_py); 163.7 (C_py); 164.7 (C_py). Anal. Calcd

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

4119

for C₁₈H₁₉N₃O₂S (341.43): C, 63.32; H, 5.61; N, 12.31; S,

9.39. Found: C, 62.99; H, 5.68; N, 12.61; S, 9.46.

gave after puriﬁcation by column chromatography (silica-

gel, eluent: dichloromethane/ethyl acetate, 5:5)) 62 mg

(80%) of 38 as a colorless solid, mp.250 8C; H NMR

1

3.7.21. 2-tert-Butyl-5-(1-hydroxyethyl)-8-methoxypyrido-

[3,4-d]pyrimidin-4(3H)-one (35). Metallation of 9 (50 mg,

0.21 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.07 mL), TMPH (8 equiv., 0.29 mL),

T¼220 8C, followed by reaction with acetaldehyde

(10 equiv., 0.10 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: ethyl acetate)

(DMSO): d 1.47 (s, 9H, tert-butyl); 4.03 (s, 3H, OMe);

8.44 (s, 1H, H₈); 11.78 (s, 1H, NH); ¹³C NMR (DMSO): d

28.6 (3Me_tert-butyl); 38.5 (CMe₃); 55.3 (OMe); 76.2 (C_py);

125.7 (C_py); 136.7 (C_py); 152.0 (CH_py); 161.1 (C_py); 161.8

(C_py); 164.3 (C_py). Anal. Calcd for C₁₂H₁₄N₃O₂I (359.16):

C, 40.13; H, 3.93; N, 11.70. Found: C, 40.09; H, 4.09; N,

11.64.

1

53 mg (90%) of 35 as a colorless solid, mp.250 8C; H

NMR (CDCl₃): d 1.44 (s, 9H, tert-butyl); 1.57 (d, J¼6.4 Hz,

3H, Me); 4.06 (s, 3H, OMe); 4.91 (d, J¼7.9 Hz, 1H, OH);

5.22 (dq, J¼6.9 Hz, 1H, CHOH); 8.09 (s, 1H, H₆); 10.52

(s, 1H, NH); ¹³C NMR (CDCl₃): d 23.4 (Me); 28.6

(3Me_tert-butyl); 37.9 (CMe₃); 55.1 (OMe); 67.6 (CHOH);

124.8 (C_py); 130.9 (C_py); 136.3 (C_py); 141.1 (CH_py); 160.3

(C_py); 163.2 (C_py); 163.5 (C_py). Anal. Calcd for C₁₄H₁₉N₃O₃

(277.32): C, 60.63; H, 6.91; N, 15.15. Found: C, 60.32; H,

7.03; N, 14.96.

3.8. Metallation of 2-tert-Butyl-5-chloropyrido[3,4-d]-

pyrimidin-4(3H)-one (22)

The titled compound (50 mg, 0.21 mmol) according to the

procedure D with n-BuLi 1.6 M (8 equiv., 1.05 mL), TMPH

(8 equiv., 0.29 mL), T¼220 8C, followed by reaction with

benzaldehyde (8 equiv., 0.17 mL), t¼1 h, gave after puri-

ﬁcation by preparative chromatography (C₁₈column (5 mm,

10£250 mm), eluent (4 mL/min): MeOH/water (55:45), UV

detection (245 nm)), 25 mg (35%) of 2-tert-butyl-5-chloro-

6-(hydroxyphenylmethyl)pyrido[3,4-d]pyrimidin-4(3H)-

one 39 and 25 mg (35%) of 2-tert-butyl-5-chloro-8-(hydroxy-

phenylmethyl)pyrido[3,4-d]pyrimidin-4(3H)-one 40.

3.7.22. 2-tert-Butyl-5-(hydroxyphenylmethyl)-8-methoxy-

pyrido[3,4-d]pyrimidin-4(3H)-one (36). Metallation of 9

(50 mg, 0.21 mmol) according to the procedure D with

n-BuLi 1.6 M (8 equiv., 1.07 mL), TMPH (8 equiv.,

0.29 mL), T¼220 8C, followed by reaction with benz-

aldehyde (8 equiv., 0.18 mL), t¼1 h, gave after puriﬁcation

by column chromatography (silicagel, eluent: ethyl acetate)

3.8.1. 2-tert-Butyl-5-chloro-6-(hydroxyphenylmethyl)-

pyrido[3,4-d]pyrimidin-4(3H)-one (39).

A

colorless

1

solid, mp 227–228 8C; H NMR (CDCl₃): d 1.39 (s, 9H,

tert-butyl); 4.99 (d, J¼7.1 Hz, 1H, OH); 6.15 (d, J¼7.1 Hz,

1H, CHOH); 7.24 (m, 5H, Ph); 8.97 (s, 1H, H₈); 11.13 (s,

1H, NH); ¹³C NMR (CDCl₃): d 28.4 (3Me_tert-butyl); 38.1

(CMe₃); 72.2 (CHOH); 123.6 (C_py); 127.0 (C_Ph); 127.7

(2CH_Ph); 128.2 (CH_Ph); 128.8 (2CH_Ph); 142.0 (C_py); 145.5

(C_py); 148.5 (CH_py); 155.0 (C_py); 161.5 (C_py); 165.5 (C_py).

Anal. Calcd for C₁₈H₁₈N₃O₂Cl (343.81): C, 62.88; H, 5.28;

N, 12.22. Found: C, 62.83; H, 5.44; N, 12.36.

1

61 mg (85%) of 36 as a colorless solid, mp.250 8C; H

NMR (CDCl₃): d 1.36 (s, 9H, tert-butyl); 4.05 (s, 3H, OMe);

5.44 (d, J¼8.7 Hz, 1H, CHOH); 6.13 (d, J¼8.6 Hz, 1H,

OH); 7.26 (m, 5H, Ph); 7.84 (s, 1H, H₆); 9.82 (s, 1H, NH);

¹³C NMR (CDCl₃): d 28.6 (3Me_tert-butyl); 37.9 (CMe₃); 55.1

(OMe); 73.1 (CHOH); 122.6 (C_py); 125.9 (C_py); 126.8

(2CH_Ph); 127.5 (CH_Ph); 128.5 (2CH_Ph); 129.2 (C_Ph); 140.5

(C_py); 143.0 (C_py); 143.4 (CH_py); 163.4 (C_py); 167.7 (C_py).

Anal. Calcd for C₁₉H₂₁N₃O₃(339.39): C, 67.24; H, 6.24; N,

12.38. Found: C, 67.19; H, 6.39; N, 12.45.

3.8.2. 2-tert-Butyl-5-chloro-8-(hydroxyphenylmethyl)-

pyrido[3,4-d]pyrimidin-4(3H)-one (40).

A

colorless

1

3.7.23. 2-tert-Butyl-5,N₃-bis(tributylstannyl)-8-mehoxy-

pyrido[3,4-d]pyrimidin-4(3H)-one (37). Metallation of 9

(50 mg, 0.21 mmol) according to the procedure D with

n-BuLi 1.6 M (8 equiv., 1.07 mL), TMPH (8 equiv.,

0.29 mL), T¼220 8C, followed by reaction with tri-n-

butylstannyl chloride (8 equiv., 0.48 mL), t¼1 h, gave after

puriﬁcation by column chromatography (silicagel, eluent:

diethyl ether) 130 mg (75%) of 37 as an oil; ¹H NMR

(CDCl₃): d 0.80 (m, 18H, Me); 1.07 (m, 24H, CH₂); 1.29 (s,

9H, tert-butyl); 1.48 (m, 12H, CH₂); 4.04 (s, 3H, OMe); 8.09

(t, J_H6–Sn¼11.7 Hz, 1H, H₆); ¹³C NMR (CDCl₃): d 11.5

(CH₂); 13.9 (Me); 14.1 (Me); 17.8 (CH₂); 27.2 (CH2); 27.7

(CH2); 28.2 (CH2); 28.7 (3Me_tert-butyl); 29.6 (CH₂); 37.8

(CMe₃); 54.8 (OMe); 125.0 (C_py); 132.2 (C_py); 135.1 (C_py);

149.8 (CH_py); 160.8 (C_py); 161.8 (C_py); 163.1 (C_py). Anal.

Calcd for C₄₄H₆₇N₃O₂Sn₂(811.36): C, 53.29; H, 8.32; N,

5.18. Found: C, 53.55; H, 8.43; N, 5.20.

solid, mp 250–251 8C; H NMR (DMSO): d 1.42 (s, 9H,

tert-butyl); 6.17 (s, 1H, OH); 6.66 (d, J¼6.0 Hz, 1H,

CHOH); 7.37 (2m, 5H, Ph); 8.57 (s, 1H, H₆); 12.39 (s, 1H,

NH); ¹³C NMR (DMSO): d 28.1 (3Me_tert-butyl); 38.0

(CMe₃); 70.9 (CHOH); 122.6 (C_py); 126.7 (C_Ph); 126.8

(2CH_Ph); 127.0 (CH_py); 127.1 (CH_Ph); 128.2 (2CH_Ph); 142.2

(C_py); 143.2 (C_py); 144.0 (C_py); 155.7 (C_py); 159.9 (C_py).

Anal. Calcd for C₁₈H₁₈N₃O₂Cl (343.81): C, 62.88; H, 5.28;

N, 12.22. Found: C, 62.95; H, 5.43; N, 12.35.

3.8.3. 2-tert-Butyl-5-(1-hydroxyethyl)pyrido[2,3-d]pyri-

(50 mg,

midin-4(3H)-one (41). Metallation of

4

0.24 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL),

T¼0 8C, followed by reaction with acetaldehyde (8 equiv.,

0.11 mL), t¼1 h, gave after puriﬁcation by column chroma-

tography (silicagel, eluent: ethyl acetate) 57 mg (95%) of 41

as a colorless solid, mp.250 8C; ¹H NMR (CDCl₃): d 1.46

(s, 9H, tert-butyl); 1.55 (d, J¼6.6 Hz, 3H, Me); 4.39 (s, 1H,

3.7.24. 2-tert-Butyl-5-iodo-8-methoxypyrido[3,4-d]pyri-

midin-4(3H)-one (38). Metallation of

9

(50 mg,

OH); 5.83 (dq, J¼6.6 Hz, 1H, CHOH); 7.49 (d, J_6–7¼

0.21 mmol) according to the procedure E with n-BuLi

1.6 M (8 equiv., 1.07 mL), TMPH (8 equiv., 0.29 mL),

T¼220 8C, followed by reaction with iodine (8 equiv.,

432 mg) in solution with anhydrous THF (5 mL), t¼1 h,

4.9 Hz, 1H, H₆); 8.87 (d, J¼4.9 Hz, 1H, H₇); 11.17 (s, 1H,

NH); ¹³C NMR (CDCl₃): d 23.7 (Me), 28.5 (3Me_tert-butyl);

38.0 (CMe₃); 68.3 (CHOH); 113.0 (C_py); 120.1 (CH_py);

156.8 (CH_py); 158.6 (C_py); 161.0 (C_py); 165.4 (C_py), 165.8

4120

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

(C_py). Anal. Calcd for C₁₃H₁₇N₃O (247.29): C, 63.14; H,

6.93; N, 16.96. Found: C, 62.98; H, 7.07; N, 16.53.

by column chromatography (silicagel, eluent: diethyl ether)

142 mg (74%) of 45 as an oil; ¹H NMR (CDCl₃): d 0.82 (m,

18H, 6Me); 1.17 (m, 24H, 12CH₂); 1.40 (s, 9H, tert-butyl);

3.8.4. 2-tert-Butyl-5-(hydroxyphenylmethyl)pyrido[2,3-d]-

pyrimidin-4(3H)-one (42). Metallation of 4 (50 mg,

0.24 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL),

T¼0 8C, followed by reaction with benzaldehyde

(8 equiv., 0.27 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: diethyl ether/

ethyl acetate, 1:1)) 73 mg (96%) of 42 as a colorless solid,

1.54 (m, 12H, 6CH₂); 7.51 (td, J_6–7¼4.5 Hz, J_H6–Sn¼

8.5 Hz, IH, H₆); 8.74 (q, J¼4.1 Hz, J_H7–Sn¼10.5 Hz, 1H,

H₇); ¹³C NMR (CDCl₃): d 9.10 (CH₂); 14.0 (Me); 14.1

(Me); 17.9 (CH₂); 27.2 (CH₂); 27.7 (CH₂); 28.2 (CH₂); 28.6

(3Me_tert-butyl); 29.5 (CH₂); 37.9 (CMe₃); 121.2 (C_py); 131.3

(CH_py); 154.2 (CH_py); 158.7 (C_py); 159.3 (C_py); 164.6 (C_py);

164.6 (C_py). Anal. Calcd for C₃₅H₆₅N₃OSn₂(781.34): C,

53.80; H, 8.39; N, 5.38. Found: C, 53.67; H, 8.24; N, 5.09.

1

mp 147–148 8C; H NMR (CDCl₃): d 1.38 (s, 9H, tert-

butyl); 5.18 (d, J¼6.8 Hz, 1H, OH); 6.50 (d, J¼6.8 Hz, 1H,

CHOH); 7.20 (d, J_6–7¼4.9 Hz, 1H, H₆); 7.25 (m, 5H, Ph);

8.82 (d, J¼4.9 Hz, 1H, H₇); 10.56 (s, 1H, NH); ¹³C NMR

(CDCl₃): d 28.5 (3Me_tert-butyl); 37.9 (CMe₃); 73.6 (CHOH);

113.6 (C_py); 122.4 (CH_py); 127.3 (2CH_Ph); 128.2 (CH_Ph);

128.8 (2CH_Ph); 141.4 (C_Ph); 156.0 (C_py); 156.7 (CH_py);

161.1 (C_py); 165.1 (C_py); 165.7 (C_py). Anal. Calcd for

C₁₈H₁₉N₃O₂(309.36): C, 69.88; H, 6.19; N, 13.58. Found:

C, 69.72; H, 6.26; N, 13.45.

3.8.8. 2-tert-Butyl-8-(hydroxyphenylmethyl)pyrido[4,3-d]-

pyrimidin-4(3H)-one (46). Metallation of 10 (50 mg,

0.24 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL), T¼

220 8C, followed by reaction with benzaldehyde (8 equiv.,

0.27 mL), t¼1 h, gave after puriﬁcation by column chroma-

tography (silicagel, eluent: (1) dichioromethane/ethyl acetate

(5:5), (2) ethyl acetate) 73 mg (96%) of 46 as a colorless

1

solid, mp 186–187 8C; H NMR (CDCl₃): d 1.40 (s, 9H,

tert-butyl); 5.65 (d, J¼6.8 Hz, 1H, OH); 6.19 (d, J¼6.8 Hz,

1H, CHOH); 7.21 (m, 3H, Ph); 7.37 (m, 2H, Ph); 8.67 (s,

1H, H₇); 9.31 (s, 1H, H₅); 11.81 (s, 1H, NH); ¹³C NMR

(CDCl₃): d 28.4 (3Me_tert-butyl); 38.7 (CMe₃); 73.5 (CHOH);

116.3 (C_py); 126.7 (2CH_Ph); 127.9 (CH_Ph); 128.7 (2CH_Ph);

133.6 (C_Ph); 143.1 (C_py); 149.8 (CH_py); 151.9 (C_py); 152.1

(CH_py); 163.5 (C_py); 167.6 (C_py). Anal. Calcd for

C₁₈H₁₉N₃O₂(309.36): C, 69.88; H, 6.19; N, 13.58. Found:

C, 69.48; H, 6.33; N, 13.49.

3.8.5. 2-tert-Butyl-5-phenylthiopyridol[2,3-d]pyrimidin-

4(3H)-one (43). Metallation of 4 (50 mg, 0.24 mmol)

according to the procedure E with n-BuLi 1.6 M (8 equiv.,

1.23 mL), TMPH (8 equiv., 0.34 mL), T¼0 8C, followed by

reaction with diphenyl disulﬂde (8 equiv., 430 mg) in

solution with anhydrous THF (5 mL), t¼1 h, gave after

puriﬁcation by column chromatography (silicagel, eluent:

(1) dichloromethane, (2) diethyl ether/dichioromethane

(3:7)) 64 mg (84%) of 43 as a yellow solid, mp 249–

1

250 8C; H NMR (CDCl₃): d 1.50 (s, 9H, tert-butyl); 6.43

3.8.9. 2-tert-Butyl-5-(hydroxyphenylmethyl)pyrido[4,3-d]-

pyrimidin-4(3H)-one (47). Metallation of 10 (50 mg,

0.24 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL),

T¼20 8C, followed by reaction with benzaldehyde

(8 equiv., 0.27 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: dichloro-

methane/ethyl acetate (1:1)) 51 mg (67%) of 47 as a

(d, J_6–7¼5.65 Hz, 1H, H₆); 7.48 (m, 3H, Ph); 7.55 (m, 2H,

Ph); 8.36 (d, J¼5.65 Hz, 1H, H₇); 11.83 (s, 1H, NH); ¹³C

NMR (CDCl₃): d 28.6 (3Me_tert-butyl); 38.3 (CMe₃); 112.2

(C_py); 118.3 (CH_py); 130.4 (C_Ph); 130.7 (CH_Ph); 130.7

(2CH_Ph); 136.4 (2CH_Ph); 154.1 (CH_py); 157.5 (C_py); 160.5

(C_py); 165.1 (C_py); 166.6 (C_py). Anal. Calcd for

C₁₇H₁₇N₃OS (311.40): C, 65.57; H, 5.50; N, 13.49; S,

10.30. Found: C, 65.48; H, 5.72; N, 13.21; S, 10.46.

1

colorless solid, mp 183–184 8C; H NMR (CDCl₃): d 1.32

(s, 9H, tert-butyl); 5.62 (d, J¼8.7 Hz, 1H, OH); 6.84 (d,

3.8.6. 2-tert-Butyl-5-iodopyrido[2,3-d]pyrimidin-4(3H)-

one (44). Metallation of 4 (50 mg, 0.24 mmol) according

to the procedure D with n-BuLi 1.6 M (8 equiv., 1.23 mL),

TMPH (8 equiv., 0.34 mL), T¼0 8C, followed by reaction

with iodine (8 equiv., 500 mg) in solution with anhydrous

THF (5 mL), t¼1 h, gave after puriﬁcation by column

chromatography (silicagel, eluent: (1) diethyl ether, (2)

ethyl acetate/diethyl ether (1:1)) 60 mg (75%) of 44 as a

J¼8.7 Hz, 1H, CHOH); 7.18 (m, 5H, Ph); 7.45 (d, J_7–8¼

5.65 Hz, 1H, H₈); 8.70 (d, J¼5.65 Hz, 1H, H₇); 10.86 (s, 1H,

NH); ¹³C NMR (CDCl₃): d 28.4 (3Me_tert-butyl); 38.1 (CMe₃);

73.4 (CHOH); 113.8 (C_py); 121.6 (CH_py); 127.7 (2CH_Ph);

127.7 (CH_Ph); 128.5 (2CH_Ph); 143.5 (C_Ph); 151.4 (CH_py);

156.8 (C_py); 162.9 (C_py); 164.2 (C_py); 167.5 (C_py). Anal.

Calcd for C₁₈H₁₉N₃O₂(309.36): C, 69.88; H, 6.19; N,

13.58. Found: C, 69.67; H, 6.24; N, 13.34.

1

colorless solid, mp 200–201 8C; H NMR (CDCl₃): d 1.49

(s, 9H, tert-butyl); 7.95 (d, J_6–7¼4.9 Hz, 1H, H₆); 8.35 (d,

J¼4.9 Hz, 1H, H₇); 11.65 (s, 1H, NH); ¹³C NMR (CDCl₃): d

27.1 (3Me_tert-butyl); 37.1 (CMe₃); 104.4 (C_py); 114.9 (C_py);

134.9 (CH_py);153.7 (CH_py); 158.2 (C_py); 161.8 (C_py); 165.1

(C_py). Anal. Calcd for C₁₁H₁₂N₃OI, (329.14): C, 40.14; H,

3.67; N, 12.77. Found: C, 40.23; H, 3.63; N, 12.26.

3.8.10. 2-tert-Butyl-8-(1-hydroxyethyl)pyrido[4,3-d]pyri-

midin-4(3H)-one (48). Metallation of 10 (50 mg,

0.24 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL), T¼

220 8C, followed by reaction with acetaldehyde (8 equiv.,

0.11 mL), t¼1 h, gave after puriﬁcation by preparative

chromatography (C₁₈column (10 mm, 4.6£250 mm), eluent

(1 mL/min): MeOH/water (7:3), UV detection (220 nm)),

49 mg (81%) of 48 as a colorless solid, mp 174–175 8C; ¹H

NMR (CDCl₃): d 1.45 (s, 9H, tert-butyl); 1.62 (d, J¼6.4 Hz,

3H, Me); 5.03 (d, J¼7.53 Hz, 1H, OH); 5.20 (m, 1H,

CHOH); 8.69 (s, 1H, H₇); 9.35 (s, 1H, H₅); 11.58 (s, 1H,

NH); ¹³C NMR (CDCl₃): d 24.6 (Me); 28.4 (3Me_tert-burtyl),

3.8.7. 2-tert-Buty1-5,N₃-bis(tributylstannyl)pyrido[2,3-d]-

pyrimidin-4(3H)-one (45). Metallation of 4 (50 mg,

0.24 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL),

T¼0 8C, followed by reaction with tri-n-butylstannyl

chloride (8 equiv., 0.54 mL), t¼1 h, gave after puriﬁcation

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

4121

38.6 (CMe₃); 68.3 (CHOH); 116.3 (C_py); 134.6 (C_py); 149.7

(CH_py); 151.1 (CH_py); 152.1 (C_py); 163.4 (C_py); 167.9 (C_py).

Anal. Calcd for C₁₃H₁₇N₃O (247.9): C, 63.14; H, 6.93; N,

16.96. Found: C, 63.02; H, 7.08; N, 16.78.

preparative chromatography (C₁₈column (5 mm,

10£250 mm), eluent (4 mL/min): MeOH/water (45:55),

UV detection (245 nm)), 39 mg (64%) of 52 as a colorless

1

solid, mp 203–204 8C; H NMR (CDCl₃): d 1.44 (s, 9H,

tert-butyl); 1.46 (d, J¼6.25 Hz, 3H, Me); 5.11 (m, 1H, OH);

5.80 (m, 1H, CHOH); 7.44 (d, J_7–8¼5.7 Hz, 1H, H₈); 8.64

(d, J¼5.7 Hz, 1H, H₇); 11.76 (s, 1H, NH); ¹³C NMR

(CDCl₃): d 25.1 (Me); 28.4 (3Me_tert-butyl); 38.2 (CMe₃);

68.5 (CHOH); 112.9 (C_py); 121.3 (CH_py); 151.3 (CH_py);

156.8 (C_py); 163.7 (C_py); 166.8 (C_py); 167.6 (C_py). Anal.

Calcd for C₁₃H₁₇N₃O (247.29): C, 63.14; H, 6.93; N, 16.96.

Found: C, 62.95; H, 7.23; N, 16.94.

3.8.11. 2-tert-Butyl-8-phenylthiopyrido[4,3-d]pyrimidin-

4(3H)-one (49). Metallation of 10 (50 mg, 0.24 mmol)

according to the procedure D with n-BuLi 1.6 M (8 equiv.,

1.23 mL), TMPH (8 equiv., 0.34 mL), T¼220 8C, followed

by reaction with diphenyl disulﬁde (8 equiv., 430 mg) in

solution with anhydrous THF (5 mL), t¼1 h, gave after

puriﬁcation by column chromatography (silicagel, eluent:

ethyl acetate/dichloromethane (1:1)) 65 mg (85%) of 49 as a

1

colorless solid, mp 223–224 8C; H NMR (CDCl₃): d 1.42

3.8.15. 2-tert-Butyl-5-phenylthiopyrido[4,3-d]pyrimidin-

4(3H)-one (53). Metallation of 10 (50 mg, 0.24 mmol)

according the procedure D A with n-BuLi 1.6 M (8 equiv.,

1.23 mL), TMPH (8 equiv., 0.34 mL), T¼20 8C, followed

by reaction with diphenyl disulﬁde (8 equiv., 430 mg) in

solution with anhydrous THF (5 mL), t¼1 h, gave after

puriﬁcation by column chromatography (silicagel, eluent:

ethyl acetate/dichloromethane (1:9)) 30 mg (40%) of 53 as a

(s, 9H, tert-butyl); 7.36 (m, 3H, Ph); 7.51 (m, 2H, Ph); 8.12

(s, 1H, H₇); 9.15 (s, 1H, H₅); 11.46 (s, 1H, NH); ¹³C NMR

(CDCl₃): d 28.4 (3Me_tert-butyl); 38.7 (CMe₃); 115.8 (C_py);

129.5 (CH_Ph); 130.2 (2CH_Ph); 130.9 (C_Ph); 133.7 (C_py);

135.0 (2CH_Ph); 146.9 (CH_py); 150.5 (CH_py); 150.8 (C_py);

163.5 (C_py); 167.4 (C_py). Anal. Calcd for C₁₇H₁₇N₃OS

(311.40): C, 65.57; H, 5.50; N, 13.49; S, 10.30. Found: C,

65.38; H, 5.61; N, 13.12; S, 10.39.

1

colorless solid, mp.250 8C; H NMR (CDCl₃): d 1.46 (s,

9H, tert-butyl); 7.10 (d, J¼5.65 Hz, 1H, H₈); 7.25 (m, 3H,

Ph); 7.53 (m, 2H, Ph); 8.29 (s, 1H, H₇); 11.88 (s, 1H, NH);

¹³C NMR (CDCl₃): d 28.5 (3Me_tert-butyl); 38.3 (CMe₃);

113.4 (C_py); 117.4 (CH_py); 129.4 (2CH_Ph); 129.4 (CH_Ph);

131.1 (C_Ph); 136.2 (2CH_Ph); 152.6 (CH_py); 156.6 (C_py);

163.6 (C_py); 164.0 (C_py); 167.5 (C_py). Anal. Calcd for

C₁₇H₁₇N₃OS (311.40): C, 65.57; H, 5.50; N, 13.49; S,

10.30. Found: C, 65.35; H, 5.74; N, 13.45; S, 10.37.

3.8.12. 2-tert-Butyl-8,N₃-bis(tributylstannyl)pyrido[4,3-d]-

pyrimidin-4(3H)-one (50). Metallation of 10 (50 mg,

0.24 mmol) according the procedure D with n-BuLi 1.6 M

(8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL), T¼220 8C,

followed by reaction with tri-n-butylstannyl chloride

(8 equiv., 0.54 mL), t¼1 h, gave after puriﬁcation by column

chromatography (silicagel, eluent: diethyl ether) 137 mg

1

(71%) of 50 as a colorless solid, mp 125–126 8C; H NMR

(CDCl₃): d 0.80 (m, 18H, 6Me); 1.19 (m, 24H, 12CH₂); 1.43

3.8.16. 2-tert-Butyl-5,N₃-bis(tributylstannyl)pyrido[4,3-d]-

pyrimidin-4(3H)-one (54). Metallation of 10 (50 mg,

0.24 mmol) according to the procedure D A with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL),

T¼20 8C, followed by reaction with tri-n-butylstannyl

chloride (8 equiv., 0.54 mL), t¼1 h, gave after puriﬁcation

by column chromatography (silicagel, eluent: ethyl acetate/

petroleum ether (1:9)) 96 mg (50%) of 54 as a glassy solid,

mp,50 8C; ¹H NMR (CDCl₃): d 0.82 (m, 18H, 6Me); 1.18

(m, 24H, 12CH₂); 1.34 (s, 9H, tert-butyl); 1.47 (m, 12H,

6CH₂); 7.28 (d, J_7–8¼5.65 Hz, lH, H₈); 8.87 (d, J¼5.65 Hz,

1H, H₇); ¹³C NMR (CDCl₃): d 11.6 (CH₂); 14.0 (Me); 14.1

(Me); 17.9 (CH₂); 27.2 (CH₂); 27.8 (CH₂); 28.2 (CH₂); 28.6

(3Me_tert-butyl); 29.6 (CH₂); 37.9 (CMe₃); 119.3 (CH_py);

121.8 (C_py); 152.7 (C_py); 154.0 (CH_py); 163.4 (C_py); 165.4

(C_py); 181.0 (C_py). Anal. Calcd for C₃₃H₆₅N₃OSn₂(781.34):

C, 53.80; H, 8.39; N, 5.38. Found: C, 54.07; H, 8.46; N,

5.26.

(s, 9H, tert-butyl); 1.52 (m, 12H, 6CH₂); 8.76 (t, J_H7–Sn

¼

11.4 Hz, 1H, H₇); 9.35 (s, 1H, H₅); ¹³C NMR (CDCl₃): d 10.7

(CH₂), 14.0 (2Me); 18.1 (CH₂); 27.2 (CH₂); 27.9 (CH₂); 28.2

(CH₂); 28.6 (3Me_tert-butyl); 29.5 (CH₂); 38.4 (CMe₃); 115.9

(C_py); 136.4 (C_py); 150.3 (CH_py); 159.6 (C_py); 160.1 (CH_py);

164.5 (C_py); 166.7 (C_py). Anal. Calcd for C₃₅H₆₅N₃OSn₂

(781.34): C, 53.80; H, 8.39; N, 5.38. Found: C, 53.71; H,

8.13; N, 5.51.

3.8.13. 2-tert-Butyl-8-iodopyrido[4,3-d]pyrimidin-4(3H)-

one (51). Metallation of 10 (50 mg, 0.24 mmol) according

to the procedure E with n-BuLi 1.6 M (8 equiv., 1.23 mL),

TMPH (8 equiv., 0.34 mL), T¼220 8C, followed by reac-

tion with iodine (8 equiv., 500 mg) in solution with

anhydrous THF (5 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: diethyl ether/

dichloromethane (1:1)) 69 mg (85%) of 51 as a colorless

1

solid, mp.250 8C; H NMR (CDCl₃): d 1.45 (s, 9H, tert-

butyl); 9.16 (s, 1H, H₇): 9.27 (s, lH, H₅); 11.19 (s, 1H, NH);

¹³C NMR (CDCl₃): d 28.5 (3Me_tert-butyl); 38.8 (CMe₃); 98.1

(C_py); 117.3 (C_py); 150.1 (CH_py); 154.3 (C_py); 161.4 (CH_py);

163.1 (C_py); 168.5 (C_py). Anal. Calcd for C₁₁H₁₂N₃OI

(329.14): C, 40.14; H, 3.67; N, 12.77. Found: C, 40.56; H,

3.83; N, 12.61.

3.8.17. 2-tert-Butyl-5-iodopyrido[4,3-d]pyrimidin-4(3H)-

one (55). Metallation of 10 (50 mg, 0.24 mmol) according

to the procedure E with n-BuLi 1.6 M (8 equiv., 1.23 mL),

TMPH (8 equiv., 0.34 mL), T¼20 8C, followed by reaction

with iodine (8 equiv., 500 mg) in solution with anhydrous

THF (5 mL), t¼1 h, gave after puriﬁcation by column

chromatography (silicagel, eluent: diethyl ether/dichloro-

methane (2.5:7.5)) 37 mg (46%) of 55 as a brown solid, mp

3.8.14. 2-tert-Butyl-5-(1-hydroxyethyl)pyrido[4,3-d]pyri-

midin-4(3H)-one (52). Metallation of 10 (50 mg,

0.24 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL),

T¼20 8C, followed by reaction with acetaldehyde

(8 equiv., 0.11 mL), t¼1 h, gave after puriﬁcation by

1

213–214 8C; H NMR (CDCl₃): d 1.45 (s, 9H, tert-butyl);

7.41 (d, J_7–8¼5.3 Hz, 1H, H₈); 8.39 (d, J¼5.3 Hz, 1H, H₇);

11.63 (s, 1H, NH); ¹³C NMR (CDCl₃): d 28.5 (3Me_tert-butyl);

38.6 (CMe₃); 117.4 (C_py); 117.9 (C_py); 122.0 (CH_py); 153.2

(CH_py); 155.9 (C_py); 162.0 (C_py); 167.7 (C_py). Anal. Calcd

4122

J. Audoux et al. / Tetrahedron 60 (2004) 4107–4123

for C₁₁H₁₂N₃OI (329.14): C, 40.14; H, 3.67; N, 12.77.

Found: C, 40.26; H, 3.87; N, 12.64.

25 mg (31%) of 59 as a colorless solid, mp 236–237 8C; ¹H

NMR (CDCl₃): d 1.45 (s, 9H, tert-butyl); 8.15 (d, J_6–7

¼

4.9 Hz, 1H, H₇); 8.31 (d, J¼4.9 Hz, 1H, H₆); 10.93 (s, 1H,

NH); ¹³C NMR (CDCl₃): d 28.7 (3Me_tert-butyl); 38.4 (CMe₃);

114.0 (C_py); 137.3 (C_py); 139.5 (CH_py); 146.6 (C_py); 149.4

(CH_py); 162.1 (C_py); 164.1 (C_py). Anal. Calcd for

C₁₁H₁₂N₃OI (329.14): C, 40.14; H, 3.67; N, 12.77. Found:

C, 40.45; H, 4.12; N, 12.57.

3.8.18. 2-tert-Butyl-8-(1-hydroxyethyl)pyrido[3,2-d]pyri-

midin-4(3H)-one (56). Metallation of 11 (50 mg,

0.24 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL),

T¼278 8C, followed by reaction with acetaldehyde

(8 equiv., 0.11 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: ethyl acetate)

3.8.22. 2-tert-Butyl-8,N₃-bis(tributylstannyl)pyrido[3,2-d]-

pyrimidin-4(3H)-one (60). Metallation of 11 (50 mg,

0.24 mmol) according to the procedure D with n-BuLi

1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv., 0.34 mL),

T¼278 8C, followed by reaction with tri-n-butylstannyl

chloride (8 equiv., 0.54 mL), t¼1 h, gave after puriﬁcation

by column chromatography (silicagel, eluent: ethyl acetate/

dichloromethane, 1:1) 159 mg (83%) of 60 as a glassy solid,

mp,50 8C; ¹H NMR (CDCl₃): d 0.82 (m, 18H, 6Me); 1.18

(m, 24H, 12CH₂); 1.41 (s, 9H, tert-butyl); 1.50 (m, 12H,

6CH₂); 7.51 (td, J_6–7¼4.15 Hz, J_H6–Sn¼18.84 Hz, 1H, H₇);

8.65 (d, J¼4.15 Hz, 1H, H₆); ¹³C NMR (CDCl₃): d 10.8

(CH₂); 13.9 (Me); 14.0 (Me); 17.9 (CH₂); 27.2 (CH₂); 27.7

(CH₂); 28.2 (CH₂); 28.9 (3Me_tert-butyl); 29.4 (CH₂); 37.9

(CMe₃); 136.1 (C_py); 137.2 (CH_py); 148.4 (CH_py); 151.3

(C_py); 157.0 (C_py); 162.0 (C_py); 163.2 (C_py). Anal. Calcd for

C₃₅H₆₅N₃OSn₂(781.34): C, 53.80; H, 8.39; N, 5.38. Found:

C, 53.62; H, 8.76; N, 5.23.

1

54 mg (89%) of 56 as a colorless solid, mp.250 8C; H

NMR (CDCl₃): d 1.43 (s, 9H, tert-butyl); 1.58 (d, J¼6.4 Hz,

3H, Me); 5.23 (q, J¼6.4 Hz, 1H, CHOH); 7.50 (d, J_6–7

¼

4.15 Hz, 1H, H₇); 8.73 (d, J¼4.15 Hz, 1H, H₆); 10.82 (s, 1H,

NH); ¹³C NMR (CDCl₃): d 24.0 (Me); 28.7 (3Me_tert-butyl);

38.1 (CMe₃); 69.1 (CHOH); 125.5 (CH_py); 137.7 (C_py);

143.9 (C_py); 150.0 (CH_py); 150.6 (C_py); 162.2 (C_py); 163.0

(C_py). Anal. Calcd for C₁₃H₁₇N₃O (247.29): C, 63.14; H,

6.93; N, 16.96. Found: C, 63.06; H, 7.09; N, 16.52.

3.8.19. 2-tert-Butyl-8-(hydroxyphenylmethyl)pyrido-

[3,2-d]pyrimidin-4(3H)-one (57). Metallation of 11

(50 mg, 0.24 mmol) according to the procedure D with

n-BuLl 1.6 M (8 equiv., 1.23 mL), TMPH (8 equiv.,

0.34 mL), T¼278 8C, followed by reaction with benz-

aldehyde (8 equiv., 0.27 mL), t¼1 h, gave after puriﬁcation

by column chromatography (silicagel, eluent: ethyl acetate)

1

68 mg (89%) of 57 as a white solid, mp 216–217 8C; H

NMR (DMSO): d 1.35 (s, 9H, tert-butyl); 6.31 (m, 1H, OH);

6.54 (m, 1H, CHOH); 7.22 (m, 3H, Ph); 7.49 (m, 2H, Ph);

7.94 (d, J_6–7¼4.9 Hz, 1H, H₇); 8.72 (d, J¼4.9 Hz, 1H, H₆);

11.07 (s, 1H, NH); ¹³C NMR (DMSO): d 28.6 (3Me_tert-butyl);

38.3 (CMe₃); 69.2 (CHOH); 124.2 (CH_py); 126.9 (2CH_Ph);

127.3 (CH_Ph); 128.3 (2CH_Ph); 137.1 (C_Ph); 142.2 (C_py);

144.4 (C_py); 148.3 (CH_py); 151.2 (C_py); 162.4 (C_py); 163.1

(C_py). Anal. Calcd for C₁₈H₁₉N₃O₂(309.36): C, 69.88; H,

6.19; N, 13.58. Found: C, 69.92; H, 5.82; N, 12.96.

References and notes

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4(3H)-one (58). Metallation of 11 (50 mg, 0.24 mmol)

according to the procedure D with n-BuLi 1.6 M (8 equiv.,

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´ ´

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´

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1

colorless solid, mp.250 8C; H NMR (CDCl₃): d 1.47 (s,

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9H, tert-butyl); 6.71 (d, J¼4.9 Hz, 1H, H₇); 7.44 (m, 3H,

Ph); 7.55 (m, 2H, Ph); 8.36 (d, J_6–7¼4.9 Hz, 1H, H₆); 11.24

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(CMe₃); 123.1 (CH_py); 129.4 (C_Ph); 130.5 (CH_Ph); 130.6

(2CH_Ph); 136.3 (2CH_Ph); 142.3 (C_py); 144.6 (C_py); 148.9

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´

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one (59). Metallation of 11 (50 mg, 0.24 mmol) according

to the procedure E with n-BuLi 1.6 M (8 equiv., 1.23 mL),

TMPH (8 equiv., 0.34 mL), T¼278 8C, followed by

reaction with iodine (8 equiv., 500 mg) in solution with

anhydrous THF (5 mL), t¼1 h, gave after puriﬁcation by

column chromatography (silicagel, eluent: ethyl acetate)

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Article Doi

First functionalization by metallation of the pyridine moiety of pyridopyrimidin-4(3H)-ones. Diazines. Part 36

DOI: 10.1016/j.tet.2004.02.040

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Full text of DOI:10.1016/j.tet.2004.02.040

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