Synthesis of diaza-anthraquinones by hetero diels-alder cycloaddition reactions

Te~raheah Vol 45, No. 14, pp. 4417 to 4484, 1989 Pnnted m Great Bntam.

tlO4&4020/89 $3.00+.00 0 1989 Mamdl PergamonMacmluaoplc

SYNTHESIS OF DIAZA-ANTHRAQUINONES BY HETERO DIELS-ALDER CYCLOADDITION REACTIONS C.

Gesto, E. de la Cuesta and C. AvendaAo*

Departamento de Quimica Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense 28040-Madrid, Spain. (Received VI UK 19April 1989)

Abstract- Using 3-methyl-1-dimethylamino-1-azabuta-1,3-diene and 3(tert-butyl dimethylsilyl)oxy-l-dimethylamino-l-azabuta-l,3-diene as 1-azadienes and quinoline-5,8-dione and carbostyrilquinone as dienophiles, several diazaanthraquinones have been obtained. Structure assignments were mainly based on IR spectroscopic data. The accessibility of N-oxidation products has been also investigated. Diazaquinomicin A (DQM, fig.1) has been isolated and characterized by l-3 , as a new neutral antifolate antibiotic, active against Gram-

Omura et al.

positive bacteria. The site of action of DQM was studied and compared with other known synthetic antibacterial and antitumor drugs such as trimethoprim, methotrexate and S-fluorouracil. It was described as a thymidilate synthase inhibitor competitively with 5,10-methylene tetrahydrofolate4. Preparation of derivatives with higher solubility was claimed to be of interest in creating new antitumor drugs. This paper deals with a synthetic approach to DQM analogues by hetero Diels-Alder cycloaddition reactions.

Figure 1 Cycloadditions between azanaphthoquinones and appropriate dienes are efficient and regioselective methods of synthesis of aza-anthraquinones 536 . Regioselective (or regiospecific) cycloadditions of an electron-rich diene with an azanaphthoquinone are controlled by the relative electron deficiencies of the carbonyl groups 6 . As carbostyrilquinone is readily available from 8hydroxyquinoline7, we investigated the reactions of such quinone with l-azadienes, compounds extensively studied by Ghosez and coworkers 899 . In this context, only one example of cycloaddition between carbostyrilquinone and 1,2-dimethylenecyclohexane has been previously reported to give anthracyclin 4477

C. GES~Oet al.

4418

analogues

10

.

The reaction with 3-methyl-1-dimethylamino-1-azabuta-1,3-diene was regioselective and yielded 1, which isomeric purity was corroborated by its 200 MHz 'H-NMR spectrum (Tables 1 and 2). The secondary product 2 is formed by addition of dimethylamine to the,starting quinone according to previously proposed reaction mechanisms for such 1-azadiene'. Structure -2 was confirmed by carrying out the direct addition. In both reactions no addition on the 3,4-double bond of carbostyrilquinone was detected.

HN(CH&

The best results (68% of l_) were obtained under N2 atmosphere and equimolecular proportion of reactants. When the reaction was performed in air and/ or 2 equivalents of the starting quinone were used, the yield of 2 was increased while that of 1 decreased. To confirm structure 1, it was transformed into 2 by treatment with phosphorus oxychloride and this derivative was compared with the two cycloaddition products 4 and 5, obtained from quinoline-5,8-dione and 3-methyl-ldimethylamino-1-azabuta-1,3-diene.

2

4

The last mentioned reaction has been studied by Potts to give the diaza6,11 as the only obtained isomer, but by mod anthraquinone 4 ifying the reactiol conditions, the regioselectivity drops to give up to 12% of _5_(see experimentall.

Synthesisofdiaza-anthraquinones

4479

1 H-NMR spectra of isomers 4 and 2 (Tables 1 and 21 are practically identical but while compound 5 only shows a carbonyl stretching IR band, 6,ll show two carbonyl

according to its greater symmetry, compounds 2 and 4

bands in agreement with their assigned structures (Table 3). The electronic effect of the pyridine nitrogen atom increases the frequent) of the neighbour carbonyl group as it is known to occur, for instance, in l-1 5 aza-5,10-anthraquinone in which the CS-carbonyl band appears at 1671 cm -1 while the ClO-carbonyl band occurs at 1686 cm . In compounds 3 and 4 the additional pyridine nitrogen atom augments the difference between the two carbonyl bands. TABLE l.- 'H-NMR data (6 values relative TMS).

General structure for compounds

5 (R=H, R'=CH3)

I,?,4 and 6

Compound

Solvent

R

R'

-1 2

Ho(R=H)

HB

DMSOd_6

OHa

C13CD

OHa

Hy

CH3

--

6.98

---

--

6.68

Ha'

Hy'

R'

NH

8.15 7.89'

8.90

8.37

2.59

b

--

--

--

d

J -e 4 3 -

C13CD

Cl

CH3

--

7.77

8.58

8.99

8.41

2.59

-

C13CD

H

CH3

7.79

8.66

9.00

8.44

2.60

-

C13CD

H

CH3

9.18 9.16

7.81

8.75

8.98

8.54

2.61

-

6

DMSOd_6

H

OH

9.08

7.88

8.52

8.62

7.75

11.53

-

a: As carbonyl tautomer.

d: Not observed.

b: Only observed in CDC13 at 9.80 ppm.

e: According with ref. 11.

c:

687=5.71; 6N(CH312=3.33.

Due to the presence of a third carbonyl group, the possibility of hydrogen bonding and the different electronic effects of both nitrogen atoms in l_, the study of the stretching carbonyl IR region is more difficult but structure 1 is confirmed from that of compound 3. Said structure is consistent with an addition reaction controlled by the greater electron-deficience of carbostyrilquinone 8-carbonyl group.

C. G!zsro et al.

4480

J Values

TABLE 2.-

in

Hz.

Compound

a:

a’y’

BY

1

__

9.5

--

2.1

-2 3

__

9.0

--

--

__

8.2

--

2.1

4

4.6

7.9

1.7

2.1

3

4.6

7.9

1.7

2.1

a

4.6

7.9

1.7

2.8

?

__

9.5

--

--

8

4.6

7.9

1 .6

1.0

9

6.6

7.8

1 .l

a

-10 11

4.5

8.0

1.7

a

6.6

7.8

1.2

a

Not

IR carbonvl

TABLE 3.-

o8

determined.

freauencies

of

diaza-anthraouinones

Compound

cm 1650

3

1670

(CS=O)

1695

(ClO=O)

4

1670

(CS=O)

1695

(ClO=O)

1675

1685

6*

1670

(CS=O and

(CS=O)

?

ClO=O) 1680

(ClO=O)

1650-1680

8:s --

1680

10+11 --

1660

* Two maxima

Diels-Alder

cm-‘).

-1

1

5

Hetero

(KBr;

of

1680

one

broad

cycloaddition

band

reaction

between

quinoline

5,8-dione

3(tert-butyldimethylsilyl)oxy-l-dimethylamino-l-azabuta-l,3-diene regioselective Once are

in

those

giving

again

the

agreement compound

to

lower

frequency

the

3-hydroxyl Assignation

in

their

treatment

IR frequency with

of

on literature

5 after the

in

values

proposed

+ we can

compound

data.

of

was also

the

the

see

5 due of

The main

difference

chemical

shift.

to

the

with

the

of

the

electron

between

l-6 --

hot

carbonyl

By comparing shift

compounds The

adduct

quinone

structure.

clearly

group. of ‘H-NMR signals

y’-protons

of

and

bands such

(Tables isomers

(Table

values

ClO-carbonyl

releasing

6 and J values

methanol.

effect

3)

with band of

1 and 2) was based 11 and 5 was found %

of

8 and y-protons in

4481

Synthesisof diaza-anthraquinones compounds

1 and 2 are

The electronic tion

of

the

effect

its

chemical

into

N-oxidation

of

and

the

the

1 with

electron-rich

11

the

for

its

a’

1.

interest

is

the

assigna-

responsible

of

of

possible

and reactivity

we study to

the

their

greater

pyridine-ring,

of

Thus,

N-oxides

oxidation

were

the

accessibility.

mixtures

Similarly,

according

substituted

3 explains

and y’-protons.

derivatives,

MCPBA gave

in

carbostyrilquinone7.

3-hydroxyl-group

biological

(7:3),

methyl

described

2-chloro-substituent of

N-oxide

10 and

those

In 6,

shift

account

diaza-anthraquinone (6:4)

of

to

B and y-protons.

upf ield

Taking

similar

obtained

of

S and 2 the

more

3 and 5

from

respectively.

9Structure troscopic

10 -

assignment data

of

(Tables

2,4

N-oxides and

7-11 was based on ‘H-NMR and IR spec-‘H-NMR spectra of compounds 3 respectively).

7-11 show significative upfield -protons. As both nitrogen atoms effects,

the

carbonyl

band

observed while

chemical in

IR spectrum that

of

11

-10 and

shifts

for

compounds for 11 --

8-11 -8 and 2 (as (as

a mixture)

pyridine have

N-oxidated

opposite

a mixture) has

two

ring

electronic has

only

carbonyl

one bands.

C. GPSTOet al.

4482 The found they

are

groups

low

yields

subject

to

interference

in

Compound

for

Solvent

Ha

-7

DMSOd_6

--

8

C13CD

as

can

be

explained

because

electron-attracting

carbonyl

(6 values

relative

TMS)

HY

Ho’

HY’

CH3

6.72a

7.98a

7.78

8.50

2.38

9.18

7.75

8.58

7.95

8.4Sb

2.49

8.58

7.61

8.11

9.00

8.36

2.58

HB

10

C13CD

9.12

7.81

8.73

8.06b

8.44b

2.49

-Y-l

C13CD Cl ,CD

8.57

7.63

8.22

8.94

8.48

2.60

These

signals

besides ric

appear

the

Not

as

for

in

the

resolved,

The observed

dd.

B-y coupling

structure

observed b:

reactions

as well

N-oxides

9

a:

N-oxidation

hindrance

.

‘H-NMR data

TABLE 4.-

the

steric 12

may be

this

extracoupling

attributed

to

of

a phenolic

The NH$OH proton

compound.

1.3

is

Hz

tautomenot

clearly

spectrum.

wide

singlet. EXPERIMENTAL

Melting melting

points

point

are

uncorrected

apparatus.

spectrophotometer

and

and were

IR spectra

were

‘H-NMR spectra

with

6-Methyl-2-oxo-1,8-diaza-9,10-anthraquinone carbostyrilquinone7 N2 atmosphere

under

6 mmol) for

was

The reaction

The precipitate

and refluxed

in

ethanol (0.9

for g,

0.5

plates

Calc.

Cl 3H8N203 : C 64.98; of

the

of

dimethylamine

in

tetrahydrofuran

formed

was

The residue an excess 58%);

above

68%);

was of

(150

hr.

C 60.52;

H 4.60;

(200

capillary

after 20 mmol)

ml, ml)

extracted

solution

with

Found: N 12.80%.

cooling,

a)

It

under

C 65.07;

was obtained

filtration

of

compound

and carbostyrilquinone for

and the

6.5

hr.

solvent

chloroform Compound

C 60.88;

temperature

ml)

l3

(0.72

in

the

g, dark

N2 atmosphere

compound

Found:

of

(200

1 crystallized H 3.59;

N 11.34.

N 11.66%.

was stirred

ether.

room

577

MHz) spectrometer.

tetrahydrofuran

was filtered

After

(2)

by filtration

petroleum

mp 226-228’C.

a Buchi

To a stirred

at

mp> 3OO’C. H 3.35;

reaction

(2.56

removed

(1) anhydrous

obtained

6-Dimethylamino-carbostyrilquinone liquors

a Brucker

was stirred

thus

as yellow for

in

with

on a Perkin-Elmer

3-methyl-1-dimethylamino-1-azabuta-1,3-diene

added.

4 days.

mmol)

(1 g,5.7

measured

recorded

and

N 13.08.

the b)

(1.05

mother

A solution g,

6 mmol)

precipitate

evaporated

extract

2 precipitated

H 4.86;

1.

The black

was the

from

in vacua.

was poured

as

crystals

Calc.

for

into

(0.76 Cl,H,0N203:

g,

Synthesis ofdiaza-anthraquinones Z-Chloro-6-methyl-‘1,g-diaza-9,1U-anthraquinone mmol) was solved heated

in phosphorus

at 130°C for

neutralized

with

chloroform

hr.

(acetone)

in vacua

was dried

yielding

C 60.50;

. Found:

was poured solution

over

N 11.10.

Calc.

into

g,

ice

3-Methyl-1,5-diaza-9,10-anthraquinone (2 g,

atmosphere,

12 hr.

was solved

diminished

column

(5)

12 mmol) in anhydrous

After

The residue

To a stirred

benzene

at room temperature and refluxed

pressure

chromatography

12%)) mp 289-290°C

mp>300°C

solution (1.34

the

in ethanol

solvent for

using

Found:

(ethanol).

g,

After

12 mmol)

solution

of

anhydrous

H 3.67;

95:s

N 12.60.

trietylamine

(2.2

sulfonate

(5.3

g,

20 mmol) were added and stirred

at room temperature,

cold

solution

was allowed

for

was evaporated

the diene external (lH,

(4.2

g,

to stand under

diminished

91%) as a yellow

reference)

0.02

(6H,

s),

Calc.

for

17.4

mmol) in

atmosphere, anhydrous trifluoromethane-

for

1 hr.

After

evaporation

pressure oil.

0.81

at room temperature

to give

‘H-NMR 6(60 MHz, C13CD; TMS as (9H, s),

2.70

(6H,

s),

4.30

(2H, d),

ws).

5,8-dione

(6)

12 mmol) in anhydrous

(2 g,

atmosphere

To a stirred

methylene

solution

chloride

of

quinoline

(75 ml) under

N2

3(tertbutyldimethylsilyl)oxy-l-dimethylamino-l-azabuta-l,3-diene

13 mmol) recently

room temperature refluxed

g,

(100 ml) was added and the -n-pentane 2 hr. at O’C. After filtration the solu-

3-Hydroxy-l,g-diaza-9,10-anthraquinone

(3 g,

(2 g,

chloride (100 ml) under nitrogen g, 21 mmol) and tertbutyldimethylsilyl

in vacua

by

(0.4

To a cold

2-oxopropyliden-N,N-dimethylhydrazine

methylene

in vacua.

evaporation

from 4 and purified

chloroform/ethanol

C 69.75;

quinoline

nitrogen

was removed

2 hr.

compound 5 was separated

on silicagel

of

(150 ml) under

H 3.59; N 12.49%. C13HgN2C2: C 69.62; 3(Tertbutyldimethylsilyl)oxy-l-dimethylamino-l-azabuta-l,3-dieneg.

6.58

with sulfate

C13H7C1N202: C 60.33;

3-methyl-1-dimethylamino-I-azabuta-1,3-diene

was added.

tion

and

sodium

75%),

for

1.9

was

was extracted

anhydrous

compound 2 (0.37

H 3.00;

g,

solution

N 10.82%.

5,8-dione14

under

mixture

The resulting

solution

Compound 1 (0.46

(10 ml) and the

The reaction

ammonia.

and the organic

and concentrated H 2.72;

0.5

aqueous

(3)

oxychloride

4483

in methanol

recrystallized

(1.2

2.88;

Calc.

N 12.27.

prepared

overnight. for g,

0.5

43%);

for

was added.

The reaction

The precipitate hr.

After

cooling

thus

at

was filtered

compound 5 was filtered

mp>300°C(methanol-water).

C12H6N203: C 63.70;

was stirred

obtained

H 2.77;

Found:

C 63.39;

and and H

N 12.38%.

N-oxidation reactions. General procedure: An excess of m-chloroperbenzoic acid (MCPBA) was added to a solution of anthraquinones in chloroform. The reaction was stirred at room temperature and was followed by thin-layer chromatography. During this time additional MCPBA was added twice. The resulting reaction mixture was washed with 10% aqueous potassium carbonate

4484

C. GESTCI et al.

and extracted with chloroform. The organic solution was dried under anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography (silicagel, chloroform: ethanol, 95:s). 3-Methyl-7-oxo-l,8-diaza-EH-9,lO-anthraquinone-l-oxide

(1) Reaction time:

30 days, 10% yield; mp>300°C. Found: C 60.75; H 3.08; N 10.78. Calc. for C,3H8N204: C 60.93; H 3.14; N 10.93%. 3-Methyl-1,8-diaza-9,10-anthraquinone-l-oxide

and 6-methyl-1,8-diaza-9,10-

anthraquinone-l-oxide

(8 - and -9) Reaction time: 10 days, 6% yield. Found: C 65.09; H 3.48; N 11.89. Calc. for C13H8N203: C 64.98; H 3.35; N 11.66%. 3-Methyl-1,5-diaza-9,10-anthraquinone-l-oxide

and 7-methyl-1,5-diaza-9,10-

(10 - and -111 Reaction time: 10 days, 5% yield. Found: C 65.64; H 3.18; N 11.42. Calc. for C13H8N203: C 64.98; H 3.35; N 11.66%.

anthraquinone-l-oxide

Acknowledgements. This work was supported by the Spanish CICYT (PA86-0317). REFERENCES 1. 2. 3. 4. 2: 7. 8. 9.

10. 11. 12.

13. 14.

Omura,S.; Iwai,Y.; Hinotozawa,K.; Tanaka,H.; Takahashi,Y.; Nakagawa,A. J. Antibiotics 1982, 35, 1425. Omura,S.; Nakagawa,A. FAoyama,H.; Hinotozawa,K.; Sano,H. Tetrahedron Lett. 1983, 24, 3643. Omura,x; Murata,M.; Kimura,K.; Matsukura,S.; Nishihara,T.; Tanaka,H. J. Antibiotics 1985, 38, 1016. masaka,T.; Tanaka,H.; Omura,S. J. Antibiotics 1985, 38, 1025. Birch,A.J.; Butler,D.N.; Sidda1,J.B. J. Chem. Sot. 1964 2941; Potts,K.T.; Bhattarcharjee,D.; Walsh,E.B. J. Ch em. Soc.'Chem. Commun. 1984, 114. Pettit,G.R.; Fleming,W.C.; Paul1,K.D. J. Or Serckx-Poncin,B.; Hesbain-Frisque,A.M.;--iX&$?Te:zt!GdgA I!.:!::1982, 23, 3261. Gliosez,L.; Serckx-Poncin,B.; Rivera,M.; Bayard,P.; Sainte,F.; Demoulin,A.; Frisque-Hesbain,A.M.; Mockel,A.; MuAoz,K.; Bernard-Henriet,C. Lect. Heterocycl. Chem. 1985, 8, 169. Oda,N.; Kobayashi,K.; Ueda,T.; Potts, K.T.; Walsh,E.B.; a) Katritzky,A.R.; Lagowsky,J.M. In "Chemistry o des"; Academic Press. New York, 1971. b) Remy,D.C. U.S. Patent, 41639, 457. 1987. Ioffe,B.V.; Zelenin,K.N. Dokl. Akad. Nauk. SSSR 1961, 141, 1369; Chem. 14038b. Abstr. 1962, Pratt,Y.T.; Drake,N.L. 56, J. Am. Chem. Sot. 1960, 82, 1155.