A new Efficient Method for the Preparation of 2,6 ...

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A new Efficient Method for the Preparation of 2,6-Pyridinedihiethyl Ditosylates from Dimethyl 2,60Pyridinedicarboxylates a

b

a

György Howáth , Cristian Rusa , Zoltán Köntös , János a

Gerencsér & Péter Huszthy

c

a

Department of Organic Chemistry, Technical University of Budapest, H-1521, Budapest, Hungary b

Department of General Chemistry, “Gh. Asach” Technical University, R-6600, Lash, Rumania c

Research Group for Alkaloid Chemistry, Hungarian Academy of Sciences, H-1521, Budapest, Hungary Version of record first published: 17 Sep 2007.

To cite this article: György Howáth , Cristian Rusa , Zoltán Köntös , János Gerencsér & Péter Huszthy (1999): A new Efficient Method for the Preparation of 2,6-Pyridinedihiethyl Ditosylates from Dimethyl 2,60-Pyridinedicarboxylates, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 29:21, 3719-3731 To link to this article: http://dx.doi.org/10.1080/00397919908086011

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SYNTHETIC COMMUNICATIONS, 29(21), 3719-3731 (1999)


A NEW EFFICIENT METHOD FOR THE PREPARATION OF 2,6-PYRIDINEDIhIETHY L DITOSYLATES FROM DIMETHY L 2,6-PY RIDINEDICARBOXY LATESt

Gyorgy Howatha, Cristian Rusab, 2 0 1 t h Kontos”, J h o s Gerencser’, Peter Huszthy.‘ Department of Organic Chemistry, Technical University of Budapest, H- 152 1 Budapest, Hungary b Department of General Chemistry, “Gh. Asach” Technical University, R-6600 lash, Rumania ‘Research Group for Alkaloid Chemistry, Hungarian Academy of Sciences, H- 152 1 Budapest, Hungary Abstract: We report here an efficient method for the preparation of 2,6pyridinedimethyl ditosylate and four of its 4-substituted derivatives, two of them have not been reported in the literature. We also describe here a modification of the reported synthesis for chelidonic and chelidamic acids with improved yields and

higher purity.

2,6-pyridinedimethyl ditosylates (1-5, see Figure) have a great importance in preparation of macrocycles such as cryptands, clefts and crown compounds.’ In the case of pyridino-crown compounds for example changing the substituents on the pyridine ring of the macrocycle can make them suitable for various purposes. ‘Dedicated to Professor Milialy Nogradi on flic occasion of 111s65111binlida! “To \choni correspondeiice should bc addressed

3719 Copyright C) 1999 by Marcel Dekker, Inc

w w w ,dekker.com

HORVATH ET AL.

3720

Figure


I

Ts 0 OTs 1 Z=H, 2 Z=OMe, 3 Z=OCHzPh, J Z=OCH,CH=CH,, 5 Z=OTHP,

For example the allyloxy group makes possible the attachment of the ligand to silica gel,'" and tetrahydropyranyloxy moiety after deblocking allows the formation of proton-ionizable ligands.l"'g*'h." Ditosylate 1 has often been used in preparation of crown ethers,lb*'c~ld.lf's clefts'P and cryptands.".'"

Iq

Since ditosylates such as 1-5 are very useful building blocks, a general method for their preparation is important. Here we report a new efficient method for their synthesis beginning with the preparation of chelidonic acid ( 6 ) for which we provide a modified procedure with higher purity and better yield than that of reported.' Chelidonic acid ( 6 ) was converted to chelidamic acid (7) by a method slightly different to that of r e p o ~ t e d Esterification .~ of 7 was done according to the literature'" resulting dimethyl chelidamate (8, see Scheme I ) . Diester 8 was treated with dimethyl sulfate, benzyl chloride and ally1 bromide, respectively in DMF


2,6-PYRIDINEDIMETHYL DITOSYLATES

7

3721

8

to obtain 4-substituted dimethyl 2,6- pyridinedicarboxylate 10,' 1 l 5 and 12,Ih respectively (see Scheme 2). Diester 9 is commercialy available and

its 4-tetrahydropyranyloxy derivative (13) was prepared as reported.lh Diesters 9-13 were reduced with NaBHJ in ethanol and the crude ethanol free 2,6-pyridinedimethanols so obtained were treated with tosyl chloride in a mixture of dichloromethane and 40% aqueous KOH to give ditosylates 15 . The reason for working with the crude 2,6-pyridinedimethanols is

different for each compound. In case of 1 and 2 the corresponding diols are more soluble in water than in organic solvents, so avoiding their isolation by the usual extraction procedure,le.Ih which would give very poor yields (about 2%, see Experimental). is essential.

HORVATH ET AL.

3722

Scheme 2 8

R-X

(X=CH~SOLI, CL Br) KlCO, / DMF

Z


I

1.) NaBH., / EtOH

2.) TsCl (aq. KOH / CH2CI2)

*

1-5

OMe

Me0

9 Z=H, 10 Z=OMe, 11 Z=OCH2Ph

12 Z=OCH:CH=CH2,13 Z=OTHP

The THP-blocked diol is very sensitive to acid, so its isolation would increase the risk of decomposition. In all cases working with the crude diols saves time and work making the preparation of ditosylates 1-5 easier and faster. It is noteworthy to mention here that, to our knowledge, the preparation of ditosylates 2 and 3 have not been reported.

EXPERIMENTAL

Infrared spectra (KBr) were obtained on a Zeiss Specord IR 75 spectrometer AW-SO

I

I{ (80 h4Hz) N b l R spectra (CDC13) weie taken on a Biukei

spect~onieter

Elemental

analyses

ueie

performed

in

Microanal\ tical Laboratory of the Department of Oiganic Chemistry. L Eotvos U n n e i s i t y . Budapest, Hungaiy Melting points were taken on a

2,6-PYRIDMEDIMETHYL DITOSYLATES

3723

Boetius micro melting point apparatus and were uncoiwcted. Starting materials were purchased from Aldrich Chemical Company unless otherwise noted. Silica gel 60 FZj4 (Merck) was used for TLC. Solvents


were dried and purified according to well established methods6 Chelidonic acid (4-0~0-3H-pyran-2,6-dicarbo~ylicacid) (6) . Sodium (23.5 g, 1.02 mol) was dissolved in 360 ml of pure and dry ethanol and to

tlus sodium ethoxide solution was added a mixture of 29 g (38 ml, 0.5 mol) of dry acetone and 155 g (144 ml, 1.06 mol) of diethyl oxalate. During the addition of the mixture a yellow precipitate formed. After addition the reaction mixture was kept at 60°C for one hour to complete the reaction then 200 ml of 37% aqueous HCI and 100 ml of water were added, and it was stirred at 50°C for one day. About 450 ml of aqueous ethanol was removed under reduced pressure then 300 ml of water and 50 ml of 37Y0 aqueous HCI were added to this mixture and stirring was continued until the silica gel TLC (eluent: 3/7 (v/v) 10% aqueous NaCl solutiodethanol) showed only one spot (R,=0.65) for 6 (about three days). The precipitated ciystals were filtered off, washed first with water then with acetone. The crude product was recrystallized from boiling water using charcoal to give 8 1 .O g, (88 %) of pure 6 as white ciystals. blp: 272°C

(decomposition), lit.? mp: 2 5 7 T (decomposition).

HORVATH ET AL.

3124

Chelidamic acid (1,4-dihidro-4-oro-2,6-pyridinedicarborylic acid) (7).

To 50 6 (218 rnmol) of chelidonic acid (6) was added 500 ml of 25% aqueous N H j solution dropwise at O'C, and the resulting suspension was


stimed at room temperature for two days (after five hours the suspension became a light orange solution). The excess of aqueous ammonia solution was removed under reduced pressure and the residue was boiled with 500

rnl of water using 10 g of charcoal for 5 minutes and then filtered. The cold solution was acidified with 37% aqueous HCl to about pH=l. The white crystals were filtered off, washed tree times with ice-cold water and dried to give 49.9 g (92. YO)of 7. Rr0.35,(silica gel TLC, 3/7 (viv) 10% aqueous NaCl solution/ethanol); mp: 265°C (decomposition), lit.3 mp: 248OC (decomposition) General

procedure

for

preparation

of

dimethyl

2,6-pyridine-

dicarboaylates (10-12). 2 g (9.5 mmol) of dimethyl chelidamate (8), 10.5 mmol of reagent (1.32 g of dimethyl sulfate, 1.33 g of benzyl chloride, and 1.27 g of ally1 bromide, respectively) and 2.2 g (15.8 mmol) of K2C03 were stirred in 20 ml of DMF at the temperature and for the time shown in Table 1 for each compound.

Reactions were followed by silica gel TLC using 1/4 (v/v) methanoVtoluene as an eluent. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in water and CHzClz


3725

Table 1. Reaction conditions of preparation, yields, melting points and solvents of recrvstallization for diesters 10-12 I


Compd

Reagent

I

-T 1 Dimethyl

10

Temp.

23

chloride

90

1

3

Ally1 12

bromide

Lit. mp.

(solvent)"

["CI

[OC1

Benzyl

11

btp.["C]

50

'solvent for recrystallization

9

I

125- 126 75

(aceton)

126.5-12Sb

110-1 11

80

(toluene)

112-1 13'

93-94 81

(methanol)

9 1-92Sd

tit.', 'lit5, dIit.'h

(100 ml of each). The aqueous phase was shaken with CH2C12 (3x50 ml).

The combined organic phase was dried over anhydrous Na2SOJ, filtered and the solvent was evaporated under reduced pressure. Yields and melting points are given in Table I . Compounds 10, 11 and 12 prepared this way had the same IR and 'H N M R specha than those of prepared by the reported proced~res.'.'.'~ General procedure for preparation of 2,6-pyridinedirnethyl ditosylates

(1-5). To

a

stirred

mixture

of

10.0 mmol

of

dimethyl

2,6-

pyridinedicarboxylates (1.9 g of 9, 2.3 g of 10, 3.0 g of 11, 2.5 g of 12, and 2.9 g of 13) and 25 ml of dry and pure ethanol was added at 0°C and under

3726

HORVATH ET AL.

argon 1.4 g (37 mmol) of NaBHJ in small portions. After addition the mixture was stirred at 0 "C for 30 minutes and then refluxed until the silica gel TLC using 114 (v/v) methanoVtoluene as an eluent showed a complete


conversion of the starting material and only one main spot for the diol. The solvent was removed under reduced pressure and the residue was dried in a vacuum desiccator over KOH. The crude 2,6-pyridinedimethanols so obtained were stirred in a mixture of CHZCI2 and 40% aqueous KOH solution (50 ml of each) at 0°C and 4.3g (22.6 mmol) of tosyl chloride was added to it in one portion. The reaction mixture was stirred for one hour at 0°C then at room temperature until silica gel TLC using 114 (viv)

methanolitoluene as an eluent showed complete conversion of the starting materials and only one main spot for the product. The mixture was washed into a separatoiy funnel with water and CH:C12 (100 ml of each). The resulting mixture was shaken well and separated. The aqueous phase was shaken with Cli2C12 (3x100 mi). The combined organic phase was dried over anhydtous Na:SO,,

filtered and the solvent was removed under

reduced pressure. The residue was triturated with dry and pure methanol to give whits crystals. Yields, melting points solvents for recrystallization and Rt values at-e shown in Table 2. As to our knowledge, ditosylates 2 and 3 are not described in the

literature, we provide ' H N M R and 1R spectral data. and also elemental


Compd

Yield" (%)

i~lp.["C]~

3727

Lit. mp. ["C] (solvent)'

Rtj


12 1- 122"

1

94

119-120

(1,2-dichloroetane-methanol) 0.75

2

85

77-78

0.60

3

80

116-117

0.80

79-81 l a 4

72-73

71

(1,2-dichloroetane-methanol)

0.50

90-9 1 I h 5

91-92

57

(ether)

0.70

analysis for these compounds here. Ditosylates 1, 4 and 5 prepared this way had the same IR and

'H NMR spectra than those of prepared by the

reported procedures. ":"

Ih

4-Methoxy-2,6-pyridinedimethyl ditosylate (2). ' H NMR, 6 (ppni): 3.39

(6H,s), 3.8 (3H, s), 4.9(4H, s), 6.75(2H, s), 7.3 (4H, d), 7 . 7 (4H, d); lR,

I.'

(cm-'): 3050, 3000, 2910, 2880, 1600, 1570, 1.190, 1.180, 1210, 1190, 1 1 10,

1050,980,890, 860,850, 690,570,580. Anal. Calcd. for C22H23N07S2:C, 55.56;H, 4.87;N, 2.94.Found: C, 55.28;H, 4.78;N,2.92.

HORVATH ET AL.

3728

J-benzyloxy-2,6-pyridinedimethyl ditosylate (3). ’ H NMR, 6 (ppm): 7.4 (6H, s), 4.9 (413, s), 5.0 (2H, s), 6.9 (2H, s), 7.3-7.5 (9H, m), 7.8 (4H, d);

IR, v(cm”): 3050, 3000, 2900, 2150, 1600, 1570, 1450, 1370, 1350, 1320,


1110, 1040, 1030, 980, 960, 880, 850, 810, 730, 700, 690, 670, 550. Anal. Calcd. for C ? X H ~ ~ N O &C,: 60.74; H, 4.91; N, 2.53. Found: C, 60.45;

H, 4.86; N, 2.60. Isolation

of

2,6-pyridinedimethanol

and

4-methoxy-2,6-pyridine-

dimethanol from the reduction products of diesters 9 and 10. When the above described reduction of 9 (1.9 g, 10 mmol) and 10 (3.0 g, 10 mmol), respectively with NaBH, ( I .4 g, 37 mmol) in EtOH (25 ml) was completed, the solvent was removed and the residue was dissolved in 80 ml of 10% aqueous NaOH and 300 ml of CHCI,. The mixture was shaken well and separated. The aqueous phase was shaken with CHCI, (3x200 ml). The combined organic phase was dried over anhydrous Na2S04,filtered and the solvent was removed under reduced pressure to give 26 rng ( I .9%) of 2,6-pyridinrdimetlianol

and

28

irig

( 1.7%)

of

4-methoxy-2,6-

pyridinedirnetlianol, respectively. These diols were identical in eveiy aspect to those of authentic samples prepared by reported procedures.’.* The veiy low isolated yields for 2,6-pyridinedimethanol and its 4-methoxy derivative w;is one of the main reasons we looked for and found a method for the preparation of 2,6-pyridinedimethyl ditosylates from dimethyl 2,6-


3729

pyridinedicarboxylates without isolating the corresponding diols. We note here that 4-allyloxy- and 4-tetrahydropyranyloxy-2,6-pyridinedimethanoI can be isolated with reasonable yields using the extraction above


procedure. le."'

Acknowledgement. Financial support of the Hungarian Scientific Fund

(OTKA T-14942 and T-25071) is gratefully acknowledged.

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3731

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