α-substituted phosphonates. 64. phosphono-substituted imidazoles and other heterocycles from...

J. prakt. Chem. 336 (1994) 29-37

Journal fur praktische Chemie Chemiker-Zei tung

0 Johann Ambrosius Barth 1994

a-Substituted Phosphonates. 64 [l]

Phosphono-substituted Imidazoles and other Heterocycles from Diethyl [(2,2- dichloro- 1-isocyano)-ethenyllphosphonate

Michael Schnell, Matthias Ramm and Angela Kockritz Berlin-Adlershof, Zentrum fur Selektive Organische Synthese

Received February 23rd. 1993

Dedicated to Professor Ernst Schmitz on the Occasion of his 65th Birthday

Abstract. The reaction of diethyl [( 1 -isocyano-2,2-dichloro)- ethenyllphosphonate (1) with mono- and bifunctional aliphatic and aromatic amines and thiols has been studied. Because 1 is a push-pull olefine, a nucleophilic attack can take place at the halide-substituted carbon atom. On the other hand, 1 possesses with the isocyano group a further reactive centre, which is able to undergo typical isocyanide reactions. With secondary and ethylene-bridged bifunctional nucleophiles the substitution of

the chloro atoms of 1 furnishes ketene N,N-, N,S- and S,S-acetals (8, 12, 14). By treating 1 with primary amines imidazoles 6 are obtained, an a-addition of an amino function to an isocyano group under mild conditions being involved. The isocyano-substituted cyclic ketene N,N-acetal 12 a inserts acceptor-substituted isocyanides forming the fused pyrazines 18. The structure of 18 a is corroborated by X-ray crystal structure analysis.

Phosphorylated imidazoles and fused imidazole derivatives have been of growing interest in the last years because of their structural analogy with physiologically ac- tive substances [2]. Recently we have published the rearrangement of l-formylimino-2,2,2-trichloroethane- phosphonate to 2,2-dichloro- 1 -isocyanoethenylphospho- nate (1) via the formimide chloride intermediate [3].

Compound 1 is an ambivalent push-pull olefine. Not only the isocyano group of 1 can undergo the typical isocyanide reactions [4], but also the C(2)-atom is accessible to nucleophilic attacks, as shown in previous communi- cations [5, 61. With suitable bifunctional reagents it should be possible to involve both the carbon atoms. Hence, we were interested in using 1 as a synthon for new phosphorylated heterocycles.

We found a more convenient method of preparing 1- isocyano-2,2-dichloroethenylphosphonate (1) in 85 % yield by reaction of phosphono-trichloroethaneforma- mide (2) with phosphorus pentachloride and subsequent addition of a base (Scheme 1).

0 0 0

P(oEt)z

NH-CHO N=CH-CI NC

2 3 1

I1 I1 I1 P(OEt)z NEr3 P(OEt)z

CI*C =( PC15 C I S < - CI,C-(

Scheme 1

With halogens and hydrazoic acid, 1 shows the typical behaviour of an isocyanide and reacts to the carbonimidic dihalides 4 a, b and the tetrazole 5 (Scheme 2).

0

4 0

5

Scheme 2

With primary amines, the isocyanide 1 undergoes cyclization to the 4-phosphono-5-amino-imidazoles (6) at 0 - 20°C (Scheme 3) . To form these rings the nucleophilic attack on the C(2)- atom of 1 is followed by an a-addition of one enamino group to the isocyano carbon atom. This is remarkable because a-additions of amines have only been described so far using catalysts (e. g. Cu, Ag, Hg salts) and higher

30 J. prakt. Chem. 336 (1994)

R 6

6 1 a b c d e ~~

RI Me Et Pr Bu 4-CH3-C,H4

Scheme 3

temperatures [7, 81. The reason for the facile imidazole formation could be the high electron density on the isocyano carbon atom owing to the push-pull system.

With secondary amines, 1 gives the ketene N,N-acetals 8 a, b via successive nucleophilic substitution (Scheme 4). In contrast to the above-mentioned reaction pattern of primary amines, it is possible to obtain and character- ize the monoamino derivatives 7 a, b as crude products.

Scheme 4

Attempts to purify 7 a, b by silica gel column chromatography (acetonehexme) led to the Passerini reaction products 9 a, b. The acid centres of silicagel support the enolization of acetone which forms with 7 a, b the oxa- zoles 9 a, b. Toluenesulphonic acid as catalyst shows the same effect. 7 a reacts with methylamine in the same manner as described above affording the imidazole 10. Acid hydrolization of the ketene N,N-acetals 8 leads to the known oxazole 11 151 via the intermediate formamide.

Similar to secondary amines, 1 reacts with ethanethiol and ethylene-bridged bifunctional nucleophiles (Scheme 5) . So iiucleophilic displacement on the C(2)-atom with- out changing the isocyano group could be observed with ethylendiamine (12 a), cysteamine (12 b), ethanedithiol (12 c) and ethanethiol (14). The isocyanide 12 a was char- acterized by its reaction with hydrazoic acid to the tetrazole 13. In contrast to the ethylenediamine substitution, the use of propylendiamine as nucleophilic agent resulted in a subsequent a-addition reaction forming the fused

imidazole 16. Compound 12 a did not form a similar bicyclus as presumed for sterical reasons.

14 16

1;IZ ; ; 1 5 l a b II

R Et 4-CH,-C6H,

EtS N=CH-NHR Y N H N H S 15

Scheme 5

The ketene dithioacetall4 reacts with amines exclusively on the isocyano moiety to afford the methanimidamides 15 a, b. A displacement of the alkylthio by amino substi- tuents, as known from bisphosphono-ketene dithioacetals [9, lo], was not observed and the C(2)-atom of 12 is less reactive towards amines than the isocyano carbon atom. The dichloro-substituted isocyanide 1 shows the reverse reactivity. That emphasized that the approach to phosphono-substituted imidazoles 6 is only possible from 1.

A very surprising result was observed by the reaction of 1 with ethylenediamine under PTC conditions (CH2CI2/aqueous NaOH/TEBA). In the "P-NMR spec- trum of the reaction solution, beside the signal of 12 a with 6 = 20.0 ppm a new one appeared with 6 = 15.8 ppm.

R-NC 12a __c

17,18 la b C

R IC12C=CH Cl,C=C-P(O)(OEt), CH,-C,H4-S02CHz

Scheme 6

After column chromatography we isolated the fused di- hydropyrazine 18 a (Scheme 6). This is a new kind of phosphono-substituted heterocycles, only pteridines phosphorylated in 6-position have been published so far 1111.

The formation of 18 a can be explained by the reaction of 12 a with 2,2-dichloroethenyl isocyanide which yields from unreacted 1 by basic hydrolysis owing to the reac-

M. Schnell et al., Phosphono-Substituted Imidazoles 31

CLI

C8

CL2

c5

Fig. 1 ORTEP drawing for 5-(2,2-dichloroethenyl)imino-8-diethoxyphosphono- 1,3,4,5-tetrahydroidazoIo[ 1,2-a]pyrazin (18 a)

tion conditions. The first reaction step is the linkage of both the isocyanide carbon atoms to a diazaallene intermediate 17 a, which is attacked in the second step by the NH group of the imidazolidine ring to form the bicyclus. Dimerization of isocyanides including C-C linkages has already been published [ 121. However, to our knowledge this cyclization is the first example for the reaction of two different isocyanides with an amino or enamino group. We assume that the reason for the formation of 18 is the push-pull character of the isocyanide 12 a. It has a high electron density on its isocyano carbon atom and so it can be connected with an electron-deficient one of an acceptor-substituted isocyanide. We could obtain the analogous compounds 18 b, c from 12 a with the acceptor-substituted 2,2-dichloro- 1 -isocyanoethenylphos- phonate and toluolsulfonyl-methylisocyanide, respectively. Experiments with cyclohexyl isocyanide and 2- (4-morpholinyl)-ethyl isocyanide failed.

It is interesting that the bicyclus 18 b is stable against hydrolysis. The elimination of the phosphono group from the side chain of 18 b failed and so did the conversion of 18 b into 18 a. That means that two competitive reactions must have taken place by treating 1 with ethylendiamine, P-C splitting and nucleophilic displacement, forming 2,2- dichloroethenyl isocyanide and 12 a, respectively. Unfor- tunately, we could not prove this reaction mechanism,

because it was neither possible to detect nor to prepare the unknown 2,2-dichloroethenyl isocyanide.

The structure of 18 a was corroborated by an X-ray crystal structure analysis [ 141. An ORTEP drawing [13] of the molecule is shown in Figure 1. Some bonds (Cll-C6,02-C9,03-C11, C9-CI0, Cl l -Cl2) are shor- tened due to high thermal motion of the corresponding atoms. The P atom is coordinated with three oxygen atoms and the carbon atom C3 thus forming a slightly disordered tetrahedron. The average derivations of the atoms from the least-squares planes of the rive- and six-membered ring are 0.026(4)A and 0.041 (4)A, respectively. The dihedral angle between these two rings amounts to 3.4(9)". The atoms 0 1 and N4 are included in an intra- and intermolecular hydrogen bond. The parameters ot the bifurcated hydrogen bonds are: 01 .." = 2.899(5)A, 01 ... HN4 = 2.43 (5 )0 A,& 01 ... HN4-N4 = 117(4)"; 0 1 ... N4" = 2.892(5)A; 01 ... HN4*-N4* = 2.21(5)A; 4 01 ... HN4*-N4* = 140(4)", * = ( 2 - ~ , l-y, 1 -z).

We would like to thank Prof. H. GroR for supporting this work and Dr. E. Grundemann and Dr. B. Costisella for record- ing of NMR spectra. We are grateful to the BAYER AG for generous support.

32 J. prakt. Chein. 336 (1994)

Experimental

'H NMR spectra were recorded with a TESLA BS 587 A using CDC13 as solvent and HMDS as internal standard. I3C NMR and 3'P NMR spectra were obtained on a Varian Gemini 300 (I3C, internal standard TMS; "P, external standard 85 % H3P04). 'H and "C NMR signals of the phosphono ester groups are not reported. Column chromatography separations (pressure 4.7 kPa) were performed by using Merck silica gel 60 (0.040- 0.063 mm). TLC analyses were done on Silufol (silica gel) pre- coated alumina plates and the spots were visualized by charring with 1 % ethanolic solution of molybdatophosphoric acid and warming the plates.

Diefhyl [(2,2-dichloro-I -isocyano)ethenyl]-l~hosphonate ( I )

7.81 g (25 mmol) of formamide 2 and 5.21 g (25 mmol) PCIs in 50 ml anhydrous CCI4 are stirred at 50 "C for 30 min. CCIJ is evaporated under reduced pressure and the residue is soluted in 200 ml absolute Et20. The solution is stirred at 0-5 "C, and 6.07 g (60 mmol) NEt, is added dropwise very slowly. After standing overnight in the refrigerator, Et3N x HCI formed is filtered off, the solvent is evaporated and the residue is chromatographed on a silica gel column (acetic ester).

yield: 83 %, nD2': 1.4839; analytical and spectroscopical data see 131.

The isonitrile 1 is not stable in substance even by standing in the refrigerator at - I8 "C: but so is the etherous solution of the

crude product. Its purity was controlled with TLC and 31P NMR spectroscopy and was satisfactory.

[(2,2-Dichloro- I-diethoxyphosphono-)ethenyl]-carbonimidic dichloride 4 a)

2.58 g (1 0 mmol) of the isocyanide 1 is dissolved in 30 ml absolute CH2C12 and 1.06 g (15 mmol) CI2 is bubbled into the ice- cold stirred solution of 1. Stirring was continued at 0 "C for 30 min. Then the solvent and excess Clz are evaporated. The residue is purified by Kugelrohr destillation (analytical and spectroscopic data see tables 1 and 2).

[(2,2-Dichloro-l -cliethox~~~1~osphono)ethenyl]-carboizimidic dibromide (4 b)

To 2.58 g (10 mmol) of 1 in 50 ml ether 0.80 g (5 mmol) Br2 is dropped at room temperature. Five minutes later the solvent is evaporated and the residue purified by Kugelrohr destillation (analytical and spectroscopic data see tables 1 and 2).

I -1(2,2-Dichloro-l -diethoxyphosphono)ethenyl]-tetruzole (5)

To 1.29 g (5 mmol) 1 in 20 ml toluene is dropped 10 ml of a 0.5 m solution of hydrazoic acid in toluene at 0 "C. The mixture is allowed to stand 3 days at 4 "C. Then the solvent is evaporated and the residue chromatographed on a silica gel column (acetic ester) (see tables 1 and 2).

Table 1 [(2,2-Dichloro- 1 -diethoxyphosphono)ethenyl]-carboniniidic dihalides (4 a, b) and - 1 -tetrazole (5)

Product Hal Yield b. p./m. p. n D Molecular [%J I"C1 ("C) Formula

Analysis calc ./fou nd C H N

4 a C1 81 110-1 15 1.5029 C7HioCl,NO1P 25.56 3.06 4.26 (40 Pa) (23) (329.0) 25.86 3.18 4.41

4 b Br 74 120-125 1 S363 C7H,&12Br2N03P 20.12 2.41 3.35 (40 Pa) (23) (4 17.9) 20.46 2.69 3.37 32 - 35

- 5 53 1.4968 C ~ H I I C W ~ O ~ ' 27.93 3.68 18.61 (24) (301 . l ) 27.45 3.63 18.20

Table 2 NMR spectroscopic data of [(2,2-dichloro- I -diethoxyphosphono)ethenyl]-carbonimidic dihalides (4 a, b) and - 1 -tetrazole (5); Gfppml, J W I Product 'H NMR 13C NMR

CP C12C other signals

( ' JCP) (2JccP)

"P NMR

134.6 122.3 134.1 (d, NC, J = 10.6) 3.6 (2 13.0) (20.2)

137. I 102.1 121.9 (d, NC, J = 20.3) 1.9 (204.5) (11.4)

5 8.76 ( 1 H, s, CH) 123.4 143.4 143.6 (CH) (213.1) (23.8)

2.7


I-Alk)~l(aryl)-5-alkyl(aryl)uinirio-4-diethoxypho.sphono-imida- Zoles (6 a-e)

and the uncoloured oily residue i b used for further reactions (analytical and spectroscopic data see tables 5 and 6).

To 1.29 g (5 mmol) 1 in 30 ml Et20 2.5 mmol of the amine are dropped under stirring at 0 "C. The stirring is continued for 2 h, then the solution is allowed to stand overnight. The precipitate is filtered off, the solvent evaporated and the residue chromatographed on a silica gel column (acetone/hexane 1 : 1) (analytical and spectroscopic data see tables 3 and 4).

Diethyl [(2-chloro-2-dialkylarnino-l -isocyano)ethenyl] phosphonates (7 a, b)

To I .29 g (5 mmol) of 1 in 20 nil absolute ether 10 mmol of the amine is added dropwise at 0°C. After I h the precipitate is filtered off, the solvent is evaporated under reduced pressure

Diethyl [(2,2-bis(dialkylarnino)- I -isacyano)ethenyl] phosphonates (8 a, b)

1.29 g (5 mmol) 1 is dissolved in 20 ml absolute ether. 30 mmol of the amine is added dropwise to the ice-cold stirred solution. Three days later the hydrochloride is filtered off, the solvent evaporated and the crude crystals are purified by column chromatography (acetic ester) (see tables 5 and 6).

5-Alkylumino-4-diethoxyphosphono-2-isopr~~~~enyl-~~.~u~~~le.s (9 a, b)

5 mmol of the crude 7 a, b are stirred with 0.4 g toluenesulfonic acid in 10 ml absolute acetone for 60 min. Then the acetone is

Table 3 1-AIkyl(aryl)-5-alkyl(aryl)amino-4-diethoxyphosphono-imidazoles (6 a-e)

Product R Yield ndm. p. Molecular Analysis calc./found [%I ("C)/["CI Formula C H N

6 a Me 61 1 SO35 C9H18N303P 43.72 7.34 17.00 (23) (247.2) 43.53 7.08 16.77

6 b Et

6 c Pr

6 d Bu

64 1.4903 C11H22N303P 47.99 8.06 15.26 (23) (275.3) 47.76 7.97 15.16

73 1.4855 c I3H26N303P 5 1.47 8.64 13.85 (25) (303.3) 5 1.45 8.68 13.74

72 1.4833 (24)

c I 5H30N303P 54.36 9.12 12.68 (331.4) 54.18 8.92 12.48

6 e 4-CH3-C6H, 53 120-1 2 1 C21H26N303P 63.15 6.56 10.52 (399.4) 63.03 6.63 10.50

Table 4 NMR spectroscopic data of 1 -alkyl(aryl)-5-alkyl(aryI)amino-4-diethoxyphosphono-imidazoles (6 a-e); Glppml, JlHzl

Product 'H NMR I3C NMR "P NMR CH = N other signals CP CH = N N2C other signals (4JHCNCP) ('JCP) (3JCNCP) (2JCCP)

6 a 7.23 2.77; 3.52 (6H, 2s, NCH3), 110.2 136.0 151.2 31.3: 35.1 (NCH?) 13.9 (2.9) (248.0) (21.4) (36.7)

6 b 7.28 1.16: 1.40 (6H, 2 t, 112.3 (2.9) NCHlCH3)2,99;3,84(4H, (247 .O)

2q, NCH?), 4.75 ( 1 H, S, NH)

6 C 7.24 0.88; 0.92 (6H, 2t, 110.5 N(CH&CH3), 1.58; 1.82; (246.3) 2.89: 3.74 (8H, NCH2CHJ

6 d 7.23 0.88; 0.93 (6H, t, 111.9 N(CHZ)?CH3), 2.94: 3.77 (247.9) (12H, m, N(CH2M

6 e 7.49 2.07; 2.22 (6H, 2 ~ , CH3), 116.5 6.79 (8H, m, aryl) (247.0)

134.8 (22.0)

135.3 (20.7)

135.3 (22.0)

136.3 (21.0)

149.3 (37.3)

149.3 (35.8)

149.7 (37.2)

143.4 (36.1)

15.3; 15.5 (NCHlCH,), 13.9 39.3; 43.9 (NCHZ)

11.2: 11.4 14.8 (N(CHXH3), 23.0; 23.5: 46.2: 5 1.1 (NCH2CH2)

13.5: 13.8 14.1 (N(CH~).ICH~), 19.9; 20.0: 31.8; 32.4; 44.4; 49.2 (N(CH&

20.5; 21.0 (CH,), 11.8 117.8; 124.0; 129.5; 130.2; 13 1 .O; 133.0; 138.4; 141.3 (aryl)

34

Table 5

J. prakt. Chem. 336 (1994)

Enamines, ketene N,N-acetals (7 a-8 b) and their reaction products (9 a-10)

Product R], R2 _ _ _ _ _ _ _ _ ~

Yield m.p. n D Molecular Analysis calc./found [%I ["CI ("C) Formula C H N

7 a Me 99"' 1 SO65

7 b C2H40C2H4 83"' 1.5258 (25)

(22) 8 a Me 73 62 - 65

8 b C2H40C2H4 28 140-45

9 a Me 25

9 b C2H40C2H4 32

10 - 38

1.5036 (23) 1 S230 (25)

b)

47.99 8.06 47.73 8.17

50.13 7.29 49.67 7.30

50.00 7.34 49.7 1 7.34

50.91 7.02 50.48 7.02

45.97 7.72 45.77 7.90

15.26 15.04

1 1.69 11.54

9.72 9.54

8.48 8.11

16.08 15.77

~~ "' crude products, b, purifying of crude products was not possible

Table 6 NMR spectroscopic data of enamines, ketene N,N-acetals (7 a-8 b) and their reaction products 9 a-10); G[ppm], J[Hz]

Product 'H NMR I3C NMR 3'P NMR

7 a 2.84; 3.10 (6H, 2 ~ , NCH3) 43.0; 44.7 (NCH3), 88.1; 89.2 (2 d, PC, 8.6, 1 1.3"'

7 b 3.37; 3.52; 3.65; 3.71 48.3; 50.6; 52.8; 66.2; 66.4 (NCH2 + OCH2), 6.7,

J = 249.0; 233.9), 154.6; 156.8 (2 d, CINC, J = 22.0; 24.8), 166.7; 167.6 (NC)"'

(8H, 4t, NCH2 + OCH2) 91.8 (d, PC, J = 245.3) 153.6; 155.8 (2d, CINC, 9.5"' J = 21.4; 23.5), 169.1; 169.4 (NC)"'

8 a 2.82; 2.84 (12H, 2s, NCH3)

40.5; 41.3 (NCH3), 69.6 (d, PC, J = 241.5), 160.8 (NC), 167.6 (d, N2C, J = 23.8)

17.3

8 b 3.30 (4H, m, NCH2), 3.72 49.6; 50.6 (NCH2), 66.2; 66.5 (OCH2), 72.3 16.7

9 a 1.99 (3H, S, CH3) 3.09 (6H, S , NCH3), 5.14; 5.54 (2H, 2 S, C = CHZ)

2.02 (3H, S, CH?), 3.65 9 b (SH, m, OCH2 + NCH2), 5.20; 5.59 (2H, 2 ~ , C = CH2)

2.79; 3.42 (9H, 2 ~ , NCH3), 10 7.31 (1H, d, CH)

(d, PC, J = 244.4), 163.0 (NC), 166.4 (d, N2, C, J = 23.5)

18.6 (CH3), 40.2 (NCHl), 99.4 (d, PC, J = 256.7) 115.1 (C=CH2), 131.0(C=CH2), 152.1 ( d , O C = N , J = 22.0), 161.7 (d, NCO, J = 37.4)

13.4

18.6 (CH,), 48.2 (NCH2), 66.2 (OCHZ), 102.3 (d, 12,l PC, J = 252.9), 116.0 (C = CHZ), 131.0 (C = CH2), 153.2 (d, OC = N, J = 22.0), 161.0 (d, NCO, J = 37.1)

30.1; 43.8 (NCH3), 119.2 (d, PC, J = 247.7), 12.7 135.3 (d, CH, J = 22.1), 150.6 (d, N2C, J = 36.1)

"' E/Z isomers

evaporated and the residue chromatographed on a silica gel column (acetonehexane 1 : 3) (see tables 5 and 6).

is filtered off and the residue is chromatographed on a silica gel column (acetonehexane 1 : 2) (see tables 5 and 6).

4-Diethoxyphosphono-5-dimethylamino-l-methyl-imidazole 4-Diethoxyphosphono-5-(4-morpholinyl)-oxazole (ZZ) (ZO)

1.33 g (5 mmol) of the crude 7 a in 20 ml absolute ether and 0.68 g (I5 mmol) dimethylamine are stirred at 0 "C for 3 h. Then the mixture is kept at this temperature for 2 days, the precipitate

1.80 g (5 mmol) 8 b in 45 ml ether and a solution of 1 ml HC1 conc. and 10 ml H20 are stirred for 15 min. Then the ether phase is separated and the aqueous phase is extracted twice with 30 ml CH2CI2. The unified organic solutions are concentrated by eva-


Table 7 Cyclic ketene N,N-, N,S- and S,S-acetals and their derivatives (12-16)

Product Yield n,/m.p. Molecular Analysis calc./found [%I (oc)/[ocl Formula C H N

12 a

12 b

12 c

13

14

15 a

15 b

16

64

61

70

57

66

48

48

42

93 -95

1.5378 (25) 66 - 75

1.5658 (26) 100-1 04

1 s455 (25) 1 s455 (26) 111-112

54-59

C9H16N303P (245.2)

CYH15N203PS (262.3)

44.08 43.86

41.21 41.05

78.70 38.56

37.50 37.34

42.70 42.34

44.05 43.79

5 1.90 52.01

46.5 1 46.39

6.58 6.49

5.77 5.71

5.05 5.23

5.94 5.92

6.52 6.86

7.68 7 69

7.02 7.08

6.64 6.90

17.14 16.97

10.68 10.46

5.01 4.89

29.16 29.61

4.53 4.70

7.90 7.83

6.73 6.60

16.27 15.98

poration and the oily residue is chromatographed on a silica gel column (acetone/hexane 1 : 2).

yield: 41 %, nD2': 1.500. Analysis and spectroscopic data are identical with an authen-

tical sample of 4-diethoxy-phosphono-5-(4-niorpholinyl)-oxa- zol [5].

Diethyl [(imidazolidine-2-yliden)isocyano)methyl] phosphonate (12 a)

2.58 g (10 mmol) of 1 is stirred in 20 ml absolute ether at 0 "C. 1.20 g (20 mmol) ethylendiamine in 10 ml absolute ether is dropped slowly to this solution. After 5 h precipitated hydrochloride is filtered off, solvent is evaporated and the product is purified by column chromatography (acetic ester) (see tables 7 and 8).

Diethyl [isocyano(thiazolidine-2-yliden)methyl]phosphonate

2.58 g (10 mmol) of 1 and 3.41 g (30 mmol) cysteaniine hydrochloride are stirred in 25 ml absolute ether. Potassium tert-butylate is given in portions to this suspension. Stirring is continued for 5 h. The precipitate is filtered off, solvent evaporated and the residue chromatographed on a silica gel column (acetonehexane 1 :4) (see tables 7 and 8).

(12 b)

Diethyl [( (1,3-dithiolane -2-yliden) isocyano)methyl] phosphonate (12 cj

2.58 g (10 mmol) of 1 and 0.94 g (10 mmol) ethanedithiol are dissolved in 25 ml absolute ether. 2.24 g (20 mmol) of potassium tert-butylate is given in portions to the stirred solution. Stirring is continued for 5 hours. The precipitate is filtered off, solvent evaporated and the residue chromatographed on a silica gel column (acetic ester) (see tables 7 and 8).

I -[Diethoxyphosphono-(thiazolidine-2-yliden)nzethylJ-tetm zole (13)

To a stirred solution of 1.23 g (5 mmol) 12 a in 30 ml toluene 10 ml of a 0.5 m solution of hydrazoic acid in toluene is dropped. Stirring is continued for 2 h. Then the solvent is evaporated under reduced pressure and the residue purified on a silica gel column (acetic ester) (see tables 7 and 8).

Diethyl [(2,2-bis(ethylthio)-l-isocyano)ethenyl]phosphonate

2.58 g (10 mmol) 1 and 1.37 g (22 mmol) ethanethiol are stirred in 30 ml absolute ether at 0 "C. Potassium tert-butylate is given in portions to this solution. After 2 h the precipitate is filtered off and the residue purified on a silica gel column (acetic ester) (see tables 7 and 8).

(14)

N-[2,2- Bis(ethy1thio)- 1 -diethoxyphosphono-jethenylj-N'- ethyl- methanimidamide ( I 5 a)

1.55 g (5 mmol) of isocyanide 14 is stirred with 0.34 g (7.5 mmol) of ethylamine at 0 "C for 3 days. Then the oily product is chromatographed on a silica gel column (acetone/hexane I :3) (see tables 7 and 8).

N-[(2,2-Bis(ethylthio-)l -diethoxyphosphono)ethenyl]-N'-4- tolyl-methanimidamide (15 b)

1.55 g ( 5 mmol) of isocyanide 14 and 0.54 g ( 5 mmol) p-tolui- dine are warmed to 50 "C for 30 min. The mixture crystallized completely. Recrystallization is carried out from benzene (see tables 7 and 8).

36

Table 8

Product 'H NMR "C NMR 3'p NMR

J. prakt. Chem. 336 ( 1 994)

NMR spectroscopic data of cyclic ketene N,N-, N,S- and S,S-acetals and their derivatives (12 a-16); Glppm], J[Hz]

CP other signals ('Jot)

12 a

12 b

12 c

13

14

15 a

15 b

16

3.60(4H, S , NCHZ), 5.72; 6.80 (2H, 2s, NH)

3.22 (2H, t, SCHZ), 3.77 (2H, t, NCHz), 7.65 (IH, S, NH)

3.50 (4H, dq, SCHJ

3.59 (4H, S, NCH2). 8.39 (IH, s, CHI

1.17 (6H, t, SCH&HJ), 2.80; 2.95 (4H, 2q, SCH2)

1.22 (15H, m, CH3), 2.78 (4H, dq, SCH2), 3.29 (2H, m, NCH2), 4.82 (lH, s, NH), 7.34 (lH, s, CH)

1 . I 1 (6H, t, SCH,CH,), 2.22 (3H, S, CH3), 2.79 (4H, q, SCH2) 6.98 (4H, m, aryl), 8.00 (IH, s, CH), 8.36 (IH, s, NH)

2.1 I (2H, q, CH-J, 3.30; 3.91 (4H, 2t, NCHJ, 7.01; 7.17 (lH, d, CH, J = 2.9)

60.0 (247.1)

76.6 (224.1)

99.9 (226.5)

64.4 (252.3)

144.7 (198.8)

145.6 (195.3)

143.1 (212.5)

100.3 (257.1)

43.3; 44.4 (NCHZ), 163.2 (NC), 164.8 (d, N2C, J = 26.6)

30.3 (SCHl), 50.6 (NCH2), 165.1 (NC), 170.7 (d, NSC, J = 22.7)

37.6; 40.8 (SCH2), 168.7 (NC) 169.9 (d, S?;C, J = 21.1)

43.8 (NCH2), 146.6 (CH), 163.9 (d, N2C, J = 30.3)

14.1; 14.7; 15.0 (SCHZCH,), 23.1; 27.1; 30.0 (SCHZ), 161.9 (d, S2C, J = 8.5), 163.2 (d, NC, J = 9.1)

14.0; 14.6; 14.9 (NCH2CH1, SCH?CH7), 26.6; 30.0 (SCHZ), 35.4 (NCH?), 130.3 (d, S2C, J = 31.8), 151.6 (CH)

14.1; 14.8 (SCH,CH,), 20.7 (CHI), 27.0; 30.0 (SCH?;), 117.2; 129.8; 132.4; 137.7 (aryl), 144.4 (d, S2C, J = 7.8), 151.1 (CH)

21.5 (CH2), 39.1; 41.2 (NCHZ) 132.0 (d, CH, J = 21.6), 147.4 (d, NZC, J = 37.1)

20.0

15.1

7.1

18.8

9.2

12.0

11.3

15.6

8-Diethoxyphosphnno-l,2,3,4-tetrahydroimidazo[ I,j-a]pyritni- dine (16)

2.58 g (10 mmol) of 1 and 2.22 g (30 mmol) 1,3-diaminopro- pane are stirred in 10 ml absolute ether for 5 h. The solvent is evaporated, the residue is dissolved in 20 ml CH2C12, extracted twice with 10 ml H 2 0 and dried over Na2S04. CH2C12 is evaporated and the product purified on a silica gel column (acetone) (see tables 7 and 8).

5-(2,2-Dichloroethei~yl)imino-8-dietl7oxy~ho.~pholzo-1,2,3,5- tetrahydroimiduzo[l.2-a]p~~razin (18 a)

To a solution of I .29 g (5 mmol) 1 in 20 ml CH2C12 a solution of 0.40 g (10 mmol) NaOH in 30 ml H20 is mixed. A spatula-

tipfull TEBA is added. Under vigorous stirring 0.30 g (5 mmol) ethylendiamine in 10 ml CH2C12 is added dropwise. Stir- ring is continued for 5 h. The phases are separated, the organic phase is extracted twice with 10 ml H20 and dried with Na2S04. The solvent is evaporated and the yellow product purified on a silica gel column (acetonehexane 1 : 3) (see tables 9 and 10).

5-[(2,2-Dichloro-l -diethoxyphosphono)ethenyl]imino-8-dieth- n,~~ip~ios/712orro- 1,2,3,5-tetra-hydroimi~azo[l.2-a Jpyrazin (I8 b)

0.52 g (2 mmol) 1 and 0.49 g (2 mmol) 12 a are stirred in 5 ml CHC13 for 3 days. Then the solvent is evaporated and the residue chromatographed on a silica gel column (see tables 9 and 10).

Table 9 Substituted 8-diethoxyphosphono-5-irnino- 1,2,3,5-tetrahydroi midazo[ 1.2-alpyrazines (18 a-c)

Product R Yield m. p. Molecular Analysis calc./found L%I ["CI Formula C H N

18 a CI2C = CH 41 185-1 86 ClZHI7C12N403P 39.25 4.67 15.26 (367.2) 39.03 4.68 15.07

18 b C12C = c- 32 138-141 ClbH26C12NJOOP2 38.19 5.21 11.13 I (503.3) 38.05 5.17 10.98

18 c Tos yl-CHi') 47 143 -1 46 C,xH25"043 49.08 5.72 12.72 (440.4) 48.8 1 5.70 12.62

(EtO)2P(O)


Table 10 NMR spectroscopic data of the substituted 8-diethoxyphosphono-5-imino- I ,2,3,5-tetrahydroimidazol[ I .2-a]pyrazines (18 a-4; G[ppml, J [Hzl

Product 'H NMR

CH=N other signals

I3C NMR

CP CH=N NzC other signals ('JCP) (?JCNCP) (*JCCP)

"P NMR

18 a 7.31 3.77 (2H, t, NCH2), 4.08 98.4 127.9 (6H, m, POCH2 + NCH?), 6.75 (259.2) (19.9) (IH, s, NH), 7.52 (IH, s, C = CH)

18 b 7.22 3.79 (ZH, t, NCHI), 4.09 97.3 129.1 (6H, m, POCH:, + NCH?), (260.6) (19.8) 6.92 (lH, s, NH)

18 c 7.39 2.38 (3H, S , CH3), 3.76 (2H, 96.8 126.9 t, NCH*), 3.99 (6H, m, POCH2 (255.7) (19.9)

6.89 (lH, s, NH), 7.28; 7.76 (4H, 2d, aryl, J = 8.2; 8.3)

+ NCH2), 4.76 (2H, S, SCHZ),

153.0 42.2; 45.2 (NCHZ) 15.8 (37.3) 114.0 (CI?C), 131,O

(C = CH), 144.3 (N = C)

152.4 42.0; 44.9 (NCH,), 119.1 8.7, (37.2) (d, CI?, C, J = 34.0) 13.5.6 15.8

(d, PC = CCI,, J = 201.8) 144.5 (d, N = C, J = 6.6)

152.6 21.7 (CH,), 42.1; 16.1 (37.1) 44.9 (NCH2), 70.0 (SCH*),

129.0; 129.5; 13.5.0; 147.8 (aryl), 144.7 (N = C)

5-( Toluenes~ilfony~n~e~h~yl)imii~o-8-diethoxyp~osphono- I , 2,3,5- tetrahydroimiduzo[l.2-a]pymzin (18 c)

1.23 g ( 5 mmol) 12 a and 0.98 g (5 mmol) tosylmethylisocya- nide are stirred in 20 ml absolute toluene for 4 days. Then the solvent is evaporated and the residue purified on silica gel column chromatography (see tables 9 and 10).

X-ray structure analysis of (I8 a) 1141

Ayellow crystal with approximate dimensions of 0.30 x 0.33 x 0.28 mm' was chosen for difractometer studies. Measurements of intensities were performed at room temperature on an auto- matic four-circle diffractometer (Enraf-Nonius CAD 4) by the 0-20 scan technique. Graphite-monochromatized MoKa (h = 0.71073 A) radiation was used. The cell dimensions were determined by least-squares refinement employing the setting angles of 25 reflections in the region 10.1"<@< 17.6". The compound crystallizes in the triclinic space group P 1 with a = lO.lOl(l), b = 10.705(5), c = 8.048(2)A, a = 105.09(3), p = 95.53(1), y = 82.33(2)". A total of 3090 reflections was measured in the region 1.5" <@< 25" (h- 12+12,k 0-+12,1-97-9). The data were corrected for Lorentz and polarisation effects. The structure was solved by MULTAN 11/82 [ 151, Fourier methods and refined using least-squares procedures which minimized the function Cw(AF)'. The applied weighting scheme was w(F) = l/02(F). Extinction correc- tion was applied. 228 parameters were refined. Full matrix least-squares refinement of the atomic positions and the aniso- tropic temperature factors for the non-H atoms and isotropic temperature factors for some H atoms located by difference Fourier synthesis reduced R to 0.056 (wR to 0.079) for 2054 reflections with Fo>30(Fo). The maximum residual electron densitya eak in the final difference Fourier map accounts to

on a VAXstation 31 00 using program system Enraf-Nonius Mo- len [ 161 with the atomic scattering factors included.

0.73 eA 1: . All crystallographic computations were performed

References [ 11 63th communication: A. Kockritz, M. Schnell, Phosphorus,

Sulfur, and Silicon, 73 (1992) I85

G. L. Matevosyan, P. M. Zavlin, Khim. Geterosikl. Soe- din. 1990, 723 A. Kockritz, G. Rohr, M. Schnell, Phosphorus, Sulfur, and Silicon 63 (1 99 1) 95 Summary: C. Grundmann in: HoubenWeyl, Methoden der Organischen Chemie, vol. E5, p. I61 1, Georg Thieme Verlag Stuttgart, New York, 198.5 S. Scheidecker, A. Kiickritz, M. Schnell, J. Prakt. Chem. 332 (1990) 968 G. Rohr, A. Kockritz, M. Schnell, Phosphorus, Sulfur, and Silicon 71 (1992) 157 T. Saegusa, Y. Ito in: I. Ugi (Ed.), Isonitrile Chemistry, p. 65, Academic Press, New York 1971 J. V. Mitin, V. R. Glushenkova, G. P. Vlasov, Zh. Obshch. Khim. 32 (1962) 3867 R. Neidlein, T. Eichinger, Synthesis 1991, 1228 D. Villemin, F. Thibault-Starzyk, E. Esprimont, Phospho- rus, Sulfur, and Silicon 70 (1992) 117 C. B. Vicentini, A. C. Veronese, M. Guarneri, P. Giori, Heterocycles 32 (1991) 79 G. Hofle, B. Lange, Angew. Chem. 89 (1977) 742 C. K. Johnson, ORTEP 11, Report ORNL-3794, revised, Oak Ridge National Laboratory, Tennessee, U.S.A., 1971 Additional material to this paper can be ordered refering to the no. CSD-57063, the names of the authors and the journal citation from the Fachinformationszentrum Energie, Physik, Mathematik GmbH, W-75 14 Eggenstein, Leopoldshafen 2, Federal Republic of Germany P. Main, S. J . Fiske, S. E. Hull, L. Lessinger, G. Germain, J.-P. Declerq, M. M. Wooifson, MLTLTAN 11/82, Univer- sity of York, England and Louvain, Belgium 1982 Enraf-Nonius Molen, Structure Determination System, 1990

Address for correspondence

Dr. Angela Kockritz Zentrum fur Selektive Organische Synthese Rudower Chaussee 5 D- 12489 Berlin, Germany

α-substituted phosphonates. 64. phosphono-substituted imidazoles and other heterocycles from...

Documents