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Re-functionalization of 9-Substituted Isocolchicides via Nucleophilic 7e/e-Substitution. A General Synthesis of ll-Alkyl(Aryl)thioisocolchicidesM arino Cavazza3, Francesco P ietra5a Dipartimento di Chimica e Chimica Industriale, Universitä di Pisa, 56126 Pisa, Italy b Istituto di Chimica, Universitä di Trento, 38050 Povo-Trento, ItalyZ. Naturforsch. 51b, 1347-1351 (1996); received May 8, 1996Alkyl(aryl)thioisocolchicides, Functionalization, Tele- vs. /pso-Substitution,Activation by Alkylthio Group, NMR Spectra

9-Substituted isocolchicides in methanol or dimethyl sulfoxide undergo /pso-substitution by sodium thiolates in mixture with the corresponding thiols, giving 9-alkyl(aryl)thio-substituted isocolchicides which are prone to in situ re/e-substitution affording ll-alkyl(aryl)thio func- tionalized isocolchicides. Such C -ll activation by dicoordinated sulfur is used here for a general synthesis of 1 l-alkyl(aryl)thioisocolchicides.

Introduction

D espite keen in terest in colchicine and its deriv­atives (colchicinoids) by chemists, biologists and pharmacologists, very little is know n about the 11- substituted isocolchicide series. U ntil recently, only two m em bers of this series were known, i.e. 11-methylthio- [1,2] and 11-amino-isocolchicide [3]. The way they are form ed is interesting: re-ex­am ination of Velluz’s reaction of isocolchicine with sodium m ethanethiolate to give 11-methylthi- oisocolchicide [1,2] led us to establish that this com pound is form ed via initial ipso replacem ent of the m ethoxy group of isocolchicine by the thio- late to give 9-methylthioisocolchicide (1); the la t­ter undergoes re/e-substitution at C - l l by the thio- late [4]. This is in keeping with general rules concerning electron acceptance by dicoordinated sulfur at C-9 in simple troponoids [5]. On this ba­sis, we recently succeeded in the C - l l refunction- alization of 9-substituted isocolchicides by prim ary or secondary amines: isocolchicides carrying a C- 9 activating nucleofugic group like SCH 3, SO C H , or Cl were found to undergo re/e-substitution at C - ll by the amine in dimethyl sulfoxide in com pe­tition with /pso-substitution at C-9 [6]. Thus, on treating 1 in dim ethyl sulfoxide at 64°C with ex­cess amine, ca. 1:1 m ixtures of 9- and 11-amino

* Reprint requests to Prof. M. Cavazza.

substituted isocolchicides were obtained, including11-piperidino [6], -11-morpholino- [7] and 11 -n- propylaminoisocolchicide [7], H ere we present an extension of the above m ethodology leading to a general synthesis of 1 l-alkyl(aryl)thioiso- colchicides.

Results and Discussion

Treatm ent of 1 or 9-tosylisocolchicide (2) with m ethanol containing ca. 35 mol. equiv. of in situ prepared sodium thiolate, led to m ixtures of 9-sub- stituted and 11-substituted isocolchicides that were collected and separated by Thin-Layer C hro­m atography after that the reaction m ixtures were left for 20 h at room tem perature (Schem e 1 and Table I). Similar results were obtained by addition of ca. 35 mol. equiv. of sodium thiolate and 1.2 mol. equiv. of thiol to solutions of 1 or 2 in di­methyl sulfoxide (Schem el). Com parison of these thiolate reactions with those of the same sub­strates with amines reveals interesting differences. Thus, while for the am ine reactions it is necessary to start with a substrate that, like 1, carries an acti­vating (i.e. re/e-directing) C-9 substituent, there is no such a need for the thiolate reactions: the more easily accessible tosylate 2 [8] proved to be quite convenient, undergoing fast irreversible ipso sub­stitution by the thiolate to give corresponding 9- alkyl(aryl)thioisocolchicide that takes part to equi­libria leading to the re/e-substitution product (Scheme 2). However, unlike in reactions with pri-

0932-0776/96/0900-1347 $06.00 © 1996 Verlag der Zeitschrift für Naturforschung. All rights reserved. D

1348 M. C avazza-F . Pietra • Re-functionalization of 9-Substituted Isocolchicides

RSNa/MeOH -------------- ►

RSNa/RSH/DMSO

X=OTS468

10

R=Bu

R=i-Pr

R=HOC2H4

R=Ph Scheme 1.

RS'

X=SMe or OTs

base H+

RS

RS1 \ H+f )

~-RS- I. L b baseH~ F \

RSSR RS r T *

Scheme 2.

Thiolate zpso-Substitutionproduct

Yield (%) te/e-Substitutionproduct

Yield (%)

BuSNa 3 43 4 42i-PrSNa 5 51 6 14HO(CH,),SNa 7 55 8 20PhSNa 9 48 10 32

Table I. Product-yield in the preparative reactions car­ried out with 1 or 2 and ex­cess thiolate in MeOH at room temperature.

M. C avazza-F . Pietra • R e-functionalization of 9-Substituted Isocolchicides 1349

mary or secondary amines, which act both as nu­cleophiles and protonating agents [9] in reactions with thiolates in aprotic dim ethyl sulfoxide an ex­tra source of protons is needed: a slight excess of free thiol was added to establish the protonation equilibria (Scheme 2). In the absence of free thiol, only /pso-substitution was observed. A lthough in some cases, e.g. with sodium /so-propanthiolate (Table I), a low tele/ipso ratio of products was ob­served, we are not aware about any o ther route to 1 l-alkyl(aryl)thio-substituted isocolchicides.

Experim ental

General

'H N M R and l3C N M R spectra were obtained with a Gem ini Varian BB spectrom eter 200 MHz, in C D C I 3 as the solvent, unless otherwise stated, TMS as an internal standard. Mass spectra (E l) were taken with a K ratos MS80 spectrom eter with a hom e-built com puterized acquisition system. M elting points were obtained with Reichert Therm ovar apparatus and are uncorrected.

Materials

C H 3O H ( RS C. E rba) was used as such. DM SO (C. E rba) was distilled from C aH 2 under A r and stored over 3 A m olecular sieves. 9-methylthioiso- colchicide 1 [4] and 9-tosyloxyisocochicide 2 [8] were prepared according to known procedures.

General Procedure

To a stirred solution obtained from Na (0.052g,2.26 mm ol) and dry M eO H (6 ml), were added, under argon, 2.8 mmol of thiol followed by 0.065 mmol of either 1 or 2. The m ixture was left for 20 h at room tem perature, evaporated under vacuum, and then w ater was added and the resulting sus­pension was extracted with CHC13. The residue from evaporation of the organic phase was sub­jected to TLC, eluent C H C l3/acetone 3:2, collect­ing 9-substituted and 11-substituted isocolchicides at the Rf values indicated below and with the yields reported in Table I.

C orrespondig reactions were carried out by add­ing to 0.05 mmol of e ither 1 or 2 in dried DMSO, under argon, 1.6 mmol of sodium thiolate followed by 0.06 mmol of thiol. These m ixtures were w orked up as for reactions in M eOH.

(S)-N-(5,6,7,10- Tetrahydro-1,2,3-trimeth oxy -9-butylthio-10-oxobenzo[a]heptalen-7-yl)acetamide(3)'

Yellow solid, Rf=0Al, m.p. 221-223°C dec.'H NMR: (3= 0!93 (3H, t, 7=7.2, C / / ,C 3H 6), 1.50

(2H, m, CH^CH 2C2H 4), 1.73 (2H, m, C 2H ,C / / 2 C H t), 2.05 (3H, s, Ac), 2 .55-2 .2 (4H, series of m,6-H and 5-H), 2.87 (2H, m, S C //2C ,H 7), 3.92, 3.89, 3.66 (3 x 3H, s, for the 3 M eO ), 4.60 (1H, td, 712.5, 6.3, 7-H), 6.56 (1H, s, 4-H), 7.41 and 6.97 [2H, AB system, 7(AB)=12.5, 11-H and 12-H], 7.40 (1H, s, 8-H).

13C NMR: 0=182.33, 169.83, 157.08, 153.78, 143.55, 141.10, 136.63, 134.82, 131.43, 125.89, 124.47, 107.43, 61.60, 61.50, 56.17, 52.95, 38.49, 31.73, 29.94, 29.75, 29.56, 22.95, 22.45, 13.78.

UV Amax(M eOH)/nrn = 260, 290,362,383,402sh.MS m/z (% ) : 457 (13, M + ), 398 (19).HRM S m/z obs: 457.19177 (M + ), calc, for

C ,sH 3,O sNS: 457.19229.

(S)-N- (5,6,7,10- Tetrahydro-1,2,3-trimethoxy-l 1 - butylthio-10-oxobenzo[aJheptalen-7-yl)acetamide(4)

Yellow solid, /?/=0.73, m.p. 95-96°C .'H NMR: 6=0.91 (3H, t, 7=7.16, C Z /^ H * ) , 1.45

(2H, m, C H 3CH2 C2H 4) 1.70 (2H, m, C2H , CH2CH 2) 2.04 (3H, s, A c), 2 .60-2 .20 (4H, series of m, 6-H and 5-H), 2.80 (2H, m, S C //2C 3H 7), 3.93,3.90, 3.67 (3x3H,s,for the 3 M eO), 4.55 (1H, td, 7=12.5, 6.3, 7-H), 6.58 (1H, s, 4-H), 7.44 and 7.06 [2H, AB system, 7(A B)= 12.5, H -8 and H-9], 7.33 (1 H,s, H-12).

13C NM R: <3=182.44, 170.01, 155.08, 153.93,151.03, 141.19, 139.29, 135.25,133.20, 132.82, 132.69, 126.51, 107.56, 61.77, 61.47, 56.15, 51.93,38.43, 31.12, 31.02, 30.06, 29.80, 23.09, 22.33, 13.68.

UV Amax(M eOH)/nrn: 267, 330, 402sh.MS m/z (% ) : 457 (15, M + ), 398 (21).HRM S m/z obs: 457.19234 (M + ), calc, for

C25H 310 5NS: 457.19229.

(5)-N-(5,6,7,10- Tetrahydro-1,2,3-trimethoxy-9-i-propylthio-10-oxobenzo[a]heptalen-7-yl)- acetamide (5)

Yellow solid, Rf=0.60, m.p. 126-127°C.'H NMR: 6 = 1.44 (6H, d, 7= 6.7, (C /Z ^ C H ),

2.04 (3H, s,AC), 2 .60-2 .20 (4H, series of m, 6-H and 5-H), 3.42 (1H, heptet, 7=6.7, M e2C //S ), 3.94,3.90, 3.69 (3x3H, s, for the 3 M eO ), 4.60 (1H, td, 7= 12.0, 4.4, 7-H), 6.20 ( 1H, d, 7=4.4, N H ), 6.56 (1H, s,4-H), 7.41 and 6.98 [2H, AB system, 7(A B )= 12.5, H - l l and H-12], 7.40 (1H, s, H -8 ). 13C NM R: 0=

1350 M. C avazza-F . Pietra • Re-functionalization of 9-Substituted Isocolchicides

181.20, 169.58, 142.88, 140.75, 136.76, 134.72,132.04, 132.00, 125.11, 107.50, 107.46, 60. 08, 56.21,56.16, 52.94, 38.65, 34.91, 30.09, 29.99, 29.91, 29.75,23.02, 22.28, 22.09.

UV Amax(M eO H )/nm : 260, 290, 363, 386, 402sh. MS m/z (% ) : 443 (11, M + ), 384 (35).H RM S m/z obs: 443.17608 (M +), calc, for

C24H 29O 5NS: 443.17664.

(S)-N-(5,6,7,10-Tetrahydro-l ,2,3-trimeth oxy -1 l-i-propylthio-10-oxobenzo[a]heptalen-7-yl)- acetamide (6 )

Gum m y yellow solid, Rf=0A2.'H N M R d=1.42 (6H, d, 7=6.7, (CH3)2CH), 2.04

(3H, s, Ac), 2 .60-2 .20 (4H, series of m, 6 -H and 5-H), 3.33 (1H, heptet, 7=6.7, M e2C //S ), 3.94, 3.91, 3.68 (3x3H, s, for the 3 M eO ), 4.55 (1H, td, 7=12,5.2, 7-H), 5.95 (1H, d, 7=5.2, N H ), 6.58 (1H, s, 4- H), 7.32 and 7.07 [2H, AB system, 7(A B)= 12.0, H -8 and H-9], 7.37 (1H, s, H-12).

U V Amax(M eO H )/nm : 267, 332, 402sh.MS m/z (% ) : 443 (14, M + ), 384 (38).H RM S m/z obs: 443.17610 (M + ), calc, for

C 24H 290 5N S : 443.17664.

(S)-N-(5,6,7,10-Tetrahydro-1,2,3-trimethoxy-9-(2' - hydroxyethylthio)-10 -oxobenzo[aJheptalen-7-yl)- acetamide (7)

Yellow solid, ^ = 0 .1 8 , m.p. 115-117°C.'H NM R: (3= 2.07 (3H, s, Ac), 2 .60-2.20 (4H,

series of m, 6 -H and 5-H), 3.14 (2H, t, S C f/2C H 2O H ), 3,90 (2H, t, H O C //2C H 2S), 3.92,3.90, 3.67 (3x3H, s, for the 3 M eO ), 4.61 (1H, m,7-H), 6.57 (1H, s, 4-H), 7.47 and 6.98 [2H, AB sys­tem, 7(AB)=12.5, H - l l and H-12], 7.66 (1H, s, H- 8), 7.95 (1H, br signal, NH).

13C NM R: (3=182.51, 170.78, 155.92, 154.00, 150.97, 145.11, 145.06, 141.92, 137.78, 135.12,131.21, 125.85, 125.62, 107.63, 61.65, 61.58, 61.48,61.44, 60.21, 56.17, 52.98, 38.28, 34.29, 30.07, 22.90.

U V Amax(M eO H )/nm : 260, 290, 383, 402sh.MS m/z (%) : 445 (2, M + ), 385 (73).H RM S m/z obs. : 445.15500 (M +), calc, for

C23H 270 6NS: 445.15591.

(S)-N-(5,6,7,10-Tetrahydro-1,2,3- trim eth oxy -11- (2'-hydroxy ethylthio )-10-oxobenzo[a Jhep taten - 7- yl)acetamide (8 )

Yellow solid, 7?y=0.16, m.p. 127-130°C.'H NM R: (3=2.04 (3H, s, Ac), 2 .60-2.20 (4H,

series of m, 6-H and 5-H), 3.06 (2H, t, 7=6.5, S C //2C H ,O H ), 3.90 (2H, t ,H O C //2CH ,S), 3.94, 3.92, 3.69 (3x3H, s, for the 3 M eO ), 4.54 (1H, td.

7= 12.0 , 6.2, 7-H), 5.98 (1H, d, 7=6.2, N H), 6.59 (1H, s, 4-H), 7.36 and 7.09 [2H, AB system, 7(AB)=12.5, 8-H and 9-H], 7.38 (lH ,s, 12-H).

13C NMR: (3=181.50, 170.00, 154.20, 154.00, 153.40, 141.34, 133.92, 133.38, 132.18, 107.94, 107.85, 107.81, 62.20, 62.00, 60.13, 56.30, 56.24, 56.17, 52.06, 38.59, 34.28, 31.00, 29.99, 23.13.

UV Amax(M eOH)/nrn: 370, 331, 401sh.MS m/z (% ) : 445 (1.5, M + ), 385 (33).HRM S m/z obs.: 445.15502 (M + ), calc, for

C23H 270 6NS : 445.15591.

(S)-N- (5,6,7, / 0- Tetrahydro-1,2,3-trimethoxy- 9-phenylthio-l 0-oxobenzofa ]heptalen-7-yl) - acetamide (9)

Yellow solid, R f=0.64, m.p. 154-155°C.>H NMR: (3=2.17 (3H, s, A c), 2 .50-2.10 (4H,

series of m, 6-H and 5-H), 3.92, 3.87, 3.65 (3x3H, s, for the 3 M eO ), 4.41 (1H, td, 7=12.7, 6.5, 7-H),5.2 (1H, d, 7=6.7, N H ), 6.52 (1H, s, 4-H), 6.93 (1H, s, 8-H), 7.43 and 7.05 [2H, AB system, 7(A B)=12.5, 12-H and 11-H], 7.52 (3H, m, phenyl), 7.63 (2H, m, phenyl).

13C NMR: 0=181.33, 169.31, 158.50, 153.82,143.02, 141.14, 136.48, 134.75, 132.42, 131.86, 130.18, 129.84, 125.30, 125.22,107.47,107.41, 61.68, 61.60, 61.51, 61.45, 56.15, 52.33, 38.66, 29.80, 23.02.

UV Amax(M eO H )/nm : 258, 360, 383, 401sh.MS m/z (% ) : 477 (14, M + ), 449 (17, M -CO),

390 (14).HRM S m/z obs. : 477.15970 (M + ), calc, for

C27H 270 5NS : 477.16099.

(S)-N-(5,6,7,10-Tetrahydro-l,2,3-trimethoxy-11 -phenylthio-10-oxobenzo [a] heptalen-7-yl)- acetamide (10)

Yellow solid, Rf= 0.35, m.p. 117-119°C.'H N M R (C D 3C O C D 3): ö =1.90 (3H, s, Ac),

2.60-2.10 (4H, series of m, 6-H and 5-H), 3.82, 3.68, 3.52 (3x3H, s, for the 3 M eO ), 4.36 (1H, td, 7=12.2, 6.2, 7-H), 6.67 (1H, s, 4-H ), 6.89 (1H, s, 12- H), 7.56 and 7.00 [2H, AB system, 7(AB)=12.6, 9- H and 8-H], 7.76 (1H, d, 7=6.2, N H ), 7.59-7.45 (5H, m, phenyl).

13C NMR: (3=181.59, 169.86, 156.15, 153.73, 141.77, 139.43, 136.34, 136.23, 134.91, 134.58, 134.49, 134.06, 132.85, 130.55, 129.73, 129.52,126.16, 107.24, 107.09, 61.40, 61.13, 56.07, 52.02, 38.57, 29.99, 29.75, 23.11.

UV 2max(M eO H )/nm : 268, 331, 380, 400sh.MS m/z (% ) : 477 (21, M + ), 449 (24, M -CO),

390 (19).HRM S m/z obs.: 477. 16043 (M + ), calc, for

C27H ,7OsNS: 477.16099.

M. C avazza-F . P ietra • R e-functionalization of 9-Substituted Isocolchicides 1351

[1] L.Velluz, G.M üller, Bull. Soc. Chim. Fr. 198 (1955).[2] B .D anieli, G. Lesm a, G. Palm isano, R .R iva, Helv.

Chim. A cta 68, 2173 (1985).[3] J.Schreiber, W. Leim gruber, M. Pesaro, A . E schen­

moser, A ngew .C hem . 71, 637 (1959).[4] M .Cavazza, F.Pietra, J. Chem . Soc., Chem . Com -

mun. 897 (1994).[5] F.Pietra, Acc. Chem . Res. 12, 132 (1979).

[6] M .Cavazza, F. Pietra, J. Chem. Soc., Perkin Trans. I 2657 (1995).

[7] M .Cavazza, unpublished results.[8] M. Staretz, S. B. H astie, J. Org. Chem . 56, 428

(1991).[9] G. Biggi, F. D el Cima, F. Pietra, J. A m . Chem . Soc.

95, 7101 (1973).