Tautomeric selectivity towards colchicinoids in the tosylation of colchiceine on a heterogeneous, easily removable catalyst.

Article abstract of DOI:10.1039/b307650b

Here is presented an easy, rapid new method of tosylation of compounds containing acidic OH groups, such as tropolones and phenols, on a solid, removable catalyst, Amberlite IRA-400(OH); of special value is the preferential selectivity for the colchiceine

Full text of DOI:10.1039/b307650b

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Tautomeric selectivity towards colchicinoids in the tosylation
of colchiceine on a heterogeneous, easily removable catalyst
Marino Cavazzaa and Francesco Pietrab
a Dipartimento di Chimica e Chimica Industriale, Università di Pisa, via Risorgimento 35,
I-56100 Pisa, Italy
b Via della Fratta 9, I-55100, Lucca, Italy
Received 4th July 2003, Accepted 22nd July 2003
First published as an Advance Article on the web 24th July 2003
Here is presented an easy, rapid new method of tosylation
of compounds containing acidic OH groups, such as
tropolones and phenols, on a solid, removable catalyst,
Amberlite IRA-400(OH); of special value is the prefer-
ential selectivity for the colchiceine tautomer 1a, leading
to 10-tosyloxycolchicide (2)—the precursor of a variety
of bioactive colchicinoids—which inverts the result of
previous tosylation methodologies leading preferentially
to useless 9-tosyloxyisocolchicide (3).
Although the overall yield is good (ca. 90%), 2 can be obtained
in only 22% isolated yield.1a This is vexing because it is just
this isomer that may give access to antimitotic, albeit toxic,
colchicine,3a,4 or, in transformation procedures, to less toxic3b
colchicine derivatives endowed with stronger antitumor
activity,3b while all known isocolchicine derivatives (prepared
from isomer 3) have proven to be biologically inactive.3a The
slowness of tosylation in pyridine,1a which is a noxious
chemical, and the somewhat difficult recovery of tosylates from
the reaction mixture, constitute additional drawbacks. Clearly,
an improved technology toward 10-tosyloxycolchicide (2) is
desirable.
Tosylation of colchiceine (1a/1b) by equimolar tosyl chloride
(TsCl) in a large-excess of pyridine at room temperature for
24 h1a has become standard technology towards a wide variety
of colchicine derivatives, resulting from the nucleophilic
replacement of the 10-tosyloxy group of 10-tosyloxycolchicide
(2). Nucleophiles include azido,1a halo,1b amino,1c alkoxy,1d,e and
alkyl- and phenylthio groups.1f With nucleophiles carrying
We provide here preliminary indications as to a new method-
ology of tosylation of colchiceine, affording 10-tosyloxycol-
chicide (2) more rapidly and cleanly, in higher yield, and with
simpler recovery than in the above described “pyridine tech-
nology”.1a From the latter we progressed as follows. On
replacing CHCl3 with CH2Cl2 in Kabalka’s general tosylation
methodology (substrate–TsCl–pyridine in molar ratio 1 : 1.5 : 2
in CHCl3),5 the HPLC-evaluated percentage of 10-tosyloxy-
colchicide (2) in the 2/3 mixture, was raised to 38.4% (Table 1).
By further replacement of pyridine6a with, in turn, brucine,6b
1,4-diazabicyclo[2.2.2]octane (DABCO),6c triethylamine,6c
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),6a and N,N,NЈ,NЈ-
tetramethyl-1,8-naphthalenediamine (proton-sponge),6a the
percentage of 2 became 38.5, 35.5, 49.5, 52.6, and 59.0%,
respectively (Table 1). Finally, the best percentage of 2 (70.5%)
was obtained under heterogeneous catalysis by dry Amberlite
IRA-400 (OH), a strongly basic gel-type resin, in CH2Cl2 at
Ϫ10 ЊC (Table 1).†
a
second reactive functionality, condensation with the
cycloheptatrienone carbonyl group may ensue, affording
1,3-diazaazulene1e and fused furano derivatives.2
Replacing TsCl with mesyl chloride, mesylation of colchi-
ceine was obtained. The best relative percentage of the desired
10-mesyloxycolchicide (4)7 (52.9%) was obtained with proton-
sponge. Amberlite IRA-400(OH), triethylamine, and pyridine
gave 4 in 41.0, 33.1, and 25.0% relative percentages.
This Amberlite IRA-400(OH) technology applies also
to other vinylogous carboxylic acids, like tropolone (6) and
β-thujaplicin (8a/8b), affording tosylates 7 and 9/10, respect-
ively, although in the latter case the relative percentage of
isomer 10 was increased by a mere 2.4% with respect to a 1 : 1
ratio from the “pyridine technology”.7 Even phenolic com-
pounds, like 4Ј-hydroxy-4-biphenylcarbonitrile 11, are tosylated
using Amberlite IRA-400(OH), like in the montmorillonite clay
technology.8 In our hands, 11 gave 129 in nearly quantitative
yield.†
Although comparing solution conditions with heterogeneous
catalysis in the liquid phase, and dealing with basicity in non-
aqueous media is difficult, it should be noticed that progress
towards better yields of the desired 10-tosyloxycolchicide (2)
runs roughly in parallel to increasing basicity of the catalyst
used (Table 1).6a,b,c,10 This behaviour may be accounted for by a
balance between acidity11 and nucleophilicity12 of 1a and 1b,
which must be a delicate affair, since the trend was disrupted for
mesylation, as shown above. Notably, this study has revealed
However, because of the vinylogous acid nature of colchi-
ceine, which means that 1a and 1b are in tautomeric equilibrium
under the tosylation conditions, this results in a mixture of
74.0% 9-tosyloxyisocolchicide (3) and 26.0% 10-tosyloxy-
colchicide (2), according to our HPLC analysis (Table 1).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 0 2 – 3 0 0 3
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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Table 1 Ionization constants (pKa) of BHϩ in H2O and HPLC-evaluated percentages of 2/3 (isolated yields) on tosylation of colchiceine (1a/1b)
Base (B)-medium
pKa
2
3
Pyridine (neat)
Pyridine-CH2Cl2
Brucine-CH2Cl2
DABCO-CH2Cl2
Triethylamine-CH2Cl2
DBU-CH2Cl2
Proton-sponge-CH2Cl2
Amberlite IRA-400 (OH)–CH2Cl2 rt
Amberlite IRA-400 (OH)–CH2Cl2 Ϫ10 ЊC
5.26a
26.0 (22)
38.4
38.5
35.5
49.5
52.6
59.0
67.0 (60)
70.4 (63)
74.0 (67)
61.6
61.5
64.5
50.5
47.4
41.0
33.0 (30)
29.5 (26)
5.26a
8.286b
8.76c
10.686c
126a
12.16a
2 M. Cavazza, G. Guella and F. Pietra, Tetrahedron, 2000, 56, 1917.
3 (a) O. Boye and A. Brossi, Tropolonic colchicum alkaloids and
allo congeners, Alkaloids (Academic Press), 1992, 41, 125; (b)
A. Muzaffar, A. Brossi, C. M. Lin and E. Hamel, J. Med. Chem.,
1990, 33, 567.
the first case of tautomeric selectivity in vinylogous acyl sulfon-
ate preparation from vinylogous carboxylic acids. Full light on
the range of applicability of this new methodology, and the
factors involved, must await further experimentation.
4 The last step of several classical colchicine total syntheses (see, for
example, J. Schreiber, W. Leimgruber, M. Pesaro, P. Schudel,
T. Threlfall and A. Eschenmoser, Helv. Chim. Acta, 1961, 44, 540;
J. Martel, E. Toromanoff and C. Huynh, J. Org. Chem., 1965, 30,
1752; D. L. Boger and C. E. Brotherton, J. Am. Chem. Soc., 1986,
108, 6713) consists of alkylation of colchiceine, which, in current
methodologies, such as diazomethane treatment ( M. Sorkin, Helv.
Chim. Acta, 1946, 29, 246) suffers from preferential isocolchicine
formation (55 : 45). The Amberlite route provided here may
considerably enhance the yield of the process.
Notes and references
† General procedure. Amberlite IRA-400(OH), Aldrich, 10 g was step-
wise washed on a sintered glass funnel with H2O, 5% NaOH (100 mL
each), H2O until neutrality, EtOH and Et2O (50 mL each), and then
dried in vacuo on P4O10 and stored under N2.
To 0.26 mmol of substrate in 5 mL CH2Cl2 were added 0.55 g of dry
Amberlite IRA-400 under N2, followed by TsCl, (0.076 g, 0.40 mmol) or
MsCl (0.046 g, 0.40 mmol) under stirring. HPLC monitoring showed
completion of the process in ca. 20 min at rt. The slurry was filtered,
then the solvent was removed in vacuo. With 1a/1b and 8a/8b the residue
was subjected to TLC for the separation of the isomeric products,
whereas with 6 and 11 the residue was simply purified by recrystalliz-
ation. For the tosylation of 1a/1b, HPLC monitoring of the reaction
mixture revealed 67.0% 2 and 33.0% 3 (Table 1). After silica-gel G F
Analtech TLC with CHCl3–(CH3)2CO 3 : 2, 2 and 3 were isolated from
the Rf = 0.62 and 0.76 bands in 60 and 30% yields, respectively. Carrying
out the tosylation of 1a/1b at Ϫ10 ЊC, the HPLC-evaluated percentage
of 2 rose to 70.5%, although the process was slowed down by one order
of magnitude with respect to rt conditions. TLC separation as above
gave 2 and 3 in 63 and 26% yields respectively (Table 1). On further
lowering the temperature, the tosylation process became impracticably
slow. No equilibration of tosylates7 was observed during these
processes.
5 G. W. Kabalka, M. Varma and R. S. Varma, J. Org. Chem., 1986, 51,
2386.
6 (a) D. Granitza, M. Beyermann, H. Wenschuh, H. Haber and
L. A. Carpino, J. Chem. Soc., Chem. Commun., 1995, 2223; (b)
J. C. Gage, Analyst, 1957, 82, 219; (c) V. Frenna, N. Vivona,
G. Consiglio and D. Spinelli, J. Chem. Soc., Perkin Trans. 2, 1985,
1865.
7 M. Cavazza and F. Pietra, Tetrahedron Lett., 2003, 44, 1895.
8 B. M. Choudary, N. S. Chowdari and M. L. Kantam, Tetrahedron,
2000, 56, 7291.
9 N. Ayako, M. Ayako, W. Takeo, I. Osami, Jpn. Kokai Tokkyo Koho
JP 06,247,911/1994, CAN 122 : 252233x; . Data for 12: Mp 102 ЊC;
IR (Nujol) ν 2223, 1607, 1596, 1369, 1197, 1179, 1154, 874, 863, 834
cmϪ1; 1H NMR (CDCl3, 200 MHz) δ 2.47 (s, 3H), 7.11 (d, J = 8.8 Hz,
2H), 7.35 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8
Hz, 2H), 7.72 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H); 13C NMR
(CDCl3) δ 21.8, 111.3, 118.7, 123.0, 127.6, 128.4, 129.8, 132.6, 138.0,
144.1, 145.6, 149.8. Anal. Calcd for C20H15NO3S: C, 68.77; H, 4.30;
N 4.01; Found: C, 68.49; H 4.20; N 3.95%.
10 In this respect, the pKa for brucine and DABCO are too close
together for the observed yield inversion (Table 1) to be significant.
11 Calculations by the Advanced Chemistry Development (ACD)
Software Solaris V4.67 gave pKa values 7.70 and 7.24 for 1a and 1b,
respectively.
1 (a) M. P. Staretz and S. Bane Hastie, J. Org. Chem., 1991, 56, 428; (b)
M. Cavazza and F. Pietra, Synth. Commun., 1997, 27, 3405;
M. Cavazza and F. Pietra, J. Chem. Soc., Perkin Trans. 1, 1995, 2657;
(c) M. Cavazza, M. Zandomeneghi and F. Pietra, Tetrahedron Lett.,
2000, 41, 9129; M. Cavazza and F. Pietra, Tetrahedron Lett., 1995,
36, 3429; (d ) M. Cavazza, M. Zandomeneghi and F. Pietra, J. Chem.
Soc., Perkin Trans. 1, 2002, 560; (e) M. Cavazza and F. Pietra, Tetra-
hedron, 1998, 54, 14059; ( f ) M. Cavazza and F. Pietra, Z. Natur-
forsch., Teil B, 1996, 51, 1347; M. Cavazza, C. Pinzino, L. Pardi,
L. Nucci, F. Pergola and F. Pietra, Tetrahedron, 2002, 58, 9553.
12 Nucleophilic substitutions on colchicides and isocolchicides bearing
an α-leaving group were previously compared: M. Cavazza and
F. Pietra, J. Chem. Soc., Perkin Trans. 1, 1995, 2657.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 3 0 0 2 – 3 0 0 3
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