Efforts directed toward the synthesis of colchicine: Application of palladium-catalyzed siloxane cross-coupling methodology

Article abstract of DOI:10.1021/jo051636h

Colchicine is an important and synthetically challenging natural product. The key synthetic step in this approach to the synthesis of colchicine involved a palladium-catalyzed cross-coupling reaction between 5-bromotropolone (4) and an aryl siloxane to form the aryl-tropolone bond. The coupling of a variety of highly functionalized aryl siloxane derivatives was investigated and optimized coupling conditions were developed. It was discovered that a palladium catalyst with a high degree of phosphine ligand coordination (5 equiv of phosphine/mol Pd) was necessary to efficiently couple aryl siloxanes with 5-bromotropolone (4). In addition, the coupling approach has provided a direct comparison between siloxane and boronic acid coupling technologies that demonstrated that aryl siloxanes and boronic acids produce similar yields of highly functionalized biaryl products.

Full text of DOI:10.1021/jo051636h

Efforts Directed toward the Synthesis of Colchicine: Application
of Palladium-Catalyzed Siloxane Cross-Coupling Methodology
W. Michael Seganish, Christopher J. Handy, and Philip DeShong*
Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742
deshong@umd.edu
Received August 4, 2005
Colchicine is an important and synthetically challenging natural product. The key synthetic step
in this approach to the synthesis of colchicine involved a palladium-catalyzed cross-coupling reaction
between 5-bromotropolone (4) and an aryl siloxane to form the aryl-tropolone bond. The coupling
of a variety of highly functionalized aryl siloxane derivatives was investigated and optimized
coupling conditions were developed. It was discovered that a palladium catalyst with a high degree
of phosphine ligand coordination (5 equiv of phosphine/mol Pd) was necessary to efficiently couple
aryl siloxanes with 5-bromotropolone (4). In addition, the coupling approach has provided a direct
comparison between siloxane and boronic acid coupling technologies that demonstrated that aryl
siloxanes and boronic acids produce similar yields of highly functionalized biaryl products.
Introduction
Colchicine has attracted the attention of many syn-
thetic chemists over the years.11 Its deceptively simple
structure poses several significant challenges, most
notably the synthesis of the tropolone ring system.12,13
In addition to the troplone ring, the formation of the 6-7-7
fused ring system of colchicine, and the 6-7-6 system in
the colchinoid analogue allocolchicine (2), present another
unique synthetic challenge.
Colchicine (1) was first isolated from the meadow
saffron Colchicum autumnale over 100 years ago and is
used in the treatment of gout.1 More recently, the activity
of colchicine as a spindle poison has been reported. Its
mechanism of action involves binding to tubulin mono-
mers and prevention of the formation of microtubules,
which are essential to cellular mitosis.2-6 Tubulin binding
leads to mitotic arrest and subsequent cell death. At-
tempts to develop colchicine as an antitumor compound
have been ineffective due to its potent broad spectrum
cytotoxicity. The mitigation of the cytotoxicity of colchi-
noids has been extensively investigated in an effort to
find new antitumor agents with improved therapeutic
properties.3-10
(1) LeHello, C. In The Alkaloids; Cordell, G. A., Ed.; Chemical
Society: London, 2000; Vol. 53.
(2) Fitzgerald, T. J. Biochem. Pharm. 1976, 25, 1383-1387.
(3) Berg, U.; Deinum, J.; Lincoln, P.; Kvassman, J. Bioorg. Chem.
1991, 19, 53-65.
(4) Bai, R.; Covell, D. G.; Pei, X.-F.; Ewell, J. B.; Nguyen, N. Y.;
Brossi, A.; Hamel, E. J. Biol. Chem. 2000, 275, 40443-40452.
(5) Andreu, J. M.; Timasheff, S. N. Biochemistry 1982, 21, 6465-
6476.
(6) Zhang, S.-X.; Feng, J.; Kuo, S.-C.; Brossi, A.; Hamel, E.; Tropsha,
A.; Lee, K.-H. J. Med. Chem. 2000, 43, 167-176.
(7) Shi, Q.; Verdier-Pinard, P.; Brossi, A.; Hamel, E.; Lee, K.-H.
Bioorg. Med. Chem. 1997, 5, 2277-2282.
The majority of the total syntheses of colchicine have
been linear in approach and suffer from one or more steps
(8) Yamato, M.; Ando, J.; Sakaki, K.; Hashigaki, K.; Wataya, Y.;
Tsukagoshi, S.; Tashiro, T.; Tsuruo, T. J. Med. Chem. 1992, 35, 267-
273.
(9) Bensel, N.; Lagnoux, D.; Niggli, V.; Wartmann, M.; Reymond,
J.-L. Helv. Chim. Acta 2004, 87, 2266-2267.
(10) Nakagawa-Goto, K.; Chen, C. X.; Hamel, E.; Wu, C.-C.; Bastow,
K. F.; Brossi, A.; Lee, K.-H. Bioorg. Med. Chem. Lett. 2005, 15, 235-
238.
10.1021/jo051636h CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/06/2005
8948
J. Org. Chem. 2005, 70, 8948-8955

Colchicine Synthesis: Pd-Catalyzed Cross-Coupling
SCHEME 1
SCHEME 2
that proceed in poor yields. Recently, several synthetic
approaches have been developed that allow for a more
efficient construction of the carbocyclic framework.11 Our
approach to the synthesis of colchicine and its derivatives
employed a palladium-catalyzed siloxane cross-coupling
reaction to form the carbon-carbon bond between the
aryl ring and the troplone ring (Scheme 1). This coupling
would allow facile access to functionalized derivatives of
Fitzgerald’s compound (3, RdH), which has been shown
to possess the same biological activity as colchicine.2
Formation of the aryl-tropolone bond by a cross-coupling
reaction has been investigated previously in model
systems using Stille couplings14 and Fitzgerald’s com-
pound (3) has been prepared using Suzuki coupling.15,16
We chose to investigate the siloxane coupling reaction
developed in our laboratory for the synthesis of the
colchicine/colchicinoid carbocyclic framework. This study
would yield a direct comparison of the siloxane reaction
to other cross-coupling strategies.
Palladium-catalyzed coupling reactions play an ever
increasing role in organic synthesis.17 The ability to
efficiently form carbon-carbon bonds in molecules with
complex chemical architecture remains a challenging
task. Work in our laboratory has focused on the formation
of aryl-aryl bonds using hypercoordinate siloxane
derivatives,18-28 a variant of the Hiyama cross-coupling
reaction.29-35 This reaction has advantages over tradi-
tional cross-coupling protocols36 such as the Suzuki-
Miyaura37-41 (organoboron) or Stille42-46 (organostannae)
coupling reactions (Scheme 2) because the siloxane
methodology eliminates the purification difficulties as-
sociated with organoboron reagents,47 and the toxic
byproducts associated with the use of organotin com-
pounds.46 The goal of this study was to demonstrate that
siloxane-based couplings could be employed effectively
in complex natural product synthesis. In addition, the
use of colchicine (1) and colchicinoids (i.e., 2) as targets
would also allow for the direct comparison of the siloxane
and boronic acid based strategies.
Results and Discussion
The aryl bromide coupling partner for the key siloxane
coupling reaction is 5-bromotropolone (4). Banwell and
co-workers have developed an efficient synthesis of this
(29) Hatanaka, Y.; Goda, K.; Okahara, Y. Tetrahedron 1994, 50,
8301-8316.
(30) Horn, K. A. Chem. Rev. 1995, 95, 1317-1350.
(31) Hiyama, T.; Shirakawa, E. Top. Curr. Chem. 2002, 219, 61-
85.
(11) Graening, T.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2004, 43,
3230-3256.
(12) Pauson, P. L. Chem. Rev. 1955, 55, 9-136.
(13) Pietra, F. Chem. Rev. 1973, 73, 293-364.
(14) Banwell, M. G.; Cameron, J. M.; Collis, M. P.; Crisp, G. T.;
Gable, R. W.; Hamel, E.; Lambert, J. N.; Mackay, M. F.; Reum, M. E.;
Scoble, J. A. Aust. J. Chem. 1991, 44, 705-728.
(15) Keenan, R. M.; Kruse, L. I. Synth. Commun. 1989, 19, 793-
798.
(32) Denmark, S. E.; Sweis, R. F. Acc. Chem. Res. 2002, 35, 835-
846.
(33) Denmark, S. E.; Ober, M. H. Aldrichim. Acta 2003, 36, 75-85.
(34) Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH Verlag GmbH: Weinheim,
1998; pp 421-452.
(35) Denmark, S. E.; Sweis, R. F. In Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004; Vol. 1, pp 163-216.
(16) Nair, V.; Powell, D. W.; Suri, S. C. Synth. Commun. 1987, 17,
1897-1900.
(17) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int.
Ed. 2005, 44, 4442-4489.
(36) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359-1469.
(18) Mowery, M. E.; DeShong, P. J. Org. Chem. 1999, 64, 1684-
1688.
(37) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633-9695.
(19) Mowery, M. E.; DeShong, P. Org. Lett. 1999, 1, 2137-2140.
(20) DeShong, P.; Handy, C. J.; Mowery, M. E. Pure Appl. Chem.
2000, 72, 1655-1658.
(38) Miyaura, N. Top. Curr. Chem. 2002, 219, 11-59.
(39) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168.
(40) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483.
(41) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions; de
Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1,
pp 41-124.
(21) Manoso, A. S.; DeShong, P. J. Org. Chem. 2001, 66, 7449-7455.
(22) Riggleman, S.; DeShong, P. J. Org. Chem. 2003, 68, 8106-8109.
(23) McElroy, W. T.; DeShong, P. Org. Lett. 2003, 5, 4779-4782.
(24) Manoso, A. S.; Ahn, C.; Soheili, A.; Handy, C. J.; Correia, R.;
Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 8305-8314.
(25) Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 1137-
1143.
(42) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508-524.
(43) Fugami, K.; Kosugi, M. Top. Curr. Chem. 2002, 219, 87-130.
(44) Espinet, P.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004,
43, 4704-4734.
(45) Farina, V.; Krishnamurthy, V.; Scott, W. J. Org. React. 1997,
50, 1-652.
(46) Mitchell, T. N. In Metal-Catalyzed Cross-Coupling Reactions;
de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vol.
1, pp 125-162.
(26) Seganish, W. M.; DeShong, P. Org. Lett. 2004, 6, 4379-4381.
(27) Seganish, W. M.; DeShong, P. J. Org. Chem. 2004, 69, 6790-
6795.
(28) Shibata, K.; Miyazawa, K.; Goto, Y. Chem. Commun. 1997,
1309-1310.
J. Org. Chem, Vol. 70, No. 22, 2005 8949

Seganish et al.
TABLE 1. Optimization of 5-Bromotropolone Coupling with Phenyl Trimethoxysilanea
Pd source
(mol%)
PR3
(mol%)
yield
(%)c
entry
solventb
1
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (5)
Pd(PPh3)4 (1)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(PPh3)4 (5)
Pd(PPh3)4 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
Pd(dba)2 (10)
[Pd(allyl)Cl]2 (10)
[Pd(allyl)Cl]2 (10)
[Pd(allyl)Cl]2 (10)
P(o-tol)3 (20)
DMF
DMF
THF
THF
THF
THF
DMF
THF
THF
THF
THF
dioxane
DMF
THF
THF
THF
DMF
DMF
THF
DMF
DMF
0
15
51
86
84
52
0
24
84
88
23
0
2
PPh3 (20)
PPh3 (40)
PPh3 (50)
PPh3 (25)
PPh3 (5)
3
4
5
6
7
8
9
PPh3 (10)
PPh3 (20)
PPh3 (10)
10
11
12
13
14
15
16
17
18
19
20
21
0
0
PPh3 (50)
PPh3 (100)
P(cy)2(o-biphenyl) (10)
P(t-Bu)2(o-biphenyl) (10)
PPh3 (20)
PPh3 (20)
P(cy)2(o-biphenyl) (10)
46
54
0
0
0
0
0
a Reactions were stirred for 10 h unless otherwise noted. b Reactions conducted in THF or dioxane were performed at the reflux
temperature of the solvent. Reactions in DMF were heated to 90 °C. c Isolated yields. In reactions that produced no product, starting
material was recovered. In reactions that yielded coupled product, the remainder of the starting material decomposed.
compound and we adopted a modified Banwell sequence
for this study.48 With this compound in hand, an inves-
tigation was undertaken to elucidate conditions that
would allow for the successful cross-coupling with phen-
yltrimethoxysilane to form 5-phenyltropolone (6) and the
results are summarized in Table 1. A variety of catalyst
and phosphine combinations were tested. The use of
palladium acetate and triphenyl phosphine in a 1:5 ratio
was found to be the optimum catalyst for the cross-
coupling reaction (entries 4 and 5). An extensive series
of reduced Pd(OAc)2:phosphine ratios in either THF or
DMF were screened (entries 1-3, data from additional
reactions not shown) and consistently lead to poor yields
of coupled product. The reaction could be conducted with
no appreciable loss in yield with as little as 5 mol %
catalyst (entry 5). Similar results could be obtained using
tetrakis(triphenylphosphine) palladium(0) with the ad-
dition of 10-20 mol % of excess phosphine (entries 9 and
10). However, it was interesting to note that, without the
additional phosphine, Pd(PPh3)4 was a poor catalyst for
the reaction (entry 8).
triphenylphosphine was added (entry 15). The addition
of further equivalents of phosphine did not improve the
yield (entry 16). Additionally, the yield was poor com-
pared to those of the palladium acetate and Pd(PPh3)4
systems.
These results indicate that even though the active
catalyst in each case is a palladium(0) triphenylphos-
phine complex, the original ligands on the palladium
source (OAc, PPh3, dba) play important roles in deter-
mining the activity of the catalyst. Particularly in the
case of Pd(dba)2, the original ligand (dba) may be ef-
fectively competing with triphenylphosphine for ligation
to the metal, thus decreasing the activity of the catalyst.
The detrimental effect of dba on palladium(0) catalyst
efficiency was observed by Amatore and Jutand.49 In
addition, other studies have shown that dba slows the
oxidative addition of Pd(0) and aryl halides.50
With the optimum conditions in hand for the pal-
ladium-catalyzed coupling of 5-bromotropolone with phe-
nyltrimethoxysilane, attention turned to the preparation
of siloxanes that would be suitable tropolone coupling
partners for the colchicine synthesis. The preparation of
functionalized siloxanes is presented in Table 2. All of
the selected siloxanes contain highly electron-rich aryl
rings, which can prove to be difficult substrates for
palladium-catalyzed coupling reactions. Using (triethox-
ysilyl)-2,3,4-trimethoxybenzene (7, entry 1) as the cou-
pling partner with 5-bromotropolone (4) would allow for
Clearly, the optimum catalyst for the reaction requires
a high degree of triphenylphosphine ligation to pal-
ladium. This observation is particularly evident when the
palladium source is changed to bis(dibenzylideneacetone)-
palladium(0) (Pd(dba)2). No cross-coupling occurred (en-
tries 13 and 14) unless a large excess (5 equiv) of
(47) Anctil, E. J. G.; Snieckus, V. In Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
2004; Vol. 2, pp 761-814.
(48) Banwell, M. G.; Lambert, J. N.; Reum, M. E.; Onrust, R. Org.
Prep. Proc. Int. 1988, 20, 393-399.
(49) Amatore, C.; Jutand, A. Coord. Chem. Rev. 1998, 178-180,
511-528.
(50) Tschoerner, M.; Pregosin, P. S.; Albinati, A. Organometallics
1999, 18, 670-678.
8950 J. Org. Chem., Vol. 70, No. 22, 2005

Colchicine Synthesis: Pd-Catalyzed Cross-Coupling
TABLE 2. Synthesis of Siloxanes as Substrates for the Palladium-Catalyzed Coupling with Bromotropolonea
a See Experimental Section for full details. b Isolated yields of purified product. c While these two compounds could have been prepared
using Grignard chemistry, ortho-metalation offers an inexpensive alternative to the use of costly aryl bromides. A discussion of this topic
is contained in ref 27.
SCHEME 3
the formation of Fitzgerald’s compound (3). Entries 2-7
would help to define the scope and limitations of the
siloxane coupling technology by demonstrating the ability
to couple highly substituted electron-rich aryl rings. All
of the siloxanes were readily prepared cleanly and in high
yields using either ortho-metalation (entries 1 and 2),27
Grignard (entries 3-6),24 or hydrosilylation (entry 7)21,51,52
reactions. These three methods are complementary and
together allow for the synthesis of virtually any aryl
siloxane (Scheme 3).
The next facet of the study was to investigate the cross-
coupling reaction between these siloxane substrates and
5-bromotropolone (4). In addition to coupling reactions
ported the synthesis of Fitzgerald’s compound (3) using
using aryl siloxanes, we were presented with an op-
boronic acid coupling. With use of the aryl stannane
portunity to directly compare the coupling efficiency of
coupling results of Banwell, and the aryl boronic acid and
aryl stannanes and boronic acids with aryl siloxanes.
siloxane couplings from our laboratory, a side-by-side
Banwell has reported the coupling of a variety of aryl
comparison of the coupling methodologies could be made.
stannanes with bromotropolone,14 and Nair16 has re-
The results of this comparison study are presented in
Table 3. In the case of aryl siloxanes, the coupling
reaction is tolerant of both meta- and para-substitution
patterns, as well as electron-rich substrates where excel-
lent yields are obtained (entries 1, 2, and 4-7). The
(51) Murata, M.; Ishikura, M.; Nagata, M.; Watanabe, S.; Masuda,
Y. Org. Lett. 2002, 4, 1843-1845.
(52) Murata, M.; Suzuki, K.; Watanabe, S.; Masuda, Y. J. Org.
Chem. 1997, 62, 8569-8571.
J. Org. Chem, Vol. 70, No. 22, 2005 8951

Seganish et al.
TABLE 3. Coupling of Aryl Siloxanes with 5-Bromotropolonea
a All coupling reactions performed with 5 mol % catalyst unless otherwise noted. See Experimental Section (boronic acid, siloxane) or
ref 14 (organostannane) for details. b Isolated yield of purified product. c Data from ref 14. d Reference 16. e Bromotropolone premixed
with a stoichiometric amount of palladium before addition of the siloxane. See Experimental Section for details. f Reaction performed
with 5 mol % catalyst.
SCHEME 4
coupling of o-methoxy-substituted siloxanes 22 and 27
(entries 3 and 8) proved to be problematic and no coupling
product was observed under standard coupling conditions
(vide infra). On the other hand, the coupling of o-methyl
siloxane (entry 4) proceeded smoothly under standard
conditions.
The o-methoxy siloxane results were not unexpected
as it had been previously observed that siloxanes con-
taining an o-methoxy substituent were rapidly protode-
silylated under the cross-coupling conditions, yielding
poor yields of coupled product.27 This propensity for
protodesilylation could be overcome, to a degree, by
increasing the catalyst loading to 50 mol % (Scheme 4).27
In the case of the tropolone ring system, increasing the
catalyst loading to 50 mol % failed to provide any coupled
product and the siloxane was quantitatively protodesi-
lylated. In contrast to the tropolone coupling, when
siloxane 8 was coupled with bromobenzene to generate
biaryl 28, good yields of coupled product could be isolated
(see Scheme 4).
In general, when the three methodologies are com-
pared, the aryl siloxanes provide similar yields to the
corresponding boronic acids, while both the siloxanes and
boronic acids provide superior yields to organostannane
reagents. All three methodologies efficiently coupled a
simple phenyl group (entry 1); however, the coupling of
electron-rich substrates proved more problematic for the
Stille couplings (entries 2, 3, and 5-8). Notable is the
fact that only the boronic acid was able to efficiently
provide coupled product for the 2,3,4-trimethoxy moiety
(27), while the Stille reaction failed to provide any
8952 J. Org. Chem., Vol. 70, No. 22, 2005

Colchicine Synthesis: Pd-Catalyzed Cross-Coupling
SCHEME 5
product,14 and the siloxane coupling required a stoichio-
metric amount of palladium to yield the desired biaryl.
The failure of the bromotropolone ring system to couple
with o-methoxy containing siloxanes is attributed to a
slower oxidative addition step for the tropolone coupling,
thus permitting protodesilylation to consume the siloxane
before coupling can occur. In support of this hypothesis,
treatment of 5-bromotropolone with a stoichiometric
amount of the palladium catalyst, followed by the addi-
tion of siloxane 8 and TBAF, gave a 92% yield of the
coupled product (Scheme 5). There are several notable
features of the coupling reaction under these conditions:
the oxidative addition product 29 was formed, and upon
addition of the siloxane and TBAF, transmetalation
occurred faster than protodesilylation to give Fitzgerald’s
compound (3). The isolation and characterization of a
palladium(0)-aryl halide oxidative addition product has
been accomplished previously.53-55 In their study, how-
ever, Hartwig and co-workers used haloarenes as sub-
strates and were able to isolate and fully characterize
the product. No studies exist that report the synthesis
and characterization of a bromotropolone oxidative inser-
tion product such as 29. Thus, we were disappointed
when all attempts at isolation and characterization of 29
were unsuccessful.56
should yield coupled product. When this experiment was
conducted, however, the yield of coupled product was low
(43%). This result indicated that the slow formation of
Pd(0) is indeed allowing significant protodesilylation to
occur; however, since the yield of coupled product is still
low after allowing the formation of Pd(0), a slow oxidative
addition is also hindering the reaction.
Based on our initial observations, we can propose
relative rates of reaction for several key steps in the
catalytic cycle for the coupling of siloxane 7 with bro-
motropolone (4) (Scheme 6). The oxidative addition
reaction for the catalytic cycle (koa) is the slowest step.
The high yield of coupled product obtained (92%) after
allowing the Pd catalyst and bromotropolone (4) to be
premixed (Scheme 5) shows that the rate of transmeta-
lation (ktrans) is much faster than the rate of protodesi-
lylation (kdemet). Without the premixing of the Pd(0)
catalyst and bromotropolone (4), no coupled product is
observed, with the only product being protodesilylated
siloxane. Because ktrans > kdemet, the lack of coupled
product is most likely due to a slow oxidative addition
step, which allows time for all of the siloxane to be
protodesilylated before any oxidative insertion product
is generated. Therefore, the relative rates for the reaction
are ktrans > kdemet . koa.
An alternative approach to the coupling reaction would
be to employ a siloxane derived from 5-bromotropolone
and 2,3,4-trimethoxybromobenzene as the coupling part-
ners. However, attempts to form the tropolone siloxane
via metalation24 or rhodium-51,52 or palladium-catalyzed21
silylation were unsuccessful. Additionally, attempts to
form the corresponding boronate ester using established
protocols were unsuccessful.59-64
In conclusion, these studies of the synthesis of aryl
tropolone derivatives have allowed for a side-by-side
comparison between tin, boron, and silicon cross-coupling
reagents. The organoboron and organosilicon reagents
were found to couple in comparable yields, with the
exception of o-methoxy containing siloxanes. Both meth-
ods produced higher yields of coupled product than the
organotin reagents. With use of a stoichiometric amount
of palladium to overcome a slow oxidative addition step,
It is plausible that the premixing of the palladium,
phosphine, and 5-bromotropolone is actually allowing
time for the formation of Pd(0), and not necessarily the
formation of the oxidative addition product. In their study
of the rates and mechanism of formation of zerovalent
palladium from Pd(OAc)2 and PPh3, Amatore and Jutand
have indicated that the reduction of Pd(II) to Pd(0)
requires approximately 10-15 min at 60 °C in THF.57,58
Consequently, if protodesilylation is complete after 10
min, then it would be expected that no coupled product
would be observed.
In view of that, premixing palladium acetate and
triphenylphosphine, followed by the simultaneous addi-
tion of 5-bromotropolone, aryl siloxane 8, and TBAF,
(53) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 13944-
13945.
(54) Stambuli, J. P.; Buhl, M.; Hartwig, J. F. J. Am. Chem. Soc.
2002, 124, 9346-9347.
(55) Hartwig, J. F.; Paul, F. J. Am. Chem. Soc. 1995, 117, 5373-
5374.
(59) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447-3450.
(56) Attempts to employ Pd[P(t-Bu)3]2 as the catalyst were unsuc-
cessful. It was observed that if the reaction mixture was allowed to
stir for longer than 15 min before the addition of the siloxane,
significant decomposition resulted. Additionally, if the reaction mixture
was quenched before the addition of the siloxane, then only tropolone
was recovered, indicating replacement of the bromide by a hydrogen.
(57) Amatore, C.; Jutand, A.; M’Barki, M. A. Organometallics 1992,
11, 3009-3013.
(60) Murata, M.; Watanabe, S.; Masuda, Y. J. Org. Chem. 1997, 62,
6458-6459.
(61) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem.
2000, 65, 164-168.
(62) Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2000, 611,
392-402.
(63) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57,
9813-9816.
(58) Amatore, C.; Carre, E.; Jutand, A.; M’Barki, M. A. Organome-
tallics 1995, 14, 1818-1826.
(64) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508-7510.
J. Org. Chem, Vol. 70, No. 22, 2005 8953

Seganish et al.
SCHEME 6
(38); HRMS (EI+) m/z calcd for C14H24O5Si 300.1393, found
300.1385.
2-(Triethoxysilyl)toluene (14). The title compound was
synthesized according to a published procedure.24 The spectral
data match those reported previously.24
the siloxane coupling to form Fitzgerald’s compound (3)
could be realized. The inability to conduct this coupling
reaction catalytically is disappointing; however, efforts
are currently underway to overcome this obstacle.
1-(Triethoxysilyl)-3,4-methylenedioxybenzene (16). The
title compound was synthesized according to a published
procedure.24 The spectral data match those reported previ-
ously.25
4-(Triethoxysilyl)anisole (18). The title compound was
synthesized according to a published procedure.24 The spectral
data match those reported previously.24
Experimental Section
4-(Triethoxysilyl)-1,2,3-trimethoxybenzene (8). Silox-
ane was prepared according to the ortho-lithiation procedure
of DeShong27 and purified by column chromatography (TLC,
Rf ) 0.41, 4:1 hexanes/EtOAc) to yield a colorless oil (77%).
IR (CCl4) 3071 (w), 2978 (s), 2940 (s), 2895 (s), 2836 (m), 1587
(s), 1493 (s), 1455 (s), 1400 (s), 1293 (s), 1234 (s), 1089 (vs),
5-(Triethoxysilyl)-1,2,3-trimethoxybenzene (20). Silox-
ane was prepared according to the hydrosilylation procedure
of Masuda51 using 1-bromo-2,3,4-trimethoxybenzene, which
was prepared according to a literature procedure.14 Title
compound was isolated as a colorless oil (66%) using column
chromatography (TLC, Rf ) 0.21, 9:1 hexane/EtOAc). IR (CCl4)
3078 (w), 2974 (s), 2926 (s), 2881 (m), 2836 (w), 1576 (s), 1500
1
958 (s); H NMR (CDCl3) δ 1.23 (t, J ) 7.0, 9H), 3.87 (q, J )
7.0, 6H), 3.83 (s, 3H), 3.85 (s, 3H), 3.91 (s, 3H), 6.65 (d, J )
8.4, 1H), 7.27 (d, J ) 8.4, 1H); 13C NMR (CDCl3) δ 18.3, 55.9,
58.6, 60.6, 60.8, 107.4, 116.7, 131.7, 141.5, 156.2, 158.7; LRMS
(FAB+) m/z 331 (M+ +H, 95), 330 (92), 285 (100), 241 (40),
163 (40); HRMS (EI+) m/z calcd for C18H26O6Si 330.1499, found
330.1513.
1
(m), 1459 (m), 1400 (s), 1307 (s), 1110 (vs), 969 (m); H NMR
(CDCl3) δ 1.27 (t, J ) 7.0, 9H), 3.86 (q, J ) 7.0, 6H), 3.87 (s,
3H), 3.89 (s, 6H), 6.88 (s, 2H); 13C NMR (CDCl3) δ 18.3, 56.1,
58.8, 60.8, 111.3, 125.8, 140.1, 153.1; LRMS (FAB+) m/z 330
(M+, 100), 329 (15), 285 (23), 162 (37); HRMS (EI+) m/z calcd
for C15H26O6Si 330.1499, found 330.1493.
2-(Triethoxysilyl)anisole (10). The title compound was
synthesized according to a published procedure.27 The spectral
data match those reported previously.27
4-(Triethoxysilyl)-1,2-dimethoxybenzene (12). Silox-
ane was prepared according to the metalation procedure
of DeShong.24 Kugelrohr distillation (130 °C, 0.1 mmHg)
yielded a colorless oil (61%). IR (CCl4) 3054 (w), 2971 (s), 2936
(s), 2898 (s), 2833 (m), 1590 (s), 1507 (s), 1466 (m), 1390 (m),
1259 (s), 1114 (vs), 962 (s); 1H NMR (CDCl3) δ 1.25 (t, J ) 7.0,
9H), 3.86 (q, J ) 7.0, 6H), 3.90 (s, 3H), 3.91 (s, 3H), 6.90 (d, J
) 8.4, 1H), 7.15 (m, 1H), 7.26 (m, 1H); 13C NMR (CDCl3)
δ 18.3, 55.7, 55.8, 58.7, 110.9, 116.8, 122.2, 128.4, 148.6, 150.9;
LRMS (FAB+) m/z 300 (M+, 100), 299 (15), 255 (48), 163
Representative Procedure for the Palladium-Cata-
lyzed Cross-Coupling of 5-Bromotropolone (4) with Aryl
Siloxanes. (a) 2-Methoxy-5-phenylcyclohepta-2,4,6-trien-
1-one (6). To a 25 mL round-bottom flask were added 5-bromo-
2-methoxy-cyclohepat-2,4,6-trien-1-one (104 mg, 0.480 mmol),
10.8 mg of Pd(OAc)2 (0.0480 mmol), 63.0 mg of PPh3 (0.240
mmol), and phenyl trimethoxysilane (180 µL, 0.970 mmol). The
flask was placed under argon and 5 mL of THF was added,
followed by 0.970 mL of a 1.0 M solution of TBAF in THF
8954 J. Org. Chem., Vol. 70, No. 22, 2005

Colchicine Synthesis: Pd-Catalyzed Cross-Coupling
(0.970 mmol). The reaction was refluxed for 12 h. Following
this time, the reaction mixture was poured into 20 mL of water
and extracted three times with CH2Cl2 (50 mL). The organic
extracts were combined and dried (Na2SO4) and evaporated
to produce a dark brown oil. Column chromatography (TLC,
Rf ) 0.38, EtOAc) yielded 86.0 mg of a light tan solid (84%)
mp 139.2-140.4 °C (lit. 140-141 °C).65 The IR, 1H NMR, and
13C NMR matched that reported by Banwell.65
(b) 2-Methoxy-5-(4′-methoxyphenyl)cyclohepta-2,4,6-
trien-1-one (21). Title compound was prepared in a similar
manner as described above using siloxane (18) and was
purified via column chromatography (TLC, Rf ) 0.30, EtOAc)
to provide 94.0 mg of a light tan solid (81%) mp 148.5-148.9
°C (lit. 151.5-152.0 °C).14 The IR, 1H NMR, and 13C NMR
matched that reported by Banwell.14
(c) 2-Methoxy-5-(2′-methylphenyl)cyclohepta-2,4,6-
trien-1-one (23). Title compound was prepared in a similar
manner as described above using siloxane (14) and was
purified via column chromatography (TLC, Rf ) 0.30, EtOAc)
to provide 88.3 mg of a light tan solid (81%) mp 110.0-110.5
°C. IR (CCl4) 3080 (w), 3057 (w), 3020 (w), 2957 (w), 2933 (w),
2863 (w), 2840 (w), 1632 (m), 1596 (s), 1483 (m), 1248 (s), 1204
(m), 1117(s); 1H NMR (CDCl3) δ 2.26 (s, 3H), 3.99 (s, 3H), 6.80
(d, J ) 10.4, 1H), 7.03 (d, J ) 10.4, 1H), 7.18 (m, 1H), 7.26-
7.29 (m, 2H), 7.46-7.55 (m, 2H), 7.65-7.70 (m, 1H); 13C NMR
(CDCl3) δ 20.2, 56.3, 112.4, 128.4, 129.1, 130.6, 130.8, 131.9,
132.6, 133.6, 139.3, 142.0, 142.3, 164.5, 180.1; LRMS (FAB+)
m/z 227 (M+, 100), 226 (10), 164 (10); HRMS (EI+) m/z calcd
for C15H15O2 227.1072, found 227.1081.
yielded 70.4 mg of a light tan powder (92%) mp 116-117 °C
1
(lit. 112-117 °C).14 The IR, H NMR, and 13C NMR matched
that reported by Banwell.14
(h) 2,3,4-Trimethoxybiphenyl (28). 4-(Triethoxysilyl)-
1,2,3-trimethoxybenzene (8) (496 mg, 1.50 mmol), bromoben-
zene (157 mg, 1.00 mmol), Pd(OAc)2 (112 mg, 0.500 mmol),
and PPh3 (262 mg, 1.00 mmol) were combined in a 25 mL
round-bottom flask and placed under argon. THF (10 mL) was
added, followed by 1.50 mL (1.50 mmol) of TBAF (1.0 M in
THF). The reaction was heated to reflux for 1 h. The reaction
mixture was cooled to room temperature and diluted with
ether (20 mL). The organic layer was washed with water (20
× 2), dried (MgSO4), and evaporated to yield a brown oil.
Column chromatography (TLC, Rf ) 0.31, 9:1 hexanes/EtOAc)
yielded a yellow oil which was recrystallized (hexane) to give
171 mg of a white solid (70%) mp 47.2-47.9 °C (lit. 46-47
°C).66 The 1H and 13C NMR and IR match that reported by
Banwell.66
Representative Procedure for the Palladium-Cata-
lyzed Cross-Coupling of 5-Bromotropolone (4) with Aryl
Boronic Acids: 2-Methoxy-5-(2′-methoxyphenyl)cyclo-
hepta-2,4,6-trien-1-one (22). 2-Bromoanisole (748 mg, 4.00
mmol) was added to a suspension of Mg (107 mg, 4.40 mmol)
in 10 mL of THF. The reaction mixture was heated to reflux
until all of the aryl bromide had been consumed (3 h). After
cooling to -78 °C, the aryl Grignard reagent was transferred
via cannula to a -78 °C solution of trimethyl borate (538 µL,
4.80 mmol) in 15 mL of THF. The reaction mixture was
allowed to warm to room-temperature overnight, at which time
the yellow solution was poured into 50 mL of 1 M HCl. The
aqueous layer was extracted three times with 40 mL of ether.
The combined ether extracts were washed with three 50 mL
portions of 1 M NaOH. The combined basic extracts were
acidified with 2 M HCl. The boronic acid was then extracted
into CH2Cl2 and dried (MgSO4) and the solvent evaporated to
provide the boronic acid as a white solid which was used
without further purification in the coupling reaction.
(d) 2-Methoxy-5-(3′,4′-methylenedioxyphenyl)cyclo-
hepta-2,4,6-trien-1-one (24). Title compound was prepared
in a similar manner as described above using siloxane (16)
and was purified via column chromatography (TLC, Rf ) 0.30,
4:1 EtOAc/ hexanes) to provide 107 mg of a light tan solid
(87%) mp 150-151 °C. IR (CCl4) 3081 (w), 3061 (w), 3009 (w),
2964 (w), 2926 (w), 2850 (w), 1635 (m), 1587 (m), 1507 (m),
1
1486 (m), 1245 (s), 1121 (m); H NMR (CDCl3) δ 3.98 (s, 3H),
The palladium-catalyzed cross-coupling reaction is a modi-
fied procedure of Nair.16 To a 50 mL round-bottom flask were
added 5-bromo-2-methoxy-cyclohepat-2,4,6-trien-1-one (4) (215
mg, 1.00 mmol) and 57.8 mg of Pd(PPh3)4 (0.05 mmol). The
flask was placed under an Ar atmosphere and 10 mL of toluene
was added. The boronic acid (228 mg, 1.50 mmol), dissolved
in 1.5 mL of EtOH, was added by syringe, followed by 1.50
mL of a 2.0 M Na2CO3 solution. The reaction mixture was
refluxed for 5 h to consume all of the aryl bromide. The
reaction was cooled to room temperature, 5 drops of 20% H2O2
was added, and the mixture was stirred for a another hour.
Following this time, the reaction mixture was poured into 20
mL of water and extracted three times with CH2Cl2 (50 mL).
The organic extracts were combined, dried (Mg2SO4), and
evaporated to produce a dark brown oil. Purification via
column chromatography (TLC, Rf ) 0.27, EtOAc) provided 194
mg (80%) of the title compound as a pale yellow oil. The IR,
1H NMR, and 13C NMR matched that reported by Banwell.14
6.02 (s, 2H), 6.81-6.94 (m, 1H), 6.95-6.96 (m, 1H), 7.19-7.22
(m, 1H), 7.29-7.32 (m, 1H), 7.47-7.50 (m, 2H), 7.68-7.69 (m,
1H); 13C NMR (CDCl3) δ 56.3, 101.5, 107.7, 108.7, 112.8, 121.2,
128.4, 128.6, 130.6, 137.0, 137.9, 141.4, 148.3, 164.1, 179.8;
LRMS (FAB+) m/z 257 (M+, 20), 245 (100), 243 (30), 239 (20);
HRMS (EI+) m/z calcd for C15H13O4 257.0814, found 257.0822.
(e) 2-Methoxy-5-(3′,4′-dimethoxyphenyl)cyclohepta-
2,4,6-trien-1-one (25). Title compound was prepared in a
similar manner as described above using siloxane (12) and was
purified via column chromatography (TLC, Rf ) 0.30, EtOAc)
to provide 115 mg of a light tan solid (88%) mp 168.1-168.3
°C (lit. 168-168.5 °C).14 The IR, 1H NMR, and 13C NMR
matched that reported by Banwell.14
(f) 2-Methoxy-5-(3′,4′,5′-trimethoxyphenyl)cyclohepta-
2,4,6-trien-1-one (26). Title compound was prepared in a
similar manner as described above using siloxane (20) and was
purified via column chromatography (TLC, Rf ) 0.40, EtOAc)
to provide 129 mg of a light tan solid (89%) mp 137-138 °C
1
(lit. 138-139 °C).14 The IR, H NMR, and 13C NMR matched
that reported by Banwell.14
Acknowledgment. We thank the National Insti-
tutes of Health, Cancer Institute (CA 82169-01), and
the University of Maryland for generous financial
support. W.M.S. thanks the Organic Division of the
American Chemical Society for a Graduate Fellowship
(sponsored by Procter and Gamble).
(g) 2-Methoxy-5-(2′,3′,4′-trimethoxyphenyl)cyclohepta-
2,4,6-trien-1-one (27). To a 25 mL round-bottom flask were
added 50.0 mg (0.233 mmol) of 5-bromotropolone, 225 mg
(0.253 mmol) of Pd(OAc)2, and 336 mg (1.28 mmol) of PPh3.
The contents of the flask were placed under argon and THF
(5 mL) was added. The reaction was refluxed for 15 min, and
154 mg (0.466 mmol) of 4-(triethoxysilyl)-1,2,3-trimethoxy-
benzene (7) in 2.0 mL of THF was added via syringe, followed
by 0.466 mL of TBAF (1.0 M in THF, 0.466 mmol). The
reaction was maintained at reflux for an additional 30 min,
poured into water (50 mL), and extracted three times with 50
mL of CH2Cl2. The organic extracts were dried (MgSO4) and
evaporated. Column chromatography (TLC, Rf ) 0.21, EtOAc)
Supporting Information Available: General experimen-
tal details, as well as 1H NMR spectra of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO051636H
(66) Banwell, M. G.; Herbert, K. A.; Buckleton, J. R.; Clark, G. R.;
Rickard, C. E. F.; Lin, C. M.; Hamel, E. J. Org. Chem. 1988, 53, 4945-
4952.
(65) Banwell, M. G.; Cameron, J. M.; Collis, M. P.; Gravatt, G. L.
Aust. J. Chem. 1997, 50, 395-407.
J. Org. Chem, Vol. 70, No. 22, 2005 8955