Solid-phase synthesis of diaryl ketones through a three-component Stille coupling reaction

Article abstract of DOI:10.1016/S0040-4039(00)01937-7

A three-component Stille coupling reaction on solid phase is described. Diaryl ketones bearing a wide variety of functional groups were prepared with polymer-bound organostannane and aryl halides in the presence of carbon monoxide.

Full text of DOI:10.1016/S0040-4039(00)01937-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 175–177
Solid-phase synthesis of diaryl ketones through a
three-component Stille coupling reaction
Weiya Yun,* Shiming Li, Bingbing Wang and Li Chen
Roche Research Center, Hoffmann-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110, USA
Received 7 August 2000; revised 30 October 2000; accepted 31 October 2000
Abstract—A three-component Stille coupling reaction on solid phase is described. Diaryl ketones bearing a wide variety of
functional groups were prepared with polymer-bound organostannane and aryl halides in the presence of carbon monoxide.
© 2000 Elsevier Science Ltd. All rights reserved.
Diaryl ketones and their reductive products, diaryl
methanes, serve as important structural scaffolds in
biologically active compounds and are frequently used
as bioisosteres for diaryl ethers in medicinal chem-
istry.1a Although many synthetic methods are available
for the preparation of this structural component in
solution phase,1 their extension to solid-phase synthesis
and chemical library production has been very limited.
In 1995, Ellman and his coworkers reported the first
diaryl ketone synthesis on solid support via palladium
catalyzed Stille coupling reactions of resin-bound aryl-
stannane with acid chlorides.2 In our recent attempt for
a high-throughput synthesis of diaryl ketones, we have
extended this method to a three-component Stille cou-
pling reaction on solid support in order to expand our
substrate pool to aryl halides bearing polar, acid chlo-
ride sensitive substituents. Herein we wish to report our
initial results on these newly developed three-compo-
nent Stille coupling conditions in which a polymer-
bound arylstannane was coupled with aryl halides in
presence of carbon monoxide.
To demonstrate the feasibility of this reaction on solid-
phase support, Rink resin (1% cross linked, 0.54 mmol/
g) bound aryl bromide 1 was first reacted with
tributylphenyltin in the presence of carbon monoxide
and Pd(Ph3P)4 in DMF (Scheme 1).3 It was found that
the coupling reaction took place selectively at the
Scheme 1. Three-component Stille coupling reaction on solid-phase support.
Scheme 2. (a) N-Hydroxysuccinimide; EDCI, DMF, 23°C, 16 h, 92% yield; (b) (Bu3Sn)2, Pd(Ph3P)4, toluene, reflux, 15 h;5 (c)
Rink amide resin, DMF, 23°C, 16 h.
Keywords: solid-phase synthesis; Stille coupling; diaryl ketone.
* Corresponding author. Tel.: (973) 235-3126; fax: (973) 235-6084; e-mail: weiya.yun@roche.com
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01937-7

176
W. Yun et al. / Tetrahedron Letters 42 (2001) 175–177
Scheme 3. (a) ArX, Pd(Ph3P)4, CO, 40 psi, DMSO, 80°C, 18 h if X=I, 3 days if X=Br; (b) 1:1 TFA/CH2Cl2, 23°C, 0.5 h.
bromine position and finished within 6 h at 80°C under
40 psi of carbon monoxide. Upon cleavage from the
polymer with TFA, aryl ketone 2 was obtained in
quantitative yield with high purity (>95%).4 Further
investigation of reaction conditions revealed that both
DMF and DMSO provided satisfactory results, and
Pd(Ph3P)4 appeared to be a better catalyst than
Pd2(dba)3. Carbon monoxide pressure of 40–60 psi
appeared to be required for high conversion.
Preparation of the polymer-bound stannane component
5 is shown in Scheme 2. 4-Bromo-2-chloro benzoic acid
was first converted to N-hydroxysuccinimide ester 3 via
carbodiimide promoted coupling. The bromine at the
para position of the activated ester was then reacted
with bis(tributyltin) in presence of a catalytic amount of
Pd(Ph3P)4 in anhydrous toluene at 140°C to afford the
arylstannyl ester 4.5 Direct reaction of the resulting 4
with Rink amide resin at 23°C in DMF for 16 h
afforded 5, and the loading was determined to be
quantitative.
The success of this reaction prompted us to explore the
reversed three-component Stille coupling on solid sup-
port with arylstannane as an immobilized component
and the more readily available aryl halides as building
blocks.
The three-component reversed Stille coupling reaction
on the polymer (Scheme 3) was carried out under
similar reaction conditions as described in Scheme 1.
Table 1. Structure of diaryl ketone prepared through a three-component Stille coupling reaction
a
Entries 7a–l were prepared from ArI, 7m and 7n from ArBr, 7o and 7p from ArOTf. b Made from 3-iodo-
L-tyrosine; the isolated product was
decarboxylated. c Product contains 2-chlorobenzamide due to partial reduction of 5.

W. Yun et al. / Tetrahedron Letters 42 (2001) 175–177
177
The reactions were performed in pressure tubes ar-
M. Jonca and Mr. G. J. Sasso for sample analysis.
ranged in a heating block on a shaker. In our case
sixteen reactions were run simultaneously. Upon cleav-
age from the resin, ketone 7 was obtained in good to
excellent yields and purity (Table 1).6 As expected,
different halide classes exhibited different reactivities
toward the organotin reagent. While chlorine is totally
inert under these reaction conditions, aryl bromides and
aryl iodides showed acceptable to excellent reactivities
toward 5 despite the fact that the stannane component
is deactivated by the para amide group. The majority of
reactions with aryl iodides finished within 6 h, although
all reactions were heated at 80°C for 18 h to ensure
complete conversions. In the case of aryl bromides,
three to four days were required. Like the solution
phase reactions previously reported,3,7 the presence of
LiCl showed no effect with aryl halides, while it indeed
enhanced the reaction rate for aryl triflates. In contrast,
unlike the reactions in solution phase, aryl triflates,
under these conditions, are less reactive than aryl bro-
mides. Although pure products were generated in the
presence of LiCl, none of the reactions could be com-
pleted in four days. In all cases, diaryl ketones were the
sole products, and no direct cross coupling products
were observed.
References
1. (a) Taber, D. F.; Sethuraman, M. R. J. Org. Chem. 2000,
65, 254 and references cited in; (b) Brunet, J. J.; Chauvin,
R. Chem. Soc. Rev. 1995, 24, 89.
2. (a) Plunkett, M. J.; Ellman, J. A. J. Am. Chem. Soc. 1995,
117, 3306; (b) Plunkett, M. J.; Ellman, J. A. J. Org. Chem.
1995, 60, 6006.
3. (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508;
(b) Scott, W. J.; Crisp, G. T.; Stille, J. K. Org. Synth.
1990, 68, 116; (c) Stille, J. K. Pure Appl. Chem. 1985, 57,
1771.
4. The isolated yield was calculated based on Rink amide
resin substitution level. The purity was determined based
on area of peak corresponding to the correct molecular
weight by
a
C18 reverse phase HPLC column
(Chromegabond WR-C18, 3m, 10–90% CH3CN/H2O con-
taining 0.02% TFA), monitored by UV detection at 215
nm and by a SEDEX 55 evaporative light scattering
detector (ELSD). The purity scores reported herein are
based on ELSD.
5. (a) Ohmomo, Y.; Murakami, K.; Hirata, M.; Magata, Y.;
Tanaka, C.; Yokoyama, A. Chem. Pharm. Bull. 1994, 42,
913; (b) Azizian, H.; Eaborn, C.; Pidcock, A. J.
Organomet. Chem. 1981, 215, 49.
The great functional group tolerance of this three-com-
ponent Stille coupling reaction has substantially in-
creased our substrate building block pool. Not only can
the aryl halides containing methoxy (7b and 7n), nitro
(7e), trifluoromethyl (7f) and hetero cyclic substituents
(7j and 7k) react smoothly with resin bound 5 to give
the desired diaryl ketone products, those containing
carboxylic acid (7a, 7d, and 7h), aniline (7a and 7g),
aldehyde (7b), ketone (7i and 7p), phenol (7c, 7h and 7l)
and even amine (7l) can also be directly coupled to
resin 5 without protection. The electronic effect of the
substituents in aryl halides to the coupling reaction was
not manifested under the aforementioned conditions
since both electron-donating groups (7c, 7g and 7n) and
electron withdrawing groups (7d–f) containing aryl
halides afforded diaryl ketones in similar yield and
purity.
6. The general procedure for the solid-phase three-compo-
nent Stille coupling is as follows. Resin 5 (100 mg), an aryl
iodide (5 equiv.) or an aryl bromide (10 equiv.), and
Pd(Ph3P)4 (0.02 equiv.) were suspended in DMSO (3 ml) in
a pressure tube (ACE catalog c: 8648-135 for the tube;
5844-76 for the Teflon adapter). The tube was capped and
connected onto a three-way valve with a carbon monoxide
tank and a vacuum source already connected (Swagelok
catalog c: SS-QC4-B-400 and SS-QC4-D-4PM). The tube
was charged with CO to 40 psi and was then evacuated.
The purging procedure was repeated four times and the
tube was finally charged with 40 psi of CO. The sealed
tube was heated to 80°C for 18 h in a heating block on a
shaker. After cooling to ambient temperature, the pressure
in the tube was released and the reaction mixture was
transferred to a filtration tube equipped with a frit at the
bottom. The resin was filtered, washed repeatedly with
CH2Cl2 and MeOH, and dried under vacuum. The diaryl
ketone generated was then cleaved from the resin with 1:1
TFA/CH2Cl2 at 23°C for 0.5 h. All diaryl ketones showed
satisfactory spectroscopic and analytical data. NMR data
for 7k: 1H NMR (400 MHz, DMSO) l 8.18 (dd, 1H,
J=4.8, 0.8 Hz), 8.05 (br s, 1H), 7.85 (d, 1H, J=1.6 Hz),
7.81 (dd, 1H, J=8.0, 2.0 Hz), 7.78 (br s, 1H), 7.74 (dd,
1H, J=4.0, 1.2 Hz), 7.61 (d, 1H, J=8.0 Hz), 7.32 (dd,
1H, J=5.2, 4.0 Hz); 13C NMR (100 MHz, DMSO) l
185.5, 167.4, 145.0, 140.3, 139.2, 136.6, 136.1, 130.0, 129.5,
129.1, 128.8, 127.4; IR (neat) wmax 3432, 3330, 3097, 1688,
In conclusion, we have successfully implemented a
three-component Stille coupling reaction on solid sup-
port. Diaryl ketones with a wide range of functional
groups were synthesized directly without tedious pro-
tection and deprotection steps. This diaryl ketone syn-
thesis constitutes a complementary approach to the
synthesis via acid chlorides and may find broad applica-
tion in high throughput synthesis and lead optimization
process in medicinal chemistry. An application of this
synthesis to ketone library production along with SAR
results will be reported in due course.
Acknowledgements
1654, 1624, 1549, 1512, 1485, 1411, 1353, 1294 cm−1
.
7. (a) Echavarren, A. M.; Stille, J. K. J. Am. Chem. Soc.
1988, 110, 1557; (b) Sieber, F.; Wentworth Jr., P.; Janda,
K. D. J. Comb. Chem. 1999, 1, 540.
The authors wish to acknowledge Mr. P. P. Riggio, Ms.
.
.