Palladium-catalyzed arylation of ketone enolates: an expeditious entry to tamoxifen-related 1,2,2-triarylethanones.

Article abstract of DOI:10.1021/ol025811h

[reaction: see text]. After a rigorous study on the effect of several catalytic systems, a simple, high yielding procedure for the preparation of 1,2,2-triarylethanones, skeletal analogues of tamoxifen, is presented. Apart from the economic and environmen

Full text of DOI:10.1021/ol025811h

ORGANIC
LETTERS
2
002
Vol. 4, No. 9
591-1594
Palladium-Catalyzed Arylation of Ketone
Enolates: An Expeditious Entry to
Tamoxifen-Related
1
1,2,2-Triarylethanones
F a´ tima Churruca, Raul SanMartin, Imanol Tellitu, and Esther Dom ´ı nguez*
Kimika Organikoa II Saila, Zientzi Fakultatea, Euskal Herriko Unibertsitatea,
P.O. Box 644, 48080 Bilbao, Spain
qopdopee@lg.ehu.es
Received March 4, 2002
ABSTRACT
After a rigorous study on the effect of several catalytic systems, a simple, high yielding procedure for the preparation of 1,2,2-triarylethanones,
skeletal analogues of tamoxifen, is presented. Apart from the economic and environmental advantages involved, this palladium-catalyzed
arylation of deoxybenzoin enolates features a lack of ortho-arylation side reactions. In addition, an alternative approach from acetophenones
to the target triarylethanone system is also announced.
In the course of our investigations on the synthesis of new
phenanthrofused heterocycles, 1,2,2-triarylethanones 1 were
to tamoxifen, the most widely used adjuvant drug therapy
for the treatment of estrogen receptor breast cancer. Ac-
1
3
envisaged as suitable precursors of an appealing pentacyclic
system, dibenzo[a,c]phenanthridines 2, with an inherent
interest due to their close relationship to biologically active
cording to an obvious C
2
1
-C ′′′ bond disconnection, the
R-arylation of deoxybenzoins 3, readily available from
4
arylacetic acids, would be a direct approach to the key
2
benzo[c]phenanthridine alkaloids. An additional feature of
intermediates 1.
such ketone intermediates 1 is their structural resemblance
In this context, during the past decade much effort has
been made to achieve a reliable method for the R-arylation
of ketones, as this reaction constitutes the key step in the
(1) (a) Olivera, R.; Pascual, S.; Herrero, M.; SanMartin, R.; Dom ´ı nguez,
E. Tetrahedron Lett. 1999, 40, 3479-3480. (b) Olivera, R.; SanMartin, R.;
Dom ´ı nguez, E. J. Org. Chem. 2000, 65, 7010-7019 and references therein.
(
2) (a) After searching the literature, only one report of a related dibenzo-
(3) The synthesis and biological effect of tamoxifen and its analogues
have attracted much attention. See: (a) Delcey, C. D.; Huel, C.; Bisagni,
E. Heterocycles 1995, 41, 1721-1730. (b) Lashley, M. R.; Nantz, M. H.
Tetrahedron Lett. 2000, 41, 3295-3298 and references therein. (c) Valliant,
J. F.; Paul Schaffer, P.; Stephenson, K. A.; Britten, J. F. J. Org. Chem.
2002, 67, 383-387.
(4) (a) Al-Maharik, N. I.; Kaltia, Seppo, A. A.; Mutikainen, I.; Waehaelae,
K. J. Org. Chem. 2000, 65, 2305-2308. (b) SanMartin, R.; Mart ´ı nez de
Marigorta, E.; Dom ´ı nguez, E. Tetrahedron 1994, 50, 2255-2264. Other
complementary procedures that allow a wider range of substitution paterns
are described in: (c) Olivera, R.; SanMartin, R.; Dom ´ı nguez, E. Solans,
X.; Urtiaga, M. K.; Arriortua, M. I. J. Org. Chem. 2000, 65, 6398-6411
and references therein.
[
a,c]phenanthridine was found. See: Kiselyov, A. S. Tetrahedron Lett. 1995,
3
6, 493-496. For recent reports on the biological properties of benzo[c]-
phenanthridines, see: (b) Asano, Y.; Yamashita, M.; Nagai, K.; Kuriyama,
M.; Yamada, K.; Tomioka, K. Tetrahedron Lett. 2001, 42, 8493-8495.
(
c) Salmore, A. K.; Hunter, M. D. J. Chem. Ecol. 2001, 27, 1713-1727.
(d) Ito, C.; Itoigawa, M.; Tokuda, H.; Kuchide, M.; Nishino, H.; Furukawa,
H. Planta Med. 2001, 67, 473-475. (e) Slaninova, I.; Taborska, E.;
Bochorakova, H.; Slanina, J. Cell Biol. Toxicol. 2001, 17, 51-63. (f)
Harayama, T.; Akiyama, T.; Akamatsu, H.; Kawano, K.; Abe, H.; Takeuchi,
Y. Synthesis 2001, 444-450. (g) Harayama, T.; Akiyama, T.; Nakano, Y.;
Shibaike, K.; Akamatsu, H.; Hori, A.; Abe, H.; Takeuchi, Y. Synthesis 2002,
2
37-241.
1
0.1021/ol025811h CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/09/2002

5
synthesis of a wide number of complex systems. Despite
the variety of procedures developed to effect such transfor-
mations, described as fundamental as the classical alkylation
of enolates, serious limitations concerning a lack of regio-
selectivity and versatility of the process or the need of
specific, usually toxic main group aryl reagents have been
Table 1. Selected R-Arylation Assays Performed on
Deoxybenzoin 3a
6
reported in many cases. However, the use of palladium
5
d,7
catalysts has emerged as a very promising alternative,
overcoming most of the problems related to this reaction,
historically difficult to conduct.
As a supporting step in this field, we wish to report an
easy, high yielding procedure for the coupling of aryl halides
4
with deoxybenzoins 3 catalyzed by palladium(II) acetate.
product
(%)a
entry
reaction conditions
t
1
2
3
4
5
6
7
8
9
Pd(OAc)2, KO Bu, toluene, 90 °C, 3 hb
3a
3a
3a
3a
b
Pd(OAc)2, K2CO3, toluene, 90 °C, 23 h
Pd2(dba)3/BINAP, KO Bu, THF, 70 °C, 6 h
Pd2(dba)3/DPPF, KO Bu, THF, 70 °C, 6 h
PdCl2, K2CO3, DMF, 100 °C, 6 hd
PdCl2, Cs2CO3, DMF, 100 °C, 6 h
PdCl2/PPh3 K2CO3, DMF, 130 °C, 6 h
PdCl2/PPh3 K2CO3, DMF, 100 °C, 6 h
Pd(OAc)2/PPh3, K2CO3, o-xylene, 170 °C, 22 h
t
b,c
t
b,c
e
d,f
1a (20)
1a (24)
e
d,g
d,f,g
b,c
1a (55)
6
(29)
1a (52)
(35)
1
0
Pd(OAc)2/PPh3, Cs2CO3, DMF, 170 °C, 0.7 hb,c
6
1
1
1
2
Pd(OAc)2/PPh3, K2CO3, o-xylene, 150 °C, 9 hh
Pd(OAc)2/PPh3, Cs2CO3, DMF, 150 °C, 0.5 hh
1a (83)
1a (85)
a
Isolated yields measured on the basis of the starting amount of diaryl
ketone 3a. b 1.3 equiv of 4a, 2.5 equiv of base, and 0.02 equiv of palladium
As shown in Table 1, 1,2-bis(3,4-dimethoxyphenyl)-
catalyst were used. c 0.05 equiv of ligand was used. d 1.2 equiv of of 4a,
e
1
.2 equiv of base, and 0.05 equiv of PdCl2 were used. Complex mixtures
ethanone 3a was treated with bromobenzene 4a under the
action of different palladium catalyst/ligand/base systems in
order to promote phenylation of position 2 to give 1,2-bis-
f
of products were obtained. 1.2 equiv of iodobenzene 5 was used instead
of 4a. g 0.2 equiv of PPh3 was used. h 3a/4a/Pd(OAc)2/PPh3/Cs2CO3 ratio
was 1:1:0.02:0.08:2.5.
(
3,4-dimethoxyphenyl)-2-phenylethanone 1a.
Despite previous reports,5
d,7a-c,8
no target triaryl derivative
9
2
and co-workers have reported the PdCl -catalyzed arylation
1
a was obtained in the absence of ligand or by using bulky
of 1,2-diphenylethanone, but according to the latter results
this procedure seems to be seriously limited by the electronic
nature of the ketone precursor. Although better yields were
bidentate phosphine ligands such as BINAP or DPPF. In
addition, the use of the PdCl catalyst provided low yields
of phenylated 1a, even when iodobenzene 5 was employed
2
2 3 2 3
obtained from the system Pd(OAc) /PPh /Cs CO in both
as the haloarene reagent (Table 1, entries 6 and 8). Miura
DMF and o-xylene solvents, there still remained the draw-
7
d,e
back of the ortho-arylation side reaction to give diphe-
nylated derivative 6. This problem was ultimately overcome
by a careful choice of the temperature, reaction times, and
relative amount of bromobenzene 4a (Table 1, entries 11
and 12), thus affording 1a in good yields.
(
5) (a) Piers, E.; Oballa, R. M. Tetrahedron Lett. 1995, 36, 5837-5860.
b) Ryan, J. H.; Stang, P. J. Tetrahedron Lett. 1997, 38, 5061-5064. (c)
Muratake, H.; Hayakawa, A.; Natsume, M. Chem. Pharm Bull. 2000, 48,
558-1566. (d) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J.
(
1
Am. Chem. Soc. 2000, 122, 1360-1370 and references included therein.
(e) Deng, H. B.; Konopelski, J. P. Org. Lett. 2001, 3, 3001-3004.
(6) (a) Beugelmans, R.; Boudet, B.; Quintero, L. Tetrahedron Lett. 1980,
2
1, 1943-1944. (b) Kessar, S. V. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon Press: New
York, 1991; Vol. 4, Chapter 2.3. (c) Pinhey, J. T. Pure Appl. Chem. 1996,
6
8, 819-824. (d) Mino, T.; Matsuda, T.; Maruhashi, K.; Yamashita, M.
Organometallics 1997, 16, 3241-3242.
7) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
(
1
1
1
1108-11109. (b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997,
19, 12382-12383. (c) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
999, 121, 1473-1478 (d) Satoh, T.; Kametani, Y.; Terao, Y.; Miura, M.;
Nomura, M. Tetrahedron Lett. 1999, 40, 5345-5348. (e) Terao, Y.;
Kametani, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron,
2
001, 57, 5967-5974. (f) Mutter, R.; Campbell, I. B.; Martin de la Neva,
E, V.; Merritt, A. T.; Wills, M. J. Org. Chem. 2001, 66, 3284-3290. (g)
Sol e´ , D.; Vallverd u´ , L.; Peidr o´ , E.; Bonjoch, J. Chem. Commun. 2001,
Once DMF was elected as the most convenient solvent,
mainly because of its shorter required reaction time, the
1
888-1889. (h) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J.
Am. Chem. Soc. 2002, 124, 1261-1268.
8) (a) Mutter, R.; Martin de la Neva, E, V.; Wills, M. Chem. Commun.
000, 1675-1676. See also: (b) Shaughnessy, K. H.; Hamann, B. C.;
Hartwig, J. F. J. Org. Chem. 1998, 63, 6546-6553.
(
2
(9) Satoh, T.; Inoh, J.-I.; Kawamura, Y.; Kawamura, Y.; Kametani, Y.;
Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 2239-2246.
1592
Org. Lett., Vol. 4, No. 9, 2002

Table 2. Synthesis of 1,2,2-Triarylethanones 1 by
Palladium-Catalyzed R-Arylation of Deoxybenzoins 3
Table 3. Palladium-Catalyzed R,R-Diarylation of
Acetophenones 7
R1
R2
R3
1 (%)a
entry
R1
R2
R3
R4
R5
1 (%)a
H
H
H
OMe
OMe
H
H
H
OMe
1i (96)
1h (85)
1o (74)
1p (49)
1
2
3
4
5
6
7
8
9
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
1a (85)
1b (51)
1c (46)
1d (47)
1e (55)
1f (12)
1g (44)
1h (74)
1i (80)
1j (73)
1k (71)
1l (57)
1m (70)
1n (54)
OMe
Me
H
OMe
H
OMe
OCH2O
OMe
H
OMe
OMe
a
GC-MS yields.
OMe
NO2
H
H
H
enough to propose that the latter method constitutes a
suitable, general tool for the preparation of 1,2,2-triaryl-
ethanones 1, thus establishing a rival alternative to the
recently reported Heck-type triarylation approach. More-
over, in contrast with the relatively complex phosphine
ligands usually employed in previous reports on the arylation
H
H
1
1
1
1
1
0
1
2
3
4
OMe
H
OMe
OCH2O
H
OMeH
OMeH
13
H
H
H
H
NO2
7
a-c,f,8,14
of enolates,
enylphosphine proved to be most efficient.
a simple, cheap ligand such as triph-
a
Isolated yield.
Encouraged by the simplicity and mild conditions of our
procedure, we foresaw that slight modification, such as an
increase in the amount of the arylating agent 4, could be the
key to obtain target ketones 1 in one step starting from
commercially available acetophenones 7. At present, the
results obtained so far are very promising (Table 3) and
already optimized coupling conditions10 were applied to a
number of deoxybenzoins 3 and bromoarenes 4. The results
are summarized in Table 2. It should be remarked that no
excess of any of the coupling reagents was employed,
whereas previous works on the intermolecular arylation of
ketones or esters with haloarenes usually report (i) a required
3
suggest that the use of such a relatively small ligand (PPh )
would be the decisive factor that enables this relevant tandem
1.1-2.3 excess of the carbonyl compound or the haloarene
15
double arylation process.
and (ii) yields measured on the basis of the starting amount
To summarize, an easy, general procedure for the prepara-
tion of 1,2,2-triarylethanones from deoxybenzoins is pre-
sented. This palladium-catalyzed R-arylation reaction is
conducted with a simple ligand such as triphenylphosphine
and avoids unwanted side reactions such as ortho-arylation
or dehalogenation of the arylbromide reagent. Moreover,
according to the latest assays performed, a slight modification
of the same experimental conditions applied to acetophenones
can constitute an additional alternative approach to the
tamoxifen-related framework of 1,2,2-triarylethanones.
We are presently exploring the feasibility of such methods
along with the synthetic potential associated with the use of
1,2-dihaloarenes in the hope of promoting further coupling
reactions.
of the haloarene.5
d,7a,d-f,9,11
Save for the low yield obtained for 1f, probably as a result
of a sterically hindered transition state for the oxidative
12
addition step, the moderate to good yields obtained in most
of the range of models assayed feature a slight dependence
on the electronic nature of the coupling partners, feeble
(10) General Procedure. Dry degassed DMF (20 mL) was added to an
oven-dried reaction flask charged with Pd(OAc)2 (0.065 mmol), Cs2CO3
(
(
7.75 mmol), PPh3 (0.25 mmol), ketone 1 (3.1 mmol), and arylbromide 4
3.1 mmol) under argon at room temperature. The resultant stirred
suspension was heated to 150 °C for 0.5-1 h. After cooling, HCl (50 mL
of a 1.4 M solution in water) was added, and the aqueous layer was extracted
with CH2Cl2 (3 × 30 mL). The combined organic extracts were washed
with saturated aqueous NH4Cl (5 × 100 mL), dried over anhydrous sodium
sulfate, and evaporated in vacuo to give a residue that was purified by flash
chromatography on silicagel using 10-50% EtOAc/hexane as eluent.
(
11) (a) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
(13) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001, 123,
8217-8225.
7
2
996-8002. (b) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc.
001, 123, 8410-8411.
(14) (a) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc.
1998, 120, 9722-9723. (b) A˙ hman, J.; Wolfe, J. P.; Trotman, M. V.;
Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120, 1918-1919.
(15) For previous reports on one-pot R,R-diarylation reactions of ketones
see refs 5d, 7a, 7c,d, and 14a. Similar diarylations of other carbonylic
compounds have been reported in refs 8b and 11a.
(12) Useful insights into the mechanism of the Pd-catalyzed arylation
of enolates and other related cross-coupling reactions can be found in: (a)
Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816-5817.
(
b) Amatore, C.; Jutand, A. Acc. Chem. Res. 2000, 33, 314-321. See also
refs 7a and 7d.
Org. Lett., Vol. 4, No. 9, 2002
1593

Acknowledgment. This research was supported by the
University of the Basque Country (Project UPV 170.310G37/
8), the Spanish Ministry of Education and Culture (PB97-
600), and the Basque Government (GV170.310-G0053/96).
Supporting Information Available: Characterization
data for all unknown triarylethanones 1b-h and 1j-m. This
material is available free of charge via the Internet at
http://pubs.acs.org.
9
0
F.C. thanks the Ministry of Education and Culture (MEC)
for a predoctoral scholarship.
OL025811H
1594
Org. Lett., Vol. 4, No. 9, 2002