Catalytic efficiency of a new tridentate ferrocenyl phosphine auxiliary: Sonogashira cross-coupling reactions of alkynes with aryl bromides and chlorides at low catalyst loadings of 10-1 to 10-4 Mol %

Article abstract of DOI:10.1021/ol048870z

(Chemical Equation Presented) The catalytic activity in Sonogashira cross-coupling reactions of alkynes with a variety of aryl halides (including chlorides) using a multidentate ferrocenyl phosphine is presented. The novel mixed ferrocenyl aryl/alkyl trip

Full text of DOI:10.1021/ol048870z

ORGANIC
LETTERS
2004
Vol. 6, No. 20
3473-3476
Catalytic Efficiency of a New Tridentate
Ferrocenyl Phosphine Auxiliary:
Sonogashira Cross-Coupling Reactions
of Alkynes with Aryl Bromides and
Chlorides at Low Catalyst Loadings of
-1
-4
10 to 10 Mol %
Jean-Cyrille Hierso,* Aziz Fihri, Re´gine Amardeil, and Philippe Meunier
Laboratoire de Synthe`se et d’Electrosynthe`se Organome´talliques UMR-CNRS 5188,
UniVersite´ de Bourgogne, 9 AVenue Alain SaVary, 21078 Dijon, France
Henri Doucet* and Maurice Santelli
Laboratoire de Synthe`se Organique associe´ au CNRS, Faculte´ des Sciences de Saint
Je´roˆme, UniVersite´ Aix-Marseille, AVenue Escadrille Normandie-Niemen,
13397 Marseille, France
Vladimir V. Ivanov
Institute of Organic Chemistry, National Academy of Sciences of Ukraine,
Vul. Murmanska 5, 02094, KieV, Ukraine
jean-cyrille.hierso@u-bourgogne.fr; henri.doucet@uniV.u-3mrs.fr
Received June 15, 2004
ABSTRACT
The catalytic activity in Sonogashira cross-coupling reactions of alkynes with a variety of aryl halides (including chlorides) using a multidentate
ferrocenyl phosphine is presented. The novel mixed ferrocenyl aryl/alkyl triphosphine is thermally stable and insensitive to air or moisture,
-1
-4
and its robustness allows aryl alkynylation at 10 to 10 mol % catalyst loadings with TONs up to 250 000. Copper-free coupling using
phenylacetylene is also accessible in good yield.
Palladium-catalyzed reactions are of utmost importance in
synthetic organic chemistry. The industrial syntheses of many
aryl-containing pharmaceuticals such as antiinflammatory
drugs (Fenbufen),1 blood-pressure regulators (antihyperten-
sive biaryls SARTANs),2,3 antibiotics (Terprenin),4 antimy-
cotics, antidepressant or antiarthritic drugs potentially include
one or several steps of palladium-catalyzed carbon-carbon
cross coupling (for instance Heck, Suzuki, Sonogashira, and
other coupling reactions).5-8
* To whom correspondence should be addressed. (J.-C.H.) Phone: +33
3 80 39 61 06. Fax: +33 3 80 39 36 82. (H.D.) Phone number: +33 4 91
28 84 16. Fax: +33 4 91 98 38 65.
(1) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.; Lee, H. M.; Yang, C.;
Nolan, S. P. J. Organomet. Chem. 2002, 653, 69-82.
10.1021/ol048870z CCC: $27.50
© 2004 American Chemical Society
Published on Web 08/27/2004

These reactions are usually carried out with catalytic
amounts of palladium in the presence of auxiliary ligands
and additives.9 A critical improvement in this field, directly
connected to both sustainable chemistry and economic
concerns, is the necessity to minimize the consumption of
depletive resources.
ligands have also been chosen as tunable catalytic auxiliaries,
amenable to systematic structural and electronic modification.
We anticipated that a geometrically “more simple” ferro-
t
cenyl triphosphine (compared to Fc(P)4 Bu) might lead, as
well, to highly active systems in palladium-catalyzed C-C
coupling. Additionally, to improve the performance of the
ligand, we chose to electronically enrich one of the phos-
phorus atoms and to provide the ferrocenyl backbone with
better flexibility via an unblocked axial rotation. This strategy
prompted us to design and synthesize the new mixed
ferrocenyl aryl/alkyl triphosphine (Scheme 1) 1,2-bis(diphen-
We initiated a program aiming to develop air-stable,
moisture- and temperature-resistant auxiliaries, which could
allow efficient catalytic reactions in the presence of very low
amounts of precious metals (less than 0.01 mol %10,11). For
this purpose, the tetradentate ferrocenyl phosphine 1,1′,2,2,′-
tetrakis(diphenylphosphino)-4,4′-di-tert-butylferrocene (Fc-
t
(P)4 Bu, Figure 1) was successfully used in our first target
Scheme 1. Synthesis of the Ferrocenyl Triphosphine
Fc(P)2 Bu(PiPr)
t
t
Figure 1. Ferrocenyl tetraphosphine Fc(P)4 Bu, a multidentate
catalytic auxiliary in Heck and Suzuki reactions.
ylphosphino)-1′-(diisopropylphosphino)-4-tert-butylferro-
t
cene [Fc(P)2 Bu(PiPr)].
The triphosphine is conveniently obtained from the suc-
cessive reaction of anhydrous FeCl2 with the appropriately
substituted cyclopentadienyllithium salts.16,17
reactions: the Suzuki cross-coupling and the Heck vinylation
of aryl bromides and chlorides.12
The first tests of Suzuki cross-coupling reactions using
For this weakly electron-donating multidentate triarylphos-
phine (compared to the electron-rich trialkylphosphines13),
the high turnover numbers (TONs) obtained are attributed
to the catalytic system stability, conferred by (i) the rigid
and blocked conformation of the ferrocenyl backbone and
(ii) the presence around the active metal center of several
phosphorus donor atoms as potential stabilizing coordination
sites.14
t
Fc(P)2 Bu(PiPr), performed following previously reported
procedures12,18 were not as promising as we expected. For
instance, a TON of 10 000 is obtained in the coupling of
the electron-poor 4-bromoacetophenone with phenylboronic
t
acid, while the tetraphosphine Fc(P)4 Bu gives a TON of
77 000 under identical conditions. Nevertheless, in an effort
to evaluate ligand properties in cross-coupling reactions
systematically, we tested the performance of the triphosphine
in the more demanding reaction of aryl alkynylation in the
Besides the fact that only a few fundamental or applied
studies of their properties exist,15 ferrocenyl polyphosphine
(15) Hierso, J.-C.; Amardeil, R.; Bentabet, E.; Broussier, R.; Gautheron,
B.; Meunier, P.; Kalck, P. Coord. Chem. ReV. 2003, 236, 143-206.
(16) Broussier, R.; Bentabet, E.; Mellet, P.; Blacque, O.; Boyer, P.;
Kubicki, M. M.; Gautheron, B. J. Organomet. Chem. 2000, 598, 365-
373.
(2) Moutevelis-Minakakis, P.; Gianni, M.; Stougiannou, H.; Zoumpou-
lakis, P.; Zoga, A.; Vlahakos, A. D.; Iliodromitis, E.; Mavromoustakos, T.
Bioorg. Med. Chem. Lett. 2003, 13, 1737-1740 and references therein.
(3) Grasa, G. A.; Viciu, M. S.; Huang, J.; Zhang, C.; Trudell, M. L.;
Nolan, S. P. Organometallics 2002, 21, 2866-2873.
(4) Kawada, K.; Arimura, A.; Tsuri, T.; Fuji, M.; Komurasaki, T.;
Yonezawa, S.; Kugimiya, A.; Haga, N.; Mitsumori, S.; Inagaki, M.;
Nakatani, T.; Tamura, Y.; Takechi, S.; Taishi, T.; Kishino, J.; Ohtani, M.
Angew. Chem., Int. Ed. 1998, 37, 973-975.
(5) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009-
3066.
(6) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
(7) Suzuki, A. J. Organomet. Chem. 1999, 576, 147-168.
(8) Negishi, E.-I.; Anastasia, L. Chem. ReV. 2003, 103, 1979-2017.
(9) Malleron, J.-L.; Fiaud, J.-C.; Legros, J.-Y. Handbook of Palladium
Organic Reactions; Academic Press: San Diego, 1997.
(10) Zapf, A.; Beller, M. Chem. Eur. J. 2001, 7, 2908-2915.
(11) Kollhofer, A.; Plenio, H. Chem. Eur. J. 2003, 9, 1416-1425 and
references therein. At that time, the authors indicated that 1 mol % Pd
catalyst for a 200 D product would add 112 Euros to the cost.
(12) Hierso, J.-C.; Fihri, A.; Amardeil, R.; Meunier, P.; Doucet, H.;
Santelli, M.; Donnadieu, B. Organometallics 2003, 22, 4490-4499.
(13) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-
4211.
(17) Synthesis. A solution of 1,2-bis(diphenylphosphino)-4-tert-butyl-
cyclopentadienyllithium (1.85 g, 3.7 mmol) in 20 mL of THF is added at
-40 °C to a stirred suspension of anhydrous FeCl2 (0.45 g, 3.55 mmol) in
10 mL of THF. After 2 h, the mixture is reacted with a THF solution of
(diisopropylphosphino)cyclopentadienyllithium (0.67 g, 3.55 mmol). The
mixture is evaporated in vacuo, and the residue is refluxed in 40 mL of
toluene for 3 h. From the cooled reaction mixture, the crude product is
obtained in solution and, after filtration, purified by chromatography on a
SiO2 column (toluene/hexane 4:1) to provide 1.80 g (70% yield) of 1,2-
bis(diphenylphosphino)-1′-(diisopropylphosphino)-4-tert-butylferrocene. An
t
analytically pure sample was recrystallized from hot EtOH. Fc(P)2 Bu(PiPr).
C44H49P3Fe (726.64): calcd C 72.7, H 6.8; found C 72.8, H 6.7. 1H NMR
(400.13 MHz, CDCl3): δ 7.73 (m, 4H, Ph), 7.40 (m, 6H, Ph), 7.12-6.95
(m, 10H, Ph), 4.21 (t, 2H, JPH ) 1.2 Hz, 3, 5HCp), 4.17 (t, 2H, 3JHH ) 2.0
Hz, 3′,4′(or 2′,5′)HCp), 3.96 (m, 2H, JPH < 2.0 Hz, 3JHH ) 2.0 Hz, 2′,5′(or
3′,4′)HCp), 1.53 (hept(d), 1H, 2JPH ) 2.6 Hz, 3JHH ) 7.0 Hz, CHiPr), 1.38
t
3
3
i
(s, 9H, Bu), 0.93 (dd, 6H, JPH ) 12.8 Hz, JHH ) 6.8 Hz, CH3 Pr), 0.67
3
3
i
(dd, 6H, JPH ) 13.0 Hz, JHH ) 7.0 Hz, CH3 Pr). 31P{1H} NMR (161.98
MHz, CDCl3): δ -0.93 (s, 1P, PiPr2), -22.01 (s, 2P, PPh2). Herein are
presented data from selective phosphorus decoupling irradiation 1H{31P}
NMR.
(14) Laurenti, D.; Feuerstein, M.; Pepe, G.; Doucet, H.; Santelli, M. J.
Org. Chem. 2001, 66, 1633-1637.
(18) Feuerstein, M.; Doucet, H.; Santelli, M. Synlett 2001, 1458-1460.
3474
Org. Lett., Vol. 6, No. 20, 2004

presence of palladium and copper (also known as Sonogash-
ira-Hakigara cross-coupling).
Good to excellent activities were found, while, surpris-
ingly, an overview of the versatile catalytic systems used in
Suzuki or Heck cross-coupling shows that they are less
efficient when they are used in the Sonogashira reaction (Pd/
PCy3, Pd/(1-Ad)2PBu, or 5 and 13; see Figure 2, Cy )
type” reactions (palladium oxidatiVe addition vs copper
transmetalation). Some studies have begun to address the
interesting and fundamental problem of the catalytic cycle
in Sonogashira cross-coupling.23,24
In terms of atom economy, Sonogashira cross-coupling
reaction procedures are powerful methods, especially when
compared to other alkynylation routes that require the
stoichiometric addition of metal cocatalysts such as zinc, tin,
boron, or aluminum compounds.8,39 Nevertheless, even if the
leading procedures reported for Sonogashira reactions allow
enyne formation in various experimental conditions (at
low26,28 or high25,29,38 temperature, in copper-free conditions,24
with aryl chlorides;20 see Figure 2) the ratio of catalytic
species to substrate usually ranges from 0.1 to 3.0 mol %
for palladium complexes, and from 1 to 20 mol % for
stabilizing auxiliaries (with the noticeable exception of 10
and the tetraphosphine 3, in Figure 2). Obviously, very low
loadings of these two expensive ingredients (without the
stoichiometric use of additives such as tetraalkylammonium
salts to limit palladium black precipitation) still remains
difficult to achieve for the Sonogashira reaction. Herein we
report on the excellent results obtained for the palladium-
catalyzed Sonogashira reaction (with or without CuI) in the
presence of 0.1-0.0001 mol % Fc(P)2 Bu(PiPr)/palladium.
t
t
We evaluated the scope and limitations of the Fc(P)2 Bu-
(PiPr)/palladium system for the coupling of a variety of aryl
bromides with phenylacetylene.40 A survey of these reactions
is provided in Table 1. In the presence of activating groups
(20) Kollhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed. 2003,
42, 1056-1058.
(21) Herrmann, W. A.; Reisinger, C.-P.; Spiegler, M. J. Organomet.
Chem. 1998, 557, 93-96.
(22) Alonso, D. A.; Najera, C.; Pacheco, M. C. Org. Lett. 2000, 2, 1823-
1826.
(23) Amatore, C.; Bensalem, S.; Ghalem, S.; Jutand, A.; Medjour, Y.
Eur. J. Org. Chem. 2004, 366-371.
Figure 2. Auxiliaries and catalyst/auxiliary systems active in
Sonogashira cross-coupling: 1a (5 mol %), Pd(PPh3)2Cl2 (2 mol
%), CuI/Et3N, 25-140 °C;25 1b (20 mol %), Pd2(dba)3 (2.5 mol
%), CuI/Bu4NI, -20 °C;26 1c (6 mol %), Pd(PhCN)2Cl2 (3 mol
%), CuI/HN(i-Pr)2, rt,19 or 1c (0.5 mol %), Pd2(dba)3 (0.5 mol %),
Et3N, rt,27 or 1c (10 mol %), {PdCl(π-allyl)}2 (2.5 mol %), DABCO,
rt;24 1d (4 mol %), Na2{PdCl4} (2 mol %), CuI/Na2SO3, 100-120
°C;20 2 (1 mol %), Et3N, -40 to 80 °C;28 3 (10-1-10-4 mol %),
(24) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.;
Hughes, D. L. Org. Lett. 2003, 5, 4191-4194.
(25) Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551-8553.
(26) Nakamura, K.; Okubo, H.; Yamaguchi, M. Synlett 1999, 549-550.
(27) Bohm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem. 2000, 3679-
3681.
(28) Mery, D.; Heuze, K.; Astruc, D. Chem. Commun. 2003, 1934-
1935.
(29) Feuerstein, M.; Berthiol, F.; Doucet, H.; Santelli, M. Org. Biomol.
Chem. 2003, 1, 2235-2237.
(30) McGuinness, D. S.; Cavell, K. J. Organometallics 2000, 19, 741-
748.
(31) Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4, 1411-
1414.
(32) Yang, C.; Nolan, S. P. Organometallics 2002, 21, 1020-1022.
(33) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642-
13643.
{PdCl(π-allyl)}2 (0.05-0.00005 mol %), CuI/K2CO3, 140 °C;29
4
(1 mol %), Et3N, 90 °C;21 5 (0.1 mol %), Et3N, 90 °C;30 6 (1 mol
%), PPh3 (1 mol %), CuI/Cs2CO3, 80 °C;31 7 (6 mol %), Pd(OAc)2
(3 mol %), CuI/Cs2CO3, 80 °C;32 8 (5 mol %), {PdCl(π-allyl)}2
(2.5 mol %), CuI/Cs2CO3, 40-60 °C;33 9 (6 mol %), Pd(PPh3)2Cl2
(3 mol %), t-BuOK/18-crown-6, 65 °C;34 10 (4 × 10-2-7 × 10-3
mol %), tetrabutylammonium bromide (150 mol %), Bu3N, 65 °C;35
11 (0.2-0.1 mol %), tetrabutylammonium bromide (100 mol %),
HNC4H8, 100 °C;36 12 (0.1 mol %), Et3N, 90 °C;37 13 (0.5 mol %)
CuI/HNC4H8, 90 °C,22 or 13 (0.1 mol %), tetrabutylammonium
acetate (110 mol %), 110-130 °C.38
(34) Ma, Y.; Song, C.; Jiang, W.; Wu, Q.; Wang, Y.; Liu, X.; Andrus,
M. B. Org. Lett. 2003, 5, 3317-3319.
(35) Buchmeiser, M. R.; Schareina, T.; Kempe, R.; Wurst, K. J.
Organomet. Chem. 2001, 634, 39-46.
(36) Najera, C.; Gil-Molto, J.; Karlstroem, S.; Falvello, L. R. Org. Lett.
2003, 5, 1451-1454.
(37) Herrmann, W. A.; Bohm, V. P. W.; Reisinger, C.-P. J. Organomet.
Chem. 1999, 576, 23-41.
cyclohexyl and Ad ) adamantyl).19-22 This discrepancy in
reactivity is rarely tackled and probably originates from a
difference in the rate-limiting step between these “Heck-
(38) Alonso, D. A.; Najera, C.; Pacheco, M. C. Tetrahedron Lett. 2002,
43, 9365-9368.
(39) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566-1568.
(40) Typical Procedure. The reaction of aryl halide (1 mmol), terminal
alkyne (2 mmol), K2CO3 (2 mmol), and possibly CuI (0.05 mmol) at 100-
t
130 °C for 20 h in DMF (10 mL) in the presence of {2Fc(P)2 Bu(PiPr)/
(19) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org.
Lett. 2000, 2, 1729-1731. See also ref. 41 for efficient systems using
electron-rich bulky monophosphines.
Pd2Cl2(C3H5)2}, under argon, affords the coupling products. Isolated yields
were obtained after addition of water, extraction with organic solvents,
separation, drying, concentration, and chromatography on silica gel.
Org. Lett., Vol. 6, No. 20, 2004
3475

t
Table 1. Palladium-Catalyzed Sonogashira Reaction with Fc(P)2 Bu(PiPr)a
entry
aryl halide
alkyne
substrate/catalyst ratio
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4-bromoacetophenone
4-bromoacetophenone
4-fluorobromobenzene
4-fluorobromobenzene
4-bromobenzonitrile
4-bromobenzonitrile
4-bromoanisole
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
phenylacetylene
dec-1-yne
100 000
1 000 000
10 000
100 000
10 000
100 000
250
1000
10 000
1000
250
250
1000
100 000
1000
94
(25)
95
(20)
89
(46)
93
4-bromoanisole
(52)
93c
90c
82c
86c
(54)c
95
62
92d
(46)d
2-trifluoromethylbromobenzene
9-bromoanthracene
4-chloroacetophenone
4-chlorobenzonitrile
4-chlorobenzonitrile
iodobenzene
4-bromoacetophenone
4-bromoacetophenone
4-bromoacetophenone
but-1-yn-4-ol
but-1-yn-4-ol
250
1000
t
a Conditions: catalyst ) {Pd(C3H5)Cl}2/Fc(P)2 Bu(PiPr) 1/2, aryl halide (1 mmol), alkyne (2 mmol), CuI (0.05 mmol), K2CO3 (2 mmol), DMF, 130 °C,
20 h, under argon, isolated yields. b Yields in parentheses are GC and NMR conversions. c Reaction performed without CuI. d Reaction performed at 100 °C.
on the aryl bromide, high reaction rates are observed. For
instance, the coupling of 4-fluorobromobenzene, 4-bromo-
acetophenone, and 4-bromobenzonitrile with phenylacetylene
CuI was employed with the more activated aryl halides,
but for the aryl chlorides it should be avoided. Depending
on the catalytic system, the copper cocatalyst has a deleteri-
ous influence on the desired reaction;41 we noticed that
secondary products (alkyne homocoupling) were obtained
when the overall coupling rate is slow.
Besides the classical catalytic auxiliaries used in “Heck-
type” C-C cross-coupling reactions such as monophos-
phines, palladacycles, and heterocyclic carbenes, multidentate
ligands and particularly robust polyphosphines appear as
suitable alternatives. The present study describes the first
example of Sonogashira cross-coupling reaction of various
aryl halides and alkynes using a ferrocenyl triphosphine.
Thereby it provides additional proof that future efforts at
multidentate catalyst development will be of interest, espe-
cially to address the case where a very low loading of
precious metal is required. As has been done for tetraphos-
phines,12,42 further studies will concern the coordination
chemistry of ferrocenic triphosphines toward catalytically
active transition metals.
t
in the presence of 0.001% Fc(P)2 Bu(PiPr)-palladium com-
plex (substrate/catalyst ) 100 000) leads to the coupling
products in 20 to 94% yields (the highest TONs obtained
are 20 000, 250 000, and 46 000, respectively, entries 1-6
in Table 1). For the lower conversions (entries 2, 4, 6), we
did not detect secondary products but mainly the starting
halides remaining unchanged. The quantitative conversion
of the strongly deactivated 4-bromoanisole requires a higher
catalyst loading (0.4 mol %) (a lower TON of 520 is
obtained, entries 7 and 8).
We observed then the influence on the reaction of the
presence of ortho substituents on the aryl bromide. With the
activated 2-trifluoromethylbromobenzene, a high conversion
is obtained with a good substrate/catalyst ratio (TON of 9300,
entry 9). Lower reaction rates are observed using the
sterically congested 9-bromoanthracene (TON of 900, entry
10). It is noteworthy that these reactions were carried out in
the absence of copper cocatalysts.
We next performed a few reactions in the presence of
iodobenzene and with activated aryl chlorides.28 A very high
TON of 95 000 is obtained for the reaction of iodobenzene
with phenylacetylene (entry 14). Activated aryl chlorides
such as 4-chlorobenzonitrile or 4-chloroacetophenone (TONs
of 540 and 205, respectively, entries 11-13) are also
converted in excellent yields with less than 1 mol % catalyst
and in the absence of copper iodide.
Acknowledgment. We thank the “Conseil Re´gional de
Bourgogne” for a postdoctoral grant to V.V.I. and S. Royer
and G. Delmas for technical assistance.
1
Supporting Information Available: H, 1H{31P}(400.13
MHz), and 31P NMR (161.98 MHz) spectra at 293 K in
t
CDCl3 for Fc(P)2 Bu(PiPr). This material is available free of
charge via the Internet at http://pubs.acs.org.
OL048870Z
Finally, we extended the scope of the catalytic reaction to
other alkynes such as dec-1-yne and but-1-yn-4-ol. With
these alkynes TONs of 620 and 460, respectively, are
obtained using 4-bromoacetophenone (entries 15-17).
(41) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42,
5993-5996.
(42) Andre-Bentabet, E.; Broussier, R.; Amardeil, R.; Hierso, J.-C.;
Richard, P.; Fasseur, D.; Gautheron, B.; Meunier, P. J. Chem. Soc., Dalton
Trans. 2002, 2322-2327.
3476
Org. Lett., Vol. 6, No. 20, 2004