Efficient route to atropisomeric ligands - Application to the synthesis of MeOBIPHEP analogues

Article abstract of DOI:10.1021/ol2011874

A highly efficient Pd-catalyzed P-C coupling reaction of easily accessible atropisomeric bisphosphane is described in the presence of various electron-poor aromatic iodides. The reactions are conducted in the presence of a Pd(II)/dppf catalyst in acetonit

Full text of DOI:10.1021/ol2011874

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3250–3253
Efficient Route to Atropisomeric
Ligands À Application to the
Synthesis of MeOBIPHEP Analogues
†
Lucie Leseurre, Florent Le Boucher d’Herouville, Kurt Puntener,
†
‡
€
Michelangelo Scalone,* Jean-Pierre Genet, and Veronique Michelet*
,‡
†
,†
^
ꢀ
Chimie ParisTech, UMR 7223, Laboratoire Charles Friedel 11 rue P. et M. Curie, 75231
Paris Cedex 05, France, and Process Research & Synthesis CoE Catalysis, F. Hoffmann-La
Roche AG, CH-4070 Basel, Switzerland
michelangelo.scalone@roche.com; veronique-michelet@chimie-paristech.fr
Received May 4, 2011
ABSTRACT
A highly efficient Pd-catalyzed PÀC coupling reaction of easily accessible atropisomeric bisphosphane is described in the presence of various
electron-poor aromatic iodides. The reactions are conducted in the presence of a Pd(II)/dppf catalyst in acetonitrile at 80 °C. The reaction
conditions are compatible with several electron-withdrawing groups such as esters, cyano, chloro, and trifluoromethyl groups and lead to
atropisomeric MeOBIPHEP derivatives in good to excellent yields and high enantiomeric purities.
The design of novel chiral ligands has been a field of
constant interplay since the discovery of the atropisomeric
binaphthyl Binap ligand.1 Binap has been the leading
ligand for asymmetric CÀC and CÀH bond formations
for a long time, and its industrial preparation has been a
source of inspiration for organic chemists.1 Considering
some technological and industrial barriers, new atropiso-
meric ligands appeared in the literature and have been the
essential chiral inducers of important breakthroughs on
asymmetric catalysis.2 One general aspect of atropisomeric
ligands is their synthesis, which is based on two main
general strategies: the first one implies a Pd- or Ni-cata-
lyzed phosphorusÀcarbon bond formation starting from
bistriflate derivatives (Scheme 1, eq1),3 whereas the second
one involves Grignard addition to phosphane intermedi-
ates (Scheme 1, eq 2).4 Both ways have been highly
successful but generally are dependent on either a resolu-
tion of racemate and/or a reduction of phosphane oxide.
Our ongoing research program on asymmetric metal-
† Chimie ParisTech.
‡ F. Hoffmann-La Roche AG.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994. (b) Ojima, I., Ed. Catalytic Asymmetric Synthesis; Wiley-
VCH: New York, 2000.
(2) For selected reviews, see: (a) Shimizu, H.; Nagasaki, I.; Saito, T.
Tetrahedron 2005, 61, 5405. (b) Berthod, M.; Mignani, G.; Woodward,
G.; Lemaire, M. Chem. Rev. 2005, 105, 1801. (c) Tang, W.; Zhang, X.
Chem. Rev. 2003, 103, 3029.
(4) (a) Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.; Kumobayashi,
H.; Taketomi, T.; Akutagawa, S.; Noyori, R. J. Org. Chem. 1986, 51,
629. (b) Mashima, K.; Kusano, K.; Sato, N.; Matsumura, Y.; Nozaki,
K.; Kumobayashi, H.; Sayo, N.; Hori, Y.; Ishizaki, T.; Akutagawa, S.;
Takaya, H. J. Org. Chem. 1994, 59, 3064. (c) Casalnuovo, A. L.;
Rajanbabu, T. V.; Ayers, T. A.; Warren, T. H. J. Am. Chem. Soc.
1994, 116, 9869. (d) Pai, C.-C.; Lin, C.-W.; Lin, C.-C.; Chen, C.-C.;
Chan, A. S. C.; Wong, W. T. J. Am. Chem. Soc. 2000, 122, 11513. (e) Qiu,
L.; Kwong, F. Y.; Wu, J.; Lam, W. H.; Chan, S.; Yu, W.-Y.; Li, Y.-M.;
Guo, R.; Zhou, Z.; Chan, A. S. C. J. Am. Chem. Soc. 2006, 128, 5955.
(f) Zhang, H.-W.; Meng, Q.-H.; Zhang, Z.-G. Chin. J. Chem. 2008, 26,
209. (g) Ma, M.-L.; Peng, Z.-H.; Chen, L.; Guo, Y.; Chen, H.; Li, X.-J.
Chin. J. Chem. 2006, 24, 1391.
(3) (a) Cai, D.; Payack, J.; Bender, D. R.; Hughes, D. L.; Verhoeven,
T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 7180. (b) Ager, D. J.; East,
M. B.; Eisenstadt, A.; Laneman, S. A. Chem. Commun. 1997, 2359. (c)
€
Knopfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira,
E. M. Angew. Chem., Int. Ed. 2004, 43, 5971. (d) Uozumi, Y.; Tanahashi,
A.; Lee, S.; Hayashi, T. J. Org. Chem. 1993, 58, 1945. (e) Driessen-
Holscher, B.; Kralik, J.; Agel, F.; Steffens, C.; Hu, C. Adv. Synth. Catal.
2004, 346, 979.
r
10.1021/ol2011874
Published on Web 05/23/2011
2011 American Chemical Society

catalyzed reactions5À7 prompted us to examine the unpre-
cedented possibility to prepare atropisomeric ligands start-
ing from a simple chiral primary bisphosphane derivative
(Scheme 1, eq 3). We wish therefore to report our pre-
liminary results on the optimization of a catalytic system
able to promote the synthesis of so far unprecedented
MeOBIPHEP analogues.7f
We next concentrated our efforts on the preparation of
diphosphanes containing electron-poor aromatic rings,
whose introduction according to the classic Grignard
methodology is delicate, requires a low temperature, and
generally is moderate-to-low yielding.7c The reactivity of 2
was also particularly tricky as easy racemization occurs at
a moderate temperature.
Table 1. Pd-Catalyzed PÀC Coupling Reactionsa (Ar =
Scheme 1. General Strategies for the Synthesis of Atropisomeric
Ligands
4-CO2Me-C6H4)
x
time
(h)
3/4
(%) of 3 (%)
yieldb
entry
ligand
(mol %)
base
Et3N
1
2
3
4
5
6
7
8
9e
/
/
48 97/3
48 95/5
20 0/100d
31
31
/
PPh3
12
12
12
8
Et3N
Et3N
t-Bu3Pc
P(4-CF3C6H4)3
dppe
i-Pr2NEt 20 79/21d
37
/
One issue for the success of this reaction has been the
accessibility to both (R) and (S) enantiomers of the primary
bisphosphane 2. Gratifyingly the availability of bisphos-
phonate 1on a large scale7c allowedustoprepare2in up to a
20 g scale by a simple reduction (Scheme 2).7f,8
Et3N
20 47/53d
dppf
8
i-Pr2NEt 18 90/10
i-Pr2NEt 18 60/40d
i-Pr2NEt 18 40/60d
67
/
dppf
4
dppf
12
8
/
dppf
i-Pr2NEtf
3
94/6
83
a Determined by 31P NMR. b Isolated yield. c Used as the HBF4 salt.
d Presence of several byproduct. e Slow addition of the primary bispho-
sphane ligand 2. f 5 equiv.
Scheme 2. Synthesis of Phosphane Ligand 2
Our initial attempts to couple (R)-2 and methyl 4-iodo-
benzoate using Ni-, Pd-, or Cu-catalyzed phosphor-
usÀcarbon procedures9 were quite disappointing as only
traces of the desired product were detected. The use of
palladium diacetate9a without additional ligands in sol-
vents such as DMF, toluene, DMA, and CH3CN afforded
the desired phosphane (R)-3 with moderate to good con-
version, the best result being observed in acetonitrile in the
presence of triethylamine (Table 1, entry 1). We therefore
tested various ligands and bases to promote the introduc-
tion of four aromatic rings. In all cases, we observed the
formation of a novel chiral dibenzo[1,2]diphosphorin de-
rivative (R)-4, most probably resulting from a dehydro-
coupling between the two RPHAr moieties of the reaction
^
(5) (a) Charruault, L.; Michelet, V.; Taras, R.;Gladiali, S.;Genet, J.-P.
Chem. Commun. 2004, 850. (b) Chao, C.-M.; Vitale, M.; Toullec, P. Y.;
Genet, J.-P.; Michelet, V. Chem.;Eur. J. 2009, 15, 1319. (c) Chao, C.-M.;
^
^
Genin, E.; Toullec, P. Y.; Genet, J.-P.; Michelet, V. J. Organomet. Chem.
ꢀ
2009, 694, 538. (d) Andreiadis, E.; Vitale, M. R.; Mezailles, N.; Le Goff,
X.; LeFloch, P.;Toullec, P. Y.;Michelet, V. Dalton Trans 2010, 39, 10608.
(e) Chao, C.-M.; Beltrami, D.; Toullec, P. Y.; Michelet, V. Chem.
Commun. 2009, 6988.
(6) (a) Genet, J.-P. Acc. Chem. Res. 2003, 36, 908. (b) Jeulin, S.;
Duprat de Paule, S.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Dellis, P.;
^
^
Champion, N. Angew. Chem., Int. Ed. 2004, 43, 320. (c) Duprat de Paule,
S.; Jeulin, S.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.;
Synthesis; Paquette, L., Fuchs, P., Crich, D., Wipf, P., Eds.; John Wiley &
^
Sons: 2008; DOI: 10.1002/047084289X.rn00832.
(8) (a) Hwan Koh, J.; Larsen, A. E.; White, P. S.; Gagne, M. R.
Deschaux, G.; Dellis, P. Org. Process. Res. Dev. 2003, 7, 399. (d) Berhal,
F.; Esseiva, O.; Martin, C.-H.; Tone, H.; Genet, J.-P.; Ayad, T.;
^
ꢀ
ꢀ
Ratovelomanana-Vidal, V. Org. Lett. 2011, DOI: 10.1021/ol200495a.
(7) (a) Schmid, R.; Cereghetti, M.; Heiser, B.; Schonholzer, P.;
Hansen, H.-J. Helv. Chim. Acta 1988, 71, 897. (b) Schmid, R.; Foricher,
Organometallics 2002, 21, 7. (b) Koh, J. H.; Larsen, A. O.; Gagne, M. R.
Org. Lett. 2001, 3, 1233.
(9) (a) Brauer, D. J.; Hingst, M.; Kottsieper, K. W.; Liek, C.; Nickel,
T.; Tepper, M.; Stelzer, O.; Sheldrick, W. S. J. Organomet. Chem. 2002,
645, 14 and references cited therein. (b) Stadler, A.; Kappe, C. O. Org.
Lett. 2002, 4, 3541. (c) Wasserscheid, P.; Waffenschmidt, H.; Machnitzki,
P.; Kottsieper, K. W.; Stelzer, O. Chem. Commun. 2001, 451. (d) Van
Allen, D.; Venkataraman, D. J. Org. Chem. 2003, 68, 4590. (e) Gelman,
D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003, 5, 2315. (f) Tani, K.;
Behenna, D. C.; McFadden, R. M.; Stoltz, B. M. Org. Lett. 2007, 9,
2529.
€
J.; Cereghetti, M.; Schonholzer, P. Helv. Chim. Acta 1991, 74, 370. (c)
Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricher, J.;
Lalonde, M.; Muller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure
Appl. Chem. 1996, 68, 131. (d) Foricher, J.; Heiser, B.; Schmid, R.
(Hoffmann-La Roche AG) U.S. Patent US5302738, 1994. (e) Crameri,
Y.; Foricher, J.; Hengartner, U.; Jenny, C.; Kienzle, F.; Ramuz, H.; Scalone,
M.; Schlageter, M.; Schmid, R.; Wang, S. Chimia 1997, 51, 303. (f) Schmid,
R.; Scalone, M. Electronic Encyclopedia of Reagents for Organic
Org. Lett., Vol. 13, No. 12, 2011
3251

intermediate. The addition of triphenylphosphane, hin-
dered tri-tert-butylphosphane, or electron-poor tri(4-tri-
fluorophenyl) phosphane (entries 2À4) did not lead to
better results. The use of bidentate ligands such as
(bis)diphenylphosphanoethane (dppe) afforded approxi-
mately a 1/1 ratio of 3 and 4 (entry 5). (Bis)diphenyl-
phosphanoferrocene was found to have a consistently
positive influence on the reaction outcome (entries 6À9).10
Finally, a thorough optimization of the amount of dppf
and of the reaction conditions (slow addition of 2) led to
the formation of the desired ligand (R)-3 in 83% isolated
yield (entry 9), with no racemization (ee = 99%, cf. Sup-
porting Information).
Table 2. Pd-Catalyzed PÀC Coupling Reactions
yielda
(%)
eeb
entry
Ar
ligand
(%)
1
3-MeO2C-C6H4
4-t-BuO2C-C6H4
4-t-BuO2C-C6H4
3-t-BuO2C-C6H4
4-BnO2C-C6H4
4-HO2C-C6H4
(R)-5
94
88
82
95
92
70
89
35
89
76
67
74
74
98
99
2
(R)-6
3
(S)-6
99
4
(R)-7
98
5
(R)-8
99
6
(R)-9
>99
>99
99
7
4-NC-C6H4
(R)-10
(R)-11
(R)-12
(R)-13
(S)-13
(R)-14
(S)-14
8
4ÀCl-C6H4
9
4-F3C-C6H4
99
10
11
12
13
3,5-(t-BuO2C)2-C6H3
3,5-(t-BuO2C)2-C6H3
3,5-(F3C)2-C6H3
3,5-(F3C)2-C6H3
>99
>99
99
99
a Isolated yield. b Determined by HPLC analysis (cf. Supporting
Information).
Figure 1. X-ray structure of [Rh((S)-3)(cod)]BF4 complex.
Scheme 3. Synthesis of MeOBIPHEP Analogues
The structure of 3 was unambiguously confirmed by
reacting (S)-3 with [Rh(cod)Cl]2 and silver tetrafluorobo-
rate in dichloromethane at room temperature. The resulting
rhodium complex [Rh((S)-3)(cod)]BF4 was analyzed by
X-ray spectroscopy (Figure 1 and Supporting Information).
The bisphosphane ligand 2 was then engaged in various
Pd-catalyzed coupling reactions in the presence of ester,
cyano, carboxylic acid, chloro, and trifluoromethyl substi-
tuted aryl iodides (Table 2). Methyl, tert-butyl, and benzyl
ester functionalized ligands 5À8(eitherRor S) (entries1À5)
were isolated in good-to-excellent yields (82À95%) and
high enantiomeric purities (>98%). The reaction condi-
tions were compatible with free carboxylic acid moieties, the
corresponding tetra acid ligand (R)-9 being isolated in 70%
yield (entry 6). Considering the importance for catalysis of
the C-3 and C-5 disubstitution on the aromatic ring of the
PAr2 moieties,11 we attempted the preparation of such
ligands according to this methodology.
at Roche according to the Grignard strategy (three-step
synthesis) and had been isolated in 20% yield starting from
the bisphosphonate 1.7c Using this new route, the (R) and
(S) analogues 14 were obtained in 74% isolated yield
(entries 12, 13).
We further challenged our methodologyfor the prepara-
tion of other ligands which do not possess electron-attract-
ing groups on the phenyl substituents at phosphorus such
as the parent ligand MeOBIPHEP7bÀd or its congener 3,5-
Me2-MeOBIPHEP,7c whose importance has been recently
highlighted in the area of gold catalysis12,13 (Scheme 3).
These ligands were obtained in lower yields (50 and 42%,
respectively) compared to the analogues reported in
Table 2. This synthetic strategy, however, could probably
Gratifyingly, 3,5-disubstituted tert-butyl ester and tri-
fluoro-methyl iodobenzenes were found to react extremely
well too (entries 10À13), and the corresponding ligands
were prepared in high yields and an enantiomeric purity
higher than 99%. The ligand 14 had already been prepared
(12) (a) Kleinbeck, F.; Toste, F. D. J. Am. Chem. Soc. 2009, 131,
9178. (b) Martı
ꢀ
nez, A.; Garcıa-Garcıa, P.; Fernandez-Rodrıguez, M. A.;
´ ´ ´ ´
(10) For recent examples in which ferrocenyl ligands have been used
to prepare chiral phosphines, see: (a) Chan, V. S.; Bergman, R. G.;
Toste, F. D. J. Am. Chem. Soc. 2007, 129, 15122. (b) Korff, C.;
Helmchen, G. Chem. Commun. 2004, 530.
(11) Trabesinger, G.; Albinati, A.; Feiken, N.; Kunz, R. W.; Pregosin,
P. S.; Tschoerner, M. J. Am. Chem. Soc. 1997, 119, 6323.
Rodrıguez, F.; Sanz, R. Angew. Chem., Int. Ed. 2010, 49, 4633.
´
(13) For recent reviews on asymmetric gold catalysis, see: (a)
Widenhoefer, R. A. Chem.;Eur. J. 2008, 5382. (b) Sengupta, S.; Shi,
X ChemCatChem 2010, 2, 609. (c) Pradal, A.; Toullec, P. Y.; Michelet, V.
Synthesis 2011, 1501.
3252
Org. Lett., Vol. 13, No. 12, 2011

compete with the industrial one in terms of step economy,
production of waste, and overall yields.
Acknowledgment. L.L. and F.LBH are grateful to the
CNRS and F. Hoffmann-La Roche AG for financial
support. Helpful discussions with R. Schmid and the
analytical support by J.-C. Jordan, M. Althaus, and A.
Alker (all F. Hoffmann-La Roche AG, Basel) are kindly
acknowledged.
In conclusion, we have demonstrated that atropisomeric
ligands bearing electron-deficient aromatic rings on phos-
phorus atoms can be prepared under mild catalytic condi-
tions starting from a chiral biphenyl bisphosphonate. The
corresponding MeOBIPHEP analogues were isolated in
high yields and excellent enantiomeric purities. This meth-
odology opens new perspectives for the design and synth-
esisof novel chiral ligands. Current studies are dedicated to
the applications of these ligands in asymmetric catalysis.
Supporting Information Available. Experimental pro-
cedure and full analyses of ligands 3À16. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Org. Lett., Vol. 13, No. 12, 2011
3253