Study of the reaction of bulky aryllithium reagents with 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane derived from ephedrine

Article abstract of DOI:10.1021/jo7014505

(Chemical Equation Presented) The ring opening of enantiomerically pure 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane (1) with a variety of bulky aryllithium reagents was studied. Our results are not in total agreement with those obtained by

Full text of DOI:10.1021/jo7014505

Study of the Reaction of Bulky Aryllithium Reagents with
3,4-Dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane
Derived from Ephedrine†
Michel (Massoud S.) Stephan,*,‡,§ Damjan Sˇterk,‡ Barbara Modec,¶ and Barbara Mohar‡
PhosPhoenix SARL, 115, rue de l’Abbe´ Groult, F-75015 Paris, France, Laboratory of Organic and
Medicinal Chemistry, National Institute of Chemistry, HajdrihoVa 19, SI-1001 Ljubljana, and Faculty of
Chemistry, UniVersity of Ljubljana, AsˇkercˇeVa 5, SI-1001 Ljubljana, SloVenia
mstephan@phosphoenix.com; michel.stephan@ki.si
ReceiVed July 11, 2007
The ring opening of enantiomerically pure 3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-2-borane
(1) with a variety of bulky aryllithium reagents was studied. Our results are not in total agreement with
those obtained by others. In fact, several 2,6-disubstituted aryl groups were successfully appended to the
phosphorus atom, furnishing the corresponding (N-ephedrino)phosphine boranes 2a-g with dr >99:1.
However, when the attack on the phosphorus atom is hindered, deprotonation on the benzylic position
occurs, leading to the formation of enantiomerically pure trans-(N-methylamino)(phenyl)(1-phenyl-1-
propenyloxy)phosphine-P-borane (3). While the attack of 2,2′-dilithio-1,1′-biarenes leads to the
corresponding (P-phenyl)phosphole derivatives (4i,j) and to [bis(N-ephedrino)](phenyl)phosphine-P-borane
(5), the attack of 1,1′-dilithiometallocenes (M ) Fe, Ru) leads to a separable diastereomeric mixture of
1,1′-bis[(N-ephedrino)(phenyl)phosphino-P-borane]metallocenes (2k,l/2k′,l′) with dr ∼80:20.
Introduction
asymmetric hydrogenation-based L-DOPA process.3 The close
proximity of a stereogenic element to the metal center of
catalysis is assumed to have a pronounced impact on the
asymmetric induction.4 Since then, various types of phosphines
were synthesized especially those possessing a stereogenic
backbone. At a fast pace, their use became widespread in
asymmetric catalysis as was the case with the atropisomeric
BINAP ligand and related type ligands (e.g., BIPHEMP, MeO-
BIPHEP), the ferrocene-based ligands (e.g., Josiphos and
Mandyphos families) and the DuPhos-type ligands.1c
Highly sought by the chemical industry in the asymmetric
transition-metal-catalyzed processes, enantiomerically pure phos-
phine ligands constitute a key component of the catalysts
conveying the chiral information to the end product.1 Soon after
the discovery of the chelating DIOP ligand by Kagan et al.,2
Knowles et al. devised the chelating P-stereogenic diphosphine
DiPAMP ligand and applied it in the rhodium-catalyzed
† This paper is dedicated to the memory of Professor Hidemasa Takaya,
deceased on October 4, 1995.
In our ongoing research program in metal-mediated asym-
metric transformations, we were interested to prepare a series
of “tailor-made” and structurally diverse C2-symmetrical P-
‡ National Institute of Chemistry.
§ PhosPhoenix SARL.
¶ University of Ljubljana.
(1) (a) Noyori, R. Asymmetric Catalysis in Organic Synthesis; John Wiley
& Sons: New York, 1994. (b) ComprehensiVe Asymmetric Catalysis I-III;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999.
(c) Asymmetric Catalysis on Industrial Scale; Blaser, H. U., Schmidt, E.,
Eds.; Wiley-VCH: Weinheim, Germany, 2004.
(3) (a) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J.; Bachman, G.
L.; Weinkauff, D. J. J. Am. Chem. Soc. 1977, 99, 5946-5952. (b) Knowles,
W. S.; Sabacky, M. J.; Vineyard, B. D. U.S. Patent 1977/4005127. (c)
Knowles, W. Angew. Chem., Int. Ed. 2002, 41, 1998-2007.
(4) Halpern, J. Science 1982, 217, 401-407.
(2) Kagan, H. B.; Dang, T. P. J. Am. Chem. Soc. 1972, 94, 6429-6433.
10.1021/jo7014505 CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/18/2007
8010
J. Org. Chem. 2007, 72, 8010-8018

Reaction of Bulky Aryllithium Reagents
SCHEME 1a
stereogenic diphosphine ligands and their precursors. One
structure of ligands would consist of a bulky aryl group on the
phosphorus atom with an ethane bridge (I) (DiPAMP-like
structure), and other families would have either a biaryl bridge
(II) or a metallocene bridge (III).
a Reagents: (a) ArLi/THF, -20 °C to rt; (b) MeOH/H+, rt; (c) RLi/
THF, -20 °C to rt.
conditions compromises the stereoselectivity. In some cases,
delaying the introduction of the most spatially demanding group
until the final stage (step c) led to an increased yield and a high
degree of stereocontrol. For example, Brown et al. have studied
the introduction of sterically encumbered groups, such as
1-adamantyl, tert-butyl, and ferrocenyl, by displacement of the
MeO group.8b Nevertheless, several failed attempts are reported
in the literature by prominent research groups to append
interesting bulky aryl groups on the phosphorus atom, for
example, 2-mesityl, 2,4,6-trimethoxyphenyl, or 9-anthryl, either
at the oxazaPB (1) ring-opening step (step a) or at the
displacement of the MeO group (step c).9a This was ascribed
to the inherent steric bulk of the aryl groups to be introduced
with no other details. Furthermore, it was reported in the
literature that the attack of 1,1′-dilithioferrocene‚2 TMEDA
adduct on 1 led to an inseparable diastereomeric mixture of 1,1′-
bis[(N-ephedrino)(phenyl)phosphino-P-borane]ferrocenes.9b,c
Though much effort has been devoted to the preparation of
some of the above-mentioned intermediates, we still decided
to reinvestigate the action of a selection of bulky aryllithium
reagents on 1. Due to the strong distortion of the five-membered
ring of 1,10 this precursor is more reactive toward the attack of
organolithium reagents than the methyl phosphinite borane
intermediate,11 and the resulting (N-ephedrino)phosphine borane
2 would allow further transformations.
We envisaged the synthesis of the targeted P-stereogenic
phosphines and their precursors via the Juge´-Stephan asym-
metric route, relying upon the enantiomerically pure 1,3,2-
oxazaphospholidine-2-borane complex (oxazaPB) (1) derived
from ephedrine.5 The synthon 1 has proven to be very useful
to access a wide array of borane-complexed P-stereogenic
organophosphorus compounds: amino-, alkoxy-, chloro-, mono-,
diphosphines, etc. The liberation of the phosphine occurs with
full retention of configuration under mild conditions.6a Other
approaches to P-stereogenic phosphines are known, as well;
however, they possess limited synthetic flexibility.6 The Juge´-
Stephan synthetic strategy is based on the sequential displace-
ment of the ephedrine auxiliary from 1; this involves first the
P-O bond fission by organolithium reagents and second the
acid-catalyzed P-N bond methanolysis to a P-OMe bond
followed by the displacement of the MeO group by another
organolithium (Scheme 1). Both configurations at the phospho-
rus atom can be prepared starting either from (+)- or (-)-
ephedrine or by a reverse order of introduction of the desired
groups. The exemplification of the interesting features of 1 was
its first use toward a practical synthesis of DiPAMP ligand.5
Moreover, it was shown that P-stereogenic (N-ephedrino)-
phosphines derived from 1 could serve as ligands in asymmetric
hydrogenation and hydroformylation.7
(8) (a) Tollefson, M. B.; Li, J. J.; Beak, P. J. Am. Chem. Soc. 1996, 118,
9052-9061. (b) Brown, J. M.; Laing, J. C. P. J. Organomet. Chem. 1997,
529, 435-444. (c) Yang, H.; Alvarez-Gressier, M.; Lugan, N.; Mathieu,
R. Organometallics 1997, 16, 1401-1409. (d) Zhang, X. WO 9713763,
1997. (e) Maienza, F.; Wo¨rle, M.; Steffanut, P.; Mezzetti, A.; Spindler, F.
Organometallics 1999, 18, 1041-1049. (f) Schuman, M.; Trevitt, M.; Redd,
A.; Gouverneur, V. Angew. Chem., Int. Ed. 2000, 39, 2491-2493. (g)
Nettekoven, U.; Kamer, P. C. J.; Widhalm, M.; van Leeuwen, P. W. N. M.
Organometallics 2000, 19, 4596-4607. (h) Nettekoven, U.; Widhalm, M.;
Kalchhauser, H.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Lutz, M.;
Spek, A. L. J. Org. Chem. 2001, 66, 759-770. (i) Colby, E. A.; Jamison,
T. F. J. Org. Chem. 2003, 68, 156-166. (j) Bauduin, C.; Moulin, D.;
Kaloun, E. B.; Darcel, C.; Juge, S. J. Org. Chem. 2003, 68, 4293-4301.
(k) Rippert, A. J.; Linden, A.; Hansen, H.-J. HelV. Chim. Acta 2000, 83,
311-321.
(9) (a) Maienza, F.; Spindler, F.; Thommen, M.; Pugin, B.; Malan, C.;
Mezzetti, A. J. Org. Chem. 2002, 67, 5239-5249. (b) Kaloun, E. B.;
Merde`s, R.; Geneˆt, J. P; Uziel, J.; Juge´, S. J. Organomet. Chem. 1997,
529, 455-463; according to this publication, three diastereomers of 1,1′-
bis{[(1S,2R)-(N-ephedrino)](phenyl)phosphino-P-borane}ferrocene were
formed in 10% yield. (c) Nettekoven, U.; Kamer, P. C. J.; van Leeuwen, P.
W. N. M.; Widhalm, M.; Spek, A. L.; Lutz, M. J. Org. Chem. 1999, 64,
3996-4004; according to this publication, attack of 1,1′-dilithioferrocene
(k)‚2 TMEDA on (-)-1 led to (RP,RP)/(RP,SP) ) 65:35; no yield is
mentioned.
Several research groups worldwide have adopted this meth-
odology to prepare a variety of enantiomerically pure P-
stereogenic organophosphorus compounds.8 However, the in-
troduction of the substituents is constrained by the steric
requirements of the carbanionic reagent, and reverting to forcing
(5) (a) Juge´, S.; Stephan, M.; Laffitte, J. A.; Geneˆt, J. P. Tetrahedron
Lett. 1990, 31, 6357-6360. (b) Juge´ S.; Geneˆt J. P. WO 9100286, 1991.
(6) (a) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K. J.
Am. Chem. Soc. 1990, 112, 5244-5252. (b) Corey, E. J.; Zhuoliang, C.;
Tanoury, G. J. J. Am. Chem. Soc. 1993, 115, 11000-11001. (c) Muci, A.
R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995, 117, 9075-
9076. (d) Ohashi, A.; Kikuchi, S.; Yasutake, M.; Imamoto, T. Eur. J. Org.
Chem. 2002, 15, 2535-2546.
(7) (a) Moulin, D.; Darcel, C.; Juge´, S. Tetrahedron: Asymmetry 1999,
10, 4729-4743. (b) Ewalds, R.; Eggeling, E. B.; Hewat, A. C.; Kamer, P.
C. J.; van Leeuwen, P. W. N. M.; Vogt, D. Chem.sEur. J. 2000, 6, 1496-
1504. (c) Darcel, C.; Kaloun, E. B.; Merde`s, R.; Moulin, D.; Riegel, N.;
Thorimbert, S.; Geneˆt, J. P.; Juge´, S. J. Organomet. Chem. 2001, 624, 333-
343. (d) In OMCOS 13, Geneva, 2005; Darcel, C.; Richard, P.; Juge´, S.
P-421.
(10) Juge´, S.; Stephan, M.; Geneˆt, J. P.; Halut-Desportes, S.; Jeannin,
S. Acta Crystallogr. 1990, C46, 1869-1872.
(11) This fact is in sharp contrast with a claim in ref 9c saying that the
reactivity of phosphinite boranes surpasses the oxazaPB one.
J. Org. Chem, Vol. 72, No. 21, 2007 8011

Stephan et al.
SCHEME 2
X-ray diffraction analysis of product 2b revealed the expected
(RP) absolute configuration resulting from retention of config-
uration (Figure 1). Despite the bulkiness of the 2,6-dimethox-
yphenyl group, the stereogeometry (bond lengths and angles)
around the phosphorus atom is comparable to the one observed
in the compound possessing an o-anisyl group in place of the
2,6-dimethoxyphenyl group.15 However, by contrast to the
o-anisyl analogue, one MeO group in 2b is engaged in a rather
short intramolecular interaction with the BH3 group [O(1)‚‚‚B
) 3.005(3) Å].
The formation of (RP)-(N-ephedrino)phosphine boranes 2b-g
was accompanied by the formation of trans-(SP)-(N-methylami-
no)(phenyl)(1-phenyl-1-propenyloxy)phosphine-P-borane (3) as
revealed by X-ray diffraction analysis (Figure 2). According to
1H, 13C, and 31P NMR analyses, a single geometrical isomer
was formed. To the best of our knowledge, this is the first
isolated enantiomerically pure compound with a structure
possessing a stereogenic phosphorus atom linked to the oxygen
of an enol.16 Interestingly, the C(11)-P-O angle [97.98(8)°]
is rather small and the phenyl group is positioned almost above
the oxygen atom. Also, with a O-P-C(11)-C(16) ) -15.8-
(2)°, the C(16) has a close interaction with the oxygen atom
[C(16)‚‚‚O ) 2.858(3) Å].
The formation of compound 3 is attributed to the ArLi attack
on the benzylic proton17 of the ephedrine moiety (Scheme 2,
pathway B) accompanied by an anti-elimination of the [N-
(methylamino)](phenyl)phosphino-P-borane group and resulting
in a net trans geometry. The formation of 3 is slower with
respect to the privileged organolithium reagent attack on the
phosphorus atom (pathway A). However, if this attack is
hindered, then the attack on the benzylic proton becomes the
predominant reaction. Thus, the ratios of products 2 against
product 3 for 2b, 2c, 2d, 2e, 2f, and 2g were 40:60, 38:62, 52:
48, 5:95 (at rt; 0:100 at -20 °C), 50:50, and 68:32, respectively.
Investigation of OxazaPB (1) Ring Opening with 2,2′-
Dilithio-1,1′-biarenes (i,j). This synthetic strategy would lead
to hybrid ligands II possessing two stereogenic elements: on
the phosphorus atom and on the side chain (Scheme 3).
According to the standard reaction conditions, the reaction
of 2,2′-dilithio-1,1′-biphenyl (i) or 2,2′-dilithio-1,1′-binaphtha-
lene (j) with (+)-1 did not afford in our hands either the desired
2,2′-bis[(N-ephedrino)(phenyl)phosphino-P-borane]-1,1′-bi-
phenyl or the 2,2′-bis[(N-ephedrino)(phenyl)phosphino-P-bo-
rane]-1,1′-binaphthalene, respectively.12,18 Instead, a complex
Results and Discussion
Investigation of OxazaPB (1) Ring Opening with ArLi (a-
h). Bulky aryllithium reagents a-h prepared in an appropriate
solvent (hexane or Et2O) were allowed to react with (-)-
(2S,4R,5S)-1 derived from (+)-ephedrine in THF from -20 °C
to rt, and the evolution of the reaction was followed by TLC
and 31P NMR (Scheme 2). After reaction workup and to our
delight, 1H and 31P NMR revealed the formation of the
corresponding (N-ephedrino)phosphine boranes 2a-g; they were
isolated after column chromatography in 4-65% yield.12 The
highest yield of 2 was attained with a, f, and g. With e, the
compound 2e was formed only when 1 was added at rt (addition
at -20 °C led solely to 3). However, with supermesityllithium
h (Mes*Li formed from Mes*Br13), no reaction occurred, and
1
after hydrolysis, Mes*H was obtained. In the case of 2a, H
NMR of the crude revealed the formation of a mixture of 8-
(15) Juge´, S.; Stephan, M.; Merde`s, R.; Geneˆt, J. P.; Halut-Desportes,
S. J. Chem. Soc., Chem. Commun. 1993, 531-533.
(16) A diastereomeric mixture of vinylphosphonamides was obtained
from 2-phenyl-1,3,2-oxazaphospholidine derived from (S)-prolinol via the
Perkow reaction. For this, see: Faure, B.; Pardigon, O.; Buono, G.
Tetrahedron 1997, 53, 11577-11594.
and 2-P-substituted 1-methoxynaphthalene (90:10 ratio).14 For
1
2e, H NMR of the crude showed the formation of the (SP)-
diastereomer in up to 3%, while for all the rest, <1% of the
other diastereomer was formed if observed at all.
(17) A deprotonation-reprotonation sequence of (2S,4S,5R)-3,4-dim-
ethyl-2-adamantyl-5-phenyl-1,3,2-oxazaphospholidine-2-oxide to (2S,4S,5S)-
3,4-dimethyl-2-adamantyl-5-phenyl-1,3,2-oxazaphospholidine-2-oxide was
observed.8b
(12) Reaction crude was systematically analyzed by 1H and 31P NMR
to verify the exclusion of (C4H9)(N-ephedrino)(phenyl)phosphine-P-borane
wherein C4H9 ) n-Bu,5a s-Bu (2n), or t-Bu.8k (RP)-(s-Butyl)[(1S,2R)-(N-
ephedrino)](phenyl)phosphine-P-borane (2n) was prepared according to the
Juge´-Stephan route (see Supporting Information).
(13) To a cold (-50 °C) solution of Mes*Br in THF was added s-BuLi
(1 equiv), and the reaction was left to stir for 30 min and then brought up
to 0 °C for 15 min. For the synthesis of Mes*Br, see: Knorr, R.; Pires, C.;
Behringer, C.; Menke, T.; Freudenreich, J.; Rossmann, E. C.; Bo¨hrer, P. J.
Am. Chem. Soc. 2006, 128, 14845-14853.
(14) (a) Shirley, D. A.; Cheng, C. F. J. Organomet. Chem. 1969, 20,
251-252. (b) (RP)-[(1S,2R)-(N-Ephedrino)](1-methoxynaphth-2-yl)(phenyl)-
phosphine-P-borane was prepared regioselectively from 2-bromo-1-meth-
oxynaphthalene and (-)-1 according to the Juge´-Stephan route, and this
will be published in due course.
(18) A quantity of 2.1 equiv of n- or s-BuLi was used to convert the
2,2′-dibromo-1,1′-biarene (at -20 to 0 °C in Et2O or THF) into 2,2′-dilithio-
1,1′-biarene (i,j) to ensure complete transmetalation. 1H and 31P NMR
analyses of the crude materials showed mainly the formation of the
corresponding (P-phenyl)phosphole derivative (4i,j) and a complex mixture
of (N-ephedrino)phosphine-P-boranes present in a small amount (δP around
+70). Use of 2,2′-dilithio-1,1′-biphenyl (i)‚2 TMEDA adduct generated in
hexane or cyclohexane from biphenyl, n-BuLi (2 equiv), and TMEDA (2
equiv) at rt within 16 h led to similar results. For the preparation of 2,2′-
dilithio-1,1′-biphenyl (i)‚2 TMEDA adduct, see: (a) Neugebauer, W.; Kos,
A. J.; von Rague Schleyer, P. J. Organomet. Chem. 1982, 228, 107-118.
(b) Schaub, T.; Radius, U. Tetrahedron Lett. 2005, 46, 8195-8197.
8012 J. Org. Chem., Vol. 72, No. 21, 2007

Reaction of Bulky Aryllithium Reagents
FIGURE 1. ORTEP drawing of (RP)-2b at the 30% probability level. Selected bond lengths (Å) and angles (°): P-B 1.924(2); P-N 1.654(2);
P-C(21) 1.812(2); P-C(11) 1.822(2); C(11)-P-B 116.5(1); C(11)-P-N 106.97(8); C(11)-P-C(21) 106.09(8); C(21)-P-B 104.9(1); C(21)-
P-N 108.43(9); B-P-N 113.45(9).
FIGURE 2. ORTEP drawing of (SP)-3 at the 30% probability level. Selected bond lengths (Å) and angles (°): P-B 1.885(3); P-N 1.633(2); P-O
1.621(1); P-C(11) 1.803(2); C(2)-C(3) 1.322(3); C(11)-P-B 114.7(1); C(11)-P-N 105.71(9); C(11)-P-O 97.98(8); O-P-B 115.0(1); O-P-N
110.18(9); B-P-N 112.1(1).
mixture was obtained from which the corresponding P-phenyl-
5H-dibenzophosphole (4i) and P-phenyl-7H-dinaphtho[2,1-b:
1′,2′-d]phosphole (4j) were isolated in up to 25% yield. 1H NMR
analysis of the crude showed no formation of compound 3 but
the formation of bis[(1R,2S)-(N-ephedrino)](phenyl)phosphine-
P-borane (5) which was isolated in 15% yield. X-ray diffraction
analysis of its dimethyl ether derivative 5a ascertained its
structure. The formation of compound 5 arises from the ring
opening of (+)-1 with the displaced (1R,2S)-N,O-dilithioephe-
drine by attack of the amide part. Product 5 was independently
prepared in 81% yield by reacting preformed (1R,2S)-N,O-
dilithioephedrine with (+)-1 in THF.
According to the literature, the attack of 2,2′-dilithio-1,1′-
biphenyl (i) on dichlorophenylphosphine, chlorodiphenylphos-
phine, and the like gives rise to the (P-phenyl)phosphole
derivative 4i.19a-c However, the attack of 2,2′-dilithio-1,1′-
binaphthalene (j) on dichlorophenylphosphine yields the (P-
phenyl)phosphole derivative 4j, but furnishes BINAP using
chlorodiphenylphosphine.19d,e
presence of a 30% excess of the reagent. In this case, after the
attack of the first aryl anion on the phosphorus atom, the ring
closure with a concomitant displacement of the ephedrine moiety
is favored by the proximity of the second aryl anion and its
slow attack on another molecule of 1. Consequently, such a
flattened cyclic arylphosphine structure readily loses the BH3
protecting group either during the reaction or upon workup. 31
P
NMR analysis of the reaction mixture showed the presence of
a small amount of the BH3 adduct (δP +25; in comparison with
an authentic sample).
Thus, we were unable to prepare via this strategy either the
desired 2,2′-bis[(N-ephedrino)(phenyl)phosphino-P-borane]-1,1′-
biphenyl or the 2,2′-bis[(N-ephedrino)(phenyl)phosphino-P-
borane]-1,1′-binaphthalene.
(19) (a) Gilman, H.; Gorsich, R. D. J. Am. Chem. Soc. 1955, 77, 6380-
6381. (b) Brunner, H; Janura, M. J. Synthesis 1998, 45-55. (c) Desponds,
O.; Schlosser, M. J. Organomet. Chem. 1996, 507, 257-261. (d) Brown,
K. J.; Berry, M. S.; Waterman, K. C.; Lingenfelter, D.; Murdoch, J. R. J.
Am. Chem. Soc. 1984, 106, 4717-4723. (e) Gladiali, S.; Dore, A.; Fabbri,
D., De Lucchi, O.; Valle, G. J. Org. Chem. 1994, 59, 6363-6371.
(20) Bishop, J. J.; Davison, A.; Katcher, M. L.; Lichtenberg, D. W.;
Merrill, R. E.; Smart, J. C. J. Organomet. Chem. 1971, 27, 241-249.
The P-N bond of the (N-ephedrino)phosphine boranes is
always preserved under the organolithium attack even in
J. Org. Chem, Vol. 72, No. 21, 2007 8013

Stephan et al.
SCHEME 3a
a Reagents: (a) 2,2′-dilithio-1,1′-biarene (0.4 molar equiv)/THF, -20 °C to rt; (b) MeI/NaH/THF, rt.
SCHEME 4a
Investigation of OxazaPB (1) Ring Opening with 1,1′-
Dilithioferrocene (k) and -ruthenocene (l). Following milder
reaction conditions than those adopted by others,9b the reaction
of 1,1′-dilithioferrocene (k)‚2 TMEDA20 adduct at -20 °C to
rt with (-)-1 furnished the desired (RP,RP)-1,1′-bis{[(1S,2R)-
(N-ephedrino)](phenyl)phosphino-P-borane}ferrocene (2k) ac-
companied by the (RP,SP)-diastereomer 2k′ and [(1S,2R)-(N-
ephedrino)](ferrocenyl)(phenyl)phosphine-P-borane21 (disubstitution/
monosubstitution ratio 95:5).12 1H NMR of the crude showed
that compound 3 was not formed. Furnishing identical diaster-
eomeric ratio, 1,1′-dilithioferrocene (k) prepared from trans-
metalation of 1,1′-dibromoferrocene with n-BuLi (2.1 equiv)
led, however, to a better yield than using the adduct prepared
from ferrocene/n-BuLi/TMEDA (Scheme 4).
The diastereomers 2k and 2k′ formed in 82:18 dr were
separated by column chromatography; the major diastereomer
2k was isolated in 64% yield, and the minor 2k′ in 10%
yield.9c,22 The absolute configuration of 2k was confirmed by
X-ray diffraction analysis of its dimethyl ether derivative 2ka.
As the opening of 1 with ferrocenyllithium occurs with a high
diastereoselectivity (de >98%), we can ascertain that after the
first nucleophilic attack the increased steric bulkiness affects
the second nucleophilic attack accounting for the obtained result
(dr ) 82:18). The lower selectivity obtained thus derives from
the second nucleophilic attack.
By analogy to ferrocene-bridged P-stereogenic diphosphine
ligands and their precursors, we aimed for the synthesis of their
yet unknown ruthenocene analogues. Thus, the reaction of 1,1′-
dilithioruthenocene (l)‚2 TMEDA23 adduct at 0 °C to rt with
(-)-1 furnished (RP,RP)-1,1′-bis{[(1S,2R)-(N-ephedrino)](phe-
a Reagents: (a) 1,1’-dilithiometallocene (i,j) (M ) Fe: with or without
TMEDA; M ) Ru: with TMEDA)/THF, -20 °C to rt; (b) MeI/NaH/THF,
rt.
nyl)phosphino-P-borane}ruthenocene (2l) accompanied by the
(RP,SP)-diastereomer 2l′, (RP)-[(1S,2R)-(N-ephedrino)](rutheno-
cenyl)(phenyl)phosphine-P-borane (2m), and a ruthenocene
three-times substituted with (N-ephedrino)(phenyl)phosphino-
P-borane group (monosubstitution/disubstitution/trisubstitution
ratio 19:72:9 of isolated products). The diastereomers 2l and
1
2l′ were formed in dr ) 80:20 (by H NMR), and the major
diastereomer 2l was isolated in 34% yield after column
chromatography. The absolute configuration of 2l (as well as
of the monosubstituted ruthenocene 2m) is assumed to be
identical to 2k. Independently, we have prepared (RP)-[(1S,2R)-
(N-ephedrino)](ruthenocenyl)(phenyl)phosphine-P-borane (2m)
(21) Independently, we have prepared (RP)-[(1S,2R)-(N-ephedrino)]-
(ferrocenyl)(phenyl)phosphine-P-borane from (-)-1 according to Nettekoven
et al.8h The authors have reported that (SP)/(RP) ) 81:9 (∼90% yield).
However, we found a dr >98:2 with monosubstitution/disubstitution ) 95:
5. Previously, Brown et al.8b have reported that the ferrocenyllithium attack
on (SP)-methyl (o-anisyl)(phenyl)phosphinite-P-borane led to 92% ee and
isolated yields of monosubstitution/disubstitution ) 67:3. Ferrocenyllithium
was prepared from ferrocene and t-BuLi according to: (a) Rebie`re, F.;
Samuel, O.; Kagan, H. B. Tetrahedron Lett. 1990, 31, 3121-3124. (b)
Herberhold, M.; Ayazi, A.; Milius, W.; Wrackmeyer, B. J. Organomet.
Chem. 2002, 656, 71-80.
1
from (-)-1 in 27% yield, and H NMR analysis revealed a dr
of 96:4.
The (RP,RP)-1,1′-bis{[(1S,2R)-(N-ephedrino)](phenyl)phos-
phino-P-borane}metallocenes (2k,l) constitute the precursors to
P-stereogenic metallocene-bridged diphosphine ligands accord-
ing to the general synthetic strategy.5,9b
(22) The attack of 1,1′-dilithioferrocene (k)‚2 TMEDA complex on (RP)-
methyl (o-anisyl)(phenyl)phosphinite-P-borane led to 1,1′-bis[(o-anisyl)-
(phenyl)phosphino-P-borane]ferrocene with (SP,SP)/(SP:RP) ) 3.5:1 (93%
yield).8e
Conclusion
We have succeeded to introduce with high stereoselectivity
bulky aryl groups on the P-stereogenic phosphorus atom by ring
(23) Bednarik, L.; Neuse, E. J. Organomet. Chem. 1979, 168, C8-C12.
8014 J. Org. Chem., Vol. 72, No. 21, 2007

Reaction of Bulky Aryllithium Reagents
(RP)-[(1S,2R)-(N-Ephedrino)](2,6-dimethoxyphenyl)(phenyl)-
phosphine-P-borane (2b). To a THF (50 mL) solution of 1,3-
dimethoxybenzene (6.22 g, 45 mmol) was added n-BuLi (45 mmol)
at 0 °C.24 The mixture was left to stir for 4 h at rt, and (-)-1 (9.10
g, 31.9 mmol) in THF (30 mL) was added at -20 °C. After stirring
at rt for 24 h, the reaction was quenched with H2O. The concentrated
residue was partitioned between CH2Cl2 (250 mL) and H2O (100
mL), and the organic layer was dried over Na2SO4 then concen-
opening of enantiomerically pure 3,4-dimethyl-2,5-diphenyl-
1,3,2-oxazaphospholidine-2-borane (1) using organolithium
reagents. We have prepared in 4-65% yield (Ar)(N-ephedrino)-
(phenyl)phosphine-P-boranes 2 with Ar ) 8-methoxynaphth-
1-yl, 2-methoxynaphth-1-yl, 2,6-dimethoxyphenyl, 2,4,6-tri-
methoxyphenyl, 9-anthryl, 2,6-dimethylphenyl, and 2-mesityl.
However, when the attack on the phosphorus atom is hindered,
the deprotonation of the benzylic proton occurs, yielding the
trans-(N-methylamino)(phenyl)(1-phenyl-1-propenyloxy)phos-
phine-P-borane (3).
While the attack of 2,2′-dilithio-1,1′-biarenes led to the
corresponding (P-phenyl)phosphole derivatives 4i,j and to [bis-
(N-ephedrino)](phenyl)phosphine-P-borane (5), the attack of
1,1′-dilithiometallocene (M ) Fe, Ru) led to a separable
diastereomeric mixture of 1,1′-bis[(N-ephedrino)(phenyl)phos-
phino-P-borane]metallocenes (2k,l/2k′,l′). The obtained dias-
tereoselectivity (dr ∼80:20) derives from the lower selectivity
occurring at the second nucleophilic attack. Thus, ruthenocenes
bearing a P-stereogenic atom were synthesized for the first time.
The application of the novel (Ar)(N-ephedrino)(phenyl)-
phosphine-P-boranes 2a-g,k,l, trans-(SP)-(N-methylamino)-
(phenyl)(1-phenyl-1-propenyloxy)phosphine-P-borane (3), bis-
[(1R,2S)-(N-ephedrino)](phenyl)phosphine-P-borane (5), and
their derivatives in organophosphorus and in asymmetric
syntheses is in progress and will be communicated in due
course.
1
trated. H and 31P NMR revealed 2b/3 ratio of 40:60. The crude
was purified on silica gel eluting with toluene, then toluene/EtOAc
8:2 (Rf 0.25 in toluene/EtOAc 9:1) and recrystallized from hexane
to yield 2b as colorless crystals (4.75 g, 35%): mp 147-150 °C;
[R]25 -23.3 (c 1.0, CHCl3); δH (300 MHz, CDCl3, TMS) 0.47-
D
1.70 (br m, 3H), 1.21 (d, J ) 6.7 Hz, 3H), 1.97 (br d, J ) 4.0 Hz,
1H), 2.58 (d, J ) 8.3 Hz, 3H), 3.48 (s, 6H), 4.40 (hept, J ) 6.1
Hz, 1H), 4.86 (m, 1H), 6.51 (dd, J ) 3.5, 8.4 Hz, 2H), 7.11-7.45
(m, 11H); δC (75 MHz, CDCl3) 12.0 (d, JC-P ) 2.2 Hz), 30.9 (d,
JC-P ) 3.6 Hz), 55.2, 58.5 (d, JC-P ) 10.5 Hz), 79.1 (d, JC-P
6.0 Hz), 104.6 (d, JC-P ) 4.4 Hz), 106.8 (d, JC-P ) 54.9 Hz),
126.5, 127.4 (d, JC-P ) 1.6 Hz), 127.5, 128.3, 128.5 (d, JC-P
)
)
2.2 Hz), 129.0 (d, JC-P ) 10.4 Hz), 133.6, 137.0 (d, JC-P ) 74.2
Hz), 142.6, 162.9 (d, JC-P ) 2.2 Hz); δP (120 MHz, CDCl3, 85%
H3PO4) +63.2 (br m). Anal. Calcd for C24H31BNO3P: C, 68.10;
H, 7.38; N, 3.31. Found: C, 68.43; H, 7.61; N, 2.98.
(RP)-[(1S,2R)-(N-Ephedrino)](2,4,6-trimethoxyphenyl)(phenyl)-
phosphine-P-borane (2c). To a THF (2 mL) solution of 1,3,5-
trimethoxybenzene (218 mg, 1.3 mmol) was added n-BuLi (1.3
mmol) at 0 °C.24 The mixture was left to stir for 1.5 h at rt, and
(-)-1 (285 mg, 1.0 mmol) was added at 0 °C. After stirring at rt
for 72 h, the reaction was quenched with H2O. The concentrated
residue was partitioned between CH2Cl2 (10 mL) and H2O (5 mL),
and the organic layer was dried over Na2SO4 then concentrated.
1H and 31P NMR revealed 2c/3 ratio of 38:62. The crude was
purified on silica gel eluting with toluene/EtOAc 9:1 (Rf 0.3) to
yield 2c as colorless viscous oil (110 mg, 24%, ∼95% purity
Experimental Section
General. All reactions were carried out under a nitrogen
atmosphere using anhydrous and degassed solvents. The starting
(-)-(2S,4R,5S)-3,4-dimethyl-2,5-diphenyl-1,3,2-oxazaphospholidine-
2-borane ((-)-oxazaPB, (-)-1) and its enantiomer were prepared
according to published procedure.5 Organolithium reagents were
prepared from the appropriate arene or bromoarene according to
known literature procedures.
1
according to H NMR): δH (300 MHz, CDCl3, TMS) 0.35-1.70
(br m, 3H), 1.22 (d, J ) 6.8 Hz, 3H), 1.95 (br d, J ) 4.3 Hz, 1H),
2.57 (d, J ) 8.4 Hz, 3H), 3.47 (s, 6H), 3.82 (s, 3H), 4.39 (m, 1H),
4.86 (m, 1H), 6.05 (d, J ) 3.1 Hz, 2H), 7.06-7.35 (m, 8H), 7.43
(m, 2H); δC (75 MHz, CDCl3) 12.2 (d, JC-P ) 1.8 Hz), 30.6 (d,
JC-P ) 3.8 Hz), 55.1, 55.3, 58.4 (d, JC-P ) 10.6 Hz), 79.0 (d, JC-P
) 6.0 Hz), 91.2 (d, JC-P ) 4.9 Hz), 98.8 (d, JC-P ) 60.5 Hz),
OxazaPB (1) Ring Opening with ArLi (a-g): (RP)-[(1S,2R)-
(N-Ephedrino)](8-methoxynaphth-1-yl)(phenyl)phosphine-P-bo-
rane (2a). To a cyclohexane (20 mL) solution of 1-methoxynaph-
thalene (1.58 g, 10.0 mmol) was added t-BuLi (10 mmol).14a The
mixture was left to stir at rt for 3-4 days until the reddish color
disappeared, then the supernatant was decanted off and the solid
was rinsed with cyclohexane (2 × 20 mL). To the cooled (0 °C)
solid was added a solution of (-)-1 (1.43 g, 5.0 mmol) in THF (15
mL). After stirring at rt for 18 h, the reaction was quenched with
H2O. Following concentration, the residue was partitioned between
CH2Cl2 (30 mL) and H2O (15 mL), and the organic layer was dried
126.6, 127.3, 127.4 (d, JC-P ) 5.7 Hz), 128.2, 128.3 (d, JC-P
)
2.3 Hz), 128.9 (d, JC-P ) 10.6 Hz), 137.3 (d, JC-P ) 74.6 Hz),
142.7, 164.1 (d, JC-P ) 2.6 Hz), 164.5 (d, JC-P ) 1.1 Hz); δP (120
MHz, CDCl3, 85% H3PO4) +61.2 (br m).
(RP)-[(1S,2R)-(N-Ephedrino)](2-methoxynaphth-1-yl)(phenyl)-
phosphine-P-borane (2d). To an Et2O (7 mL) solution of 1-bromo-
2-methoxynaphthalene (570 mg, 3.6 mmol) was added n-BuLi (3.6
mmol) at 0 °C. The mixture was left to stir for 3 h at rt, and a
solution of (-)-1 (855 mg, 3.0 mmol) in THF (7 mL) was added
at 0 °C. After stirring at rt for 24 h, the reaction was quenched
with H2O. The concentrated residue was partitioned between CH2-
Cl2 (30 mL) and H2O (10 mL), and the organic layer was dried
1
over Na2SO4 then concentrated. H NMR of the crude showed a
mixture consisting of 8- and 2-P-substituted 1-methoxynaphthalene
(90:10 ratio). Purification on silica gel eluting with toluene (Rf 0.1)
yielded 2a (1.44 g, 65%) as a white powder: mp 130-133 °C
1
over Na2SO4 then concentrated. H and 31P NMR revealed 2d/3
(hexane); [R]25 -146.3 (c 0.4, CHCl3); δH (300 MHz, CDCl3,
D
ratio of 52:48. The crude was purified on silica gel eluting with
toluene/EtOAc 9:1 (Rf 0.1 in toluene) to yield 2d as yellowish oil
(505 mg, 38%, ∼95% purity according to 1H NMR): δH (300 MHz,
CDCl3, TMS) 0.50-1.58 (br m, 3H), 1.21 (d, J ) 6.9 Hz, 3H),
1.72 (br d, J ) 3.8 Hz, 1H), 2.72 (d, J ) 8.0 Hz, 3H), 3.31 (s, 3H),
4.50 (m, 1H), 4.96 (m, 1H), 7.11-7.50 (m, 13H), 7.79 (m, 1H),
7.97 (d, J ) 9.1 Hz, 1H), 8.66 (d, J ) 8.7 Hz, 1H); δC (75 MHz,
CDCl3) 11.3 (d, JC-P ) 4.2 Hz), 31.4 (d, JC-P ) 3.3 Hz), 55.5,
TMS) 0.50-1.85 (br m, 3H), 1.28 (d, J ) 6.7 Hz, 3H), 2.01 (br s,
1H), 2.36 (d, J ) 7.0 Hz, 3H), 3.01 (s, 3H), 4.60 (br s, 1H), 5.00
(d, J ) 4.1 Hz, 1H), 6.54 (dd, J ) 7.6, 1.1 Hz, 1H), 7.10-7.57
(m, 13 H), 7.77-7.91 (m, 2H); δC (75 MHz, CDCl3) 12.0 (d, JC-P
) 2.5 Hz), 31.3 (d, JC-P ) 3.3 Hz), 51.9, 57.9 (d, JC-P ) 8.1 Hz),
78.7 (d, JC-P ) 3.4 Hz), 105.5, 120.7, 125.1 (d, JC-P ) 50.6 Hz),
125.3 (d, JC-P ) 10.5 Hz), 126.1, 126.5, 126.6 (d, JC-P ) 7.0 Hz),
127.1, 127.6 (d, JC-P ) 10.8 Hz), 128.1, 129.0 (d, JC-P ) 2.5 Hz),
129.5 (d, JC-P ) 10.4 Hz), 131.4 (d, JC-P ) 2.6 Hz), 132.6 (d,
JC-P ) 7.2 Hz), 134.8 (d, JC-P ) 74.4 Hz), 135.7 (d, JC-P ) 6.9
Hz), 142.9, 154.1; δP (120 MHz, CDCl3, 85% H3PO4) +77.9 (br
s); HRMS (ESI) m/z calcd for C27H32BNO2P [M+ + H] 444.226,
found 444.227. Anal. Calcd for C27H31BNO2P: C, 73.15; H, 7.05;
N, 3.16. Found: C, 73.31; H, 7.18; N, 3.02.
58.5 (d, JC-P ) 9.7 Hz), 79.0 (d, JC-P ) 3.3 Hz), 110.2 (d, JC-P
60.9 Hz), 113.6 (d, JC-P ) 5.1 Hz), 123.9, 125.9, 126.0 (d, JC-P
)
)
(24) Brandsma, L.; Verkruijsse, H. D. In PreparatiVe Polar Organome-
tallic Chemistry; Springer-Verlag: Berlin, Heidelberg, 1987; Vol. 1, pp
203-204.
J. Org. Chem, Vol. 72, No. 21, 2007 8015

Stephan et al.
1
7.2 Hz), 126.8, 127.2, 127.9 (d, JC-P ) 10.9 Hz), 128.2, 128.5 (d,
JC-P ) 1.2 Hz), 129.00 (d, JC-P ) 10.7 Hz), 129.02 (d, JC-P ) 2.0
Hz), 129.4 (d, JC-P ) 7.6 Hz), 134.7 (d, JC-P ) 1.9 Hz), 135.4 (d,
JC-P ) 9.1 Hz), 137.6 (d, JC-P ) 67.7 Hz), 142.6, 160.5 (d, JC-P
) 1.1 Hz); δP (120 MHz, CDCl3, 85% H3PO4) +64.0 (br s); HRMS
(ESI) m/z calcd for C27H32BNO2P [M+ + H] 444.226, found
444.227.
then concentrated. H and 31P NMR revealed 2g/3 ratio of 68:32.
The crude was purified on silica gel eluting with toluene (Rf 0.3)
to yield 2g as a colorless oil (465 mg, 57%): [R]25 -128.9 (c
D
1.0, CHCl3); δH (300 MHz, CDCl3, TMS) 0.55-1.95 (br m, 3H),
1.04 (d, J ) 7.0 Hz, 3H), 1.36 (br d, J ) 2.9 Hz, 1H), 2.15 (s, 6H),
2.27 (s, 3H), 2.64 (d, J ) 7.3 Hz, 3H), 4.35 (m, 1H), 4.91 (s, 1H),
6.84 (d, J ) 3.5 Hz, 2H), 7.18-7.49 (m, 8H), 7.81 (m, 2H); δC
(75 MHz, CDCl3) 9.5 (d, JC-P ) 6.8 Hz), 20.8 (d, JC-P ) 1.1 Hz),
(RP)-[(1S,2R)-(N-Ephedrino)](9-anthryl)(phenyl)phosphine-P-
borane (2e). To a THF (5 mL) solution of 9-bromoanthracene (668
mg, 2.6 mmol) was added t-BuLi (5.2 mmol) at -78 °C.25 The
mixture was left to stir for 15 min at this temperature, then brought
up to rt, and a solution of (-)-1 (570 mg, 2.0 mmol) in THF (5
mL) was added. After stirring at rt for 1 h, the reaction was
quenched with H2O. The concentrated residue was partitioned
between CH2Cl2 (30 mL) and H2O (10 mL), and the organic layer
was dried over Na2SO4 then concentrated. 1H and 31P NMR revealed
2e/3 ratio of 5:95. The crude was purified on silica gel eluting with
hexane/EtOAc 9:1 (Rf 0.15). Product 2e was isolated as a yellow
powder (37 mg, 4%, ∼95% purity according to 1H NMR): δH (300
MHz, CDCl3, TMS) 0.50-2.15 (br m, 3H), 1.18 (d, J ) 7.0 Hz,
3H), 1.75 (br s, 1H), 2.40 (d, J ) 7.5 Hz, 3H), 4.60 (m, 1H), 5.11
(d, J ) 2.4 Hz, 1H), 7.17-7.45 (m, 12 H), 7.58 (m, 2H), 8.00
(dm, J ) 8.5 Hz, 2H), 8.27 (dm, J ) 9.1 Hz, 2H), 8.59 (s, 1H); δC
(75 MHz, CDCl3) 9.7 (d, JC-P ) 6.7 Hz), 30.9 (d, JC-P ) 3.3 Hz),
58.4 (d, JC-P ) 10.1 Hz), 78.7, 119.1 (d, JC-P ) 64.1 Hz), 124.9,
125.3, 125.7, 126.6 (d, JC-P ) 7.1 Hz), 127.2, 128.2, 128.5 (d,
JC-P ) 10.5 Hz), 129.0, 130.5 (d, JC-P ) 2.2 Hz), 130.8 (d, JC-P
) 10.7 Hz), 131.2 (d, JC-P ) 8.4 Hz), 133.0 (d, JC-P ) 2.8 Hz),
134.1 (d, JC-P ) 7.2 Hz), 134.4 (d, JC-P ) 60.1 Hz), 142.3; δP
(120 MHz, CDCl3, 85% H3PO4) +68.5 (br m).
23.6 (d, JC-P ) 4.3 Hz), 31.2 (d, JC-P ) 4.0 Hz), 58.4 (d, JC-P
)
10.2 Hz), 78.6, 123.5 (d, JC-P ) 68.9 Hz), 125.5, 127.1, 128.2,
128.5 (d, JC-P ) 10.2 Hz), 130.5 (d, JC-P ) 2.1 Hz), 130.8 (d,
JC-P ) 10.1 Hz), 131.3 (d, JC-P ) 9.1 Hz), 134.4 (d, JC-P ) 57.0
Hz), 140.3 (d, JC-P ) 2.5 Hz), 142.8 (d, JC-P ) 28.8 Hz), 142.9;
δP (120 MHz, CDCl3, 85% H3PO4) +67.2 (br m); HRMS (ESI)
m/z calcd for C25H34BNOP [M+ + H] 406.2471, found 406.2472.
Anal. Calcd for C25H33BNOP: C, 74.08; H, 8.21; N, 3.46. Found:
C, 74.43; H, 8.29; N, 3.49.
trans-(SP)-(N-Methylamino)(phenyl)(1-phenyl-1-propenyl-
oxy)phosphine-P-borane (3). This product derives from the
reaction of 2,6-dimethoxyphenyllithium (45 mmol) with (-)-1 (9.10
g, 31.9 mmol) and was purified on silica gel eluting with toluene
(Rf 0.6). It was recrystallized from hexane (5.10 g, 56%) as colorless
crystals: mp 65-69 °C; [R]25D -69.6 (c 1.0, CHCl3); δH (300 MHz,
CDCl3, TMS) 0.03-1.40 (br m, 3H), 1.78 (dd, J ) 7.3, 2.7 Hz,
2H), 2.29 (dd, J ) 10.7, 5.7 Hz, 3H), 2.92 (m, 1H), 5.67 (qd, J )
7.3, 2.7 Hz, 1H), 7.27-7.52 (m, 8H), 7.74-7.83 (m, 2H); δC (75
MHz, CDCl3) 12.9 (d, JC-P ) 1.1 Hz), 27.3 (d, JC-P ) 6.8 Hz),
112.2 (d, JC-P ) 6.1 Hz), 127.9, 128.1, 128.5 (d, JC-P ) 11.0 Hz),
128.6 (d, JC-P ) 1.1 Hz), 130.8 (d, JC-P ) 90.4 Hz), 131.2 (d,
JC-P ) 11.2 Hz), 131.5 (d, JC-P ) 2.2 Hz), 135.1 (d, JC-P ) 2.2
Hz), 147.2 (d, JC-P ) 6.6 Hz); δP (120 MHz, CDCl3, 85% H3PO4)
+105.8 (br m); HRMS (ESI) m/z calcd for C16H21BNNaOP [M+
+ Na] 308.135, found 308.136. Anal. Calcd for C16H21BNOP: C,
67.40; H, 7.42; N, 4.91. Found: C, 67.53; H, 7.54; N, 4.78.
OxazaPB (1) Ring Opening with 2,2′-Dilithio-1,1′-biarenes
(i,j). General Procedure: To a cold (-20 °C) solution of 2,2′-
dilithio-1,1′-biarene18 (0.48 mmol) was added a solution of (+)-1
(342 mg, 1.2 mmol), and the mixture was stirred at rt overnight.
The reaction was quenched with H2O and concentrated. The residue
was partitioned between CH2Cl2 (30 mL) and H2O (10 mL), and
the organic layer was dried over Na2SO4 then concentrated. The
crude was purified on silica gel eluting with hexane/CH2Cl2 (10:1
to 4:1).
(RP)-[(1S,2R)-(N-Ephedrino)](2,6-dimethylphenyl)(phenyl)-
phosphine-P-borane (2f). To a cold (-20 °C) solution of (-)-1
(570 mg, 2.0 mmol) in THF (4 mL) was added 2,6-dimethylphe-
nyllithium26 (2.3 mmol in Et2O). After stirring at rt for 2 h, the
reaction was quenched with H2O. The concentrated residue was
partitioned between CH2Cl2 (30 mL) and H2O (10 mL), and the
1
organic layer was dried over Na2SO4 then concentrated. H and
31P NMR revealed 2f/3 ratio of 50:50. The crude was purified on
silica gel eluting with toluene (Rf 0.35) to yield 2f as a colorless
oil (360 mg, 46%): [R]25 -141.6 (c 1.0, CHCl3); δH (300 MHz,
D
CDCl3, TMS) 0.60-1.95 (br m, 3H), 1.02 (d, J ) 7.0 Hz, 3H),
1.41 (br d, J ) 3.6 Hz, 1H), 2.17 (s, 6H), 2.61 (d, J ) 7.1 Hz, 3H),
4.34 (m, 1H), 4.86 (s, 1H), 7.00 (m, J ) 3.5 Hz, 2H), 7.15-7.48
(m, 9H), 7.80 (m, 2H); δC (75 MHz, CDCl3) 9.4 (d, JC-P ) 6.8
Hz), 23.6 (d, JC-P ) 4.4 Hz), 31.2 (d, JC-P ) 4.2 Hz), 58.3 (d,
JC-P ) 10.4 Hz), 78.5, 125.4, 126.9 (d, JC-P ) 66.9 Hz), 127.0,
128.1, 128.5 (d, JC-P ) 10.0 Hz), 130.1 (d, JC-P ) 2.0 Hz), 130.3
P-Phenyl-5H-dibenzophosphole (4i): Rf 0.45 in hexane/CH2-
Cl2 9:1; δH (300 MHz, CDCl3, TMS) 7.19-7.37 (m, 7H), 7.43-
7.50 (m, 2H), 7.70 (m, 2H), 7.95 (d, J ) 7.8 Hz, 2H); δP (120
MHz, CDCl3, 85% H3PO4) -9.5 (s).
P-Phenyl-7H-dinaphtho[2,1-b:1′,2′-d]phosphole (4j): Rf 0.45
in hexane/CH2Cl2 9:1; δH (300 MHz, CDCl3, TMS) 7.16-7.35 (m,
5H), 7.46-7.55 (m, 4H), 7.75-7.90 (m, 4H), 7.96 (m, 2H), 8.47
(m, 2H); δP (120 MHz, CDCl3, 85% H3PO4) -4.1 (s).
(d, JC-P ) 8.8 Hz), 130.5 (d, JC-P ) 2.3 Hz), 130.7 (d, JC-P
)
10.2 Hz), 134.3 (d, JC-P ) 57.2 Hz), 142.5, 142.9 (d, JC-P ) 9.2
Hz); δP (120 MHz, CDCl3, 85% H3PO4) +67.0 (br m); HRMS (ESI)
m/z calcd for C24H32BNOP [M+ + H] 392.232, found 392.232.
Anal. Calcd for C24H31BNOP: C, 74.08; H, 8.21; N, 3.46. Found:
C, 74.43; H, 8.29; N, 3.49.
Bis[(1R,2S)-N-ephedrino](phenyl)phosphine-P-borane (5). To
a THF (2 mL) solution of (-)-ephedrine (165 mg, 1.0 mmol) was
added n-BuLi (2 mmol) at -50 °C. The mixture was stirred at this
temperature for 30 min then at 0 °C for 10 min. Then, a solution
of (+)-1 (285 mg, 1.0 mmol) in THF (2 mL) was added. After
stirring at rt for 16 h, the reaction was quenched with H2O. The
concentrated residue was partitioned between CH2Cl2 (10 mL) and
H2O (10 mL), and the organic layer was dried over Na2SO4 then
concentrated. The crude was purified on silica gel eluting with
toluene (Rf 0.3 in toluene/EtOAc 9:1), then precipitated from hexane
(RP)-[(1S,2R)-(N-Ephedrino)](2-mesityl)(phenyl)phosphine-P-
borane (2g). To a THF (4 mL) solution of 2-bromomesitylene (500
mg, 2.5 mmol) was added t-BuLi (5.0 mmol) at -78 °C.27 The
mixture was left to stir for 15 min at this temperature, then brought
up to rt and stirred for 15 min. To this mixture at -40 °C was
added a solution of (-)-1 (570 mg, 2.0 mmol) in THF (5 mL).
After stirring at rt for 2 h, the reaction was quenched with H2O.
The concentrated residue was partitioned between CH2Cl2 (30 mL)
and H2O (10 mL), and the organic layer was dried over Na2SO4
to yield 5 as viscous oil (365 mg, 81%): [R]25 +16.2 (c 1.0,
D
CHCl3); δH (300 MHz, CDCl3, TMS) 0.10-1.80 (m, 6H), 1.11
and 1.14 (2d, J ) 6.9 Hz, 6H), 2.15 and 2.21 (2d, J ) 3.7 Hz,
2H), 2.52 (d, J ) 7.8 Hz, 3H), 2.62 (d, J ) 7.6 Hz, 3H), 4.06 (m,
2H), 4.91 (m, 2H), 7.17-7.43 (m, 15H); δC (75 MHz, CDCl3) 11.1
(d, JC-P ) 4.5 Hz), 12.2 (d, JC-P ) 1.8 Hz), 30.7 (d, JC-P ) 3.9
Hz), 30.9 (d, JC-P ) 2.8 Hz), 57.0 (d, JC-P ) 10.9 Hz), 57.4 (d,
JC-P ) 9.4 Hz), 78.7 (d, JC-P ) 6.6 Hz), 78.8 (d, JC-P ) 2.8 Hz),
(25) Sakurai, H.; Sakamoto, K.; Nakamura, A.; Kira, M. Chem. Lett.
1985, 497-498.
(26) Anderson, S.; Hill, A. F.; White, A. J. P.; Williams, D. J.
Organometallics 1998, 17, 2665-2668.
(27) Pelter, A.; Williams, L.; Wilson, J. W. Tetrahedron Lett. 1983, 24,
627-630.
8016 J. Org. Chem., Vol. 72, No. 21, 2007

Reaction of Bulky Aryllithium Reagents
125.8, 126.3, 127.4, 127.5, 128.1, 128.2, 128.4, 128.5, 130.4, 130.4,
131.8, 131.9, 132.1 (d, JC-P ) 87.1 Hz), 142.5, 142.8; δP (120
MHz, CDCl3, 85% H3PO4) +93.8 (br m). Anal. Calcd for C26H36-
BN2O2P: C, 69.34; H, 8.06; N, 6.22. Found: C, 69.51; H, 8.21;
N, 6.08.
followed by MeI (310 µL, 5 mmol). After stirring at rt for 20 h,
the reaction was quenched with H2O. The concentrated residue was
purified on silica gel eluting with toluene (Rf 0.35) and recrystallized
from hexane/CH2Cl2 to yield amber colored crystals (373 mg,
95%): mp 163-167 °C; [R]25 +75.5 (c 0.5, CHCl3); δH (300
D
MHz, CDCl3, TMS) 0.23-1.70 (m, 6H), 1.18 (d, J ) 6.9 Hz, 6H),
2.38 (d, J ) 8.2 Hz, 6H), 3.21 (s, 6H), 4.07 (m, 2H), 4.20 (m, 2H),
4.30 (d, J ) 5.4 Hz, 2H), 4.58, 4.63, and 4.71 (3m, 6H), 7.23-
7.42 (m, 20H); δC (75 MHz, CDCl3) 13.1 (d, JC-P ) 2.3 Hz), 30.6
(d, JC-P ) 2.7 Hz), 56.9, 57.5 (d, JC-P ) 10.0 Hz), 72.8-74.7
(m), 88.5 (d, JC-P ) 5.2 Hz), 127.3, 127.5, 128.2 (d, JC-P ) 10.2
Hz), 128.3, 130.5 (d, JC-P ) 2.3 Hz), 131.3 (d, JC-P ) 10.2 Hz),
132.7 (d, JC-P ) 69.5 Hz), 139.8; δP (120 MHz, CDCl3, 85% H3-
PO4) +69.1 (br m). Anal. Calcd for C44H56B2FeN2O2P2: C, 67.38;
H, 7.20; N, 3.57. Found: C, 67.72; H, 7.47; N, 3.28.
Bis[(1R,2S)-N-(O-methylephedrino)](phenyl)phosphine-P-bo-
rane (5a). To a THF (1 mL) solution of 5 (90 mg, 0.20 mmol)
was added NaH (12 mg, 0.5 mmol) followed by MeI (0.61 mL, 10
mmol). After stirring at rt for 16 h, the reaction was quenched with
H2O. The concentrated residue was purified on silica gel eluting
with toluene (Rf 0.8 in toluene/EtOAc 9:1), then recrystallized from
hexane to yield 5a as colorless crystals (87 mg, 91%): mp 146-
148 °C; [R]25D -28.1 (c 0.4, CHCl3); δH (300 MHz, CDCl3, TMS)
0.10-1.60 (m, 6H), 1.14 and 1.19 (2d, J ) 6.9 Hz, 6H), 2.65 and
2.67 (2d, J ) 4.2 Hz, 6H), 3.25 and 3.29 (2s, 6H), 3.90-4.15 (m,
2H), 4.42 (d, J ) 3.5 Hz, 1H), 4.50 (d, J ) 4.2 Hz, 1H), 7.17-
7.45 (m, 15H); δC (75 MHz, CDCl3) 11.2 (d, JC-P ) 5.0 Hz), 12.3
(d, JC-P ) 2.4 Hz), 30.9 (m), 56.9 (d, JC-P ) 8.2 Hz), 57.0 (d,
JC-P ) 11.4 Hz), 57.5 (d, JC-P ) 10.4 Hz), 88.8 (d, JC-P ) 5.8
Hz), 89.0 (d, JC-P ) 2.6 Hz), 126.7, 127.2, 127.3, 127.4, 128.19,
128.24, 128.5, 128.6, 130.46, 130.49, 131.7, 131.9, 132.5 (d, JC-P
) 86.3 Hz), 139.8, 140.0; δP (120 MHz, CDCl3, 85% H3PO4) +93.6
(br m). Anal. Calcd for C28H40BN2O2P: C, 70.29; H, 8.43; N, 5.86.
Found: C, 70.52; H, 8.58; N, 5.54.
OxazaPB (1) Ring Opening with 1,1′-Dilithioferrocene (k) and
-ruthenocene (l): (RP,RP)-1,1′-Bis{[(1S,2R)-(N-ephedrino)](phe-
nyl)phosphino-P-borane}ferrocene (2k) and (RP,SP)-1,1′-Bis-
{[(1S,2R)-(N-ephedrino)](phenyl)phosphino-P-borane}-
ferrocene (2k′). To a cold (-50 °C) THF (5 mL) solution of 1,1′-
dibromoferrocene (688 mg, 2 mmol) was added n-BuLi (4.2 mmol)
and stirred at -30 °C for 1 h, then at 0 °C for 10 min. To this
mixture at -20 °C was added a solution of (-)-1 (1.26 g, 4.4 mmol)
in THF (10 mL) and stirred at rt for 4 h. The reaction was quenched
with H2O, concentrated, and the residue was partitioned between
CH2Cl2 (30 mL) and H2O (20 mL). The organic layer was dried
over Na2SO4 and concentrated. 1H NMR of the crude showed a dr
2k/2k′ ) 82:18. Products were purified on silica gel eluting with
toluene/EtOAc 95:5 to yield 2k (980 mg, 64%) and 2k′ (150 mg,
10%).
(RP,RP)-1,1′-Bis{[(1S,2R)-(N-ephedrino)](phenyl)phosphino-
P-borane}ruthenocene (2l). To a cold (0 °C) solution of ru-
thenocene (925 mg, 4.0 mmol) in hexane (30 mL) was added
n-BuLi (8.0 mmol) followed by TMEDA (1.2 mL, 8.0 mmol), and
the mixture was stirred at rt overnight.23 The beige colored
precipitate was washed with hexane (2 × 10 mL), and to it was
added a solution of (-)-1 (2.44 g, 8.5 mmol) in THF (20 mL) at
0 °C. The mixture was stirred at rt for 2 h, quenched with H2O,
concentrated, and the residue was partitioned between CH2Cl2 (30
mL) and H2O (20 mL). The organic layer was dried over Na2SO4
1
and concentrated. H NMR of the crude showed 2l/2l′ ) 80:20.
This was purified on silica gel eluting with a gradient of toluene/
EtOAc (100:0 to 95:5).
Major diastereomer (2l): 1.09 g (34%), beige powder (Rf 0.25
in toluene/EtOAc 9:1); mp 145-146 °C (hexane/CH2Cl2); [R]25
D
+95.2 (c 1.0, CHCl3); δH (300 MHz, CDCl3, TMS) 0.25-1.35 (m,
6H), 1.25 (d, J ) 6.8 Hz, 6H), 1.83 (br s, 2H), 2.41 (d, J ) 8.4 Hz,
6H), 4.15 (m, 2H), 4.54 (m, 2H), 4.81-4.86 (m, 4H), 4.94 and
4.99 (2m, 4H), 7.18-7.45 (m, 20H); δC (75 MHz, CDCl3) 13.4 (d,
JC-P ) 1.2 Hz), 30.4 (d, JC-P ) 3.3 Hz), 57.7 (d, JC-P ) 9.6 Hz),
75.0 (d, JC-P ) 13.5 Hz), 76.5-77.4 (m), 77.6 (d, JC-P ) 5.9 Hz),
78.5 (d, JC-P ) 13.5 Hz), 126.6 127.7, 128.1 (d, JC-P ) 10.4 Hz),
128.4, 130.5 (d, JC-P ) 2.2 Hz), 131.4 (d, JC-P ) 10.0 Hz), 131.9
(d, JC-P ) 71.5 Hz), 142.4; δP (120 MHz, CDCl3, 85% H3PO4)
+68.99 (br s). Anal. Calcd for C42H52B2N2O2P2Ru: C, 62.94; H,
6.54; N, 3.50. Found: C, 62.86; H, 6.50; N, 3.63.
Major diastereomer (2k): orange needles (Rf 0.25 in toluene/
EtOAc 9:1), mp 151-153 °C (hexane/CH2Cl2); [R]25 +72.7 (c
D
0.7, CHCl3); δH (300 MHz, CDCl3, TMS) 0.45-1.65 (m, 6H), 1.22
(d, J ) 6.8 Hz, 6H), 1.85 (d, J ) 3.8 Hz, 2H), 2.35 (d, J ) 8.3 Hz,
6H), 4.12-4.20 (m, 4H), 4.60, 4.65 and 4.73 (3m, 6H), 4.87 (m,
2H), 7.26-7.40 (m, 20H); δC (75 MHz, CDCl3) 13.0, 30.5 (d, JC-P
) 2.4 Hz), 57.7 (d, JC-P ) 9.0 Hz), 72.9 (m), 73.9 (m), 74.8 (d,
JC-P ) 6.6 Hz), 78.7 (d, JC-P ) 5.3 Hz), 126.5, 127.6, 128.2 (d,
JC-P ) 10.4 Hz), 128.4, 130.6, 131.3 (d, JC-P ) 9.7 Hz), 132.4 (d,
JC-P ) 69.9 Hz), 142.5; δP (120 MHz, CDCl3, 85% H3PO4) +68.8
(br m). Anal. Calcd for C42H52B2FeN2O2P2: C, 66.70; H, 6.93; N,
3.70. Found: C, 66.84; H, 7.09; N, 3.56.
Minor diastereomer 2l′: 0.39 g, yellowish oil (Rf 0.3 in toluene/
EtOAc 9:1), containing 30% of 2l; δH (300 MHz, CDCl3, TMS)
0.35-1.50 (m, 6H), 1.17 and 1.20 (2d, J ) 6.9 Hz, 6H), 1.85 (br
d, J ) 11.7 Hz, 2H), 2.35 (d, J ) 9.5 Hz, 3H), 2.49 (d, J ) 8.2
Hz, 3H), 3.80 and 4.10 (2m, 2H), 4.47 (m, 1H), 4.62 (m, 2H), 4.72
(m, 1H), 4.76-4.87 (m, 6H), 7.18-7.46 (m, 18H), 7.57 (m, 2H);
δP (120 MHz, CDCl3, 85% H3PO4) +69.0 (br m). 2m: 0.25 g
(12%); containing 3% of its (SP)-diastereomer.
A compound consisting of a ruthenocene three-times substituted
with (N-ephedrino)(phenyl)phosphino-P-borane group according to
1H NMR and to preparation of 1,1′-dilithioruthenocene (l)‚2
TMEDA:23 0.27 g (6%).
Minor diastereomer (2k′): viscous brown oil (Rf 0.3 in toluene/
EtOAc 9:1); [R]25 +2.5 (c 1.0, CHCl3); δH (300 MHz, CDCl3,
D
TMS) 0.35-1.65 (br m, 6H), 1.12 and 1.16 (2d, J ) 6.8 Hz, 6H),
1.85 (br d, J ) 11.7 Hz, 2H), 2.27 (d, J ) 8.4 Hz, 3H), 2.43 (d, J
) 9.7 Hz, 3H), 3.59 (m, 1H), 4.05-4.14 (m, 2H), 4.26-4.34 (m,
3H), 4.50, 4.54, 4.58, and 4.66 (4m, 4H), 4.71 and 4.81 (2m, 2H),
7.12-7.60 (m, 20H); δC (75 MHz, CDCl3) 12.4 (d, JC-P ) 1.6
Hz), 12.9 (d, JC-P ) 2.2 Hz), 30.2 (d, JC-P ) 2.6 Hz), 30.5 (d,
JC-P ) 2.8 Hz), 57.6 (d, JC-P ) 2.2 Hz), 57.7 (d, JC-P ) 5.8 Hz),
71.0-74.8 (m), 78.1 (d, JC-P ) 4.7 Hz), 78.7 (d, JC-P ) 5.3 Hz),
126.3, 126.4, 127.6, 127.7, 128.2, 128.3, 128.36, 128.39, 130.6 (d,
JC-P ) 2.2 Hz), 131.1 (d, JC-P ) 2.2 Hz), 131.3 (d, JC-P ) 10.3
Hz), 131.8 (d, JC-P ) 12.1 Hz), 131.9 (d, JC-P ) 10.5 Hz), 132.7
(d, JC-P ) 17.24 Hz), 142.5, 142.8; δP (120 MHz, CDCl3, 85%
H3PO4) +68.8 (br m).
(RP)-[(1S,2R)-(N-ephedrino)](ruthenocenyl)(phenyl)phosphine-
P-borane (2m). To a cold (0 °C) solution of ruthenocene (231 mg,
1.0 mmol) in THF (3 mL) was added t-BuLi (0.67 mL, 1.0 mmol)
and stirred for 5 min.28 Hexane (3 mL) was added, the reaction
mixture cooled to -70 °C, the precipitated beige solid decanted,
and washed with hexane (3 × 3 mL). To this solid was added a
solution of (-)-1 (340 mg, 1.2 mmol) in THF (3 mL) at 0 °C,
slowly warmed to rt, stirred for 3 h, quenched with H2O,
concentrated, and partitioned between CH2Cl2 (20 mL) and H2O
(10 mL). The residue was purified on silica gel eluting with toluene/
EtOAc 9:1 (Rf 0.5) to yield 2m (139 mg, 27%) as a yellowish
foam: 1H NMR revealed the presence of 4% of the (SP)-
(RP,RP)-1,1′-Bis{[(1S,2R)-N-(O-methylephedrino)](phenyl)-
phosphino-P-borane}ferrocene (2ka). To a THF (2 mL) solution
of 2k (378 mg, 0.5 mmol) was added NaH (20 mg, 0.8 mmol),
(28) (a) Rausch, M. D.; Fischer, E. O.; Grubert, H. J. Am. Chem. Soc.
1960, 82, 76-82. (b) Allcock, H. R.; Lavin, K. D.; Riding, G. H.; Suszko,
P. R.; Whittle, R. R. J. Am. Chem. Soc. 1984, 106, 2337-2347.
J. Org. Chem, Vol. 72, No. 21, 2007 8017

Stephan et al.
diastereomer (δH 2.54 (d, J ) 7.7 Hz, 3H); [R]25 +112.7 (c 1.0,
C26H31BNOPRu: C, 60.47; H, 6.05; N, 2.71. Found: C, 60.37; H,
6.19; N, 2.83.
D
CHCl3); δH (300 MHz, CDCl3, TMS) 0.20-1.45 (br m, 3H), 1.24
(d, J ) 6.8 Hz, 3H), 2.06 (br s, 1H), 2.38 (d, J ) 8.3 Hz, 3H), 4.17
(m, 1H), 4.50 (m, 1H), 4.60 (s, 5H), 4.72-4.81 (m, 3H), 4.89 (m,
1H), 7.17-7.44 (m, 10H); δC (75 MHz, CDCl3) 13.4, 30.3 (d, JC-P
) 3.3 Hz), 57.6 (d, JC-P ) 9.4 Hz), 72.6 (d, JC-P ) 2.2 Hz), 72.7,
Acknowledgment. Financial support of the Ministry of
Higher Education, Science, and Technology of the Republic of
Slovenia through Grant P1-242 and of the Ministry of National
Education, Research, and Technology of France through Grant
00P141 to PhosPhoenix SARL is kindly acknowledged.
73.6 (d, JC-P ) 14.3 Hz), 74.4 (d, JC-P ) 7.4 Hz), 75.5 (d, JC-P
)
64.9 Hz), 78.5 (d, JC-P ) 6.5 Hz), 126.6, 127.7 (d, JC-P ) 18.6
Hz), 128.0, 128.3, 130.2 (d, JC-P ) 2.2 Hz), 131.5 (d, JC-P ) 10.0
Hz), 132.3 (d, JC-P ) 71.4 Hz), 142.5; δP (120 MHz, CDCl3, 85%
H3PO4) +69.3 (br m); HRMS (ESI) m/z calcd for C26H32
BNOPRu [M+ + H] 518.136, found 518.136. Anal. Calcd for
Supporting Information Available: Experimental procedure
1
for 2n, H and 13C NMR spectra of all new compounds, X-ray
crystallographic data for 2b, 2ka, 3, and 5a (cif files). This material
is available free of charge via the Internet at http://pubs.acs.org.
JO7014505
8018 J. Org. Chem., Vol. 72, No. 21, 2007