Enantioselective desymmetrization of diphenylphosphinamides via (-)-sparteine-mediated ortho-lithiation. synthesis of P-chiral ligands

Article abstract of DOI:10.1021/ol902545q

[Chemical equation presented] Asymmetric ortho-lithiation of N-dialkyl-P,P-diphenylphosphinamides using [n-BuLi·(-)-sparteine] is described as an efficient method for the synthesis of P-chiral ortho-functionalized derivatives in high yields and ee's from

Full text of DOI:10.1021/ol902545q

ORGANIC
LETTERS
2010
Vol. 12, No. 3
428-431
Enantioselective Desymmetrization of
Diphenylphosphinamides via
(-)-Sparteine-Mediated Ortho-Lithiation.
Synthesis of P-Chiral Ligands
Cristinel Popovici,† Pascual On˜a-Burgos,† Ignacio Ferna´ndez,† Laura Roces,‡
Santiago Garc´ıa-Granda,‡ Mar´ıa Jose´ Iglesias,† and Fernando Lo´pez Ortiz*,†
´
Area de Qu´ımica Orga´nica, UniVersidad de Almer´ıa, Carretera de Sacramento s/n,
04120 Almer´ıa, Spain, and Departamento de Qu´ımica F´ısica y Anal´ıtica, UniVersidad
de OViedo, C/ Julia´n ClaVer´ıa 8, 33006 OViedo, Spain
flortiz@ual.es
Received November 3, 2009
ABSTRACT
Asymmetric ortho-lithiation of N-dialkyl-P,P-diphenylphosphinamides using [n-BuLi·(-)-sparteine] is described as an efficient method for the
synthesis of P-chiral ortho-functionalized derivatives in high yields and ee’s from 45 to >99%. The method allows access to new enantiomerically
pure P-chiral phosphine and diimine ligands.
Ortho-directed metalation has become one of the most
employed strategies in organic synthesis for derivatizing
arenes.1 Although a broad range of functional groups promote
ortho-deprotonation, P-containing derivatives have been less
exploited.2 PdX-Directed (X ) O, S) ortho-dilithiation
strategies have been also described.3 To the best of our
knowledge, there are no precedents on asymmetric ortho-
deprotonation of aryl systems using chiral reagents (third-
generation method).4,5 Recently, we have achieved the
diastereoselective desymmetrization of the P(O)Ph2 (Pop)
group of chiral diphenylphosphinamides.6 As part of our
ongoing project on selective phosphinamide-directed lithia-
tions7 we report herein (1) an efficient method for the
enantioselective lithiation of diisopropylphosphinamide 1a
using (-)-sparteine as source of chirality, (2) the extension
of the procedure to other Pop derivatives such as 1b-1f, (3)
(2) For representative examples, see: (a) Stuckwisch, C. G. J. Org. Chem.
1976, 41, 1173. (b) Dashan, L.; Trippett, S. Tetrahedron Lett. 1983, 24,
2039. (c) Yoshifuji, M.; Ishizuka, T.; Choi, I. J.; Inamoto, N. Tetrahedron
Lett. 1984, 25, 553. (d) Brown, J. M.; Woodward, S. J. Org. Chem. 1991,
56, 6803. (e) Desponds, O.; Schlosser, M. J. Organomet. Chem. 1996, 507,
257. (f) Cray, M.; Chapel, B. J.; Felding, J.; Taylor, N. J.; Snieckus, V.
Synlett 1998, 422. (g) Mehring, M.; Schurmann, M.; Jurkschat, K.
Organometallics 1998, 17, 1227. (h) Baier, F.; Fei, Z.; Gornitzka, H.; Murso,
A.; Neufeld, S.; Pfeiffer, M.; Ru¨demauer, I.; Steiner, A.; Stey, T.; Stalke,
D. J. Organomet. Chem. 2002, 661, 111. (i) Hartung, C. G.; Fecher, A.;
Chapell, B.; Snieckus, V. Org. Lett. 2003, 5, 1899. (j) Boubekeur, L.; Ricard,
L.; Mezailles, N.; Demange, M.; Auffrant, A.; Le Floch, P. Organometallics
2006, 25, 3091. (k) Widhalm, M.; Brecker, L.; Mereiter, K. Tetrahedron:
Asymmetry 2006, 17, 1355. (l) Garc´ıa-Lo´pez, J.; Ferna´ndez, I.; Serrano-
Ruiz, M.; Lo´pez-Ortiz, F. Chem. Commun. 2007, 4674.
† Universidad de Almer´ıa.
‡ Universidad de Oviedo.
(1) (a) Mugesh, G.; Singh, H. B. Acc. Chem. Res. 2002, 35, 226. (b)
Clayden, J. In The Chemistry of Organolithium Compounds; Rappoport,
Z., Marek, I., Eds.; John Wiley: Chichester, 2004; p 495. (c) Whisler, M. C.;
MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206.
(d) Schlosser, M. Angew. Chem., Int. Ed. 2005, 44, 376. (e) Mulvey, R. E.;
Mongin, F.; Uchiyama, M.; Kondo, Y. Angew. Chem., Int. Ed. 2007, 46,
3802.
(3) (a) Lampine, J. P.; Mathey, F. J. Organomet. Chem. 1974, 71, 239.
(b) Craig, D. C.; Roberts, N. K.; Tonswell, J. L. Aust. J. Chem. 1990, 43,
1487. (c) Agou, T.; Kobayashi, J.; Kawashima, T. Heteroatom Chem. 2004,
15, 437. (d) Tsuhji, H.; Komatsu, S.; Kanda, Y.; Umehara, T.; Saeki, T.;
Tamao, K. Chem. Lett. 2006, 35, 758.
10.1021/ol902545q  2010 American Chemical Society
Published on Web 01/07/2010

the application of the method to the synthesis of enantio-
merically pure phosphine bidentate ligands, and (4) salen-
type ligands containing P-chiral phosphinamide chelating
arms including preliminary coordination chemistry with
standard copper salts.
First, optimized reaction conditions were established for
the prototypal asymmetric deprotonation-stannylation of
phosphinamide 1a (Table 1).
°C during 1 h caused only a slight decrease of the ee (entry
5) and that stannylation with n-Bu3SnCl afforded 3b in a
yield and ee similar to 3a (entry 6). An excess of (-)-
sparteine does not affect the performance of the reaction
(entries 3 and 4). Fortunately, recrystallization from cold
hexane provided enantiomerically pure 3a in 30-35% yield.
We have previously prepared racemic 3a through tin-lithium
transmetalation of ortho-lithiated 1a in THF.6 The process
described here represents the first example of asymmetric
desymmetrization of the Pop group.
Preformation of complex [n-BuLi·L*] proved to be de-
terminant for the asymmetric induction observed. Stepwise
lithiation of 1a with t-BuLi8 followed by addition of (-)-
sparteine and subsequent reaction with Me3SnCl afforded
racemic 3a in 71% yield (Scheme 1a). Most importantly,
reversing the order of addition of chiral reagent and base, in
this case n-BuLi, gave 3a in high yield but also without
enantiodiscrimination (Scheme 1b).
Table 1. Asymmetric Ortho-Lithiation-Stannylation of 1aa,b
entry temp (°C) t1 (h)
R
t2 (h) convnc (%)
eed (%)
1
-90
-90
-90
-90
-35
-90
1
12
1
Me
Me
Me
Me
Me
n-Bu
0.5
0.5
0.5
0.5
1
86 (35)e
75 (30)e
83 (33)e
81
58 (>99)e
60 (>99)e
59 (>99)e
50
2
3f
4g
5
1
Scheme 1
.
Stepwise Lithiation, Addition of (-)-Sparteine (L*),
and Stannylation of 1a
1
1
75
50
6
0.5
82
50
a [n-BuLi·L*] (L* ) (-)-sparteine) preformed during 30 min. b A ratio
of 1a/[n-BuLi·L*] 1:1.5 was used. c Established on the basis of 31P{1H}
NMR spectra. d Determined by chiral HPLC. e After recrystallization. f 1.1
equiv of [n-BuLi·L*] and Me3SnCl were used. g 1.1 equiv of n-BuLi, 1.5
equiv of L*.
The best results were obtained by treating 1a with
[n-BuLi·L*] (L* ) (-)-sparteine) in toluene for 1 h at -90
°C followed by addition of Me3SnCl at the same temperature.
After reaction during 30 min, stannane 3a was obtained in
86% conversion and with an ee of 58% (Table 1, entry 1).
Increasing the metalation time up to 12 h led to similar
results, which indicates that the degree of enantioselection
is established in the first hour of lithiation and that the
complexes (R)-2 and (S)-2 formed do not interconvert with
each other (entry 2). This hypothesis is supported by the
observation that carrying out the electrophilic quench at -35
To extend the scope of our asymmetric method, the ortho-
lithiated substrate was treated with a variety of electrophiles
providing products 4-8 in good conversions and ee’s in the
range of 45-63% (Table 2). The stannilation process was
complemented with the introduction of the Ph3Sn moiety
which required reaction times up to 18 h to obtain 3c in
acceptable yields (entry 3).
The synthesis of o-iodo derivative 4 was attempted using
iodine and 1,2-diiodoethane as I+ synthetic equivalents9
(entries 4 and 5). The latter proceeded with higher conversion
in shorter reaction time probably due to the higher solubility
of the electrophile. Importantly, product 4 could be isolated
optically pure after recrystallization (isolated yield of 22%).
This compound is a valuable precursor for metal-mediated
cross-coupling reactions,10 a methodology successfully ap-
plied to the synthesis of chiral biphenyl derivatives bearing
achiral phosphorus substituents.11
(4) For enantioselective lithiation of ferrocenes, see: (a) Price, D.;
Simpkins, N. L. Tetrahedron Lett. 1995, 36, 61235. (b) Nishibayashi, Y.;
Arikawa, Y.; Ohe, K.; Uemura, S. J. Org. Chem. 1996, 61, 1172. (c)
Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.; Taylor, N. J.;
Snieckus, V. J. Am. Chem. Soc. 1996, 118, 685. (d) Jendralla, J.-H. Patent
to Hoechst. US5856540, 1999. (e) Laufer, R. S.; Veith, U.; Taylor, N. J.;
Snieckus, V. Org. Lett. 2000, 2, 629. (f) Laufer, R.; Veith, U.; Taylor, N. J.;
Snieckus, V. Can. J. Chem. 2006, 84, 356. (g) Fukuda, T.; Koga, Y.; Iwao,
M. Heterocycles 2008, 76, 1237.
(5) For enantioselective PCR deprotonations, see: (a) Muci, A. R.;
Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995, 117, 9075. (b) Genet,
C.; Canipa, S. J.; O’Brien, P.; Taylor, S. J. Am. Chem. Soc. 2006, 128,
9336. (c) Gammon, J. J.; Canipa, S. J.; O’Brien, P.; Kelly, B.; Taylor, S.
Chem. Commun. 2008, 3750.
(6) Ferna´ndez, I.; On˜a-Burgos, P.; Ruiz-Gomez, G.; Bled, C.; Garc´ıa-
Granda, S.; Lo´pez-Ortiz, F. Synlett. 2007, 611.
(8) In the absence of complexing reagent, n-BuLi is almost inert against
phosphinamide 1a.
(7) (a) Lo´pez-Ortiz, F.; Iglesias, M. J.; Ferna´ndez, I.; Andu´jar-Sa´nchez,
C. M.; Ruiz-Go´mez, G. Chem. ReV. 2007, 107, 1580. (b) Ruiz-Go´mez, G.;
Iglesias, M. J.; Serrano-Ruiz, M.; Lo´pez-Ortiz, F. J. Org. Chem. 2007, 72,
9704. (c) On˜a-Burgos, P.; Ferna´ndez, I.; Iglesias, M. J.; Garc´ıa-Granda, S.;
Lo´pez-Ortiz, F. Org. Lett. 2008, 10, 537. (d) On˜a-Burgos, P.; Ferna´ndez,
I.; Roces, L.; Torres-Ferna´ndez, L.; Garc´ıa-Granda, S.; Lo´pez-Ortiz, F. Org.
Lett. 2008, 10, 3195. (e) On˜a-Burgos, P.; Ferna´ndez, I.; Roces, L.; Torre-
Ferna´ndez, L.; Garc´ıa-Granda, S.; Lo´pez-Ortiz, F. Organometallics 2009,
28, 1739.
(9) (a) Qiu, L; Qi, J.; Pai, C.; Chan, S.; Zhou, Z.; Choi, M. C. K.; Chan,
A. S. C. Org. Lett. 2002, 4, 4599. (b) Metallinous, C.; Snieckus, V. Org.
Lett. 2003, 5, 1935.
(10) For reviews, see: (a) Hartung, C. G.; Snieckus, V. In Modern Arene
Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, 2002; p 330. (b) Anctil,
E. J. G.; Snieckus, V. J. Organomet. Chem. 2002, 653, 150. (c) Anctil,
E. J. G.; Snieckus, V. In Metal-Catalyzed Cross-Coupling Reactions, 2nd
ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004;
Chapter 14, p 761.
Org. Lett., Vol. 12, No. 3, 2010
429

Next, substrate scope was investigated by varying the
substituents at the nitrogen, 1b-d, and phosphorus atom,
1e (Scheme 2). As can be deduced from Scheme 2, ortho-
deprotonation of 1b-e under the conditions optimized for
1a followed by addition of Me3SnCl gave the corresponding
tin derivatives in moderate to high yield. However, the level
of asymmetric induction achieved was very low in all cases.
Changing the solvent to diethyl ether produced only a modest
increase of the ee.
Table 2. Asymmetric Ortho-Lithiation-Substitution of 1aa
entry
E+
E
t2 (h) temp (°C) convnb (%) eec (%)
1
2
3
4
5
6
7
8
9
Me3SnCl Me3Sn
Bu3SnCl Bu3Sn
Ph3SnCl Ph3Sn
0.5
0.5
-90
-90
-90
-90
-90
-90
-35
-90
-35
86 (3a)
82 (3b)
51(3c)
53 (4)
58 (>99)d
50
18
45
I2
I
14
1
60 (>99)d
63 (>99)d
59
47/63
52 (>99)d
55
Scheme 2.
Asymmetric Ortho-Stannylation of 1b-ea
(CH2I)2
I
Me
86 (4)
MeIe
2
83 (5)
PhCHO PhCHOH
1
85f (6/6′)
80 (7)
DMFe
Ph2PClg Ph2P
CHO
2
1
75 (8)
a A ratio of 1a/[n-BuLi·L*] 1:1.5 was used. b Established on the basis
of31P{1H}NMRspectra.c DeterminedbychiralHPLC.d Afterrecrystallization.
e 5 equiv of E+ was used. f Diastereoisomers in the C-OH, dr 1:2. g 1.1
equiv of [n-BuLi·L*] was used.
Alkylation with MeI afforded the corresponding o-methyl
derivative 5 (entry 6). Good results were found by using 5
equiv of electrophile. Under standard reaction conditions,
small amounts of a new compound 9 (3-13%) were always
formed. After isolation through flash chromatography, 9 was
identified as the product of lateral lithiation12 of 5 and
subsequent methylation (Supporting Information). This side
deprotonation might be effected by remaining [n-BuLi·L*]
in solution or via ortho-lithiated phosphinamide 2. Benzal-
dehyde reacted smoothly with anions 2 to give alkylated
derivatives 6/6′ in high conversion although with low face
selectivity (entry 7, Table 2). The major diastereoisomer was
obtained in higher optical purity (ee of 63 vs 47%).
a All of the reactions were carried out using a ratio of 1/[n-BuLi·L*]
1:1.5.
Hemilabile P,X-bidentate ligands (X ) O, N) are of great
interest due to their utility in coordination chemistry.13
ꢀ-Phosphine phosphinamide (SP)-8 is a new member of this
type of ligands containing a chiral PdO very close to a P(III)
binding site. We are not aware of P,O-ligands featuring the
characteristics of (SP)-8.13,14 For practical applications of
(SP)-8 in asymmetric catalysis, a workable route to a product
of high optical purity is needed. Attempts to improve the ee
of 55% of (SP)-8 by recrystallization failed. We envisaged
an alternative route based on tin-lithium transmetalation
using enantiomerically pure (SP)-3a. The reaction of (SP)-3a
(ee >99%) with [n-BuLi·TMEDA] in toluene at -50 °C and
subsequent addition of Ph2PCl allowed the synthesis of the
potential new ligand (SP)-8 (yield of 75%, ee >99%) in a
straightforward manner (Scheme 3a). The generality of this
strategy is evidenced by the analogous preparation of
optically pure (SP)-3b (Scheme 3b). These results indicate
that (SP)-3a can be considered as a synthetic equivalent of
the optically pure lithium derivative (SP)-2 (Table 1), thereby
allowing the entry of a large variety of enantiomerically pure
The use of DMF as quenching reagent furnished the
o-formyl product 7 in high yield (entry 8). To our delight,
three-time recrystallization from hexane returned 7 with ee
>99% in an isolated yield of 30%. The X-ray structure
allowed us to establish the absolute configuration as SP
(Supporting Information). Based on the lithiation process
discussed above, we assigned the same configuration to the
major stereoisomer of all ortho-substituted phosphinamides
3-8 synthesized. The CHO moiety present in (SP)-7 offers
a good chance of further manipulations (see below). Finally,
the treatment of enantiomerically enriched ortho-lithium
phosphinamide 1a with chlorodiphenylphosphine led to 8
in a yield of 75% and ee of 55%. The 31P NMR spectrum
measured in CDCl3 shows a diagnostic pattern with two
3
doublets of JPP ) 6.1 Hz at δ -10.95 and 33.36 ppm
corresponding to the P(III) and P(V) atoms, respectively.
(11) For recent examples see: (a) Shiintani, R.; Yashio, K.; Nakamura,
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S. S.; O’Shea, D. F. J. Org. Chem. 2008, 73, 6041.
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.
430
Org. Lett., Vol. 12, No. 3, 2010

Scheme 3
.
Synthesis of Enantiopure (SP)-3b and (SP)-8 by
Tin-Lithium Exchange Reactions
Scheme 4. Synthesis of (1R,2R,SP,SP′)-14 and Its Cu(I) Complex
spectra of an equimolecular mixture of (1R,2R,SP,SP′)-14 and
CuBr in in CDCl3 evidenced the quantitative formation of a
new Cu(I) complex, [Cu·14]Br (Scheme 4, Supporting
Information).
P-chiral phosphinamide derivatives via Sn-Li exchange
followed by electrophilic addition reactions. Moreover, the
lack of partial racemization in these transformations provides
definitive proof of the configurational stability of the ortho-
lithiated phosphinamide (SP)-2 (Table 1).
A further application of the asymmetric Pop-desymme-
trization method described above consists of the synthesis
of an optically pure diimine “salen”-type ligand15 incorporat-
ing chiral phosphinamide chelating groups. C2-Symmetric
(1R,2R,SP,SP′)-14 was prepared through condensation of
(SP)-7 with (1R,2R)-1,2-diaminocyclohexane in DCM (Scheme
4).
NMR monitoring of the reaction showed the initial
formation of the monocondensation adduct (δP 34.04 ppm),
which transformed quantitatively into 14 (δP 33.83 ppm) as
evidenced by the appearance of a singlet at δ 9.23 ppm in
the 1H NMR spectrum and the absence of the aldehyde CHO
resonance. The structure of 14 was confirmed through X-ray
analysis (Supporting Information).
In summary, asymmetric ortho-deprotonation of the Pop
group of phosphinamides using [n-BuLi·(-)-sparteine] has
been described for the first time. Electrophilic quench of the
configurationally stable ortho anions provides an efficient
method for synthesizing P-chiral ortho-functionalized deriva-
tives. Enantiomerically pure products can be obtained in a
straightforward manner by simple recrystallization and
tin-lithium exchange reactions. A new family of compounds
capable of participating in cross-coupling reactions and
complex formation with transition metals have been prepared.
Applications of the new chiral ligands in catalysis are
currently under investigation.
Acknowledgment. We thank the Ministerio de Ciencia e
Innovacio´n (project no. CTQ2008-117BQU) for financial
support. I.F. thanks the Ramo´n y Cajal program for financial
support.
Inspired by the catalytic capabilities of other bifunctionally
hemilabile phosphorus ligands,14 we decided to explore the
metal-binding abilities of 14 against copper(I) bromide. NMR
Supporting Information Available: Experimental details,
characterization data, and crystallographic data for (S)-7 and
(1R, 2R, SP, SP′)-14. This material is available free of charge
via the Internet at http://pubs.acs.org.
(15) Wezenberg, S. J.; Kleij, A. W. Angew. Chem., Int Ed. 2008, 47,
2354.
OL902545Q
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