Directed ortho -lithiation of aminophosphazenes: An efficient route to the stereoselective synthesis of P -chiral compounds

Article abstract of DOI:10.1021/ol400971q

Ortho-directed lithiation of P,P-diphenylaminophosphazenes followed by electrophilic quench is described as an efficient process for synthesizing P-chiral ortho-functionalized derivatives in high yields and diastereoselectivities. The method allows the tu

Full text of DOI:10.1021/ol400971q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Directed Ortho-Lithiation of
Aminophosphazenes: An Efficient Route
to the Stereoselective Synthesis
of P‑Chiral Compounds
†
‡
‡
†
ꢀ
´
´
´
Marıa Casimiro, Laura Roces, Santiago Garcıa-Granda, Marıa Jose Iglesias, and
,†
ꢀ
Fernando Lopez Ortiz*
ꢀ
Area de Quımica Organica, Universidad de Almerıa, Carretera de Sacramento s/n,
´
04120 Almerıa, Spain, and Departamento de Quımica Fısica y Analıtica,
ꢀ
´
´
Universidad de Oviedo, C/Julian Claverıa 8, 33006 Oviedo, Spain
´
´
´
ꢀ
´
flortiz@ual.es
Received March 21, 2013
ABSTRACT
Ortho-directed lithiation of P,P-diphenylaminophosphazenes followed by electrophilic quench is described as an efficient process for
synthesizing P-chiral ortho-functionalized derivatives in high yields and diastereoselectivities. The method allows the tunable preparation of
structurally diverse enantiopure P-chiral compounds including phosphinic and phosphinothioic amides, phosphinic esters, phosphine oxides,
and o-aminophosphines.
The enantioselective deprotonations of prochiral PMe2
moieties of phosphine-boranes and sulfides are well-
established methods to synthesize P-chiral compounds.1
Both enantiomers can be prepared by using alkyllithiums
in the presence of stoichiometric2 or catalytic3 amounts of
(ꢀ)-sparteine and (þ)-sparteine surrogates as bases. In
contrast, the stereoselective deprotonation of enantiotopic
PPh2 groups has been much less studied. Recently, we
reported the desymmetrization of diphenylphosphinic
amides via directed ortho-lithiation (DoLi)-electrophilic
trapping reactions.4 Although diverse functionalities could
be introduced, the stereoselectivities obtained were low
(dr4a e 5:1; ee4b of 60%). Furthermore, ortho-lithiation of
† Universidad de Almerı
´
a.
‡ Universidad de Oviedo.
(1) (a) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc.
1995, 117, 9075. Reviews: (b) Kolodiazhnyi, O. I. Tetrahedron: Asym-
metry 2012, 23, 1. (c) Grabulosa, A.; Granell, J.; Muller, G. Coord.
Chem. Rev. 2007, 251, 25.
(2) (a) Johansson, M. J.; Schwartz, L. O.; Amedjkouh, M.; Kann,
N. C. Eur. J. Org. Chem. 2004, 1894. (b) Johansson, M. J.; Andersson,
K. H. O.; Kann, N. J. Org. Chem. 2008, 73, 4458.
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Harvey, J. S.; Gouverneur, V. Chem. Commun. 2010, 46, 7477. (c) See
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P.; Kelly, B. J. Org. Chem. 2011, 76, 4794. (f) Wu, X.; O’Brien, P.;
Ellwood, S.; Secci, F.; Kelly, B. Org. Lett. 2013, 15, 192.
ꢀ
~
ꢀ
(4) (a) Fernandez, I.; Ona-Burgos, P.; Ruiz Gomez, G.; Bled, C.;
ꢀ
Garcıa-Granda, S.; Lopez-Ortiz, F. Synlett 2007, 4, 611. (b) Popovici,
´
~
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C.; Ona-Burgos, P.; Fernandez, I.; Roces, L.; Garcıa-Granda, S.;
´
ꢀ
Iglesias, M. J.; Lopez-Ortiz, F. Org. Lett. 2010, 12, 428.
ꢀ ꢀ
a-Lopez, J.; Fernandez, I.;
(5) El Hajjouji, H.; Belmonte, E.; Garcı
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Iglesias, M. J.; Roces, L.; Garcıa-Granda, S.; El Laghdach, A.; Lopez-Ortiz,
F. Org. Biomol. Chem. 2012, 10, 5647.
´
´
r
10.1021/ol400971q
XXXX American Chemical Society

chiral phosphinothioic amides proceeded without chiral
induction.5
Table 1. Ortho-LithiationꢀStannilation of Aminophosphazene 4a
We have shown that CR-lithiated phosphazenes 2 are
effective directors of ortho-lithiations leading to like CR,
Cortho dianions 3 in which the Ph2P moiety has been
desymmetrized (Scheme 1).6 Although 3 is configuration-
ally stable, the very low barrier of racemization of the
precursor CR-anion 2 renders this route inefficient for the
synthesis of enantiopure products. We reasoned that ami-
nophosphazenes4 may behave similarly tophosphazenes1
in DoLi reactions7 providing access to a new family of N,
Cortho dilithiated species 6 in which chirality could be easily
introduced via the amino fragment.
t1
t2
conversion
(%)b
entry
base
equivalentsa (h)
(h)
1
nBuLi/TMEDA
nBuLi/TMEDA
tBuLi
2.2
2.2
2.2
2.2
4
9
12
12
12
12
1.5
12
1.5
0
2c
9
0
3
2
34
44
80
77
95
4
5c
tBuLi
9
tBuLi
9
6
tBuLi
3
9
Scheme 1. Rational for DoLi of Aminophosphazenes
7
tBuLi
3
15
a Equimolar amounts of base and electrophile were used. b Deter-
mined based on 31P{1H} NMR spectra. c Reaction performed at ꢀ70 °C.
dianion 6a formed with Me3SnCl afforded stannane 7 in
95% conversion (Table 1, entry 7; 90% isolated yield). The
conversion decreased notably by reducing the time of
metalation (entry 6) and/or the amount of base added
(entries 3, 4). Lithiation with a larger excess of base
(4 equiv) during 9 h at ꢀ70 °C also resulted in lower
conversion (entry 5). The use of nBuLi in the presence of
TMEDA as base at either ꢀ90 or ꢀ70 °C failed to produce
ortho-lithiation (entries 1, 2).
Once optimized reaction conditions for the Cortho-lithiationꢀ
stannilation of 4a were available, we examined the reactiv-
ity of dianion 6atowarda variety of electrophiles (Table 2).
These include heteroatom- and carbon-based halides
(Me3SiCl, Ph2P(O)Cl, MeI, allylBr), 1,2-diiodoethane as
an Iþ synthetic equivalent, and Ph2CdO. In all cases the
reaction proceeded smoothly to give ortho-functionalized
products 7ꢀ14 in high yield. In the reaction with benzo-
phenone a mixture of adduct 13 (15%) and the heterocycle
14 (72%) formed via cyclocondensation of 13 with elim-
ination of isopropyl amide was obtained. Purification
through flash column chormatography (ethyl acetate/
hexane 2:1) afforded 14 in 50% yield.
Herein, we report an efficient procedure for the N, Cortho
double deprotonation of aminophosphazenes 4 and the
ortho-functionalization of the dianion through carbonꢀ
carbon and carbonꢀheteroatom bond-forming reactions
witha seriesof electrophiles, the extension ofthemethodto
C-chiral aminophosphazenes, and its application to the
highly stereoselective synthesis of structurally diverse P-
chiral organophosphorus compounds.
The aminophosphazenes used in this study were pre-
pared through one-pot reactions of Ph2PCl with the corre-
sponding amine and subsequent addition of N3CO2Me.
Precipitation from Et2O furnished compounds 4 in high
yield (g85%, Supporting Information (SI)).
At the start of our investigation, we studied the ortho-
lithiation of aminophosphazene 4a using Me3SnCl as the
electrophile for establishing the degree of Cortho-lithiation
achieved (Table 1). We have found that dilithiation of 4a is
efficiently accomplished by the reaction with 3 equiv of
tBuLi in THF at ꢀ90 °C for 15 h. The reaction of the
The products in Table 2 indicate that the DoLi method-
ology is a valuable method for synthesizing new ortho-
functionalized aminophosphazenes showing wide struc-
tural diversity. Furthermore, products 7, 8, and 10 can
be considered as precursors for additional manipulations
via metal-mediated cross-coupling reactions.8 Compound
9 containing two different PdX groups may be envisaged
ꢀ ꢀ ꢀ
(6) (a) Garcıa-Lopez, J.; Fernandez, I.; Serrano-Ruiz, M.; Lopez-
´
ꢀ
ꢀ~
Ortiz, F. Chem. Commun. 2007, 4674. (b) Garcia-Lopez, J.; Yanez-
Rodriguez, V.; Roces, L.; Garcia-Granda, S.; Martinez, A.; Guevara-Garcia,
ꢀ
A.; Castro, G. R.; Jimenez-Villacorta, F.; Iglesias, M. J.; Lopez-Ortiz, F.
J. Am. Chem. Soc. 2010, 132, 10665.
(7) DoLi of phosphazenes: (a) Stuckwisch, C. G. J. Org. Chem. 1976,
41, 1173. (b) Steiner, A.; Stalke, D. Angew. Chem., Int. Ed. Engl. 1995,
34, 1752. Selected recent applications: (c) Aguilar, D.; Contel, M.;
Navarro, R.; Urriolabeitia, E. P. Organometallics 2007, 26, 4604. (d)
(8) Review: (a) Anctil, E. J. G.; Snieckus, V. In Metal-Catalyzed
Cross-Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, FRG, 2004; Chapter 14, p 761. See also: (b)
Schneider, C.; Broda, E.; Snieckus, V. Org. Lett. 2011, 13, 3588. (c)
Wang, X.; Fu, J.-M.; Snieckus, V. Helv. Chim. Acta 2012, 95, 2680.
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X. F.; Le Floch, P. Dalton Trans. 2009, 1659.
ꢀ
~
Aguilar, D.; Fernandez, I.; Cuesta, L.; Yanez-Rodrıguez, V.; Soler, T.;
´
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Navarro, R.; Urriolabeitia, E. P.; Lopez-Ortiz, F. J. Org. Chem. 2010,
75, 6452. (e) Martinez-Arripe, E.; Jean-Baptiste-dit-Dominique, F.;
Auffrant, A.; Le Goff, X.-F.; Thuilliez, J.; Nief, F. Organometallics
2012, 31, 4854. (f) Zhang, Q.; Zhang, X.-Q.; Wang, Z.-X. Dalton Trans.
2012, 41, 10453.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Ortho-LithiationꢀSubstitution of 4a
Table 3. Diastereoselective ortho-LithiationꢀSubstitution of 4b
entry
Eþ
E
product conversion (%)a yield (%)
1
2
3
4
5
6
7
Me3SnCl Me3Sn
Me3SiCl Me3Si
Ph2P(O)Cl Ph2P(O)
7
95
90
88
84
88
95
90
8
75
9
60
ICH2CH2I
MeI
I
10
11
12
75
entry
Eþ
E
product
yield (%)
Me
Allyl
75
AllylBr
90
1
2
Me3SnCl
Me3SiCl
Ph2P(O)Cl
BrCN
Me3Sn
Me3Si
Ph2P(O)
Br
15
16
17
18
19
20
21
22
23
24
94
93
70
75
89
85
78
85
50
50
Ph2CdO Ph2CꢀOH 13 þ 14 15(13)/72(14)
a Established based on 31P{1H} NMR spectra.
50(14)
3
4
5
ICH2CH2I
TosN3
I
6
N3
as a new chelating hemilabile ligand with potential appli-
cations in coordination chemistry.9
7
MeI
Me
8
AllylBr
Ph2CdO
MeO2CCl
Allyl
Next, we sought to extend the scope of the process to
chiral aminophosphazene 4b containing the readily acces-
sible (R)-R-methylbenzylamine as a chiral auxiliary. We
were pleased to find that the ortho-lithiation of 4b under
the conditions optimized for 4a followed by the addition of
Me3SnCl gave the ortho-stannyl derivative 15 in very high
yield (94%) and diastereoselectivity (dr of 95:5) (Table 3,
entry 1). The major stereoisomer could be readily isolated
through flash column chromatography. The synthesis of
15 represents the most efficient desymmetrization of a
Ph2P moiety reported to date.
The high diastereoselectivity observed in the formation
of 15 implies that the ortho-deprotonation of one of the
diastereotopic P-phenyl rings of 4b is largely favored and
that the ortho-anion generated is configurationally stable
during the 15 h needed to complete the lithiation step.
These features allow the preparation of new chiral deriva-
tives through anion trapping withelectrophiles. The results
are shown in Table 3. In all cases, the 31P NMR spectra of
the crude reaction mixtures showed that the diastereos-
electivity attained in the ortho-lithiation was preserved in
the final products. The reaction with Me3SiCl and
Ph2P(O)Cl lead to the silyl and phosphoryl products 16
and 17, respectively, in high yield (entries 2, 3). Bromination
and iodination of the ortho-anion of 4b by quenching with
BrCN and (CH2)2I2, respectively, provided the appropriate
halogenated aminophosphazenes 18 and 19 (entries 4, 5)
Crystals of 19 suitable for X-ray diffraction were grown
from a diethyl ether solution at ambient temperature. The
X-ray structure allowed the absolute configuration as
(SP,RC) to be established (Table 3, SI). Based on the lithiation
procedure used we assigned the same configuration to the
major stereoisomer of all ortho-substituted aminopho-
sphazenes synthesized. The treatment of the ortho-anion
with tosyl azide afforded the valuable o-azido derivative
20 in high yield (entry 6). CꢀC bond-forming reactions
also proceeded efficiently. Alkylation with MeI and allylBr
9
10
furnished the respective ortho-methylated, 21, and allyl-
ated, 22, products (entries 7, 8). The reactivity toward
carbonyl reagents was assayed using benzophenone and
methyl chloroformate as electrophiles. The products ob-
tained were the heterocyclic phosphinic ester 23 and amide
24, respectively (entries 9, 10). A reasonable mechanism
explaining the formation of these compounds is given in
the SI. We assume that nucleophilic attack to the PN
linkage involved in the synthesis of 23 proceeds with
inversion of configuration at phosphorus.
Phosphazenes can be easily converted into other phos-
phorus-containing functional groups. We envisaged that
DoLi reactions of chiral aminophosphazenes combined
with functional group transformations may be a useful
synthetic strategy for accessing the structurally diverse
enantiopure P-chiral compounds. These are important
ligands1b,c,3a,3b,10 and organocatalysts11 in asymmetric
synthesis. The aza-Wittig12 reaction of 19 and 21 with
phenylisothiocyanate is assumed to take place with reten-
tion of the P-configuration to give the enantiopure phos-
phinothioic amides 25 and 26, respectively, in good yield
(Scheme 2).13
(10) Recent reviews: (a) Guerrero Rios, I.; Rosas-Hernandez, A.;
Martin, E. Molecules 2011, 16, 970. (b) Xie, J.-H.; Zhu, S.-F.; Zhou,
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Xie, M.; Chen, Y.-C. Chem. Soc. Rev. 2012, 41, 4101. (d) Gomez, C.;
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10.1002/cctc.201200442.
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Tsuge, O.; Kanemasa, S.; Matsuda, K. J. Org. Chem. 1984, 49, 2688. (c)
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Org. Lett., Vol. XX, No. XX, XXXX
C

More elaborated difunctional products such as o-for-
mylphosphinic amide 29 can be easily prepared starting
from aminophosphazene 18. Deprotonation with KHMDS
and subsequent addition of methyl triflate produced the
N-methylated derivative 27. The latter undergoes PdN to
PdO conversion by reaction with acetaldehyde,12d and
the phosphinic amide 28 obtained is transformed into
azidoester with Ph3P gave phosphazene 32, which upon
treatment with MeMgBr afforded the phosphine oxide
(RP)-33 (ee 92.8%) through substitution of a P-phenyl ring
of the phosphazenyl moiety17 and the methoxy group
by a methyl group.13,18 Finally, methylation of 33 with
MeOTf and subsequent reduction with NaBH4 provided
phosphine-borane (RP)-34 with excellent optical purity
(ee 97.4%).13,19
i
(RP,RC)-29 through Grignard formation with PrMgBr
followed by quench with DMF.13 The syntheses of 25ꢀ27
represent the most efficient route to P-chiral o-functionalized
phosphinic4 and phosphinothioic5 amides described to
date. Furthermore, the formyl group of 29 opens the way
to additional straightforward derivatization, e.g., via
imine formation reactions.14
Scheme 3. Stereoseletive Synthesis of P-Chiral
o-Aminophosphine-borane (SP)-34
Scheme 2. Synthesis of P-Chiral Compounds via
o-Desymmetrized Aminophosphazenes
In conclusion, directed ortho-lithiationꢀelectrophilic
quench of aminophosphazenes is introduced as a very
efficient procedure for desymmetrization of the prochiral
Ph2PdN moiety. The usefulness of the method was shown
with the preparation under mild reaction conditions of a
variety of functionalized P-chiral compounds in high yield
and excellent stereoselectivity, including phosphinic esters,
amidesand thioamides, and phosphine oxides, and the first
stereoselective synthesis of (2-aminophenyl)phosphine-
boranes. The availability of both enantiomers of the chiral
auxiliary ensures access to both product antipodes.
Further work expanding the applications of this method-
ology in asymmetric synthesis and in coordination chem-
istry is in progress.
P-Chiral (ortho-amino)phosphines are ligands of great
interest commonly prepared by resolution of racemates.15
The stereoselective synthesis of these species remains
a challenge. The synthesis of enantiopure P-protected
(o-amino)phosphine (SP)-34 nicely illustrate the potential
of applications of directed ortho-lithiations of aminophos-
phazenes (Scheme 3). The sequence of transformations
beginswith the aza-Wittig reaction of 20withacetaldehyde
to yield (RP,RC)-30.13 HCl catalyzed methanolysis of this
o-azidophosphinic amide furnished methyl phosphinate
(RP)-31 (ee 92%).16 The Staudinger reaction of this
Acknowledgment. Dedicated to Prof. R. Claramunt
ꢀ ꢀ
(Departamento de Quımica Organica y Bio-Organica,
´
Facultad de Ciencias, UNED, Spain) on the occasion of
her 65th birthday. We thank the MICINN, MEC, and
FEDER program for financial support (projects:
CTQ2008-117BQU, CTQ2011-27705, PTA-2009-2346-I,
(13) The descriptor of the P-configuration changes/is unaffected due
to differences of priorities of the substituents linked to the phosphorus.
(14) Hoveyda, A. H.; Hird, A. W.; Kacprzynski, M. A. Chem.
Commun. 2004, 1779.
(15) (a) Barclay, C. E.; Deeble, G.; Doyle, R. J.; Elix, S. A.; Salem, G.;
Jones, T. L.; Wild, S. B.; Willis, A. C. J. Chem. Soc., Dalton Trans. 1995,
57. (b) Doyle, R. J.; Salem, G.; Willis, A. C. J. Chem. Soc., Dalton Trans.
1997, 2713. (c) Bock, F.; Fischer, F.; Schenk, W. A. J. Am. Chem. Soc.
2006, 128, 68.
and CSD2006-015, Consolider Ingenio 2010, “Factorı
´
a de
ꢀ
Crystalizacion”). M.C. (University of Almerı
MICINN for a Ph.D. fellowship.
´
a) thanks
(16) The reaction proceeds with inversion of the P-configuration. (a)
Tyssee, D. A.; Bausher, L. P.; Haake, P. J. Am. Chem. Soc. 1973, 95,
8066. (b) Harger, M. J. P. J. Chem. Soc., Chem. Commun. 1976, 520. (c)
ꢀ
ꢀ
ꢀ
Fernandez, I.; Ruiz-Gomez, G.; Alfonso, I.; Iglesias, M. J.; Lopez-Ortiz,
Supporting Information Available. Experimental de-
tails, suggested mechanism of formation of 23 and 24,
characterization data, and crystallographic data for 19.
This material is available free of charge via the Internet at
http://pubs.acs.org.
F. Chem. Commun. 2005, 5408.
(17) Cao, T.-P.-A.; Payet, E.; Auffrant, A.; Le Goff, X. F.; Le Floch,
P. Organometallics 2010, 29, 3991.
(18) The reaction proceeds with inversion of the P-configuration.
Korpiun, O.; Mislow, K. J. Am. Chem. Soc. 1967, 89, 4784.
(19) The reaction proceeds with inversion of the P-configuration. A
slight increase of the ee as compared with (RP)-33 is observed. Rajendran,
K. V.; Gilheany, D. G. Chem. Commun. 2012, 48, 817.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX