Stereoselective synthesis of P-stereogenic aminophosphines: Ring opening of bulky oxazaphospholidines

Article abstract of DOI:10.1021/ja200988c

A highly diastereoselective and efficient synthesis of P-stereogenic bulky alkyl and aryl aminophosphines that relies on ring opening of tert-butyl-oxazaphospholidine 2 is described. Ring opening with several organometallic reagents takes place with inversion of configuration at the phosphorus center as it has been demonstrated by X-ray analysis of two ring-opened intermediates. The unprecedented reactivity observed is attributed to the presence of a free NH functionality that facilitates the attack of the organometallic reagent in an S_N2@P-type process.

Full text of DOI:10.1021/ja200988c

COMMUNICATION
pubs.acs.org/JACS
Stereoselective Synthesis of P-Stereogenic Aminophosphines: Ring
Opening of Bulky Oxazaphospholidines
Thierry Leꢀon, Antoni Riera,* and Xavier Verdaguer*
Unitat de Recerca en Síntesi Asimꢁetrica (URSA-PCB), Institute for Research in Biomedicine (IRB Barcelona) and Departament
de Química Orgꢁanica, Universitat de Barcelona, C/Baldiri Reixac 10, E-08028 Barcelona, Spain
S Supporting Information
b
Scheme 1. Jugꢀe’s Strategy for Synthesizing P-Stereogenic
Tertiary Phosphines
ABSTRACT: A highly diastereoselective and efficient
synthesis of P-stereogenic bulky alkyl and aryl aminophos-
phines that relies on ring opening of tert-butyl-oxazaphos-
pholidine 2 is described. Ring opening with several organo-
metallic reagents takes place with inversion of configuration
at the phosphorus center as it has been demonstrated by
X-ray analysis of two ring-opened intermediates. The un-
precedented reactivity observed is attributed to the presence
of a free NH functionality that facilitates the attack of the
organometallic reagent in an SN2@P-type process.
fficient and readily available chiral ligands remain a principal
E
target in catalysis. Bulky P-stereogenic phosphines (P*) have
demonstrated efficiency in myriad catalytic processes.1 However,
their synthesis in an enantiomerically pure form is often tedious.2 The
work of Evans and co-workers in 1995 represented a breakthrough in
this field.3 These authors unveiled that alkyl(dimethyl)phosphine
borane complexes could be selectively deprotonated at one of their
methyl groups in the presence of (ꢀ)-sparteine. This strategy was
later utilized by Imamoto and others for the synthesis of C2
symmetric bulky diphosphine ligands.4 Its chief drawbacks are that
it requires very low temperatures and that only the naturally occurring
enantiomer of sparteine is available. For stereoselective synthesis of
P*-compounds, the main alternative to enantioselective deprotona-
tion is ring opening of oxazaphospholidines (Scheme 1). The
pioneering work of Jugꢀe5aꢀc showed that both the condensation of
a bis(dialkylamino) phenylphosphine with (ꢀ)-ephedrine and the
ring opening of the resulting oxazaphospholidine (I) with alkyl-
lithium reagents to give II are highly diastereoselective.5 This elegant
work has been used to prepare several P-stereogenic ligands.5
However, it is not amenable to the synthesis of bulky P*-building
blocks, due to the lack of reactivity of intermediate II when a bulky
group is attached to the phosphorus.6
Figure 1. Bulky P-stereogenic aminophosphines and their correspond-
ing PnP ligands.
low diastereoselectivity of the DKR step. At this point, in the search
for a more efficient synthesis of P*-aminophosphine building blocks,
we turned our attention to oxazaphospholidine chemistry. Herein
we report the synthesis of new, bulky tert-butyl-oxazaphospholidines
and their diastereoselective ring opening and subsequent reductive
cleavage. This methodology constitutes a novel, practical, and
efficient route to P*-aminophosphines and their PnP derivatives.
Among the commercially available β-amino alcohols, we choose
for our study the cis-1-amino-2-indanol 1, which has been utilized to
prepare chiral sulfoxides and sulfinamides.9 Compound 1 contains a
benzylic amine, and both of its enantiomers are equally available in
bulk, characteristics essential to our strategy.10 A possible incon-
venience of amino alcohol 1 was that, to the best of our knowledge,
there were no oxazaphospholidines with the free NH function-
ality described in the literature.11 With this in mind, we began
to screen the condensation of 1 with different tert-butylphosphine
reagents (Table 1). Dichloro-tert-butylphosphine and tert-butyl-bis-
(diethylamino)-phosphine reagents provided the desired product
with good selectivity but in low yields (Table 1, entries 1 and 2). The
best reagent was the racemic chloro-tert-butyl(diethylamino)-
phosphine, which provided the corresponding condensation product
in an excellent yield of 78% and with diastereomeric ratios of up to
18:1 (Table 1, entry 4). Most conveniently, the major diastereomer
was separated by crystallization to afford 2 in diastereomerically pure
form. As confirmed by X-ray analysis, the bulky tert-butyl group in 2
was positioned trans to the Indane fragment, thereby avoiding steric
We recently described the synthesis of bulky aminophos-
phines of type V as valuable P*-building blocks for ligand
synthesis.7 We showed that these compounds can be readily
and efficiently converted into useful PnP ligands of type VI such
as MaxPHOS (Figure 1).8
Compounds of type V were obtained via dynamic kinetic
resolution (DKR) of racemic chlorophosphines with chiral amines
as resolving agents, followed by reductive cleavage of the benzylic
amine. Although this strategy afforded aminophosphines V in
optically pure form (>99% ee), the synthesis was hindered by the
Received: February 1, 2011
Published: March 29, 2011
r
2011 American Chemical Society
5740
dx.doi.org/10.1021/ja200988c J. Am. Chem. Soc. 2011, 133, 5740–5743
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Condensation of (1S,2R)-cis-1-Amino-2-indanol
(ꢀ)-1 with Different tert-Butylphosphine Derivatives
Temp
Time
(h)
Yield
(%)a
drb
Entry
R1
Cl
R2
Cl
Base
(°C)
(RP/SP)
1
2
3
4
NEt3
ꢀ
ꢀ
ꢀ
rt
5
4
7
8
22
18
0
10:1
11:1
n.a.
NEt2
Clc
Clc
NEt2
NEt2
NEt2
60
rt
Figure 2. X-ray structure of compound 3a (ORTEP drawing showing
50% probability ellipsoids).
reflux
78
18:1
a Yields correspond to the mixture of diastereomers. b Diastereomeric
ratios were determined by 31P NMR. c Racemic.
Scheme 2. Synthesis and Failed Attempt at Ring Opening of
N-Methyl-2-tert-butyl-1,3,2-oxazaphospholidine 4
Table 2. Nucleophilic Ring Opening of 2
instead of MeLi (Table 2, entry 4). Although the Grignard
reagent was less reactive than methyl lithium, it provided a
cleaner reaction. This enabled increasing the reaction tempera-
ture up to 100 °C in toluene to afford 3a in an excellent yield
(91%) and with total selectivity.13
We next explored the scope of this ring-opening process using
different alkyl and aryl Grignard reagents. We were pleased to
find that primary and even secondary alkylmagnesium reagents
provided excellent yields and total selectivity as determined by
1H NMR (Table 2, entries 5, 6, and 7). Furthermore, a reaction
with both alkynyl- and arylmagnesium reagents took place with
near to perfect yields and selectivity (Table 2, entries 8, 9, and
10). Finally, we tested two aluminum reagents. Although they
were also effective in this process, they provided compounds 3a
and 3b with lower selectivity than did the organomagnesium
reagents (Table 2, entries 11 and 12).
Temp
Yield
(%)b
Entry
R[MX]a
MeLid
MeLie
(°C)
drc
n.a.
Product
1
ꢀ78
40
0
3a
3a
3a
3a
3b
3c
3d
3e
3f
2
47
76
91
91
77
85
96
96
94
90
88
>96:4f
>96:4f
>99:1g
>96:4f
>96:4f
>96:4f
>96:4f
96:4
3
MeLi
40
4
MeMgBr
EtMgBr
BuMgCl
i-PrMgCl
H3CCCMgBr
PhMgBr
2-MeOPhMgBr
Me3Al
100
100
100
100
100
100
100
80
5
6
7
8
9
10
11
12
>96:4f
3g
3a
3b
93:7
Et3Al
100
90:10
Most unexpectedly, X-ray analysis of compound 3a (Figure 2)
showed that the phosphorus atom had the S configuration.14 Con-
sequently, the ring opening of 2 gave an inversion of configuration at
the phosphorus center. Moreover, X-ray analysis of 3f revealed that
both alkyl- and aryl-magnesium reagents proceed with the same
stereochemical pathway.15 To our knowledge, this behavior is
unprecedented, since the ring opening of oxazaphospholidines type
I (Scheme 1) usually occurs with retention of configuration.5 Jugꢀe
et al. has suggested that metal coordination of the LiꢀRreagenttothe
ring-oxygen atom facilitates the alkyl attack to phosphorus, leading to
a pentacoordinate phosphorus center that ultimately forces out the
oxygen leaving group.16 In the case of 2, we sought to clarify whether
the free NH group was accountable for the distinct stereochemical
behavior that we had observed. To check this hypothesis, we prepared
N-methyl oxazaphospholidine 4 and then submitted it to ring open-
ing with MeLi, MeMgBr, and AlMe3 (Scheme 2). Remarkably, under
the same reaction conditions used for 2, compound 4 did not
undergo ring opening, and the starting material was recovered. The
lack of reactivity of 4 confirmed that the free NH group is crucial for
opening the bulky oxazaphospholidine 2. Moreover, the requirement
of >2 equiv of the alkylating reagent for ring opening indicates that the
a Between 2.2 and 4.5 equiv of organometallic reagent were used. b Yield
corresponds to the mixture of diastereomers. c Determined by 1H NMR.
d Et2O was used as solvent. e THF was used as solvent. f A single isomer
1
was observed by H NMR. g The minor isomer was not detected by
HPLC analysis.
encumbrance. When the (1S,2R) isomer ((ꢀ)-1) was used as
starting material, the phosphorus center in 2 had the R
configuration.12
We then turned our attention to the ring opening of oxazaphos-
pholidine 2 with different organometallic reagents (Table 2).
The standard reaction conditions for the ring opening of N-
methyloxazaphospholidines employ an alkyllithium reagent at
low temperature (ꢀ78 °C).5 Attempts at the ring opening of 2
using 2 equiv of MeLi under these conditions failed to produce
the desired product (Table 2, entry 1). However, increasing the
reaction temperature to 40 °C and using toluene as solvent
enabled the preparation of 3a, isolated in 76% yield and with
complete stereoselectivity, as determined by 1H NMR (Table 2,
entry 3). Ring opening was further improved using MeMgBr
5741
dx.doi.org/10.1021/ja200988c |J. Am. Chem. Soc. 2011, 133, 5740–5743

Journal of the American Chemical Society
COMMUNICATION
Scheme 3. Mechanistic Hypothesis for the Ring Opening of 2
with Lithium, Magnesium, and Aluminum Reagents
Scheme 4. Hydrolytic Cleavage of Aryl Aminophosphines
Table 3. Reductive Cleavage of Ring-Opened Compounds 3
Scheme 5. Synthesis of Secondary Aminophosphine from 3a
Yield
Entry
S.M.
R
Product
R0
Me
(%)
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Me
Et
6a
6b
6c
6d
6e
6f
71a
78
71
71
81
Et
Bu
Bu
i-Pr
i-Pr
n-C3H7
Ph
enabled the synthesis of the ortho-methoxyphenylaminophosphine
6g, again in excellent yields and in optically pure form.
H3CCC
Ph
b
ꢀ
Compounds 3aꢀf can also be used as intermediates in
the synthesis of P-stereogenic secondary aminophosphines
(Scheme 5). To demonstrate this, we methylated compound 3a at
both its oxygen and nitrogen atoms to give 9 in quantitative yield.
Treatment of 9 with Li/NH3 afforded the secondary aminophos-
phine 10 in 79% yield and an optically pure form. As we have
previously reported, secondary aminophosphines are also valuable
building blocks for P-stereogenic aminodiphosphines.7
In summary, we have described a highly diastereoselective and
efficient synthesis of P-stereogenic bulky alkyl and aryl aminophos-
phines that relies on the ring opening of tert-butyl-oxazaphos-
pholidine 2. Attack of the organometallic reagent occurs with
inversion of configuration at the phosphorus center. This unprece-
dented reactivity of the bulky oxaphospholidine 2 is due to the
presence of a free NH functionality that facilitates the attack of the
organometallic reagent. These findings greatly expand the potential
of oxazaphospholidine chemistry in the field of P* synthesis and
provide a practical, stereoselective and high-yielding route to chiral
aminophosphines, key intermediates to useful PnP ligands. Further
experimental and theoretical studies to elucidate the mechanism of
the ring opening are underway in our laboratories and will be
reported in due course.
a GC analysis on a chiral stationary phase revealed >99% ee. b Birch-type
reduction at the phenyl group attached to phosphorus was obtained as
described in refs 7 and 19.
NꢀH group is deprotonated. These facts suggest that the resulting
Nꢀ group coordinates the organometallic reagent and guides its
attack at phosphorus (Scheme 3). In this scenario, the alkyl transfer
occurs from the opposite side of the leaving group enabling an
SN2@P-type process.17,18
With the open-chain products 3aꢀf in hand, we assayed
reductive cleavage at the benzylic position to attain the desired
borane-protected P*-aminophosphines (Table 3). Reduction of
recrystallized 3a with lithium in ammonia in the presence of tert-
BuOH afforded the desired compound 6a in 71% yield and 99% ee
as determined by chiral GC. This indicated that the reaction is
stereospecific. It is worth noting that 6a is the key intermediate in the
synthesis of the ligand MaxPHOS. Following the same procedure,
compounds 3b, 3c, and 3d were successfully reduced to provide the
corresponding novel P*-aminophosphines (Table 3, entries 2, 3, and
4, respectively). Dissolved metal reduction of 3e, which bears a
1-propynyl group, afforded the fully reduced tert-butyl-n-propyl-
aminophosphine 6e in 81% yield (Table 3, entry 5). Finally,
reduction of the phenyl-containing intermediate 3f did not produce
the desired aryl-tert-butylaminophosphine but instead gave the
corresponding Birch-reduction product, as we and others have
recently described (Table 3, entry 6).7,19
To overcome this limitation, we developed an alternative hydro-
lytic route to the desired arylaminophosphines (Scheme 4). Starting
from 3f, mesylate formation and elimination using a MeONa/MeOH
mixture gave the corresponding iminophosphine 8f in excellent
yields. Finally, acidic hydrolysis of 8f in EtOH/H2O afforded the
desired arylaminophosphine 6f in excellent yield. Chiral HPLC
analysis revealed that no racemization at the P center had occurred
during the hydrolytic cleavage, since 6f was isolated in >99% ee as
determined by chiral HPLC. The same procedure, starting from 3g,
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures,
b
compound characterization data and spectra for all new com-
pounds, and CIF files for compounds 2, 3a, and 3f. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
antoni.riera@irbbarcelona.org; xavier.verdaguer@irbbarcelona.org
5742
dx.doi.org/10.1021/ja200988c |J. Am. Chem. Soc. 2011, 133, 5740–5743

Journal of the American Chemical Society
COMMUNICATION
’ ACKNOWLEDGMENT
Z.-H.; Magiera, D.; Senanayake, C. H. Angew. Chem., Int. Ed. 2003,
42, 2032.
(10) Bulk price for both enantiomers is $800/kg.
MICINN (CTQ2008-00763/BQU), the Generalitat de Cata-
lunya (2009SGR 00901), IRB Barcelona, and Enantia are
thanked for financial support. T.L. thanks the Generalitat de
Catalunya for a fellowship.
(11) Richter, W. J. Chem. Ber. 1984, 2328–2336.
(12) The absolute configuration has been reliably determined by the
anomalous dispersion method, Flack = ꢀ0.03(5). See Supporting
Information for crystallographic data of compound 2.
(13) The minor diastereomer was not detected when analyzing the
reaction crude by HPLC.
’ REFERENCES
(14) The absolute configuration has been reliably determined by the
anomalous dispersion method, Flack = ꢀ0.02(5). See Supporting
Information for crystallographic data of compound 3a.
(15) The absolute configuration has been reliably determined by the
anomalous dispersion method, Flack = ꢀ0.03(5). See Supporting
Information for crystallographic data of compound 3f.
(16) Jugꢀe, S.; Stephan, M.; Merdꢁes, R.; Genet, J. P.; Halut-Desportes,
S. J. Chem. Soc., Chem. Commun. 1993, 531–533.
(17) For an example of nucleophilic substitution at phosphorus in
tertiary phosphines, see: Kyba, E. P. J. Am. Chem. Soc. 1975,
97, 2554–2555.
(18) (a) van Bochove, M. A.; Swart, M.; Bickelhaupt, F. M. J. Am.
Chem. Soc. 2006, 128, 10738–10744. (b) van Bochove, M. A.; Swart, M.;
Bickelhaupt, F. M. ChemPhysChem 2007, 8, 2452–2463. (c) van
Bochove, M. A.; Swart, M.; Bickelhaupt, F. M. Phys. Chem. Chem. Phys.
2009, 11, 259–267.
(1) For recent examples of the use of bulky P* ligands, see: (a) Geng,
H.; Zhang, W.; Chen, J.; Hiou, G.; Zhou, L.; Zou, Y.; Wu, W.; Zhang, X.
Angew. Chem., Int. Ed. 2009, 48, 6052–6054. (b) Noh, D.; Chea, H.; Ju,
J.; Yun, J. Angew. Chem., Int. Ed. 2009, 48, 6062–6064. (c) Taylor, A.;
Altman, R. A.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 9900–9901.
(d) Shibata, Y.; Tanaka, K. J. Am. Chem. Soc. 2009, 131, 12552–12553.
(e) Chen, I.; Yin, L.; Itano, W.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2009, 131, 11664–11665. (f) Tamura, K.; Sugiya, M.; Yoshida, K.;
Yanagisawa, A.; Imamoto, T. Org. Lett. 2010, 12, 4400–4403. (g) Jiang,
X.; Minnaard, A. J.; Hessen, B.; Feringa, B. L.; Duchateau, A. L. L.;
Andrien, J. G. O.; Boogers, J. A. F.; de Vries, J. G. Org. Lett. 2003,
5, 1503–1506. (h) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.; Tan, Z.;
Tang, W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.; Yee, N. K.;
Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600–7601. (i)
Yanagisawa, A.; Takeshita, S.; Izumi, Y.; Yoshida, K. J. Am. Chem. Soc.
2010, 132, 5328–5329. (j) Ito, H.; Okura, T.; Matsuura, K.; Sawamura,
M. Angew. Chem., Int. Ed. 2010, 49, 560–563. (k) Tang, W.; Capacci,
A. G.; White, A.; Ma, S.; Rodriguez, S.; Qu, B.; Savoie, J.; Patel, N. D.;
Wei, X.; Haddad, N.; Grinberg, N.; Yee, N. K.; Krishnamurthy, D.;
Senanayake, C. H. Org. Lett. 2010, 12, 1104–1107. (l) Hoge, G.; Wu, H.;
Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao, J. J. Am. Chem. Soc. 2004,
126, 5966–5967. (m) Landert, H.; Spindler, F.; Wyss, A.; Blaser, H.;
Pugin, B.; Ribourduoille, Y.; Gschwend, B.; Ramalingam, B.; Pfaltz, A.
Angew. Chem., Int. Ed. 2010, 49, 6873–6876.
(19) Stankevic, M.; Pietrusiewicz, K. M. Tetrahedron Lett. 2009,
50, 7093–7095.
(2) (a) Phosphorus Ligands in Asymmetric Catalysis; B€orner, A., Ed.;
Wiley-WCH: Weinheim, 2008; Vol. IꢀIII. (b) Grabulosa, A.; Granell, J.;
Muller, G. Coord. Chem. Rev. 2007, 251, 25–90.
(3) Muci, A. R.; Campos, K. R.; Evans, D. A. J. Am. Chem. Soc. 1995,
117, 9075–9076.
(4) (a) Imamoto, T.; Watanabe, J.; Wada, Y.; Masuda, H.; Yamada,
H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi, K. J. Am. Chem. Soc. 1998,
120, 1635–1636. (b) Yamanoi, Y.; Imamoto, T. J. Org. Chem. 1999,
64, 2988–2989. (c) Sugiya, M.; Nohira, H. Bull. Chem. Soc. Jpn. 2000,
73, 705–712. (d) Tang, W.; Zhang, X. Angew. Chem., Int. Ed. 2002,
41, 1612–1614. (e) Crꢀepy, K. V. L.; Imamoto, T. Top. Curr. Chem. 2003,
No. 229, 1–40.
(5) (a) Jugꢀe, S.; Genet, J. P. Tetrahedron Lett. 1989, 30, 2783–2786.
(b) Kaloun, E. B.; Merdꢁes, R.; Gen^et, J.-P.; Uziel, J.; Jugꢀe, S. J. Organomet.
Chem. 1997, 529, 455–463. (c) Bauduin, C.; Moulin, D.; Kaloun, E. B.;
Darcel, C; Jugꢀe, S. J. Org. Chem. 2003, 68, 4293–4301. (d) Leyris, A.;
Nuel, D.; Giordano, L.; Achard, M.; Buono, G. Tetrahedron Lett. 2005,
46, 8677–8680. (e) den Heeten, R.; Swennenhuis, B. H. G.; van
Leeuwen, P. W. N. M.; de Vries, J. G.; Kamer, P. C. J. Angew. Chem.,
Int. Ed. 2008, 47, 6602–6605. (f) Zupancic, B.; Mohar, B.; Stephan, M.
Org. Lett. 2010, 12, 3022–3025 and references therein.
(6) (a) Brown, J. M.; Laing, J. C. P. J. Organomet. Chem. 1997,
529, 435–444. (b) Maienza, F.; Spindler, F.; Thommen, M.; Pugin, B.;
Malan, C.; Mezzetti, A. J. Org. Chem. 2002, 67, 5239–5249. (c) Mohar,
B.; Modec, B.; Sterk, D.; Stephan, M. M. S. J. Org. Chem. 2007,
72, 8010–8018.
(7) Revꢀes, M.; Ferrer, C.; Leꢀon, T.; Doran, S.; Etayo, P.; Vidal-Ferran,
A.; Riera, A.; Verdaguer, X. Angew. Chem., Int. Ed. 2010, 49, 9452–9455.
(8) Ramꢀon, R.; Martín-Gago, P.; Verdaguer, X.; Macias, M. J.;
Martin-Malpartida, P.; Fernꢀandez-Carneado, J.; Gomez-Caminals, M.;
Ponsati, B.; Lꢀopez-Ruiz, P.; Cortꢀes, M. A.; Colꢀas, B.; Riera, A. Chem-
BioChem 2011, 12, 625–632.
(9) (a) Han, Z.; Krishnamurthy, D.; Grover, P.; Fang, Q. K.;
Senanayake, C. H. J. Am. Chem. Soc. 2002, 124, 7880–7881. (b) Han
Z.; Krishnamurthy, D.; Grover, P.; Wilkinson, H. S.; Fang, Q. K.; Su, X.;Lu,
5743
dx.doi.org/10.1021/ja200988c |J. Am. Chem. Soc. 2011, 133, 5740–5743