Generation of chiral phosphonium dialkyl phosphite as a highly reactive P-Nucleophile: Application to Asymmetric Hydrophosphonylation of Aldehydes

Full text of DOI:10.1021/ja810043d

Published on Web 02/27/2009
Generation of Chiral Phosphonium Dialkyl Phosphite as a Highly Reactive
P-Nucleophile: Application to Asymmetric Hydrophosphonylation of Aldehydes
Daisuke Uraguchi, Takaki Ito, and Takashi Ooi*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya UniVersity, Nagoya 464-8603, Japan
Received December 24, 2008; E-mail: tooi@apchem.nagoya-u.ac.jp
Dialkyl phosphonates (dialkyl phosphites) are versatile chemical
reagents for the asymmetric construction of the phosphorus-carbon
(PsC) bond to synthesize chiral phosphonic acid derivatives,1,2
an important class of naturally occurring compounds with regard
to biological applications.3 There is now substantial agreement
among chemists that dialkyl phosphonates undergo phosphite-
phosphonate tautomerism and exist largely, if not entirely, in the
phosphonate form under neutral conditions (eq 1).4
phosphite as a highly reactive P-nucleophile. This phenomenon can
be successfully applied to the establishment of highly efficient and
enantioselective hydrophosphonylation of aldehydes.
First, we attempted to detect the reactive phosphite form as a
metallophosphite by using a low-temperature (-98 °C) 31P NMR
technique.14 When dimethyl phosphonate (3, pKa ) 18.4 in DMSO15)
was mixed with KOtBu (1 equiv, the pKa value of tBuOH is 32.2 in
DMSO16) in THF, the original signal at 9.5 ppm underwent a
significant downfield shift to 150.6 ppm (Figure 1a), which indicated
Thus, the chemistry of dialkyl phosphonates as a P-nucleophile is
rather complicated and influenced by the fact that the phosphite
tautomer, which is reactive and believed to be an actual nucleophilic
species in the bond-forming step, would only be present in ∼10-4 %.4a
For instance, this equilibrium would significantly affect the rate of
their addition reactions such as the simple hydrophosphonylation of
aldehydes,2,5 which particularly relies on electrophilic activation.6-10
In fact, previously elaborated chiral Lewis acid catalysts unfortunately
required relatively high loading and a long reaction time,7,8 except
for Yamamoto’s system wherein fluorinated phosphite was nicely
utilized as a reactive nucleophile.9 On the other hand, the activation
of phosphonate using an appropriate base is expected to be advanta-
geous for achieving sufficient reactivity because the equilibrium could
shift toward the reactive phosphite form under such conditions.
Although this possibility has been proposed and also implicated in
the effectiveness of chiral bifunctional catalysts7,8e including the
titanium-BINOL-cinchonidine complex introduced by You,10 no
experimental insight has yet been gained into the contribution of the
phosphite tautomer. Largely associated with this situation, the develop-
ment of an asymmetric catalysis of a chiral organic base for the
hydrophosphonylation of aldehydes remains almost unexplored ever
since Wynberg’s pioneering efforts using cinchona alkaloids.11 In
conjunction with our research program directed at the molecular design
and synthetic applications of a chiral tetraaminophosphonium salt
1·Cl,12 we envisaged that a spectroscopic evaluation of the behavior
Figure 1. Charts of the 31P NMR analysis at -98 °C.
the clean formation of the corresponding potassium salt
(MeO)2PO-K+.17 With this information in hand, we examined the
behavior of 3 in the presence of several representative organic bases.
The addition of DBU and TMG (pKa ) 16.6, 15.3 in THF,
respectively18,19) essentially caused no change in the spectrum,
probably because of their insufficient basicity. Even the use of BEMP
(pKa ) 27.6 in MeCN,20 –3.17 ppm) allowed the detection of anionic
species only by the signal of protonated BEMP at 21.0 ppm
(Figure 1b).21 Interestingly, however, an initial preparation of triami-
noiminophosphorane 2a (44.6 ppm) by treating 1a·Cl with KOtBu12
and subsequently mixing it with 3 resulted in the considerable
generation of anionic phosphite at 132.7 ppm, with concomitant
formation of the phosphonium counterion 1a (34.8 ppm) (Figure 1c).22
Note that the addition of an excess amount of 3 forced this acid-base
equilibrium to further shift toward the phosphonium phosphite, as
estimated by the decrease in the peak area of 2a with the increase in
that of 1a (Figure 1d).22 These observations suggest that the stability
of the anion would be important for enhancing its contribution to the
equilibrium and could be increased by the double H-bonding ability
of a countercation. In fact, treatment of 3 with TBD (pKa ) 19.4 in
THF18,19) afforded an intensive signal at 132.6 ppm, supporting our
interpretation (Figure 1e).
of dialkyl phosphonates under the influence of triaminoiminophos-
phorane (2),13 prepared in situ from 1·Cl and KOtBu,12 in comparison
with a series of strong organic bases would provide an ideal platform
for not only the elucidation of the phosphite-phosphonate tautomerism
but also a further revelation of the unique property of 1 as an anion-
recognizable chiral organic cation. Herein, we describe that the structure
of 1 capable of double H-bonding is suitable for stabilizing the
phosphite anion and imparting remarkable nucleophilicity to it, thereby
allowing a substantial generation of chiral phosphonium dialkyl
9
3836 J. AM. CHEM. SOC. 2009, 131, 3836–3837
10.1021/ja810043d CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
To elucidate the relationship between the base-dependent generation
of the requisite phosphite anion revealed by the NMR study and its
reactivity as a P-nucleophile, the catalytic activity of each organic base
was systematically examined in the hydrophosphonylation of benzal-
dehyde with 3 (Table 1). DBU and TMG showed similar reactivities,
In conclusion, the generation of chiral tetraaminophosphonium
phosphite has been detected by low-temperature NMR analysis, and
its synthetic relevance has been successfully demonstrated by its
application to the establishment of highly efficient and enantioselective
hydrophosphonylation of aldehydes. A comparison of 2 with repre-
sentative strong organic bases clearly shows that the molecular structure
of the cationic conjugate acid is a key element for substantial generation
of phosphite anions with an unprecedented level of nucleophilicity as
well as for rigorous stereocontrol. We believe that the present study
offers a general yet valuable framework for designing even more
superior chiral organic base catalysts.
Table 1. Dependence of Reaction Efficiency on Catalyst
Structurea
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research on Priority Areas “Advanced Molecular
Transformation of Carbon Resources” from MEXT and Grants of
JSPS for Scientific Research.
entry
catalyst
x
temp (°C)
time (h)
yieldb (%)
eec (%)
d
1
2
3
4
5
6
7
8
9
10
DBU
TMG
BEMP
TBD
2a
5
5
5
5
5
5
5
5
1
1
-20
-20
-78
-78
-78
-78
-78
-78
-78
-98
2
2
2
2
1
4
0.5
0.25
1
-
-
-
-
85
78
92
78
91
98
43 (45)
d
30 (33)
97
95
97
98
92
99
99
97
Supporting Information Available: Representative experimental
procedures and the details of the NMR study. This material is available
free of charge via the Internet at http://pubs.acs.org.
2b
2c
2d
2c
References
2c
4
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a See Supporting Information for details. b Isolated yield. c Determined by
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and the P-C bond formation proceeded slowly at -20 °C (entries 1,
2). In contrast, other bases, with which the existence of the phosphite
anion was detected, enabled a considerably faster reaction even at -78
°C (entries 3-5). Among these, in situ generated iminophosphorane
2a turned out to be the most reactive catalyst, and fortunately, the
desired R-hydroxy phosphonate was obtained with 85% ee.23 It should
be emphasized that an electronic effect of the aromatic substitutions
(Ar) was observed, particularly on its catalytic activity (entries 5-8).
While the reaction with 2b prepared from 1b possessing electron-
withdrawing functionality required 4 h for completion, large accelera-
tion was induced with increasing the electron density of the aryl
groups.24 The most enantioselective catalyst 2c was then used for
further experiments. Catalyst loading can be reduced to 1 mol%, and
the prominent reactivity of the phosphonium phosphite made it feasible
to perform the reaction at -98 °C, where the reaction product was
isolated almost quantitatively with excellent enantioselectivity (entries
9, 10).
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Dalgarno, S.; Ward, C. V.; Jiang, M.; Halcrow, M. A.; Kilner, C.; Thornton-
Pett, M.; Kee, T. P. C. R. Chimie 2004, 7, 809. (c) Saito, B.; Egami, H.;
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Finally, the generality of this 2c-catalyzed, highly efficient, and
enantioselective hydrophosphonylation was investigated. As listed
in Table 2, a series of aromatic aldehydes with substituents having
Table 2. Substrate Scopea
(14) See Supporting Information for details of the NMR experiment.
(15) Acidity of dialkyl phosphonates: Li, J.-N.; Liu, L.; Fu, Y.; Guo, Q.-X.
Tetrahedron 2006, 62, 4453.
time yieldb eec
(h) (%) (%) entry
time yieldb eec
(h) (%) (%)
entry
R1
R1
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1
2
3
4
5
o-F-C6H4
3
4
4
8
3
97 98
98 96
97 97
99 94
6
7
8
9
m-Br-C6H4
1-naphthyl
2-furyl
6.5 98 98
o-Me-C6H4
p-F-C6H4
3
2
96 99
90 98
90 96
99 91
d
(18) Rodima, T.; Kaljurand, I.; Pihl, A.; Ma¨emets, V.; Leito, I.; Koppel, I. A.
J. Org. Chem. 2002, 67, 1873, and references therein.
p-MeO-C6H4
p-Me-C6H4
(E)-PhCHdCH 13
91 96 10 Ph(CH2)2
6
(19) The pKa values of DBU and TBD in MeCN were 24.3 and 26.0,
respectively. See: Kaljurand, I.; Ku¨tt, A.; Soova¨li, L.; Rodima, T.; Ma¨emets,
V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019.
a-c See footnotes in Table 1. d The reaction was performed at -78 °C.
(20) Schwesinger, R.; Schlemper, H. Angew. Chem., Int. Ed. Engl. 1987, 26, 1167.
(21) The signal corresponding to the anionic species was detectable in DMF
at -60 °C. See Supporting Information for details.
different electronic properties were employable (entries 1-7). In
the case of 2-furylaldehyde, a smooth reaction and virtually
complete stereocontrol were achieved at -78 °C (entry 8).
Moreover, the present system tolerated R,ꢀ-unsaturated as well as
aliphatic aldehydes (entries 9, 10).
(22) The peak area of anionic phosphite corresponds to that of 1a.
(23) The origin of the higher efficiency of 2 than that of TBD is unclear at present.
(24) For the effect of the aromatic substituents of 2 on its ability of generating
a phosphite anion, see the 31P NMR analysis in the Supporting Information.
JA810043D
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J. AM. CHEM. SOC. VOL. 131, NO. 11, 2009 3837