The Hydroxyalkyl Moiety As a Protecting Group for the Stereospecific Alkylation of Masked Secondary Phosphine-Boranes

Article abstract of DOI:10.1021/acs.orglett.5b03450

The synthesis of functionalized tertiary phosphine-boranes has been developed via a chemodivergent approach from readily accessible (hydroxymethyl) phosphine-boranes under mild conditions. O-Alkylation or decarbonylative P-alkylation product could be excl

Full text of DOI:10.1021/acs.orglett.5b03450

Letter
pubs.acs.org/OrgLett
The Hydroxyalkyl Moiety As a Protecting Group for the
Stereospecific Alkylation of Masked Secondary Phosphine-Boranes
Sebastien Lemouzy, Marion Jean, Laurent Giordano, Damien Herault,* and Gerard Buono*
́
́
́
Aix Marseille Universite,
́
Centrale Marseille, CNRS. iSm2 UMR 7313, 13397, Marseille, France
S
* Supporting Information
ABSTRACT: The synthesis of functionalized tertiary phosphine-boranes
has been developed via a chemodivergent approach from readily accessible
(hydroxymethyl) phosphine-boranes under mild conditions. O-Alkylation
or decarbonylative P-alkylation product could be exclusively obtained.
The P-alkylation reaction was found to proceed in moderate to very good
yields and very high enantiospecificity (es >95%) using a variety of alkyl
halides as electrophiles. The configurational stability of the sodium
phosphido-borane intermediate was also investigated and allowed a
deeper understanding of the reaction mechanism, furnishing secondary phosphine-boranes in moderate yield and enantiopurity.
n asymmetric catalysis, the use of chiral phosphines has
was the precipitation of one diastereomer of the lithiated
Iallowed a wide array of enantioselective transformations, phosphine-borane−sparteine complex at 25 °C, involving
probably a crystallization-induced process.7b The metal-
where the phosphine can be used either as a ligand for
transition metals1 or as an organocatalyst.2 While most of the
catalyzed dynamic kinetic resolution (DKR) of secondary
phosphine has also been investigated by Toste and Glueck
employing chiral ruthenium(II)8a,b or platinum(II)8c−e com-
plexes as catalysts. Indeed, using methyl (aryl) phosphine, the
authors described the preparation of a variety of chiral mono-
and bis-phosphines, which may then be quenched by BH3−
THF8a,b to yield the corresponding phosphine-boranes. More
recently, our group also developed the stereospecific alkylation
of enantioenriched tert-butyl (aryl) SPB using n-BuLi as a
base.9a
The reaction was found to occur with high conservation of
chiral information as long as the reaction was run at −78 °C.
Despite the remarkable efficiency of these methods, access to
aryl(alkyl) or diaryl SPBs remains difficult, especially for
enantioenriched compounds. Furthermore, although the
alkylation of configurationally stable dialkylphosphido-boranes
proceeds in high conservation of chiral information,9c the use of
aryl(alkyl) or diaryl SPBs can be problematic, as partial
racemization may occur following the alkylation temper-
ature.9a,b The use of excess organolithium compounds as a
base can also be prejudicial to the functional-group tolerance
and, thus, limits the use of functionalized electrophiles
(especially with carbonyl and halogen functional groups).
Recently, Hayashi described the palladium-catalyzed decarbon-
ylative arylation of (hydroxymethyl) phosphine sulfides in
excellent yields10 (Scheme 2). This retroaddition process had
already been observed earlier by Imamoto under basic and
thermal conditions,11 and more recently by Kann, who noted
the formation of racemic P-alkylation products.11c Pietrusie-
wicz12a and our group12b independently reported the stereo-
phosphine ligands used in asymmetric transition-metal catalysis
have a chiral backbone,3 the ones bearing the chiral center at
the phosphorus atom (P-stereogenic phosphines) have been
given much less attention, mostly due to their difficult
asymmetric synthesis. However, in some cases, P-stereogenic
phosphines feature better reactivity and/or selectivity than their
chiral-backboned counterparts.4 In this context, the synthesis of
P-stereogenic phosphines remains a challenging area of
research. Among the numerous methods leading to these
chiral compounds, functionalization of secondary phosphines
(SPs) or phosphine-boranes (SPBs) has been intensively
documented.5 More specifically, the design of P-stereogenic
tertiary phosphines through alkylation of P-chiral secondary
phosphines has been investigated6 (Scheme 1). Indeed, in the
late 1990s, Livinghouse described the sparteine-mediated
Dynamic Thermodynamic Resolution (DTR) of tert-butyl
(phenyl) SPB.7a The key point of the success of this method
Scheme 1. Asymmetric Alkylation of SPs and SPBs
Received: December 4, 2015
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.5b03450
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Scheme 2. Decarbonylations of (Hydroxymethyl)
Phosphorus Compound
Table 1. Optimization of the Reaction Conditions
specific reduction of α-hydroxyphosphine oxides under mild
conditions (Scheme 2).
When a carbon substituent was present on the α atom, we
observed an erosion of the diastereoselectivity, and some SPB
was isolated, along with the desired product.13b We also
attributed this fact to the possible retroaddition of the
hydroxyalkyl moiety under borane conditions. On the basis of
these observations, we turned our attention to the development
of a selective method for the decarbonylative alkylation of
hydroxymethyl phosphine-boranes, which are readily obtained
from H-adamantylphosphinates12b,13 (Scheme 3).
a
1a: er = 98:2. 1b: dr ∼1/1, er = 95:5 (both diastereomers). 1c: dr
=2.6/1, er (major dia) = 98.5:1.5 and er (minor dia) = 87:13.
Scheme 3. Envisioned Strategy for the Alkylation of Masked
SPBs
b
c
Determined by 31P NMR of the crude. DMF used as solvent.
d
e
Toluene used as solvent. 2-(Bromomethyl)pyridine hydrobromide
f
used as the electrophile. 3 equiv of NaH were used.
phosphido-borane intermediate in a more dissociating
solvent.11c Then, we turned our attention to the influence of
an alkoxide counterion using THF as solvent, and we observed
that the more the ion pair was separated, the more formation of
3a was favored (entries 2, 5−9). However, in the case of the
ammonium counterion, this was also accompanied by complete
racemization at the phosphorus atom (entry 9). This is
consistent with the formation of tert-butyl(phenyl)phosphido
borane, the configurational stability of which would depend on
the counterion.9b,14 It is worth noting that when using strongly
coordinated Mg or Li counterions (entries 5−6), the reaction
did not proceed at room temperature. When changing the
leaving group on the electrophile from Cl to Br, only product
2a was obtained in 80% isolated yield and 97:3 er (entry 10).
This is also in accordance with retroaddition of the
hydroxymethyl group, as when using a better leaving group
(X = Br), SN2 of the alkoxide on the alkyl halide (i.e.,
“Williamson”-type reaction) may kinetically outcompete the
retroaddition, thus allowing the selective formation of 2a.
Finally, we evaluated the influence of substitution on the α-
carbon on the selectivity. When a carbon substituent was
present (R= Me, Ph, entries 11−12), highly selective formation
of 3 was observed. Indeed, the use of methyl substituted
substrate 1b did furnish the desired product 3 without any
detectable amount of the O-alkylated product 2b, in a moderate
57% yield and high enantiomeric ratio (er = 93:7, entry 11).
The use of phenyl substituted substrate 1c gave similar
To optimize the conditions, we first screened the reaction
parameters, using compound 1a and o-(chloromethyl)pyridine
hydrochloride as an electrophile. When the reaction was run at
room temperature in THF and sodium hydride as the base, a
nearly 1:1 mixture of O-alkylation (2a) and decarbonylative P-
alkylation (3a) products was obtained in moderate yield (Table
1, entry 1). The formation of the latter product, resulting from
the retro-addition (i.e., decarbonylation) of the α-hydroxyalkyl-
phosphine-borane, was postulated to go through a sodium
phosphido-borane, which would then be trapped by the
electrophile in situ. When conducting the reaction on
enantioenriched starting material, we obtained 29% of 2a
with nearly fully conserved chiral information (er = 97.5:2.5,
entry 2) and 32% of 3a, also with minor loss of enantiomeric
excess (er = 95.5:4.5, entry 2). When looking at the influence of
the solvent, we observed that both polar and nonpolar solvents
favored the formation of 2a, although THF gave a nearly 1:1
mixture (entries 2−4).
In the case of DMF, the enantiomeric ratio of 2a decreased
to 83:17 (entry 3), suggesting racemization of the sodium
B
DOI: 10.1021/acs.orglett.5b03450
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reactivity and selectivity for the formation of 3 (36% yield, er =
93:7, entry 12). Finally, when the amount of sodium hydride
was raised to 3 equiv, the reaction of 1b gave the desired
compound 3a in a good 77% yield and very good enantiomeric
ratio (er = 95:5, entry 13). The substitution occurred
stereospecifically with retention of configuration at the
phosphorus atom, as the reaction of the other enantiomer
gave a similar yield and afforded the other enantiomer of the
product in nearly equal selectivity (entry 14). Unlike previously
reported protocols,11b the reactions did not lead to detectable
amounts of aldehyde reduction products by the sodium
phosphido-borane at operating temperature (assessed by the
absence of degradation products on 31P NMR). With these
optimized conditions in hand, we turned our attention to
expanding the scope of the decarbonylative P-alkylation of 1b,
using a variety of alkyl halides (Figure 1). When a variety of
benzylic halides were used (Figure 1, 3b−f), electron-donating
groups on the aromatic ring favored the reaction.
Scheme 4. Alkylation of Other Group Functionalized P-
Stereogenic Phosphine-Borane
the method, which allows the formation of enantioenriched
compounds which are challenging to access using reported
methods.8a To gain information on the reaction mechanism, we
used a proton source as the electrophile. The corresponding
SPB was obtained, and its enantiomeric ratio was assessed by
derivatizing to the corresponding P-Me compound9a (Scheme
5). When the deprotonation was run at 5 °C for 2 h, 45% of
Scheme 5. Configurational Stability of Sodium Phosphido-
Borane
SPB was isolated, and substantial racemization occurred. At
−10 °C, the reaction outcome was similar to the case for 5 °C,
although racemization was diminished. At −25 °C, the reaction
provided desired SPB in low yield (17%) but without erosion of
enantiomeric ratio, accounting for the higher stability of the
alkoxide at low temperature.
These results suggest that the sodium secondary phosphido-
borane seems to be configurationally more stable than its
lithium counterpart.9b,14 However, as detectable racemization
occurs despite the temperature, this does not explain the
complete stereospecifity observed during the alkylation process.
To rationalize this result, we propose a mechanism where the
sodium phosphido-borane would be generated in a catalytic
amount through the reaction time, and in the presence of the
electrophile, alkylation at the phosphorus atom would be faster
than racemization of the anionic intermediate (k2 ≫ krac,
Scheme 6). This mechanism would also explain complete
racemization using the ammonium counterion, as in this case of
k2 < krac. In the case of a less electrophilic secondary alkyl
halide, a diminished k2 value may account for the decrease in
stereoselectivity of the process (k2 ≈ krac).
Figure 1. Scope of the P-alkylation of compound 1b (dr ∼1/1, er =
95:5 (both diastereomers)).
The use of methyl iodide or allyl bromide also allowed the
formation of compounds 3h and 3i, respectively, in moderate
yields. In all these cases, minor to no erosion of the
stereochemical information was observed (es >95%).15 This
method also allowed the use of (chloromethyl) chiral oxazoline
as an electrophile, to furnish P, C stereogenic phosphine/
oxazoline preligands (compounds 3j) in moderate yields and
with high diastereo- and enantioselectivity. Again, no
racemization was observed on the product. Indeed, as a chiral
electrophile is used in this case, the racemization can be
assessed by comparing the er of the starting material with the dr
of the product, given that the carbon center does not undergo
racemization under these conditions. The use of less reactive
secondary alkyl bromide resulted in decreased reactivity and
selectivity using the optimized conditions (3k, 30% yield, er =
66.5:33.5). In this case, 36% of SPB (resulting from unreacted
sodium phosphido-borane) was also isolated.
Scheme 6. Proposed Reaction Scenario
Using methyl(phenyl) masked SPB 4a, the access to tertiary
phosphine 5a was enabled under the same conditions. In this
case, the reaction was found to be slower but occurred in
similar enantiospecificity, as only minor racemization occurred
(Scheme 4). This remarkable result testifies to the versatility of
C
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Letter
Commun. 2011, 47, 3239. For a review, see: Alayrac, C.; Lakhdar, S.;
Abdellah, I.; Gaumont, A.-C. Top. Curr. Chem. 2014, 361, 1.
(6) For the alkylation of racemic secondary phosphine-boranes, see:
Lebel, H.; Morin, S.; Paquet, V. Org. Lett. 2003, 5, 2347.
(7) (a) Wolfe, B.; Livinghouse, T. J. Am. Chem. Soc. 1998, 120, 5116.
For another example of CIAT involving phosphorus compounds, see:
(b) Kortmann, F. A.; Chang, M. C.; Otten, E.; Couzijn, E. P. A.; Lutz,
M.; Minnaard, A. J. Chem. Sci. 2014, 5, 1322.
(8) For ruthenium-catalyzed DKR of secondary phosphine, see:
(a) Chan, V. S.; Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am.
Chem. Soc. 2006, 128, 2786. (b) Chan, V. S.; Chiu, M.; Bergman, R.
G.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 6021. For platinum-
catalyzed DKR of secondary phosphine, see: (c) Scriban, C.; Glueck,
D. S. J. Am. Chem. Soc. 2006, 128, 2788. (d) Anderson, B. J.; Glueck,
D. S.; DiPasquale, A. G.; Rheingold, A. L. Organometallics 2008, 27,
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Rheingold, A. L. Organometallics 2010, 29, 378.
(9) (a) Gatineau, D.; Giordano, L.; Buono, G. J. Am. Chem. Soc.
2011, 133, 10728. (b) Our group recently conducted both theoretical
and experimental investigations on the racemization of the lithium
(tert-butyl) (phenyl) phosphido-borane intermediate: After 3 h at −15
°C in THF, this compound was found to largely racemize (19% ee
from 96% ee of starting SPB). “A contribution of the synthesis of P-
stereogenic phosphorus ligands for asymmetric catalysis: understanding the
inversion mechanism of lithium tert-butylphenylphosphido-borane” ,
In conclusion, we have synthesized a variety of functionalized
tertiary phosphine-boranes by a straightforward approach, with
moderate to good yields and excellent enantiomeric ratios. In
the present report, the configurational instability of alkyl(aryl)-
phosphido-boranes has been circumvented by catalytic in situ
generation of these reactive species under mild conditions via
decarbonylation of hydroxyalkylphosphine-borane. The syn-
thesis of these compounds has been achieved in a three-step
enantiospecific sequence, from readily available, enantiopure H-
adamantyl phosphinate (which are separated via semiprepar-
ative chiral HPLC).13a
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03450.
Experimental procedures, products characterization,
NMR spectra, and HPLC traces (PDF)
AUTHOR INFORMATION
■
́
Fortrie, R.; Gatineau, D.; A. Beal, Naubron, J.V.; Giordano, L.;
Corresponding Authors
Buono, G. SFC’ Lille, 2015, July 4th−9th. (c) Miura, T.; Yamada, H.;
Kikuchi, S.-I.; Imamoto, T. J. Org. Chem. 2000, 65, 1877.
(10) Hayashi, M.; Matsuura, T.; Tanaka, I.; Ohta, H.; Watanabe, Y.
Org. Lett. 2013, 15, 628.
*E-mail: damien.herault@centrale-marseille.fr.
*E-mail: gerard.buono@univ-amu.fr.
Notes
(11) (a) Nagata, K.; Matsukawa, S.; Imamoto, T. J. Org. Chem. 2000,
65, 4185. This phenomenon has also been highlighted later:
(b) Barozzino Consiglio, G.; Queval, P.; Harrison-Marchand, A.;
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
́
Mordini, A.; Lohier, J.-F.; Delacroix, O.; Gaumont, A.-C.; Gerard, H.;
■
Maddaluno, J.; Oulyadi, H. J. J. Am. Chem. Soc. 2011, 133, 6472.
(c) Johansson, M. J.; Berglund, S.; Hu, Y.; Andersson, K. H. O.; Kann,
N. ACS Comb. Sci. 2012, 14, 304.
The authors wish to thank Pr. A. Martinez, Dr. A. Tenaglia, and
Dr. K. Le Jeune for insightful discussions. Dr. N. Vanthuyne is
also gratefully acknowledged for performing both analytical and
preparative chiral HPLC. C. Chendo and Dr. V. Monnier are
thanked for high resolution mass spectroscopy measurements.
(12) (a) Sowa, S.; Stankevic, M.; Szmigielska, A.; Maluszynska, H.;
Koziol, A. E.; Pietrusiewicz, K. M. J. Org. Chem. 2015, 80, 1672.
(b) Lemouzy, S.; Nguyen, D.-H.; Camy, V.; Jean, M.; Gatineau, D.;
We are also grateful to MESR Aix-Marseille Universite
grant for S.L.).
́
(PhD
Giordano, L.; Naubron, J.-V.; Vanthuyne, N.; Her
Chem. - Eur. J. 2015, 21, 15607.
(13) (a) Gatineau, D.; Nguyen, D.-H.; Her
́
ault, D.; Buono, G.
́
ault, D.; Vanthuyne, N.;
Leclaire, J.; Giordano, L.; Buono, G. J. Org. Chem. 2015, 80, 4132. For
the generation of similar compounds via the methyl-phosphinate
strategy: (b) Leyris, A.; Bigeault, J.; Nuel, D.; Giordano, L.; Buono, G.
Tetrahedron Lett. 2007, 48, 5247. (c) Xu, Q.; Zhao, C.-Q.; Han, L.-B. J.
Am. Chem. Soc. 2008, 130, 12648. (d) Berger, O.; Montchamp, J.-L.
Angew. Chem., Int. Ed. 2013, 52, 11377.
(14) For a comparative study of lithium, sodium, and potassium
phosphido-boranes, see: (a) Izod, K.; Watson, J. M.; Clegg, W.;
Harrington, R. W. Inorg. Chem. 2013, 52, 1466. (b) Izod, K.; Watson,
J. M.; Clegg, W.; Harrington, R. W. Eur. J. Inorg. Chem. 2012, 2012,
1696−1701.
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