Unexpected racemization of 2-hydroxymethylphenylphosphine oxides

Article abstract of DOI:10.1080/10426507.2012.744018

2-Hydroxymethylphenylphosphine oxides undergo partial racemization in the reaction with mesyl anhydride or mesyl chloride. A possible mechanism is discussed.

Full text of DOI:10.1080/10426507.2012.744018

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Unexpected Racemization of 2-
Hydroxymethylphenylphosphine Oxides
Sylwia Kaczmarczyk a , Lidia Madalińska a & Piotr Kiełbasiński a
a Department of Heteroorganic Chemistry , Centre of Molecular and
Macromolecular Studies, Polish Academy of Sciences , Sienkiewicza ,
Łódź , Poland
Accepted author version posted online: 29 Nov 2012.Published
online: 08 May 2013.
To cite this article: Sylwia Kaczmarczyk , Lidia Madalińska & Piotr Kiełbasiński (2013) Unexpected
Racemization of 2-Hydroxymethylphenylphosphine Oxides, Phosphorus, Sulfur, and Silicon and the
Related Elements, 188:1-3, 249-253, DOI: 10.1080/10426507.2012.744018
To link to this article: http://dx.doi.org/10.1080/10426507.2012.744018
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Phosphorus, Sulfur, and Silicon, 188:249–253, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.744018
UNEXPECTED RACEMIZATION
OF 2-HYDROXYMETHYLPHENYLPHOSPHINE
OXIDES
Sylwia Kaczmarczyk, Lidia Madalin´ska, and Piotr Kiełbasin´ski
Department of Heteroorganic Chemistry, Centre of Molecular and
Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza, Ło´dz´, Poland
GRAPHICAL ABSTRACT
Abstract 2-Hydroxymethylphenylphosphine oxides undergo partial racemization in the reac-
tion with mesyl anhydride or mesyl chloride. A possible mechanism is discussed.
Keywords 2-Hydroxymethylphenylphosphine oxides; racemization; hypervalent phospho-
ranes
INTRODUCTION
In the course of our studies on the application of enzymes in stereocontrolled trans-
formations of chiral heteroatom derivatives,1,2 we have recently focused our attention on
the synthesis of chiral heteroorganic ligands/catalysts for asymmetric synthesis. Previously,
we succeeded in the chemoenzymatic preparation of enantiopure tridentate sulfinyl ligands
3 (Scheme 1), which proved to be highly efficient catalysts in a number of stereoselective
C–C bond formation reactions (yields up to 98%, ee’s up to 98%).3,4
Received 15 September 2012; accepted 23 October 2012.
Financial support by the Polish Ministry of Science and Higher Education, Grant No N204 131140 (for
Piotr Kiełbasin´ski) and by CMMS PAS, grant 551-23 for PhD students (for S. Kaczmarczyk), is gratefully
acknowledged.
Address correspondence to Piotr Kiełbasin´ski, Department of Heteroorganic Chemistry, Centre of Molecular
and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Ło´dz´, Poland. E-mail:
piokiel@cbmm.lodz.pl
249

250
S. KACZMARCZYK ET AL.
Scheme 1
These results encouraged us to replace the stereogenic sulfinyl moiety in the ligands
with a variety of stereogenic phosphorus-containing groups in the hope of getting new
classes of chiral catalysts. Trying to accomplish this, we have recently succeeded in the
enzyme-promoted preparation of the desired precursors of such catalysts, i.e., each enan-
tiomer of 2-hydroxymethylphenyl(methyl)phenylphosphine oxide 4 and enantiomerically
pure (2-acetoxymethylphenyl)-(2’-hydroxymethylphenyl)phosphine oxide 7 (Scheme 2).5
Subsequently, we have tried to subject them to the transformations shown in Scheme 1.
Scheme 2

RACEMIZATION OF 2-HYDROXYMETHYLPHENYLPHOSPHINE OXIDES
251
RESULTS AND DISCUSSION
Unexpectedly, attempts to replace the hydroxyl group with an enantiomerically pure
chiral amine moiety via mesylation of enantiomerically pure 4 and 7 (Scheme 3) always
led to mixtures of diastereomers (which was not the case for the corresponding sulfinyl
analogs 2), which means that racemization must have taken place at one of the stages of
the synthesis.
Scheme 3
Although racemization of 7 could be easily explained by an acetyl group migration
between two hydroxyl groups (interestingly, such a migration was not observed in the
sulfinyl derivatives), no such explanation could be provided for the racemization of 4.
Since the optical rotations of the mesyl derivative 9 varied significantly depending on the
reaction conditions, it is the mesylation step that was considered to be responsible for the
racemization. Indeed, hydrolysis of 9, obtained from enantiomerically pure 4, proved that
the recovered substrate 4 was always partially racemized (Scheme 4).
Scheme 4
When mesyl chloride was used instead of mesyl anhydride, the corresponding chlo-
ride 11 was formed in addition to 9. The chloride was also partially racemized (Scheme 5).
However, silylation of 4, followed by hydrolysis of the silyl ether formed 12, gave
the recovered substrate with no racemization (Scheme 6).
The proposed mechanism of racemization is shown in Scheme 7. It is assumed
that the substrate 4 exists in an equilibrium with the hypervalent phosphorane 13.

252
S. KACZMARCZYK ET AL.
Scheme 5
Scheme 6
Such an assumption seems justified in the light of the fact that the analogous bis-(2-
hydroxymethylphenyl)phosphine oxide 6 undergoes spontaneous acid-catalyzed cycliza-
tion to the corresponding spirophosphorane 8 (formed also during the enzymatic acetylation
of 6, see Scheme 2).5 Mesylation of the P-hydroxy group in 13 to form 14, followed by the
attack of the mesylate anion at the α carbon atom and departure of the mesylate – a good
leaving group – results in the formation of the mesyl derivative 9 with inversion of config-
uration at phosphorus. In the same way, the formation of a partially racemized chloride 11
can be rationalized. A different result of the silylation reaction may be explained in terms
of weak leaving abilities of the silyloxy moiety.
Scheme 7
Attempts to prove the existence of 13 by recording 31P NMR spectra at low to ambient
temperature have been so far unsuccessful. No trace of the expected phosphoranes 13 or 14
could be detected. Further investigations are in progress.

RACEMIZATION OF 2-HYDROXYMETHYLPHENYLPHOSPHINE OXIDES
253
REFERENCES
1. Kiełbasin´ski, P.; Mikołajczyk, M. Chiral heteroatom-containing compounds. In: T. Matsuda
(Ed.), Future Directions in Biocatalysis; Elsevier: Amsterdam, 2007; pp. 159-203.
2. Kiełbasin´ski, P. Phosphorus Sulfur Silicon Relat. Elem. 2011, 186, 1104-1118.
3. Rachwalski, M.; Kwiatkowska, M.; Drabowicz, J.; Kłos, M.; Wieczorek, W. M.; Szyrej, M.;
Sieron´, L.; Kiełbasin´ski, P. Tetrahedron: Asymmetry 2008, 19, 2096-2101.
4. Rachwalski, M.; Les´niak, S.; Kiełbasin´ski, P. Tetrahedron: Asymmetry 2011, 22, 1325-1327 and
references therein.
5. Kaczmarczyk, S.; Kwiatkowska, M.; Madalin´ska, L.; Barbachowska, A.; Rachwalski, M.;
Błaszczyk, J.; Sieron´, L.; Kiełbasin´ski, P. Adv. Synth. Catal. 2011, 353, 2446-2454.