New chiral organophosphorus derivatizing agent for the determination of enantiomeric composition of chloro- and bromohydrins by 31P NMR spectroscopy

Article abstract of DOI:10.1016/S0957-4166(00)00062-8

The synthesis of a new chiral organophosphorus derivatizing agent prepared from (S)-2-anilinomethylpyrrolidine 1 and its successful use in the determination of enantiomeric composition of various halohydrins by ³¹P NMR spectroscopy is described

Full text of DOI:10.1016/S0957-4166(00)00062-8

Tetrahedron: Asymmetry 11 (2000) 1273±1278
New chiral organophosphorus derivatizing agent for the
determination of enantiomeric composition of chloro- and
31
bromohydrins by P NMR spectroscopy
Sebastien Reymond, Jean Michel Brunel and Gerard Buono*
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Ecole Nationale Superieure de Syntheses, de Procedes et d'Ingenierie Chimiques d'Aix Marseille, UMR CNRS 6516,
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Faculte de St Jerome, Av. Escadrille Normandie Niemen, 13397 Marseille, Cedex 20, France
Received 30 December 1999; accepted 11 February 2000
Abstract
The synthesis of a new chiral organophosphorus derivatizing agent prepared from (S)-2-anilino-
methylpyrrolidine 1 and its successful use in the determination of enantiomeric composition of various
halohydrins by 31P NMR spectroscopy is described. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The steadily growing use of enantiomerically pure materials as chiral building blocks, auxiliaries
or chiral ligands in numerous asymmetric syntheses1 demands fast and accurate methodology for
enantiomeric excess determination. Direct chromatographic analyses by GC or HPLC on chiral
stationary phases are ideal;2 however, this approach is still of limited generality and NMR
spectroscopy continues to be one of the most important methods to determine the enantiomeric
purity of chiral compounds.3 The utility of chiral derivatizing agents (CDAs) is well documented.
Two of the major problems associated with using CDAs are the observation and resolution of
appropriate signals in complex NMR spectra and the potential for asymmetric induction during
the preparation of the derivatized substrate. 31P NMR spectroscopy provides a very convenient
method for determining the enantiomeric excess of chiral phosphorus compounds because the
chemical shift dispersion is usually large and spectra are simple, when broad band proton
decoupling is applied.4,5 Thus, several organophosphorus chiral derivatizing agents as well as
* Corresponding author. Fax: 04-91-02-77-76; e-mail: buono@spi-chim.u-3mrs.fr
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00062-8

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achiral reagents for the analysis of chiral diols, amines or alcohols by 31P NMR have been
successfully used.6 Nevertheless, no convenient method for the measurement of the enantiomeric
composition of chiral halohydrins has been reported to date.
2. Results and discussion
We wish to report herein the ®rst, simple and very ecient 31P NMR method for the deter-
mination of enantiomeric purity of various chiral halohydrins based on the use of (2R,5S)-2-
dimethylamino-3-phenyl-1,3-diazaphosphabicyclo[3.3.01,5]octane 2 as new chiral derivatizing
agent. CDA 2 was easily prepared by the exchange reaction of tris(dimethylamino)phosphine and
(S)-2-anilinomethylpyrrolidine 1 in re¯uxing toluene (Scheme 1).
Scheme 1.
After completion of the reaction, CDA 2 was obtained as a single diastereomer in 78% yield
after distillation (anti-2, 31P NMR: ꢀ=116.9 ppm) and no trace of formation of the other dia-
stereomer syn-2 has been detected during the conversion.7 Furthermore, the structure of anti-2
has been fully characterized by 31P, 1H and 13C NMR spectroscopy and by X-ray structure analysis
of its corresponding borane complex adduct 38 (Fig. 1).
Figure 1.

S. Reymond et al. / Tetrahedron: Asymmetry 11 (2000) 1273±1278
1275
Scheme 2.
Table 1
CDA anti-2 is stable for weeks under inert atmosphere and not sensitive to moisture. For easy
handling, CDA anti-2 was stored as 0.5 M solution in toluene under argon and taken by syringe
when needed. The reaction between anti-2 and a racemic halohydrin was performed for 1.5 h in
re¯uxing toluene (Scheme 2).

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In all cases, the reaction is quantitative and leads to the exclusive synthesis of diastereomeric
compounds anti-4a and anti-4b without formation of any byproducts. Analysis of the crude mixture
of diastereomeric derivatives anti-4a and anti-4b was performed by 31P NMR spectroscopy in
CDCl3 and the results obtained with several halohydrins are summarized in Table 1. The
enantiomeric purity can be accurately measured by integration of the signals of the dia-
stereomeric phosphorus compounds and no kinetic resolution has been observed. Thus integration
of the racemic mixtures always corresponds to 50:50 (þ2).9
The diastereomeric pairs of derivatives exhibit typical NMR shift di€erences between 0.2
and 12.9 ppm. It is worth mentioning that the presence of a lone pair of electrons on phosphorus
tends to increase the chemical shift di€erence. Reagent anti-2 shows excellent reactivity toward
chlorohydrin and bromohydrin and in all these cases the enantiomeric purity can be accurately
measured. Moreover, it should be noted that CDA anti-2 can be used in slight excess, since its
chemical shift does not interfere with those of anti-4a and anti-4b. On the other hand, attempts to
determine the enantiomeric purity of various iodohydrins failed due to the high reactivity and
instability of these compounds, which lead only to the formation of numerous unidenti®ed
byproducts.
3. Conclusion
In conclusion, this procedure proved to be very ecient for an easy determination of the enantio-
meric purity of various chiral halohydrins. Studies are now in progress to extend this methodology
to the measurement of the enantiomeric purity of chiral azido alcohols and cyanohydrins.
4. Experimental
1H, 13C and 31P NMR spectra were recorded on Bruker AC100 and AC200 spectrometers in
CDCl3 as solvent. The chemical shifts (ppm) were determined relative to Me4Si (1H and 13C) and
85% H3PO4 (31P). Toluene was distilled from sodium/benzophenone ketyl immediately prior to
use. (S)-2-Anilinomethyl pyrrolidine 1 was prepared according to the procedure previously
reported in the literature.11
4.1. General procedure for the determination of the enantiomeric composition of chiral halohydrins
To a 25 mL two-necked round-bottomed ¯ask under argon atmosphere containing 30 mL of dry
toluene were dropped (S)-anilinomethylpyrrolidine 1 (2.64 g, 15 mmole) and tris(dimethylamino)-
phosphine (2.44 g, 15 mmole). The solution was heated to re¯ux and monitored by 31P NMR
spectroscopy. After 3 h, 1 mL of this 0.5 M solution was introduced into a small round-bottomed
¯ask under argon and 1 equivalent of the desired racemic chlorohydrins was added. This mixture
was re¯uxed for 1.5 h and then the solvent removed under vacuum. The residue was transferred
under argon into a 5 mm NMR tube along with 100 mL of CDCl3 and the 31P NMR spectrum
was recorded at 40.539 MHz.

S. Reymond et al. / Tetrahedron: Asymmetry 11 (2000) 1273±1278
1277
A sample of the crude derivatizing reagent anti-2 was subjected to fractional distillation under
reduced pressure for analysis: bp 148ꢀC/5Â10^3 mbar; ‰ꢁŠ2D0=^350.7 (c=1.13, CH2Cl2); 31P NMR
ꢀ 117.9; 1H NMR ꢀ 1.55±1.90 (m, 3H), 1.93±2.12 (m, 1H), 2.63 (s, 3H), 2.67 (s, 3H), 3.05±3.30 (m,
2H), 3.42±3.60 (m, 1H), 3.79 (t, J=7.0 Hz, 1H), 4.10±4.22 (m, 1H), 6.75±6.95 (m, 3H), 7.25 (t,
J=7.2 Hz, 2H); 13C NMR ꢀ 25.4 (d, J=4.1 Hz), 32.3, 36.7, 37.0, 50.4 (d, J=40.6 Hz), 54.4 (d,
J=4.7 Hz), 62.3 (d, J=7.3 Hz), 114.4 (d, J=11.6 Hz), 117.5, 128.9, 146.5 (d, J=14.4 Hz).
References
1. For example: (a) Martens, J. In Topics in Current Chemistry; Springer-Verlag: Berlin, 1984; Vol. 125, p. 165. (b)
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via Acetals and Enamines, Modern Synthetic Methods; Springer-Verlag: Berlin, 1986; pp. 125±129. (c) Decker, M.
Handbook of Chiral Chemicals; Ager, D. J., Ed.; Marcel Dekker: New York, 1999.
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Jinno, K., Ed.; Wiley-VCH: New York, 1997.
3. For a review of NMR methods, see: Parker, D. Chem. Rev. 1991, 91, 1441.
4. Verkade, J. G.; Quin, L. D. In Phosphorus 31 NMR Spectroscopy in Stereochemical Analysis: Organic Compounds
and Metal Complexes; VCH publishers, Inc.: Deer®eld Beach, Florida, 1987; Vol. 8.
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(c) Johnson, C. R.; Elliot, R. C.; Penning, T. D. J. Am. Chem. Soc. 1984, 106, 5019. (d) Feringa, B. L.; Smaardijk,
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Alexakis, A.; Mutti, S.; Mangeney, P. J. Org. Chem. 1992, 57, 1224. (h) Brunel, J. M.; Pardigon, O.; Ma€ei, M.;
Buono, G. Tetrahedron: Asymmetry 1992, 3, 1243. (i) Brunel, J. M.; Faure, B. Tetrahedron: Asymmetry 1995, 6,
2353. (j) Garner, C. M.; McWhorter, C.; Goerke, A. R. Tetrahedron Lett. 1997, 38, 7717. (k) Oshikawa, T.;
Kumagai, S.; Kobayashi, J.; Yamashita, M.; Seo, K. J. Chem. Soc., Chem. Commun. 1995, 435. (l) Hulst, R.;
Zijlstra, R. W. J.; Feringa, B. L.; de Vries, N. K.; Hoeve, W. T.; Wynberg, H. Tetrahedron Lett. 1993, 34, 1339.
(m) de Parrodi, C. A.; Moreno, G. E.; Quintero, L.; Juaristi, E. Tetrahedron: Asymmetry 1998, 9, 2093.
7. The notations of the syn and anti diastereomers are according to the methylene substituent of the pyrrolidine ring
with respect to the dimethylamino group. If they are on the same side of the ®ve-membered phosphorus-containing
ring, we call it a syn diastereomer; otherwise, it is an anti diastereomer. syn (unlike)=(2S,5S)-2-dimethylamino-3-
phenyl-1,3-diazaphosphabicyclo[3.3.01,5]octane and anti (like)=(2R,5S)-2-dimethylamino-3-phenyl-1,3-diaza-
phosphabicyclo[3.3.01,5]octane. (a) Cros, P.; Buono, G.;Pei€er, G.; Denis, D.; Mortreux, A.; Petit, F. New J.
Chem. 1987, 11, 573. (b) Brunel, J. M.; Chiodi, O.; Faure, B.; Fotiadu, F.; Buono, G. J. Organomet. Chem. 1997,
529, 285.
8. X-Ray structure analysis of 3: a plate white monocrystal of C13H23B1N3P, obtained by recrystallization in ethyl
acetate, with approximate dimensions 0.2Â0.2Â0.2 mm was mounted on a glass capillary. All the measurements
were made on a Rigaku di€ractometer with Mo-Ka radiation. Cell constants and the orientation matrix for data
collection were obtained from a least square re®nement using setting angles of 30 re¯ections in the range y=1±25ꢀ,
which corresponded to a monoclinic cell with dimensions: a=7.9186(2), b=9.6315(3), c=19.5340(7) A. For Z=5
and M=263.13, rmeas=1.25 g cm^3. The space group was determined to be P212121 from the systemic absences.
A total of 1503 re¯ections were collected at T=298 K. The standards were measured after every 158 re¯ections.
Selected bond distances (A): P1±N3, 1.648(1); P1±N4, 1.691(1); P1±N20, 1.632(1); P1±B19, 1.912(1); N3±C7,
1.479(2); N3±C13, 1.471(2); N4±C6, 1.418(2). Selected bond angles (ꢀ): N3±P1±N4, 92.5(1); N3±P1±N20,
109.4(1); N4±P1±N20, 108.1(1); P1±N3±C7, 114.7(1); P1±N3±C13, 125.5(1); C7±N3±C13, 111.6(1); P1±N4±C12,
111.9(1); P1±N4±C6, 123.9(1); C6±N4±C12, 119.8(1); P1±N20±C22, 124.5(1); P1±N20±C21, 121.2(1). CCDC
139376.
9. It is noteworthy that when the reaction time is not long enough, traces of syn-4a and syn-4b diastereomers can be
characterized. In this case, integration of the signals can still be correlated to the enantiomeric purity of the con-
sidered halohydrin.

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10. 31P NMR enantiomeric composition of racemic and enantiomerically enriched chlorohydrin 5. Enantiomeric
excess of 5 has also been determined by HPLC analysis on a Daicel Chiralcel OD-H column using hexane:i-PrOH
(90:10) as eluent (¯ow rate: 0.5 mL/min, 254 nm), tR: 13.46 min (minor); tS: 14.53 min (major).
11. Brunel, J. M.; Constantieux, T.; Buono, G. J. Org. Chem. 1999, 64, 8940.