Menthyloxycarbonyl phosphonium chlorides: New derivatives for determining the enantiomeric excess of chiral tertiary phosphines

Article abstract of DOI:10.1016/j.tetlet.2013.07.155

The direct alkoxycarbonylation of tertiary phosphines with alkyl chloroformates has been examined and the products characterised by NMR and X-ray crystallographic analysis. The derivatisation of representative chiral tertiary phosphines with enantiopure m

Full text of DOI:10.1016/j.tetlet.2013.07.155

Accepted Manuscript
Menthyloxycarbonyl phosphonium chlorides: new derivatives for determining
the enantiomeric excess of chiral tertiary phosphines
A. Christopher Garner, Roy C. Hodgkinson, John D. Wallis
PII:
S0040-4039(13)01335-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.155
TETL 43355
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31 July 2013
Please cite this article as: , Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.155
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Menthyloxycarbonyl phosphonium
chlorides: new derivatives for determining
the enantiomeric excess of chiral tertiary
phosphines
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A. Christopher Garner,* Roy C. Hodgkinson, John D. Wallis

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Menthyloxycarbonyl phosphonium chlorides: new derivatives for
determining the enantiomeric excess of chiral tertiary phosphines
A. Christopher Garner,* Roy C. Hodgkinson, John D. Wallis
School of Science and Technology, Nottingham Trent University, Clifton Lane, Nottingham, UK. E-mail: christopher.garner@ntu.ac.uk
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The direct alkoxycarbonylation of tertiary phosphines with alkyl chloroformates has been
examined and the products characterised by NMR and X-ray crystallographic analysis. The
derivatisation of representative chiral tertiary phosphines with enantiopure menthyl
chloroformate allows the determination of the enantiomeric excess of scalemic mixtures by 31
NMR spectroscopic analysis.
P
Available online
Keywords:
Oxycarbonyl phosphonium salts
ee determination
2009 Elsevier Ltd. All rights reserved.
Menthyl chloroformate
Phosphine
Phosphorus NMR
Chiral phosphines continue to enjoy popularity as the ligand of
choice in a wide variety of asymmetric catalytic processes and the
asymmetric synthesis of these compounds is an area of significant
research.1 In the absence of other functionality, methods for the
determination of the enantiomeric excess of chiral synthetic
phosphines are limited and they are often determined by HPLC of
phosphines or protected phosphines over chiral stationary phases.2
This method offers advantages of high sensitivity and accuracy, but
at the expense of time-consuming method development, and these
methods may not be amenable to the rapid evaluation of
enantiomeric excesses.
NMR techniques, involving both chiral solvating agents and
derivatisation methods, are well established for compounds
containing amine and hydroxyl functional groups,3 but such methods
are not applicable to the many chiral ligands utilised in asymmetric
transition metal catalysis containing only phosphine functionality.
Despite the ability to readily measure 31P NMR spectra, NMR based
methods for assessing chiral phosphines4 are limited to utilising
chiral transition metal complexes5 and some related examples using
chiral liquid crystal phase experiments.6
Figure 1.
Preliminary studies revealed that alkoxycarbonyl phosphonium
chlorides could be prepared from the reaction of phosphines with
moderately sterically hindered alkyl chloroformates. Hence,
treatment of dimethylphenyl phosphine (1) with iso-propyl or iso-
butyl chloroformate in toluene gave precipitates which were
collected directly via filtration to afford alkoxycarbonyl
phosphonium chlorides 2 and 3 as amorphous solids in excellent
yields of 80% and 97%, respectively (Scheme 1).13
Acyl phosphonium ions7 (A, Figure 1) are generally considered to be
unstable compounds,8 implicated as important reactive intermediates
in nucleophilic catalysis9 and other synthetic processes.10 The related
oxycarbonyl phosphonium ions (B, Figure 1) may be expected to
exhibit greater stability, however these compounds have not been
well studied or characterised to date. In 1937, Jensen reported the
adducts from the reaction of triethylphosphine and a number of
chloroformates,11 however subsequent reports of such species have
been sparse.12 The direct generation of oxycarbonyl phosphonium
ions from chloroformates is a synthetically attractive process and we
wished to explore this chemistry and develop a simple 31P NMR
spectroscopic method to assay the enantiomeric purity of tertiary
phosphines.
Scheme 1. Reagents and conditions: (i) iso-propyl-, iso-butyl- , (S)-
(+)-pantolactone-, (-)-borneol- or (S)-(+)-menthyl chloroformate,
toluene, room temperature.

2
Tetrahedron
13C NMR spectroscopic data were consistent with the expected P-
C=O connectivity and both compounds exhibited a doublet for the
carbonyl carbon peak with 1JPC couplings of 135 and 136 Hz,
respectively, and proved to be bench-stable for a period of several
weeks. In further support of this structural assignment, the structure
of 2 was confirmed by X-ray crystallographic analysis of the
corresponding PF6 salt at 120 K (Figure 2).14
Scheme 2. Reagents and conditions: (i) (-)-(1R,2S,5R)-menthyl
chloroformate, toluene.
The 13C NMR spectrum of the mixture was consistent with the
expected oxycarbonyl phosphonium chlorides and both compounds
exhibited a carbonyl carbon peak with a 1JPC coupling of 119 Hz.
The 13C and 1H NMR spectra also revealed contamination of the
sample with excess of menthyl chloroformate. These data
demonstrate that this reagent fulfills the requirements for a chiral
derivatising agent for NMR analysis in that: (1) salt formation is
rapid, (2) no kinetic resolution occurs in the formation of the
diastereoisomeric salts, and (3) there is a significant, baseline
resolved, difference in chemical shifts between the 31P NMR signals
of the derived salts.
Having demonstrated menthyl chloroformate as an effective chiral
derivatising agent for a P-chirogenic tertiary phosphine containing
no other functionality, the application of this method to a
representative chiral tertiary mono-phosphine 10, exhibiting
backbone chirality was explored.
Figure 2. Ball and stick representation of the X-ray crystal structure
of the PF6 salt of 2 (counter ion omitted for clarity).15
In structure 2 the P+-C(=O) bond is 1.855(2) Å long, being
significantly longer than the three P+-C bonds to the phenyl and
methyl groups [1.775(2) - 1.782(2) Å]. At the carbonyl carbon the
widest angle is between the two O atoms [129.1(2)o] and the
smallest between the alkoxy O and the P atom [111.37(16)o]. The
only related structures known are those of the frustrated lone pair
complexes of carbon dioxide with a phosphine and borane, which
show a longer P-C(=O) bond (1.893-1.900 Å ).16
Having established the rapid and clean formation of these adducts,
our investigation then turned to realising the potential of this reaction
for the assay of the enantiomeric purity of tertiary phosphines
utilising a chiral chloroformate as the derivatising agent.
Initially, the reactivity of the achiral tertiary phosphine, phenyl
dimethyl phosphine (1) towards chiral chloroformates was examined.
The addition of phosphine 1 to a toluene solution of (S)-pantolactone
chloroformate17 afforded the corresponding phosphonium chloride 4
as an unstable oil, while similar reactions with (-)-borneol and (S)-
(+)-menthol derived chloroformates17 afforded phosphonium
chlorides 5 and 6 as amorphous solids in 72% and 71% isolated
yields, respectively (Scheme 1).18
Given that menthyl chloroformate is cheap and commercially
available in both enantiomeric forms,19 it was chosen for further
investigation as a chiral derivatising agent. Initially, the preparation
of a menthyl oxycarbonyl phosphonium chloride salt of a P-
chirogenic tertiary phosphine was examined. Treatment of a racemic
mixture of iso-propyl methyl phenylphosphine 720 (0.2 M solution in
CDCl3) with a small excess of (1R,2S,5R)-menthyl chloroformate
(1.1 equivalents, 0.5 M solution in CDCl3) afforded a 1:1 mixture of
(RP,1R,2S,5R)- and (SP,1R,2S,5R)-menthyl oxycarbonyl-(iso-
propyl-methyl-phenyl)phosphonium chlorides 8 and 9 (Scheme 2).
Examination of the 31P {1H} NMR spectrum showed complete
conversion of the starting material into two baseline resolved singlet
peaks of equal intensity (P = 30.4 and 31.4 ppm,  = 1.0 ppm).
Phospholane 10 is commercially available in both enantiomeric
forms, but not as a racemate, and it was convenient to determine the
enantiodiscriminating capacity of the chiral derivatising agent by
treating the enantiopure substrate with racemic menthyl
chloroformate.
Hence, in an NMR tube, a small excess of racemic menthyl
chloroformate17 (1.1 equivalents, 0.5 M solution in CDCl3) was
added to (S,S)-phospholane 10 in CDCl3 (0.2 M solution in CDCl3)
and the 31P NMR spectrum recorded after 30 minutes. Examination
of this spectrum revealed that all the starting phosphine had been
consumed and showed two baseline resolved singlet peaks of near
equal area (52:48, P = 57.6 and 56.4 ppm, 1.2 ppm)
corresponding to (S,S)-phosphine/(R)-menthyl oxycarbonyl adduct
11 and (S,S)-phosphine/(S)-menthyl oxycarbonyl adduct 12,
respectively (Scheme 3).21 Examination of the 1H and 13C NMR
spectra of the mixture supported the formation of the two
diastereoisomeric phosphonium salts and also revealed an excess of
menthyl chloroformate.

3
6. For enantiodiscrimination of chiral phosphine oxides and boranes, see:
(a) Rivard, M.; Guillen, F.; Fiaud, J-C.; Aroulanda C.; Lesot, P. Tetrahedron:
Asymmetry, 2003, 14, 1141-52; For chiral phosphonium salts, see: Meddour,
A.; Uziel, J.; Courtie J.; Juge, S. Tetrahedron: Asymmetry, 2006, 17, 1424-29.
7. For a review of acyl phosphonium and ammonium species, see: (a)
Kolesinska, B. Cent. Eur. J. Chem., 2010, 8, 1147-71; For early reports, see:
(b) Yakshin, V. V.; Sokal'skaya, L. I. Zh. Obshch. Khim., 1973, 43, 440; (c)
Lukashev, N. V.; Artyushin, O. I.; Lazhko, E. I.; Tafeenko, V. A.; Kazankova
M. A.; Lutsenko, I. F. Zh. Obshch. Khim., 1988, 58, 316-327. (d) Thamm R.;
Fluck, E. Z. Naturforsch. Pt B, 1982, 37B, 965-74; (e) Gololobov, Y. G.;
Pinchuk, V. A.; Thoennessen H.; Jones P.G.; Schmutzler, R. Phosphorus,
Sulfur Silicon Relat. Elem, 1996, 115, 19-37.
8. Isolated salts are reported to be very hygroscopic but stable in the absence
of moisture, see reference 7(b).
9. For reviews, on phosphine-based nucleophilic catalysis, see: (a) Zhou, Z.;
Wang, Y.; Tang C. Curr. Org. Chem., 2011, 15, 4083-4107; (b) Marinetti,
A.; Voituriez, A. Synlett, 2010, 174-194; (c) Cowen, B. J.; Miller, S. J. Chem.
Soc. Rev., 2009, 38, 3102-3116; (d) Methot, J. L.; Roush, W. R.; Adv. Synth.
Calat., 2004, 346, 1035-1050.
10. For examples of acylated phosphines as stoichiometric intermediates, see:
(a) Maeda, H.; Maki T.; Ohmori, H. Tetrahedron Lett., 1995, 36, 2247-50; (b)
Maeda, H.; Okamoto, J.; Ohmori, H. Tetrahedron Lett., 1996, 37, 5381-84;
(c) Maeda, H.; Takahashi K.; Ohmori, H. Tetrahedron, 1998, 54, 12233-42;
(d) Maeda, H.; Huang, Y.; Hino, N.; Yamauchi Y.; Hidenobu, O. Chem.
Commun., 2000, 2307-8; (e) Maeda, H.; Hino, N.; Yamauchi, Y.; Ohmori, H.
Chem. Pharm. Bull., 2000, 48, 1196-99. See also: (f) Weiss, R.; Bess M.;
Huber S. M.; Heinemann, F. W. J. Am. Chem. Soc., 2008, 130, 4610-17.
11. Jensen, K. A. J. Prakt. Chem., 1937, 148, 101-106.
12. (a) Vedejs E.; Donde, Y. J. Am. Chem. Soc., 1997, 119, 9293-4; (b)
Uncharacterised oxycarbonyl phosphonium salts have been reported as
intermediates, see reference 10c. For an example of the related carbamoyl
phosphine boranes, see: (c) Imamoto, T.; Tamura, K.; Ogura, T.; Ikematsu,
Y.; Mayama D.; Sugiya, M. Tetrahedron: Asymmetry, 2010, 21, 1522-8.
13. General procedure for the preparation of phosphonium salts.
The phosphine was added to a solution of the chloroformate in toluene. This
mixture was stirred at room temperature for 30 min. The resulting precipitate
was collected by filtration and washed with toluene and dried to yield the
alkoxycarbonyl phosphonium salt.
Scheme 3. Reagents and conditions: CDCl3, room temperature.
Having demonstrated effective enantiodiscrimination, the
enantiomeric excess of scalemic mixtures of phospholanes (S,S)-10
and (R,R)-10 in ratios of 90:10 and 99:1 were determined by
derivatisation with (R)-menthyl chloroformate.22 These results
showed that a reliable measurement of enantiomeric excess of up to
98% could be obtained by this technique.
In conclusion, the utility of menthyl chloroformate as a cheap,
commercially available reagent for the determination of the
enantiomeric excess of representative chiral tertiary phosphines has
been demonstrated. This method is ideally suited to assessing the
enantiomeric excess of nucleophilic chiral phosphines for application
in organocatalysis and as ligands in transition metal catalysis, and
provides a convenient and simple alternative to complementary
chromatographic methods.
iso-Butoxycarbonyl dimethylphenylphosphium chloride (3)
Prepared using the general procedure, using dimethylphenyl phosphine (1)
(1.0 g, 1.0 mL, 7.2 mmol), iso-butyl chloroformate (1.18 g, 1.1 mL, 8.64
mmol) and toluene (2 mL), to yield phosphonium salt 3 (2.29 g, 97%) as a
white solid. Decomposition point: 95-97 oC; νmax cm-1: 2963, 2875, 1727,
Acknowledgements
i
1440, 1211, 962, 912; H (400 MHz, CDCl3) 0.88 (3H, s, Pr(Me)), 0.90 (3H,
i
i
The authors would like to thank the Leverhulme Trust for funding
Project Grant F/01 374/H (R.C.H.) and the EPSRC Mass
Spectrometry Service at Swansea University.
s, Pr(Me)), 2.05 (1H, hept, J = 7 Hz, Pr(CH)), 2.95 (6H, d, J = 15 Hz, P-
Me2), 4.23 (2H, dd, J = 6 and 1 Hz, CH2O), 7.61-7.66 (2H, m, Ph), 7.71-7.75
(1H, m, Ph), 7.88-7.94 (2H, m, Ph); C (100 MHz, CDCl3) 8.5 (2C, 1JPC = 55
3
Hz), 18.8 (2C), 27.5, 75.5 (d, JPC = 4 Hz), 117.5 (1JPC = 117 Hz), 130.2 (2C,
d, 2JPC = 14 Hz), 131.7 (2C, d, 3JPC = 10 Hz), 135.1 (d, 4JPC = 4 Hz), 163.2 (d,
1JPC = 136, Hz); P (161 MHz, CDCl3) +20.9. LRMS(ESI+): 239.1 ([M-Cl]+,
100%), 240.1 (14); HRMS (ESI+): 239.1193 ([M-Cl]+ C13H20O2P requires
239.1195).
References and notes
1. Phosphorus Ligands in Asymmetric Catalysis, Vol. 3 (Ed.: Borner A.),
Wiley-VCH, New York, 2008, 1175.
2. (a) Colby E. A.; Jamison, T. F., J. Org. Chem. 2003, 68, 156-166; (b)
Muci, A. R.;Campos, K. R.; Evans, D. A. J. Am. Chem. Soc., 1995, 117,
9075-76.
14. The PF6 salt of 2 was prepared by metathesis of the chloride of (iso-
propyl-oxycarbonyl) dimethylphenyl phosphonium chloride with sodium
hexafluorophosphate in acetone.
Crystal data for the PF6 salt of 2: C12H18O2P·PF6, Mr = 370.20, monoclinic, a
= 8.6809(3), b = 14.0685(5), c = 14.1748(5) Å, β = 105.488(4) o, V =
1668.27(10) Å3, Z = 4, P21/c, Dc = 1.47 g cm3,  = 0.322 mm1, T = 120 K,
3875 unique reflections, 3212 with F2 > 2, R(F, F2>2) = 0.051, Rw(F2, all
data) = 0.12. There are two orientations of the PF6- anion in the ratio 2:1.
Crystallographic data (excluding structure factors) have been deposited with
the Cambridge Crystallographic Data Centre as supplementary publication
number CCDC 931374. Copies of the data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44
(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
15. Molecular illustration was prepared with Mercury (Macrae, C.F.;
Edgington, P.R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler,
M.; van de Streek, J. J. Appl. Crystallogr., 2006, 39, 453-457) and POV-RAY
(Persistence of Vision Pty. Ltd. 2004. Persistence of Vision™ Raytrace,
Persistence of Vision Pty. Ltd., Williamstown, Victoria, Australia,
http://www.povray.org).
3. For a recent review, see: (a) Wenzel, T. J.; Chisholm, C. D. Prog. Nucl.
Magn. Reson. Spectrosc., 2011, 59, 1-63; (b) Wenzel, T. J. Discrimination of
Chiral Compounds Using NMR Spectroscopy, Wiley Interscience, Hoboken,
NJ, 2007; (c) Duddeck H.; Gomez, E. D. Chirality, 2009, 21, 51-68; (d)
Donnoli, M. I.; Superchi, S.; Rosini, C. Mini-Rev. Org. Chem., 2006, 3, 77-
92; (e) Blazewska, K. M.; Gadja, T. Tetrahedron: Asymmetry, 2009, 20,
1337-61.
4. In contrast, chiral phosphorus based reagents for derivatising amines and
alcohols exploit 31P NMR spectroscopy to assess ee, see: (a) Hulst, R.;
Kellogg R. M.; Feringa, B. L. Recl. Trav. Chim. Pay-B, 1995, 114, 115-138 ;
For recent examples, see: (b) Reiner, T.; Naraschewski, F. N.; ; Eppinger, J.
Tetrahedron: Asymmetry, 2009, 20, 362-67; (c) Gulea, M.; Kwiatkowska, M.;
Lyzwa, P.; Legay, R.; Gaumont A-C.; Kielbasinski, P. Tetrahedron:
Asymmetry, 2009, 20, 293-297; (d) Mastranzo, V. M.; Quintero L.; De
Parrodi, C. A. Chirality, 2007, 19, 503-507.
16. (a) Sgro, M. J.; Domer, J.; Stephan, D. W. Chem. Commun., 2012, 48,
7253-55; (b) Momming, C.; Otten, E.; Kehr, G.; Frohlich, R.; Grimme, S.;
Stephan, D.W.; Erker, G. Angew. Chem. Int. Ed., 2009, 48, 6643-46.
17. Prepared from the corresponding alcohol and phosgene, see reference
12(a).
5. (a) Wild, S. B. Coord. Chem. Rev., 1997, 166, 291-311; (b) Dunina, V. V.;
Kuz'mina, L. G.; Kazakova, M. Y.; Grishin, Y. K.; Veits, Y. A.; Kazakova, E.
I. Tetrahedron: Asymmetry, 1997, 8, 2537-2545. (c) For references to similar
ee assays, see:, Ng, J. K. P;. Chen, S.; Tan, G. K.; Leung P-H. Tetrahedron:
Asymmetry, 2007, 18, 1163-69.

4
Tetrahedron
18. {[(1S,2R,5S)-2-iso-Propyl-5-methylcyclohexyloxy]carbonyl}-
dimethyl(phenyl) phosphonium chloride 6
Prepared using the general procedure, using dimethylphenyl phosphine (1)
(221 mg, 0.2 mL, 1.60 mmol), (1S,2R,5S)-menthyl chloroformate (350 mg,
1.60 mmol), and toluene (1 mL), to yield phosphonium salt 6 (403 mg, 71%)
as a white solid. Decomposition point: 188-190 oC; νmax cm-1: 2958, 1714,
1634, 1438, 1294, 1204, 1113, 960, 939, 906; H (400 MHz, CDCl3) 0.57
(3H, d, J = 7 Hz, iPr(Me)), 0.72 (3H, d, J = 7 Hz, iPr(Me)), 0.86 (3H, d, J = 7
Hz, Me), 0.91-1.02 (1H, m, CH), 1.10 (1H, q, J = 12 Hz, CH), 1.39-1.44 (3H,
m, CH), 1.61-1.65 (2H, m, CH), 2.13 (1H, app. d, J =12 Hz, CH), 2.87 (3H,
d, J =15 Hz, PMe), 2.94 (3H, d, J =15 Hz, PMe), 4.98 (1H, td, J = 11 and 5
Hz, CH), 7.58-7.62 (2H, m, ArH), 7.68-7.70 (1H, m, ArH), 7.86-7.92 (2H, m,
ArH); C (100 MHz, CDCl3) 8.0 (d, 1JPC = 28 Hz), 8.5 (d, 1JPC = 30 Hz), 15.9,
20.5, 21.7, 23.1, 26.2, 31.6, 33.7, 40.1, 47.0, 81.9, 117.5 (d, 1JPC = 72 Hz),
130.2 (2C, d, 2JPC = 13 Hz), 131.8 (2C, d, 3JPC = 9 Hz), 135.1 (d, 4JPC = 4 Hz),
163.5 (d, 1JPC = 142 Hz); P (161 MHz, CDCl3) +20.2. [α]20 = - 51.9 (c 0.01,
CHCl3). LRMS(ESI+): 321.2 ([M-Cl]+, 100%), 322.2 (22); HRMS (ESI+):
321.1981 ([M-Cl]+ C19H30O2P requires 321.1978).
19. Both the (R)- and (S)-enantiomers are available from Sigma Aldrich for
£2.50/g and £4.70/g, respectively.
20. Freshly prepared by deprotection of the borane complex of iso-
propylmethylphenyl phosphine with piperazinomethyl polystyrene.
21. These results reflect that no kinetic resolution has occurred in the
derivatisation process and any inconsistencies in the 31P NMR response
between diastereoisomeric products is negligible.
22. This experiment affords mixtures of adducts 11 and ent-12, which is
spectroscopically identical to 12. The 31P NMR chemical shifts of adducts 11
and ent-12 (and hence also adduct 12) were determined by separate
preparation from (R)-menthyl chloroformate and enantiopure phospholanes
(S,S)-10 and (R,R)-10, respectively.