Application of phosphorylated reagents derived from N,N'-di-[(S)-α- phenylethyl]-cyclohexane-1,2-diamines in the determination of the enantiomeric purity of chiral alcohols

Article abstract of DOI:10.1016/S0957-4166(98)00219-5

The synthesis of two new N-[(S)-α-phenylethyl] substituted P-chloro- 1,3-diazaphospholidines derived from C₂-symmetric trans-1,2- diaminocyclohexanes, and their application as chiral derivatizing agents in the determination of enantiomeric puri

Full text of DOI:10.1016/S0957-4166(98)00219-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2093–2099
Application of phosphorylated reagents derived from
N,N0-di-[(S)-α-phenylethyl]-cyclohexane-1,2-diamines in the
determination of the enantiomeric purity of chiral alcohols
Cecilia Anaya de Parrodi,a,∗ Gloria E. Moreno,b Leticia Quintero b,∗ and Eusebio Juaristi c,∗
aDepartamento de Química y Biología, Universidad de las Américas-Puebla, Santa Catarina Mártir, Cholula, 72820 Puebla,
México
bCentro de Investigación de la Facultad de Ciencias Químicas, Universidad Autónoma de Puebla, Puebla, 72570 Puebla,
México
cDepartamento de Química, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, 07000
México D. F.
Received 15 April 1998; accepted 21 May 1998
Abstract
The synthesis of two new N-[(S)-α-phenylethyl]substituted P-chloro-1,3-diazaphospholidines derived from C2-
symmetric trans-1,2-diaminocyclohexanes, and their application as chiral derivatizing agents in the determination
of enantiomeric purities of chiral alcohols by means of 31P NMR spectroscopy is described. © 1998 Elsevier
Science Ltd. All rights reserved.
1. Introduction
trans-1,2-Diaminocyclohexane derivatives have been shown to be useful chiral reagents and lig-
ands for catalysis, with applications in asymmetric synthesis.1 By the same token, (R)- and (S)-α-
phenylethylamine are simple, yet powerful stereodifferentiating auxiliaries in organic transformations.2
In view of the continuing need for the development of chiral derivatizing agents for the determination
of enantiomeric purities,3 and with consideration of the high sensitivity provided by 31P NMR spectro-
scopic methods in this endeavour,4 we were attracted by the report of Alexakis and coworkers,5 who pre-
sented convincing evidence for diazaphospholidine A, prepared from (R,R)-N,N0-dimethylcyclohexane-
1,2-diamine and hexamethylphosphorous triamide, as an excellent reagent for the determination of the
enantiomeric excess of chiral alcohols.6 (Eq. 1).
∗
Corresponding authors. E-mail: anaya@mail.pue.udlap.mx, lquintero@siu.cen.buap.mx and juaristi@chem.cinvestav.mx
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00219-5

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(1)
Among the most useful characteristics of reagent A are its very rapid reaction with most alcohols, and
the substantial differences in 31P NMR chemical shifts (∆δ) exhibited by the resulting diastereoisomeric
phosphonamides.5
The present paper describes the preparation and examination of the related P-chloro-1,3-diaza-
phospholidines (1R,2R,10S,100S)-1 and (1S,2S,10S,100S)-1 as chiral derivatizing agents in the determin-
ation of enantiomeric purity. It was anticipated that the presence of the α-phenylethyl substituents in these
reagents could lead to even larger (∆δ) values in the 31P NMR spectra of the derived phosphonamides.
2. Results and discussion
The preparation of diastereoisomeric diazaphospholidines 1 was accomplished according to
the synthetic route outlined in Scheme 1. (1R,2R,10S)- and (1S,2S,10S)-2-[N-(α-Phenylethyl)-
amino]cyclohexanols 2 were prepared by aminolysis of cyclohexene oxide according to the literature
procedure.7,8 The resulting diastereoisomeric mixture of (1R,2R,10S)- and (1S,2S,10S)-2 was mesylated
according to standard procedures,9 to furnish the expected N-[(S)-α-phenylethyl]cyclohexene aziridine
(1R,2S,10S)-3 as generated via spontaneous intramolecular mesylate displacement.10 trans-Cyclohexane-
1,2-diamines (1R,2R,10S,100S)- and (1S,2S,10S,100S)-4 were then prepared via the opening of aziridine 3
with (S)-α-phenylethylamine,11 catalyzed with lithium perchlorate.12,13 The separation of diastereomeric
diamines 4 was accomplished by fractional crystallization, and assignment of the absolute configuration
at the cyclohexane stereogenic centers was possible from an X-ray diffraction analysis carried out on the
(1S,2S,10S,100S)-isomer.14
Once separated, (1R,2R,10S,100S)-1 and (1S,2S,10S,100S)-1 were examined as chiral derivatizing agents
via their corresponding P-chloro-1,3-diazaphospholidines, which were formed directly in the NMR tube
employed for 31P NMR analysis. To this end, 1,2-diamine 4 in CDCl3 solvent (lock signal) was treated
with one equivalent of PCl3 in CH2Cl2 to give the required phospholidine 1. The exocyclic P–Cl bond is
readily cleaved,5 so derivatization is carried out by addition of 0.8 equivalents of the racemic alcohol to
afford phosphonamides 5, whose 31P NMR spectra were then recorded (Tables 1 and 2).
The NMR spectroscopic observations summarized in Tables 1 and 2 reveal the effectiveness of
chlorophospholidines 1 for the determination of enantiomeric ratios in mixtures of chiral alcohols.
Indeed, with one exception (entry 2 in Table 1) the diastereomeric pair of derivatives 5 was always

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2095
Scheme 1.
observed, and integration of the signals corresponded to the expected 50:50ꢀ2% ratio; i.e., no kinetic
resolution takes place.
P-Alkoxy-1,3-diazaphosphonamides 5, in particular those derived from the all-(S)-isomer (Table 2),
generally gave larger values of the difference of chemical shifts (∆δ) than those observed with the N-
methyl analogues developed by Alexakis and coworkers.5 For example, with 2-butanol (entries 1 in
Tables 1 and 2) diastereomeric phosphonamides derived from A (Eq. 1) gave ∆δ=0.27 ppm, while the
corresponding ∆δ values in diastereomeric 5 are 0.38 and 1.07 ppm. Furthermore, the largest value of
the difference of chemical shift (∆δ 3.7 ppm) obtained with A,5 can be compared with the largest value
obtained with (1S,2S,10S,100S)-1, ∆δ 6.34 ppm (entry 5, Table 2).
1
In our hands, H and 13C NMR spectra of diastereomeric phosphonamides 5 were not useful for the
determination of the isomeric composition, owing to insufficient differences in chemical shifts with these
nuclei (1H and 13C). In this regard, the half-height line width of 31P signals in the NMR spectra of 5 is
26.5ꢀ0.5 Hz.
Diastereomeric phosphonamides 5 can be detected by TLC (eluent: petroleum ether:EtOAc=95:5)
but have not been isolated and purified. Treatment with sulfur powder affords the corresponding
thiophosphonamides, which are known to be stable derivatives.5
In summary, reagents 1 incorporating N-(α-phenylethyl) substituents, are convenient chiral derivatiz-
ing agents for the determination of the enantiomeric purity of chiral alcohols. The quantitative and fast
P–Cl bond cleavage upon alcoholysis allows phosphonamide formation directly in the NMR tube prior
to measurement. Very large differences in the 31P NMR chemical shifts (∆δ) for the diastereoisomeric
phosphonamides were observed, allowing accurate integration and quantitative determination of the
diastereoisomeric ratios.

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Table 1
Evaluation of chiral derivatizing agent (1R,2R,10S,100S)-1 with various chiral alcohols
3. Experimental section
Melting points were taken using a Mel-Temp apparatus and are uncorrected. 1H and 13C NMR spectra
were measured at 200 MHz on a Varian Gemini-200 spectrometer, with tetramethylsilane (TMS) as
an internal standard. 31P NMR were recorded on a 400 MHz JEOL spectrometer. Chemical shifts
are given as δ values (ppm) and coupling constants J are given in Hz. Optical rotations [α]D were
measured at ambient temperature in 0.1 dm cells, using a Perkin–Elmer 241 spectrophotometer. FT-
IR spectra were recorded on a GBC instrument. Mass spectra were recorded on a Hewlett Packard
5989A spectrometer. Microanalyses were performed by Galbraith Laboratories, Inc., Knoxville, TN.
All reagents were purchased from Aldrich Chemical Co.

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Table 2
Evaluation of chiral derivatizing agent (1S,2S,10S,100S)-1 with various chiral alcohols
3.1. N-[(S)-α-Phenylethyl]cyclohexene aziridine, (1R,2S,10S)-3
In a two-necked flask provided with an addition funnel, condenser and a magnetic stirrer, under
argon, the diastereoisomeric mixture of (1R,2R,10S)- and (1S,2S,10S)-2 (2.2 g, 10.0 mmol)7 and dry
triethylamine (5 ml) were dissolved in dry CH2Cl2 (20 ml). To the ice-cooled mixture was added
dropwise a mixture of methanesulfonyl chloride (1.1 g, 10.0 mmol) in dry CH2Cl2 (5 ml). The reaction
mixture was stirred at 0°C until no more β-aminoalcohols (1R,2R,10S)- and (1S,2S,10S)-2 were detected
by TLC (ca. 24 h), and then the in situ mesylated compounds were allowed to warm to rt for 8 h to give the
desired product. The cool reaction mixture was poured over ice cooled 1 N HCl (30 ml) and the organic
layer was extracted with CH2Cl2 (3×25 ml). The combined organic extracts were dried over Na2SO4,
filtered and concentrated in vacuo. The crude products were purified by flash chromatography (petroleum
ether:ethyl acetate=30:1) to provide aziridine (1R,2S,10S)-3, as a yellow liquid. Vacuum distillation (5

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mmHg, 80°C) afforded pure (1R,2S,10S)-3 (1.4 g, 70.0% yield) as a colorless liquid, [α]D=−42.4 (c=1.4,
CHCl3). 1H NMR (CDCl3): δ 1.2 (m, 2H), 1.4 (d, 3H, J=7), 1.5 (m, 3H), 1.8 (m, 5H, J=7), 2.5 (q, 1H,
J=7), 7.2–7.5 (m, 5H). 13C NMR (CDCl3): δ 21.1, 21.2, 24.1, 25.1, 25.4, 38.4, 38.7, 70.4, 127.0, 127.2,
128.6, 146.1. Anal. calcd C14H19N (201.3) C 83.54%, H 9.51%; found C 83.32%, H 9.75%.
3.2. (1R,2R,10S,100S)- and (1S,2S,10S,100S)-N,N0-Di(α-phenylethyl)-1,2-cyclohexanediamine, (1R,2R,
10S,100S)- and (1S,2S,10S,100S)-4
In a dry two-necked flask provided with an addition funnel, condenser and magnetic stirrer, was placed
with stirring and under argon an equimolar mixture of N-[(S)-α-phenylethyl]cyclohexene aziridine
(1R,2S,10S)-3 (2.0 g, 10 mmol) and anhydrous lithium perchlorate (1.1 g, 10 mmol) in freshly dried
acetonitrile (ca. 10 ml) until complete dissolution of the lithium salt. The reaction mixture was cooled
in an ice–water bath to 0°C before the dropwise addition of (S)-α-phenylethylamine (10 mmol). The
resulting solution was then heated to reflux until the reaction was complete, ca. 30 h. Water (25 ml) was
added to the reaction mixture and the organic phase was extracted with CH2Cl2 (3×25 ml). The combined
organic extracts were dried over anhydrous Na2SO4, filtered and concentrated in vacuo affording a
mixture of the 1,2-diamines, (1R,2R,10S,100S)- and (1S,2S,10S,100S)-4, in a 1:2 rat0i0o. The mixture of 1,2-
diamines was treated with an ethereal solution of hydrochloric acid. (1R,2R,10S,1 S)-4 Dihydrochloride
was separated by fractional crystallization from AcOEt:MeOH (3:1). (1S,2S,10S,100S)-4 Dihydrochloride
was crystallized from petroleum ether:CH2Cl2 (3:1).
3.3. 1,2-Diamine (1R,2R,10S,100S)-4 dihydrochloride
1
White crystals, mp 205.0°C, [α]D=−80.5 (c=1.0, CHCl3). H NMR (CDCl3): δ 1.1 (m, 2H); 1.2
(m, 2H), 1.6 (d, 6H), 1.7 (m, 2H), 2.1 (m, 2H), 2.5 (m, 2H), 4.1 (q, 2H), 5.9 (broad, 4H), 7.3–7.5
(m, 10H). 13C NMR (CDCl3): δ 23.6, 24.6, 29.8, 55.0, 58.0, 127.1, 128.4, 129.2, 141.3. Anal. calcd
C22H30N2·2HCl·MeOH (427.4): C 64.63%, H 8.48%; found C 64.98%, H 8.70%.
Free 1,2-diamine (1R,2R,10S,100S)-4, colorless liquid, 0.58 g (18.0% yield), [α]D=−120.0 (c=1.0,
CHCl3). 1H NMR (CDCl3): δ 0.8 (m, 2H), 1.0 (t, 2H), 1.3 (d, 6H, J=6), 1.6 (d, 2H), 1.8 (broad, 2H), 1.9
(m, 2H), 2.0 (m, 2H), 3.9 (q, 2H, J=6), 7.2–7.5 (m, 10H). 13C NMR (CDCl3): δ 25.3, 26.1, 31.8, 54.8,
58.5, 127.2, 128.8, 128.9, 146.4.
3.4. 1,2-Diamine (1S,2S,10S,100S)-4 dihydrochloride
1
White crystals mp 198–200°C, [α]D=+45.0 (c=1.0, CHCl3). H NMR (CDCl3): δ 1.1 (m, 2H), 1.2
(m, 2H), 1.4 (m, 2H), 1.5 (m, 2H), 1.6 (d, 6H), 2.6 (m, 2H), 3.9 (q, 2H), 5.0 (broad, 4H), 7.3–7.4
(m, 10H). 13C NMR (CDCl3): δ 22.5, 24.1, 30.0, 57.4, 60.1, 127.1, 129.1, 129.2, 141.0. Anal. calcd
C22H30N2·2HCl·H2O (413.4): C 63.91%, H 8.28%; found C 64.05%, H 8.29%.
Free 1,2-diamine (1S,2S,10S,100S)-4, colorless liquid, 1.7 g (53.0% yield), [α]D=+40.5 (c=1.0, CHCl3).
1H NMR (CDCl3): δ 0.9 (m, 2H), 1.1 (t, 2H), 1.3 (d, 6H, J=6), 1.6 (d, 2H), 1.8 (m, 2H), 1.9 (broad, 2H),
2.3 (m, 2H), 3.8 (q, 2H, J=6), 7.2–7.5 (m, 10H). 13C NMR (CDCl3): δ 24.5, 25.5, 33.1, 56.6, 60.9, 127.0,
127.1, 128.9, 148.0.

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3.5. Procedure for chiral alcohol derivatization with (1R,2R,10S,100S)- and (1S,2S,10S,100S)-4 to give
diastereomeric 5
In an NMR tube are placed with vigorous stirring 51 mg (0.16 mmol) of free 1,2-diamine
(1R,2R,10S,100S)- or (1S,2S,10S,100S)-4, 0.5 ml of CDCl3, 119 mg (0.80 mmol) of diethylaniline, and 23
mg (0.16 mmol) of PCl3 previously dissolved in 50 µl of CH2Cl2, affording the chlorodiazaphospholidine
(1R,2R,10S,100S)- or (1S,2S,10S,100S)-1. (1R,2R,10S,100S)-1 31P NMR (CDCl3): δ 176.7. (1S,2S,10S,100S)-
1
31P NMR (CDCl3): δ 179.5. Immediately after 0.13 mmol of racemic secondary alcohol is added
(Tables 1 and 2) and the resulting mixture is stirred for 30 minutes before 31P NMR spectra are recorded
at rt.
Acknowledgements
We thank CONACYT for financial support (Projects No. L0006E and 3983-E and Grant No. 91276).
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