P[(S,S,S)-PhHMeCNCH2CH2]3N: A new chiral 31P and 1H NMR spectroscopic reagent for the direct determination of ee values of chiral azides

Article abstract of DOI:10.1021/jo991304a

A facile and economical procedure for the synthesis of the C₃ chiral α-phenylethylamino trisaminoamine [(S,S,S)-PhHMeCNHCH₂CH₂]₃N in good yield is reported. The corresponding bicyclic proazaphosphatrane P[(S,S,S)- PhHMeCNCH₂CH₂]₃N, its bicyclic phosphoryl derivative, and its tricyclic P- protonated azaphosphatrane were also synthesized and characterized. It is found that the proazaphosphatrane is an efficient derivatizing agent for the direct determination of enantiomeric ratios of chiral azides by means of ³¹P and ¹H NMR spectroscopy.

Full text of DOI:10.1021/jo991304a

J . Org. Chem. 2000, 65, 701-706
701
1
P [(S,S,S)-P h HMeCNCH2CH2]3N: A New Ch ir a l 31P a n d H NMR
Sp ectr oscop ic Rea gen t for th e Dir ect Deter m in a tion of ee Va lu es
of Ch ir a l Azid es
Xiaodong Liu, Palanichamy Ilankumaran, Ilia A. Guzei, and J ohn G. Verkade*
Department of Chemistry, Iowa State University, Ames, Iowa 50011
Received August 17, 1999
A facile and economical procedure for the synthesis of the C3 chiral R-phenylethylamino trisami-
noamine [(S,S,S)-PhHMeCNHCH2CH2]3N in good yield is reported. The corresponding bicyclic
proazaphosphatrane P[(S,S,S)-PhHMeCNCH2CH2]3N, its bicyclic phosphoryl derivative, and its
tricyclic P-protonated azaphosphatrane were also synthesized and characterized. It is found that
the proazaphosphatrane is an efficient derivatizing agent for the direct determination of enantio-
1
meric ratios of chiral azides by means of 31P and H NMR spectroscopy.
In tr od u ction
and for the synthesis of a chiral fluorescence agent.13 As
a result of such applications, 1b has become commercially
available.14 Recently, we have discovered that 1b and 1c
are also efficient nonionic base catalysts for transesteri-
fication,15 â-nitroalkanol synthesis,16 Michael additions,17
â-hydroxy nitrile synthesis,18 and R,â-unsaturated nitrile
synthesis.19
In recent years we have been exploring the chemistry
of proazaphosphatranes such as 1a -f,1-6 some of which
are proving to be exceedingly potent catalysts, promoters
and strong nonionic bases that facilitate a variety of
useful organic transformations. For example, 1b is an
Chiral azides are important starting materials for the
synthesis of amines that are used as ligands, chiral
auxiliaries, pharmaceutical intermediates and building
blocks for the asymmetric synthesis of natural products.20
Although amines can be made in several ways, the azide
reduction method is often employed because it is facile
and well documented in the literature. Hence numerous
methods have been developed to synthesize azides in
enantiomeric forms.21 While a variety of approaches can
be taken to establish the enantiomeric purity of chiral
compounds, 31P NMR spectroscopic analysis is very
popular because of the attractive features of this nucleus.22
Several derivatizing agents have been developed for such
analyses of chiral alcohols, amines, and thiols.21e How-
ever, no derivatizing agent has been reported for the
efficient catalyst for the trimerization of aryl and alkyl
isocyanates that function as additives in the manufacture
of nylon-6,7 for the protective silylation of a wide variety
of sterically hindered and deactivated alcohols,8 and for
the acylation of such substrates.9 Proazaphosphatrane
1b is much stronger as a base than DBU,10 a commonly
used nonionic base in organic synthesis. Thus it is a
superior base for the synthesis of porphyrins,11 for the
dehydrohalogenation of secondary and tertiary halides,12
(13) Tang, J .-S.; Verkade, J . G. J . Org. Chem. 1996, 61, 8750.
(14) Strem Chemical Company. 7 Mulliken Way, Dexter Industrial
Park, Newburyport, MA 01950‚4098.
(15) Ilankumaran, P.; Verkade, J . G. J . Org. Chem. 1999, 64, 3086.
(16) Kisanga, P.; Verkade, J . G. J . Org. Chem. 1999, 64, 4298.
(17) Kisanga, P.; Ilankumaran, P.; Verkade, J . G. J . Org. Chem.,
submitted for publication.
(18) Kisanga, P.; McLeod, D.; D’Sa, B.; Verkade, J . G. J . Org. Chem.
1999, 64, 3090.
(19) D’Sa, B. A.; Kisanga, P.; Verkade, J . G. J . Org. Chem. 1998,
63, 3961.
(20) (a) J adhav, P. K.; Man, H, W. Tetrahedron Lett. 1996, 37, 1153.
(b) Lundquist, J . T.; Dix, T. A. Tetrahedron Lett. 1998, 39, 775. (c)
Corey, E. J .; Link, O. J . Am. Chem. Soc. 1992, 114, 1906. (d)
Skarzewski, J .; Gupta, A. Tetrahedron: Asymmetry 1997, 8, 1861. (e)
Brunner, H.; Bugler, H.; Nuber, B. Tetrahedron: Asymmetry 1995, 6,
1699. (f) Pini, D.; Iuliano, A.; Rosini, C.; Salvadori, P. Synthesis 1990,
1023.
* Ph: (515) 294-5023. Fax: (515) 294-0105. Email: jverkade@
iastate.edu.
(1) Verkade, J . G. Acc. Chem. Res. 1993, 26, 483.
(2) Verkade, J . G. Coord. Chem. Rev. 1994, 137, 233.
(3) Laramay, M. A. H.; Verkade, J . G. Z. Anorg. Allg. Chem. 1991,
605, 163.
(4) Schmidt, H.; Lensink, C.; Xi, S. K.; Verkade, J . G. Z. Anorg. Allg.
Chem. 1989, 578, 75.
(5) Wroblewski, A. E.; Pinkas, J .; Verkade, J . G. Main Group Chem.
1995, 1, 69.
(6) Liu, X.; Bai, Y.; Verkade, J . G. J . Organomet. Chem. 1999, 582,
16.
(7) Tang, J .-S.; Mohan, T.; Verkade, J . G. J . Org. Chem. 1994, 59,
4931.
(8) D’Sa, B.; Verkade, J . G. J . Am. Chem. Soc. 1996, 118, 832.
(9) D’Sa, Bosco A.; Verkade, J . G. J . Org. Chem. 1996, 61, 2963.
(10) Tang, J .-S.; Dopke, J .; Verkade, J . G. J . Am. Chem. Soc. 1993,
115, 5015.
(11) Tang, J .-S.; Verkade, J . G. J . Org. Chem. 1994, 59, 7793.
(12) Mohan, T.; Arumugam, S.; Wang, T.; J acobson, R. A.; Verkade,
J . G. Heteroat. Chem. 1996, 7, 455.
(21) (a) Mitrochkine, A. A.; Blain, I.; Bit, C.; Canlet, C.; Pierre, S.;
Courtieu, L.; Reglier, M. J . Org. Chem. 1997, 62, 6204. (b) Wu, M. H.;
J acobsen, E. N. Tetrahedron Lett. 1997, 38, 1699. (c) Trost, B. M.;
Pulley, S. R. Tetrahedron Lett. 1995, 36, 8737. (d) Besse, P.; Vescham-
bre, H.; Chenevert, R.; Dickman, M. Tetrahedron: Asymmetry 1994,
5, 1727. (e) Mischitz, M.; Faber, K. Tetrahedron Lett. 1994, 35, 81. (f)
Yamashita, H. Bull. Chem. Soc. J pn. 1988, 61, 1213. (g) Sato, T.;
Mizutani, T.; Okumura, Y.; Fujisawa, T. Tetrahedron Lett. 1989, 30,
3701. (h) Fadnavis, N. M.; Vadivel, S. K.; Sharfuddin, M.; Bhalerao,
U. T. Tetrahedron: Asymmetry 1997, 8, 4003. (i) Besse, P.; Veschambre,
H.; Dickman, M.; Chenevert, R. J . Org. Chem. 1994, 59, 8288.
10.1021/jo991304a CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/06/2000

702 J . Org. Chem., Vol. 65, No. 3, 2000
Liu et al.
Sch em e 1
aq
H
rt
Sch em e 2
direct determination of ee values of chiral azides by
1
means of 31P or H NMR spectroscopy.
We report herein a simple and efficient procedure for
the synthesis of the C3 chiral tripodal trisaminoamine 3
from commercially available inexpensive (S)-R-phenyl-
ethylamine 4, and the conversion of 3 to the correspond-
ing tricyclic azaphosphatrane 5(Cl), which can be depro-
tonated to the bicyclic proazaphosphatrane 6. The new
chiral nonionic base 6 is found to be an excellent tagging
agent for the direct determination of enantiomeric ex-
Sch em e 3
1
cesses of chiral azides using 31P and H NMR spectros-
copy. Upon oxidation, proazaphosphatrane 6 yields the
new C3 chiral phosphine oxide 7.
The synthesis of 11 involves nucleophilic ring opening
of the aziridine derived from 10.24 The drawbacks of this
synthesis are that the enantiopure amino alcohol used
as the starting material is expensive, and five steps are
required to obtain the desired product. Although (S)-
proline 12, the starting material for 13, is readily
available and inexpensive, seven synthetic steps are
required to obtain the final product, including two
condensations, three LiAlH4 reductions, a protection, and
a deprotection.25 By contrast, our route to 3 utilizes
inexpensive nitrilotriacetic acid 8 and (S)-(-)-R-phenyl-
ethylamine 4, only two steps are required to obtain the
final product, and the workup is quite simple, involving
only extraction and recrystallization. Moreover, the chiral
substituents can be readily replaced with other chiral
amines to tune the steric and electronic properties of the
proazaphosphatrane derivatives. Chiral 3 represents the
first example of a tripodal trisaminoamine in which the
chiral centers are not on the CH2CH2 moiety.
Syn th esis of 5(Cl), 6, a n d 7. The protonated aza-
phosphatrane 5(Cl) shown in Scheme 4 was synthesized
according to our established procedure for analogues of
this cation.3 However, formation of the tricyclic phos-
phatrane cage was not complete even after 1 week of
reaction. Thus only 75% conversion and a 62% isolated
yield were realized, which is considerably lower than the
95% conversion and 90% isolated yield for the analogous
synthesis of 2b. Raising the temperature to 60 °C gave
no improvement in either yield or purity of the product.
The main impurity is 3‚3HCl (see Experimental Section).
The formation of 3‚3HCl may be due to steric hindrance
of the R-phenylethyl groups, which could lower the rate
of cage formation relative to protonation of 3. In the
presence of KO-t-Bu, using THF as the solvent, 5(Cl) was
easily converted into proazaphosphatrane 6 in 82% yield
within 2 h. Oxidation of 6 with (Me3SiO)2 in benzene gave
7 in 90% yield.
Resu lts a n d Discu ssion
Syn th esis of 3. The synthetic route to the chiral
trisaminoamine 3 is shown in Scheme 1. In the first step,
nitrilotriacetic acid 8 is condensed with 3.0 equiv of 4 in
the presence of P(OPh)3 using pyridine as the solvent at
100 °C to give (S,S,S)-amidoamine 9. The synthesis of 9
reported earlier23 required tedious column chromatogra-
phy for purification, and the yield was only moderate
(65%). In the present work, spectroscopically pure 9 was
obtained in good yield (85%) upon recrystallization from
THF/hexanes at -20 °C. To ensure complete reduction
of all three amido groups of 9 to give optically pure 3, it
was necessary to carry out the second step in the
presence of excess LiAlH4 in refluxing THF for 5 days.
The yield of 3 (82%) is surprisingly good.
The only two tripodal chiral trisaminoamines that have
been reported possess chiral centers at the â carbon of
the tertiary nitrogen24,25 as shown in Schemes 2 and 3.
(22) (a) Cuvinot, D.; Mangeney, P.; Alexakis, A.; Normant, J .-F.;
Lellouche, J .-P. J . Org. Chem. 1989, 54, 2420. (b) Mangeney, P.;
Alexakis, A. Tetrahedron: Asymmetry 1993, 4, 2431. (c) Mangeney,
P.; Mutti, S.; P.; Alexakis, A. J . Org. Chem. 1992, 57, 1224. (d) Alexakis,
A.; Mutti, S.; P.; Mangeney, P. J . Org. Chem. 1994, 59, 3326. (e) Hulst,
R.; Koen de Vries, N.; Feringa, B. L Tetrahedron: Asymmetry 1994, 5,
669. (f) Devitt, P. G.; Mitchel, M. C.; Weetman, J . M.; Tayler, R. J .;
Kee, T. P. Tetrahedron: Asymmetry 1993, 4, 2431.
(23) Hammes, B. S.; Ramos-Maldonado, D.; Yap, G. P. A.; Liable-
Sands, L.; Rheingold, A. L.; Young, V. G.; Borovik, A. S. Inorg. Chem.
1997, 36, 3210.
(24) Cernerud, M.; Adolfsson, H.; Moberg, C. Tetrahedron: Asym-
metry 1998, 8, 2655.
(25) Ishihara, K.; Karumi, Y.; Kondo, S.; Yamamoto, H. J . Org.
Chem. 1998, 63, 5692.
Str u ctu r a l Con sid er a tion s. The computer drawing

Direct Determination of ee Values of Chiral Azides
J . Org. Chem., Vol. 65, No. 3, 2000 703
Sch em e 4
F igu r e 1. The molecular structure of cation 5 of 5(Cl) drawn
with the thermal ellipsoids at the 30% probability level. All
hydrogen atoms except the H atom on the phosphorus were
omitted for clarity.
F igu r e 3. The molecular structure of 7 drawn with the
thermal ellipsoids at the 30% probability level. The hydrogen
atoms have been omitted for clarity.
transannular N-P distance of 3.274 Å in 6 is only about
2% shorter than the van der Waals sum of 3.35 Å and is
very close to that of 1c5 (3.293 Å). The remaining bond
distances and angles are unremarkable (Table 4), and
the crystallographic data are collected in Table 3.
Like its nonchiral analogue 14,7 compound 7 (Figure
3) displays a nearly tetrahedral geometry around the
bridgehead P [av NeqPNeq ) 107.81(13)°] and a nearly
planar trigonal geometry around the bridgehead nitrogen
[av CNaxC ) 119.999(6)°], compared with 107.6(1)° and
118.9(2)°, respectively, in 14.7 The P-Nax distance in 7
F igu r e 2. The molecular structure of 6 drawn with the
thermal ellipsoids at the 30% probability level. The hydrogen
atoms have been omitted for clarity.
of 5(Cl) in Figure 1 features a P-Nax distance of
1.967(10) Å (which is 40% shorter than the sum of the P
and N van der Waals radii26), a nearly tetrahedral
bridgehead nitrogen [av CNaxC ) 112.54(7)°], and a
nearly ideal trigonal bipyramidal phosphorus with Neq-
P-Neq angles averaging 119.4(10)°. All these metrics are
consistent with a fully transannulated structure. The
P-Nax distance of cation 5 is within experimental error
of those of the less sterically hindered analogues 2b26 and
2c5 (as judged by the 3 × esd criterion). The remaining
bond distances and angles (Table 2) are unremarkable,
and the crystallographic data are collected in Table 3.
Compound 6 is the first example of a chiral proaza-
phosphatrane characterized by X-ray crystallography
(Figure 2). Its geometry around P is pyramidal [av Neq-
PNeq ) 104.16(14)°], but the bridgehead axial nitrogen
(angle sum ) 357.3°) possesses an essentially planar
configuration. This planarity is attributed to van der
Waals repulsions among the methylene protons adjacent
to the bridgehead nitrogen, which tend to draw the
nitrogen from a downward directed pyramidal sp3 geom-
etry into a hybridized nearly planar sp2 geometry.5 The
[3.081(5) Å] is about 8% shorter than the sum of the P
and N van der Waals radii, but it is still very close to
the P-Nax distance in 14 [3.152(3) Å].7 The remaining
bond distances and angles (Table 5) are unremarkable,
and crystallographic data are summarized in Table 3.
P r oa za p h osp h a tr a n e 6 a s a Ch ir a l Der iva tizin g
Agen t for Ch ir a l Azid es. In previous work10 we showed
that proazaphosphatrane 1b reacts with organic azides
to give iminophosphines quantitatively. In the present
work, diastereomeric iminophosphine derivatives were
quantitatively prepared by heating the chiral proaza-
phosphatrane 6 with enantiomeric mixtures of azides in
C6D6 at 50 °C in an NMR tube for 2 h, as represented in
reaction 1. The 1H and proton-decoupled 31P NMR spectra
(26) Lensink, C.; Xi, S. K.; Verkade J . G. J . Am. Chem. Soc. 1989,
111, 3478.

704 J . Org. Chem., Vol. 65, No. 3, 2000
Ta ble 1. 31P a n d 1H NMR Da ta for Azid es Der iva tized by 6
Liu et al.
Ta ble 2. Cr ysta llogr a p h ic Da ta for 5(Cl), 6, a n d 7
5(Cl)
6
7
formula
fw
C
30H40ClN4P
C30H39N4P
486.62
C30H39N4P
502.62
523.08
cryst syst
space group
cryst color, habit
a, Å
rhombohedral
R3
monoclinic
P21
rhombohedral
R3
colorless rod
15.7922(10)
15.7922(10)
9.8706(6)
2131.9(2)
3
colorless block
9.245(3)
14.7103(8)
10.918(4)
1379.3(7)
2
colorless block
14.5268(10)
14.5268(10)
11.3942(18)
2082.4(4)
3
b, Å
c, Å
V, Å3
Z
D(calc), g cm-3
temp, K
1.222
173(2)
1.172
293(2)
1.202
296(2)
diffractometer
abs correction
radiation
µ, mm-1
Bruker CCD-1000
empirical (SADABS)
Mo KR (λ ) 0.71073 Å)
0.216
2.54-26.50
19563
1963
2.26
6.16
1.054
Siemens P4RA
none
Cu KR (λ ) 1.54178 Å)
1.058
2.06-56.54
2475
2034
3.62
9.54
Siemens P4RA
semiempirical
Cu KR (λ ) 1.54178 Å)
1.095
2.62-56.35
844
691
3.83
10.05
1.030
θ range, deg
no. of measd reflections
no. of obsd reflections
R, %a
Rw, %a
GOF
1.058
a
Quantity minimized ) R(wF2) ) Σ[w(Fo2-Fc2)]/Σ[(wFo2)2]1/2; R ) Σ∆/Σ(Fo), ∆ ) |(Fo-Fc).

Direct Determination of ee Values of Chiral Azides
J . Org. Chem., Vol. 65, No. 3, 2000 705
Ta ble 3. Selected Bon d Len gth s (Å) a n d An gles (d eg) for
5(Cl)a
Bond Distances
P-N(1)
N(1)-C(1)
1.6752(10) N(1)-C(3)
1.4577(15) N(2)-C(2)
1.4818(15)
1.4888(13)
Bond Angles
N(1)-P-N(1)#2 119.404(10) C(3)-N(1)-P
121.88(8)
C(2)#2-N(2)-C(2) 112.54(7)
C(1)-N(1)-C(3) 117.04(10)
was observed. After reacting 16 with (()-neomenthyl
azide in C6D6 at 50 °C for 2 h, only one singlet (30.3 ppm)
was observed in the 31P NMR spectrum. Although the
C(1)-N(1)-P
121.06(8)
a
Symmetry transformations used to generated equivalent
1
atoms: #1 -y, x - y, z; #2 -x + y, -x, z.
corresponding H NMR spectrum indicated some chemi-
cal shift separation of the N-methyl group protons in
moiety 16 of the corresponding diastereomers, the mul-
tiplet character of the peaks gave rise to excessive
overlap, thus preventing adequate integration. These
observations may be attributable to the presence of only
two chiral centers in 16, which apparently do not gener-
ate a sufficiently chiral environment around phosphorus
in 16 to allow differentiation of the diastereomeric
products spectroscopically. In chiral proazaphosphatrane
6 and hence in the iminophosphine product 15, the three
chiral substituents held rigidly by the cage structure
probably afford an enhanced chiral phosphorus environ-
ment. The azide substrates 17-22 used in this work and
the results of the NMR measurements on the diastere-
omeric derivatives are given in Table 1.
Ta ble 4. Selected Bon d Len gth s (Å) a n d An gles (d eg) for
6
Bond Lengths
P-N(1)
1.694(3) P-N(2)
1.689(3)
1.455(5)
1.468(4)
1.461(4)
1.437(5)
1.440(5)
P-N(3)
1.703(3) N(1)-C(1)
1.470(5) N(2)-C(3)
1.476(4) N(3)-C(5)
1.474(4) N(4)-C(4)
1.439(5) N(4)-C(6)
N(1)-C(7)
N(2)-C(15)
N(3)-C(23)
N(4)-C(2)
Bond Angles
N(1)-P-N(2)
N(2)-P-N(3)
C(1)-P-N(3)
103.91(14) N(1)-P-N(3)
104.15(15)
117.0(3)
115.5(2)
125.6(2)
104.42(14) C(1)-N(1)-C(7)
125.5(3)
C(3)-N(2)-C(15) 116.9(3)
C(7)-N(1)-P
C(3)-N(2)-P
C(15)-N(2)-P
C(5)-N(3)-P
C(4)-N(4)-C(2)
C(2)-N(4)-C(6)
115.9(2)
124.9(2)
120.2(4)
119.8(3)
C(5)-N(3)-C(23) 116.2(3)
C(23)-N(3)-P
115.5(2)
119.2(4)
C(4)-N(4)-C(6)
In general, the phosphorus imine derivatives examined
by decoupled 31P NMR spectroscopy displayed excellent
diastereomeric peak separation, allowing accurate inte-
gration and quantitative determination of the diastere-
Ta ble 5. Selected Bon d Len gth s (Å) a n d An gles (d eg) for
7a
1
omeric ratios. H NMR analysis also gave good diaster-
Bond Lengths
P-O
1.482(5) N(1)-C(3)
1.654(3) N(2)-C(2)
1.449(5)
1.499(5)
1.435(4)
eomeric peak separation, although the spectra were more
complex as a result of P-H and H-H coupling, as well
as overlap with closely neighboring signals. The advan-
tage of decoupled 31P NMR spectroscopic analysis is that
no signals other than the two singlets associated with
the diastereomeric derivatives are observed in the spec-
tra. For substrate 22, however, no evidence for the
expected diastereomeric derivatives appeared in the 31P
NMR spectrum, and only a peak for cation 5 (-10 ppm)
that is characteristic of the protonated form of 6 was
observed. This result is attributed to facile deprotonation
of the azido carbon, which was confirmed by the dis-
appearance of the NMR spectroscopic resonance of this
P-N(1)
N(1)-C(1)
Bond Angles
N(1)#1-P-N(1)
C(1)-N(1)-C(3)
C(3)-N(1)-P
C(2)-N(2)-C(2)#1 120.0(3)
N(1)-C(1)-C(2)
107.81(12) N(1)-C(3)-C(4)
112.4(4)
111.09(12)
124.4(3)
116.0(3)
119.4(3)
O-P-N(1)
C(1)-N(1)-P
N(2)-C(2)-C(1) 112.0(4)
N(1)-C(3)-C(5) 109.0(3)
114.0(3)
a
Symmetry transformations used to generate equivalent at-
oms: #1 -y, x - 7, z.
of these derivatives were obtained directly without
further purification. To evaluate the derivatizing ability
of 6, (()-neomenthyl azide was reacted with 6 in C6D6 at
50 °C for 2 h. Two 31P NMR singlets (32.55 and 31.41
ppm) in a very nearly 1:1 ratio (Table 1) indicated the
expected presence of a racemic mixture. 1H NMR spectra
also showed good diastereomeric peak separations for the
benzylic proton Ha in the proazaphosphatrane moiety and
Hb attached to the R-carbon in the azide moiety (5.65,
5.79 ppm and 4.18, 4.32 ppm, respectively) thus facilitat-
ing verification of ee values obtained by 31P NMR
spectroscopy.
1
hydrogen. Both the H and 13C NMR spectra were quite
complicated, however, suggesting that side reactions of
the anion ensued.
Exp er im en ta l Section
CH3CN was dried with CaH2. THF and Et2O were dried
with sodium, and other solvents were dried with molecular
sieves. All solvents were freshly distilled before use, and all
reactions were carried out under an Ar atmosphere. The
racemic azides used in this work were synthesized by heating
NaN3 with the corresponding bromides in DMF at 60 °C for
24 h. Chemicals employed were purchased from Aldrich
Chemical Co. and were used without further purification.
Elemental analyses were performed in the Instrument Services
Laboratory of the Chemistry Department at Iowa State
University.
Syn th esis of (S,S,S)-Tr is(2-(r)-m eth ylben zylca r ba m -
oylm eth yl)a m in e (9). Although the synthesis of 9 has been
reported,23 an easier procedure is described here. Nitrilotri-
acetic acid 8 (19.1 g, 100 mmol) was added to 250 mL of
pyridine. The slurry was stirred vigorously while (S)-(-)-(R)-
methylbenzylamine 4 (37.0 g, 305 mmol) was introduced. The
solution was warmed to 50 °C,and P(OPh)3 (99.2 g, 320 mmol)
was added. The reaction mixture was kept at 100-105 °C for
When (-)-neomenthyl azide was reacted under the
same conditions, only one singlet was observed at 31.44
ppm in the 31P NMR spectrum and there were two
multiplets in the 1H NMR spectrum (5.65 and 4.32 ppm),
corresponding to Ha and Hb, respectively, in 15 thus
relating the NMR data to a specific enantiomer. A 1:1
mixture of (() and (-)-neomenthyl azide employed to test
the reliability of this method gave a ratio of (-) to (+)
enantiomers from both the 31P and H NMR spectra of
very nearly 3:1 as expected. When commercially available
chiral phosphorus triamide 16 was used in a parallel
reaction for comparison, no diastereomeric differentiation
1

706 J . Org. Chem., Vol. 65, No. 3, 2000
Liu et al.
10 h, followed by removal of pyridine via vacuum distillation.
The resulting yellow oil was dissolved in 600 mL of CHCl3,
and then, sequentially, distilled H2O (3 × 600 mL), 10%
aqueous NaHCO3 (10 × 600 mL), distilled H2O (3 × 600 mL),
and brine (2 × 600 mL) were used to wash the organic phase.
The organic phase was dried over MgSO4 and concentrated
under reduced pressure, giving the crude product as a pale
yellow solid. Recrystallization of the crude product from THF
(200 mL) and hexanes (50 mL) at -20 °C for 24 h gave pure
Syn th esis of Ch ir a l P r oa za p h osp h a tr a n e Oxid e (7).
Bistrimethylsilyl peroxide (180 mg, 1.00 mmol) was added to
a solution of 6 (250 mg, 0.51 mmol) in benzene (10 mL) at 0
°C. After standing for 5 h at room temperature, the reaction
mixture was filtered, and the solvent was evaporated in a
vacuum to give 7 as a white solid (230 mg, 90%). The crystal
for X-ray analysis was obtained by dissolving 7 in hot THF,
followed by cooling at -20 °C for 24 h.
Cr ysta llogr a p h ic Str u ctu r a l Deter m in a tion s of 5(Cl),
6, a n d 7. The systematic absences in the diffraction data were
consistent with space groups R3 and R3h for 5(Cl) and 7,
respectively, and for space groups P21 and P21/m for 6. In all
cases the E-statistics strongly suggested the noncentrosym-
metric space groups. The chosen chiral space groups R3 for
5(Cl) and 7 and P21 for 6 yielded chemically reasonable and
computationally stable refinement results. The structures were
solved using direct methods that provided locations for most
non-hydrogen atoms from the E-map.27 The remaining non-
hydrogen atoms were located in an alternating series of least-
squares cycles and difference Fourier maps. All non-hydrogen
atoms were refined with anisotropic displacement coefficients.
All hydrogen atoms were included in the structure factor
calculation at idealized positions and were allowed to ride on
the neighboring atoms with relative isotropic displacement
coefficients. In the case of 5(Cl) the empirical absorption
corrections were based on fitting a function to the empirical
transmission surface as sampled by multiple equivalent
measurements.28 In the case of 7 the semiempirical absorption
correction data were collected by the ψ-scan technique. Ab-
sorption corrections were not required for 6 because the
variations in the integrated ψ-scan intensities were less than
10%. In the structure of 5(Cl), the cation and anion reside on
a 3-fold crystallographic axis that passes through atoms P,
N(2), H(0A), and Cl. This structure was refined with a fixed
phosphorus-hydrogen distance of 1.400(1) Å. Structures 6 and
7 were refined with soft restraints on thermal displacement
parameters to conserve data. Molecule 7 occupies a crystal-
lographic 3-fold axis that passes through atoms P, O, and N(2).
Gen er a l P r oced u r e for 1H a n d 31P NMR Sp ectr a l
Deter m in a tion of ee Va lu es of Ch ir a l Azid es w ith 6. To
an azide (0.05 mmol) in an NMR tube sealed with a rubber
septum was added a solution of 6 (29 mg, 0.06 mmol) in C6D6
(0.6 mL) at room temperature under an Ar atmosphere. The
NMR tube was then heated at 50 °C for 2 h. After the NMR
1
9 as a white solid (42.5 g, 85%). H and 13C NMR data were
consistent with those in the literature.23
Syn t h esis of (S,S,S)-Tr is(2-(r)-m et h ylb en zyla m in o-
eth yl)a m in e (3). A solution of 9 (10.0 g, 20.0 mmol) in THF
(150 mL) was added dropwise at room temperature to a
suspension of LiAlH4 (20.0 g, 520 mmol) in THF (300 mL).
This mixture was vigorously stirred and heated under reflux
for 5 days, after which it was cooled to room temperature. Then
50 mL of 10% aqueous KOH was slowly added, and the
resulting mixture was heated under reflux until the salts
turned white. After the reaction mixture cooled to room
temperature, the salts were removed by filtration. The salts
were again heated under reflux for 1 h in a mixture of THF
(400 mL) and H2O (10 mL). After removal of the salts by
filtration, the THF layers were combined and concentrated
under reduced pressure. The resulting yellow oil was placed
in a 20% aqueous KOH (50 mL) solution and extracted with
CH2Cl2 (2 × 70 mL). After the extract was dried over MgSO4
and concentrated under reduced pressure, 3 was obtained as
a pale yellow oil (7.51 g, 82%) that was used in the following
reaction without further purification. The sample for charac-
terization was purified by silica gel column chromatography
using a mixture of CH2Cl2 and MeOH (10:1) as the eluent.
Syn t h esis of (S,S,S)-Tr is(2-(r)-m et h ylb en zyla m in o-
eth yl)a m in e Hyd r och lor id e (3‚3HCl). Crude 3 (4.60 g, 10.0
mmol) was placed in a 10% aqueous HCl (50 mL) solution.
After the mixture stirred at room temperature for 2 h, CH2-
Cl2 (4 × 50 mL) was used to extract the product. After drying
over MgSO4, complete evaporation under reduced pressure,
and purification of the residue by silica gel column chroma-
tography using a mixture of CH2Cl2 and MeOH (10:1) as the
eluent, 3‚3HCl was obtained as a white solid (2.20 g, 48%).
Syn th esis of (S,S,S)-Aza p h osp h a tr a n e (5(Cl)). To a
solution of PCl3 (47.0 mg, 0.33 mmol) in CH3CN (10 mL) was
added P(NMe2)3 (110 mg, 0.67 mmol) at 0 °C with a syringe.
The resulting solution was stirred at 0 °C for 1 h, and then a
solution of 3 (458 mg, 1.00 mmol) in CH3CN (2 mL) was added.
After the mixture stirred at room temperature for 12 h, the
volatiles were removed under vacuum. The residue was then
purified by silica gel column chromatography using a mixture
of CH2Cl2 and MeOH (15:1) as the eluent, giving 5(Cl) (330
mg, 62%) as a white solid upon drying over MgSO4 and
evaporation under vacuum. A crystal for X-ray analysis was
obtained by diffusing Et2O into a solution of 5(Cl) in CH3CN
at room temperature for 3 days.
1
tube cooled to room temperature, the 31P and H NMR spectra
were recorded, and the ee value of the racemic azide was
determined from both NMR peak integrations (Table 1).
Ack n ow led gm en t. The authors are grateful to the
donors of the Petroleum Research Fund administered
by the American Chemical Society for a grant in support
of this research.
Su p p or tin g In for m a tion Ava ila ble: Analytical and spec-
tral data (NMR and mass) for 3, 3‚HCl, 5(Cl), 6, 7, and 18.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Syn th esis of Ch ir a l P r oa za p h osp h a tr a n e (6). A solution
of 5(Cl) (330 mg, 0.63 mmol) in THF (10 mL) was added at
room temperature to a suspension of KO-t-Bu (125 mg, 1.10
mmol) in THF (20 mL). After the reaction mixture was stirred
for 2 h at room temperature, the volatiles were removed in
vacuo, and the residue was extracted with benzene (2 × 50
mL). The extract was filtered, and the solvent was removed
under vacuum giving 6 as a white solid (250 mg, 82%). A
crystal for X-ray analysis was obtained by slow evaporation
of a solution of 6 in THF at room temperature.
J O991304A
(27) All software and sources of the scattering factors are contained
in the SHELXTL (version 5.1) program library (G. Sheldrich, Bruker
Analytical X-ray Systems, Madison, WI).
(28) Blessing, R. Acta Crystallogr. 1995, A51, 33.