Diastereoselective alkylations of chiral, phosphorus-stabilized carbanions: N-alkyl substituent effects in P-alkyl-1,3,2-diazaphosphorinane 2-oxides

Article abstract of DOI:10.1139/v99-251

A systematic study of the diastereoselective alkylation of anions derived from racemic N-substituted P-alkyl 1,3,2,-diazaphosphorinane 2-oxides we carried out with variation of the N-substituent. High diastereoselectivity for the methylation of a P-benzyl

Full text of DOI:10.1139/v99-251

673
Diastereoselective alkylations of chiral,
phosphorus-stabilized carbanions: N-alkyl
substituent effects in P-alkyl-1,3,2-
diazaphosphorinane 2-oxides
Scott E. Denmark and Jung-Ho Kim
Abstract: A systematic study of the diastereoselective alkylation of anions derived from racemic N-substituted P-alkyl
1,3,2-diazaphosphorinane 2-oxides was carried out with variation of the N-substituent. High diastereoselectivity for the
methylation of a P-benzyl anion has been achieved with N-neopentyl derivative 5d. Similarly, a P-ethyl anion derived
from N-neopentyl derivative 6d showed high diastereoselectivity upon benzylation. The observed difference in
alkylation diastereoselectivity between P-ethyl and P-benzyl anions for various N-alkyl substituents is discussed.
Key words: phosphonamide-stabilized carbanions, alkylation, asymmetric, stereoselective, organolitihium.
Résumé : On a réalisé une étude systématique de l’alkylation diastéréosélective d’anions dérivés de 2-oxydes de
P-alkyl-1,3,2-diazaphosphorinanes N-substitués racémiques portant divers substituants sur l’azote. Avec l’anion 5d qui
porte des groupes P-benzyle et N-néopentyle, la méthylation se fait avec une diastéréosélectivité élevée. Il en est de
même lors de la réaction de benzylation de l’anion 6d qui porte des groupes P-éthyle et N-néopentyle. On discute des
différences observées dans la diastéréosélectivité des anions P-éthyle et P-benzyle portant divers substituants N-alkyles.
Mots clés : carbanions phosphonamides stabilisés, alkylation, asymétrique, stéréosélective, organolithium.
[Traduit par la Rédaction] Denmark and Kim 688
Introduction and background
recovery conditions, and (iii) structural simplicity while pro-
viding high stereochemical bias. Auxiliaries (4, 5) and con-
troller groups (6) of C2-symmetry have been utilized a great
deal in asymmetric synthesis. In the chemistry of phospho-
rus-stabilized anions as well, Hanessian has pioneered the
use of the 1,2-cyclohexanediamine based auxiliary for con-
trolling the environment in a phosphonamide (7). Cyclic
phosphonamides derived from C2-symmetric diamines exist
as a single pair of enantiomers because phosphorus is not a
stereogenic center. Therefore, these auxiliaries can eliminate
problems associated with amino alcohol auxiliaries in which
the P-atom is stereogenic and contains a strong P—O bond
(3f). As part of our examination of the relationship of anion
structure and reaction stereoselectivity, we were interested
in evaluating the various aspects of ring size, polycyclic
structure, and nitrogen substituent in the design of phospho-
rus-based auxiliaries and the investigation of the anions de-
rived therefrom. With this in mind we have chosen a collection
of candidates in the C2-diamine family to survey (Chart 1).
In recent years there has been considerable interest in car-
bon–carbon single-bond forming reactions involving hetero-
atom-stabilized carbanions (for reviews see ref. (1)). Among
them, phosphorus-based reagents have great potential for
auxiliary-based chiral modification (2). As part of an ongo-
ing program on the chemistry of chiral, phosphorus-
stabilized carbanions (3) we have been interested in develop-
ing general auxiliaries which give rise to highly selective
transformations at the anionic carbon. The design criteria we
formulated require that the auxiliary be capable of biasing
the rotameric population about the C—P bond and also shield
one of the anion faces to achieve a highly selective approach
of the electrophilic reagents. In addition, other practical con-
siderations were: (i) ease of synthesis in enantiomerically
pure form, (ii) chemical stability under the attachment and
Received July 28, 1999. Published on the NRC Research
Press website on May 19, 2000.
Our previously reported X-ray crystal structural analysis
(8) of the lithio 2-benzyl-1,3-dimethyl-1,3,2-diazaphosphorinane
2-oxide showed that the anion is intrinsically chiral as the
nitrogens are pyramidal and the N-methyl groups are ori-
ented in equatorial and axial positions (Fig. 1). Furthermore,
the key features of this structure are: (i) there is no C-Li
contact, (ii) the carbanion is almost planar, and (iii) the
phenyl group is oriented anti to the P=O bond (O–P–C–C
dihedral angle = 168.9°). Further studies on the dynamic,
solution behavior (8a, 9) of this and related anions and
computational studies (10) have shown that the rotational
Dedicated to Professor Stephen Hanessian in recognition of
his significant contributions to the art of organic synthesis
S.E. Denmark1 and J.-H. Kim. Roger Adams Laboratory,
Department of Chemistry, University of Illinois, Urbana, IL
61801, U.S.A.
1Author to whom correspondence may be addressed at:
University of Illinois, Department of Chemistry, 245 Roger
Adams Laboratory, Box 18, 600 S. Mathews Avenue,
Urbana, IL 61801, U.S.A. Telephone: (217) 333-0066.
Fax: (217) 333-3984. e-mail: denmark@scs.uiuc.edu
Can. J. Chem. 78: 673–688 (2000)
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Can. J. Chem. Vol. 78, 2000
Chart 1.
Fig. 1. Chem-3D presentation of lithio 2-benzyl-1,3-dimethyl-
1,3,2-diazaphosphorinane 2-oxide (8).
barrier around the C—P bond in the benzyl anion is ex-
tremely low (ca. 6–8 kcal/mol). On the basis of the observa-
tions in the simple six-membered ring system, the chirally
modified diazaphosphorinane ii was selected to investigate
alkylation behavior of the derived P-alkyl anions. By com-
parison to five- and seven-membered analogs i and iii, sys-
tem ii has the advantage of having the N-alkyl group closest
to the anionic center due to ring angles2.
The key controlling attribute to obtaining high selectivity
in alkylation was expected to be the ability to preordain the
disposition of the N-substituents which in turn provide the
chiral environment necessary for asymmetric reaction. On
the basis of the assumption that chirally modified system ii
would maintain the basic features of the parent system as
elucidated in the X-ray crystal structure (8), diamines 1 and
2 were chosen as specific models to be investigated (Fig. 2).
As shown in Fig. 2, the two proposed mechanisms for con-
trolling the disposition of the N-substituents are:
(i ) annulating two five-membered rings to the central 1,3,2-
diazaphospholidine ring thus leading to the dipyrrolidino-
methane 1, and (ii ) placing substituents at the C(4) and
C(6) positions to influence the hybridization of the nitrogen
through torsional interactions. The P-alkyl anions derived
from 1 and 2 provide six-membered ring phosphorus hetero-
cycles which are expected to maintain a chair conformation,
though the distortions due to the axially oriented phenyl
group were not a priori obvious. Additionally, the P-benzyl-
1,3,2-diazaphosphorinane 2-oxide anions generated from
diamines 1 and 2 should adopt a conformation similar to the
model in which the nitrogens are pyramidal. Thus, the dis-
position of the N-alkyl groups or the two N-methylenes of
the fused rings distinguish the faces in the anions.
In a preliminary study we prepared the tricyclic P-benzyl
diazaphosphorinane 3 derived from 1 by simple condensa-
tion with benzylphosphonic dichloride3 (11). The methyl-
ation diastereoselectivity of the lithio anion derived from 3
Fig. 2. Chiral 1,3-diamine design to control nitrogen substituent pyramidality.
2 In the five-membered-ring analog i, the N-substituents are pulled away from the anion due to the external bond angles. In the seven-
membered analog iii, the ring is considerably more flexible allowing the N-substituents to avoid the anionic center.
3 The diamine 3 was prepared in enantiomerically enriched form (96% ee) from L-proline in nine steps and convertd to 3 using
benzylphosphonic dichloride.
© 2000 NRC Canada

Denmark and Kim
Table 1. Preparation of the cyclic phosphoramides 7b–7f.
675
Entry
Diamine
R
Phosphite
Yield (%)a
1
2
3
4
5
2b
2c
2d
2e
2f
Et
i-Pr
t-BuCH2
PhCH2
7b
7c
7d
7e
7f
63b
82
96
92
82b
2,4,6-(CH3)3C6H2CH2
aYields are for isolated products after chromatography.
bTriethylamine was used.
Scheme 2.
Scheme 1.
was 5.7/1 (Scheme 1). Since perhydropyrimidines normally
exist in chair conformations (12), we expected the tricyclic
system 3 to adopt a cis/anti/cis chair conformation thereby
forcing the two different methylene units to orient in equato-
rial and axial positions. Thus, electrophiles approach away
from the axial N-methylene unit. Unfortunately, the steric
bulk of the methylene unit does not provide a sufficiently
strong π-facial discrimination. Further variation was consid-
ered to be impractical since placing additional substituents
in the five-membered rings would be synthetically challeng-
ing. Consequently, we chose to pursue the opportunities pro-
vided by the acyclic 1,3-diamine 2 which is much more
amenable to variation in the size of the N-substituent. We
describe herein a systematic examination of the effect of
steric bulk of the N-substituent in the alkylation selectivity
of anions derived from diamine 2.
ing N,N′-dimethyl-1,3-diphenyl-1,3-propanediamine (2a) was
amenable to these reaction conditions, providing P-benzyl-
and P-ethyl diazaphosphorinane 5a and 6a in 86% and 96%
yield, respectively (Scheme 2). Unfortunately, other higher
alkyl diamines (2b–f) did not provide products in reasonable
yield presumably due to the steric bulk of the diamines.
Fortunately, diamines 2b–f did react with phosphorus
trichloride (PCl3) in the presence of N-methylmorpholine
(NMM) or triethylamine (Et3N) to afford P-chlorodiazaphos-
phorinanes which upon hydrolysis produced cyclic hydrogen
phosphites 7b–f in good yield (63–96%) (Table 1). Phosphites
7b–f were unexpectedly stable and could be purified by silica
gel column chromatography. It is important to note the but-
tressing effect of the 4 and 6-phenyl groups toward N-alkyl
groups which will make the phosphorus center more sterically
hindered and thus less sensitive to oxidation. The characteris-
tic structural feature of phosphites 7b–f is strong tautomeric
preference for cyclic hydrogen phosphondiamide structure as
evidenced by a strong infrared stretching band for the P=O
group (1217–1246 cm–1) and a diagnostic stretching band for
the P—H unit (2211–2384 cm–1) (16). The magnitude of the
P—H coupling constant (JPH = 595–629 Hz) is strongly sug-
gestive of an axial P—H bond (17) The characteristic NMR
spectral data are summarized in Table 2. Unlike trivalent
trialkyl phosphites in which the phosphorus resonance appears
in the neighborhood of 140 ppm (17), all resonances of the
hydrogen phosphonamides 7b–f appeared at –0.86–12.69 ppm.
Results
Preparation of P-alkyl-1,3,2-diazaphosphorinanes
For the systematic study of the steric effect of N-alkyl
substituents, six different P-benzyl-1,3,2-diazaphosphorinanes
(N-methyl (5a), N-ethyl (5b), N-isopropyl (5c), N-neopentyl
(5d), N-benzyl (5e), and N-mesitylmethyl (5f)) and three dif-
ferent P-ethyl-1,3,2-diazaphosphorinanes (N-methyl (6a), N-
isopropyl (6c), and N-neopentyl (6d)) were chosen. All six
requisite diamines (2a–f) were prepared by our previously
reported procedures (13). Generally, the preparation of
P-alkyl-1,3,2-diazaphosphorinanes was accomplished in a
straightforward manner by combining the appropriate alkyl-
phosphonic dichlorides (14) with the requisite diamines in
the presence of triethylamine (2, 15). Sterically less demand-
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Can. J. Chem. Vol. 78, 2000
Table 2. 31P NMR data of phosphites 7b–f and phosphorinanes 5a–f and 6a, 6c, 6d.
Entry
R
Phosphite, 7, δ (ppm)
R′
Phosphorinane, 5/6, δ (ppm)
1
2
3
4
5
6
7
8
9
Me
Me
Et
i-Pr
CH2Ph
Et
CH2Ph
CH2Ph
Et
CH2Ph
Et
CH2Ph
CH2Ph
5a, 27.67
6a, 31.73
5b, 24.96
5c, 21.64
6c, 27.51
5d, 24.45
6d, 30.99
5e, 24.84
5f, 26.87
7b, 3.61
7c, –0.86
i-Pr
t-BuCH2
t-BuCH2
PhCH2
(CH3)3C6H2CH2
7d, 12.69
7e, 5.81
7f, 3.09
Table 3. Preparation of P-alkyl 1,3,2-diazaphosphorinane 2-oxides.
Entry
Phosphite
R
Phosphonamide
Yield (%)a
1
2
3
4
5
6
7
7b
7c
7c
7d
7d
7e
7f
Et
i-Pr
i-Pr
t-BuCH2
t-BuCH2
PhCH2
2,4,6-(CH3)3C6H2CH2
5b
5c
6c
5d
6d
5e
5f
93
61
97
81
62
83
61
aYields are for isolated products after chromatography.
Though less acidic than the corresponding dioxa analogs,4
the hydrogen phosphonamides 7b–f are sufficiently acidic to
be deprotonated by n-BuLi at low temperature (–78°C).
Importantly, no nucleophilic addition products to the phos-
phorus center were observed in the diaza analogs, presum-
ably due to a combination of steric hindrance coupled with
electronic deactivation of phosphonamides versus
phosphonates. The use of triethylamine led to a sluggish re-
action even at elevated temperatures and hydride bases such
as NaH and KH were not suitable, affording unidentified
side products. However, treatment of hydrogen phos-
phites 7b–f with n-BuLi followed by alkylation with ethyl
iodide and benzyl bromide afforded P-alkyl-1,3,2-diazaphos-
phorinane 2-oxides 5b–f, 6c, and 6d, in reasonable yields
(61–97%) (Table 3).
methods. First, in the 13C NMR spectra, the α-methylene
carbons displayed resonances at 38.55–43.40 ppm (1JCP
=
102.7–121.6 Hz) for P-benzyl-1,3,2-diazaphosphorinane 2-
oxides 5a–f and 25.43–29.35 ppm (1JCP = 121.8–129.7 Hz)
for P-ethyl-1,3,2-diazaphosphorinanes 6a, 6c, and 6d. Sec-
ond, diagnostic α-methylene protons showed phosphorus-
coupled eight-line patterns at 3.35–3.69 ppm for P-benzyl-
1,3,2-diazaphosphorinanes 5a–f and 1.88–2.38 ppm for P-
ethyl-1,3,2-diazaphosphorinanes 6a, 6c, and 6d. Finally, the
observation of a strong, characteristic P=O stretch (1208–
1271 cm–1) obviously eliminated the possibility of the for-
mation of regioisomeric O-alkylated products. It is notewor-
thy that the reaction of the lithiated phosphite with silylating
agents provided O-silylated phosphite exclusively (18). Ad-
ditional characteristic features were noted in the 31P NMR as
all P-alkyl 1,3,2-diazaphosphorinane 2-oxides displayed
resonances in the region shifted downfield (21.64–31.73 ppm)
The structures of the P-alkyl-1,3,2-diazaphosphorinanes
5a–f and 6a, 6c, 6d, and were secured by spectroscopic
4 Diethyl hydrogenphosphonate is easily deprotonated at 0°C using NaH or Et3N.
© 2000 NRC Canada

Denmark and Kim
Table 4. Methylations of P-benzyl-1,3,2-diazaphosphorinane 2-oxides 5a–f.
677
Yield
(%)a
Entry
5
R
Time (h)
Temp (°C)
d.s.
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
Me
Et
i-Pr
t-BuCH2
PhCH2
2.5
3.0
3.0
3.0
2.0
2.0
–78
7.7:1b
1.6:1b
1.4:1c
11.5:1c
3.0:1c
2.9:1c
8a, 91
8b, 78d
8c, 87
8d, 82e
8e, 96
8f, 94
–78 to –60
–78 to –60
–78 to –60
–78
(CH3)3C6H2CH2
–78
aYields are for isolated products after chromatography.
bRatio determined by HPLC.
cRatio determined by 31P NMR.
d15% of 5b recovered.
e11% of 5d recovered.
Table 5. Diastereoselective benzylations of P-ethyl-1,3,2-diazaphosphorinane 2-oxide 6a, 6c, and 6d.
Entry
6
R
d.s.
Yield (%)a
1
2
3
6a
6c
6d
Me
i-Pr
t-BuCH2
1.3:1b
3.6:1c
11.5:1c
9a, 83
9c, 96
9d, 98
aYields are for isolated products after chromatography.
bRatio determined by 31P NMR.
cRatio determined by HPLC.
compared to those of hydrogen phosphoramides 7b–f
(Table 2). The ring conformation is believed to adopt an
axial P=O unit on the basis of X-ray crystallographic evi-
dence (19) and the large difference in H NMR resonances
for HC(4) and HC(6) in 5 and 6 compared to 7.
benzylic carbanions Li+5a–f– proceeded with moderate to
high diastereoselectivity. Interestingly, diastereoselectivity
was not merely a function of the steric bulk of the alkyl
group on the nitrogen as the N-methyl analog 5a afforded re-
markably high diastereoselectivity compared to the corre-
sponding N-ethyl (5b) and N-isopropyl (5c) analogs. The
most sterically demanding N-neopentyl analog 5d showed
the highest selectivity (entry 4). Moderate selectivities were
found in the case of benzyl and mesityl analogs 5e and 5f.
1
Diastereoselective methylation of P-benzyl-1,3,2-
diazaphosphorinane 2-oxides 5a–f
The methylation of benzylic carbanions derived from 5a–f
was examined first. The sterically least demanding N-methyl
analog 5a and N-benzylic derivatives 5e, and 5f reacted rap-
idly and were completely methylated at –78°C within 2 to
2.5 h. However, in the case of sterically demanding sub-
strates 5b, 5c, and 5d, the reaction was sluggish at –78°C
but proceeded at –60°C within 3 h. Clearly, the steric bulk of
the N-alkyl group controlled the facility of the approach of
the electrophile to the anionic center. N-Benzylic derivatives
5e and 5f, which are somewhat bulkier than methyl groups,
may also benefit from contributions of the aromatic ring. As
shown in Table 4, the methylation of the P-stabilized
Diastereoselective benzylations of P-ethyl-1,3,2-
diazaphosphorinanes 6a, 6c, and 6d
P-Ethyl anions were much more reactive than the corre-
sponding P-benzyl anions as evidenced by the consumption
of educt which was complete at –78°C within 30 min. More-
over, in contrast to the alkylation behavior of the P-benzyl
anions, the benzylation of the P-ethyl anions from 6a, 6c,
and 6d showed a qualitative linear dependency of diastereo-
selectivity as a function of steric bulk of the N-alkyl groups
(Table 5). The most sterically demanding N-neopentyl
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Can. J. Chem. Vol. 78, 2000
Table 6. Data for the methylation products 8a–8f.
N-Substituent
8
ratio
31P NMR (δ, ppm)
HPLC (tR, min)a
major
minor
major
minor
Me
Et
i-Pr
t-BuCH2
PhCH2
8a
8b
8c
8d
8e
8f
7.7:1
31.80
29.34
29.16
28.47
29.54
30.42
29.82
28.76
28.13
29.55
29.54
32.15
1.6:1
1.4:1
11.5:1
3.4:1
2.4:1
8.37
8.57
7.25
7.30
8.30
9.62
19.15
16.39
(CH3)3C6H2CH2
aColumn: Supelco LC-NH2.
tion orders for the two diastereomeric methylation products
(Table 6). For the N-methyl (8a), N-ethyl (8b), and N-isopropyl
(8c) alklyation products, the major diastereomer displays a
lower field 31P NMR chemical shift and is more strongly re-
tained on the HPLC (aminopropyl silica). The N-benzyl
alkylation products (8e) display a single 31P resonance, but
have a similar behavior on HPLC. Curiously, the N-neopentyl
(8d) and N-mesityl (8f) analogs exhibit the reverse trend,
i.e., the major diastereomer appears at higher field and is
less retained on the HPLC. We thus suspected that the sense
of relative asymmetric induction for 5a–5c and 5e might be
different from that for 5d and 5f. This is an intriguing hy-
Fig. 3. ORTEP (35% thermal ellipsoids) representation of
(S*,S*,S*)-8a.
pothesis which would require
a
complex confor-
mational/mechanistic analysis to explain the reversal. It
would however, help clarify the “non-linear” dependence of
alkylation selectivity on N-substituent. Thus, to verify this
hypothesis we elected to independently establish the config-
urations of the major alkylation products from the most se-
lective representatives in the series, 8a and 8d.
The sense of asymmetric induction in the major alkylation
product 8a was established by a single crystal X-ray analysis
of the racemic compound. The ORTEP image is shown in
Fig. 3. Simple inspection of the structure provides the an-
swer that the (S,S)-diazaphosphorinane induced the S config-
uration at the newly created stereogenic center in the
alkylation. Other implications of the structure and an inter-
pretation of the origin of stereoselection are provided in the
discussion section.
To establish the stereochemical course for the alkylation
reaction of 5d, diamine 2 was resolved with dibenzoyl-D-tar-
taric acid according to the literature procedure (20). The
enantiomeric purity of the diamine was determined for the
N,N-dineopentyldiamine derivative 2d by analyzing the
Pirkle derivative by chiral HPLC on an N-naphthyl-L-alanine
column (21). The enantiomeric excesses were 94% for the
(S,S)-enantiomer and 98% for (R,R)-enantiomer (Scheme 3).
Preparation of enantiomerically enriched (S,S)-5d was
carried out following the procedure for the racemic material
described previously (Scheme 4). Thus, treatment of diamine
(S,S)-2d with PCl3 and Et3N followed by hydrolytic workup
gave phosphite (S,S)-7d in 90% yield. Subsequent transfor-
mation of (S,S)-7d to (S,S)-5d was performed in 81% yield.
The asymmetric methylation of (S,S)-5d was accomplished
by treatment with n-BuLi followed by addition of an excess
of methyl iodide to give a 15.7:1 ratio of mixture of
diastereomers of (–)-8d and 21% of unreacted (S,S)-5d. The
analog 6d gave the highest selectivity (entry 3) whereas the
sterically least demanding N-methyl analog 6a afforded the
lowest selectivity (entry 1). The disparate behavior of the
P-benzyl and P-ethyl series may ultimately relate to the
differences in conformational composition and rotational
barriers (vide infra). The discrepancy between N-isopropyl
analogs 5c and 6c might also be explained by the size differ-
ence of the electrophiles (benzyl vs. methyl). An electro-
phile dependence in the alkylation of related P-benzyl 1,3,2-
oxazaphosphorinane 2-oxides has been previously noted,
however in this case, methylation proceeds with higher se-
lectivity than benzylation (3c)5.
Stereochemical course of the reaction
In the course of the routine characterization of the
alkylation products we noticed an interesting trend which
suggested that the sense of asymmetric induction may not be
the same for all of the substrates 5a–5f. The two diagnostic
features are the 31P NMR chemical shifts and the HPLC elu-
5 Attempted benzylation of Li+5d– at –60°C was unsuccessful. Warming to –20°C resulted in a diastereomeric mixture (2:1) of benzylated
products.
© 2000 NRC Canada

Denmark and Kim
679
Scheme 3.
Scheme 4.
mixture of diastereomers was subjected to conventional
hydrolysis conditions to give the phosphonic acid: 1 N HCl
in THF, 6 N or 12 N HCl in dioxane. However, the very
sterically hindered alkylation product (–)-8d was unaffected
by these conditions. Eventually, (–)-8d was cleanly hydro-
lyzed with aqueous 48% HBr in refluxing acetic acid to give
phosphonic acid (–)-13. The phosphonic acid (–)-13 was pu-
rified by ion-exchange column chromatography and then
was converted to the dimethyl phosphonate ester (–)-14 by
treatment with diazomethane (70% yield) followed by fur-
ther purification by silica gel column chromatography. The
absolute configuration of the dimethyl phosphonate (–)-14
was confirmed to be S by comparison of its specific rotation
with the literature value (3c, 3f). Therefore, net result of the
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Can. J. Chem. Vol. 78, 2000
Fig. 4. Limiting chair-like conformations of the anions.
Fig. 5. Rationale for the diastereoselective methylation of P-
benzyl-1,3,2-diazaphosphorinanes (5).
Fig. 6. Proposed skewed conformation of the anions.
reaction is stereochemical conversion of 2-benzyl-1,3,2-di-
azaphosphorinane 2-oxide ((S,S)-5d) to dimethyl phosphonate
(S)-14. This fact then establishes unambiguously that the
stereochemical course of alkylation of 5a and 5d proceeded
in the same relative sense.
sible for the different alkylation selectivities or the reactive
species are monomeric.
Discussion
The second critical issue is the conformation of the anion.
Without direct spectroscopic information, we can only spec-
ulate about the ring conformation on the basis of the X-ray
structures of unsubstituted anions and the neutral alkylation
product (S*,S*,S*)-8a. Close inspection of this structure re-
veals a surprising, albeit understandable deviation from the
ideal chair conformation usually seen for these structures.
The ring in (S*,S*,S*)-8a is a flattened boat. The reason for
this conformation most likely originates in a second unusual
feature namely the axial positioning of the 1-phenylethyl
group which itself results from an avoidance of non-bonding
interactions of this phosphorus substituent with the neigh-
boring N-methyl groups. Thus, to avert severe 1,3-diaxial in-
teractions with one of the phenyl groups, the ring distorts to
a boat. The flattening of the ring is due to the near planarity
of the nitrogen atoms. It is however noteworthy that N(1) is
slightly pyramidalized (Σangles = 356.3°) compared to
N(2) (Σangles = 359.9°). Finally, the locations of the periph-
eral N-alkyl groups are determined by a combination of the
ring conformation, gauche interactions with the phenyl
groups at C(3) and C(5) and the hybridization of the nitro-
gen atoms.
Clearly, the proximal N-alkyl groups of the anions served
as the chiral controlling elements during the course of the
alkylation reaction. If we assume that the anion takes up a
chair-like conformation, the limiting structures to consider at
depicted in Fig. 4. We propose that the preferred anion is
represented by structures a/a′ in which the phosphonyl oxy-
gen (and attendant lithium counterion with solvent) is in an
axial position and the phenyl group is antiperiplanar to the
P—O bond (R1 = H, R2 = Ph). The a/a′ equilibrium relates
The central issue in all of our studies of phosphorus-
stabilized anions is to create a structural model of reactivity
which provides an understanding and ultimately a prediction
of the stereochemical course of the reactions at the anionic
centers. For the molecules examined in this study, the key
question is the way in which the chirality of the 1,3,2-diaza-
phosphorinane skeleton (due to the phenyl substituents) is
manifest in the dissymetry of the two faces of the benzylic
anion.
To begin the analysis, we make recourse to the X-ray
crystal structures of the achiral, unsubstituted lithio 1,3,2-
oxazaphosphorinane 2- oxides, e.g., Fig. 1. The first point of
consideration is the aggregation state of the anions. Even
though the model anion crystallized as a dimer (8), the more
sterically demanding 3,5-diphenyl substituted chiral anions
might exist as monomeric species. Moreover, the aggrega-
tion state of these anions has been shown to be dependent on
the nature of the substituents on nitrogen. For example, the
anion derived from highly sterically demanding 1,3-bis(tert-
butyl)-2-isopropyl-1,3,2-diazaphosphorinane has shown
characteristic dynamic solution behavior of a monomer
(10)6. That notwithstanding, Denmark et al. (8) have previ-
ously shown that aggregation effects for the oxaza-analog
did not influence diastereoselectivity (21). Indeed, the anion
derived from enantiomerically enriched (94% ee) diazaphos-
phorinane (S,S)-5d produced a diastereomeric mixture in a
similar ratio compared to the anion derived from (±)-5d. Ad-
dition of the highly coordinating triamine, pentamethyl-
diethylentriamine, to the reaction in THF did not change the
reaction selectivity. This implied that either the aggregate
structure (homochiral vs. heterochiral dimers) is not respon-
6 P.C. Miller. Unpublished results from these laboratories.
© 2000 NRC Canada

Denmark and Kim
681
to the alternative invertomers at the nitrogen atoms assum-
ing, as is the case in all 1,3,2-diazaphosphorinane 2-oxide
anions, that one substituent is axial and one is equatorial.
Examination of the non-bonding interactions of the substitu-
ents around the ring shows that vicinally located pair of N-
alkyl C-phenyl groups prefer invertomer a due to the elimi-
nation of one gauche interaction.
and a comprehensive understanding of the structure of the
anions, new C2-symmetric diamine-based auxiliaries and
their utilities in the reaction of the phosphorus-based alkyl
anions can be developed in the future.
Experimental section
The high diastereoselectivity obtained from N-neopentyl
analog 5d results from a strong stereochemical bias between
two π-faces of the derived planar anion Li+5d– in which the
phenyl ring might similarly orient anti to the P=O bond as
shown in the model. The simplified structure of the anti-
periplanar anion is depicted as iv and Newman projection v
in Fig. 5. The electrophile would approach from the side
away from the axially disposed N-alkyl group to avoid van
der Waals interactions. For the neopentyl derivatives, the dif-
ferentially disposed N-tert-butyl groups tethered by a methy-
lene chain locate differently with respect to the anionic
center.
The low diastereoselectivity observed from the P-benzyl
anions derived from N-ethyl and N-isopropyl derivatives is
believed to arise from a change in location of the phenyl
ring. The phenyl group of the anion is believed to exist in a
skew form and thus reside anticlinal (±150°) to the P=O
bond to avoid non-bonding interaction with the substituent
on the axially disposed N-alkyl group. The reactive confor-
mation of this anion (vi) along with its Newman (vii) are
shown in Fig. 6. Approach of the electrophile to either face
of this anion experiences similar interactions with either of
the N-substituents thus affording little bias in the alkylation
event.
The direct relationship of the diastereoselectivity to steric
bulkiness of the N-alkyl groups in the case of benzylation of
the P-ethyl anion is explained by invoking the antiperiplanar
anionic conformer vii. Since the α-methyl group of the an-
ion is comparably small, the interaction with axially dis-
posed N-alkyl group is insufficient to force the anion to be
skewed. Thus, the diastereoselectivity directly reflects the
steric bulkiness of N-alkyl groups. The erosion of selectivity
for P-ethyl anions is mostly due to the low rotation barrier
of the P—C bond and the lesser bias toward the antiper-
planar vs. the synplanar conformation.7
It should also be recognized that the anions may exist in
flattened boat-like conformations with an axially standing P-
benzyl group. Here, the shielding of the anion faces is much
less predictable. Moreover, the anion ring conformation may
in fact be dependent on the ring substituents, making a con-
sistent analysis impossible.
General Methods
See supporting information.8
Starting materials
The diamines 2a–f were prepared in these laboratories and
the procedures have been reported elsewhere (14). Ethyl-
phosphonic dichloride is commercially available. Benzyl-
phosphonic dichloride was prepared by
procedure and used after recrystallization from pentane (15).
a literature
(RS)-(4l,6l)-2-Benzyl-1,3-dimethyl-4,6-diphenyl-1,3,2-
diazaphosphorinane 2-oxide (5a): In a 25-mL, three-necked
round bottom flask equipped with a reflux condenser, a N2
inlet tube, a rubber septum, and a magnetic stirring bar was
placed with 0.57 mL (4.13 mmol) of Et3N in 5 mL of
CH2Cl2. This solution was heated to reflux and then 420 mg
(1.65 mmol) of diamine 2a in 6 mL of CH2Cl2 and 362 mg
(1.73 mmol) of benzylphosphonic dichloride in CH2Cl2
(6 mL) were simultaneously added over 1 h by syringe
pump. After heating to reflux for 10 h, the oil bath was re-
moved. The cooled reaction mixture was poured into water
(20 mL) and extracted with CH2Cl2 (3 × 30 mL). The ex-
tracts were dried (Na2SO4), filtered, and concentrated to give
700 mg of yellow orange oil, which was purified by SiO2
column chromatography (EtOAc/i-PrOH, 19:1) to give
552 mg (86%) of diazaphosphorinane 5a as a colorless solid.
An analytical sample was obtained by recrystallization from
pentane/Et2O: mp 147–148°C. IR (CCl4): 3065 w, 1271 s.
1
TLC: Rf 0.35 (EtOAc/i-PrOH, 19:1). H NMR (300 MHz):
7.45–7.29 (m, 11 H), 7.18 (t, J = 3.0, 2 H), 6.79 (dd, J = 6.0,
3.0, 2 H), 4.23 (dt, J = 13.7, 3.8, 1 H), 3.75 (dd, J = 11.5,
3.5, 2 H), 3.51 (dd, J = 19.4, 4.8, 1 H), 3.36 (dd, J = 18.5,
4.8, 1 H), 2.66 (d, J = 8.2, 3 H), 2.48 (d, J = 9.0, 3 H), 1.80
(m, 2 H, 2 H). 13C NMR (75.5 MHz): 142.38 (JCP = 6.5),
140.15, 134.76 (JCP = 8.9), 129.82, 129.74, 128.67, 128.34,
128.29, 128.24, 127.36, 127.15, 126.84, 126.48, 126.41,
62.65, 58.58, 41.43 (JCP = 3.5), 38.55 (JCP = 121.6), 34.07
(JCP = 4.6), 32.28 (JCP = 3.0). 31P NMR (121.6 MHz): 27.67.
MS (70 eV): 390 (M+ < 0.1), 299 (100). Anal. calcd. for
C24H27N2OP (390.46): C 73.83, H 6.97, N 7.17, P 7.93;
found: C 73.79, H 6.98, N 7.11, P 7.84.
In summary, the methylation of Li+5a––Li+5h– proceeds
with moderate to high diastereoselectivity and was highly
conformation dependent due to the N-alkyl substituents. The
benzylation selectivity of Li+6a–, Li+6c–, and Li+6d– showed
linear dependency on the N-alkyl steric bulk. N-Neopentyl
analogs 5d and 6d afforded the highest selectivities (92:8) in
both cases. From a systematic study of N-alkyl substituents
(RS)-(4l,6l)-1,3-Dimethyl-4,6-diphenyl-2-ethyl-1,3,2-diaza-
phosphorinane 2-oxide (6a): In a 50-mL, three-necked round
bottom flask equipped with a N2 inlet tube, a septum and a
magnetic stirring bar was placed 370 mg (1.45 mmol) of
diamine 2a and 0.51 mL (3.63 mmol) of Et3N in 15 mL of
CH2Cl2. Ethylphosphonic dichloride (170 µL, 1.60 mmol)
was then added by a syringe over a time period of 5 min.
7 S.E. Denmark, K.A. Swiss, R.L. Dorow, P.C. Miller, and S.R. Wilson. In a detailed NMR study, no decoalescence of the achiral parent of
1
6a was detected down to –117°C (500 MHz, H NMR observation). Manuscript in preparation.
8 General experimental methods along with full spectroscopic data and assignments for 5a-f, 6a, 6c, 6d, 7b-f, 8a-f, 9a, 9c, 9d, and 14 (15
pages). Copies of material on deposit may be purchased from the Depository of Unpublished Data, Document Delivery, CISTI, National
Research Council of Canada, Ottawa, ON, K1A OS2, CANADA.
© 2000 NRC Canada

682
Can. J. Chem. Vol. 78, 2000
(RS)-(4l,6l)-1,3-Bis-(1-methylethyl)-4,6-diphenyl-1,3,2-diaza-
phosphorinane 2-oxide (7c): From 315 mg (1.02 mmol) of
diamine 2c, 95 µL (1.09 mmol) of PCl3 and 0.36 mL
(3.27 mmol) of N-methylmorpholine followed by purifica-
tion by SiO2 column chromatography (hexane/EtOAc/i-
PrOH, 35:62:3) was obtained 288 mg (79%) of 7c as a col-
orless solid. A lager scale reaction gave 82% of 7c. An ana-
lytical sample was obtained by recrystallization from
pentane/Et2O: mp 126–127°C. IR (CCl4): 3067 w, 1275 s.
TLC: Rf 0.32 (hexane/EtOAc/i-PrOH, 35:62:3). 1H NMR
(300 MHz): 7.83 (d, J = 595.4, 1 H), 7.51 (d, J = 7.2, 2 H),
7.41–7.27 (m, 8 H), 4.24 (m, 1 H), 4.11 (ddd, J = 13.2, 8.5,
5.1, 1 H), 3.58 (heptet, J = 6.8, 1 H), 3.38 (heptet, J = 6.8, 1
H), 2.40 (m, 2 H), 1.32 (d, J = 6.8, 3 H), 1.22 (d, J = 6.8, 3
H), 1.08 (d, J = 6.8, 3 H), 0.96 (d, J = 6.8, 3 H). 13C NMR
(75.5 MHz): 142.58, 128.28, 127.01, 126.69, 126.15, 55.56,
After stirring for 22 h at rt, the reaction mixture was concen-
trated under reduced pressure. The residue was treated with
EtOAc (15 mL), filtered, and the filter cake was washed
with EtOAc (2 × 10 mL). The combined filtrates were
washed with brine (15 mL) and the aqueous layer was ex-
tracted with EtOAc (2 × 10 mL). The combined organic ex-
tracts were dried (Na2SO4), filtered, and concentrated to give
a colorless oil, which was purified by SiO2 column chroma-
tography (hexane/EtOAc/i-PrOH, 35:62:3, then EtOAc/i-
PrOH (9:1) to afford 457 mg (96%) of diazaphosphorinane
6a as a foam. An analytical sample was obtained by
recrystallization from pentane/TBME: mp 66–68°C. TLC: Rf
1
0.30 (EtOAc/i-PrOH, 9:1). IR (CCl4): 3030 w, 1267 s. H
NMR (300 MHz): 7.50–7.11 (m, 10 H), 4.33 (dt, J = 13.4,
3.8, 1 H), 3.78 (dd, J = 10.1, 1.7, 1 H), 2.70 (d, J = 8.1, 3
H), 2.54 (d, J = 8.8, 3 H), 2.40 (ddd, J = 14.2, 12.4, 4.6, 1
H), 2.20–1.88 (m, 3 H), 1.31 (dt, J = 19.3, 7.5, 3 H). 13C
NMR (75.5 MHz): 142.01 (JCP = 5.0), 140.06, 128.44,
128.33, 127.13, 126.93, 126.29, 126.11, 62.33, 59.42, 41.90
55.37, 49.73 (JCP = 5.1), 48.16 (JCP = 8.2), 43.67 (JCP
=
10.6), 22.00 (JCP = 2.8), 21.68, 21.05 (JCP = 4.1), 20.86. 31P
NMR (121.6 MHz): –0.86. MS (70 eV): 356 (M+, 16), 176
(100). Anal. calcd. for C21H29N2OP (356.45): C 70.76, H
8.20, N 7.86, P 8.69; found: C 70.91, H 8.20, N 7.83, P
8.53.
(JCP = 5.2), 33.52 (JCP = 4.7), 32.66 (JCP = 3.1), 25.43 (JCP
=
129.7), 7.68 (JCP = 6.3). 31P NMR (121.6 MHz) 31.73. MS
(70 eV): 329 (M+ + 1, 22), 328 (M+, 98), 299 (100). Anal.
calcd. for C19H25N2OP (328.39): C 69.49, H 7.67, N 8.53, P
9.43; found: C 69.49, H 7.69, N 8.51, P 9.40.
(RS)-(4l,6l)-1,3-Bis(2,2-dimethylpropyl)-4,6-diphenyl-1,3,2-
diazaphosphorinane 2-oxide (7d): From 410 mg (1.12 mmol)
of diamine 2d, 107 µL (1.23 mmol) of PCl3, and 0.41 mL
(3.73 mmol) of N-methylmorpholine followed by purifica-
tion by SiO2 column chromatography (hexane/EtOAc, 4:1)
was obtained 379 mg (82%) of 7d as a sticky oil. A larger
scale reaction gave 96% yield of 7d. A sample of (S,S)-7d
was also prepared from (S,S)-2d (94% ee) in 90% yield. For
(S,S)-7d: [α]D –37.5 (c = 1.34, CHCl3). IR (CCl4): 3065 w,
1246 s. TLC: Rf 0.33 (hexane/EtOAc, 2:1). 1H NMR
(300 MHz): 7.77 (d, J = 608.9, 1 H), 7.42–7.20 (m, 10 H),
4.33 (ddd, J = 17.1, 7.6, 5.2, 1 H), 4.18 (quintet, J = 5.8, 1 H),
3.05 (dd, J = 15.2, 12.8, 1 H), 2.98 (dd, J = 14.8, 12.3, 1 H),
2.74 (dd, J = 14.8, 9.1, 1 H), 2.39 (m, 2 H), 2.34 (dd, J =
15.2, 12.8, 1 H), 0.76 (s, 9 H), 0.72 (s, 9 H). 13C NMR
(75.5 MHz): 141.35, 140.66, 128.55, 128.52, 127.18,
126.61, 62.09, 60.97, 58.89 (JCP = 3.7), 56.95 (JCP = 4.3),
42.10 (JCP = 12.6), 34.26 (JCP = 1.5), 33.62 (JCP = 1.9),
28.14, 28.08. 31P NMR (121.6 MHz): 12.69. MS (70 eV):
412 (M+), 355 (100). Anal. calcd. for C25H37N2OP (412.55):
C 72.78, H 9.04, N 6.79, P 7.51; found: C 72.56, H 9.01, N
6.65, P 7.42.
Representative procedure for the preparation of cyclic
hydrogen phosphites 7b-f
The detailed procedure for the preparation of 7b is given.
For all of the other phosphites only the amounts of reagents
and methods of purification are provided along with the ana-
lytical data.
(RS)-(4l,6l)-1,3-Diethyl-4,6-diphenyl-1,3,2-diazaphosphorinane
2-oxide (7b): In a 25-mL, three-necked, round bottom flask,
equipped with a reflux condenser, a rubber septum, a N2 in-
let tube and a magnetic stirring bar was placed 109 µL
(1.25 mmol) of PCl3, and a solution of 0.35 mL (2.51 mmol)
of Et3N in 5 mL of CH2Cl2. The mixture was heated to re-
flux and a solution of 335 mg (1.19 mmol) of diamine 2b in
CH2Cl2 (5 mL) was added via syringe over a time period of
5 min. After heating to reflux for an additional 1.5 h,
0.18 mL (1.25 mmol) of Et3N was added. The oil bath was
removed and the reaction mixture was poured into 20 mL of
water and extracted with CH2Cl2 (3 × 20 mL). The com-
bined extracts were dried (Na2SO4) and concentrated to give
a yellow oil which was purified by SiO2 column chromatog-
raphy eluting with EtOAc/i-PrOH (19:1) to give 247 mg
(63%) of cyclic phosphite 7b as a colorless oil which solidi-
fied at –20°C. An analytical sample was obtained by
recrystallization from Et2O: mp 111–112°C. IR (CCl4): 3031
(RS)-(4l,6l)-1,3-Dibenzyl-4,6-diphenyl-1,3,2-diazaphosphor-
inane 2-oxide (7e): From 84 µL (0.97 mmol) of PCl3,
358 mg (0.88 mmol) of 2e, and 0.39 mL (2.77 mmol) of N-
methylmorpholine followed by purification by SiO2 column
chromatography (hexane/EtOAc, 2:1) was obtained 366 mg
(92%) of 7e as a colorless oil which solidified on standing at
–20°C. An analytical sample was obtained by recrystalli-
zation from pentane/Et2O: mp 59–60°C. IR (CCl4): 3065 w,
1227 s. TLC: Rf 0.41 (hexane/EtOAc, 1:1). 1H NMR
(300 MHz): 8.14 (d, J = 628.9, 1 H), 7.36–7.11 (m, 20 H),
4.73 (dd, J = 14.6, 9.9), 4.66 (dd, J = 15.6, 10.9, 1 H), 4.12
(quintet, J = 5.5, 1 H), 3.93 (m, 1 H), 3.70 (dd, J = 15.6, 9.8,
1 H), 3.62 (dd, J = 14.6, 11.3, 1 H), 2.30 (ddd, J = 14.5, 9.3,
4.7, 1 H), 2.13 (ddd, J = 14.5, 6.0, 4.8, 1 H). 13C NMR
(75.5 MHz): 140.57 (JCP = 1.4) 139.43, 136.89 (JCP = 2.8),
136.74, 129.42, 128.67, 128.46, 128.40, 128.16, 128.08,
1
w, 1240 s. TLC: Rf 0.34 (EtOAc/i-PrOH, 19:1). H NMR
(300 MHz): 7.74 (d, J = 599.4, 1 H), 7.45–7.23 (m, 10 H),
4.27–4.14 (m, 2 H), 3.37–3.16 (m, 2 H), 2.91–2.81 (m, 2 H),
2.36 (m, 2 H), 1.03 (t, J = 7.1, 3 H), 0.97 (t, J = 7.1, 3 H).
13C NMR (75.5 MHz): 141.39, 140.72, 128.49, 128.41,
127.30, 127.35, 126.72, 126.28, 57.67, 57.47, 42.42 (JCP
=
9.6), 40.45 (JCP = 5.6), 40.25 (JCP = 8.1), 14.08, 13.44. 31P
NMR (121.6 MHz): 3.61. MS (70 eV): 328 (M+, 29), 134
(100). Anal. calcd. for C19H25N2OP (328.39): C 69.49, H
7.67, N 8.53, P 9.43; found: C 69.50, H 7.67, N 8.50, P
9.37.
© 2000 NRC Canada

Denmark and Kim
683
127.46, 127.36, 127.33, 127.27, 126.80, 126.59, 57.45,
140.55, 134.90 (JCP = 8.4), 129.97, 129.89, 128.45, 128.34,
128.31, 128.21, 127.30, 127.12, 126.94, 126.78, 126.35,
126.31, 58.14, 54.58, 41.66 (JCP = 4.7), 40.54 (JCP = 121.3),
39.87 (JCP = 4.6), 38.87 (JCP = 3.6), 13.52 (JCP = 2.4),
13.36. 31P NMR (121.6 MHz): 24.96. MS (70 eV): 328 (M+
+ 1 – PhCH2, 22), 327 (M+ – PhCH2, 100). Anal. calcd. for
C26H31N2OP (418.52): C 74.62, H 7.47, N 6.69, P 7.40;
found: C 74.49, H 7.57, N 6.63, P 7.25.
56.50, 48.51 (JCP = 6.9), 48.29 (JCP = 5.6), 41.58 (JCP
=
12.6). 31P NMR (121.6 MHz): 5.81. MS (70 eV): 452 (M+,
3), 91 (100). Anal. calcd. for C29H29N2OP (452.53): C
76.97, H 6.46, N 6.19, P 6.84; found: C 76.94, H 6.48, N
6.18, P 6.82.
(RS)-(4l,6l)-1,3-Bis-(2,4,6-trimethylphenylmethyl)-4,6-diphenyl-
1,3,2-diaza-phosphorinane 2-oxide (7f): From 127 µL
(1.45 mmol) of PCl3, 0.62 mL (4.46 mmol) of NEt3, and
680 mg (1.39 mmol) of 2f followed by purification by SiO2
column chromatography (hexane/EtOAc, 2:1) was obtained
612 mg (82%) of 7f as a gummy solid. An analytical sample
was obtained by recrystallization from pentane/TBME: mp
178–190°C. IR (CCl4): 3029 w, 1217 s. TLC: Rf 0.36 (hex-
ane/EtOAc, 2:1). 1H NMR (300 MHz): 7.48–7.09 (m, 10 H),
7.22 (d, J = 616.0, 1 H), 6.78 (s, 2 H), 6.67 (s, 2 H), 4.36
(dd, J = 13.5, 3.3, 1 H), 4.27 (dd, J = 13.5, 7.2, 1 H), 4.06
(dd, J = 12.7, 5.1, 1 H), 4.01–3.92 (m, 2 H), 3.68 (t, J =
12.7, 1 H), 2.34 (m, 2 H), 2.24 (s, 3 H), 2.16 (s, 3 H), 2.13
(s, 6 H), 2.08 (s, 6 H). 13C NMR (75.5 MHz): 141.46,
140.89, 138.34 (JCP = 4.3), 137.33, 136.81, 128.93, 128.83,
128.60, 128.21, 127.98, 127.91, 127.24, 126.78, 125.82,
(RS)-(4l,6l)-2-Benzyl-1,3-bis-(1-methylethyl)-4,6-diphenyl-1,3,2-
diaza-phosphorinane 2-oxide (5c): From 195 mg (0.55 mmol)
of diamine 7c, 0.33 mL (0.61 mmol) of n-BuLi (1.84 M),
and 78 µL (0.66 mmol) of benzyl bromide followed by puri-
fication by SiO2 column chromatography (hexane/EtOAc/i-
PrOH, 45:52:3) was obtained 198 mg (81%) of 5c as a col-
orless solid. An analytical sample was obtained by recry-
stallization from Et2O: mp 144–145°C. IR (CCl4): 3065 w,
1
1240 s. TLC: Rf 0.54 (hexane/EtOAc/i-PrOH, 45:52:3). H
NMR (300 MHz): 7.63–7.07 (m, 15 H), 4.56 (dt, J = 14.9,
3.7, 1 H), 3.91–3.82 (m, 2 H, HC(4)), 3.59 (dd, J = 18.6,
14.6, 1 H), 3.50–3.33 (m, 1 H), 3.38 (dd, J = 17.6, 14.6, 1
H), 2.28 (ddd, J = 15.2, 14.3, 3.9, 1 H), 2.12 (dt, J = 14.2,
4.1, 1 H), 1.12 (d, J = 6.6, 3 H), 1.03 (d, J = 7.0, 3 H), 0.87
(d, J = 6.7, 3 H), 0.76 (d, J = 6.7, 3 H). 13C NMR
(75.5 MHz): 144.35 (JCP = 3.0), 142.82, 134.80 (JCP = 7.8),
130.28, 130.19, 128.25, 128.15, 128.13, 128.02, 127.11,
59.29, 55.88, 48.59 (JCP = 6.9), 44.99 (JCP = 6.6), 42.12 (JCP
=
9.0), 20.76, 20.60, 19.86, 19.61. 31P NMR(121.6 MHz):
3.09. MS (70 eV): 536 (M+, 2), 133 (100). Anal. calcd. for
C35H41N2OP (412.55): C 78.33, H 7.70, N 5.22, P 5.77;
found: C 78.31, H 7.79, N 5.14, P 5.56.
126.93, 126.60, 126.28, 126.25, 58.34, 53.40, 49.64 (JCP
2.7), 46.22 (JCP = 5.4), 43.60 (JCP = 7.2), 43.40 (JCP
=
=
117.6), 23.51, 22.23, 21.30, 20.13 (JCP = 2.5). 31P NMR
(121.6 MHz) 21.64. MS (70 eV): 446 (M+), 355 (100). Anal.
calcd. for C28H35N2OP (446.57): C 75.31, H 7.90, N 6.27, P
6.94; found: C 75.26, H 7.94, N 6.24, P 6.86.
Representative procedure for the preparation of 2-alkyl-
1,3,2-diaza-phosphorinane 2-oxides
The detailed procedure for the preparation of 5b is given.
For all of the other diazaphosphorinanes only the amounts of
reagents and methods of purification are provided along with
the analytical data.
(RS)-(4l,6l)-2-Benzyl-1,3-bis-(2,2-dimethylpropyl)-4,6-diphenyl-1,3,2-
diaza-phosphorinane 2-oxide (5d): From 150 mg (0.36 mmol)
of 7d, 0.27 mL (0.40 mmol) of n-BuLi (1.48 M), and 87 µL
(0.73 mmol) of benzyl bromide followed by purification by
SiO2 column chromatography (hexane/EtOAc, 4:1) was ob-
tained 123 mg (67%) of 5d as a viscous oil. A sample of
(S,S)-5d was also prepared from (S,S)-7d in 81% yield. For
(S,S)-5d: [α] = –2.1 (c = 1.44, CHCl3), [α] = – 15.1 (c =
1.44, CHCl3). IR (CCl4): 3065 w, 1235 s. TLC: Rf 0.44 (hex-
ane/EtOAc, 4:1). 1H NMR (300 MHz): 7.65–7.05 (m, 15 H),
4.62 (dt, J = 15.3, 4.0, 1 H), 4.13 (ddd, J = 11.5, 7.2, 4.2, 1
H), 3.69 (dd, J = 18.4, 14.8, 1 H), 3.48 (dd, J = 17.4, 14.8, 1
H), 3.13 (dd, J = 14.8, 8.9, 1 H), 2.84 (dd, J = 14.9, 8.6, 1
H), 2.75 (dd, J = 14.9, 7.8, 1 H), 2.50 (ddd, J = 15.1, 12.0,
3.9, 1 H), 2.42 (dd, J = 14.8, 11.2, 1 H), 2.15 (dt, J = 13.9,
4.1, 1 H), 0.78 (s, 9 H), 0.72 (s, 9 H). 13C NMR (75.5 MHz):
141.62, 140.46, 134.98 (JCP = 7.4), 130.23, 130.14 128.35,
128.30, 128.12, 127.33, 127.31, 127.17, 127.03, 126.27,
126.24, 61.98, 59.32, 58.33 (JCP = 2.3), 55.91 (JCP = 2.8),
(RS)-(4l,6l)-2-Benzyl-1,3-diethyl-4,6-diphenyl-1,3,2-diazaphosphor-
inane 2-oxide (5b): To a flame-dried, 25-mL, three-necked,
round bottom flask equipped with a thermometer, a rubber
septum, a N2 inlet, and a magnetic stirring bar was added a
solution of 180 mg (0.55 mmol) of phosphite 7b in THF
(10 mL). The mixture was cooled to –78°C and 0.34 mL
(0.58 mmol) of n-BuLi (1.71 M) was slowly added to give a
yellow-orange solution which was stirred at –78°C for
15 min. Benzyl bromide (71 µL, 0.60 mmol) was then added
via syringe and the color dissipated immediately. After being
stirred for 1 h at –78°C, the reaction mixture was warmed to
rt, poured into water (20 mL), extracted with EtOAc (3 ×
15 mL), washed with brine (10 mL), and dried (Na2SO4).
Filtration followed by concentration gave a yellow oil which
was purified by SiO2 column chromatography (hex-
ane/EtOAc/i-PrOH, 35:62:3) to afford 140 mg (61%) of
diazaphosphorinane 5b as a foam. An analytical sample was
obtained by recrystallization from pentane/Et2O: mp 98–
99°C. IR (CCl4): 3031 w, 1239 s. TLC: Rf 0.22 (hex-
43.23 (JCP = 115.2), 42.88 (JCP = 9.3), 33.66, 33.02 (JCP
=
3.4), 28.98, 28.83. 31P NMR (121.6 MHz): 24.45. MS
(70 eV): 446 (M+ + 1 – (CH3)3C, 16), 445 (M+ – (CH3)3C,
51), 91 (100). Anal. calcd. for C32H43N2OP (502.68): C
76.46, H 8.62, N 5.57, P 6.16; found: C 76.32, H 8.62, N
5.53, P 6.20.
1
ane/EtOAc/i-PrOH, 34:63:3). H NMR (300 MHz): 7.52–
7.16 (m, 13 H), 6.77 (m, 2 H), 4.49 (dt, J = 15.4, 3.7, 1 H),
3.93 (dd, J = 12.0, 3.0, 1 H), 3.45 (d, J = 18.9, 2 H), 3.51–
3.35 (m, 1 H), 3.24 (heptet, J = 7.3, 1 H), 2.90 (heptet, J =
7.3, 1 H), 2.53–2.36 (m, 1 H), 2.07 (ddd, J = 14.0, 12.3, 4.3,
1 H), 1.91 (dt, J = 14.0, 3.2, 1 H), 1.01 (t, J = 7.1, 3 H), 0.96
(t, J = 6.9, 3 H). 13C NMR (75.5 MHz): 141.35 (JCP = 5.0),
(RS)-(4l,6l)-1,2,3-Tribenzyl-4,6-diphenyl-1,3,2-diazaphosphorinane
2-oxide (5e): From 288 mg (0.64 mmol) of 7e, 0.45 mL
(0.77 mmol) of n-BuLi (1.70 M), and 83 µL (0.70 mmol) of
© 2000 NRC Canada

684
Can. J. Chem. Vol. 78, 2000
benzyl bromide followed by purification by SiO2 column
chromatography (hexane/EtOAc, 2:1) afforded 285 mg
(83%) of 5e as a colorless solid. An analytical sample was
obtained by recrystallization from pentane/Et2O: mp 137–
138°C. IR (CCl41): 3065 w, 1219 s. TLC: Rf 0.35 (hex-
ane/EtOAc, 2:1). H NMR (300 MHz): 7.54–7.14 (m, 23 H)
and 6.85–6.82 (m, 2 H), 4.76 (dd, J = 15.7, 8.6, 1 H), 4.48
(dd, J = 14.5, 8.6, 1 H), 4.35 (dt, J = 15.0, 3.7, 1 H), 3.85
(dd, J = 15.7, 5.8, 1 H), 3.68 (dd, J = 19.8, 14.6, 1 H), 3.70–
3.62 (m, 1 H), 3.51 (dd, J = 17.9, 14.6, 1 H), 3.18 (t, J =
13.8, 1 H), 2.30 (ddd, J = 14.1, 12.6, 4.4, 1 H), 1.88 (dt, J =
14.4, 3.2, 1 H). 13C NMR (75.5 MHz): 141.14 (JCP = 4.4),
139.06, 137.26 (JCP = 4.2), 136.63, 134.33 (JCP = 8.3),
130.10, 130.05, 128.61, 128.40, 128.37, 127.67, 127.45,
127.30, 127.09, 127.06, 126.93, 126.53, 126.49, 58.53,
1.19 (d, J = 6.5, 3 H), 1.17 (d, J = 6.8, 3 H), 0.93 (d, J = 7.2,
3 H), 0.90 (d, J = 7.2, 3 H). 13C NMR (75.5 MHz): 144.76
(JCP = 3.2), 142.67, 128.21, 127.79, 126.91, 126.71, 126.63,
126.24, 55.73, 52.90, 48.69 (JCP = 3.2), 45.61 (JCP = 6.0),
43.54 (JCP = 7.3), 27.88 (JCP = 123.7), 23.01 (JCP = 2.5),
22.72, 21.19, 19.92, 8.31 (JCP
=
6.3). 31P NMR
(121.6 MHz): 27.51. Anal. calcd. for C23H33N2OP (384.50):
C 71.85, H 8.65, N 7.29, P 8.06; found: C 71.93, H 8.64, N
7.30, P 8.08.
(RS)-(4l,6l)-1,3-Bis-(2,2-dimethylpropyl)-4,6-diphenyl-2-ethyl-
1,3,2-diaza-phosphorinane 2-oxide (6d): From 670 mg
(1.52 mmol) of phosphite 7d, 1.05 mL (1.79 mmol) of
n-BuLi (1.70 M), and 195 µL (2.44 mmol) of ethyl iodide
followed by purification by SiO2 column chromatography
(hexane/EtOAc, 3:1–2:1) afforded 697 mg (97%) of diaza-
phosphorinane 6d as a foam. An analytical sample was ob-
tained by recrystallization from pentane: mp 124–125°C. IR
(CCl4): 3031 w, 1246 m. TLC: Rf 0.34 (hexane/EtOAc, 2:1).
1H NMR (300 MHz): 7.55 (d, J = 7.4, 2 H), 7.41 (t, J = 7.5,
2 H), 7.33–7.24 (m, 4 H), 7.12 (d, J = 7.1, 2 H), 4.62 (dt, J =
15.0, 4.0, 1 H), 4.10 (ddd, J = 11.8, 7.4, 4.5, 1 H), 3.30 (dd,
J = 14.8, 9.2, 1 H), 3.05 (dd, J = 14.7, 8.0, 1 H), 2.70 (dd, J =
14.8, 9.2, 1 H), 2.64 (dd, J = 14.7, 10.9, 1 H), 2.52–2.28 (m,
2 H), 2.18–1.97 (m, 2 H), 1.38 (dt, J = 18.5, 7.6, 3 H), 0.88
(s, 9 H), 0.79 (s, 9 H). 13C NMR (75.5 MHz): 142.03,
140.17, 128.41, 128.18, 127.26, 127.12, 127.09, 126.92,
55.41, 48.88 (JCP = 4.6), 47.85 (JCP = 3.2), 42.90 (JCP
=
121.6), 41.82 (JCP = 5.2). 31P NMR (121.6 MHz): 24.84. MS
(70 eV): 91 (100). Anal. calcd. for C36H35N2OP (542.66): C
79.68. H 6.50, N 5.16, P 5.71; found: C 79.62, H 6.53, N
5.07, P 5.65.
(RS)-(4l,6l)-2-Benzyl-1,3-bis-(2,4,6-trimethylphenylmethyl)-
4,6-diphenyl-1,3,2-diazaphosphorinane 2-oxide (5f): From
570 mg (1.06 mmol) of phosphite 7f, 0.65 mL (1.11 mmol)
of n-BuLi (1.71 M), and 138 µL (1.17 mmol) of benzyl bro-
mide followed by purification by SiO2 column chromatogra-
phy (hexane/EtOAc, 4:1–2:1) afforded 402 mg (61%) of
diazaphosphorinane 5f as a foam. An analytical sample was
obtained by recrystallization from pentane/Et2O: mp 149–
150°C. IR (CCl4): 3063 w, 1223 s. TLC: Rf 0.54 (hex-
61.44, 59.55, 57.35 (JCP = 3.0), 56.50 (JCP = 2.5), 42.29 (JCP
=
9.4), 33.79, 33.23 (JCP = 2.9), 29.35 (JCP = 121.8), 28.89,
28.85, 8.60 (JCP = 6.0). 31P NMR (121.6 MHz): 30.99. MS
(70 eV): 425 (M+ – CH3, 2.7), 383 (100). Anal. calcd. for
C27H41N2OP (440.61): C 73.60, H 9.38, N 6.36, P 7.03;
found: C 73.65, H 9.42, N 6.34, P 6.98.
1
ane/EtOAc, 2:1). H NMR (300 MHz): 7.63 (d, J = 7.5, 1
H), 7.40–7.22 (m, 9 H), 6.99 (dd, J = 5.1, 1.6, 2 H), 6.74
(dd, J = 7.5, 3.7, 2 H), 6.64 (s, 2 H), 6.32 (s, 2 H), 4.33–4.24
(m, 4 H), 4.10 (dd, J = 13.5, 9.1, 1 H), 3.36 (quintet, J =
5.6), 3.48 (dd, J = 19.7, 14.4, 1 H), 3.35 (dd, J = 17.4, 14.4,
1 H), 2.46 (m, 1 H), 2.10 (m, 1 H), 2.19 (s, 6 H), 2.14 (s, 3
H), 2.00 (s, 3 H), 1.68 (s, 6 H, 2 X). 13C NMR (75.5 MHz):
142.97 (JCP = 2.7), 141.01, 138.21 (JCP = 7.8), 136.72,
136.15, 134.26 (JCP = 7.3), 130.25, 130.16, 129.60, 129.46
(JCP = 5.5), 128.83, 128.19, 128.11, 127.38, 126.61, 126.39,
Representative procedure for the alkylation of 1,3,2-
diazaphosphorinane 2-oxides
The detailed procedure for the methylation of 5a to afford
8a is given. For all of the other alkylations, only the amounts
of reagents, methods of analysis of diastereomeric mixtures
and purification of the products are provided, along with the
analytical data.
126.32, 126.29, 126.10, 125.67, 59.92, 57.14, 45.96 (JCP
2.4), 44.81 (JCP = 2.0), 43.41 (JCP = 6.4), 42.57 (JCP
=
=
(RS)-(4l,6l,1′x)-1,3-Dimethyl-4,6-diphenyl-2-(1-phenylethyl)-
1,3,2-diaza-phosphorinane 2-oxide (8a): A flame-dried, 25-
mL, three-necked, round-bottomed flask was charged with
105 mg (0.27 mmol) of diazaphosphorinane 5a and 4 mL of
THF. The flask was cooled to –78°C using a dry ice-acetone
bath. n-BuLi (0.16 mL, 0.27 mmol, 1.71 M) was added to
give a pale-yellow solution which was stirred for 30 min.
Methyl iodide (65 µL, 1.04 mmol) was added by a syringe
and the color dissipated slowly. After stirring for 1.1 h at
–78°C, the reaction mixture was quenched with water
(0.2 mL), then poured into water (10 mL), extracted with
EtOAc (3 × 10 mL), and dried (Na2SO4). Filtration followed
by concentration gave a pale yellow oil, which was assayed
by HPLC (Supelco LC-NH2) and found to be a mixture of
diastereomers (87:13). Purification by column chromatogra-
phy (hexane/EtOAc/i-PrOH, 35:62:3) gave 19 mg (17.5%)
of minor 8a′ and 79.8 mg (73.3%) of major 8a as a colorless
solids. Data for 8a: mp 141–142°C (pentane/Et2O). IR
(CCl4): 3065 w, 1267 s. TLC: Rf = 0.3 (hexane/EtOAc/i-
102.7), 20.60, 20.40, 20.09, 19.55. 31P NMR (121.6 MHz):
26.87. MS (70 eV): 626 (M+, 1), 133 (100). Anal. calcd. for
C42H47N2OP (626.82): C 80.48, H 7.56, N 4.47, P 4.94;
found: C 80.60, H 7.62, N 4.40, P 4.86.
(RS)-(4l,6l)-1,3-Bis-(1-methylethyl)-4,6-diphenyl-2-ethyl-1,3,2-
diaza-phosphorinane 2-oxide (6c): From 310 mg (0.87 mmol)
of phosphite 7c, 0.56 mL (0.96 mmol) of n-BuLi, and
104 µL (1.31 mmol) of ethyl iodide followed by purification
by SiO2 column chromatography (hexane/EtOAc/i-PrOH,
35:62:3) afforded 310 mg (93%) of diazaphosphorinane 6c
as a colorless solid. An analytical sample was obtained by
recrystallization from Et2O/pentane: mp 141–142°C. IR
(CCl4): 3063 w, 1246 s. MS (70 eV): 384 (M+, 22), 355
(100). TLC: Rf 0.31 (hexane/EtOAc/i-PrOH, 35:62:3). 1H
NMR (300 MHz): 7.60 (d, J = 7.4, 2 H), 7.38 (t, J = 7.5, 2
H), 7.30–7.17 (m, 4 H), 7.16 (d, J = 6.8, 2 H), 4.51 (dt, J =
10.9, 3.7, 1 H), 3.98 (dheptet, J = 15.9, 6.9, 1 H), 3.85 (dt, J =
11.4, 4.7, 1 H), 3.68 (dheptet, J = 15.9, 6.9, 1 H), 2.30–2.12
(m, 3 H), 1.96 (octet, J = 7.5, 1 H), 1.39 (dt, J = 19.1, 7.6),
1
PrOH, 35:62:3). H NMR (300 MHz): 7.48–7.17 (m, 13 H),
© 2000 NRC Canada

Denmark and Kim
685
6.91 (m, 2 H), 4.08 (ddd, J = 11.7, 4.7, 2.6, 1 H), 3.69 (dd,
J = 11.9,3.1, 1 H), 3.51 (dq, J = 20.3, 7.3, 1 H), 2.78 (d, J =
7.8, 3 H), 2.45(d, J = 8.9, 1 H), 1.77 (dd, J = 17.1, 7.4, 3 H),
1.59 (m, 1 H), 1.47 (ddd, J = 14.3, 12.0, 4.8, 1 H). 13C NMR
(75.5 MHz): 141.56 (JCP = 6.5), 140.43 (JCP = 6.7), 140.35,
128.77, 128.69, 128.62, 128.12, 128.08, 128.04, 127.22,
127.14, 126.91, 126.64, 126.59, 126.53, 61.16, 59.12, 44.16
(JCP = 121.3), 40.86 (JCP = 3.3), 34.45 (JCP = 4.4), 33.99
(JCP = 1.7), 15.80 (JCP = 4.2). 31P NMR (121.6 MHz): 31.80.
MS (70 eV): 300 (M+ +1 – PhC2H4, 20), 626 (M+ – PhC2H4,
100). Anal. calcd. for C25H29N2OP (404.49): C 74.24, H
7.23, N 6.93, P 7.66; found: C 74.31, H 7.26, N 6.94, P
7.76. Data for 8a′: TLC: Rf = 0.42 (hexane/EtOAc/i-PrOH,
ple was obtained by recrystallization from pentane/Et2O: mp
114–117°C. IR (CCl4): 2904 s, 1252 s. TLC: Rf 0.41 (hex-
ane/EtOAc/i-PrOH, 35:60:5). HPLC: tR = 7.30 min (42%),
8.57 min (58%), Supelco LC-NH2, (hexane/EtOAc, 3:2),
flow rate = 1.0 mL/min). 1H NMR (CDCl3, 300 MHz):
7.48–7.17 (m, 15 H), 4.55 (dt, J = 13.1, 3.7, 0.4 H), 4.46 (dt,
J = 9.9, 3.8, 0.6 H), 4.14 (dt, J = 12.4, 3.0, 0.6 H), 4.04–3.77
(m, 1 H), 3.69–3.26 (m, 1.4 H), 2.62–2.52 (m, 0.6 H), 2.33–
2.23 (m, 0.4 H), 1.98–1.80 (m, 1 H), 1.82 (dd, J = 17.5, 7.2,
1.8 H), 1.74 (dd, J = 17.4, 7.3, 1.2 H), 1.29 (d, J = 6.8, 1.8
H) 1.22 (d, J = 6.7, 1.2 H), 1.16 (d, J = 6.9, 1.2 H), 0.96 (d,
J = 6.8 1.8 H), 0.86 (d, J = 6.6, 1.2 H), 0.72 (d, J = 6.7, 1.8
H), 0.54 (d, J = 6.8, 1.2 H), 0.48 (d, J = 6.7, 1.8 H). 13C
NMR (75.5 MHz): 145.30 (JCP = 3.8), 144.33 (JCP = 4.7),
143.47, 143.43, 141.50 (JCP = 5.2), 141.12 (JCP = 4.8),
129.25, 129.17, 129.06, 128.98, 128.42, 128.21, 128.19,
128.00, 127.97, 127.93, 127.91, 127.83, 127.26, 127.11,
127.07, 127.03, 126.95, 126.84, 126.49, 126.45, 126.30,
126.28, 55.20, 54.97, 54.47 (JCP = 1.9), 54.25, 49.35, 48.57
(JCP = 117.6), 47.54 (JCP = 3.4), 47.01 (JCP = 4.3), 46.85
(JCP = 119.6), 43.10 (JCP = 6.2), 43.00, 25.15, 24.74, 23.12
1
35:62:3). H NMR (300 MHz): 7.51–7.09 (m, 15 H), 4.26
(dt, J = 11.3, 3.5, 1 H), 3.77 (dd, J = 12.2, 1.5, 1 H), 3.35
(dq, J = 17.8, 7.2, 1 H), 2.59 (d, J = 8.4, 3 H), 2.45 (m, 1 H),
2.07 (d, J = 7.4, 3 H), 2.03 (m, 1 H), 1.77 (dd, J = 117.6,
7.2, 3 H). 31P NMR (121.6 MHz): 29.82. MS (70 eV): 313
(14), 300 (M+ + 1 – PhC2H4, 20), 626 (M+ – PhC2H4, 100).
(RS)-(4l,6l,1′x)-1,3-Diethyl-4,6-diphenyl-2-(1-phenylethyl)-
1,3,2-diaza-phosphorinane 2-oxide (8b): From 98 mg
(0.23 mmol) of 5b, 138 µL (0.23 mmol) of n-BuLi (1.70 M),
and 44 µL (0.71 mmol) of methyl iodide followed by purifi-
cation by SiO2 column chromatography (hexane/EtOAc/i-
PrOH, 31:62:7) was obtained 80 mg (78%) of a 61:39
(HPLC) diastereomeric mixture of 8b as a sticky oil and
14.3 mg (13%) of recovered 5b. An analytical sample was
obtained by recrystallization from pentane/Et2O at –78°C:
mp 49–53°C. IR (CCl4): 3029 w, 1239 s. TLC: Rf 0.44 (mi-
nor), 0.34 (major) (hexane/EtOAc/i-PrOH, 31:62:7). HPLC:
tR = 7.25 min (39%), 8.37 min (61%), (Supelco LC-NH2,
(JCP = 3.3), 21.91 (JCP = 2.6), 21.89, 21.36, 20.22 (JCP
=
4.2), 18.71 (JCP = 3.4), 18.27 (JCP = 4.1), 18.06 (JCP = 3.4).
31P NMR (121.6 MHz): 29.16 (major), 28.13 (minor). MS
(70 eV): 445 (M+ – CH3), 355 (100). Anal. calcd. for
C29H37N2OP (460.60): C 75.62, H 8.10, N 6.08, P 6.72;
found: C 75.42, H 8.17, N, 5.99, P 6.74.
(RS)-(4l,6l,1′x)-1,3-Bis-(2,2-dimethylpropyl)-4,6-diphenyl-2-
(1-phenylethyl)-1,3,2-diazaphosphorinane 2-oxide (8d): From
180 mg (0.36 mmol) of 5d, 211 µL (0.36 mmol) of n-BuLi
(1.70 M), and 67 µL (1.07 mmol) of methyl iodide followed
by purification by SiO2 column chromatography (hex-
ane/EtOAc, 2:1) was obtained 152 mg (82%) of a 92:8 (31P
NMR) diastereomeric mixture of 8d as a foam and 19.5 mg
(11%) of recovered 5d. An analytical sample was obtained
by recrystallization from TBME. Enantiomerically enriched
(–)-8d was also prepared from (S,S)-5d in 74% yield with
94:6 ratio of diastereomers: mp 150–152°C. For (–)-8d:
[α] = – 98.4 (c = 1.04, CHCl3), [α] = – 281.5 (c = 1.04,
CHCl3). IR (CCl4): 3065 w, 1244 s. TLC: Rf 0.54 (hex-
ane/EtOAc, 2:1). HPLC: tR = 8.30 min (92%), 9.62 min
(8%), (Supelco LC-NH2, (hexane/EtOAc, 85:15), flow rate =
1
(hexane/EtOAc, 30:70), flow rate = 1.0 mL/min). H NMR
(300 MHz): 7.57–7.08 (m, 15 H), 4.50–4.45 (m, 1H), 4.02–
3.95 (m, 1 H), 3.53–3.19 (m, 2.6 H), 3.04–2.90 (m, 1 H),
2.64–2.52 (m, 1 H), 2.42 (ddd, J = 14.0, 10.2, 4.1, 0.4 H),
2.31 (dheptet, J = 9.2, 6.9, 0.4 H), 2.07 (dt, J = 14.6, 3.1, 0.4 H),
1.95 (ddd, J = 16.8, 14.2, 4.3, 0.6 H), 1.83–1.78 (m, 0.6 H),
1.77 (dd, J = 9.6, 7.4, 1.8 H), 1.74 (dd, J = 10.0, 7.3, 1.2 H),
1.08 (t, J = 7.1, 1.8 H), 1.03 (t, J = 7.0, 1.2 H), 0.96 (t, J =
6.9, 1.8 H), 0.44 (t, J = 7.1, 1.2 H). 13C NMR (75.5 MHz):
142.20 (JCP = 4.8), 141.38 (JCP = 5.3), 140.94 (JCP = 5.7),
140.81 (JCP = 6.2), 140.31, 140.05, 129.03, 128.99, 128.59,
128.44, 128.39, 128.29, 128.12, 128.06, 127.42, 127.38,
127.22, 127.20, 127.10, 126.99, 126.92, 126.67, 126.60,
1
1.0 mL/min). H NMR (300 MHz): 7.60–7.14 (m, 15 H),
4.65–4.58 (m, 0.08 H), 4.39–4.33 (m, 1.84 H), 4.24–4.17
(m, 0.08 H), 3.46 (dq, J = 14.3, 7.3, 1 H), 3.29 (dd, J = 14.6,
8.0, 0.92 H), 3.22 (dd, J = 14.8, 8.4, 0.08 H), 3.12 (dd, J =
14.8, 5.9, 0.08 H), 2.96 (dd, J = 15.2, 8.5, 0.08 H), 2.73
(ddd, J = 16.5, 12.9, 4.2, 0.92 H), 2.55–2.44 (m, 1.92 H),
2.34–2.21 (m, 0.08 H), 2.15–1.93 (m, 2 H), 1.77 (dd, J =
17.6, 7.2, 0.24 H), 1.75 (dd, J = 16.8, 7.2, 2.76 H). 13C NMR
(75.5 MHz): 142.07, 141.86 (JCP = 5.5), 141.67, 129.38,
129.29, 129.06, 128.99, 128.66, 128.28, 128.03, 127.62,
127.41, 127.33, 127.19, 127.10, 127.01, 126.85, 126.57,
126.54, 126.42, 63.44, 61.36 (JCP = 1.7), 60.89, 58.75,
126.58, 126.46, 57.87, 57.41, 55.05, 54.18, 48.46 (JCP
121.7), 45.86 (JCP = 122.0), 41.61 (JCP = 5.8), 41.27 (JCP
4.2), 39.93 (JCP = 2.9), 39.85, 39.81, 39.64, 17.63 (JCP
3.2), 17.26 (JCP = 3.7), 13.59, 13.33 (JCP = 3.7), 13.28,
12.20 (JCP = 3.6). 31P NMR (121.6 MHz): 29.34 (major),
28.76 (minor). MS (70 eV): 328 (M+ +1 – PhC2H4, 22), 327
(M+ – PhC2H4, 100). Anal. calcd. for C27H33N2OP (432.54):
C 74.97, H 7.69, N 6.48, P 7.16; found: C 74.88, H 7.87, N
6.36, P 6.94.
=
=
=
(RS)-(4l,6l,1′x)-1,3-Bis(1-methylethyl)-4,6-diphenyl-2-(1-phenyl-
ethyl)-1,3,2-diazaphosphorinane 2-oxide (8c): From 170 mg
(0.38 mmol) of 5c, 224 µL (0.38 mmol) of n-BuLi (1.70 M),
and 71 µL (1.14 mmol) of methyl iodide followed by purifi-
cation by column chromatography (hexane/EtOAc/i-PrOH,
35:60:5) was obtained 153 mg (87%) of a 58:42 (31P NMR)
diastereomeric mixture of 8c as a foam. An analytical sam-
57.98, 57.70 (JCP = 2.7), 56.11 (JCP = 1.9), 55.19 (JCP
2.2), 49.64 (JCP = 109.5), 47.11 (JCP = 110.0), 42.78 (JCP
=
=
9.5), 42.49 (JCP = 7.2), 34.27, 33.52, 32.46 (JCP = 3.7),
31.68 (JCP = 3.2), 29.34, 29.23, 29.09, 28.27, 20.19 (JCP
=
4.9), 18.66 (JCP = 4.2). 31P NMR (121.6 MHz): 29.55 (mi-
nor), 28.47 (major). MS (70 eV): 501 (M+ – CH3, 2.2), 411
© 2000 NRC Canada

686
Can. J. Chem. Vol. 78, 2000
(100). Anal. calcd. for C29H37N2OP (516.71): C 76.71, H
8.78, N 5.42, P 5.99; found: C 76.64, H 8.79, N 5.40, P
5.97.
129.74, 129.67, 129.63, 129.55, 129.39, 129.31, 128.96,
128.88, 128.74, 128.66, 128.27, 128.20, 127.40, 126.96,
126.93, 126.81, 126.71, 126.64, 126.52, 126.41, 126.12,
126.07, 125.99, 125.60, 125.43, 60.87, 60.44, 56.61, 56.43,
49.40, 47.57 (JCP = 113.4), 46.93 (JCP = 2.9), 45.57, 44.41
(JCP = 2.0), 43.31, 42.98 (JCP = 10.6), 22.22, 20.87, 20.59,
(RS)-(4l,6l,1′x)-1,3-Dibenzyl-4,6-diphenyl-2-(1-phenylethyl)-
1,3,2-diaza-phosphorinane 2-oxide (8e): From 192 mg
(0.35 mmol) of 5e, 0.21 mL (0.35 mL) of n-BuLi (1.70 M),
and 66 mL (1.06 mmol) of methyl iodide followed by purifi-
cation by SiO2 column chromatography (hexane/EtOAc,
4:1–2:1) was obtained 189 mg (96%) of a 75:25 (HPLC)
diastereomeric mixture of 8e as a colorless solid. An analyti-
cal sample was obtained by recrystallization from
pentane/Et2O: mp 175–179°C. IR (CCl4): 3065 w, 1210 s.
MS (70 eV): 451 (100). TLC: Rf 0.47 (hexane/EtOAc, 4:1).
HPLC: tR = 16.39 min (25%), 19.15 min (75%), (Supelco
LC-NH2, (hexane/EtOAc, 85:15), flow rate = 1.0 mL/min).
1H NMR (300 MHz): 7.70–6.49 (m, 25 H), 4.90 (dd, J =
16.5, 8.1, 0.75 H), 4.86 (dd, J = 14.0, 7.0, 0.25 H), 4.40 (dd,
J = 14.8, 7.8, 0.75 H), 4.36 (dt, J = 15.4, 3.5, 0.75 H), 4.11
(dt, J = 12.7, 3.6, 0.25 H), 4.03 (dd, J = 16.5, 4.0, 0.75 H),
3.88 (dd, J = 14.7, 7.3, 0.25 H), 3.79–3.75 (m, 0.25 H), 3.67
(dd, J = 14.7, 3.4, 0.25 H), 3.60–3.40 (m, 2 H), 2.89 (t, J =
14.2), 2.57–2.47 (m, 0.25 H), 2.29–2.19 (m, 0.75 H), 1.87
(dd, J = 17.9, 7.3, 0.75 H), 1.76 (dd, J = 17.4, 7.2, 2.25 H),
1.76 (dd, J = 17.4, 7.2, 2.25 H), 1.87–1.64 (m, 1 H). 13C
NMR (75.5 MHz): 141.81 (JCP = 3.7), 141.04 (JCP = 6.1),
140.61 (JCP = 4.7), 138.88, 138.67, 137.32 (JCP = 4.8),
136.73 (JCP = 4.9), 136.60 (JCP = 7.3), 130.52, 130.26,
129.15, 129.06, 128.98, 128.71, 128.47, 128.45, 128.32,
128.20, 128.18, 128.12, 128.06, 127.77, 127.51, 127.56,
127.43, 127.29, 127.18, 126.98, 126.89, 126.82, 126.61,
126.53, 59.30, 58.77, 55.34, 55.14, 50.48 (JCP = 3.3), 49.43
(JCP = 3.9), 48.98 (JCP = 120.7), 48.72 (JCP = 123.7), 48.39
20.51, 20.36, 20.07, 19.71, 19.43 (JCP = 3.5), 17.60 (JCP
=
4.8), 14.08, 13.96. 31P NMR (121.6 MHz): 32.15 (minor),
30.42 (major). MS (70 eV): 640 (M+, 0.7), 133 (100). Anal.
calcd. for C43H49N2OP (640.85): C 80.59, H 7.71, N 4.37, P
4.83; found: C 80.64, H 7.71, N 4.35, P 4.79.
(RS)-(4l,6l,1′x)-1,3-Dimethyl-4,6-diphenyl-2-(1-methyl-2-phenyl-
ethyl)-1,3,2-diazaphosphorinane 2-oxide (9a): From 230 mg
(0.70 mmol) of 6a, 0.45 mL (0.70 mmol) of n-BuLi (1.55 M),
and 125 µL (1.05 mmol) of benzyl bromide followed by pu-
rification by SiO2 column chromatography (hexane/EtOAc/i-
PrOH, 35:60:5) was obtained 243 mg (83%) of a 65:35 (31P
NMR) diastereomeric mixture of 9a as a viscose oil. IR
(CCl4): 3067 w, 1267 s. TLC: Rf 0.51 (hexane/EtOAc/i-
1
PrOH, 35:60:5). H NMR (300 MHz): 7.47–7.12 (m, 15 H),
4.43–4.35 (m, 1 H), 3.82–3.79 (m, 1 H), 3.48 (ddd, J =
112.1, 8.1, 2.9, 0.35 H), 3.38 (ddd, J = 12.5, 9.0, 2.4, 0.65
H), 2.75 (d, J = 7.6, 3 H), 2.64 (d, J = 8.2, 1.95 H), 2.61 (d,
J = 7.8, 1.05 H), 2.71–2.46 (m, 2 H), 2.43–2.24 (m, 1 H),
2.13–2.04 (m, 1 H), 1.22 (dd, J = 17.8, 7.3, 1.95 H), 1.19
(dd, J = 17.5, 7.2, 1.05 H). 13C NMR (75.5 MHz): 142.00
(JCP = 5.1), 140.17, 140.06, 139.93, 139.87, 139.84, 128.72,
128.67, 128.55, 128.40, 128.17, 128.13, 127.23, 127.09,
126.46, 126.33, 126.18, 126.00, 125.89, 125.85, 62.32,
62.20, 59.87, 59.80, 42.43 (JCP = 126.6), 41.64 (JCP = 4.4),
41.49 (JCP = 5.3), 40.40 (JCP = 126.9), 37.02, 36.59, 34.31,
34.26, 34.18, 33.59, 13.54 (JCP = 3.7), 12.99 (JCP = 3.3). 31P
NMR (121.6 MHz): 33.82 (minor), 33.76 (major). MS (70 eV):
418 (M+, 5), 91 (100). Anal. calcd. for C36H31N2OP
(418.52): C 74.62, H 7.47, N 6.69, P 7.40; found: C 74.47,
H 7.53, N 6.62, P 7.28.
(JCP = 2.7), 48.08 (JCP = 2.1), 41.61 (JCP = 5.1), 18.76 (JCP
=
4.3), 18.06 (JCP = 3.8). 31P NMR (121.6 MHz): 29.54 (as a
mixture). Anal calcd. for C29H37N2OP (556.69): C 75.62, H
8.10, N 6.08, P 6.72; found: C 75.42, H 8.17, N 5.99, P
6.74.
(RS)-(4l,6l,1′x)-4,6-Diphenyl-1,3-bis-(2,4,6-trimethylphenyl-
methyl)-2-(1-phenylethyl)-1,3,2-diazaphosphorinane 2-oxide
(8f): From 250 mg (0.40 mmol) of 5f, 0.24 mL (0.40 mmol)
of n-BuLi (1.70 M), and 75 µL (1.05 mmol) of methyl io-
dide followed by purification by SiO2 column chromatogra-
phy (hexane/EtOAc, 4:1) was obtained 240 mg (94%) of a
74:26 (31P NMR) diastereomeric mixture of 8f as a colorless
solid. An analytical sample was obtained by recrystallization
from Et2O: mp 208–209°C. IR (CCl4) 3063 m, 1229 s. TLC:
(RS)-(4l,6l,1′x)-1,3-Bis-(1-methylethyl)-4,6-diphenyl-2-(1-methyl-
2-phenylethyl)-1,3,2-diazaphosphorinane 2-oxide (9c): From
240 mg (0.62 mmol) of 6c, 0.40 mL (0.62 mmol) of n-BuLi
(1.56 M), and 111 µL (0.93 mmol) of benzyl bromide fol-
lowed by purification by SiO2 column chromatography (hex-
ane/EtOAc/i-PrOH, 35:62:3) was obtained 286 mg (96%) of
a 78:22 (HPLC) diastereomeric mixture of 9c as a colorless
solid. An analytical sample was obtained by recrystallization
from pentane/TBME: mp 138–142°C. IR (CCl4): 3029 w,
1231 s. TLC: Rf 0.56 (hexane/EtOAc/i-PrOH, 35:60:5).
HPLC: tR = 19.08 min (78%), 23.20 min (22%), (Supelco
1
Rf 0.42 (hexane/EtOAc, 4:1). H NMR (300 MHz): 7.63 (d,
J = 7.4, 2 H), 7.38 (t, J = 7.3, 2 H), 7.27–6.80 (m, 11.26 H),
6.85 (m, 1.48 H), 6.57 (s, 0.74 H), 6.53 (s, 0.26 H), 6.43 (d,
J = 7.6, 0.26 H), 6.40 (s, 0.26 H), 6.27 (s, 0.74 H), 4.90 (dd,
J = 13.8, 6.3, 0.76 H), 4.68 (dd, J = 13.4, 7.7, 0.26 H), 4.51
(dd, J = 13.8, 8.1, 0.26 H), 4.42 (dd, J = 13.8, 4.4, 0.76 H),
4.41–4.34 (m, 0.26 H), 4.12 (m, 0.74 H), 3.98 (dd, J = 13.5,
6.0, 0.74 H), 3.91–3.84 (m, 1.52 H), 3.71–3.65 (m, 0.26 H),
3.59 (dq, J = 14.1, 7.1, 0.74 H), 3.41 (dq, J = 16.3, 7.4, 0.26
H), 2.85–2.74 (m, 0.74 H), 2.62 (d, J = 13.5, 0.78 H), 2.49–
2.38 (m, 0.26 H), 2.34 (s, 0.78 H), 2.13–1.79 (m, 20.44 H).
1
LC-NH2, (hexane/EtOAc, 4:1), flow rate = 1.0 mL/min). H
NMR (300 MHz): 7.67–7.19 (m, 15 H), 4.59 (dt, J = 14.6,
3.6, 1 H), 4.08–3.95 (m, 2 H), 3.84–3.59 (m, 2 H), 2.65
(ddd, J = 12.9, 12.6, 3.9, 1 H), 2.63–2.33 (m, 2 H), 2.02 (dt,
J = 14.3, 3.6, 1 H), 1.40–1.19 (m, 4 H), 1.38 (d, J = 6.8),
1.27 (d, J = 6.7), 0.98 (d, J = 6.8), 0.94 (d, J = 6.8, 12 H),
0.91 (d, J = 6.9), 0.87 (d, J = 6.9). 13C NMR (75.5 MHz):
144.53 (JCP = 4.7), 143.03, 140.71 (JCP = 17.3), 128.75,
128.67, 128.19, 128.17, 127.78, 126.94, 126.80, 126.65, 126.42,
13C NMR (75.5 MHz): 142.53 (JCP = 4.5), 142.22 (JCP
2.1), 142.07 (JCP = 1.7), 141.40 (JCP = 5.1), 140.78 (JCP
=
=
125.84, 125.79, 55.24, 54.74, 53.64, 53.58, 49.39 (JCP =
1.9), 48.83 (JCP = 2.8), 46.49 (JCP = 7.4), 46.41 (JCP = 5.3),
43.54 (JCP = 7.4), 43.46 (JCP = 5.7), 39.98 (JCP = 124.1),
5.4), 138.78, 138.01, 137.73, 136.62, 136.45, 136.18,
© 2000 NRC Canada

Denmark and Kim
687
38.72 (JCP = 125.4), 38.49, 37.52, 24.21, 23.89, 22.91 (JCP
=
Acknowledgment
3.2), 22.54 (JCP = 2.2), 21.48, 21.39, 20.13 (JCP = 4.0), 19.96
(JCP = 3.5), 15.01 (JCP = 3.6), 13.75 (JCP = 2.8). 31P NMR
(121.6 MHz): 31.58 (minor), 31.23 (major). MS (70 eV):
355 (100). Anal. calcd for C30H39N2OP (474.62): C 75.92, H
8.28, N 5.90, P 6.53; found: C 75.86, H 8.34, N 5.85, P
6.42.
We wish to thank the National Institute of Health (PHS
R01 GM45532) for financial support. We are grateful to Dr.
Michael Kranz for obtaining the X-ray crystal structure of
(S*,S*,S*)-8a.
References
(RS)-(4l,6l,1′x)-1,3-Bis-(2,2-dimethylpropyl)-4,6-diphenyl-2-
(1-methyl-2-phenylethyl)-1,3,2-diazaphosphorinane 2-oxide (9d):
From 265 mg (0.60 mmol) of 6d, 0.38 mL (0.60 mmol) of
n-BuLi, and 107 µL (0.90 mmol) of benzyl bromide fol-
lowed by purification by SiO2 column chromatography (hex-
ane/EtOAc, 2:1) was obtained 314 mg (98%) of a 92:8
(HPLC) diastereomeric mixture of 9d as a foam. An analyti-
cal sample was obtained by recrystallization from Et2O: mp
208–209°C. IR (CCl4): 3065 w, 1200 s. TLC: Rf 0.48 (hex-
ane/EtOAc, 2:1). HPLC: tR = 46.13 min (8%), 49.36 min
(92%), (LC-Prep-Si (hexane/EtOAc/i-PrOH, 79.8:20:0.2),
1. (a) J.-F. Biellmann and J.P. Ducep. Org. React. (N.Y.), 27, 1
(1982); (b) D. Hoppe. Angew. Chem. Int. Ed. Engl. 23, 932
(1984); (c) N.H. Werstiuk. Tetrahedron, 39, 205 (1983); (d) S.
Oae and Y. Uchida. In The chemistry of sulfones and
sulfoxides. Edited by C.J.M. Sterling, S. Patai, and Z.
Rappoport. Wiley–Interscience, New York. 1988. Chap. 12;
(e) G. Solladie. Chimia, 38, 233 (1984); ( f ) G. Solladie. Syn-
thesis, 185 (1981); (g) A. Krief. Tetrahedron, 36, 2531 (1980);
(h) P. Beak, W.J. Zajdel, and D.B. Reitz. Chem. Rev. 84, 47
(1984); (i) A.I. Meyers. Aldrichimica Acta, 18, 59 (1985);
(j) T. Kramer, J.-R. Schwork, and D. Hoppe. Tetrahedron Lett.
30, 7037 (1989); (k) D. Seebach, R. Hassig, and J. Gebriel.
Helv. Chim. Acta, 66, 308 (1983); (l) H. Siegal. Top. Curr.
Chem. 106, 55 (1982); (m) J.I.G. Cadogan (Editor).
Organophosphorus reagents in organic synthesis. Academic
Press, New York. 1979; (n) J. Clayden and S. Warren. Angew.
Chem. Int. Ed. Engl. 35, 241 (1996); (o) C.R. Johnson.
Aldrichimica Acta, 18, 3 (1985); (p) B. Zwannenburg and
A.J.H. Klunder (Editors). Perspectives in the organic chemis-
try of sulfur. Elsevier, Amsterdam. 1987; (q) S. Oae and Y.
Uchida. In The chemistry of sulfones and sulfoxides. Edited by
S. Patai, Z. Rappoport, and C.J.M. Stirling. Wiley, New York.
1988. Chap. 12; (r ) H.J. Reich. In Organoselenium chemistry.
Edited by D. Liotta. Wiley, New York. 1987. Chap. 5.
1
flow rate = 1.2 mL/min). H NMR (300 MHz): 7.61–7.13
(m, 15 H), 4.70 (dt, J = 15.1, 3.6, 0.92 H), 4.69 (dt, J = 14.4,
3.6, 0.08 H), 4.36–4.20 (m, 1 H), 3.72–3.66 (m, 0.92 H),
3.56–3.47 (m, 0.08 H), 3.39–3.22 (m, 2 H), 3.04 (dd, J =
14.8, 6.1, 0.08 H), 2.93 (dd, J = 14.9, 5.6, 0.92 H), 2.81–
2.43 (m, 4 H), 2.12 (dt, J = 14.5, 3.8, 1 H), 1.36 (dd, J =
17.3, 6.9, 0.06 H), 1.22 (dd, J = 18.0, 7.0, 2.7 H), 0.87 (s, 9 H),
0.85 (s, 9 H). 13C NMR (75.5 MHz): 141.51, 140.68, 140.45,
139.80, 128.92, 128.79, 128.43, 128.30, 128.27, 127.50,
127.24, 127.16, 127.07, 126.06, 125.96, 61.42, 61.05, 58.35
(JCP = 2.6), 58.28 (JCP = 1.8), 58.04, 57.46, 55.98(JCP = 1.7),
55.77 (JCP = 1.9), 42.77 (JCP = 7.0, 42.62 (JCP = 2.9), 41.35
(JCP = 120.6), 38.00, 37.77, 33.99, 33.04, 32.91 (JCP = 3.9),
32.77 (JCP = 3.6), 29.51, 29.38, 29.18, 29.11, 14.66 (JCP
=
2. (a) H.J. Bestmann, E. Heid, W. Ryschka, and J. Lienert.
Liebigs Ann. Chem. 1684 (1974); (b) C.R. Johnson, R.C.
Elliott, and N.A. Meanwell. Tetrahedron Lett. 23, 5005
(1982); (c) B.M. Trost and D.P. Curran. J. Am. Chem. Soc.
102, 5699 (1980); (d) P.A. Bartlett and K.L. Mclaren. Phos-
phorus Sulfur Relat. Elem. 37, 1 (1987); (e) D.H. Hua, R.
Chan-Yu-King, J.A. Kakie, and L.J. Myer. Am. Chem. Soc.
109, 5026 (1987); ( f ) M. Sting and W. Steglich. Synthesis,
132 (1990); (g) M. Sawamura, Y. Ito, and T. Hayashi. Tetra-
hedron Lett. 30, 2247 (1989); (h) R. Jacquier, F. Ouazzani,
M.L. Roumestant, and P. Villefont. Phosphorus Sulfur Relat.
Elem. 36, 73 (1988).
3. (a) S.E. Denmark and J.E. Marlin. J. Org. Chem. 52, 5742
(1987); (b) S.E. Denmark, G. Rajendra, and J.E. Marlin. Tetra-
hedron Lett. 30, 2469 (1989); (c) S.E. Denmark and R.L.
Dorow. J. Org. Chem. 55, 5926 (1990); (d) S.E. Denmark, H.
Stadler, R.L. Dorow, and J.H. Kim. J. Org. Chem. 56, 5063
(1991); (e) S.E. Denmark, N. Chatani, and S.V. Pansare. Tetra-
hedron, 48, 2191 (1992); ( f ) S.E. Denmark and C.-T. Chen. J.
Org. Chem. 59, 2922 (1994); (g) S.E. Denmark and C.-T.
Chen. Heteroat. Chem. 6, 133 (1995); (h) S.E. Denmark and
C.-T. Chen. J. Am. Chem. Soc. 117, 11879 (1995); (i) S.E.
Denmark and J.-H. Kim. J. Org. Chem. 60, 7535 (1995).
4. (a) J.K. Whitesell. Chem. Rev. 89, 1581 (1989); (b) K.
Tomioka. Synthesis, 541 (1990).
2.0), 14.31 (JCP = 3.1). 31P NMR (121.6 MHz): 33.18 (as a
mixture). MS (70 eV): 515 (M+ – CH3, 2.7), 473 (100).
Anal. calcd. for C34H47N2OP (530.73): C 76.95, H 8.93, N
5.28, P 5.84; found: C 76.90, H 9.03, N 5.26, P 5.82.
(S)-Dimethyl-1-phenylethylphosphonate (14): In a 25-mL,
round-bottomed flask equipped with a reflux condenser was
placed a solution of (–)-8d in 4 mL of HOAc acid and 48%
HBr solution. The reaction mixture was heated to reflux for
15 h, then was concentrated under reduced pressure to give a
yellow orange oil. The oil was passed through ion-exchange
resin column (AG® 50W-X8) using water as eluent. The ma-
jor fraction was collected and concentrated to give a white
solid. The solid was dissolved in water and basified with 1 N
NaOH solution (pH ~ 13), reacidified, concentrated, and the
acidic residue dissolved in methanol. The methanolic solu-
tion of 13 was treated with excess etheneal diazomethane di-
luted with water (10mL) and extracted with diethyl ether
(3 × 10 mL). The combined organic layers were dried
(Na2SO4), filtered, and concentrated to give a yellow oil.
The oil was purified by SiO2 column chromatography
(EtOAc/i-PrOH, 99:1) to give 53 mg (70%) of (S)-14 as a
colorless oil. An analytical sample was obtained by Kugelrohr
distillation: bp 115°C (0.3 Torr (1 Torr = 133.322 Pa)).
[α]405 –15.7 c = 1.1, CH2Cl2) ((S)-configuration, 87% ee).
5. (a) D. Cubinot, P. Mangeney, A. Alexakis, J.F. Normant, and
J.P. Lellouche. J. Org. Chem. 54, 2420 (1989); (b) P.
Mangeney, A. Alexakis, and J.F. Normant. Tetrahedron Lett.
29, 2677 (1988); (c) A. Alexakis, R. Sedrani, P. Mangeney,
and J.F. Normant. Tetrahedron Lett. 29, 4411 (1988); (d) E.J.
Corey and S.S. Kim. J. Am. Chem. Soc. 112, 4976 (1990);
1
TLC: Rf 0.23 (EtOAc/i-PrOH, 99:1). H NMR (300 MHz):
7.37–7.24 (m, 5 H), 3.69 (d, J = 10.0, 3 H), 3.53 (d, J =
10.0, 3 H), 3.21 (dq, J = 22.7, 7.7, 1 H), 1.58 (dd, J = 18.5,
7.5, 3 H). 31P NMR (121.6 MHz): 32.75.
© 2000 NRC Canada

688
Can. J. Chem. Vol. 78, 2000
(e) E.J. Corey and D.-H. Lee. J. Am. Chem. Soc. 113, 4026
(1991); ( f ) E.J. Corey, C.-M. Yu, and D.-H. Lee. J. Am.
Chem. Soc. 112, 878 (1990).
10. (a) S.E. Denmark and C.J. Cramer. J. Org. Chem. 55, 1806
(1990); (b) S.E. Denmark and M. Kranz. J. Org. Chem. 60,
5867 (1995); (c) S.E. Denmark, M. Kranz, K.A. Swiss, and
S.R. Wilson. J. Org. Chem. 61, 8551 (1996).
6. (a) E.J. Corey, C.-M. Yu, and S.S. Kim. J. Am. Chem. Soc.
111, 5495 (1989); (b) E.J. Corey, P.D. Jardine, S. Virgil, P.-W.
Yuen, and R.P. Connell. J. Am. Chem. Soc. 111, 9243 (1989);
(c) K. Tomioka, M. Nakajima, and K. Koga. J. Am. Chem.
Soc. 109, 6213 (1989); (d) K. Tomioka, M. Shindo, and K.
Koga. J. Am. Chem. Soc. 111, 8266 (1989); (e) M. Tokles and
J.K. Snyder. Tetrahedron Lett. 27, 3951 (1986); ( f ) W. Zhang,
J.L. Loebach, S.R. Wilson, and E.N. Jacobsen. J. Am. Chem.
Soc. 112, 2801 (1990); (g) T. Oishi and M. Hirama. J. Org.
Chem. 54, 5834 (1989); (h) M. Hirama, T. Oishi, and S. Ito. J.
Chem. Soc. Chem. Commun. 665 (1989); (i) H. Nishiyama, H.
Sakaguchi, T. Nakamura, M. Horihata, M. Kondo, and K. Itoh.
Organometallics, 8, 846 (1989); ( j ) H. Brunner and A.
Kurzinger. J. Organomet. Chem. 346, 413 (1988); (k) M.
Yoshioka, T. Kawakita, and M. Ohno. Tetrahedron Lett. 30,
1657 (1989); (l) K. Tomioka, M. Shindo, and K. Koga. J. Am.
Chem. Soc. 111, 8266 (1989); ( m) K. Maruoka, T. Itoh, T.
Shirasaka, and H. Yamamoto. J. Am. Chem. Soc. 110, 310
(1988).
7. (a) S. Hanessian, D. Delorme, S. Beaudoin, and Y. LeBlanc. J.
Am. Chem. Soc. 106, 5754 (1984); (b) S. Hanessian, D.
Delorme, S. Beaudoin, and Y. Leblanc. Chem. Scr. 25, N55
(1985); (c) S. Hanessian, Y.L. Bennani, and D. Delome. Tetra-
hedron Lett. 31, 6461 (1990.); (d) S. Hanessian and Y.L.
Bennani. Tetrahedron Lett. 31, 6465 (1990); (e) S. Hanessian
and S. Beaudoin. Tetrahedron Lett. 33, 7655 (1992); ( f ) S.
Hanessian and S. Beaudoin. Tetrahedron Lett. 33, 7659
(1992); (g) S. Hanessian, A. Gomtsyan, A. Payne, Y. Hervé,
and S. Beaudoin. J. Org. Chem. 58, 5032 (1993); (h) S.
Hanessian, D. Andreotti, and A. Gomtsyan. J. Am. Chem. Soc.
117, 10393 (1995); (i) Y.L. Bennani and S. Hanessian. Tetra-
hedron, 52, 13837 (1966); ( j) Y.L. Bennani, and S. Hanessian.
Chem. Rev. 97, 3161 (1997).
11. J.-H. Kim. Ph.D. thesis, Univerisity of Illinois, Urbana-
Champaign. 1992.
12. (a) H. Booth and R.U. Lemieux. Can. J. Chem. 49, 777
(1971); (b) R.O. Hutchins, L.D. Kopp, and E.L. Eliel. J. Am.
Chem. Soc. 90, 7174 (1968); (c) R.A.Y. Jones, A.R. Katritzky,
and A.C. Richards. J. Chem. Soc. Chem. Commun. 708
(1969); (d) F.G. Riddel and D.A.R. William. Tetrahedron Lett.
2073 (1971).
13. S.E. Denmark and J.-H. Kim. Synthesis, 229 (1992).
14. (a) N.N. Bhongle, R.H. Notter, and J.G. Turcotte. Synth.
Commun. 17, 1071 (1987); (b) T. Morita, Y. Okamoto, and H.
Sakurai. Chem. Lett. 435 (1980); (c) T. Morita, Y. Okamoto,
and H. Sakurai. Tetrahedron Lett. 2523 (1978); (d) M.H.B.
Stowell, J.M. Ueland, and R.W. McClard. Tetrahedron Lett.
31, 3261 (1990).
15. (a) R.S. Edmundson. J. Chem. Soc. C, 2730 (1969); (b) J.H.
Billman, J.L. Misenheimer, and R.A. Awl. J. Med. Chem. 7,
366 (1964); (c) R. Kraemer and J. Navech. Bull. Soc. Chim.
Fr. 3580 (1971).
16. (a) J.C. Tebby. In Organophosphorus chemistry, specialist peri-
odical reports. Edited by S. Tripett. 1976. Chap. 12.; (b) E.N.
Tsvetkov and M.I. Kabachnik. Russ. Chem. Rev. (Engl. Transl.),
40, 97 (1971); (c) L.C. Thomas. The Interpretation of the in-
frared spectra of phosphorus compounds. Heydon, London.
1974.
17. (a) J.R. Van Wazer, J.H. Letcher, V. Mark, C.H. Dungan.
Crutchfield, In Topics in phosphorus chemistry. Edited by M.
Grason and E.J. Griffith. Interscience, New York. 1968. Vol. 5;
(b) J.C. Tebby. Handbook of phosphorus-31 nuclear magnetic
resonance data. CRC Press, Boca Raton. 1991.
18. L. Wozniak and J. Chojnowski. Tetrahedron, 45, 2465 (1989).
19. R.L. Dorow. Ph.D. dissertation. University of Illinois, Urbana.
1990.
20. S. Arakawa, K. Kashiwabara, J. Fujita, and K. Saito. Bull.
Chem. Soc. Jpn. 50, 2108 (1977).
21. W.H. Pirkle, G. Mahler, and M.H. Hyun. J. Liq. Chromatogr.
9, 443 (1986).
8. (a) S.E. Denmark and R.L. Dorow. J. Am. Chem. Soc. 112,
864 (1990); (b) S.E. Denmark, K.A. Swiss, R.L. Dorow, P.C.
Miller, and S.R. Wilson. J. Am. Chem. Soc. 116, 2437 (1994).
9. S.E. Denmark, P.C. Miller, and S.R. Wilson. J. Am. Chem.
Soc. 113, 1468 (1991).
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