Development of P-stereogenic 2-phenyl-1,3,2-oxazaphosphorine ligands and their unexpected sensitivity to oxidation

Article abstract of DOI:10.1016/j.tetasy.2008.12.027

P-Stereogenic oxazaphosphorine compounds of the form 4 have not previously been reported as asymmetric ligands for metal-catalyzed reactions. In an effort to explore the behavior of such oxazaphosphorine ligands, monomeric oxazaphosphorine borane 9 and di

Full text of DOI:10.1016/j.tetasy.2008.12.027

Tetrahedron: Asymmetry 20 (2009) 69–77
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Development of P-stereogenic 2-phenyl-1,3,2-oxazaphosphorine ligands
and their unexpected sensitivity to oxidation
*
Wendy L. Benoit, Masood Parvez, Brian A. Keay
Department of Chemistry, University of Calgary, Calgary, AB, Canada T2N 1N4
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 July 2008
Accepted 11 December 2008
Available online 31 January 2009
P-Stereogenic oxazaphosphorine compounds of the form 4 have not previously been reported as asym-
metric ligands for metal-catalyzed reactions. In an effort to explore the behavior of such oxazaphospho-
rine ligands, monomeric oxazaphosphorine borane 9 and dimeric oxazaphosphorine boranes 25 and 26
were synthesized as catalyst precursors. The absolute configuration of the phosphorus center contained
in the oxazaphosphorines was determined by X-ray crystallography. Rhodium-catalyzed hydrogenation
of methyl 2-acetamidoacrylate using a dimerized spiro oxazaphosphorine ligand was performed with up
to 15% ee. The extreme sensitivity of the oxazaphosphorine ligands toward oxidation prevented further
optimization of the enantioselectivity.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
several approaches have been developed for the synthesis and
use of P-stereogenic ligands over the last four decades.8
Phosphines are a popular ligand choice for transition metal-cat-
alyzed asymmetric organic reactions. These ligands have an affinity
to coordinate with a wide variety of metals and their steric bulk and
electronic properties can be manipulated thoroughly and systemat-
ically.1 Phosphines have been shown to be useful in many different
types of reactions, including rhodium and ruthenium-catalyzed
hydrogenations,2 palladium-catalyzed allylic alkylations,3 copper-
catalyzed conjugate additions,4 copper-catalyzed hydrosilylations,5
as well as numerous cross-coupling reactions.6 Phosphines are also
ideal for creating a well-defined chiral environment around the
metal center. These phosphine ligands can be synthesized with
C-stereogenic elements in the backbone and/or with P-stereogenic
centers. This choice of chirality type greatly increases their versatil-
ity as potential ligands. Phosphines with backbone stereogenic ele-
ments are readily accessible using appropriate organic fragments
available from the chiral pool, and their ease of preparation has
led to their prominent use in the literature.2f,7
In contrast, phosphorus ligands with P-stereogenic centers are
much more challenging synthetic targets, as no P-stereogenic com-
pounds are found in the chiral pool. The stereogenic phosphorus
center must be introduced via asymmetric synthesis. Due to the
synthetic challenges posed by P-stereogenic centers, less work
has been carried out in this area of phosphorus-based ligands.
Despite this, P-stereogenic ligands are uniquely attractive for
asymmetric catalysis because they bring the center of chirality clo-
ser to the metal than the chirality from the backbone. Therefore,
There are many reports on the use of heterofunctionalized P-
stereogenic compounds 1 as ligands for metal-catalyzed asymmet-
ric reactions9 and 2-alkylated-1,3,2-oxazaphosphorine-2-oxides 2
as substrate-bound chiral auxiliaries for asymmetric synthetic
transformations (Fig. 1).10,11 Surprisingly, no reports could be
found in which 2-arylated-1,3,2-oxazaphosphorine-2-oxides 312
or 3-phenyl-1,3,2-oxazaphosphorines 425,13, have been used as
substrate-bound chiral auxiliaries or as metal-bound ligands in
asymmetric transformations. Our interest in the use of spiro 1,3-
amino alcohol 5 as an auxiliary in Diels–Alder reactions14 and in
palladium-catalyzed allylation reactions15 prompted us to investi-
gate whether 5 could be tethered to a phosphorus atom to make
2-phenyl-1,3,2-oxazaphosphorine 6, or dimerized to make a diphos-
phine ligand 7. The advantage of ligands 6 and 7 is that both have
P-stereogenic atoms and a backbone chirality for enhancing the
enantioselectivity in metal-catalyzed reactions. We herein report
the preparation of 6 and 7, and their use in a Rh-catalyzed hydroge-
nation of methyl 2-acetamidoacrylate and their observed high pro-
pensity for oxidation.
2. Results
Spiro 1,3-amino alcohol (ꢀ)-5 was prepared as previously de-
scribed14,15 and mono-N-methylated via a modified procedure
reported by Paquette and Tae16 to give 8 (94% over two steps,
Scheme 1). The direct treatment of 8 with dichlorophenylphosphine
Only one report was found in which a stereogenic center was found in the 1,3,2-
oxazaphosphorine ring; however, it was not used in any asymmetric reactions since it
readily oxidized to the corresponding oxide. See Ref. 12i.
* Corresponding author.
E-mail address: keay@ucalgary.ca (B.A. Keay).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.027

70
W. L. Benoit et al. / Tetrahedron: Asymmetry 20 (2009) 69–77
ture of diastereomers. The solution was not worked up at this stage
O
O
X
Ar
Ph
O
R
R
but further treated with borane–methyl sulfide to give a 2.5:1 mix-
ture of diastereomers 9 and 10 in a 90% yield. The major isomer 9
was crystallized from isopropanol/hexanes and its structure deter-
mined by X-ray crystallography (Fig. 2). The crystal structure
showed that the thermodynamically favored isomer (+)-9 had an
(R)-configuration at the phosphorus atom. The borane was
removed by heating 9 at 50 °C in the presence of 10 equiv of DAB-
CO19 for 2 days in chloroform to afford oxazaphosphorine 11 and a
small amount of oxazaphosphorine-2-oxide 12. The crude product
11 was obtained as a clear, colorless oil. Despite the use of de-
gassed solvents under an inert atmosphere, this sample always
contained some of the phosphorine-2-oxide 12, as noted by 31P
NMR analysis.à Any attempt to purify 11 by column chromatography
or distillation resulted in the formation of 12. Therefore, 11 was not
isolated but used directly in subsequent hydrogenation reactions.
P
P
P
P
O
O
O
N
N
N
N
R1
R1
R1
R1
1
2
X=OR
or NR2
3
4
.
.
Ph
O
P
H2N
OH
H
N
R
H
x
5
6 R=CH3, x=1
7 R=CH2, x=2
Figure 1.
(PhPCl2) gave a complex mixture consisting of two diastereomers
of 6 and two diastereomers of the corresponding phosphine oxides,
along with unidentified products. In order to minimize the forma-
tion of the phosphine oxides, a longer procedure was developed
that involved treatment of a precooled solution of dichlorophenyl-
phosphine at ꢀ78 °C with triethylamine (Et3N) and 8. This mixture
was then heated at reflux overnight to allow equilibration through
an inversion at the phosphorus atom17,18 to give an unequal mix-
BH3
Me
P
N
O
H
O
H2N
OH
H
NH
OH
H
OMe
pyr, DCM
1) Cl
H
(+)-9
Figure 2. X-ray crystal structure of (+)-9 (hydrogen atoms omitted for clarity).
2) LiAlH4, THF
85 oC, 24h
(94% 2 steps)
(-)-5
8
The crude mixture of 11 and oxide 12 was dissolved in degassed
methanol to make a stock solution. A portion was added to each of
Rh(NBD)2BF4 13, Rh(COD)BF4 14, and Rh(COD)2OTf 15 (Scheme 2).
1) PhPCl2, tol
2) BH3-Me2S
(90% 2 steps)
H2 (2 atm), MeOH
Ac
Ac
N
H
CO2Me
N
H
CO2Me
1 mol% 13, 14 or 15
2.2 mol % 11
24h
BH3
Ph
BH3
P
16
17
only racemic mixtures isolated
P
O
O
Ph
N
N
+
Scheme 2.
Methyl 2-acetamidoacrylate 16 was added to each reaction vial
and each was placed under two atmospheres of H2 (30 psi). These
reaction vessels were reacted in a Parr Shaker for 24 h. Each of
these hydrogenation attempts resulted in racemic product 17.
These products were analyzed by chiral GC, indicating that the
hydrogenations were not taking place in an appropriate chiral
environment to induce enantioselectivity. Thus, either the desired
chiral rhodium(I) catalyst did not form from the reaction of 13–15
with ligand 11, or the environments provided by the chiral cata-
lysts were unsuitable for inducing enantioselectivity.
(-)-10
(+)-9
10 equiv DABCO
CHCl3, 50 oC, 2 d
O
P
P
O
O
Ph
Ph
N
N
+
à
The reactions with DABCO to remove the borane from
9 were continually
monitored by 31P NMR for the formation of
a
peak at 114 ppm that indicated
12
11
phosphorine 11 had formed. If the reaction was left for too long, phosphorine-2-oxide
Scheme 1.
12 was formed, which was identified by a peak at 19 ppm in the 31P NMR spectrum.

W. L. Benoit et al. / Tetrahedron: Asymmetry 20 (2009) 69–77
71
To confirm that the oxazaphosphorine ligand was able to form a
complex with the rhodium metal, an attempt was made to form
and then isolate rhodium(I) complex 18 as shown in Scheme 3.
modified to form dichlorophenylphosphine borane in situ before
reaction with 3-amino-1-propanol. This resulted in the formation
of the desired phosphorine-borane complex 24 in 28% yield. Repeat-
ing the reaction with spiro 1,3-amino alcohol (ꢀ)-5 afforded a 57%
yield of 19 and 20 (1:1 ratio) that were readily separated by column
chromatography (Scheme 4).
Following a procedure analogous to that reported by Zhang,20
a
sample of mostly oxazaphosphorine 11 (some oxide was unavoid-
able) was dissolved in degassed THF and added to a solution of
Rh(NBD)2BF4 13 in THF at 0 °C. After 15 min, degassed diethyl ether
was added rapidly in an attempt to precipitate the complex out of
solution. A brown sludge resulted, and upon filtration this sludge
gave a thick black tar. This black/brown tar was soluble in deutero-
chloroform, and analysis of the 31P NMR spectrum showed a dou-
blet at d 119 ppm with a coupling constant of 202 Hz. This coupling
constant is characteristic of phosphorus–rhodium one-bond cou-
pling. There was also a singlet at d 20 ppm. This singlet was due
to oxidized oxazaphosphorine 12. Several other minor by-products
were also present, and attempts to crystallize the rhodium com-
plex for further analysis were unsuccessful.
BH3
BH3
O
Ph
O
NH2
OH
H
P
P
Ph
H
a or b
N
N
+
H
(-)-5
19
20
HO
O
Ph
H2N
O
P
O
PhPCl2
N
H
NEt3, THF, rt
(69%)
.
.
21
22
O
Rh(NBD)2BF4
THF
N
P
BH3
P
O
Ph
P
Ph
O
1. BH3-Me2S, THF, -78 oC to rt
N
Rh+
Ph
Ph
PhPCl2
O
HO
2.
NEt3, THF, rt
(28%)
P
N
H
H2N
-
BF4
N
23
24
11
18
observed by 31P NMR
Scheme 4. Reagents and conditions: (a) (i)PhPCl2 , tol, NEt3, 110 °C, 12 h; (ii) BH3–
Me2S (ꢁ4%over two steps); (b) premix PhPCl2 and BH3–Me2S, THF, ꢀ78°C to rt; then
add NEt3 and (ꢀ)-5 (57%, 1:1 mixture).
Scheme 3.
Dioxazaphosphorine borane 19 was coupled to itself by treat-
ment with potassium t-butoxide (DMF, 2 h) followed by the addi-
tion of dibromomethane to afford 25 (18% yield, Scheme 5).§ The
reaction was repeated with 20 to give 26 (36% yield, Scheme 5). Both
dimers 25 and 26 were purified by column chromatography or crys-
tallization from ethyl acetate/hexanes.
The 31P NMR evidence indicated that spiro oxazaphosphorine
11 was able to bind to rhodium metal. Since the hydrogenation
reactions all provided 17 as racemic mixtures, the chiral environ-
ment created by 11 around the metal center did not induce any
enantioselectivity during the reaction. This issue has been raised
with many other monomeric ligands in comparison with their
bidendate counterparts.2f,7c,21 Since the bidendate ligands are less
labile than their monodendate counterparts,1e they can often cre-
ate a more rigid, controlled chiral environment around a metal
center. In an effort to create an optimal environment for asymmet-
ric reactions, it was desirable to access a dimerized form of spiro
oxazaphosphorine 11 that could act as a bidendate ligand with a
metal center. This dimer 7 (Fig. 1) would then be tested under sim-
ilar hydrogenation conditions to determine if the enantioselectivi-
ty could be achieved.
An attempt was made to repeat the successful route to oxa-
zaphosphorine borane 9 (Scheme 1), substituting spiro 1,3-amino
alcohol (ꢀ)-5 (Scheme 4) for methylated amino alcohol 8 (Scheme
1), but this led to a complex mixture. Chromatographic purification
of the crude product gave a small amount (ꢁ4% yield) of 19 and 20
along with their corresponding oxides. Therefore, a more practical
synthetic route to 19 and 20 was developed. To facilitate the rapid
optimization of the synthesis of 19 and 20, 3-amino-1-propanol
was used in place of spiro 1,3-amino alcohol (ꢀ)-5 (Scheme 4).22
The reaction of 3-amino-1-propanol with tricoordinate phospho-
rus compounds dichlorophenylphosphine or bis(diethylamino)-
phosphine (in toluene or THF solution) followed by the addition of
borane–methyl sulfide solution resulted in complex mixtures. A
literature precedent for the formation of an oxazaphosphorine oxide
from phenylphosphonic dichloride and a primary amino alcohol23
prompted an attempt to synthesize oxide 22 from phenylphosphon-
ic dichloride 21 (69% yield, Scheme 4). This success indicated that a
tetracoordinate phosphorus center would be a better substrate for
reaction with a primary amino alcohol such as 3-amino-1-propanol
or spiro 1,3-amino alcohol 5. Therefore, the order of addition was
BH3
P
BH3
BH3
P
Ph
O
Ph
O
Ph
O
1) KOtBu
DMF, 2h
P
N
N
N
2) CH2Br2, rt
18h
H
(18%)
25
19
BH3
P
BH3
O
BH3
Ph
1) KOtBu
DMF, 2h
P
P
O
O
Ph
Ph
N
N
N
H
2) CH2Br2, rt
18h
(36%)
26
20
Scheme 5.
After purification of 25 by flash chromatography (7:1 hexanes/
ethyl acetate), a crystal structure was obtained from one of the col-
umn fractions (Fig. 3). This allowed the assignment of the absolute
configuration at phosphorus to be (SP) in 25. This meant that oxa-
zaphosphorine borane 19 also had an (SP)-configuration, and there-
fore by default the other diastereomer 26 and its precursor 20
would have to be (RP).
§
The reaction conditions for the coupling of 19 (or 20) to itself with methylene
bromide were worked out using model oxazaphosphorine borane 24. For details, see
Ref. 22.

72
W. L. Benoit et al. / Tetrahedron: Asymmetry 20 (2009) 69–77
With compound 25 (and 26) in hand, steps were then taken to
remove the borane protecting groups and to form a rhodium com-
plex that could be tested in asymmetric hydrogenations. The
deprotection was carried out with care and precautions to avoid
unwanted oxidation of the phosphorus atoms. Borane 25 was trea-
ted with 20 equiv of freshly sublimed DABCO18,19 under an argon
atmosphere in an NMR tube containing degassed CDCl3. The
NMR tube was placed into an oil bath at 60 °C for 18 h. 31P NMR
analysis revealed that the major component was deboronated
compound 27 (Spectrum a, Fig. 4) along with a small amount of
starting material 25 and bis-phosphine oxide 29. The solution of
dioxazaphosphorine 28 was transferred via syringe to another
NMR tube containing Rh(NBD)2BF4 13 under nitrogen. Examination
of the 31P NMR spectrum at this stage showed the complete disap-
pearance of the deprotected oxazaphosphorine signal at d 139.2
ppm and the formation of a clean doublet at d 127.6 ppm with a
BH3
P
1
coupling constant of JP–Rh = 197.0 Hz, (Spectrum b, Fig. 4). This
provided strong evidence for the formation of complex 28. All
attempts to crystalize 28 failed; the 31P NMR spectra showed the
obtained crystalline solid and the mother liquor was mainly
bis-phosphine oxide 29 and small amount of starting material 25
(Spectra c and d, Fig. 4). This evidence indicated that the rhodium
complex 28 was extremely sensitive. Since any attempt to isolate
28 resulted in the rapid formation of bis-phosphine oxide 29,
O
N
BH3
P
N
O
H
H
25
Figure 3. X-ray crystal structure of 25 (hydrogen atoms omitted for clarity).
.
.
.
O
O
.
Ph
O
Ph
O
Ph
O
Ph
O
a
P
P
P
P
BH3
BH3
Ph
O
Ph
O
N
N
N
N
P
P
N
N
29
27
25
O
Ph
b
P
N
Rh+
Ph
N
P
-
BF4
O
28
c
O
O
Ph
O
Ph
O
d
P
P
N
N
29
150
145
140
135
130
125
120
115
25
20
15
10
5
0
31P (ppm)
Figure 4. 31P NMR spectra showing the generation of spiro dioxazaphosphorine Rh(I) complex 28, followed by decomposition to bis-phosphine oxide 29; (a) Deprotected spiro
oxazaphosphorine 27 in CDCl3, (b) rhodium complex 28 in CDCl3, (c) precipitate from crystallization attempt in CDCl3, (d) mother liquor from crystallization attempt in CDCl3.

W. L. Benoit et al. / Tetrahedron: Asymmetry 20 (2009) 69–77
73
Rh-complex 28 was generated in situ and used directly in subse-
quent hydrogenation reactions. Hydrogenation of olefin 16 with
28, which was generated in situ (2 atm H2), gave 17 with 15% ee
(Scheme 6).
with olefin 16 to form a mixture of diastereomers 31. Every at-
tempt to follow the procedure outlined in Scheme 7 did not show
any evidence of the formation of olefin-bound complexes 31.
Consequently no further analysis of the enantioselective nature
of 31 could be made.
Ph
O
Ph
O
3. Discussion
DABCO
20 equiv.
P
P
N
N
To gain some perspective on this observed sensitivity to oxida-
tion, the literature was searched for comments on the sensitivity
and handling of other heterofunctionalized tricoordinate phospho-
rus ligands, specifically those with O, N, and C atoms attached.
However, very few examples of heterobifunctionalized oxa-
zaphosphorines of the general format 32 as shown in Figure 5 have
been reported. For quite some time this was attributed to the fact
that they are derived from 1,3-amino alcohols, as opposed to the
more common 1,2-amino alcohols that can be obtained readily
21
CDCl3
27
Rh(NBD)2BF4
10 min, rt
O
from
a-amino acids. On closer examination, however, we found
O
Ph
Ph
numerous examples of oxazaphosphorines of general structure
33 in the literature. This structural unit is part of many anti-cancer
drugs.25 This observation supported our conclusion that oxa-
zaphosphorines of general structure 32 are especially air sensitive
and difficult to handle.
P
-
P
BF4
N
N
O
Et2O
Rh+
O
N
N
P
P
A few oxazaphosphorines of general structure 32 were found in
the literature and these structures have the same level of sensitiv-
ity as noted with 11 and 27 (Fig. 5). Oxazaphosphorine 34 was
formed by Pietrusiewicz and Salamonczyk but was unable to be
isolated ‘due to its pronounced propensity to oxidation’, therefore
it was immediately transformed into oxide 35 in situ.12i Benzimid-
azole derivative 36 has been described by Contreras et al. as being
‘very reactive to oxygen and moisture, and is easily transformed
Ph
Ph
O
O
29
28
H2 (30 psi)
MeOH
Ac
Ac
N
CO2Me
N
CO2Me
H
H
28
16
15% ee
17
O
R
R
Scheme 6.
P
P
O
O
The measureable ee obtained using catalyst 28, although mod-
est (15%), was encouraging. In order to obtain a further under-
standing of the ligand–catalyst system, the reaction was repeated
in a J-Young tube for closer monitoring. The objective was to be
able to observe the 31P NMR spectrum of the olefin-bound rhodium
complex and determine if any mechanistic insight could be gained
by examining the ratio of diastereomeric olefin-bound complexes
31 (Scheme 7).24 The steps envisioned to achieve this goal are out-
lined in Scheme 7. To form the desired olefin-bound complexes 31,
complex 28 would be prepared as previously described (Scheme 6),
taken up into methanol-d4 to form 30, then subsequently treat
R1
N
N
R1
32
33
R1= H, alkyl, or aryl
R = alkyl or aryl
R1 = H, alkyl, or aryl
R = alkyl or aryl
R = amino group
O
H
N
P
Ph
Ph
O
N
O
N
28
P
P
X
H2 (30 psi)
MeOH-D4
Ph
X
Ph
36
34
X = lone pair
X = lone pair
35 X = O
37
X = O
1. degas
-
O
BF4
O
CO2Me
Ph
reaction
mixture
Ph
P
P
H
HN
O
N
N
N
N
Ph
O
O
Me
H
Rh+
2. 16
Rh+
P
R1
R2
O
O
O
-
P N
N
BF4
P
Ph
P
Me
Ph
Ph
O
O
30
31
38
39
Scheme 7.
Figure 5.

74
W. L. Benoit et al. / Tetrahedron: Asymmetry 20 (2009) 69–77
into its oxide’ 37.26 Oxazaphosphorine 38 was reported,27 and
although no comments were made about the sensitivity of oxa-
zaphosphorine 38, it should be noted that crystals were grown at
low temperature (ꢀ20 °C) and then mounted in a sealed capillary
under argon for X-ray crystal analysis at low temperature (ꢀ125
°C). Therefore, it is assumed that the sensitivity to oxidation of
the oxazaphosphorine unit was taken into account during the
X-ray crystal analysis.
The sensitivity to oxidation observed with ligands 11 and 27 and
alluded to in reports of compounds 34, 36, and 38 contrasts with the
behavior of other heterosubstituted phosphorus ligands, such as
Feringa’s phosphoramidites 39 (Fig. 5), which are known to be
‘remarkably stable to air and moisture’.28 This is in contrast with
what might be expected according to trends in basicity, as trialkyl-
phosphines are generally more basic and more susceptible to oxida-
tion than triarylphosphines and heterosubstituted phosphines.29
acid in D2O set to 0 ppm. Melting points were obtained on a melt-
ing point apparatus, and are uncorrected. Optical rotations were
measured using a polarimeter at 589 nm using a path cell length
of 1 dm. The corresponding concentration (g/100 mL) and solvent
for each sample are listed in parentheses. Infrared spectra were ob-
tained using a FT-IR spectrometer. Liquid samples were analyzed
neat between KBr plates, and solid samples were analyzed as thin
films from CHCl3 or CH2Cl2 solutions between KBr plates. Low and
high resolution mass spectra and elemental analyses were ac-
quired at the University of Calgary through the Department of
Chemistry.
5.2. Synthesis of (5R,6R)-6-methylamino-spiro[4.4]nonan-1-ol
(ꢀ)-8
Pyridine (1.02 mL, 12.6 mmol) and methyl chloroformate (0.96
mL, 12.4 mmol) were added to a solution of (ꢀ)-spiro 1,3-amino
alcohol (ꢀ)-5 (0.370 g, 2.38 mmol) in dichloromethane (12 mL).
The reaction mixture was stirred at room temperature overnight.
The reaction was quenched with 10% HCl(aq) (20 mL) and then ex-
tracted with dichloromethane (3 ꢂ 20 mL). The combined organic
layers were washed with saturated Na2CO3 solution (30 mL), dried
over Na2SO4, filtered, and concentrated under reduced pressure to
give a yellow-white solid that was identified as the corresponding
methyl carbamate of (ꢀ)-5 (0.490 g, 2.30 mmol, 96%): mp 110–112
4. Conclusion
1,3,2-Oxazaphosphorine boranes 9, 25, and 26 were success-
fully synthesized in enantiopure form to explore their use as P-ste-
reogenic ligand precursors, but the sensitivity to the oxidation of
oxazaphosphorines 11 and 27 precluded their effective use in
asymmetric reactions. The few examples of general oxazaphosph-
orine structure 32 in the literature also support the high propensity
of systems such as 32 to oxidation. Combined with the success of
other heterosubstituted phosphorus ligands and the unexpected
opposition to trends in basicity, it was not possible to forsee the ex-
treme challenges phosphorus oxidation would pose for the appli-
cation of 11 or 27 as chiral ligands in asymmetric catalysis.
A more thorough analysis of the factors that influence the oxi-
dation rates of tricoordinate phosphorus compounds is currently
ongoing. There have been no successful examples of P-stereogenic
ligands with C, N, and O atoms attached to phosphorus reported.
Recent investigations have been focused on how this particular
combination of heteroatom substituents might be effecting the
oxazaphosphorine’s reactivity toward oxygen.
°C; ½a 2D0
ꢃ
¼ ꢀ9:6 (c 0.4, CHCl3); IR (film) 3252, 2958, 2923, 1672,
1553, 1427, 1266, 1090 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 5.29–
5.10 (br s, 1H), 3.99 (br s, 1H), 3.91–3.81 (m, 2H), 3.67 (s, 3H),
2.06–1.84 (m, 2H), 1.82–1.64 (m, 6H), 1.60–1.51 (m, 2H), 1.35–
1.20 (m, 2H); 13C NMR (75 MHz, CDCl3) d 157.9, 78.0, 58.4, 52.4,
32.7, 32.5, 32.2, 31.4, 20.7, 20.0; MS: m/z 214 (M++1, 100),
120(5), 59(17); HRMS calcd for C11H19NO3 213.13649, found
213.13562. Anal. Calcd for C11H19NO3: C, 61.95; H, 8.98; N, 6.57.
Found: C, 61.89; H, 8.93; N, 6.43.
A solution of the above-mentioned methyl carbamate of (ꢀ)-5
(0.490 g, 2.30 mmol) in THF (20 mL) was added dropwise to a slur-
ry of LiAlH4 (0.456 g, 12.0 mmol) in THF (5 mL) at 0 °C. The solution
was gradually warmed to rt, then heated at reflux for 24 h. The
reaction mixture was then cooled to 0 °C, quenched with 10% NaO-
H(aq) (150 mL), and extracted with Et2O (3 ꢂ 50 mL). The combined
organic layers were washed with 10% NaOH(aq) (50 mL) and brine
(50 mL), then dried over Na2SO4, filtered, and concentrated under
reduced pressure to yield (ꢀ)-8 as a thick clear colorless oil
5. Experimental
5.1. General considerations
(0.380 g, 2.24 mmol, 98%): ½a D19
ꢃ
¼ ꢀ88:5 (c 0.2, CHCl3); IR (film)
All reactions were carried out under an inert atmosphere of
nitrogen or argon gas unless otherwise stated. Glassware was dried
in a 120 °C oven overnight or flame dried immediately prior to use,
and then cooled to room temperature under a nitrogen or argon
atmosphere. When needed, solvents and reagents were purified
according to standard methods. Tetrahydrofuran was distilled from
sodium benzophenone ketyl immediately prior to use. Toluene and
dichloromethane were distilled from calcium hydride immediately
prior to use. DABCO was routinely sublimed at 0.02 Torr and stored
under an argon or nitrogen atmosphere. Triethylamine was dis-
tilled from calcium hydride and stored in Sure/Seal bottles. Recrys-
tallizations were performed with a mixed solvent technique. The
crude material was dissolved in the minimum volume of hot sol-
vent (isopropanol or ethyl acetate), and then cold hexane was
added until cloudiness was observed. Mixtures were then cooled
to room temperature and placed in a freezer to allow more com-
plete crystallization.
3300, 2853, 2865, 1472, 1384, 1101 cmꢀ1
;
1H NMR (300 MHz,
CDCl3) d 4.97–4.17 (br s, 2H), 4.09 (m, 1H), 2.99 (t, J = 6.4 Hz,
1H), 2.47 (s, 3H), 1.90–0.91 (m, 12H); 13C NMR (75 MHz, CDCl3) d
78.5, 68.1, 56.3, 35.6, 35.4, 34.3, 33.4, 29.9, 21.1, 21.0; MS: m/z
170 (M++1, 100); HRMS calcd for C10H19NO 169.14666, found
169.14617.
5.3. Synthesis of (5R,6aR,9aR)-6-methyl-5-phenyl-decahydro-4-
oxa-6-aza-5-phosphacyclopenta-[d]indene borane (+)-9
Triethylamine (0.85 mL, 6.1 mmol) was added dropwise to a
solution of dichlorophenylphosphine (0.367 g, 2.05 mmol) in tolu-
ene (4.5 mL) at ꢀ78 °C. After 5 min, a solution of methylated spiro
1,3-amino alcohol (ꢀ)-8 (0.380 g, 2.24 mmol) in toluene (5.5 mL)
was added and the solution was gradually warmed to room tem-
perature over 2 h. The reaction mixture was then heated at reflux
overnight. The mixture was then cooled to room temperature and a
solution of BH3ꢄSMe2 in toluene (1.12 mL, 2 M, 2.24 mmol) was
added. After 5 h, the mixture was filtered to remove NEt3ꢄHCl salts
and the remaining filtrate was concentrated under reduced pres-
sure to give a thick yellow oil (0.5311 g, 1.837 mmol, 90%), which
was a mixture of two diastereomers. The crude product was recrys-
NMR spectra were obtained on either a 200 MHz, 300 MHz, or
400 MHz spectrometer. All samples were run in deuterochloroform
unless otherwise noted. Proton spectra were referenced to the
residual chloroform signal at 7.27 ppm. Carbon spectra were refer-
enced to the deuteriochloroform signal at 77.0 ppm. Phosphorus
spectra were referenced to an external standard of 30% phosphoric

W. L. Benoit et al. / Tetrahedron: Asymmetry 20 (2009) 69–77
75
tallized from iPrOH/hexanes to give pure white crystals of diaste-
reomer (+)-9 (0.2151 g, 0.7439 mmol, 36%): mp 110–113 °C;
(2.023 g, 11.30 mmol) in THF (120 mL) at ꢀ78 °C. The reaction
mixture was gradually warmed to room temperature over 2 h.
This solution was then cannulated into a room temperature solu-
tion of 3-amino-1-propanol (1.5 mL, 19.2 mmol) and triethyl-
amine (4.7 mL, 34 mmol) in THF (200 mL). After stirring at
room temperature for 15 min, the solution was filtered to remove
NEt3ꢄHCl salts. The filtrate was concentrated under reduced pres-
sure to give a thick yellow oil (4.41 g, 22.6 mmol, 200%). After
flash chromatography (1:1 hexanes/ethyl acetate), oxazaphospho-
rine borane 24 was obtained as a white solid (0.621 g, 3.18 mmol,
28%): mp 82–84 °C; IR (film) 3347, 2954, 2923, 2239, 1652, 1436,
½
a 2D3
ꢃ
¼ þ27:1 (c 7.0, CHCl3); IR (film) 2952, 2868, 2371, 1589,
1447, 1427, 1369, 1214 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.69–
;
7.62 (m, 2H), 7.51–7.41 (m, 3H), 4.00 (m, 1H), 3.19 (m, 1H), 2.92
(d, J = 11.1 Hz, 3H), 2.16–2.01 (m, 2H), 1.99–1.80 (m, 3H), 1.68–
1.36 (m, 7H), 1.32–0.06 (br q, J = 90.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3) d 134.8 (d, J = 57.4 Hz), 131.2 (d, J = 2.0 Hz), 130.6 (d,
J = 11.3 Hz), 128.3 (d, J = 9.7 Hz), 80.9 (d, J = 9.0 Hz), 65.1 (d,
J = 2.1 Hz), 51.8 (d, J = 3.7 Hz), 37.6 (d J = 12.1 Hz), 35.8, 35.4,
31.9, 31.8, 31.6 (d, J = 1.0 Hz), 21.0, 20.1; 31P NMR (121 MHz,
CDCl3)
d
108.0 (q, J = 80.9 Hz); MS: m/z 289 (M+, 1), 275
1383, 1119, 931 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.74–7.67 (m,
;
(M+ꢀBH3, 43), 198 (65), 156 (41), 121 (100); HRMS calcd for
C16H22NOP (M+ꢀBH3) 275.14390, found 275.14574. Anal. Calcd
for C16H25BNOP: C, 66.46; H, 8.71; N, 4.84. Found: C, 66.13; H,
8.81; N, 4.81.
2H), 7.50–7.49 (m, 3H), 4.27–4.17 (m, 1H), 4.06–3.97 (m, 1H),
3.39–3.03 (m, 3H), 2.19–2.04 (m, 1H), 1.39 (br d, J = 14.1 Hz,
1H), 0.62 (br q, J = 89.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
131.7, 131.0, 130.9, 130.8, 129.4, 129.3, 66.0, 41.8, 26.3; 31P
NMR (120 MHz, CDCl3) d 104.4 (q, J = 69.6 Hz) ; MS: m/z 195
(1, M+), 194 (6, M+ꢀH+), 182 (11), 181 (100, M+ꢀBH3); HRMS
calcd for C9H14BNOP (M+ꢀH+) 194.09061, found 194.08922. Anal.
Calcd for C9H15BNOP: C, 55.39; H, 7.75; N, 7.18. Found: C, 55.36;
H, 7.71; N, 7.08.
X-ray crystal data for (+)-9: orthorhombic P212121; a =
8.992(3) Å, b = 11.237(2) Å, c = 16.336(4) Å, a = 90°, b = 90°, g =
90°, V = 1650.6(7) Å3; Z = 4; R = 0.038; Rw = 0.093.
5.4. The in situ deboronation of (+)-9 and rhodium-catalyzed
hydrogenation of methyl 2-acetamidoacrylate 16
5.7. Synthesis of (Sp)-(5R,6aR,9aR)-5-phenyl-decahydro-4-oxa-
6-aza-5-phosphacyclopenta[d]-indene borane 19 and (Rp)-(5R,
6aR,9aR)-5-phenyl-decahydro-4-oxa-6-aza-5-phosphacyclopenta-
[d]indene borane 20
Freshly sublimed DABCO (0.060 g, 0.53 mmol) was added to a
solution of dioxazaphosphorine borane (+)-9 (0.015 g, 0.027 mmol)
in chloroform (0.6 mL). The mixture was heated in a 60 °C oil bath
for 18 h. The reaction mixture was then cooled to room tempera-
ture and bis(norbornadiene)rhodium(I) tetrafluoroborate (0.011
g, 0.027 mmol) was added. After 15 min, the solution was com-
pletely homogeneous and appeared clear orange. The chloroform
was removed in vacuo. The orange residue was dissolved in de-
gassed methanol (0.6 mL) and chloroform (2 drops for solubility)
and methyl 2-acetamidoacrylate 16 (0.038 g, 0.27 mmol) were
added. The reaction vessel was placed under H2 (30 psi) for 7 h.
The mixture was concentrated in vacuo and taken up into 1:1 ethyl
acetate/hexanes for filtration through a plug of silica. The enantio-
meric excess of the product was determined by chiral GC, (Cyclo-
dex-B column, isothermal 90 °C, t1 = 31.2 min, t2 = 32.1 min),
which indicated that the product 17 was a racemic mixture.
A solution of BH3ꢄSMe2 in THF (3.4 mL, 2 M, 6.7 mmol) was
added to a solution of dichlorophenylphosphine (0.600 g, 3.35
mmol) in THF (60 mL) at ꢀ78 °C. The solution was gradually
warmed to room temperature over 1 h and was then cannulated
into a solution of (ꢀ)-spiro 1,3-amino alcohol (ꢀ)-5 (1.04 g, 6.71
mmol) and triethylamine (1.03 mL, 7.38 mmol) in THF (100 mL)
at rt. The mixture was stirred for 15 min and then vacuum filtered
to remove the insoluble NEt3ꢄHCl salts. The filtrate was concen-
trated under reduced pressure to give a clear colorless thick oil
(1.955 g, 212%). After flash chromatography (5:1 hexanes/ethyl
acetate), a mixture of diastereomers A and B was isolated as a clear
colorless thick oil (0.526 g, 1.91 mmol, 57%). This mixture of diaste-
reomers A and B was then submitted to flash chromatography
(30:1 hexanes/ethyl acetate) to isolate each diastereomer. The first
diastereomer to elute 19 was a thick clear colorless oil that dis-
5.5. Synthesis of 2-phenyl-[1,3,2]oxazaphosphorine 2-oxide 22
played the following data: ½a D20
ꢃ
¼ þ11:75 (c 0.4, CHCl3); 1H NMR
Phenylphosphinic dichloride (0.193 g, 0.989 mmol) in THF (9
mL) was added dropwise to a solution of 3-amino-1-propanol
(0.08 mL, 1 mmol) and triethylamine (0.28 mL, 2.0 mmol) in THF
(16 mL). The mixture was stirred at room temperature for 24 h.
The solution was filtered to remove the NEt3ꢄHCl salts and the
resulting filtrate was concentrated under reduced pressure to give
a clear colorless oil (0.161 g, 0.82 mmol, 82%). The crude oil was
purified by flash chromatography (absolute ethanol) to give 22 as
a thick, clear colorless oil (0.135 g, 0.68 mmol, 69%): 1H NMR
(400 MHz, CDCl3) d 7.85–7.80 (m, 2H), 7.56–7.45 (m, 3H), 4.53–
4.44 (m, 1H), 4.19–4.11 (m, 1H), 3.50–3.40 (m, 1H), 3.32–3.19
(m, 2H), 2.13–2.01 (m, 1H), 1.83–1.74 (m, 1H); 13C NMR (100
MHz, CDCl3) d 131.9 (d, J = 3.1 Hz), 131.6, 131.4 (d, J = 10.4 Hz),
128.6 (d, J = 14.5 Hz), 67.5 (d, J = 6.8 Hz), 40.9 (d, J = 2.7 Hz), 26.4
(d, J = 7.4 Hz); 31P NMR (120 MHz, CDCl3) d 19.8; MS: m/z 198
(M++H+); HRMS calcd for C9H12NO2P 197.06057, found
197.06233. Anal. Calcd for C9H12NO2P: C, 54.82; H, 6.13; N, 7.10.
Found: C, 54.10; H, 6.08; N, 6.46.
(300 MHz, CDCl3) d 7.81–7.74 (m, 2H), 7.51–7.46 (m, 3H), 4.44–
4.41 (m, 1H), 3.17–3.13 (m, 1H), 2.72–2.53 (m, 1H), 2.13–1.44
(m, 12H), 1.27–0.17 (m, 3H); 13C NMR (100 MHz, CDCl3) d 131.6
(d, J = 2.2 Hz), 130.8, 130.4 (d, J = 11.8 Hz), 128.4 (d, J = 10.8 Hz),
84.2 (d, J = 4.7 Hz), 58.9 (d, J = 4.6 Hz), 57.9 (d, J = 5.2 Hz), 36.9,
36.6, 34.4 (d, J = 6.5 Hz), 32.6 (d, J = 8.0 Hz), 23.1, 22.7; 31P NMR
(121 MHz, CDCl3) d 106.7 (q, J = 75.4 Hz); MS: m/z 276 (100,
M++H+), 262 (25); HRMS calcd for C15H24BNOP (M++H+)
276.1689, found 276.1677.
The second diastereomer to elute 20 was a thick clear colorless
oil that displayed the following data: ½a D20
¼ ꢀ2:6 (c 0.4, CHCl3);
ꢃ
IR (film) 3357, 2954, 2870, 1652, 1436, 1346, 1120, 1058 cmꢀ1
;
1H NMR (300 MHz, CDCl3) d 7.79–7.72 (m, 2H), 7.50–7.43 (m,
3H), 4.08 (br s, 1H), 3.50–3.33 (m, 1H), 2.99–2.92 (m, 1H),
2.19–2.10 (m), 2.00–1.87 (m), 1.75–1.15 (m), 1.20–0.04 (m, 3H);
13C NMR (75 MHz, CDCl3) d 133.8 (d, J = 66.0 Hz), 131.4 (d,
J = 2.2 Hz), 130.9 (d, J = 11.2 Hz), 128.5 (d, J = 10.2 Hz), 81.6 (d,
J = 9.1 Hz), 57.3 (d, J = 4.8 Hz), 51.2 (d, J = 6.4 Hz), 35.6, 34.6,
33.4 (d, J = 1.7 Hz), 32.4 (d, J = 6.6 Hz), 20.7, 20.6; 31P NMR (121
MHz, CDCl3) d 98.4 (q, J = 79.8 Hz); MS: m/z 276 (95), 261
(100); HRMS calcd for C15H20NOP (M+ꢀBH3) 261.12825, found
261.12795.
5.6. Synthesis of 2-phenyl-[1,3,2]oxazaphosphorine 2-borane 24
A solution of BH3ꢄSMe2 in THF (9.6 mL, 2 M, 19 mmol) was
added dropwise to a stirred solution of dichlorophenylphosphine

76
W. L. Benoit et al. / Tetrahedron: Asymmetry 20 (2009) 69–77
5.8. Synthesis of (Sp)-bis[(5R,6aR,9aR)-6-methyl-5-phenyl-deca-
hydro-4-oxa-6-aza-5-phospha-cyclopenta[d]indene borane]
methane (ꢀ)-25
degassed methanol (0.6 mL) and chloroform (2 drops for solubility)
and methyl 2-acetamidoacrylate 16 (0.038 g, 0.27 mmol) was
added. The reaction vessel was placed under H2 (30 psi) for 7 h.
The mixture was concentrated in vacuo and taken up into 1:1 ethyl
acetate/hexanes for filtration through a plug of silica. The enantio-
meric excess of the product 17 was determined by chiral GC
(Cyclodex-B column, isothermal 90 °C, t1 = 31.2 min, t2 = 32.1
min), and was found to be 15% ee.
Potassium tert-butoxide (0.11 g, 0.99 mmol) was added to a
solution of 19 (0.136 g, 0.490 mmol) in DMF (1.5 mL). After 1.5
h, dibromomethane (0.03 mL, 0.4 mmol) was added and the reac-
tion mixture was stirred for 16 h. The mixture was then concen-
trated in vacuo, taken up into ethyl acetate, and filtered through
a plug of silica. The ethyl acetate solution was concentrated in va-
cuo and crystallized from ethyl acetate/hexanes to give a pale yel-
low solid (ꢀ)-25 (0.025 g, 0.044 mmol, 18%): mp 239–241 °C,
5.11. Attempt to observe diastereomeric olefin-bound rhodium(I)
complexes 31 (see Fig. 4)
½
a 2D0
ꢃ
¼ ꢀ54:5 (c 0.5, CHCl3); IR (film) 2930, 2867, 1658, 1455,
All solvents were rigorously degassed before use (three succes-
sive freeze–pump–thaw cycles), the reaction was performed using
a double manifold line, and all reagents/solvents were added with-
in the inert atmosphere of a dry box. The progress of the reaction
was monitored by 31P NMR spectroscopy (162 MHz). Freshly sub-
limed DABCO (0.044 g, 0.39 mmol) was added to a solution of
dioxazaphosphorine borane (ꢀ)-25 (0.011 g, 0.020 mmol) in deute-
rochloroform (0.6 mL) in a J-Young tube. The mixture was heated
in a 60 °C oil bath for 18 h and then cooled to room temperature.
The 31P NMR analysis showed the formation of a prominent singlet
at d 139.2 ppm corresponding to 27. The addition of bis(norborna-
diene)rhodium(I) tetrafluoroborate (0.008 g, 0.020 mmol) then re-
sulted in a clear orange solution. The 31P NMR spectrum showed
the disappearance of the singlet for 27 at d 139.2 ppm and the for-
mation of a new doublet at d 127.6 ppm (J = 197.0 Hz) correspond-
ing to complex 28. The deuterochloroform was then removed in
vacuo and the residue was taken up into methanol-d4. The 31P
NMR spectrum at this stage showed the loss of the doublet at d
139.2 ppm. A new doublet at d 139.8 ppm (J = 161.0 Hz) had
formed, along with a roughly equal size signal at d 17.7 ppm. Intro-
duction of H2 (30 psi) did not cause any change to the 31P NMR
spectrum. The reaction mixture was once again placed under an in-
ert atmosphere (hydrogen was removed through three successive
freeze–pump–thaw cycles) and olefin 16 was added to the solu-
tion. Again, no change was observed in the 31P NMR spectrum.
The reaction mixture was once again placed under H2 (30 psi).
After 7 h, the mixture was concentrated in vacuo and taken up into
1:1 ethyl acetate/hexanes for filtration through a plug of silica. The
enantiomeric excess of the product was determined by chiral GC,
Cyclodex-B column, isothermal 90 °C, t1 = 31.2 min, t2 = 32.1 min.
The reaction showed only unreacted olefin 16 (t = 19.4 min). This
indicated it was unlikely that the species in methanol-d4 observed
by 31P NMR spectroscopy was the same species involved in the
hydrogenation of 16 that resulted in a measurable ee.
1434, 1406, 1120 cmꢀ1 1H NMR (300 MHz, CDCl3) d 7.95–7.91
;
(m, 4H), 7.62–7.58 (m, 2H), 7.54–750 (m, 4H), 4.49 (br d, J = 3.6
Hz, 2H), 3.50–3.48 (m, 2H), 3.16–3.08 (m, 2H), 2.32–2.25 (m, 2H),
2.07–1.70 (m, 6H), 1.62–1.26 (m, 10H), 1.05–0.94 (m, 2H), 1.16–
0.12 (m, 3H), 0.06–0.04 (m, 2H); 13C NMR (75 MHz, CDCl3) d
133.0 (d, J = 2.0 Hz,), 132.3 (d, J = 13.0 Hz), 131.3, 128.6 (d,
J = 10.9 Hz), 80.9 (d, J = 4.4 Hz), 57.9 (d, J = 2.3 Hz), 55.7 (t,
J = 13.8 Hz), 51.6 (d, J = 5.1 Hz), 35.4, 34.1, 32.1 (d, J = 7.6 Hz),
26.4, 20.6, 20.0; 31P NMR (121 MHz, CDCl3) d 117.7 (m); MS: m/z
563 (M++1), 274 (17); HRMS calcd for C31H43BN2O2P2 (M+ꢀBH3)
548.2892, found 548.28540. Anal. calcd for C31H46B2N2O2P2: C,
66.22; H, 8.25; N, 4.98. Found: C, 65.92; H, 8.44; N, 4.80.
X-ray crystal data for (ꢀ)-25: monoclinic P21; a = 11.660(3) Å,
b = 22.710(3) Å, c = 11.946(4) Å, a = 90°, b = 93.546(15)°,
V = 3157.2(14) Å3; Z = 4; R = 0.119; Rw = 0.360.
c = 90°,
5.9. Synthesis of (Rp)-bis[(5R,6aR,9aR)-6-methyl-5-phenyl-deca-
hydro-4-oxa-6-aza-5-phospha-cyclopenta[d]indene borane]
methane (ꢀ)-26
Potassium tert-butoxide (0.087 g, 0.78 mmol) was added to a
solution of 20 (0.107 g, 0.39 mmol) in DMF (1.3 mL). After 1.5 h,
dibromomethane (0.03 mL, 0.42 mmol) was added and the reac-
tion mixture was stirred for 16 h. The mixture was then concen-
trated in vacuo, taken up into ethyl acetate, and filtered through
a plug of silica. The ethyl acetate solution was concentrated in
vacuo and crystallized from ethyl acetate/hexanes to give a pale
yellow solid (ꢀ)-26 (0.039 g, 0.069 mmol, 36%): ½a D20
¼ ꢀ19:1 (c
ꢃ
1.1, CHCl3); IR (film) 2950, 2243, 1652, 1635, 1436, 1099 cmꢀ1;1H
NMR (300 MHz, CDCl3) d 7.56–7.47 (m, 10H), 5.15 (t, J = 7.4 Hz,
2H), 4.11–4.05 (m, 2H), 3.87–3.75 (m, 2H), 2.44–2.31 (m, 2H),
2.26–2.13 (m, 2H), 2.09–1.89 (m, 8H), 1.71–1.03 (m, 12H), 1.08–
0.15 (br m, 6H); 13C NMR (75 MHz, CDCl3) d 135.4 (d, J = 54.9
Hz), 131.2 (d, J = 1.7 Hz), 130.3 (d, J = 10..9 Hz), 128.6 (d, J = 9.5
Hz), 81.0 (d, J = 9.1 Hz), 56.5 (d, J = 3.8 Hz), 50.4 (d, J = 3.4 Hz),
34.9, 34.8, 31.4 (d, J = 7.7 Hz), 29.7 (d, J = 5.5 Hz), 20.2, 19.9; 31P
NMR (121 MHz, CDCl3) d 104.0 (m); MS: m/z 563 (M++1), 274
(17); HRMS calcd for C31H43BN2O2P2 (M+ꢀBH3) MS: m/z ; HRMS
calcd for C31H43B1N2O2P2 (M+ꢀBH3) 548.28623, found 548.28929.
Anal. Calcd for C31H46B2N2O2P2: C, 66.22; H, 8.25; N, 4.98. Found:
C, 65.91; H, 8.40; N, 4.80.
Acknowledgments
We thank the Natural Sciences and Engineering Research Coun-
cil of Canada and the University of Calgary for financial support.
References
1. (a) Caminade, A.-M.; Servin, P.; Laurent, R.; Majoral, J.-P. Chem. Soc. Rev. 2008,
37, 56; (b) Allen, D. W. Organophosphorus Chem. 2006, 35, 1; (c) Shimizu, H.;
Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405; (d) Katti, K. V.; Pillarsetty, N.;
Raghuraman, K. Top. Curr. Chem. 2003, 229, 207; (e) Crabtree, R. H. The
Organometallic Chemistry of the Transition Metals, 3rd ed.; John Wiley and Sons:
New York, 2001.
2. (a) Minnaard, A. J.; Feringa, B. L.; Lefort, L.; de Vries, J. G. Acc. Chem. Res. 2007,
40, 1267; (b) Jakel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912; (c) Cui, X.;
Burgess, K. Chem. Rev. 2005, 105, 3272; (d) Gridnev, I. D.; Imamota, T. Acc. Chem.
Res. 2004, 37, 633; (e) Clark, T. P.; Landis, C. R. Tetrahedron: Asymmetry 2004, 15,
2123; (f) Tang, W. J.; Zhang, X. M. Chem. Rev. 2003, 103, 3029; (g) Genet, J.-P.
Acc. Chem. Res. 2002, 74, 77; (h) Burk, M. J. Acc. Chem. Res. 2000, 33, 363.
3. (a) Trost, B. M.; Fandrick, D. R. Aldrichim. Acta 2007, 40, 59; (b) Trost, B. M.;
Machacek, M. R.; Aponick, A. Acc. Chem. Res. 2006, 39, 747; (c) Lloyd-Jones, G. C.;
Stephen, S. C.;Fairlamb, I. J. S.;Martorell, A.;Dominguez, B.;Tomlin, P. M.;Murray,
5.10. Attempts at rhodium-catalyzed hydrogenation of methyl
2-acetamidoacrylate 16 using ligand 25
Freshly sublimed DABCO (0.060 g, 0.53 mmol) was added to a
solution of dioxazaphosphorine borane (ꢀ)-25 (0.015 g, 0.027
mmol) in chloroform (0.6 mL). The mixture was heated in a 60
°C oil bath for 18 h. The reaction mixture was then cooled to room
temperature and bis(norbornadiene)rhodium(I) tetrafluoroborate
(0.011 g, 0.027 mmol) was added. After 15 min, the solution was
completely homogeneous and appeared clear orange. The chloro-
form was removed in vacuo. The orange residue was dissolved in

W. L. Benoit et al. / Tetrahedron: Asymmetry 20 (2009) 69–77
77
M.; Fernandez, J. M.; Jeffery, J. C.; Riis-Johannessen, T.; Guerziz, T. Pure Appl. Chem.
2004, 76, 589; (d) Trost, B. M.; VanVranken, D. L. Chem. Rev. 1996, 96, 395.
4. (a) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M. Chem. Rev.
2008, 108, 2796; (b) Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221; (c)
Cote, A.; Boezio, A. A.; Charette, A. B. Angew. Chem., Int. Ed. 2004, 43, 6525.
5. (a) Diez-Gonzalez, S.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 349; (b) Deutsch, C.;
Krause, N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916; (c) Rendler, S.; Oestreich,
M. Angew. Chem., Int. Ed. 2007, 46, 498; (d) Lipshutz, B. H.; Shimizu, H. Angew.
Chem., Int. Ed. 2004, 43, 2228.
6. (a) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874; (b) Arrayas, R. G.; Adrio,
J.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45, 7674; (c) Frisch, A. C.; Beller,
M. Angew. Chem., Int. Ed. 2005, 44, 674; (d) Valentine, D. H.; Hillhouse, J. H.
Synthesis 2003, 2437; (e) Widhalm, M.; Brecker, L.; Mereiter, K. Tetrahedron:
Asymmetry 2006, 17, 1355.
7. (a) Berthod, M.; Mignani, G.; Woodward, G.; Lemaire, M. Chem. Rev. 2005, 105,
1801; (b) Li, Y.-M.; Kwong, F.-Y.; Yu, W.-Y.; Chan, A. S. C. Coord. Chem. Rev.
2007, 251, 2119; (c) Pavlov, V. A. Tetrahedron 2008, 64, 1147; (d) Ojima, I.
Catalytic Asymmetric Synthesis, 2nd ed.; Wiley-VCH: New York, 2000; (e)
Berkessel, A.; Gröger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim,
2005.
8. (a) Holz, J.; Gensow, M.-N.; Zayas, O.; Börner, A. Curr. Org. Chem. 2007, 11, 61;
(b) Engel, R.; Rizzo, J. I. Curr. Org. Chem. 2006, 10, 2393; (c) Grabulosa, A.;
Granell, J.; Muller, G. Coord. Chem. Rev. 2007, 251, 25; (d) Johansson, M. J.; Kann,
N. C. Mini-Rev. Org. Chem. 2004, 1, 233; (e) Molt, O.; Schrader, T. Synthesis 2002,
2633; (f) Mathey, F. Phosphorus-Carbon Heterocyclic Chemistry: The Rise of a New
Domaine; Pergamon: Amsterdam, 2001; (g) Ohff, M.; Holz, J.; Quirmbach, M.;
Borner, A. Synthesis 1998, 1391; (h) Pietrusiewicz, K. M.; Zablocka, M. Chem.
Rev. 1994, 94, 1375.
F.; Pihlaja, K. Eur. J. Org. Chem. 2005, 1189; (e) Sorensen, M. D.; Blaehr, L. K. A.;
Christensen, M. K.; Hoyer, T.; Latini, S.; Hjarnaa, P.-J. V.; Bjorkling, F. Biorg. Med.
Chem. 2003, 11, 5461; (f) Fulop, F.; Forro, E.; Martinek, T.; Gunther, G.;
Sillanpaa, R. J. Mol. Struct. 2000, 554, 119; (g) Martinek, T.; Forro, E.; Guenther,
G.; Sillanpaeae, R.; Fueloep, F. J. Org. Chem. 2000, 65, 316; (h) Oshikawa, T.;
Yamashita, M.; Kaneoka, K.; Usui, T.; Osakabe, N.; Takahashi, C.; Seo, K.
Heterocycl. Commun. 1996, 2, 261; (i) Pietrusiewicz, K. M.; Salamonczyk, I.;
Wieczorek, W.; Brandi, A.; Cicchi, S.; Goti, A. Tetrahedron 1991, 47, 9083; (j)
Goodridge, R. J.; Hambley, T. W.; Ridley, D. D. Aust. J. Chem. 1986, 39, 591; (k)
Ludeman, S. M.; Zon, G.; Egan, W. J. Med. Chem. 1979, 22, 151.
13. For the preparation and use of 2-alkyl or aryl-1,3,2-oxazaphosphorinanes
which do not contain stereogenic centres, see: (a) Hernández-Díaz, J.; Flores-
Parra, A.; Contreras, R. Heteroat. Chem. 2004, 15, 307; (b) Pudovik, M. A.;
Terent’eva, S. A.; Pudovik, A. N. Russ. J. Gen. Chem. 1997, 67, 1940; (c)
Vollbrecht, A.; Neda, I.; Fischer, A.; Jones, P. G.; Reinhard, S. Phosphorus, Sulfur
Silicon Relat. Elem. 1995, 107, 69; (d) Lamande, L.; Munoz, A. Phosphorus,
Sulfur Silicon Relat. Elem. 1993, 75, 241; (e) Huang, Y.; Mullah, M. N.; Sopchik,
A. E.; Arif, A. M.; Bentrude, W. G. Tetrahedron Lett. 1991, 32, 3900; (f) Huang,
Y.; Mullah, M. N.; Sopchik, A. E.; Arif, A. M.; Bentrude, W. G. Tetrahedron Lett.
1991, 32, 899; (g) Appel, R.; Kuendgen, U.; Knoch, F. Chem. Ber. 1985, 118,
1352; (h) Kobayashi, S.; Narukawa, Y.; Takeo, S. Synth. Commun. 1982, 12,
539.
14. (a) Henderson, J. R.; Parvez, M.; Keay, B. A. Org. Lett. 2007, 9, 5167; (b) Lait, S.
M.; Parvez, M.; Keay, B. A. Tetrahedron: Asymmetry 2003, 14, 749.
15. Lait, S. M.; Parvez, M.; Keay, B. A. Tetrahedron: Asymmetry 2004, 15, 155.
16. Paquette, L. A.; Tae, J. J. Org. Chem. 1998, 63, 2022.
17. (a) Brown, J. M.; Carey, J. V.; Russell, J. H. Tetrahedron 1990, 46, 4877; (b) Carey,
J. V.; Barker, M. D.; Brown, J. M.; Russell, M. J. H. J. Chem. Soc., Perkin Trans. 1
1993, 831.
18. Jugé, S.; Stephan, M.; Laffitte, J. A.; Genet, J. P. Tetrahedron Lett. 1990, 31, 6357.
19. (a) Imamoto, T.; Kusumoto, T.; Suzuki, N.; Sato, K. J. Am. Chem. Soc. 1985, 107,
5301; (b) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K. J. Am.
Chem. Soc. 1990, 112, 5244; (c) Brisset, H.; Gourdel, Y.; Pellon, P.; Le Corre, M.
Tetrahedron Lett. 1993, 34, 4523.
9. (a) Reetz, M. T.; Gosberg, A.; Goddard, R.; Kyung, S.-H. Chem. Commun. 1998,
2077; (b) Pena, D.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc.
2002, 124, 14552; (c) Hulst, R.; de Vries, N. K.; Feringa, B. L. Tetrahedron:
Asymmetry 1994, 5, 699; (d) Hu, W.; Yan, M.; Lau, C.-P.; Yang, S.-M.; Chan, A. S.
C. Tetrahedron Lett. 1999, 40, 973; (e) Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.;
Wang, L.-X.; Zhou, Q.-L. Angew. Chem., Int. Ed. 2002, 41, 2348; (f) Fu, Y.; Xie,
J.-H.; Hu, A.-G.; Zhou, H.; Wang, L.-X.; Zhou, Q.-L. Chem. Commun. 2002, 480; (g)
Chan, A. S. C.; Hu, W.; Pai, C.-C.; Lau, C.-P.; Jiang, Y.; Mi, A.; Yan, M.; Sun, J.; Lou,
R.; Deng, J. J. Am. Chem. Soc. 1997, 119, 9570.
20. Tang, W.; Chi, Y.; Zhang, X. Org. Lett. 2002, 4, 1695.
21. (a) Blaser, H.-U. Chem. Rev. 1992, 92, 935; (b) Whitesell, J. K. Chem. Rev. 1989,
89, 1581; (c) Desimoni, G.; Faita, G.; Jorgensen, K. A. Chem. Rev. 2006, 106,
3561; (d) Bhowmick, K. C.; Joshi, N. N. Tetrahedron: Asymmetry 2006, 17, 1901.
22. Benoit, W. L. Ph.D. Thesis, University of Calgary, September 2007.
23. Kivela, H.; Zalan, Z.; Tahtinen, P.; Sillanpaa, R.; Fulop, F.; Pihlaja, K. Eur. J. Org.
Chem. 2005, 1189.
24. Halpern, J. Science 1982, 217, 401.
25. Bentrude, W. G.; Setzer, W. N.; Sopchik, A. E.; Chandrasekaran, S.; Ashby, M. T.
J. Am. Chem. Soc. 1988, 110, 7119.
26. Hernandez-Diaz, J.; Flores-Parra, A.; Contreras, R. Heteroat. Chem. 2004, 15, 307.
27. Huang, Y.; Arif, A. M.; Bentrude, W. G. J. Org. Chem. 1993, 58, 6235.
28. Arnold, L. A.; Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L.
Tetrahedron 2000, 56, 2865.
29. Quin, L. D. A Guide to Organophosphorus Chemistry; John Wiley and Sons: New
York, NY, 2000.
10. For a review on the use of 1,3-aminoalcohols in asymmetric reactions, see: Lait,
S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007, 107, 767.
11. For alkylations, see: (a) Denmark, S. E.; Chen, C.-T. J. Org. Chem. 1994, 59, 2922;
(b) Gordon, N. J.; Evans, S. A., Jr. J. Org. Chem. 1993, 58, 5293; (c) Denmark, S. E.;
Dorow, R. L. J. Org. Chem. 1990, 55, 5926; For Claisen rearrangements, see: (d)
Denmark, S. E.; Marlin, J. E. J. Org. Chem. 1987, 52, 5742; For Michael additions,
see: (e) Afarinkia, K.; De Pascale, E.; Amara, S. ARKIVOC 2002, 205; (f) Denmark,
S. E.; Kim, J.-H. J. Org. Chem. 1995, 60, 7535; For stereoselective synthesis of
phosphite triesters, see: (g) Wang, J.-C.; Just, G. J. Org. Chem. 1999, 64, 8090.
12. (a) Dujois, F.; Mulliez, M. Eur. J. Org. Chem. 2006, 1959; (b) Juhasz, M.;
Martiskainen, O.; Zalan, Z.; Fulop, F.; Pihlaja, K. Rapid Commun. Mass. Spectrom.
2006, 20, 433; (c) Frank, E.; Kazi, B.; Ludanyi, K.; Keglevich, G. Tetrahedron Lett.
2006, 47, 1105; (d) Kivelae, H.; Zalan, Z.; Taehtinen, P.; Sillanpaeae, R.; Fueloep,