Synthesis of P-stereogenic compounds based on the diastereoselective ortho-lithiation of phosphinimidic amides

Article abstract of DOI:10.1016/j.tetasy.2014.12.001

The extension of the diastereoselective functionalization of the Ph₂P group of C-chiral P,P-diphenyl phosphinimidic amides via directed ortho-lithiation (DoLi)-electrophilic quench reactions as a method for the preparation of structurally diverse P-stereogenic compounds is described. Transformations at both the phosphorus-containing and the ortho-functional groups provide access to a large variety of P-stereogenic derivatives with excellent stereocontrol. These transformations include aza-Wittig reactions, N-alkylations, methanolysis, nucleophilic displacements with Grignard reagents, phosphine oxide reductions, azide to amine conversions, halogen/metal exchange, and Suzuki cross-coupling and condensation reactions. These transformations increase the diversity of functional groups at the ortho-disubstituted phenyl ring and enable the synthesis of enantiopure ortho-formyl- and ortho-stannyl-phosphinic amides that are difficult to prepare by other methods. The new products synthesized might be used as building blocks for the construction of high value added P-stereogenic compounds. This is illustrated by the synthesis of [1,5,2]diazaphosphinin-6(5H)-one 21, a phosphazenylphosphinate (S_PN,R_PO)-22 and the analogues of relevant bidentate and tridentate privileged structures such as PHOX-like 23 and the heteroatomic N,O,P-tridentate ligand 25.

Full text of DOI:10.1016/j.tetasy.2014.12.001

Tetrahedron: Asymmetry 26 (2015) 53–66
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of P-stereogenic compounds based on the
diastereoselective ortho-lithiation of phosphinimidic amides
María Casimiro a, Guilherme P. Guedes b, María José Iglesias a, Fernando López Ortiz a,
⇑
a Área de Química Orgánica, Universidad de Almería, Carretera de Sacramento s/n, 04120 Almería, Spain
b Instituto de Ciências Exatas, Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23870-000 Seropédica, RJ, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 November 2014
Accepted 3 December 2014
The extension of the diastereoselective functionalization of the Ph2P group of C-chiral P,P-diphenyl phos-
phinimidic amides via directed ortho-lithiation (DoLi)-electrophilic quench reactions as a method for the
preparation of structurally diverse P-stereogenic compounds is described. Transformations at both the
phosphorus-containing and the ortho-functional groups provide access to a large variety of P-stereogenic
derivatives with excellent stereocontrol. These transformations include aza-Wittig reactions, N-alkyla-
tions, methanolysis, nucleophilic displacements with Grignard reagents, phosphine oxide reductions,
azide to amine conversions, halogen/metal exchange, and Suzuki cross-coupling and condensation reac-
tions. These transformations increase the diversity of functional groups at the ortho-disubstituted phenyl
ring and enable the synthesis of enantiopure ortho-formyl- and ortho-stannyl-phosphinic amides that are
difficult to prepare by other methods. The new products synthesized might be used as building blocks for
the construction of high value added P-stereogenic compounds. This is illustrated by the synthesis of
[1,5,2]diazaphosphinin-6(5H)-one 21, a phosphazenylphosphinate (SPN,RPO)-22 and the analogues of rel-
evant bidentate and tridentate privileged structures such as PHOX-like 23 and the heteroatomic N,O,P-tri-
dentate ligand 25.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
X = BH3, S
X
s
X
P
1) [sBuLi·(+)-3]
X
P
2
1) [ BuLi·(-)- ]
P-Stereogenic organophosphorus compounds are an important
focus of interest due to their applications in asymmetric synthesis
in both organocatalytic1 and transition-metal mediated reactions.2
Compounds with chirogenic phosphorus centers are expected to be
advantageous for asymmetric induction as compared with systems
with a stereogenic backbone. They bring the chiral environment
closer to the reaction center, which might favor a more sterically
and electronically defined architecture about the metal atom. Fur-
thermore, P-stereogenic compounds containing additional donor
atoms near the phosphorus are particularly interesting. Hybrid
ligands consisting of donor functions showing different stereoelec-
tronic properties are very attractive for generating complexes with
unusual reactivities and applications.3
P
E
Me
R1
2) E+
2) E+
Me
Me
R1
R1
Me
(RP)-4
E
4
(SP)-
1
H
N
H
N
Me
N
N
H
2
(-)-
(-)-sparteine
(+)-3
Scheme 1. Synthesis of P-chirogenic compounds through the desymmetrization of
dimethylphosphine-boranes and sulfides.
deprotonation of enantiotopic methyl groups of phosphine-bor-
anes and sulfides 1 represents a very efficient route for the prepa-
ration of a wide variety of enantiomerically pure P-stereogenic
compounds (Scheme 1). First reported by Evans et al. in 1995,5 this
strategy has evolved into a general method thanks to the work of
Imamoto et al.,6 Livinghouse et al.,7 Kann et al.8 and O’Brien et al.9
among other research groups. The discrimination between the
enantiotopic methyl groups is performed efficiently by the chiral
Over the past few decades, a number of methods have been
developed for the synthesis of P-stereogenic compounds.4 The
major limitations of these methods are usually the lack of flexibil-
ity in terms of structural diversity and the difficulties in the avail-
ability of both enantiomeric forms. The enantioselective
⇑
Corresponding author. Tel.: +34 950015478; fax: +34 950015008.
E-mail address: flortiz@ual.es (F. López Ortiz).
s
base formed upon complexation of BuLi with (ꢀ)-sparteine (ꢀ)-2
http://dx.doi.org/10.1016/j.tetasy.2014.12.001
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

54
M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
or the surrogate of (+)-sparteine (+)-3.10 In this way, both antipo-
Me
Me
O
N
O
C
10
des of the PC -carbanion are formed and after reaction with elec-
(THF)m
a
Li
trophiles, they afford the respective functionalized derivatives
with enantiomeric excesses usually above 90%. The scope of this
method has been expanded through the development of a catalytic
variant in which substoichiometric amounts of chiral auxiliaries
are utilized11 for the preparation of phosphine–borane libraries.12
Many privileged chiral ligands (e.g., PHOX, SEGPHOS, BINAP,
JOSIPHOS, etc.) contain PPh2 groups as key donor sites for complex
formation in which the chirality resides in the backbone at a point,
axis, or plane of chirality.9a,13 The stereoselective functionalization
of the prochiral PPh2 moiety transforms the phosphorus atom into
a stereogenic center which, as noted above, may enhance the per-
formance of the resulting ligand in asymmetric catalysis. We cur-
rently are interested in the synthesis of polyfunctionalized
organophosphorus derivatives via the directed ortho-lithiation
(DoLi)-electrophilic quench sequence of reactions.14 The P-based
directing metallation groups (DMG) include phosphazene,15 phos-
phinic acid,16 phosphinic amide,17 and phosphinothioic amide18 of
P,P-diphenyl derivatives. Since the process involves the selective
ortho-lithiation of a P-phenyl ring, the products obtained are P-ste-
reogenic. In this context, we have reported on the enantioselective
deprotonation of N,N-diisopropyl-P,P-diphenylphosphinic amide
5a using [nBuLiꢁ(ꢀ)-sparteine] as a chiral base (Scheme 2).19 Elec-
trophilic trapping of the anion afforded P-stereogenic ortho-func-
tionalized phosphinimic amides (SP)-6 with modest ee (60%).
Enantiopure compounds could be obtained after three recrystalli-
zation cycles. The diastereoselective route to P-stereogenic com-
N
P
O
Li
N
P
O
THF
THF
Li(THF)n
tBuLi
Me
H
Me
Me
Ph
H
8
tBuLi
O
N
CO2Me
MeO2C
Ph
(THF)m
N
N
P
Me
1) tBuLi,
THF
N
P
O
Li
2) E+
Ph2P
NH
Ph
Li
N
H
Ph
-90 ºC
(THF)n
Me
E
Ph
Me
dr 95:5
(SP,RC)-12
H
(RC)-9
11
E = Me, Allyl, Br, I, N3, Me3Sn, Me3Si, Ph2P(O)
Scheme 3. Diastereoselective DoLi of phosphazenes and phosphinimidic amides.
phenyl rings does not take place) and that 10 adopts a conforma-
tion that favors the almost exclusive abstraction of one ortho-pro-
ton of the pro-S phenyl ring by the organolithium base. The
structural characterization of 10 supports these statements.21 The
chiral amine present in 9 is one of the simplest chiral auxiliaries
and both enantiomers are readily available, which warrants access
to both antipodes of 12.
The applications of the synthesis of (SP,RC)-12 can be expanded
through elaboration of the phosphinic amide moiety and the func-
tional groups introduced at the ortho-position. Some examples are
included in the literature (e.g., phosphinic amides, phosphine oxi-
des, aminophosphines, etc.).20 The scope of this chemistry is shown
herein. Efficient functional group transformations performed on 12
including aza-Wittig, Staudinger, N-alkylation, and Suzuki cross-
coupling reactions as well as imine and oxazoline synthesis to
allow the modular and tunable preparation of new families of
enantiopure P- and C-stereogenic compounds of high potential as
ligands in metal-assisted asymmetric synthesis.
pounds via abstraction of an ortho-proton from
a chiral
phosphinic amide 5b with an organolithium base also proved to
be unsatisfactory. The diastereomeric ratios of the products 7 ran-
ged from 1:1 to 1:5.17b It seems clear that the efficient stereoselec-
tive ortho-lithiation of diphenylphosphinic acid derivatives
remains a challenge.
E
Me3Sn
O
O
Me
Ph
O
(a)
(b)
P
P
NiPr2
Ph2P
N
NR1R2
5a
5b
2. Results and discussion
H
Me
i
, R1 = R2 = Pr
5a
6
7
(SP)-
(SP,RC)-
5b, R1 = H, R2
=
2.1. Transformations of the phosphorus containing functional
group
Ph
(ee 60%)
(dr 1:2)
Scheme 2. Stereoselective ortho-functionalization of P,P-diphenylphosphinic
amides. Reagents and conditions: (a) (1) [n-BuLiꢁ(ꢀ)-2], toluene, ꢀ90 °C; (2) E+;
(3) H2O. (b) (1) n-BuLi, THF, ꢀ35 °C; (2) Me3SnCl; (3) H2O.
As indicated above, the presence of the NH in the starting phos-
phinimidic amide is essential for achieving the diastereoselective
formation of the dilithiated species 11. The NH/NLi exchange pro-
duced in the first step of the reaction pre-organizes the molecule
for the selective ortho-deprotonation and protects the P@NCO2Me
moiety from nucleophilic attack by the organolithium base. How-
ever, the nucleophilic character of the lithiated nitrogen atom of
11 may be incompatible with some attractive ortho-substituents.
This was the case for the formyl group (see below). In order to
avoid this limitation, we investigated the N-alkylation of a series
of ortho-substituted phosphinimidic amides 12. The deprotonation
of 12a–d with 1 equiv of KHMDS in THF at 0 °C for 2 h followed by
reaction with 1 equiv of methyl triflate at the same temperature
overnight afforded the respective N-methylated products 13a–d
in good yield (method A, Table 1). Under these reaction conditions,
the ortho-stannylated derivative 12e did not undergo N-methyla-
tion. We then set out to explore an alternative methodology. Thus,
12e was converted quantitatively into compound 13e when
4 equiv of NaH and MeI were used as the base and methylating
reagent, respectively (entry 5, method B). The yield of the reaction
decreased to 65% when proton abstraction was carried out using
half of the equivalents of base, most probably due to the heteroge-
A solution to the problem came from the observation that C ,-
a
Cortho-dilithiated phosphazenes exist exclusively in a like configu-
ration 8 stabilized by the double C,N- and C,O-chelation structure
involving the P@NCO2Me phosphazenyl system (Scheme 3).15a
The rigidity of the dilithiated architecture in 8 appears to be the
reason for the formation of a single diastereoisomer. We thought
that mono-deprotonation of phosphinimidic amide 9, in which
the alkyl group of the phosphazene precursor of 8 is replaced by
a chiral amine, would afford a structure similar to 8, with the
added advantage of including a chiral auxiliary close to the DMG
group. The treatment of (RC)-9 with 2.8 equiv of tert-butyllithium
in THF at ꢀ90 °C followed by electrophilic quenching afforded
the ortho-functionalized derivatives (SP,RC)-12 in high yield and
with excellent diastereoselectivity (dr of 95:5).20 The stereoselec-
tivity of the process correlates with the configuration of the
N,Cortho-dilithiated species (SP,RC)-11 formed in the DoLi reaction
of the monolithiated intermediate (RC)-10. This fact suggests that
11 is configurationally stable (i.e., Li/H exchange between the P-

M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
55
Table 1
of phosphinimidic amides 12 will be transferred to the C@N by-
product with retention of the P-configuration in the phosphinic
amides 15 generated. The results obtained are shown in Table 2.
As a starting point, we achieved firstly the aza-Wittig reaction of
(RC)-9. A standard procedure consists of treating a P@N containing
compound, usually a phosphazene, with an isocyanate or an alde-
hyde as a source of the carbonyl group in a given solvent.22,23 The
reaction of 9 with phenylisocyanate in THF at room temperature
for 24 h gave the phosphinic amide (RC)-14a in 91% yield. Under
these conditions ortho-substituted phosphinimidic amide (SP,RC)-
12a was recovered unaltered. The transformation succeeded when
the isocyanate was used as the solvent and the reaction was heated
at 120 °C for 24 h (method A). In this way, (RP,RC)-15a was obtained
in 90% yield (entry 1).24 The formation of the P@O linkage was
readily established through NMR spectroscopy by the disappear-
ance of the methoxy signal in the 1H NMR spectrum and the slight
shielding observed for the phosphorus signal in the 31P NMR spec-
trum of 15a (d 26.9 ppm) as compared with 12a (d 27.7 ppm). The
X-ray structure of (RP,RC)-15a confirmed that the reaction pro-
ceeded with retention of the phosphorus configuration (Fig. 1).
Extending this method to phosphinimidic amides 12b–d (E = Br,
I, SiMe3) furnished the respective phosphinic amides 15b–d in high
yield (entries 2–4). However, when applied to the ortho-azido
derivative (SP,RC)-12f the reaction led to a mixture of products in
which the target compounds constituted ca. 40% of all components.
The use of an acetaldehyde as the carbonyl compound allowed us
to perform the reaction under much milder conditions compatible
with the azido group. Quantitative formation of 15f was achieved
when 12f was treated with an excess of acetaldehyde in ethanol
at room temperature for 15 h (method B, entry 5). The analogous
synthesis of 15g also proceeded in high yield (80%), although in
this case the reaction was carried out at reflux in ethanol to over-
come the steric hindrance produced by the bulky ortho-diphenyl-
phosphinoyl substituent (entry 6).
Synthesis of N-methylphosphinimidic amides (SP,RC)-13a
MeO2C
Ph
MeO2C
N
P
Me
1) KHMDS
2) MeOTf
N
P
Me
Ph
N
H
Ph
or
N
Ph
1) NaH
2) MeI
Me
E
E
13
12
Entry
13
E
Method
Isolated yield (%)
1
2
3
4
5
a
b
c
d
e
Me
Br
I
SiMe3
SnMe3
A
A
A
A
B
79
78
80
50
95
a
Method A: (1) 1 equiv KHMDS, 0 °C, THF, 2 h; (2) MeOTf, 0 °C, THF, 12 h. Method
B: (1) 4 equiv NaH, 0 °C, THF, 2 h; (2) 4 equiv MeI, 0 °C, THF, 12 h.
neous nature of the reaction. Phosphinimidic amides 13 are enan-
tiopure compounds containing functional groups at the ortho-posi-
tion suitable for further transformations. In particular, compounds
13b,c,e can be considered as masked Cortho monoanions accessible
via exchange reactions with the appropriate sources of alkaline and
alkaline earth metals (see below).
Aza-Wittig-type reactions represent the most straightforward
route of converting phosphinimidic amides 12/13 into other valu-
able P-stereogenic compounds. This is a methatetical process that
exchanges the N/O atoms of P@N/C@O couples via a [2+2] cycload-
dition to give a 1,3,2k5-oxazaphosphetidine, followed by a [2+2]
cycloreversion to yield the corresponding P@O/C@N derivatives.22
This process is a very useful method for carbon–nitrogen double-
bond formation in which the organophosphorus fragment is gener-
ally eliminated as a phosphine oxide. In this case, our interest
resides in the P-containing compound formed. The NCO2Me moiety
Table 2
Synthesis of phosphinic and phosphinothioic amides (RC)-14 and (RP,RC)-15 through aza-Wittig-type reactionsa
MeO2C
Ph
PhNCX,
X
P
Me
X
Me
N
P
Me
(E = R1 = H)
PhNCX
Ph
neat,
120 ºC
Ph2P
N
R1
Ph
N
H
Ph
N
R1
Ph
or
THF, rt
MeCHO,
EtOH
E
E
14a
(RC)-
, X = O (91%)
9
,
12, 13
15
(RP,RC)-
(X = O, S)
(RC)-14b, X = S (80%)
Entry
15
E
X
R1
Method
Yieldb (%)
95c
100
Isolated yield (%)
1
2
3
4
5
6
7
8
a
b
c
d
f
g
h
i
j
k
l
m
n
o
Me
Br
I
SiMe3
N3
Ph2P(O)
Me
Br
I
SiMe3
Me
I
O
O
O
O
O
O
O
O
O
O
S
H
H
H
H
H
H
Me
Me
Me
Me
H
H
Me
Me
A
A
A/B
A
B
B/A
A
A
90
96
88
85
91
80
90
95
90
87
70
65
70
100
100
100d
90e/100
100
100
100
95
82/100
70
9
A
A
10
11
12
13
14
C/LRf
C
S
S
S
Me
I
C/LRg
C
60/77
25
h
—
a
b
c
Method A: 6 equiv PhNCO, 120 °C, 24 h. Method B: 10 equiv MeCHO, EtOH, 25 °C, 15 h. Method C: 6 equiv PhNCS, 120 °C, 24 h.
Determined from the integrals of the 31PNMR spectra of the crude reaction mixture.
No reaction took place under the conditions used for the synthesis of 14a (1.2 equiv PhNCO, 25 °C, 24 h).
The reaction with PhNCO gave a mixture of products.
Performed at reflux of ethanol. No reaction took place at room temperature.
Thionation of 15a with Lawesson’s reagent in refluxing toluene for 15 h.
Thionation of 15h using Lawesson’s reagent in refluxing toluene for 7 days.
Non-isolated compound.
d
e
f
g
h

56
M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
Figure 1. ORTEP representation of the asymmetric unit of compound (RP,RC)-15a (thermal ellipsoids shown at 50% probability) including atomic numbering. Hydrogen atoms
were omitted for sake of clarity.
The complementarity of both methods is shown by the quanti-
tative preparation of 15c and 15g through methods B and A,
respectively (entries 3 and 6). In sharp contrast, substrate 12e
did not undergo the aza-Wittig reaction under any of the method-
ologies previously described. The recovery of the starting material
in all cases may be caused by some interaction between the stan-
nyl substituent and the phosphazene moiety, making it inert
toward P@N transformation. As might be expected, N-meth-
ylphosphinimidic amides 13a–d also undergo P@N/P@O exchange
under method A conditions to give phosphinic amides 15h–k in
very high yield in almost all cases (entries 7–10).
In principle, phosphinothioic amides could be prepared in a
similar manner via aza-Wittig-type reactions of 9/12 with hetero-
cumulenes such as carbon disulfide and phenylisocyanate.23 Phos-
phinimidic amide 9 failed to react with either CS2 or PhNCS in THF
at reflux for 24 h. The P@N to P@S conversion could be achieved by
treatment of 9/12 with PhNCS at 120 °C for 24 h (method C). In this
way, compounds 14b (80%) and 15l,m (65–70%) were obtained in
good yields (entries 11 and 12). The phosphinothioic derivatives
showed 31P chemical shifts in the expected range for the N-P@S
moiety (d 57.8–62.0 ppm). The analogous reactions of 13a,c with
phenylthioisocyanate (method C) proceeded less efficiently leading
to compounds 15n and 15o in 60% and 25% yield, respectively
(crude yield, entries 13 and 14). Given the relatively poor perfor-
mance of these reactions, the thionation of selected phosphinic
amides 15 was assayed as an alternative to improve access to P-
stereogenic phosphinothioic amides. Compounds 15a and 15h
undergo a stereospecific O/S exchange in the presence of Lawes-
son’s reagent in refluxing toluene to afford the respective phos-
phinothioic amides 15l (15 h, 100%, entry 11) and 15n (7 days,
77%, entry 13) in high yield. These transformations indicated the
feasibility of efficient P@O to P@S conversion of 15 with preserva-
tion of the enantiomeric purity.24,25 In contrast to the Lawesson’s
reagent, thionation of 15h with P4S10 in refluxing toluene for 1 h
led to a mixture of diastereoisomers in a yield of 60% and a ratio
of 33:67.
structurally, electronically, and sterically diverse P-stereogenic
organophosphorous systems, lies in the combination of the reactiv-
ity of the P-containing and ortho-functional groups of 12/15. In
order to achieve this goal, additional functional group transforma-
tions were explored. Phosphinic amides 15 can be considered as
the entry to P-stereogenic phosphines via a well-established syn-
thetic route, which began with the transformation into an alkyl
phosphinate followed by nucleophilic displacement of the alkoxy
group with an organolithium or Grignard reagent and, finally,
reduction of the P@O linkage. Each step of this sequence of reac-
tions is known to proceed with inversion of the P-configuration.28
Firstly, we examined the HCl catalyzed methanolysis of 15 as a
standard method of NR/OR exchange in phosphinic amides. The
reaction of 15a dissolved in THF with 0.5 M HCl in dry methanol
for 12 h at room temperature afforded methyl phosphinate 16a
in 67% yield (Table 3, entry 1).28d Under these reaction conditions,
the N-methylated derivative 15h underwent methanolysis notably
slower. Thus, 3 days of reaction were necessary to obtain 16a in
good yield (74%, entry 2). Although this process is immaterial for
the synthesis of 16a, it shows the feasibility of the methanolysis
of tertiary phosphinic amides without a loss of enantiomeric pur-
ity. This transformation might become relevant in cases where
the substituent at the ortho-position is not compatible with the
Table 3
Synthesis of methyl phosphinates (RP)-16 and phosphine-borane (RP)-18
9-12 Ph
8
O
P
Me
O
P
Ph
O2Me
1) HCl, MeOH
7
N
H
Ph
3
13
E
rt, 12 h
(ee: 92-96%)
6
4
E
5
15
16
(RP,RC)-
(RP)-
E = Me
(ee 96%)
2) MeMgBr
O
9-12 Ph
BH3
Ph
8
2
P
P
The synthesis of products 15 outlined above is a very expedient
route for the preparation of enantiopure P-stereogenic phosphinic
amides and phosphinothioic amides as compared with the alterna-
tive methods for the enantio- and diastereoselective deprotonation
of the corresponding diphenylphosphinic acid derivatives
(Scheme 2). Furthermore, compounds 15 are interesting ligands
for applications in coordination chemistry26 and catalysis, in par-
ticular the bidentate derivative 15g due to the possibility of acting
as hemilabile O,O-chelating ligand containing two different oxygen
coordination sites.27
7
Me
Me
3) MeOTf
4) NaBH4
3
13
Me
6
4
Me
5
17
18
(RP)-
(RP)-
(ee 96%)
(ee 98%)
Entry
16
E
[HCl] (M)
Solvent Isolated yield (%)
1
2
3
4
5
a
a
a
b
c
Me
Mea
Meb
Ib
0.5
0.5
1.25
1.25
1.25
THF
THF
67
74
98
90
98
b
N3
We have shown so far the introduction of structural diversity at
the P-stereogenic center of phosphinimidic amides 12. The real
potential of these compounds as scaffolds for the construction of
a
Reaction carried out with the N-methylated derivative (reaction time: 3 days).
Solvent free reaction.
b

M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
57
presence of an NH in the P(O)N moiety. Quantitative conversion of
15a into 16a took place when the methanolysis was carried out
with a more concentrated 1.25 M HCl/MeOH solution (entry 3).
Compound 16a showed a characteristic doublet in the 1H NMR
spectrum for the methoxy group at d 3.73 ppm (3PH = 11 Hz) and
a 31P signal at d 34.65 ppm in the 31P NMR spectrum. This method
was equally effective for the synthesis of methyl phosphinates 16b
and 16c containing an iodine and an azido ortho-substituent,
respectively (entries 4 and 5). The enantiomeric purity of 16a–c
was established through chiral HPLC.
The transformation of methyl phosphinates 16 into P-stereo-
genic phosphines is illustrated with the synthesis of the phos-
phine-borane (RP)-18. Displacement of the methoxy group of 16a
by a methyl group was readily accomplished by treatment with
MeMgBr in THF at room temperature for 16 h to give the phos-
phine oxide (RP)-17 in 98% yield (dP 32.31 ppm) and an ee of 96%
(Table 3).24
The deoxygenation of phosphine oxides is commonly carried
out with halosilanes as reducing agents.29 The reaction of (RP)-17
with HSiCl3 in the presence of triethylamine afforded the corre-
sponding phosphine in high yield (90%), but as a racemic com-
pound. Fortunately, reduction of (RP)-17 with inversion of the P-
configuration could be successfully achieved in two steps involving
O-methylation with MeOTf followed by reduction with NaBH4.28i
In this way, the deoxygenated product with the P(III) protected
as a phosphine-borane (RP)-18 was obtained in 75% yield and
excellent optical purity (ee 98%).
The exchange reactions were assayed with both organomagne-
sium and organolithium reagents. Phosphinic amide 15j undergoes
quantitative conversion into the ortho-deuterated derivative 15p
i
by treatment with 2.2 equiv of PrMgBr30 in THF at ꢀ40 °C for
40 min and subsequent quench with methanol-d4 (entry 1). This
result indicates that an iodine/magnesium exchange in tertiary
phosphinic amides can be performed without compromising the
configuration of the phosphorus. The reaction of the organomagne-
sium iodide of 15j with DMF as the electrophile overnight provided
the desired o-formylphosphinic amide 15q, albeit in moderate
yield (60%, entry 2). Iodine/lithium exchange of 15j with 1.2 equiv
of tBuLi at ꢀ90 °C followed by the addition of DMF did not improve
the yield of (RP,RC)-15q (62%) and instead favors the formation of
the (SP,RC)-15q diastereoisomer in a yield of 20% (entry 3). The best
results were obtained by the addition of the Grignard reagent of
phosphinic amide 15i to DMF. The intermediate magnesium bro-
mide of 15i was generated in the same manner as for 15j, furnish-
ing (RP,RC)-15q in 85% yield (entry 4).
To conclude this study, we carried out the I/Li exchange of 15j
with nBuLi at ꢀ78 °C in THF for 30 min. The reaction of the result-
ing ortho-lithiated species with Me3SnCl afforded the o-stannylat-
ed derivative 15r in 65% yield. Under these conditions, the process
took place without erosion of the enantiomeric purity of the start-
ing phosphinic amide. Thus, the halogen metal exchange comple-
ments the synthesis of ortho-functionalized P-stereogenic
phosphinic acid derivatives that are difficult to access by other
methods.
In addition, the ortho-iodine derivatives offer additional possi-
bilities regarding the insertion of different functionalities at the
ortho-position through Pd-catalyzed cross-coupling reactions.
Aryl-aryl bond formation is efficiently accomplished through
Suzuki coupling reactions between an aromatic organic electro-
phile (aryl halide) and an arylboronic acid. This cross-coupling
reaction involves transmetallation into aryl-palladium(II) halides
and proceeds smoothly when they are activated with suitable
bases. We assayed the coupling between the ortho-iodine deriva-
tive 15j and (2-methoxyphenyl)boronic acid using Pd(OAc)2 as pal-
ladium(II) source (Scheme 4).31
2.2. Transformations of the ortho-functional group
As mentioned earlier, the structure of the N-deprotonated spe-
cies 10 (Scheme 3) determines the stereochemical course of the
ortho-lithiation of the Ph2P group. However, the negatively charged
nitrogen of the N ,Cortho-dianion 11 is not compatible with the
a
presence of the important formyl group at the ortho-position.
Nucleophilic attack by the nitrogen anion to the C@O group fur-
nishes a 5-membered-ring substituted with a hydroxyl group.
The limitations of this method that arise from the presence of an
NLi anion can be obviated by using ortho-anions of P-stereogenic
N-methylated phosphinic amides. Such anions can be prepared
via halogen/metal exchange reactions of 15i and 15j (Table 4). This
methodology also allowed us to synthesize 15r which could not be
prepared by the aza-Wittig reaction of the o-stannylated derivative
12e (entry 5).
4
Me
5-8
Me
N
9
Me
Pd(OAc)2 (5 mol%),
K2CO3 (2 equiv),
Ph
3
Ph
Ph
Me
N
16-19
toluene, 120 ºC, 36 h
P
Ph
P
O
25
24
22
15
13
10
O
I
OMe
23
14
(1.5 equiv)
20
11
Table 4
12
Halogen/metal exchange in 15i,j and electrophilic quencha
21
B(OH)2
MeO
26
15j
1) iPrMgBr
or
(RP,RC)-
O
P
Me
O
P
Me
Ph
Ph
15s (82%)
dr 70:30
N
Ph
N
Ph
RLi, THF
Me
Me
2) E+
Scheme 4. Synthesis of biphenylphosphinic 15s via Suzuki coupling.
X
E
15i
, X = Br
(RP,RC)-15p-r
15j, X = I
Refluxing the mixture in toluene in the presence of Cs2CO3 for
20 h furnished the desired product 15s in 46% yield. This yield
increased to 70% when K2CO3 was used as the base. A further
improvement of the coupling reaction was achieved by prolonging
the reaction time to 36 h. In this manner, compound 15s was
formed in 82% yield as a mixture of two atropisomers in a ratio
of 70:30. Variable temperature 1H NMR measurements showed
the coalescence temperature at 90 °C.
The ortho-azido group present in phosphinimidic amide 12f,
phosphinic amide 15f and methyl phosphinate 16c, is an excellent
candidate for extending the structural diversity of the P-stereogen-
ic compounds. For instance, the conversion into a NH2 group opens
Entry
X
Reagent
T (°C)
E+
15
E
Yieldb (%)
1
2
3
4
5
I
I
I
Br
I
iPrMgBr
iPrMgBr
tBuLi
ꢀ40
ꢀ40
ꢀ90
ꢀ40
ꢀ78
CD3OD
DMF
DMF
p
q
q
q
r
D
100/97
60
CHO
CHO
CHO
Me3Sn
62c
iPrMgBr
nBuLi
DMF
90/85
72/65
Me3SnCld
a
Reaction conditions: (1) 2.2 equiv of Grignard or organolithium reagent, THF,
40 min; (2) 6 equiv of electrophile, 15 h.
Determined from the integrals of the 31P NMR spectra of the crude reaction
b
mixture/isolated yield.
1.2 equiv of tBuLi were used. 20% of the (SP,RC)-15 isomer was formed.
c
d
Reaction time of 1 h with Me3SnCl.

58
M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
up the way to carry out condensation reactions. This transforma-
tion was easily achieved with 12f by reaction with tert-butyllith-
ium at ꢀ70 °C in THF (Table 5, entry 1).32 After half an hour the
reaction was complete. The 31P NMR spectrum of the crude mix-
ture revealed the formation of two compounds assigned as the
adduct 19 (dP 32.3 ppm) and the product 20a (dP 31.3 ppm). The
arrangement of the donor sites can be easily prepared by a one-
pot reaction of phosphine-borane (RP)-18 with the ortho-
azidophosphinate (RP)-16c (Scheme 5, Eq. 1). Heating 18 in toluene
at 40 °C in the presence of DABCO for 4 h releases the correspond-
ing phosphine, which undergoes a Staudinger reaction23a with the
azido group of 16c at room temperature for 4 h to give the methyl
phosphazenylphosphinate (SPN,RPO)-22 (80%, ee 98%).
triazenyl derivative 19a showed the tert-butyl moiety at
d
1.28 ppm in the 1H NMR spectrum and underwent spontaneous
evolution to 20 either upon standing at room temperature or dur-
ing purification through column chromatography. The analogous
reaction of phosphinic amide 15f and phosphinate 16c provided
the respective o-amino products 20b and 20c in excellent yields
(entries 2 and 3). A straightforward application of this transforma-
tion consisted of the first synthesis of the P-stereogenic
benzo[1,5,2]diazaphosphinin-6(5H)-one 21 (Table 5). Compound
20a underwent quantitative conversion into heterocycle 21 upon
refluxing in toluene for 12 h. Similar cyclocondensations of N-
methoxycarbonyl-b-enaminophosphazenes have been reported to
give achiral [1,5,2]diazaphosphinin-6(1H)-ones.33,34
9-1P2h
O
8
2
BH3
P
P
7
OMe
3
Ph
1) DABCO
toluene
5
Me
6
4
N
P
(1)
Ph
22-25
O
Me
15
Ph
2)
20
Me
P
21
16
OMe
18
(RP)-
Me
17
19
(ee 98%)
18
N3
22
(SPN,RPO)-
(RP)-16c
(ee 96%)
(ee 98%)
HO
5
Me
1)
R1
R2
6-9
Ph
Table 5
3
Me
N
Me
4
Synthesis of o-amino-P-stereogenic compounds 20 and diazaphosphininone 21
H2N
N
Ph
Ph
Me
O
16-19
X
CH2Cl2, MS 4Å,
14 h, rt
P
Ph
Ph
O
20
P
P
Y
15
O
N
10
(2)
23
2) 1 equiv NBS,
30min
14
tBuLi
R1
11
CHO
7Me
6
22
NLi
N
12
13
R2
5
HN
24,24'
NtBu
X
P
25,25
18-21
X
P
Ph
(RP,RC)-15q
: R1 = R2 = Me
23a
(RP,RC)-
(RP,RC,SC)-
Ph
Ph
Ph
Me
8-11
19
24
17
: R1 = H, R2
=
P
16
15
23b
3 equiv tBuLi
Y
Y
N
Δ
12
Me
3
20a
-70 ºC, 30 min
4 Me
N3
NH2
O
N
H
O
OH
13
14
5-8
tBu
20
12f
: X = NCO2Me;
3
Ph
21
(SP,RC)-
H
Y = (R)-NHCH(CH3)Ph
2
9
NH
15f: X = O; Y = (R)-NHCH(CH3)Ph
15-18Ph
14
Me
16c
O
P
: X = O; Y = OMe
13
(3)
O
tBu
Ph
P
27
OH
22
Entry
20
X
Y
Isolated yield (%)
N
H
Ph
29
N
12
10
20
toluene, reflux
MS (4Å)
60 h
11
1
2
3
a
b
c
NCO2Me
O
O
(R)-NCH(Me)Ph
(R)-NCH(Me)Ph
OMe
85
97
94
NH2
21
28
23
24
26
20b
(RP,RC)-
25
31
(RP,RC)-25
30
2.3. Synthesis of P-stereogenic multidentate ligands
Scheme 5. Synthesis of polydentate P-stereogenic ligands.
The DoM-electrophilic quench process developed for synthesiz-
ing P-stereogenic phosphinimidic amides20 and the derivatization
reactions described in the previous sections furnished a wide vari-
ety of compounds containing functional groups that can be further
used to synthesize more complex molecules. With this aim, we
explored different alternatives for broadening the range of P-stere-
ogenic systems accessible through this methodology with the
preparation of a variety of polydentate ligands structurally related
to P-achiral compounds of interest for use in catalysis and coordi-
nation chemistry.
Compound 22 represents a new type of bidentate chiral ligand
containing the important P@O and P@N donor groups. This ligand
can be further transformed into a P-stereogenic o-aminophosphine
following the same synthetic route reported in the literature
(methoxy displacement by a Grignard reagent followed by reduc-
tion of the phosphine oxide formed; see also Table 3).20
The phosphinooxazoline ligands PHOX are recognized as one
type of privileged13 ligands due to their ability to induce high lev-
els of asymmetry in a broad range of metal-catalyzed transforma-
tions. This family of N,P-bidentate ligands consist of vicinal
diphenylphosphino and oxazoline groups connected through a
phenyl ring, and the chirality resides only at the carbon next to
the nitrogen atom of the heterocycle.40 Helmchen et al. have
reported the synthesis of a number of P-stereogenic PHOX ligands
via diastereoselective electrophilic or nucleophilic substitutions
and Pd-catalyzed stereoselective P-CAr bond-forming reactions of
P(III)-based reagents.41,42
The o-NC6H4P(X)R2 moiety of ortho-amino phosphines, phos-
phine oxides, phosphine sulfides and alkyl phosphinates repre-
sents a very useful scaffold for complexation with transition
metals.35 In addition to their applications as bidentate ligands
toward metal centers, compounds containing this framework show
properties as diverse as selective inhibitors of the transient recep-
tor potential melastatin-5 ion channel,36 inhibitors of taste
proteins,37 herbicidal and plant growth regulators.38 Typically,
35
the P-based functional group consists of the achiral PPh2 or
P(adamantyl)2 groups as in the family of DalPhos N,P ligands.39
Oxazolines can be prepared by condensation reactions between
1,2-aminoalcohols and a carbonylic compound (e.g., aldehydes,
P-stereogenic mixed donor N,P(X) ligands with an ortho-

M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
59
oximes, carboxylic acids, acid halides, esters, carboxamides,
nitriles, etc.).43 Of the products described above, phosphinic amide
(RP,RC)-15q bearing an ortho-formyl substituent is the ideal precur-
sor for synthesizing P-stereogenic PHOX-like ligands. For this pur-
pose, the method of Schwekendiek and Glorius was applied
(Scheme 5, Eq. 2).44 As a proof of concept, we carried out the con-
densation of 15q with 2-amino-2-methylpropan-1-ol in dichloro-
methane at room temperature for 14 h in the presence of
molecular sieves. Then, in situ oxidation of the oxazolidine formed
with N-bromosuccinimide (NBS) for 30 min provided the oxazo-
line-phosphinic amide 23a in 85% yield. In contrast, the analogous
reaction with the chiral amino alcohol (S)-2-amino-3-methylb-
utan-1-ol proceeded in a disappointing 25% yield. The efficiency
of the process increased significantly simply by increasing the
reaction time of the condensation step to 36 h. In this way, (RP,RC,-
SC)-23b was obtained in a yield of 80%. Compound 23b is a valuable
chiral N,O mixed ligand that might chelate metal ions through
coordination of the oxygen of the phosphinic amide group and
the nitrogen of the heterocycle.26,27 Furthermore, as shown above
(Table 3), the phosphinic amide moiety can be smoothly trans-
formed into a phosphine oxide or a phosphine with excellent con-
trol of the P-configuration. These features broaden the applicability
of the ligand in transition-metal catalyzed reactions and are cur-
rently under investigation.
The last desymmetrization of a Ph2P system that we will con-
sider is that of Schiff bases ROC6H4CH@NC6H4PPh2 24 formed by
the condensation reaction between 2-(diphenylphosphino)aniline
and substituted salicylaldehydes. These relevant heteroatomic
N,O,P-tridentate ligands were first described by Parr et al.45 in
the late nineties and, since then, have attracted considerable atten-
tion mostly due to the applications of a variety of metal complexes
of this family of ligands in polymerization reactions.46 More
recently, the complexation behavior of analogous phosphine oxide
and sulfides has begun to be examined.47 Access to P-stereogenic
tridentate N,O,P-derivatives of 25 is straightforward using ortho-
aminophosphinic amide 20b as an amino component for imine
synthesis (Scheme 5, Eq. 3). The reaction of ortho-aminophosphinic
amide 20b with 1 equiv of 3,5-di-tert-butyl-2-hydroxybenzalde-
hyde in refluxing toluene for 12 h in the presence of molecular
sieves (4 Å) provided the imine (RP,RC)-25 in a yield of 30%. This
yield increased to 90% by extending the reaction time for 5 days.
PHOX-like 23 and N,O,P-tridentate 25 ligands. Furthermore, the
complementarity between some ortho-functional groups allowed
for the modular synthesis of new P,P-chiral ligands 22. Further
work in the applications of these ligands in coordination chemistry
and transition-metal catalyzed asymmetric reactions is currently
in progress.
4. Experimental
4.1. Analytical methods and reagents
Reactions were performed under an inert atmosphere of nitro-
gen using Schlenk techniques. An anhydrous solvent was obtained
via elution through a solvent column drying system, except from
THF, which was freshly distilled from potassium/benzophenone.
Commercial reagents were distilled prior to their use, except alkyl-
lithiums. TLC was performed on plates with aluminum backing and
silica gel 60 F254 and for column chromatography silica gel 60 (40–
63 lm) was used. High-resolution mass spectra (HRMS) were
acquired in the electron spray ionization mode (ESI) using a TOF
mass analyzer. In compounds with relatively abundant multiiso-
topic elements the mass given corresponds to the most abundant
isotopes (e.g., 28Si, 32S, 79Br, 35Cl, 120Sn). 1H (300.13 MHz), 13C
(75.47 MHz) and 31P (121.47 MHz) NMR spectra were measured
at room temperature on a spectrometer equipped with a QNP
1H/13C/19F/31P probe. CDCl3 was used as the NMR solvent in all
cases. Chemical shifts are referred to internal tetramethylsilane
(TMS) for 1H and 13C and to external 85% H3PO4 for 31P. Diastere-
oselectivities were determined by integration of 1H and/or 31P
NMR spectra of the crude reactions. Quantitative 31P NMR mea-
surements were performed by using the inverse-gated pulse
sequence, an excitation pulse of 15° and a repetition delay of 7 s.
Full characterization of the products was carried out through anal-
ysis of the following 2D spectra: 1H,13C-HMQC, 1H,13C-HMBC,
1H,31P-HMQC and COSY45. The enantiomeric excesses were deter-
mined by chiral HPLC analysis with a diode array detector. Optical
rotations were measured in a 1 dm cell of 2 mL capacity. We have
already reported on the synthesis and structural elucidation of
compounds 13b, 15f, 15i, 15l, 15m, 15q and 16c,20 14a and
15r,17b 14b,18 1720 and 18.28i The numbering scheme used for the
structural characterization of the new compounds are indicated
in Tables 3,5, Schemes 4,5 and Figure 2.
3. Conclusion
In conclusion, we have developed efficient and useful method-
ologies for the synthesis of structurally, electronically and steri-
cally diverse P-stereogenic organophosphorus compounds based
on the discrimination of the diastereotopic phenyl rings of a Ph2P
group. The highly stereoselective route developed starts with a
directed ortho-lithiation (DoLi)-electrophilic quench reaction of
phosphinimidic amides. Aza-Wittig reaction of the enantiopure
phosphinimidic amides furnished the corresponding phosphinic
and phosphinothioic amides while preserving the enantiomeric
purity. P-Stereogenic phosphines can be synthesized through a
process that involves the transformation of the P(O)N moiety into
an alkyl phosphinate via methanolysis reactions followed by nucle-
ophilic displacement with Grignard reagents and, finally, reduction
of the resulting phosphine oxide. Extension of the structural diver-
sity of the P-stereogenic compounds was performed through the
elaboration of the ortho-substituents via Suzuki cross-coupling
reactions, halogen/metal exchange-formylation and azide to amine
conversion reactions. In this way, relevant functional groups such
as an aromatic ring, a formyl and an amine group were introduced.
The usefulness of these derivatization reactions is demonstrated
with the preparation of novel and interesting P-stereogenic
4MeO2C3
7
O
P
4Me
3
15-18 Ph
14
X
P
4Me
3
16-19
15
N
P
Me
6
19-22
Ph
Ph
2
2
18
5
13
14
N
Ph
N
Ph
17
16
N
Ph
9
10
H
13
5-8
5-8
8-11
Me
13
Me
9
12
10
E
12
E
20
E
11
14
11
12
15
23
15h,j,k,n,p
(SP,RC)-13
(RP,RC)-15
19
19
20-23
E = Me, I, SiMe3, P(O)Ph2
15
a
c
d
g
4
MeO2C3
7
4 Me
Me
15-18
Ph
9-12Ph
O
N
P
O
P
18-21 Ph
5
2
2
14
8
17
P
16
N
H
Ph
8-11
13
12
N
H
Ph
5-8
7
6
OMe
6
3
12
9
3
15
NH2
NH2
NH2
13
10
4
14
11
5
20a
20b
20c
Figure 2. Numbering scheme used for compounds 13, 15 and 20.

60
M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
3
3
4.2. Chemical transformations
H-23), 1.64 (d, 3H, JHH 7.1 Hz, H-7), 2.48 (d, 3H, JPH 10.3 Hz, H-
3
3
12), 3.66 (s, 3H, H-4), 4.90 (dq, 1H, JHH 6.9 Hz, JPH 9.5 Hz, H-6),
3
4
4.2.1. General procedure for the synthesis of N-methylated
(SP,RC)-phosphinimidic amides 13
7.2–7.5 (m, 10H, H-Ar), 7.63 (ddd, 1H, JHH 7.8 Hz, JHH 1.0 Hz,
3JPH 14.0 Hz, H-18), 7.78 (m, 2H, H-20), 7.88 (ddd, 1H, JHH
3
4
4
Method A. To a solution of the corresponding phosphinimidic
amide (SP,RC)-12 (1 mmol; 1 equiv) in THF (10 mL; 0.1 M) cooled
at 0 °C, KHMDS (230 mg; 1.1 mmol; 1.1 equiv) was added. After
2 h of stirring, MeOTf (0.12 mL; 1.1 mmol; 1.1 equiv) was added
and the reaction mixture was allowed to warm to room tempera-
ture overnight. The reaction was then quenched with MeOH. Stan-
dard aqueous workup afforded the N-methylated derivatives 13.
Method B. ortho-Stannylated phosphinimidic amide (SP,RC)-12e
(302 mg, 0.56 mmol; 1 equiv) was added to a suspension of NaH
(90 mg, 2.24 mmol; 4 equiv) in THF (10 mL; 0.06 M) at 0 °C. After
2 h of stirring, MeI (0.14 mL, 2.24 mmol; 4 equiv) was added and
the reaction mixture was allowed to warm to room temperature
overnight. The reaction was then quenched with MeOH, washed
with H2O (2 ꢂ 5 mL), extracted with CH2Cl2 (2 ꢂ 5 mL) and dried
over anhydrous Na2SO4. Solvent evaporation under vacuum fur-
nished 13e. The purification method used for the isolation of com-
pounds 13 is included as part of the characterization data.
7.6 Hz, JHH 1.1 Hz, JPH 4.4 Hz, H-15) ppm. 13C NMR d 2.4 (s, C-
3
2
23), 17.0 (d, JPC 1.4 Hz, C-7), 29.8 (d, JPC 3.7 Hz, C-12), 52.2 (d,
4JPC 3.7 Hz, C-4), 53.6 (d, JPC 4.2 Hz, C-6), 127.2 (C-11), 127.8 (d,
2
3JPC 13.4 Hz, C-17), 128.1 (C-10), 128.11 (C-9), 128.4 (d, JPC
3
1
4
12.5 Hz, C-21), 130.6 (d, JPC 117.9 Hz, C-13/19), 130.6 (d, JPC
3.2 Hz, C-16), 131.9 (d, JPC 2.8 Hz, C-22), 132.9 (d, JPC 10.2 Hz,
C-20), 133.4 (d, JPC 13.5 Hz, C-15), 134.0 (d, JPC 135.9 Hz, C-13/
4
2
3
1
2
3
19), 137.1 (d, JPC 15.7 Hz, C-18), 140.8 (d, JPC 5.6 Hz, C-8), 147.4
(d, JPC 17.4 Hz, C-14), 161.7 (d, JPC 2.3 Hz, C-3) ppm. 31P NMR d
2
2
33.7 ppm. IR (KBr,
m
cmꢀ1): 1640 (s, CO), 1435 (m), 1302 (s, PN),
1107 (m), 982 (w), 913 (m), 844 (m), 742 (m), 699 (m), 523 (m).
HRMS (ESI) calcd for C26H33N2O2PSi: 465.2127 (MH+), found:
465.2121.
4.2.1.4. Methyl ((SP)-(2-(trimethylstannyl)phenyl){methyl[(1R)-
1-phenylethyl]amino}phenylphosphanylidene)carbamate
13e. Method B. Yield after chromatography (ethyl acetate/hexane
1:2) 95%. Oil. [
23), 1.64 (d, 3H, JHH 7.1 Hz, H-7), 2.74 (d, 3H, JPH 11.1 Hz, H-
a]
25 = 2.6 (c 1, CH2Cl2). 1H NMR d 0.41 (s, 9H, H-
D
3
3
4.2.1.1. Methyl ((SP)-(2-methylphenyl){methyl[(1R)-1-phenyl-
ethyl]amino}phenylphosphoranylidene)carbamate 13a. Method
A. Yield after chromatography (ethyl acetate/hexane 1:2) 79%.
3
3
12), 3.72 (s, 3H, H-4), 4.59 (dq, 1H, JHH 6.8 Hz, JPH 8.4 Hz, H-6),
7.2–7.5 (m, 10H, H-Ar), 7.8–8.0 (m, 4H, H-Ar) ppm. 13C NMR d -
2
4
Mp: 60–61 °C. [
a]
25 = +16.2 (c 1, CH2Cl2). 1H NMR d 1.55 (d, 3H,
3.2 (C-23), 16.8 (C-7), 30.5 (d, JPC 2.5 Hz, C-12), 52.2 (d, JPC
3.1 Hz, C-4), 53.8 (d, JPC 4.1 Hz, C-6), 127.2 (C-11), 127.6 (C-10),
128.0 (d, JPC 13.7 Hz, C-17), 128.3 (C-9), 128.9 (d, JPC 12.2 Hz, C-
21), 129.1 (d, JPC 113.4 Hz, C-19), 130.9 (d, JPC 3.1 Hz, C-16),
D
3JHH 7.1 Hz, H-7), 2.28 (s, 3H, H-23), 2.35 (d, 3H, JPH 10.5 Hz, H-
3
2
3
3
3
3
12), 3.61 (s, 3H, H-4), 5.09 (dq, 1H, JHH 6.9 Hz, JPH 9.5 Hz, H-6),
7.2–7.6 (m, 12H, H-Ar), 7.79 (m, 2H, H-20) ppm. 13C NMR d 16.7
1
4
3
3
2
4
3
(d, JPC 1.4 Hz, C-7), 21.7 (d, JPC 3.8 Hz, C-23), 28.8 (d, JPC 4.7 Hz,
132.0 (d, JPC 3.1 Hz, C-22), 132.6 (d, JPC 14.2 Hz, C-15), 132.8 (d,
4
2
1
2
C-12), 52.7 (d, JPC 3.7 Hz, C-4), 53.4 (d, JPC 3.8 Hz, C-6), 125.8 (d,
2JPC 9.7 Hz, C-20), 133.4 (d, JPC 149.5 Hz, C-13), 137.6 (d, JPC
3JPC 12.6 Hz, C-17), 126.4 (d, JPC 113.8 Hz, C-19/13), 127.3 (C-11),
16.3 Hz, C-18), 140.6 (d, JPC 8.1 Hz, C-8), 153.3 (d, JPC 14.7 Hz,
1
3
2
3
128.2 (C-9), 128.3 (C-10), 128.6 (d, JPC 13.0 Hz, C-21), 129.6 (d,
C-14), 162.0 (C-3) ppm. 31P NMR d 31.1 ppm. IR (KBr, cmꢀ1):
m
1JPC 128.3 Hz, C-13/19), 131.9 (d, JPC 10.3 Hz, C-20), 132.0 (d, JPC
1629 (s, CO), 1435 (m), 1292 (s, PN), 1263 (m), 1105 (m), 907
(m), 729 (m), 696 (m). HRMS (ESI) calcd for C26H33N2O2PSn:
557.1385 (MH+), found: 557.1381.
2
4
3
4
2.8 Hz, C-16/22), 132.1 (d, JPC 9.3 Hz, C-15), 132.2 (d, JPC 2.8 Hz,
2
3
C-16/22), 134.0 (d, JPC 10.1 Hz, C-18), 140.6 (d, JPC 4.9 Hz, C-8),
2
2
142.6 (d, JPC 11.0 Hz, C-14), 161.9 (d, JPC 4.0 Hz, C-3) ppm. 31P
NMR d 33.8 ppm. IR (KBr,
cmꢀ1): 1634 (s, CO), 1438 (m), 1300
(m), 1260 (s, PN), 1138 (m), 1111 (m), 1030 (m), 906 (m), 724
m
4.2.2. General method for the transformation of phosphinimidic
amides into phosphinic amides 15a–k and phophinothioic amides
15l–o
(m), 698 (m), 636 (m). HRMS (ESI) calcd for
C24H27N2O2P:
407.1888 (MH+), found: 407.1905.
Method A/C. Solvent free reaction. The corresponding ortho-
functionalized phosphinimidic amides (1 mmol; 1 equiv) and
phenylisocyanate (method A, 0.65 mL; 6 equiv)) or phenylisothio-
cyanate (method C, 0.72 mL; 6 equiv) were stirred at 120 °C under
an N2 atmosphere for 24 h. The reaction crude was then dissolved
into methylenedichloride, washed with H2O (2 ꢂ 5 mL), extracted
with CH2Cl2 (3 ꢂ 5 mL) and dried over anhydrous Na2SO4. Solvent
evaporation under vacuum furnished the corresponding product,
which was purified as indicated below. Method B: To a solution
of the corresponding ortho-functionalized phosphinimidic amides
(1 mmol; 1 equiv) in EtOH (10 mL; 0.07 M) was added acetalde-
hyde (0.6 mL; 10 equiv). The reaction mixture was stirred at room
temperature overnight. The solvent was then removed in vacuo to
give a solid, which was washed with diethylether in order to obtain
the pure product. Method LR: A solution of the corresponding
ortho-functionalized phosphinic amide (0.2 mmol; 1 equiv) and
Lawesson’s reagent (0.1 mmol; 0.5 equiv) in toluene (4 mL;
0.05 M) was heated at reflux overnight. The solvent was then
removed in vacuo and the reaction crude was dissolved in CH2Cl2
(5 mL), washed H2O (2 ꢂ 2 mL), dried over anhydrous Na2SO4
and concentrated in vacuo. The products were purified as indicated
below.
4.2.1.2. Methyl ((SP)-(2-iodophenyl){methyl[(1R)-1-phenyl-
ethyl]amino}phenylphosphoranylidene)carbamate 13c. Method
A. Yield after chromatography (ethyl acetate/hexane 1:1.5) 80%.
Mp: 125–127 °C. [
3H, JHH 7.1 Hz, H-7), 2.34 (d, 3H, JPH 10.4 Hz, H-12), 3.63 (s, 3H,
H-4), 5.10 (dq, 1H, JHH 6.9 Hz, JPH 9.8 Hz, H-6), 7.17 (m, 1H, H-
a
]
25 = +51.9 (c 1, CH2Cl2). 1H NMR d 1.57 (d,
D
3
3
3
3
16), 7.57 (m, 9H, H-Ar), 7.54 (m, 2H, H-15, H-22), 7.77 (ddd, 2H,
3
3JHH 7.7 Hz, JPH 12.7 Hz, H-20), 8.0 (m, 1H, H-18) ppm. 13C NMR
3
2
4
d 16.9 (d, JPC 1.7 Hz, C-7), 28.9 (d, JPC 4.6 Hz, C-12), 52.8 (d, JPC
2
2
3.7 Hz, C-4), 53.6 (d, JPC 4.2 Hz, C-6), 99.6 (d, JPC 9.6 Hz, C-14),
127.4 (C-11), 127.5 (d, JPC 10.8 Hz, C-17), 127.9 (d, JPC 137.0 Hz,
3
1
3
C-19), 128.2 (C-10), 128.4 (C-9), 128.51 (d, JPC 13.2 Hz, C-21),
4
1
132.1 (d, JPC 2.9 Hz, C-22), 132.3 (d, JPC 114.7 Hz, C-13), 132.3
2
4
3
(d, JPC 9.9 Hz, C-20), 132.9 (d, JPC 2.9 Hz, C-16), 136.0 (d, JPC
3
2
9.1 Hz, C-15), 140.4 (d, JPC 4.8 Hz, C-8), 142.4 (d, JPC 10.3 Hz, C-
18), 161.5 (d, JPC 4.8 Hz, C-3) ppm. 31P NMR d 35.5 ppm. IR (KBr,
2
m
cmꢀ1): 1637 (s, CO), 1436 (m), 1604 (s, PN), 1111 (m), 1098
(m), 987 (w), 934 (w), 732 (m), 695 (m), 517 (m). HRMS (ESI) calcd
for C23H24IN2O2P: 519.0698 (MH+), found: 519.0721.
4.2.1.3.
Methyl
{(SP)-{methyl[(1R)-1-phenylethyl]amino}-
(phenyl)[2-(trimethylsilyl)phenyl]phosphoranylidene}carbamate
4.2.2.1. (RP)-P-(2-Methylphenyl)-P-phenyl-N-[(R)-1-phenylethyl]-
phosphinic amide 15a. Method A. Yield after chromatography
13d. Method A. Yield after chromatography (ethyl acetate/hexane
1:1) 50%. Oil. [
a]
25 = ꢀ2.6 (c 1, CH2Cl2). 1H NMR d 0.29 (s, 9H,
(ethyl acetate/hexane 2:1) 90%. Mp: 120–121 °C. [
a]
25 = ꢀ8.6
D
D

M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
61
2
4
(c 1, CH2Cl2). 1H NMR d 1.59 (d, 3H, 3JHH 6.9 Hz, H-4), 2.44 (s, 3H, H-
19), 3.18 (dd, 1H, JPH 8.4 Hz, JHH 9.4 Hz, H-2), 4.50 (m, 1H, H-3),
4JPC 2.9 Hz, C-23), 131.1 (d, JPC 9.9 Hz, C-210), 131.3 (d, JPC
2
3
2
4
2.9 Hz, C-230), 131.8 (d, JPC 10.4 Hz, C-16), 131.9 (d, JPC 2.9 Hz,
3
4
2
3
2
7.1–7.5 (m, 11H, H-Ar), 7.68 (ddd, 1H, JHH 7.7 Hz, JHH 1.4 Hz,
C-18), 134.5 (dd, JPC 13.5 Hz, JPC 10.5 Hz, C-11), 136.0 (dd, JPC
3JPH 13.5 Hz, H-14), 7.68 (ddd, 2H, JHH 8.1 Hz, JHH 1.5 Hz, JPH
10.6 Hz, JPC 6.5 Hz, C-14), 145.8 (d, JPC 2.3 Hz, C-5) ppm. 31P
3
4
3
3
3
12.2 Hz, H-16) ppm. 13C NMR d 21.6 (d, JPC 4.1 Hz, C-19), 26.0
NMR d 25.3 (d, JPC 11.2 Hz, P-1), 33.31 (d, JPC 11.2 Hz, P-22)
3
3
3
3
2
3
(d, JPC 3.6 Hz, C-4), 51.2 (d, JPC 1.0 Hz, C-3), 125.2 (d, JPC
12.2 Hz, C-13), 126.0 (C-7), 127.1 (C-8), 128.4 (d, JPC 12.7 Hz, C-
17), 128.5 (C-6), 130.3 (d, JPC 127.4 Hz, C-9/15), 131.7 (d, JPC
10.2 Hz, C-16), 131.7 (d, JPC 3.1 Hz, C-12/18), 131.7 (d, JPC
ppm. IR (KBr,
m
cmꢀ1): 3204 (s, NH), 1488 (m), 1437 (m), 1183 (s,
3
PO), 1118 (s, PO), 913 (s), 745 (s), 696 (m), 532 (m), 421 (m). HRMS
(ESI) calcd for C32H29NO2P2: 522.1752 (MH+), found: 522.1761.
1
2
4
3
4
2
11.7 Hz, C-11), 131.8 (d, JPC 2.6 Hz, C-12/18), 133.3 (d, JPC
4.2.2.5. (RP)-N-Methyl-P-phenyl-N-((R)-1-phenylethyl)-P-(o-
tolyl)phosphinic amide 15h. Method A. Yield after chromatogra-
1
2
10.2 Hz, C-14), 133.3 (d, JPC 125.1 Hz, C-9/15), 142.6 (d, JPC
10.2 Hz, C-10), 145.0 (d, JPC 6.1 Hz, C-5) ppm. 31P NMR
d
phy (ethyl acetate/hexane 2:1) 90%. Oil. [
a]
25 = +4.5 (c 1, CH2Cl2).
3
D
3
3
26.9 ppm. IR (KBr,
m
cmꢀ1): 3191 (s, NH), 3060 (w), 2969 (w),
1H NMR d 1.56 (d, 3H, JHH 7.1 Hz, H-4), 2.06 (d, 3H, JPH 12.6 Hz,
3
3
2925 (w), 1456 (m), 1437 (m), 1180 (s, PO), 1115 (m), 1085 (w),
1027 (w), 964 (w). HRMS (ESI) calcd for C21H22NOP: 336.1517
(MH+), found: 336.1527.
H-9), 2.40 (s, 3H, H-20), 4.99 (dq, 1H, JHH 7.0 Hz, JPH 9.1 Hz, H-
3), 7.2–7.6 (m, 12H, H-Ar), 7.75 (m, 2H, H-17) ppm. 13C NMR d
3
3
2
16.7 (d, JPC 2.3 Hz, C-4), 21.6 (d, JPC 3.7 Hz, C-20), 28.2 (d, JPC
5.1 Hz, C-9), 52.7 (d, JPC 3.7 Hz, C-3), 125.3 (d, JPC 13.0 Hz, C-
14), 127.1 (C-8), 128.1 (C-7), 128.2 (C-6), 128.4 (d, JPC 12.5 Hz,
C-18), 129.7 (d, JPC 126.2 Hz, C-10/16), 131.6 (d, JPC 2.8 Hz, C-
13/19), 131.8 (d, JPC 2.3 Hz, C-13/19), 131.9 (d, JPC 12.0 Hz, C-
12), 132.1 (d, JPC 9.7 Hz, C-17), 132.9 (d, JPC 112.4 Hz, C-10/16),
2
3
3
4.2.2.2. (RP)-P-(2-Iodophenyl)-P-phenyl-N-[(R)-1-phenylethyl]-
phosphinic amide 15c. Method A and B. Yield after chromatogra-
1
4
4
3
phy (ethyl acetate/hexane 1:1) 88%. Mp: 80–81 °C. [
a
]
25 = ꢀ22.3
D
3
2
1
(c 1, CH2Cl2). 1H NMR d 1.65 (d, 3H, JHH 6.8 Hz, H-4), 3.68 (t, 1H,
3JHH 8.4 Hz, H-2), 4.64 (m, 1H, H-3), 7.1–7.6 (m, 10H, H-Ar), 7.76
133.2 (d, JPC 11.6 Hz, C-15), 140.9 (d, JPC 4.2 Hz, C-5), 143.3 (d,
2
3
3
4
3
(ddt, 2H, JHH 6.9 Hz, JHH 1.5 Hz, JPH 13.0 Hz, H-16), 7.87 (ddd,
2JPC 9.3 Hz, C-11) ppm. 31P NMR d 35.9 ppm. IR (KBr, cmꢀ1):
m
3
4
4
3
1H, JHH 8.0 Hz, JHH 1.0 Hz, JPH 3.9 Hz, H-11), 8.04 (ddd, 1H, JHH
1450 (m), 1182 (s, PO), 1110 (m), 927 (m), 908 (m), 723 (m), 697
(m). HRMS (ESI) calcd for C22H24NOP: 350.1595 (MH+), found:
350.1680.
7.6 Hz, JHH 1.7 Hz, JPH 12.5 Hz, H-14) ppm. 13C NMR d 25.4 (d,
4
3
3JPC 5.6 Hz, C-4), 51.0 (d, JPC 0.9 Hz, C-3), 99.1 (d, JPC 8.3 Hz, C-
2
2
3
10), 126.2 (C-7), 127.1 (C-8), 127.7 (d, JPC 11.1 Hz, C-13), 128.3
3
2
(C-6), 128.5 (d, JPC 13.0 Hz, C-17), 131.6 (d, JPC 10.6 Hz, C-16),
4.2.2.6.
(RP)-P-(2-Iodophenyl)-N-methyl-P-phenyl-N-((R)-1-
phenylethyl)phosphinic amide 15j. Method A. Yield after chroma-
4
1
132.0 (d, JPC 3.2 Hz, C-18), 132.1 (d, JPC 130.9 Hz, C-9/15), 132.7
4
1
(d, JPC 2.8 Hz, C-12), 135.7 (d, JPC 125.31 Hz, C-9/15), 136.2 (d,
tography (ethyl acetate/hexane 1:2) 90%. Mp: 62–63 °C.
3JPC 8.7 Hz, C-11), 141.1 (d, JPC 9.7 Hz, C-14), 144.2 (d, JPC
[a
]
D
25 = +0.8 (c 1, CH2Cl2). 1H NMR d 1.61 (d, 3H, JHH 7.0 Hz, H-4),
2
3
3
3
3
3
4.6 Hz, C-5) ppm. 31P NMR d 27.6 ppm. IR (KBr, cmꢀ1): 3200 (s,
m
2.42 (d, 3H, JPH 10.3 Hz, H-9), 5.02 (dq, 1H, JHH 7.0 Hz, JPH
NH), 1437 (m), 1192 (s, PO), 1114 (w), 753 (m), 730 (m), 693
(m), 530 (m). HRMS (ESI) calcd for C20H19INOP: 448.0282 (MH+),
found: 448.0320.
9.0 Hz, H-3), 7.15 (m, 1H, H-13), 7.3–7.6 (m, 11H, H-Ar), 7.74 (m,
2H, H-17), 8.04 (ddd, 1H, JHH 7.9 Hz, JHH 0.9 Hz, JPH 3.9 Hz, H-
3
4
3
3
2
15) ppm. 13C NMR d 17.1 (d, JPC 2.5 Hz, C-4), 28.7 (d, JPC 4.6 Hz,
2
2
C-9), 53.2 (d, JPC 4.6 Hz, C-3), 99.8 (d, JPC 7.4 Hz, C-11), 127.2
(C-8), 127.5 (d, JPC 11.6 Hz, C-14), 128.1 (C-7), 128.2 (C-6), 128.4
(d, JPC 13.2 Hz, C-18), 131.3 (d, JPC 128.1 Hz, C-16), 131.7 (d, JPC
2.9 Hz, C-13), 132.3 (d, JPC 9.9 Hz, C-17), 132.7 (d, JPC 2.5 Hz, C-
3
4.2.2.3.
(RP)-P-Phenyl-N-[(R)-1-phenylethyl]-P-[2-(trimethyl-
3
1
4
silyl)phenyl]phosphonic amide 15d. Method A. Yield after chro-
matography (ethyl acetate/hexane 1:3) 85%. Mp: 105–107 °C.
2
4
3
1
[
a
]
25 = ꢀ6.4 (c 1, CH2Cl2). 1H NMR d 0.43 (s, 9H, H-19), 1.59 (d,
19), 135.3 (d, JPC 9.9 Hz, C-12), 135.4 (d, JPC 129.9 Hz, C-10),
D
3
3
2
3
2
3H, JHH 6.7 Hz, H-4), 3.10 (dd, 1H, JHH 9.3, JPH 7.1 Hz, Hz, H-2),
4.39 (m, 1H, H-3), 7.1–7.5 (m, 11H, H-Ar), 7.74 (ddd, 1H, JHH
140.8 (d, JPC 3.7 Hz, C-5), 142.4 (d, JPC 9.9 Hz, C-15) ppm. 31P
3
NMR d 35.6 ppm. IR (KBr,
m
cmꢀ1): 1415 (m), 1190 (s, PO), 1130
4
3
3
7.6 Hz, JHH 1.0 Hz, JPH 12.9 Hz, H-14), 7.68 (ddd, 2H, JHH 6.4 Hz,
(m), 1109 (m), 988 (w), 926 (m), 906 (m), 724 (m), 694 (m). HRMS
4JHH 1.5 Hz, JPH 11.7 Hz, H-16) ppm. 13C NMR d 1.9 (C-19), 25.72
(ESI) calcd for C21H21INOP: 462.0484 (MH+), found: 462.0496.
3
3
2
(d, JPC 3.2 Hz, C-4), 51.4 (d, JPC 1.4 Hz, C-3), 126.0 (C-7), 127.1
(C-8), 128.0 (d, JPC 12.5 Hz, C-13), 128.3 (d, JPC 12.5 Hz, C-17),
128.5 (C-6), 130.5 (d, JPC 3.2 Hz, C-12), 131.5 (d, JPC 2.8 Hz, C-
18), 131.8 (d, JPC 9.7 Hz, C-16), 134.4 (d, JPC 123.5 Hz, C-9/15),
3
3
4.2.2.7. (RP)-N-Methyl-P-phenyl-N-((R)-1-phenylethyl)-P-(2-(tri-
methylsilyl)phenyl)phosphinic amide 15k. Method A. Yield after
4
4
2
1
chromatography (ethyl acetate/hexane 1:4) 87%. Oil. [
a
]
25 = +20.8
D
3
2
3
133.7 (d, JPC 12.9 Hz, C-11), 136.3 (d, JPC 16.2 Hz, C-14), 136.8
(c 1, CH2Cl2).1H NMR d 0.40 (s, 9H, H-20), 1.63 (d, 3H, JHH
1
3
2
3
3
(d, JPC 131.8 Hz, C-9/15), 145.1 (d, JPC 6.9 Hz, C-5), 147.0 (d, JPC
6.9 Hz, H-4), 2.40 (d, 3H, JPH 10.6 Hz, H-9), 4.61 (dq, 1H, JHH
18.5 Hz, C-10) ppm. 31P NMR d 26.8 ppm. IR (KBr, cmꢀ1): 3280
m
7.0 Hz, JPH 9.3 Hz, H-3), 7.2–7.6 (m, 11H, H-Ar), 7.83 (m, 3H, H-
3
3
(s, NH), 1709 (m), 1496 (w), 1421 (m), 1199 (m, PO), 1114 (m),
908 (w), 844 (m), 736 (m), 693 (m), 531 (m). HRMS (ESI) calcd
for C23H28NOPSi: 394.1756 (MH+), found: 394.1756.
15, H-17) ppm. 13C NMR d 1.9 (s, C-20), 17.3 (d, JPC 3.1 Hz, C-4),
2
2
28.2 (d, JPC 3.6 Hz, C-9), 54.0 (d, JPC 3.6 Hz, C-3), 126.9 (C-8),
3
127.5 (C-6), 128.1 (d, JPC 12.7 Hz, C-14), 128.2 (C-7), 128.4 (d,
3JPC 12.2 Hz, C-18), 130.5 (d, JPC 4.1 Hz, C-13), 131.4 (d, JPC
4
4
2
1
4.2.2.4. (RP)-P-(2-(Diphenylphosphoryl)phenyl)-P-phenyl-N-((R)-
1-phenylethyl)phosphinic amide 15g. Method A. Yield after chro-
3.6 Hz, C-19), 132.2 (d, JPC 9.7 Hz, C-17), 133.0 (d, JPC 123.6 Hz,
C-10/16), 133.1 (d, JPC 12.2 Hz, C-12), 136.6 (d, JPC 16.3 Hz, C-
3
2
1
3
matography (AcOEt/hexane 2:1) 80%. Mp: 100–102 °C.
15), 137.0 (d, JPC 132.8 Hz, C-10/16), 141.3 (d, JPC 4.6 Hz, C-5),
3
2
[
a]
D
25 = +14.6 (c 1, CH2Cl2). 1H NMR d 1.69 (dd, 3H, JHH 6.7 Hz,
147.4 (d, JPC 18.3 Hz, C-11) ppm. 31P NMR d 34.7 ppm. IR (KBr,
4JPH 1.2 Hz, H-4), 4.81 (m, 1H, H-3), 6.45 (dd, 1H, JHH 9.8 Hz, JPH
m
cmꢀ1): 1497 (m), 1438 (m), 1177 (s, PO), 1115 (m), 908 (m),
3
2
9.1 Hz, H-2), 6.9–7.6 (m, 22H, H-Ar), 7.97 (m, 1H, H-11), 8.69 (m,
727 (s), 690 (s). HRMS (ESI) calcd for C24H30NOPSi: 408.1913
3
2
1H, H-14) ppm. 13C NMR d 25.8 (d, JPC 7.9 Hz, C-4), 49.5 (d, JPC
(MH+), found: 408.1925.
3
1.7 Hz, C-3), 126.2 (C-8), 126.3 (C-7), 127.2 (d, JPC 13.7 Hz, C-17),
3
3
128.0 (C-6), 128.2 (d, JPC 12.4 Hz, C-22), 128.4 (d, JPC 12.4 Hz, C-
4.2.2.8. (RP)-N-Methyl-P-phenyl-N-((R)-1-phenylethyl)-P-(o-tolyl)-
phosphinothioic amide 15n. Method C. Yield after chromatogra-
4
3
2
220), 129.5 (dd, JPC 2.9 Hz, JPC 12.8 Hz, C-13), 131.0 (d, JPC
9.9 Hz, C-21), 131.2 (dd, JPC 2.4 Hz, JPC 8.2 Hz, C-12), 131.1 (d,
4
3
phy (ethyl acetate/hexane 1:10) 70%. Oil. [a]
25 = +10.0 (c 1, CH2Cl2).
D

62
M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
1H NMR d 1.43 (d, 3H, 3JHH 7.0 Hz, H-4), 2.33 (d, 3H, 3JHH 10.6 Hz, H-
(s, PO), 1126 (m), 925 (m), 909 (m), 724 (s), 696 (s). HRMS (ESI)
calcd for C28H28NO2P: 442.1936 (MH+), found: 442.1944.
9), 2.40 (s, 3H, H-20), 5.86 (m, 1H, H-3), 7.1–7.5 (m, 12H, H-Ar),
3
7.84 (m, 2H, H-17) ppm. 13C NMR d 21.8 (d, JPC 5.1 Hz, C-20),
3
2
2
25.5 (d, JPC 4.2 Hz, C-4), 28.2 (d, JPC 5.1 Hz, C-9), 51.7 (d, JPC
4.2.4. General procedure for the synthesis of methyl phosphi-
nates 16
3
0.9 Hz, C-3), 125.4 (d, JPC 12.9 Hz, C-14), 126.2 (C-7), 127.1 (C-8),
3
2
128.3 (d, JPC 12.9 Hz, C-18), 128.4 (C-6), 131.1 (d, JPC 11.1 Hz, C-
The corresponding phosphinic amide (RP,RC)-15 (1 mmol;
1 equiv) was dissolved in a solution of HCl in methanol (1.25 M,
3 mmol; 2.4 mL). The reaction was stirred overnight at room tem-
perature. Next, CH2Cl2 (15 mL) was added and the reaction mixture
was washed with 1 M NaOH (3 ꢂ 10 mL). The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo to give
the pure compounds.
4
4
17), 131.4 (d, JPC 3.2 Hz, C-13/19), 131.5 (d, JPC 3.2 Hz, C-13/19),
132.0 (d, JPC 11.1 Hz, C-15), 132.2 (d, JPC 11.6 Hz, C-12), 132.8
2
3
1
1
(d, JPC 101.7 Hz, C-10/16), 135.1 (d, JPC 99.0 Hz, C-10/16), 141.2
(d, JPC 11.1 Hz, C-11), 144.8 (d, JPC 5.1 Hz, C-5) ppm. 31P NMR d
2
3
67.2 ppm. IR (KBr,
m
cmꢀ1): 3380 (s, NH), 3054 (w), 2966 (w),
2926 (w), 1456 (w), 1437 (m), 1105 (m), 1080 (w), 1031 (w), 960
(w), 748 (m), 719 (m), 694 (s, PS), 634 (m), 509 (w). HRMS (ESI)
calcd for C22H24NPS: 366.1445 (MH+), found: 366.1436.
4.2.4.1. Methyl (R)-phenyl(o-tolyl)phosphinate 16a. Yield 98%.
Mp: 120–122 °C. [
2.40 (d, 3H, JPH 1.1 Hz, H-13), 3.73 (d, 3H, JPH 11.0 Hz, H-2),
a
]
25 = ꢀ9.5 (c 1, CH2Cl2). ee 96%. 1H NMR d
D
4
3
4.2.2.9. Synthesis of (RP)-N-methyl-P-phenyl-P-(phenyl-2-d)-N-
((R)-1-phenylethyl)phosphinic amide 15p. To a solution of phos-
phinic amide (RP,RC)-15i (150 mg; 0.36 mmol) in THF (6 mL;
3
7.1–7.5 (m, 6H, H-Ar), 7.73 (m, 2H, H-10), 7.89 (ddd, 1H, JHH
4
3
7.7 Hz, JHH 1.5 Hz, JPH 12.9 Hz, H-8) ppm. 13C NMR d 21.2 (d,
i
3JPC 4.2 Hz, C-13), 51.1 (d, JPC 6.0 Hz, C-2), 125.5 (d, JPC 13.0 Hz,
2
3
0.06 M) was added PrMgBr (0.24 mL of a 3 M solution in THF;
3
1
0.72 mmol; 2 equiv) at ꢀ40 °C. After 30 min of stirring the reaction
was quenched with CD3OD and allowed to reach room tempera-
ture. The crude mixture was washed with H2O (2 ꢂ 5 mL),
extracted with CH2Cl2 (2 ꢂ 5 mL) and dried over anhydrous Na2-
SO4. Solvent evaporation under vacuum furnished the pure com-
C-7), 128.4 (d, JPC 13.0 Hz, C-11), 129.0 (d, JPC 134.6 Hz, C-3/9),
3
1
131.4 (d, JPC 12.5 Hz, C-5), 131.5 (d, JPC 134.6 Hz, C-3/9), 131.6
2
4
4
(d, JPC 10.6 Hz, C-10), 132.0 (d, JPC 2.8 Hz, C-12), 132.4 (d, JPC
2
2
2.8 Hz, C-6), 133.2 (d, JPC 9.3 Hz, C-8), 141.9 (d, JPC 11.1 Hz, C-4)
ppm. 31P NMR d 34.6 ppm. IR (KBr, cmꢀ1): 1439 (m), 1215 (s,
m
pound. Yield 97%. Oil. [
a
]
25 = 17.2 (c 1, CH2Cl2). 1H NMR d 1.61
D
PO), 1141 + 1120 (m, CO), 1085 (w), 1034 (s), 748 (s), 694 (m),
666 (m). HRMS (ESI) calcd for C14H15O2P: 247.0888 (MH+), found:
247.0877.
3
3
(d, 3H, JHH 7.3 Hz, H-4), 2.38 (d, 3H, JPH 11.6 Hz, H-9), 4.75 (dq,
3
3
1H, JHH 7.0 Hz, JPH 8.8 Hz, H-3), 7.27 (m, 1H, H-8), 7.37 (m, 2H,
H-6), 7.47 (m, 8H, H-Ar), 7.91 (m, 3H, H-15, H-17) ppm. 13C NMR
d 17.0 (d, JPC 2.3 Hz, C-4), 27.8 (d, JPC 3.7 Hz, C-9), 53.2 (d, JPC
3
2
2
4.2.4.2. Methyl (R)-(2-iodophenyl)(phenyl)phosphinate 16b. Yield
3
90%. Oil. [a D
]
25 = ꢀ3.8 (c 1, CH2Cl2). ee 96%. 1H NMR d 3.77 (d, 3H, 3JPH
3.2 Hz, C-3), 127.0 (C-8), 127.6 (C-7), 128.2 (C-6), 128.4 (d, JPC
3
4
12.5 Hz, C-12), 128.5 (d, JPC 12.5 Hz, C-18, C-14), 131.6 (d, JPC
11.3 Hz, H-2), 7.1–7.5 (m, 6H, H-Ar), 7.79 (m, 2H, H-10), 7.95 (ddd,
4
1
3
4
4
3
2.8 Hz, C-19), 131.6 (d, JPC 2.3 Hz, C-13), 132.0 (d, JPC 129.0 Hz,
1H, JHH 7.8 Hz, JHH 1.2 Hz, JPH 4.0 Hz, H-5), 8.07 (ddd, 1H, JHH
1
4
3
2
7.7 Hz, JHH 1.7 Hz, JPH 12.4 Hz, H-8) ppm. 13C NMR d 51.5 (d, JPC
C-10), 132.1 (bs, C-11), 132.3 (d, JPC 128.5 Hz, C-16), 132.3 (d,
2JPC 9.2 Hz, C-17), 132.4 (d, JPC 9.3 Hz, C-15), 141.1 (d, JPC
2
3
2
3
6.0 Hz, C-2), 97.9 (d, JPC 8.8 Hz, C-4), 127.7 (d, JPC 11.1 Hz, C-7),
6.0 Hz, C-5) ppm. 31P NMR d 31.4 ppm. IR (KBr,
m
cmꢀ1): 1438
3
1
128.3 (d, JPC 13.4 Hz, C-11), 129.7 (d, JPC 141.5 Hz, C-9), 132.3 (d,
2JPC 10.6 Hz, C-10), 132.3 (d, JPC 2.8 Hz, C-12), 133.4 (d, JPC
4
4
(m), 1182 (s, PO), 1139 (m), 1111 (m), 908 (m), 863 (m), 723 (s),
696 (s). HRMS (ESI) calcd for C21H21DNOP: 337.1532 (MH+), found:
337.1605.
1
3
2.8 Hz, C-6), 134.3 (d, JPC 137.8 Hz, C-3), 135.8 (d, JPC 8.8 Hz, C-
5), 141.7 (d, JPC 10.6 Hz, C-8) ppm. 31P NMR d 33.3 ppm. IR (KBr,
2
m
cmꢀ1): 1438 (w), 1215 (s, PO), 1135 + 1120 (m, CO), 1033 (s),
4.2.3. Synthesis of (RP)-P-(20-methoxy-[1,10-biphenyl]-2-yl)-N-
methyl-P-phenyl-N-((R)-1-phenylethyl)phosphinic amide 15s
746 (s), 691 (m), 664 (m). HRMS (ESI) calcd for C13H12IO2P:
358.9698 (MH+), found: 358.9704.
To
0.22 mmol) in toluene (5 mL; 0.04 M), Pd(OAc)2 (3 mg; 5%),
K2CO3 (60 mg; 0.43 mmol; 2 equiv) and (2-methoxy-
a solution of phosphinic amide (RP,RC)-15j (100 mg;
4.2.5. Synthesis of (RP)-methyl(phenyl)(o-tolyl)phosphine oxide
17
phenyl)boronic acid (50 mg; 0.32 mmol; 1.5 equiv) were added.
The reaction mixture was heated at reflux for 48 h. The crude mix-
ture was filtered through Celite,Òthen washed with H2O (2 ꢂ 5 mL),
extracted with CH2Cl2 (2 ꢂ 5 mL), dried over anhydrous Na2SO4
and concentrated in vacuo.
To a solution of (RP)-16a (1 mmol; 1 equiv) in THF (10 mL;
0.1 M) at room temperature was added MeMgBr (2.1 mL of a solu-
tion 1 M; 3 equiv). The mixture was stirred overnight and then was
poured into ice water, extracted with CH2Cl2 (2 ꢂ 5 mL) and dried
over anhydrous Na2SO4. Solvent evaporation under vacuum fur-
nished the pure compound.
4.2.3.1.
(RP)-P-(20-Methoxy-[1,10-biphenyl]-2-yl)-N-methyl-P-
4.2.5.1. Synthesis of (RP)-methyl(phenyl)(o-tolyl)phosphine
phenyl-N-((R)-1-phenylethyl)phosphinic amide 15s. Yield after
oxide 17. Yield 90%. Mp 110–111 °C. [a]
25 = +29.6 (c 1, CH2Cl2).
D
chromatography (AcOEt/hexane 1:1) 75%. Oil. [
a]
25 = ꢀ1.1 (c 1,
D
2
ee 96%. 1H NMR d 2.06 (d, 3H, JPH 12.9 Hz, H-2), 2.40 (s, 3H, H-
13), 7.25 (m, 1H, H5), 7.32 (m, 1H, H7), 7.41–7.57 (m, 4H, H-Ar),
7.67 (m, 2H, H-10), 7.69 (m, 1H, H8) ppm. 13C NMR d 15.2 (C-13),
CH2Cl2). 1H NMR d 1.28 (d, 3H, JHH 7.1 Hz, H-4), 1.32 (d, 3H, JHH
3
3
3
3
7.3 Hz, H-40), 2.12 (d, 3H, JPH 10.1 Hz, H-9), 2.21 (d, 3H, JPH
10.3 Hz, H-90), 3.11 (s, 3H, H-260), 3.34 (s, 3H, H-26), 4.52 (quin,
1
3
3
3
3
1H, JHH = 3JPH 7.2 Hz, H-30), 4.91 (quin, 1H, JHH = 3JPH 7.2 Hz, H-
21.3 (d, JPC 4.6 Hz, C-2), 125.5 (d, JPC 12.5 Hz, C-7), 128.6 (d, JPC
2
2
3
3
3), 6.54 (d, 1H, JHH 8.1 Hz, H-25), 6.86 (d, 1H, JHH 8.1 Hz, H-250),
12.0 Hz, C-11), 130.4 (d, JPC 9.9 Hz, C-10), 131.4 (d, JPC 10.2 Hz,
C-8), 131.5 (d, JPC 100.3 Hz, C-3/9), 131.5 (d, JPC 2.1 Hz, C-12),
131.8 (d, JPC 9.9 Hz, C-5), 132.0 (d, JPC 1.9 Hz, C-6), 131.8 (d, JPC
1
4
6.7–7.7 (H-Ar) ppm. 13C NMR d 16.6 (d, JPC 1.6 Hz, C-9), 16.7 (d,
2
2
4
2
2JPC 1.6 Hz, C-90), 28.3 (d, JPC 4.1 Hz, C-4), 28.7 (d, JPC 4.1 Hz, C-
3
3
1
2
2
2
40), 51.9 (d, JPC 3.7 Hz, C-3), 52.7 (d, JPC 2.5 Hz, C-30), 54.8 (C-
26), 55.2 (C-260), 110.0 (C-25), 110.7 (C-250), 111.2 (C-Ar), 119.2
(C-Ar), 119.5 (C-Ar), 120.7 (C-Ar), 127.1–135.7 (C-Ar) ppm. 31P
9.9 Hz, C-5), 134.6 (d, JPC 99.9 Hz, C-3/9), 142.1(d, JPC 7.7 Hz, C-
4) ppm. 31P NMR d 32.3 ppm. IR (KBr, cmꢀ1): 1437 (m), 1175 (s,
m
PO), 880 (s), 739 (s), 694 (s). HRMS (ESI) calcd for C14H15OP:
231.0939 (MH+), found: 231.0932.
NMR d 31.0 (P), 31.1 (P0) ppm. IR (KBr,
m
cmꢀ1): 1436 (m), 1191

M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
63
4.2.6. General method for the synthesis of compounds 20
4.2.7. Synthesis of (SP)-1-phenyl-1-(((R)-1-phenylethyl)amino)-
To a solution of the ortho-azide derivatives 12f, 15f, or 16c
1k5-benzo[c][1,5,2]diazaphosphinin-3(4H)-one 21
A solution of (SP,RC)-20a (100 mg; 0.26 mmol) in toluene (5 mL;
0.05 M) was heated at reflux overnight. The solvent was then
removed in vacuo.
(0.2 mmol; 1 equiv) in THF (5 mL; 0.05 M) was added a solution
t
of BuLi (0.4 mL of a 1.7 M solution in cyclohexane; 0.72 mmol;
3 equiv) at ꢀ70 °C. After 30 min of stirring the reaction was com-
pleted. Next, CH2Cl2 (10 mL) was added and the reaction mixture
was washed with a saturated solution of NH4Cl (2 ꢂ 5 mL). The
organic layer was dried over anhydrous Na2SO4 and concentrated
in vacuo.
4.2.7.1. (SP)-1-Phenyl-1-(((R)-1-phenylethyl)amino)-1k5-benzo-
[c][1,5,2]diazaphosphinin-3(4H)-one 21. Yield after chromatog-
raphy (ethyl acetate/methanol 95:5) 80%. Oil. 1H NMR d 1.60 (d,
3
3
3H, JHH 6.6 Hz, H-7), 3.56 (t, 1H, JHH = 2JPH 7.1 Hz, H-5), 4.36
3
3
3
(dquin, 1H, JHH 7.1 Hz, JPH 11 Hz, H-6), 6.79 (dt, 1H, JHH 7.6 Hz,
4.2.6.1. Methyl ((SP)-(2-aminophenyl)(phenyl){[(1R)-1-phenyl-
ethyl]amino}phosphoranylidene)carbamate 20a. Yield after
chromatography (ethyl acetate/hexane 1:1.5) 85%. Oil.
4JPH 2.0 Hz, H-16), 7.10 (dd, 1H, JHH 7.9 Hz, JPH 5.8 Hz, H-14),
3
4
7.15–7.4 (m, 7H, H-Ar), 7.47–7.61 (m, 3H, H-Ar), 7.98 (m, 2H, H-
3
19), 10.11 (s, H-4) ppm. 13C NMR d 25.2 (d, JPC 5.1 Hz, C-7), 51.0
3
[
a
]
25 = ꢀ58.5 (c 1, CH2Cl2). 1H NMR d 1.56 (d, 3H, JHH 6.7 Hz, H-
D
2
3
2
(d, JPC 1.5 Hz, C-6), 125.9 (C-10), 127.3 (C-11), 128.5 (C-9), 128.7
7), 3.62 (s, 3H, H-4), 4.16 (dd, 1H, JHH 9.6 Hz, JPH 3.6 Hz, H-5),
4.33 (m, 1H, H-6), 5.75 (bs, 2H, H-22), 6.53 (m, 1H, H-16), 6.62
(m, 1H, H-14), 7.11 (m, 1H, H-17), 7.2–7.6 (m, 9H, H-Ar), 7.85 (m,
3
2
(C-16), 128.9 (d, JPC 13.4 Hz, C-20), 129.8 (C-Ar), 131.6 (d, JPC
3
10.2 Hz, C-19), 132.9 (C-Ar), 134.1 (C-Ar), 143.9 (d, JPC 6.5 Hz, C-
8), 146.5 (d, JPC 5.8 Hz, C-13), 155.6 (d, JPC 2.3 Hz, C-3) ppm. 31P
2
2
2H, H-19) ppm. 13C NMR d 25.5 (d, JPC 4.1 Hz, C-7), 51.9 (d, JPC
3
2
NMR d 18.8 ppm. IR (KBr,
m
cmꢀ1): 3480 (bb, NH), 3174 (bb, NH),
4
1
1.5 Hz, C-6), 52.5 (d, JPC 3.6 Hz, C-4), 107.0 (d, JPC 136.0 Hz, C-
3
3
1622 (s, CO), 1573 (m), 1490 (m), 1351 (s, PN), 1115 (m), 913
(m), 698 (m). HRMS (ESI) calcd for C21H20N3OP: 362.1422 (MH+),
found: 362.1426.
12), 116.9 (d, JPC 13.7 Hz, C-16), 117.2 (d, JPC 10.7 Hz, C-14),
3
125.8 (C-10), 127.1 (C-11), 128.5 (C-9), 128.6 (d, JPC 12.7 Hz, C-
1
2
20), 129.3 (d, JPC 124.1 Hz, C-18), 132.2 (d, JPC 10.2 Hz, C-19),
4
4
132.2 (d, JPC 3.1 Hz, C-21), 133.7 (d, JPC 2.5 Hz, C-15), 133.7 (d,
2JPC 10.7 Hz, C-17), 144.9 (d, JPC 6.1 Hz, C-8), 152.2 (d, JPC
3
2
4.2.8. Synthesis of methyl (RP)-(2-(((SP)-methyl(phenyl)(o-tolyl)-
k5-phosphanylidene)amino)phenyl)(phenyl)phosphinate 22
To a stirred solution of MeOTf (0.04 mL; 0.38 mmol) in dime-
thoxyethane (1 mL) was added dropwise a solution of the phos-
phine oxide (RP)-17 (60 mg; 0.25 mmol) in dimethoxyethane
(2 mL) at room temperature under a nitrogen atmosphere. The
reaction mixture was heated at reflux for 2 h. After cooling to room
6.1 Hz, C-13), 162.7 (s, C-3) ppm. 31P NMR d 31.3 ppm. IR (KBr,
m
cmꢀ1): 3330 (bb, NH), 3270 (bb, NH), 1630 (s, CO), 1590 (m),
1496 (m), 1292 (s, PN), 1112 (m), 906 (m), 727 (m), 695 (m). HRMS
(ESI) calcd for C23H26N3O2P: 394.1684 (MH+), found: 394.1691.
4.2.6.2.
(RP)-P-(2-Aminophenyl)-P-phenyl-N-((R)-1-phenyl-
temperature,
a
solution of sodium borohydride (14 mg;
ethyl)phosphinic amide 20b. Yield after precipitation from
0.38 mmol) in diglyme (2 mL) was added to the reaction mixture.
This mixture was heated at reflux for 2 h. The reaction mixture
was cooled to room temperature, washed with deionized water,
and the isolated organic layer was dried over anhydrous MgSO4.
The drying agent was filtered off and the solvent was removed in
vacuo. Purification of the product was performed through a short
silica gel column. Next, the corresponding phosphine borane 18
(57 mg; 0.25 mmol) and DABCO (29 mg; 0.25 mmol; 1 equiv) were
solved in degassed toluene (2.5 mL; 0.1 M). After 4 h of stirring at
40 °C, the mixture was allowed to reach room temperature and
phosphinate 16c (75 mg; 0.275 mmol; 1.1 equiv) solved in toluene
(2.5 mL) was added dropwise. The reaction was stirred for 4 h at
room temperature. The crude mixture was washed with H2O
(1 ꢂ 3 mL), extracted with CH2Cl2 (2 ꢂ 5 mL), dried over anhydrous
Na2SO4 and concentrated in vacuo.
diethyl ether 97%. Mp 120–122 °C. [
a
]
25 = ꢀ80.8 (c 1, CH2Cl2). 1H
D
3
3
NMR d 1.63 (d, 3H, JHH 6.8 Hz, H-4), 3.23 (dd, 1H, JHH 9.9 Hz,
2JPH 6.6 Hz, H-2), 4.50 (m, 1H, H-3), 5.55 (bs, 2H, H-19), 6.55 (ddt,
3
4
4
3
1H, JHH 7.4 Hz, JHH 0.9 Hz, JPH 2.7 Hz, H-14), 6.62 (ddd, 1H, JHH
4
4
8.1 Hz, JHH 0.9 Hz, JPH 5.5 Hz, H-11), 7.15–7.54 (m, 10H, H-Ar),
7.87 (m, 2H, H-16) ppm. 13C NMR d 26.1 (d, JPC 3.1 Hz, C-4), 51.2
3
2
1
3
(d, JPC 1.1 Hz, C-3), 110.7 (d, JPC 131.2 Hz, C-9), 116.5 (d, JPC
3
12.2 Hz, C-13), 116.6 (d, JPC 10.2 Hz, C-11), 125.9 (C-7), 127.1 (C-
8), 128.4 (d, JPC 12.7 Hz, C-17), 128.6 (C-6), 133.2 (d, JPC
127.7 Hz, C-15), 131.6 (d, JPC 9.7 Hz, C-16), 131.7 (d, JPC 2.5 Hz,
3
1
2
4
4
2
C-18), 133.2 (d, JPC 2.5 Hz, C-12), 133.4 (d, JPC 8.7 Hz, C-14),
145.0 (d, JPC 7.1 Hz, C-5), 152.6 (d, JPC 7.1 Hz, C-10) ppm. 31P
3
2
NMR d 29.3 ppm. IR (KBr,
m
cmꢀ1): 3322 (bb, NH), 3205 (bb, NH),
1611 (s, CO), 1482 (m), 1450 (s), 1172 (s, PO), 1113 (s), 752 (m),
698 (m), 516 (m). HRMS (ESI) calcd for C20H21N2OP: 337.1470
(MH+), found: 337.1477.
4.2.8.1. Methyl (RP)-(2-(((SP)-methyl(phenyl)(o-tolyl)-k5-phos-
phanylidene)amino)phenyl)(phenyl)phosphinate 22. Yield after
chromatography (ethyl acetate) 70%. Oil. [
a
]
25 = ꢀ14.3 (c 1, CH2-
4.2.6.3. Methyl (RP)-(2-aminophenyl)(phenyl)phosphinate
20c. Yield after chromatography (ethyl acetate/hexane 5:1) 94%.
D
2
Cl2). ee 96%. 1H NMR d 1.82 (d, 3H, JPH 12.6 Hz, H-15), 2.04 (s,
25 = +115.5 (c 1, CH2Cl2). ee 96%. 1H NMR d 3.82 (dd, 1H,
3
3
Oil. [
a
]
3H, H-26), 3.77 (d, 3H, JPH 11.2 Hz, H-2), 6.16 (ddt, 1H, JHH
D
3
3JHH 9.4 Hz, JPH 11.2 Hz, H-2), 4.70 (bs, 2H, H-13), 6.67 (ddd, 1H,
4
4
3
8.2 Hz, JHH = 4JP(N)H 0.9 Hz, JP(O)H 6.5 Hz, H-5), 6.70 (ddt, 1H, JHH
3JHH 8.2 Hz, JHH 0.7 Hz, JPH 5.7 Hz, H-5), 6.70 (m, 1H, H-7), 7.26
(m, 1H, H-6), 7.35 (ddd, 1H, JHH 7.9 Hz, JHH 1.9 Hz, JPH 13.6 Hz,
4
4
4
4
3
7.5 Hz, JHH = 0.9 Hz, JPH 3.2 Hz, H-7), 7.07 (dddd, 1H, JHH 7.5 Hz,
3
4
3
3JHH 8.2 Hz, JHH = 1.7 Hz, JPH 1.0 Hz, H-6), 7.1–7.7 (m, 13H, H-
4
5
3
4
H-8), 7.45 (m, 2H, H-11), 7.53 (m, 1H, H-12), 7.82 (m, 2H, H-10)
Ar), 7.80 (m, 2H, H-10), 7.95 (dddd, 1H, JHH 7.5 Hz, JHH 1.7 Hz,
2
1
ppm. 13C NMR d 51.5 (d, JPC 6.0 Hz, C-2), 110.0 (d, JPC 134.6 Hz,
3JPH 12.7 Hz, JPH 2.4 Hz, H-8) ppm. 13C NMR d 14.4 (d, JPC
5
1
3
3
3
2
C-3), 116.7 (d, JPC 10.2 Hz, C-5/7), 117.0 (d, JPC 12.5 Hz, C-5/7),
128.4 (d, JPC 13.4 Hz, C-11), 131.1 (d, JPC 10.2 Hz, C-10), 131.7
(d, JPC 140.6 Hz, C-9), 132.1 (d, JPC 3.2 Hz, C-12), 132.8 (d, JPC
66.1 Hz, C-15), 20.7 (d, JPC 4.6 Hz, C-26), 50.7 (d, JPC 6.0 Hz, C-
2), 115.7 (d, JPC 13.4 Hz, C-7), 119.4 (d, JPC 135.9 Hz, C-9), 119.7
(dd, JPC 13.4 Hz, JPC 9.7 Hz, C-5), 125.8 (d, JPC 11.1 Hz, C-20),
127.4 (d, JPC 13.4 Hz, C-11), 128.4 (d, JPC 12.5 Hz, C-24), 129.5
3
2
3
1
1
4
2
3
3
3
4
2
3
3
9.1 Hz, C-8), 133.7 (d, JPC 2.3 Hz, C-6), 151.7 (d, JPC 7.4 Hz, C-4)
ppm. 31P NMR d 38.2 ppm. IR (KBr, cmꢀ1): 3430 (NH), 3330
m
1
4
(d, JPC 131.8 Hz, C-16/22), 130.6 (d, JPC 2.8 Hz, C-12), 131.2 (d,
1JPC 111.9 Hz, C-16/22), 131.3 (d, JPC 10.2 Hz, C-10), 131.4 (d, JPC
2
4
(NH), 1616 (CO), 1598 (m), 1482 (m), 1449 (m), 1320 (m), 1198
2
3
(s, PO), 1125 (s), 1022 (s), 794 (m), 750 (m), 717 (m), 694 (m).
2.8 Hz, C-25), 131.4 (d, JPC 10.6 Hz, C-23), 131.7 (d, JPC 10.6 Hz,
C-18), 132.0 (d, JPC 2.8 Hz, C-19), 132.0 (d, JPC 10.2 Hz, C-21),
133.1 (d, JPC 2.3 Hz, C-6), 134.0 (d, JPC 140.1 Hz, C-3), 135.2 (dd,
C
13H14NO2P: 248.0840 (MH+), found:
4
2
HRMS (ESI) calcd for
248.0849.
4
1

64
M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
4
2
2
2JPC 7.9 Hz, JPC 3.7 Hz, C-8), 142.7 (d, JPC 8.8 Hz, C-4) ppm. 31P
3JPC 2.5 Hz, C-5), 18.6 (C-25), 19.1 (C-250), 28.0 (d, JPC 4.6 Hz, C-
4
4
2
NMR d 37.2 (d, JPC 2.2 Hz, PO), 3.6 (d, JPC 2.2 Hz, PN) ppm. IR
(KBr,
cmꢀ1): 1582 (CO), 1462 (m), 1436 (m), 1339 (PN), 1179
(s, PO), 1037 (s), 1016 (s), 746 (s), 694 (m). HRMS (ESI) calcd for
27H27NO2P2: 460.1595 (MH+), found: 460.1595.
3), 32.7 (C-24), 52.7 (d, JPC 3.6 Hz, C-4), 70.9 (C-23), 72.8 (C-22),
127.0 (C-9), 127. 7 (C-8), 128.2 (C-7), 128.2 (d, JPC 13.2 Hz, C-
18), 129.9 (d, JPC 11.6 Hz, C-14), 131.0 (d, JPC 2.5 Hz, C-19),
3
m
3
4
2
4
C
131.1 (d, JPC 9.2 Hz, C-17), 131.4 (d, JPC 2.5 Hz, C-13), 132.1 (d,
3JPC 9.7 Hz, C-12), 131.4 (d, JPC 2.8 Hz, C-13), 131.0 (d, JPC
4
1
2
1
4.2.9. Synthesis of (RP)-P-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-
yl)phenyl)-N-methyl-P-phenyl-N-((R)-1-phenylethyl)phosphinic
amide 23a
127.7 Hz, C-10/16), 133.3 (d, JPC 8.1 Hz, C-15), 133.1 (d, JPC
2
3
117.0 Hz, C-10/16), 138.8 (d, JPC 13.4 Hz, C-11), 141.5 (d, JPC
4.6 Hz, C-6), 162.9 (d, JPC 2.5 Hz, C-20) ppm. 31P NMR
d
3
A
solution of phosphinic amide (RP,RC)-15q (150 mg;
32.7 ppm. IR (KBr,
m
cmꢀ1): 1663 (N@CAO), 1438 (w), 1187 (s,
0.41 mmol; 1 equiv) and 2-amino-2-methylpropan-1-ol (40 mg;
0.41 mmol; 1 equiv) in CH2Cl2 (4 mL; 0.1 M) was stirred for 14 h
at room temperature in the presence of molecular sieves (4 Å;
615 mg). Next, NBS (73 mg; 0.41 mmol; 1 equiv) was added and
the reaction mixture was stirred for 30 min. The crude mixture
was filtered and washed with a saturated solution of NaHCO3.
The aqueous layer was then extracted with CH2Cl2 (2 ꢂ 3 mL)
and the isolated organic layer was dried over anhydrous MgSO4.
The drying agent was filtered off and the solvent was removed in
vacuo.
PO), 1133 (m), 1110 (m), 1027 (s), 987 (s), 725 (s), 697 (s). HRMS
(ESI) calcd for C27H31N2O2P: 447.2202 (MH+), found: 447.2192.
4.2.11. Synthesis of (RP)-P-(2-(((E)-3,5-di-tert-butyl-2-hydroxy-
benzylidene)amino)phenyl)-P-phenyl-N-((R)-1-phenylethyl)-
phosphinic amide 25
A
solution of phosphinic amide (RP,RC)-20b (100 mg;
0.45 mmol) in toluene (5 mL; 0.06 M) was heated at reflux for
5 days in the presence of molecular sieves (4 Å; 675 mg). Next,
the solvent was removed in vacuo, and the crude mixture was dis-
solved in CH2Cl2 (10 mL) and washed with deionized water
(2 ꢂ 5 mL). The isolated organic layer was then dried over anhy-
drous MgSO4 and the solvent was removed in vacuo.
4.2.9.1.
(RP)-P-(2-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)phe-
nyl)-N-methyl-P-phenyl-N-((R)-1-phenylethyl)phosphinic
amide 23a. Yield after chromatography (ethyl acetate/hexane 1:3)
80%. Oil. [
a
]
25 = ꢀ60 (c 1, CH2Cl2). 1H NMR d 1.15 (s, 3H, H-24), 1.29
4.2.11.1.
(RP)-P-(2-(((E)-3,5-Di-tert-butyl-2-hydroxybenzylid-
D
(s, 3H, H-24), 1.56 (d, 3H, 3JHH 7.7 Hz, H-5), 2.30 (d, 3H, 3JHP 10.1 Hz,
ene)amino)phenyl)-P-phenyl-N-((R)-1-phenylethyl)phosphinic
amide 25. Yield after chromatography (ethyl acetate/hexane 1:2)
84%. Oil. [
H-3), 3.55 (d, 1H, 2JHH 7.9 Hz, H-23), 3.97 (d, 1H, 2JHH 7.9 Hz, H-230),
3
3
5.04 (dq, 1H, JHH 6.9 Hz, JPH 9.0 Hz, H-4), 7.3–7.8 (m, 13H, H-Ar),
7.65 (ddd, 1H, 3JHH 7.7 Hz, 4JHH 1.4 Hz, 3JPH 13.0 Hz, H-15), 7.72 (m,
2H, H-17), 7.82 (ddd, 1H, 3JHH 7.6 Hz, 4JHH 1.4 Hz, 3JPH 4.3 Hz, H-12)
ppm. 13C NMR d 16.9 (d, 3JPC 2.5 Hz, C-5), 27.6 (s, C-24), 28.0 (s, C-
240), 28.0 (d, 2JPC 4.4 Hz, C-3), 52.8 (d, 2JPC 3.9 Hz, C-4), 67.4 (C-22),
79.3 (C-23), 127.0 (C-9), 127.9 (C-8), 128.2 (C-7), 128.3 (d, JPC
13.0 Hz, C-18), 129.9 (d, JPC 11.8 Hz, C-14), 131.1 (d, JPC 9.9 Hz,
C-17), 131.1 (d, JPC 3.0 Hz, C-19/13), 131.3 (d, JPC 10.6 Hz, C-12),
131.4 (d, JPC 2.8 Hz, C-19/13), 132.2 (d, JPC 132.9 Hz, C-10/16),
a
]
D
25 = +2.0 (c 1, CH2Cl2). 1H NMR d 1.32 (s, 9H, H-31),
3
1.39 (s, 9H, H-29), 1.58 (d, 3H, JHH 6.9 Hz, H-4), 3.26 (dd, 1H,
3JHH 9.2 Hz, JPH 10.8 Hz, H-2), 4.55 (m, 1H, H-3), 5.30 (s, 1H, H-
3
3
4
3
27), 6.88 (dd, 1H, JHH 7.7 Hz, JPH 4.8 Hz, H-11), 6.92 (d, 2H, JHH
2.2 Hz, H-6), 7.0–7.6 (m, 10H, H-Ar), 7.78 (m, 3H, H-16/H-Ar),
3
3
4
3
8.26 (ddd, 1H, JHH 7.5 Hz, JHH 1.5 Hz, JPH 12.9 Hz, H-14), 12.18
3
2
3
(s, 1H, H-20) ppm. 13C NMR d 25.5 (d, JPC 5.1 Hz, C-4), 29.2 (C-
4
3
2
31), 31.4 (C-29), 34.1 (C-30), 34.9 (C-28), 50.5 (d, JPC 1.1 Hz, C-
3), 117.8 (C-21), 118.9 (d, JPC 8.7 Hz, C-11), 125.9 (C-26), 125.9
(C-7), 126.0 (d, JPC 121.1 Hz, C-9), 126.8 (C-8), 127.2 (C-24),
128.2 (C-6), 128.3 (d, JPC 13.2 Hz, C-17), 128.5 (d, JPC 10.7 Hz, C-
4
1
3
2
1
1
133.3 (d, JPC 8.1 Hz, C-15), 133.9 (d, JPC 136.6 Hz, C-10/16),
2
3
3
3
138.8 (d, JPC 13.4 Hz, C-11), 141.4 (d, JPC 4.6 Hz, C-6), 161.5 (d,
3JPC 2.3 Hz, C-20) ppm. 31P NMR d 32.9 ppm. IR (KBr, cmꢀ1):
m
13), 133.5 (d, JPC 130.2 Hz, C-15), 131.0 (d, JPC 10.7 Hz, C-16),
1
2
4
4
1664 (N@CAO), 1444 (w), 1186 (s, PO), 1135 (m), 1107 (m),
1026 (s), 988 (s), 728 (s), 699 (s). HRMS (ESI) calcd for C26H29N2O2-
P: 433.2045 (MH+), found: 433.2041.
131.7 (d, JPC 3.1 Hz, C-18), 133.4 (d, JPC 2.0 Hz, C-12), 135.1 (d,
2JPC 6.6 Hz, C-14), 136.8 (C-25), 140.5 (C-23), 144.5 (d, JPC 4.1 Hz,
3
2
4
C-5), 151.3 (d, JPC 5.6 Hz, C-10), 157.4 (C-22), 164.9 (d, JPC
1.1 Hz, C-20) ppm. 31P NMR d 23.4 ppm. IR (KBr, cmꢀ1): 3202
m
4.2.10. Synthesis of (RP)-P-(2-((R)-4-isopropyl-4,5-
dihydrooxazol-2-yl)phenyl)-N-methyl-P-phenyl-N-((R)-1-
phenylethyl)phosphinic amide 23b
(bb, NH), 2960 (bb, OH), 1644 (s), 1440 (s), 1199 (s), 1172 (s, PO),
1113 (m), 751 (m), 698 (m), 535 (m). HRMS (ESI) calcd for C35H41-
N2O2P: 553.2984 (MH+), found: 553.2985.
A
solution of phosphinic amide (RP,RC)-15q (150 mg;
0.41 mmol; 1 equiv) and (S)-2-amino-3-methylbutan-1-ol
4.3. Single crystal structural determination of (RP,RC)-15a
(42 mg; 0.41 mmol; 1 equiv) in CH2Cl2 (4 mL; 0.1 M) was stirred
for 36 h at room temperature in the presence of molecular sieves
(4 Å; 615 mg). Next, NBS (73 mg; 0.41 mmol; 1 equiv) was added
and the reaction mixture was stirred for 30 min. The crude mixture
was filtered and washed with a saturated solution of NaHCO3. The
aqueous layer was then extracted with CH2Cl2 (2 ꢂ 3 mL) and the
isolated organic layer was dried over anhydrous MgSO4. The drying
agent was filtered off and the solvent was removed in vacuo.
Suitable crystals were obtained by slow evaporation of a diethyl
ether solution. Single crystal X-ray diffraction data were collected
on a Bruker AXS Smart Apex diffractometer at 100(2) K, using
graphite monochromatic MoK radiation (k = 0.71069 Å). Data col-
a
lection and cell refinement were performed with Bruker SMART
program,48 while the data reduction was carried out using SAINT.49
Empirical multiscan absorption correction using equivalent reflec-
tions was performed with the SADABS program.50 The structure
solutions and full-matrix least-squares refinements based on F2
were performed with the SHELXS-97 and SHELXL-97 program
packages.51 All atoms except hydrogen were refined anisotropi-
cally. Hydrogen atoms were treated by constrained refinement.
The structure was drawn by ORTEP-3 program.52 An ORTEP repre-
sentation of the asymmetric unit of (RP,RC)-15a is depicted in Fig-
ure 1. CCDC ID: 1013041 contains the supplementary
crystallographic data for (RP,RC)-15a. Copies of the data can be
obtained free of charge on application to the CCDC, 12 Union Road,
4.2.10.1. (RP)-P-(2-((R)-4-Isopropyl-4,5-dihydrooxazol-2-yl)phe-
nyl)-N-methyl-P-phenyl-N-((R)-1-phenylethyl)phos-phinic
amide 23b. Yield after chromatography (ethyl acetate/hexane 1:1)
3
76%. Oil. [
a]
25 = ꢀ25.4 (c 1, CH2Cl2). 1H NMR d 0.87 (d, 3H, JHH
D
3
3
6.7 Hz, H-25), 0.98 (d, 3H, JHH 6.7 Hz, H-250), 1.55 (d, 3H, JHH
3
6.9 Hz, H-5), 1.71 (m, 1H, H-24), 2.30 (d, 3H, JPH 10.5 Hz, H-3),
2
3
3.67 (m, 1H, H-22), 3.84 (dd, 1H, JHH 8.4 Hz, JHH 9.6 Hz, H-23),
3.92 (dd, 1H, JHH = 3JHH 8.4 Hz, H-230), 5.09 (dq, 1H, JHH 7.1 Hz,
2
3
3JPH 8.8 Hz, H-4), 7.3–7.8 (m, 14H, H-Ar) ppm. 13C NMR d 16.8 (d,

M. Casimiro et al. / Tetrahedron: Asymmetry 26 (2015) 53–66
65
Iglesias, M. J.; Roces, L.; García-Granda, S.; López-Ortiz, F. J. Am. Chem. Soc.
2012, 134, 19504–19507.
16. Yáñez-Rodríguez, V.; del Águila, M. Á.; Iglesias, M. J.; López-Ortiz, F.
Tetrahedron 2012, 68, 7355–7362.
Cambridge CB2 IEZ, UK. Fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.ik.
17. (a) López-Ortiz, F.; Iglesias, M. J.; Fernández, I.; Andújar-Sánchez, C. M.; Ruiz-
Gómez, G. Chem. Rev. 2007, 107, 1580–1691; (b) Fernández, I.; Oña-Burgos, P.;
Ruiz-Gomez, G.; Bled, C.; García-Granda, S.; López-Ortiz, F. Synlett 2007, 611–
614; (c) Fernández, I.; Oña-Burgos, P.; Oliva, J. M.; López-Ortiz, F. J. Am. Chem.
Soc. 2010, 132, 5193–5204.
18. El Hajjouji, H.; Belmonte, E.; García-López, J.; Fernández, I.; Iglesias, M. J.;
Roces, L.; García-Granda, S.; El Laghdach, A.; López-Ortiz, F. Org. Biomol. Chem.
2012, 10, 5647–5658.
Acknowledgments
We thank the MICINN, MEC, MINECO and FEDER program for
financial support (CTQ2011-27705). M.C. thanks MEC for a Ph.D.
fellowship.
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