Synthesis of P-stereogenic diarylphosphinic amides by directed lithiation: Transformation into tertiary phosphine oxides via methanolysis, aryne chemistry and complexation behaviour toward zinc(II)

Article abstract of DOI:10.1039/c5dt02860d

The highly diastereoselective synthesis of P-stereogenic phosphinic amides via directed ortho lithiation (DoLi) of (S_C)-P,P-diphenylphosphinic amides with t-BuLi followed by electrophilic quench reactions is described. Functionalised derivatives containing a wide variety of ortho substituents (Cl, Br, I, OH, N₃, SiMe₃, SnMe₃, P(O)Ph₂, Me, allyl, ^tBuOCO) have been prepared in high yields with diastereomeric ratios up to 98:2. The X-ray diffraction structure of the ortho-stannylated and ortho-iodo compounds showed that the pro-S P-phenyl ring was stereoselectively ortho-deprotonated by the organolithium base. The usefulness of the method is supported by two key transformations, the synthesis of P-stereogenic methyl phosphinates through replacement of the chiral auxiliary by a methoxy group and the first example of the insertion of benzyne into the P-N bond of a P-stereogenic phosphinic amide. A DFT study of this reaction showed that the insertion proceeds through a [2 + 2] cycloaddition and a subsequent ring-opening with retention of the P-configuration. Explorative coordination chemistry of the new P-stereogenic ligands provided access to a chiral phosphinic amide-phosphine oxide Zn(ii) complex, the crystal structure of which is reported.

Full text of DOI:10.1039/c5dt02860d

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DOI: 10.1039/C5DT02860D
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ARTICLE
Synthesis of P-stereogenic diarylphosphinic amides
by directed lithiation. Stereospecific transformation
into tertiary phosphine oxides via methanolysis, aryne
chemistry and complexation behaviour toward
zinc(II)
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Miguel A. del Águila-Sánchez,a Yolanda Navarro,a Jesús García López,a
Guilherme P. Guedesb and Fernando López Ortiz*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
The highly diastereoselective synthesis of P-stereogenic phosphinic amides via directed ortho
lithiation (DoLi) of (SC)-P,P-diphenylphosphinic amides with
quench reactions is described. Functionalised derivatives containing a wide variety of ortho
substituents (Cl, Br, I, OH, N3, SiMe3, SnMe3, P(O)Ph2, Me, allyl, -BuCO) have been
t-BuLi followed by electrophilic
t
prepared in high yields and a diastereomeric ratios up to 98:2. The X-ray diffraction structure
of the ortho-stannylated and ortho-iodo compounds showed that the pro-S P-phenyl ring was
stereoselectively ortho-deprotonated by the organolithium base. The usefulness of the method
is supported by two key transformations, the synthesis of P-stereogenic methyl phosphinates
through replacement of the chiral auxiliary by a methoxy group and the first example of the
insertion of benzyne into the P-N bond of a P-stereogenic phosphinic amide. A DFT study of
this reaction showed that the insertion proceeds through a [2 + 2] cycloaddition and a
subsequent ring-opening with retention of the P-configuration. Explorative coordination
chemistry of the new P-stereogenic ligands provided access to a chiral phosphinic amide-
phosphine oxide Zn(II) complex, the crystal structure of which is reported.
phosphinimidic amides 2 are a valuable entry to a variety of
enantiopure P-stereogenic compounds including phosphinic and
Introduction
phosphinothioic amides 3, alkyl phosphinates 4, phosphine oxides 5
and phosphines 6.9 Most of these transformations start with the
stereospecific conversion of the N-P=N moiety of 2 into a
phosphinic amide (N-P=O) 3 through aza-Wittig reactions (Scheme
1).
P-stereogenic compounds constitute
a prominent family of
molecules due to their applications in asymmetric synthesis as
organocatalyst and ligands for transition-metal catalysed reactions.1
Phosphorus-based chirogenicity brings asymmetry close to the
catalytic center, thus promoting high chiral induction levels in these
processes.2
A number of efficient methodologies have been
developed for the stereoselective synthesis of P-stereogenic
compounds,3 including substrate-controlled induction by chiral
auxiliaries4
and
the
desymmetrization
of
prochiral
dimethylphosphine-boranes and sulfides via enantioselective
deprotonation-trapping reactions.5 We have used a combination of
both strategies for accessing P-stereogenic P,P-diarylphosphinimidic
amides 2 based on the discrimination of the diastereotopic phenyl
rings of the Ph2P group through the directed ortho lithiation (DoLi)
of a C-chiral substrate 1 (Scheme 1).6 Abstraction of the ortho proton
of the pro-S P-phenyl ring of
1 proceeds with very high
diastereoselectivity (dr 95:5).7 The products of electrophilic trapping
2 contain additional donor sites at the ortho position, what makes
these compounds interesting hybrid ligands.8 Furthermore,
Scheme 1 Synthesis of P-stereogenic compounds via DoLi of
(R)-1.
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The direct synthesis of the P-stereogenic phosphinic amides 3
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would be a significant methodological improvement that, in addition
to simplifying the synthetic route, would avoid the use of hazardous
azides. However, the analogous DoLi reaction of phosphinic amide
(R)-7a afforded the ortho-stannylated derivative 8 with very low
diastereoselectivity (dr range of 1:1 to 1:5)10 and the enantioselective
desymmetrization of the Ph2P group of 7b using the complex
[nBuLi·(-)-sparteine] as a chiral base took place with very modest
stereoselectivity to give after electrophilic quench the ortho
functionalized products 9 with an ee of 60% (Scheme 2).11
DOI: 10.1039/C5DT02860D
Scheme 3 Stereoselective synthesis of P-stereogenic phosphinic
amides via sequential nucleophilic substitution reactions (eq 1)
and metal-assisted direct C-H functionalization (eq 2 – 3).
Scheme 2 Stereoselective DoLi-trapping reactions of P,P
-
diphenylphosphinic amides.
The DoLi pathways to P-stereogenic compounds shown in
Schemes 1 and 2 remedy these limitations. However, regarding
asymmetric induction with phosphinic amides there is clearly room
for improvement (Scheme 2). The poor dr observed in the ortho
deprotonation of phosphinic amide 7a (Scheme 2) reflects the failure
of the chiral auxiliary to control the stereoselective approach of the
base to the diastereotopic P-phenyl rings.
We thought that higher chiral induction could be accomplished
by increasing the difference of size of the groups attached to the
stereogenic center. We describe here a very efficient procedure for
the synthesis of P-stereogenic phosphinic amides based on the highly
diastereoselective ortho deprotonation of a chiral 3,3-dimethylbutan-
2-amino derivative and subsequent electrophilic trapping. Products
bearing a wide variety of ortho substituents, such as alkyl, halides,
azo, hydroxy, alkoxycarbonyl, trimethylstannyl, trimethylsilyl, and
diphenylphosphinoyl were readily synthesized in high yield and with
dr up to 98:2. The chiral auxiliary can be removed by acid catalysed
methanolysis leading to P-stereogenic methyl phosphonates,
precursors for the preparation of phosphine oxides and phosphines.
Two additional applications are reported: the first example of
benzyne insertion into the P-N bond of a P-stereogenic phosphinic
amide and the formation of a complex of a chiral phosphinic amide-
phosphine oxide with zinc chloride.
Very recently, the synthesis of P-stereogenic phosphinic amides
has been the focus of great attention. Z. S. Han et al. used a C-chiral
1,3,2-benzoxazaphosphinine-2-oxide 10 as a phosphinyl transfer
agent to prepare
a
variety of P-stereogenic diaryl and
alkylarylphosphinic amides 11 via sequential displacement of the P-
N and P-O bonds of the phosphonamidate moiety by carbon and
nitrogen nucleophiles, respectively (Scheme 3, eq (1)).12
Interestingly, Park, Chang and co-workers reported the first example
of the metal assisted direct C-H stereoselective functionalization of a
Ph2P group. The reaction of C2-symmetric chiral phosphinic amides
12 with sulfonylazides 13 catalized by [IrCl2(Cp*)]2 in the presence
of AgNTf2 furnished phosphinic amides 14 in high yield (83% -
93%) and with diastereomeric excesses in the range of 77 – 93%
(Scheme 3, eq (2)).13
A
breakthrough solution to the
desymmetrization of diarylphosphinic amides has been reported by
the group of F.-S. Han. They achieved the enantioselective direct
ortho functionalization by Pd(II) catalysed C-H arylation of 15 with
arylboronic acids 16. Using N-Boc protected amino acids as chiral
ligands, P-stereogenic derivatives 17 with enantioselectivities up to
98% were obtained (Scheme 3, eq (3)).14 Similarly, the Pd(0)15a or
Pd(II)15b
bromoaryl)diarylphosphinic
catalysed intramolecular C-H arylations of N-(2-
amides using TADDOL-
a
phosphoramidite as chiral source were developed as valuable
methods of synthesizing cyclic P-stereogenic phosphinic amides.
The elegant transformations indicated above suffer from a few
weaknesses, such as the modest structural diversity introduced,
which consists of variations in the substitution pattern of a given
structural motif, the use of sophisticated reagents and the difficulties
of accessing to both enantiomeric forms of the products.
Results and discussion
Diastereoselective DoLi-stannylation of diphenylphosphinic
amides
In order to increase steric encumbrance around the stereogenic
center of the chiral auxiliary in phosphinic amide 7a it was decided
to replace the phenyl ring by a 1-naphthyl moiety and a t-Bu group.
2 | J. Name., 2012, 00, 1-3
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The required chiral phosphinic amides 7c and 7d are known in the instantaneous discoloration of the solution, the time of the quenching
literature. They have been prepared by enantioselective reduction of reaction was set to 15 min for all subsequent experiments.
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the corresponding N-diphenylphosphinyl ketimines.16 The synthesis Phosphinic amide 7d was recovered unchanged when diethyl ether
of (R)-7c by nucleophilic displacement of chloride from or toluene were used as solvent in the tempeDraOtuI:r1e0.r1a0n3g9e/Co5fD-T70828ºC60tDo
diphenylphosphinyl
chloride
with
(R)-1-(naphthalen-1- -35 ºC and the same happened in the attempted ortho deprotonation
yl)ethanamine has been also reported.17 We used
a
slight with organolithium bases such as LDA, nBuLi or the complex
modification of the latter procedure for synthesizing (S)-7c and (S)- [nBuLi·TMEDA]. Shortening the time of deprotonation with BuLi
7d, consisting of the condensation of chlorodiphenylphosphine with to 1 h had an almost negligible effect on the performance of the
the corresponding amine and subsequent oxidation with H2O2. reaction (yield to 77%, entry 2). However, the decrease of the
Column chromatography purification furnished 7c, 7d in high yield equivalents of tBuLi and electrophile used to 2.5 was detrimental for
t
(Scheme 4).
the reaction. The yield decreased to 35% (entry 3). According to
entry 2, long deprotonation times are unnecessary and may be the
reason for the low yield shown in entry 3 due to partial protonation
of the ortho anion. These facts suggest that abstraction of an ortho
proton of 7d could be feasible using almost stoichiometric amounts
of tBuLi, which would in turn make possible to reduce the amount of
electrophile added. We were pleased to see that when a 0.33 M
O
P
1) THF, Et3N (2.5 equiv)
-78 ºC to rt
Ph
Ph
R1
Ph2PCl
+
H2N
N
R1
2) H2O2, 0 ºC
H
(S)- , R1 = 1-Naphthyl (70%)
7c
(S)- , R1 = tBu (75%)
7d
1) tBuLi, THF,
-78 ºC
t
solution of (S)-7d was deprotonated with 2.2 equiv of BuLi for 1 h
Me3Sn
at -78 ºC in of THF and the resulting ortho anion was reacted with
1.2 equiv of Me3SnCl allowing to reach room temperature for 15
min, compound (SP,SC)-19 was obtained in 87% yield and a dr
(SP,SC)-19: (RP,SC)-19′ of 95:5. Column chromatography purification
provided enantiomerically pure (SP,SC)-19.
O
2) Me3SnCl
3) H2O
Me
R1
P
N
H
dr 93:7, R1 = 1-Naphthyl (42%)
dr 95:5, R1 = tBu (81%)
18:18'
19:19'
Table 1 Synthesis of (SP,SC)-19 via diastereoselective ortho
lithiation-stannilation of 7d.
Scheme 4 Synthesis of (S)-7c, 7d and diastereoselective ortho
stannylation to give 18 and 19, respectively.
As a proof of concept, we carried out the diastereoselective ortho
deprotonation-stannylation of 7c, 7d under reaction conditions
analogue to those applied to 7a (Scheme 2), except for the
temperature and the organolithium base employed. The working
temperature was lowered to -78 ºC with the aim of improving the
selectivity of the proton abstraction step. This made it necessary to
Equiv
tBuLia
Equiv
Me3SnCl
[c] (M)
THFa
Entry
Time (h)
Yield (%)
t
use a stronger base, such as BuLi. The increased bulkiness of this
1
2
3.5
3.5
3.5
3.5
16
1
0.1
0.1
81
77
n
base as compared with BuLi could also benefit the chiral induction
of the process.
The treatment of phosphinic amide (S)-7c bearing the (S)-(1-
(naphthalen-1-yl)ethyl) chiral auxiliary with 3.5 equiv of BuLi in
3
2.5
2.5
16
0.1
35
t
4
2.2
1.2
1
0.33
87
THF (reaction concentration of 0.1 M) at -78 ºC for 16 h followed by
quench with 3.5 equiv of trimethyltin chloride for 30 min afforded,
after aqueous workup, a mixture of the diastereoisomers 18:18′ in a
yield of 42% and a ratio of 93:7 (Scheme 4). Importantly, the
analogous reaction of (S)-7d proceeded much more efficiently to
give a mixture of 19:19′ in 81% yield and a ratio of 95:5 (Scheme
4). To ensure comparability of data, we achieved the same reaction
using phosphinic amide 7a as starting material. In this case, a
mixture of isomers 8:8′ was obtained in high yield (80%), albeit with
low diastereoselectivity (dr 80:20). The outcome of these reactions
confirmed that steric hindrance is essential for directing the
stereochemical course of the otho deprotonation of phosphinic
amides 7 and revealed the superior performance of the (S)-3,3-
dimethylbutan-2-amine as a chiral inductor with respect to that of
(S)-1-(naphthalen-1-yl)ethanamine and (R)-1-phenylethanamine.
Building on these initial findings, a brief optimization of the
ortho stannylation of (S)-7d was conducted (Table 1). Given that the
addition of Me3SnCl to the ortho anion produced the almost
LDA, nBuLi or [nBuLi·TMEDA] failed to achieve ortho
deprotonation. In toluene or Et2O as solvent 7d was recovered
a
b
quantitatively.
Recrystallization of a mixture of 19:19′ in ethyl acetate:hexanes
afforded crystals of both compounds suitable for X-ray diffraction
studies (see below). The solid-state structure revealed that the
absolute configuration of the phosphorus stereocenter of the major
product 19 is SP (Fig 1a). This means that tBuLi selectively
deprotonated the pro-S P-phenyl ring of 7d.
Generalization of the diastereoselective DoLi-trapping of
diphenylphosphinic amides
Once determined the optimized conditions for the highly
diastereoselective DoLi-stannylation of (S)-7d, the scope of the
methodology was investigated by treating the intermediate N,Cortho
dianion formed in the deprotonation step with a broad range of
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electrophiles. These were selected according to one or more of the
Next, additional carbon-heteroatom bond forming reactions were
following properties of the groups being introduced at the ortho assayed aimed at introducing new coordination sites that would
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position: (1) enable further derivatization, (2) provide a new donor expand the applications of P-stereogenicDOphI:o1s0p.1h0i3n9ic/C5aDmTi0d2e8s60aDs
site leading to a chelating hemilabile ligand and (3) increase the ligands. Tosyl azide was used as transfer reagent of the azido group
difference in size between the aryl groups linked to the phosphorus to the ortho anion. The azido derivative 24 was obtained in 89%
stereocenter. The results obtained are collected in Table 2.
yield and a dr of 95:5 (entry 6). Organic azides are valuable ligands
in coordination chemistry and can be readily converted into other
Table 2 Synthesis of P-stereogenic phosphinic amides (SP,SC)-19-28. important nitrogen-containing donor groups via dipolar
9,18
cycloadditions, Staudinger reaction, reduction, etc.
Ortho-
functionalization with hydroxy and diphenylphosphinoyl groups was
achieved by reacting the lithiated intermediate with dioxygen and
chlorodiphenylphosphine. In this way, products 25 and 26 were
obtained in good to high yield, respectively (entries 7 and 8). The
latter was isolated as the phosphine oxide due to quantitative
oxidation of the phosphine moiety during aqueous workup.
Allyl bromide and Boc anhydride were used as representative
carbon-based electrophiles for alkylation and acylation reactions.
Products 27 and 28 bearing the ortho-allyl and the bulky ortho-tert-
butylcarbonyl group, respectively were formed in good yield and
high dr (entries 9 and 11).
Table 2 shows small changes of the dr depending on the
electrophile used. The data are consistently reproducible through
several runs, i.e., they are not a consequence of the inaccuracy of the
integration of the NMR spectra. These changes may be associated to
slight differences of reactivity of the electrophiles. Although the time
for trapping the ortho anion is only 15 min, during that time the
temperature of the reaction is allowed to increase. Less reactive
electrophiles would give a chance for the appearance of competing
processes such as anion traslocation11 and thus a small degree of
phosphorus epimerization would be observed. The increase of the dr
in the reaction with allyl bromide as electrophile carried out at -84
ºC together with the decrease of the reaction yield (cf entries 9 and
10) support this view.
Yield
(%)a
d.r.b
(SP:RP)
Entry
E+
E
Product
1
2
Me3SnCl
SnMe3
87
95:5
19
20
(ICH2)2
(BrCH2)2
C2Cl6
I
Br
80
72
95
54
89
66
93
74
64
60
93:7
97:3
93:7
98:2
95:5
95:5
94:6
91:9
93:7c
96:4d
3
4
21
22
23
24
25
26
27
27
28
Cl
5
Me3SiCl
TsN3
SiMe3
N3
6
7
O2
OH
8
Ph2PCl
AllylBr
AllylBr
P(O)Ph2
Allyl
Allyl
C(O)OtBu
9
10
11
To conclude this section, one can say that we have developed a
general methodology for the synthesis of enantiopure P-stereogenic
phosphinic amides based on the highly diastereoselective DoLi of a
C-stereogenic precursor and subsequent electrophilic quench. The
method provides wide structural diversity using simple reagents and
readily accessible chiral auxiliaries in both enantiomeric forms.
Further derivatizations can be readily envisaged based on well-
established functional group transformations.
Boc2O
Isolated yield. Determined through integration of the 31P NMR
spectrum of the crude reaction mixture. c Reaction performed at -84
a
b
d
ºC. Addition of electrophile at -90 ºC and hydrolysis at low
temperature.
Ortho halogenation using 1,2-diiodoethane, 1,2-dibromoethane
and hexachloroethane as electrophiles proceeded in high yield to
give the respective iodine, bromine and chlorine derivatives 20, 21
and 22 (entries 2-4). Compound 20 crystallised from ethyl
acetate:hexanes. As expected, the solid-state structure confirmed the
assignment of the S configuration at the phosphorus center (Fig. 1b,
see below). The reaction with Me3SiCl afforded the ortho-
trimethylsilylaled product 23 in excellent dr (98:2), albeit in
moderate yield (54%, entry 5). Phosphinic amides 19-23 provide an
easy entry to more elaborated P-stereogenic products via transition-
metal catalysed cross-coupling reactions. Furthermore, the ortho-
stannylated phosphinic amide 19 is an air-stable equivalent of the
ortho-lithiated species that can be readily regenerated through
tin/lithium exchange reactions.9
Derivatization of P-stereogenic phosphinic amides
P-stereogenic phosphinic amides may serve as a gateway to other
chiral organophosphorus compounds. Among them, without a doubt,
P-stereogenic phosphines attract most attention. Access to this
family of products requires the conversion of the phosphinic amide
into an alkyl phosphinate. This transformation is usually achieved by
acid catalysed alcoholysis of the P-N linkage.14,19 In sterically
encumbered systems harsh reaction conditions are necessary for
breaking the P-N bond.20
The treatment of the ortho-iodo derivative (SP,SC)-20 with a
diluted methanolic solution of HCl for 48 h at ambient temperature
furnished the methyl phosphinate 29 in 80% of isolated yield and
with an ee of 98% (Scheme 5). In addition, the chiral auxiliary (S)-
3,3-dimethylbutan-2-amine is recovered. As with analogue
4 | J. Name., 2012, 00, 1-3
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substitution reactions, inversion of the configuration at the
As far as we know, this is the first example of benzyne insertion
n
phosphorus center is assumed.9,19,21 Phosphinate (SP)-29 is the key into a P-stereogenic phosphinic amide bond. The use of BuLi as a
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product for the preparation of phosphines via nucleophilic base implies that phosphinic amide 20 undergoes N-deprotonation to
DOI: 10.1039/C5DT02860D
displacement of the methoxy group by an organolithium or Grignard give species I. Charge delocalization through the P=O linkage will
reagent and subsequent reduction of the phosphine oxide formed.6,14 contribute to increase the sp2 character of the P-N bond. In this way,
The application of this process to the synthesis of phosphine-borane benzyne insertion into the P=N bond of I resembles the analogous
complex (RP)-30 starting on (RP)-29 has been described.9
reaction of phosphazenes that provides o-aminophosphonium salts.23
Assuming a stereospecific reaction pathway consisting of a [2+2]
cycloaddition and subsequent [2+2] cycloreversion,24 the benzyne
insertion will take place with retention of the configuration at the
phosphorus center.25
The aryne insertion chemistry into heteroatom-heteroatom
double bonds has been very little investigated.22,23 The mechanistic
details of the process remain unknown.26 We have carried out a DFT
computational study of the formation of 32 at the M06-
2X(SMD,THF)/6-311+G(d,p)//M06-2X/6-31G(d) level of theory.
All energies were calculated at a temperature of 333 K. N-H
deprotonation of 22 by n-BuLi provides species A in which the
lithium ion is bonded to both the nitrogen and oxygen atoms of the
phosphinamde moiety and completes the tetrahedral coordination by
binding to two THF molecules (Figs. 1 and S18, ESI). The four-
membered Li-N-P-O metallacycle of A is analogous to the Li-N-P-C
heterocycle characteristic of Cα-lithiated phosphazenes.27 The
Scheme 5 Formal synthesis of P-stereogenic phosphines 30 via
methyl phosphinate (SP)-29.
Recently, it has been reported the insertion of arynes into the P-
N bond of N-arylphosphinic amides as a method of synthesizing
ortho aniline-substituted triarylphosphine oxides.22 We thought that
the extension of this method to P-stereogenic N-alkyl derivatives
such as 19-28 will expand their range of applications and, at the
same time, will provide insight into the stereochemical course of the
reaction.
First attempt using the same reaction conditions described for N-
arylphosphinic amides22 was disappointing. Only a 4% conversion to
unidentified products was observed. Due to this failure, we
undertook a study of the parameters that may affect the reaction
progress: stoichiometry of the reagents, solvent (toluene, acetonitrile,
THF), base (NaH, KHMDS, Cs2CO3, nBuLi), temperature (range of -
78 ºC to 40 ºC), time (range of 1 to 40 h) and source of benzyne (31,
o-dibromobenzene). After extensive experimentation we found that
the reaction of N-lithiated (SP,SC)-22 with benzyne generated in situ
by fluoride ion-promoted desilylation of 2-(trimethylsilyl)phenyl
triflate 31 under reflux in THF in the presence of 18-crown-6 for 16
h afforded the ortho-aminophosphine oxide (RP,SC)-32 as a single
diastereoisomer in a yield of 48% (Scheme 6).
reaction of A with benzyne II is highly exothermic (
kcal/mol), takes place through transition state TS1 (energy barrier of
G‡ = 20.0 kcal/mol) to give the [2+2] cycloadduct E. As in
∆G = -35
∆
computational studies regarding Wittig olefination via 1,2-
oxaphosphetane intermediates,28 1,2λ5-azaphosphete E originates
from a concerted and highly asynchronous four-center double
nucleophilic addition (N to C/C to P). The structure of TS1 reveals
that the formation of the N-C1 bond is well advanced (distance of
2.463 Å) and occurs with concurrent breakdown of the N-Li bond
(distance of 3.159 Å). In contrast, the interaction between C2 and the
phosphorus atom is of electrostatic nature, since the P-C2 distance
(4.136 Å) is larger than the sum of the respective van der Waals radii
(3.5 Å). The gauche orientation of the benzyne moiety with respect
to the C-N-P angle of the phosphinic amide fragment seems to be
stabilized by hydrogen-bonding between the negatively charged C2
atom and the hydrogen atom linked to C3 of the nearby P-phenyl
ring (distance of 2.367 Å, angle C2···H3-C3 of 162.6º).
The phosphorus atom of E shows a highly distorted trigonal
bipyramid (TBP) geometry with the amino and ortho-clorophenyl
ligands at the apical positions (angle N-P-C4 of 162.2º, Figs 1 and
S18). The degree of distortion can be described through the topology
parameter TP, having limiting values of 0 and 1 for an ideal square
pyramid (SP) and TBP, respectively.29 For E, the calculated TP is of
0.4. The P-N distance in E (2.021 Å), although longer than the sum
of the van der Waals radii (1.81 Å), is almost half-way between the
extreme P-N bond lengths of 1.839(6) Å30 and 2.170(3) Å31 found in
the only two 1,2λ5-azaphosphete characterized by X-ray
crystallography. The intrinsic reaction coordinate calculation (IRC)
allowed to identify three key structures, B, C and D in the pathway
from TS1 to E (Figs 1, S19). They are non stationary points lying on
several plateaus along the IRC at the level of theory used. The
betaine B arising from the formal nucleophilic addition of the
nitrogen of A to benzyne is found at an IRC of 11.5%. Cyclization
Scheme 6: Synthesis of aminophosphine oxide (RP,SC)-32 by
benzyne insertion into the phosphinic amide bond.
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DOI: 10.1039/C5DT02860D
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Ring-closing
Pseudorotation
Ring-opening
THF
THF
Ar= 2-chlorophenyl
THF
THF
Li O
THF
THF
Li
THF
THF
THF
THF
THF
THF
N
P
Ph
Ar
THF
THF
Li
THF
THF
Li
Li
O
Li
Li
O
P
Li O Ph
O
P
Ph
Ar
O
P
PhO
O
P
P
Ph
Ar
Ph
Ar
Ph
Ar
Ph
Ar
N
N
P
Ar
N
A
N
P
Ar
N
N
N
+
TBP
SP
TBP
II
B
C
D
E
F
TS1
TS2
20.0
0.0
-34.2
-35.0
-57.9
Reaction pathway
Figure 1 Computed pathway for the reaction between N-lithiated phosphinic amide A and benzyne II.
through nucleophilic attack of the carbanion in B to the positively stabilized by the bond formed between the nitrogen and lithium
charged phosphorus atom leads to structure C (IRC of 48.9%). The atoms (distance of 2.007 Å) that generates a six-membered
geometry of the phosphorus atom in C can be described as a metallacycle Li-N-C1-C2-P-O1. The alternating bond distances in
distorted TBP (TP = 0.7) with the apical positions occupied by an the carbocycle bearing the nitrogen and phosphorus substituents
oxygen atom and the carbon atom C2 belonging to the benzyne indicate that species F is best described as a dearomatised
moiety (angle O1-P-C2 of 163.3º). P-N bond breaking in this adduct phosphorus ylide stabilized by conjugation through
a 1,3-
requires that the nitrogen atom departs from an apical position. The cyclohexadiene system and a C=N double bond. This finding is in
isomerization of C into E is achieved through a Berry pseudorotation agreement with the structure of the intermediate identified in the
using the unsubstituted P-phenyl ring as the pivot ligand.32 The insertion of benzyne into the P=N bond of phosphazenes.23b
structure D generated halfway this process of SP geometry at the Importantly, the computational study predicts that the insertion
phosphorus center (TP = 0) is identified at an IRC of 72.8%. The V- reaction into (SP,SC)-A is stereospecific, which is in agreement with
shaped pattern of the topology parameter29 connecting C and E the experimental result, and takes place with retention of the
supports the participation of a Berry pseudorotation in the C D E configuration at the phosphorus atom.33
interconversion (Fig S19).
Finally, as an illustrative application of P-stereogenic phosphinic
[2+2] Cycloreversion of E involves P-N/C=C bond breaking and amides in coordination chemistry, we explored the complexation of
C=N/C=P bond formation. The transformation proceeds through mixed bidentate ligand 26 with zinc dichloride. Zinc complexes of
phosphinic amides have received little attention. A literature search
transition state TS2 almost without energy barrier32 G‡ = 0.8
(∆
provided only one X-ray structure of this family of complexes, that
of the polymeric chain generated in the reaction of N-(4-methyl-2-
pyrimidinyl)-P,P-diphenyl-phosphinic amide with ZnCl2.34 In this
kcal/mol) to give the highly stable lithiated species of aryne insertion
(RP,SC)-F ( G = -57.9 kcal/mol). This species is additionally
∆
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complex the ligand acts as a O,N bridging ligand through the oxygen geometry at Sn is midway between a trigonal bipyramid and a
atom of the phosphinic amide group and the less hindered nitrogen tetrahedron as deduced from the deviation of 0.496 Å /0.474 Å of the
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atom of the pyrimidine heterocycle. We have recently reported the Sn atom from the plane defined by the aDtoOmI:s10C.120,39C/2C05DaTn0d28C602D1
synthesis and structural characterization of complexes of o- (limiting value of 0.71 for an ideal tetrahedron) and the difference
chalcogenophosphorylphosphinic amides (chalcogeno = oxygen,
sulphur, selenium) with ZnCl2, 33 (Scheme 7).35 The reaction of
ligand 26 with ZnCl2 in a mixture of acetonitrile:dichloromethane
(1:1) at room temperature lead to the quantitative formation of
complex 34 (Scheme 7). Single crystals of 34 were obtained through
slow diffusion of Et2O into a dichloromethane:acetonitrile (1:1)
solution of the compound (see next section). Molecular weight
determination of the complex using soft high resolution mass
spectrometry techniques failed (ESI-TOF, voltages in the range 5 V -
25 V). In all cases, only the quasimolecular ion corresponding to the
free ligand was detected. This feature suggests that the ligand in
complex 34 is weakly bound to the metal center.
between the sum of the equatorial Σθeq and axial Σθax angles, ∆Σθ =
Σθeq – Σθax = 35.2º/37.9º (limiting values are 0º for a tetrahedron and
90º for a trigonal bipyramid).36 The Sn-O coordination is supported
by the Sn1-O1 distance of 2.717(4) Å/2.713(4) Å, ca. 1 Å shorter
than the sum of the van der Waals radii (3.69 Å), and similar to the
Sn-O distance found in ortho-triphenylstannylphosphonates37
(2.803(3)-2.793(2) Å). In agreement with this Sn-O contact, the Sn-
Me bond distance for the pseudo-axial methyl group C20 (2.167(6)
Å/ 2.196(8) Å) is slightly longer than those of the pseudo-equatorial
Sn-Me bonds (limiting values of 2.118(7) and 2.149(5) Å) and the
P1-O1 bond (1.492(4) Å/1.496(4) Å) is slightly elongated with
respect to uncoordinated (N-alkyl)-P,P-diphenylphosphinic amides
(average 1.485 Å).38 However, this interaction seems to be very
weak given that the P=O bond distance matches that of (R)-7a.39,40
Compound 20 crystallizes in the orthorhombic space group
P212121, having four molecules in the asymmetric unit. The
molecular structure is depicted in Fig. 2c. Structural parameters for
compound 20 are given in Tables S2 and S3 (ESI). Intermolecular
N-H···O hydrogen bonding (H1…O1 = 2.235, <O1-H1…N1 = 162º
and N1…O1i = 2.976(5), i=x-1/2, -y+5/2, -z+2) generates a three-
dimensional network of parallel chains running along the a axis
Interestingly, the iodine atom and the P=O group are in the same
plane (torsion angle O1-P1-C1-C2 of 176.5(3)º) with the former
directed to the phosphorus atom. The I1···P1 distance of 3.607(1) Å
is notably shorter than the sum of the respective van der Waals radii
(3.78 Å). However, there appears to be no I···P coordination. The
phosphorus atom shows the expected tetrahedral geometry with
min/max bond angles of 105.0(2)º/113.2(2)º and a P1-O1 bond
distance of 1.467(3) Å that is the shortest reported for N-
alkyldiphenylphosphinic amides.38 Only three molecular structures
containing ortho P=O and iodine groups related to 20 have been
reported. These are phosphine oxides in which the oxygen and
iodine atoms are oriented either syn (torsion angle O-P-C-C of -
14.40º)41 or gauche (torsion angles O-P-C-C of -46.09º and
61.55º).42 The unprecedented anti arrangement of the oxygen and
iodine atoms of 20 may arise from the combined effect produced by
the intermolecular hydrogen bonding and the intramolecular
Coulombic interaction between both heteroatoms.
Ph2
X
P
Cl 33a, X = O
Zn
33b, X = S
33c, X = Se
O
P
NiPr2
Cl
Cl
O
Zn
Cl
Me
tBu
Ph2P
O
Ph2P
O
O
Me
tBu
ZnCl2
100%
P
P
N
H
N
H
(SP,SC)-26
(SP,SC)-34
Scheme 7 Synthesis of phosphinic amide-phosphine oxide zinc
complex (SP,SC)-34.
Molecular structure of compounds 19, 19’, 20 and 34
Compound 19 crystallizes in the orthorhombic space group P212121
containing four discrete monomeric molecules in the unit cell. The
isomer 19’ crystallizes in the tetragonal P43212 space group with a
unit cell consisting of 8 molecules. The crystal structures of 19 and
19’ are shown in Figs. 2a and 2b, and selected data are summarized
in Tables S2 and S3 (see electronic supplementary information,
ESI). In the following, structural data for these compounds are
reported in the form 19/19’ due to their similarity. The P=O group is
directed toward the tin atom showing an almost linear arrangement
of the atoms O1, Sn1 and C19 (angle of 174.7(2)º/176.2(2)º). This
linearity indicates the existence of a weak Sn-O interaction. The
b)
a)
c)
Figure 2 Crystal structures of (a) (SP,SC)-19, (b) (RP,SC)-19’ and (c) (SP,SC)-20. Hydrogen atoms have been omitted for clarity.
Color codes: grey:carbon; orange: phosphorus; blue: nitrogen; red: oxygen; green: tin and purple: iodine.
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DOI: 10.1039/C5DT02860D
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Complex 34 is a monomer which crystallise in the orthorhombic
We have developed a new method for the efficient synthesis of
space group (P212121). The molecular structure is presented in Fig. enantiopure P-stereogenic diarylphosphinic amides consisting of the
3. Selected crystal data and bond lengths and angles are given in directed ortho lithiation of (S)-N-(3,3-dimethylbutan-2-yl)-P,P-
Tables S2 and S3, respectively (ESI). The structure and bonding diphenylphosphinic amide by treatment with 2.2 equiv of t-BuLi at -
parameters in complex 34 are very similar to those of the analogous 78 ºC and subsequent trapping of the ortho anion with a large variety
complex 33a.35 As expected, compound 26 acts as an O,O-chelate to of electrophiles. Major advantages associated with this methodology
bind to the zinc atom of ZnCl2. This coordination mode gives rise to include the excellent stereocontrol of the deprotonation step
a
seven-membered metallacycle that exist in a twist-boat affording diastereomeric ratios up to 98:2, the feasibility of
conformation. The zinc atom is at the center of a distorted introducing wide structural diversity via carbon-carbon and carbon-
tetrahedron delimited by the two oxygen atoms and the two chlorine heteroatom bond forming reactions (C-N, C-O, C-Si, C-Sn, C-P, C-
atoms of the molecule.
halogen with halogen = Cl, Br and I), the easy availability of both
enantiomeric forms of the starting material, and the mild reaction
conditions employed. The stereochemical course of the reaction has
been ascertained through the X-ray structures of both ortho-
trimethyltin diastereosiomers and the major ortho-iodo isomer. The
chiral auxiliary can be recovered through acid catalysed
methanolysis of the P-N bond. The resulting methyl phosphinate is
the known entry to P-stereogenic phosphine oxides and phosphines
through well established procedures. Furthermore, we have achieved
for the first time the benzyne insertion into the P-N bond of a P-
stereogenic phosphinic amide. The reaction provides ortho-
aminophosphine oxides with retention of the configuration at the
phosphorus center as shown by computational studies. Additional
derivatisation can be envisaged through functional group
transformations involving the ortho substituents. The ability of the
new P-stereogenic compounds to act as ligands is supported by the
synthesis and x-ray structural characterization of the complex arising
from the reaction of the orto- phosphinic amide-phosphine oxide
derivative with zinc dichloride.
Figure 3 Crystal structure of the complex 34. Hydrogen atoms have
been omitted for clarity. Color codes: grey:carbon; orange:
phosphorus; blue: nitrogen; red: oxygen; cyano: zinc and green:
chlorine.
Major differences between the structures of complexes 33 and 34
proceed from the geometry of the metallacycle involving the metal
center. The bond angle Cl1-Zn1-Cl2 increases from 114.89(5)º in 33
to 120.75(3)º in 34 , whereas the metallacycle of the latter complex
is less twisted (cf torsion angles O1-Zn1-O2-P2 of 21.47º and 3.77º
in 33 and 34, respectively). As for the tin complexes 19/19’, no
hydrogen bonding is observed for the N-H bond of 34. The geometry
of the benzometallacycle fragment present in 34 can be considered
as a distorted half-boat having the metal at the apex of the boat
substructure connected with the plane defined by the benzo
condensed ring and the two phosphorus atoms. In this arrangement,
the approach to the zinc atom through the pro-S face would be
favored. Access to the metal ion through the pro-R face would be
hindered by the two pseudo-axial P-phenyl substituents. Compound
34 is the first example of an enantiomerically pure zinc complex of a
mixed phosphinic amide-phosphine oxide ligand.
Experimental
Materials and methods
All reactions and manipulations were carried out in a dry N2
gas atmosphere using standard Schlenk procedures. THF was
distilled from sodium/benzophenone immediately prior to use.
Commercial reagents were distilled prior to their use, except
alkyllithiums, quiral amines and 2-(trimethylsilyl)phenyl
trifluoromethanesulfonate. In the reaction with molecular
oxygen an O2 filled balloon was used. TLC was performed on
Merck plates with aluminum backing and silica gel 60 F254
Purifications were carried out by column chromatography using
silica gel 60 (40-63 m) from Scharlau and different mixtures
.
µ
of ethyl acetate:hexanes as eluent.
NMR spectra were measured in a Bruker Avance 300 (1H,
300.13 MHz; 13C, 75.47 MHz; 31P, 121.49 MHz) and a Bruker
Avance 500 spectrometer equipped with a third radiofrequency
channel (1H, 500.13 MHz; 13C, 125.76 MHz; 31P, 202.45 MHz)
Conclusions
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1
using a 5 mm QNP H/13C/19F/31P probe and a direct 5 mm
TBO 1H/31P/BB triple probe, respectively. The spectral
(S)-N-(1-(naphthalen-1-yl)ethyl)-P,P-diphenylphosphinic amide,
7c: Yield after chromatography (50% AcOEt:HexanesV)i:ew70A%rtic.leWOnhliintee
1
references used were internal tetramethylsilane for H and 13C,
external 85% H3PO4 for 31P. Diastereoselectivities were
determined by integration of 31P NMR spectra of the crude
reactions. Quantitative 31P NMR measurements were performed
by using the inverse-gated pulse sequence, an excitation pulse
of 15º and a repetition delay of 2s. Standard Bruker software
was used for acquisition and processing routines. Infrared
spectra were recorded in a Bruker Alpha FTIR equipment. High
resolution mass spectra were recorded on Agilent Technologies
LC/MSD TOF and HP 1100 MSD equipment with electrospray
ionization. Melting points were recorder on a Büchi B-540
capillary melting point apparatus and are uncorrected.
DOI: 10.1039/C5DT02860D
solid. Mp: 165-166 ºC. [α]D +60.6 (c 0.9, CH2Cl2). 1H NMR
(CDCl3) δ 1.72 (d, 3H, 3JHH 6.7 Hz, H2´), 3.49 (dd, 1H, 3JHH 9.1 Hz,
2JPH 5.7 Hz, H1), 5.26 (tc, 1H, 3JPH = 3JHH 9.1, 3JHH 6.7 Hz, H2), 7.26
(m, 2H, H15), 7.37 (m, 1H, H16), 7.43 (m, 1H, H6), 7.44 (m, 2H,
H15´), 7.47 (m, 1H, H7), 7.49 (m, 1H, H16´), 7.50 (m, 1H, H11),
7.66 (m, 1H, H12), 7.77 (m, 1H, H10), 7.78 (m, 2H, H14), 7.84 (m,
1H, H8), 7.89 (m, 1H, H5), 7.94 (m, 2H, H14´) ppm. 13C NMR
(CDCl3) δ 26.1 (d, 3JPC 2.5 Hz, C2´), 47.1 (d, 2JPC 0.6 Hz, C2), 122.5
(s, C12), 123.0 (s, C5), 125.4 (s, C11), 125.6 (s, C7), 126.0 (s, C6),
20
3
3
127.8 (s, C10), 128.3 (d, JPC 12.7 Hz, C15), 128.4 (d, JPC 12.4 Hz,
4
C15´), 128.7 (s, C8), 130.1 (s, C4), 131.7 (d, JPC 2.8 Hz, C16),
4
2
131.8 (d, JPC 2.8 Hz, C16´), 131.9 (d, JPC 9.3 Hz, C14), 132.1 (d,
1JPC 130.0 Hz, C13), 132.2 (d, JPC 9.8 Hz, C14´), 133.3 (d, JPC
2
1
X-ray crystallography
127.5 Hz, C13´), 133.8 (s, C9), 141.1 (s, JPC 7.0 Hz, C3) ppm. 31P
3
Single crystal X-ray diffraction data for compounds 19 and 20
were collected on a Bruker AXS Smart Apex diffractometer
NMR (CDCl3) δ 23.7 (s) ppm. IR (ATR, υ cm-1): 3175 (bs, NH),
1183 (s, P=O). HRMS (ESI) calcd for C24H23PNO: 372.1517 (MH)+,
found: 372.1515.
using graphite monochromatic MoK
α radiation (λ = 0.71069
Å) at 100(2) K and 293(2) K, respectively. Data collection and
cell refinement were performed with Bruker SMART
program.43 For compound 19’ and 34, the crystallographic data
were collected on a Bruker D8 Venture diffractometer at 100 K,
(S)-N-(3,3-dimethylbutan-2-yl)-P,P-diphenylphosphinic amide,
7d: Yield after chromatography (50% AcOEt:Hexanes): 75%. White
20
solid. Mp: 143-144 ºC. [α]D +121.4 (c 0.9, CH2Cl2). 1H NMR
using CuK
refinement were performed with Bruker Instrument Service
v4.2.2 and APEX2,44 respectively. Data reduction for 19
19’
α radiation (λ = 1.54178 Å). Data collection and cell
(CDCl3) δ 0.90 (s, 9H, H4), 1.21 (d, 3H, 3JHH 6.7 Hz, H2´), 2.68 (dd,
3
1H, 3JHH 11.1 Hz, 2JPH 5.2 Hz, H1), 2.90 (ddc, 1H, JHH 11.1, 3JPH
=
,
,
8.7, 3JHH 6.7 Hz, H2), 7.45 (m, 6H, H7-H8), 7.92 (m, 4H, H6) ppm.
13C NMR (CDCl3) δ 19.2 (d, 3JPC 1.9 Hz, C2´), 26.4 (s, C4), 34.8 (d,
20 and 34 were carried out using SAINT.45 Empirical multiscan
absorption correction using equivalent reflections was
performed with the SADABS program.46 The structure
solutions and full-matrix least-squares refinements based on F2
were performed with the SHELXS-97 and SHELXL-97
program packages.47 All atoms except hydrogen were refined
anisotropically. Hydrogen atoms were treated by a mixture of
independent and constrained refinement. The structures were
drawn by ORTEP-348 and Mercury programs.49 The thermal
ellipsoids are shown in Fig. S23-S26 (ESI).
3JPC 7.2 Hz, C3), 56.0 (d, JPC 2.7 Hz, C2), 128.2 (d, JPC 12.6 Hz,
2
3
3
4
C7), 128.4 (d, JPC 12.4 Hz. C7´), 131.6 (d, JPC 2.8 Hz, C8), 131.7
4
2
2
(d, JPC 2.7 Hz, C8´), 132.0 (d, JPC 9.4 Hz, C6), 132.3 (d, JPC 9.0
Hz, C6´), 132.6 (d, 1JPC 130.2 Hz, C5), 133.6 (d, 1JPC 127.9 Hz, C5´)
ppm. 31P NMR (CDCl3) δ 22.5 (s) ppm. IR (ATR, υ cm-1): 3298 (bs,
NH), 1185 (s, P=O), 1106 (s). HRMS (ESI) calcd for C18H25PNO:
302.1674 (MH+), found: 302.1671.
Optimized conditions for the diastereoselective synthesis of P-
quiral phosphinic amides. To a solution of phosphinic amide 7 (1
g, 3.32 mmol) in 10 mL of THF, a solution of tert-BuLi (4.3 mL of a
1.7 M solution in pentane, 2.2 mmol) was added at -78 ºC
(acetone/CO2). After one hour of metallation, the corresponding
electrophile (1.2 mmol) was added. The reaction was allowed to
reach room temperature gradually stirring for 15 additional minutes.
Then, the reaction was poured out into water, extracted with ethyl
acetate (3x15 mL), washed with ammonium chloride (sat., 2x15
mL), dried over anhydrous sodium sulfate and concentrated in
Computational Methods
The geometries of all compounds were optimized with the
meta-hybrid density functional M06-2X50 and a 6-31G(d) basis
set in gas phase. Single point energy calculations were
performed with the M06-2X functional and a 6-311+G(d,p)
basis. The SMD51 solvation model was used in M06-2X single
point energy calculations. THF was used as solvent. All
stationary points were characterized as minimum or transition
states and checked by vibrational analysis. The reported free
energies and enthalpies include zero-point energies and thermal
corrections calculated at 298K. All calculations were performed
with Gaussian 09.52 The 3D structures of molecules were
generated using CYLView (http://www.cylview.org).
vacuo.
Purification
through
column
chromatography
(AcOEt:hexanes) afforded reaction products. Pure diastereomers
were obtained by recrystallization using ethyl acetate:hexane as
solvent except for 14a where tert-butyl methyl ether was used. See
ESI for the numbering scheme used.
(S
or
R)-N-((S)-1-(naphthalen-1-yl)ethyl)-P-phenyl-P-(2-
General procedure for the preparation of phosphinic amides 5
and 7. To a cooled at -78 ºC solution of 1.1 equivalents of chiral
amine and 2.5 equivalents of Et3N in THF, 1.0 equivalents of
diphenylphosphine chloride was added slowly. The reaction was
allowed to reach room temperature and stirred for 2 h. Then, 0.3
mL/mmol of a 33% aqueous solution of hydrogen peroxide was
added at 0 ºC. After 15 min, the reaction mixture was poured into
water and extracted with methylene chloride (3x5mL). The organic
layers were washed with a saturated ammonium chloride solution
(2x5 mL), dried over Na2SO4, filtered and the solvent was removed
in a rotavapor. Purification was carried out by flash chromatography.
See ESI for the numbering scheme used.
(trimethylstannyl)phenyl)phosphinic amide, 18 or 18´: Yield after
chromatography (50% AcOEt:Hexanes): 40%. White solid. Mp:
165-166 ºC. [α]D +85.2 (c 0.6, CH2Cl2). H NMR (CDCl3) δ 0.42
(d, 9H, JSnH 55.6 Hz, H14´), 1.73 (d, 3H, JHH 6.7 Hz, H2´), 3.38
20
1
3
3
3
2
3
3
(dd, 1H, JHH 8.9, JPH 5.5 Hz, H1), 5.16 (tc, 1H, JPH4 = JHH 8.9,
3JHH 6.7 Hz, H2), 7.13 (tdd, 1H, JHH 7.5, JPH 3.6, JHH 1.3 Hz,
H17), 7.37 (m, 1H, H16), 7.46 (m, 2H, H21), 7.5 (m,
H6+H7+H11+H22), 7.63 (m, 1H, H12), 7.65 (m, 1H, H18), 7.78 (m,
1H, H15), 7.79 (m, 1H, H10), 7.81 (m, 1H, H5), 7.86 (m, 1H, H8),
7.96 (m, 2H, H20) ppm. 13C NMR (CDCl3) δ -4.8 (dd, 4JPC 0.9, 1JSnC
3
4
3
380.1 Hz, C14´), 26.1 (d, JPC 2.5 Hz, C2´), 47.3 (s, C2), 122.6 (s,
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3JPC 9.9 Hz, C7) ppm. 31P NMR (CDCl3) δ 26.6 ppm. IR (ATR, υ
C12), 122.9 (s, C5), 125.5 (s, C11), 125.6 (s, C7), 126.1 (s, C6),
3
3
cm-1): 3402 (bs, NH), 1193 (s, P=O). HRMS (ESI) calcd for
127.8 (s, C10), 127.8 (d, JPC 12.7 Hz, C17), 128.6 (d, JPC 12.3 Hz,
C21), 128.9 (s, C8), 130.1 (s, C4), 130.7 (d, 4JPC 3.3 Hz, C16), 131.9
(d, 4JPC 2.9 Hz, C22), 131.9 (d, 2JPC 9.5 Hz, C20), 132.4 (d, 2JPC 13.4
Hz, C18), 133.6 (d, 1JPC 125.6 Hz, C19), 133.9 (s, C9), 136.4 (d, 1JPC
C18H24PNOI: 428.0640 (MH)+, found: 428.0629.
View Article Online
DOI: 10.1039/C5DT02860D
(S)-P-(2-bromophenyl)-N-((S)-3,3-dimethylbutan-2-yl)-P-phenyl-
2
3
134.2 Hz, C13), 137.0 (d, JPC 17.7 Hz, C15), 141.1 (s, JPC 7.3 Hz,
phosphinic amide, 21: Yield after chromatography (50%
C3), 151.3 (d, 2JPC 18.7 Hz, C14) ppm. 31P NMR (CDCl3) δ 25.3 (d, AcOEt:Hexanes): 72%. White solid. Mp: 139-140 ºC. [α]D +121.1
20
1
3JSnP = 19.3 Hz) ppm. IR (ATR, υ cm-1): 3228 (bs, NH), 1174 (bs, (c 0.6, CH2Cl2). H NMR (CDCl3) δ 0.83 (s, 9H, H4), 1.32 (d, 3H,
2
3
P=O). HRMS (ESI) calcd for C26H27NOPSn: 520.0858 (M-Me)+, 3JHH 6.6 Hz, H2´), 3.16 (dd, 1H, JPH 14.4, JHH 10.1 Hz, H1), 3.40
3
3
3
found: 520.0856.
(tc, 1H, JPH = 3JHH 10.1, JHH 6.6 Hz, H2), 7.39 (tdd, 1H, JHH 7.9,
4JHH 1.9, JPH 1.4 Hz, H8), 7.43 (m, 2H, H13), 7.50 (m, 1H, H9),
7.52 (m, 1H, H14), 7.60 (ddd, 1H, JHH 7.9, JPH 4.2, JHH 1.2 Hz,
4
3
4
4
(S)-N-((S)-3,3-dimethylbutan-2-yl)-P-phenyl-P-(2-(trimethyl-
3
4
stannyl)phenyl)phosphinic amide, 19: Yield after chromatography H7), 7.69 (m, 2H, H12), 8.30 (ddd, 1H, JPH 12.3, 3JHH 7.6, JHH 1.9
20
3
Hz, H10) ppm. 13C NMR (CDCl3) δ 19.6 (d, JPC 2.9 Hz, C2´), 26.3
(20% AcOEt:Hexanes): 80%. White solid. Mp: 123-124 ºC. [α]D
1
2
3
2
+234.3 (c 1.2, CH2Cl2). H NMR (CDCl3) δ 0.36 (d, 9H, JSnH 55.6 (3C, s, C4), 34.6 (d, JPC 4.1 Hz, C3), 55.1 (d, JPC 1.7 Hz, C2),
Hz, H6´), 0.91 (s, 9H, H4), 1.25 (d, 3H, 3JHH 6.5 Hz, H2´), 2.67 (dd, 124.7 (d, 2JPC 5.9 Hz, C6), 127.3 (d, 3JPC 10.7 Hz, C9), 128.3 (d, 3JPC
3
2
3
3
2
4
1H, JHH 11.2, JPH 3.0 Hz, H1), 2.82 (ddc, 1H, JHH 11.4, JPH 8.1, 13.3 Hz, C13), 131.1 (d, JPC 10.9 Hz, C12), 131.7 (d, JPC 2.9 Hz,
4
3
3JHH 6.6 Hz, H2), 7.39 (tdd, 1H, 3JHH 7.4, 4JPH 3.6, 4JHH 1.4 Hz, H9), C14), 132.9 (d, JPC 2.4 Hz, C8), 133.7 (1d, JPC 8.4 Hz, C7), 134.3
7.46 (m, 1H, H8), 7.47 (m, 3H, m, H13+H14), 7.80 (m, 1H, H7), (1d, 1JPC 124.9 Hz, C11), 134.4 (d, 1JPC 130.7 Hz, C5), 136.0 (d, 3JPC
7.90 (m, 1H, H10), 7.95 (m, 2H, H12) ppm. 13C NMR (CDCl3) δ - 7.0 Hz, C10) ppm. 31P NMR (CDCl3) δ 24.9 ppm. IR (ATR, υ cm-1):
4
1
3
4.7 (dd, JPC 0.9, JSnC 381.5 Hz, C6´), 19.3 (d, JPC 1.2 Hz, C2´), 3229 (bs, NH), 1184 (s, P=O). HRMS (ESI) calcd for C18H24PNOBr:
26.5 (s, C4), 34.9 (d, JPC 8.4 Hz, C3), 56.0 (d, JPC 2.9 Hz, C2), 380.0779 (MH)+, found: 380.0779.
3
2
3
3
127.8 (d, JPC 12.5 Hz, C9), 128.5 (d, JPC 12.2 Hz, C13), 130.5 (d,
4JPC 3.4 Hz, C8), 131.7 (d, JPC 2.7 Hz, C14), 131.8 (d, JPC 9.0 Hz,
4
2
(S)-P-(2-chlorophenyl)-N-((S)-3,3-dimethylbutan-2-yl)-P-phenyl-
C12), 132.7 (d, JPC 13.1 Hz, C10), 134.1 (d, JPC 125.8 Hz, C11), phosphinic amide, 22: Yield after chromatography (50%
2
1
1
3
20
136.5 (d, JPC 136.5 Hz, C5), 136.9 (d, JPC 17.5 Hz, C7), 151.7 (d, AcOEt:Hexanes): 95%. White solid. Mp: 142-143 ºC. [α]D +121.1
3
1
2JPC 18.6 Hz, C6) ppm. 31P NMR (CDCl3) δ 24.4 (d, JSnP 17.5 Hz) (c 0.9, CH2Cl2). H NMR (CDCl3) δ 0.81 (s, 9H, H4), 1.28 (d, 3H,
2
3
3JHH 6.6 Hz, H2´), 3.05 (dd, 1H, JPH 13.4 Hz, JHH 10.4 Hz, H1),
ppm. IR (ATR, υ cm-1): 3339 (w, NH), 1180 (s, P=O). HRMS (ESI)
3
3
3
calcd for C21H32PNOSnNa: 488.1145 (M+Na)+, found: 488.1155.
3.34 (ddc, 1H, JHH 10.4, JPH 9.7, JHH 6.6 Hz, H2), 7.43 (m, 6H,
H8+H9+H10+H13+H14), 7.72 (m, 2H, H12), 8.23 (m, 1H, H7)
3
ppm. 13C NMR (CDCl3) δ 19.4 (d, JPC 2.4 Hz, C2´), 26.3 (s, C4),
(R)-N-((S)-3,3-dimethylbutan-2-yl)-P-phenyl-P-(2-(trimethyl-
3
2
2
stannyl)phenyl)phosphinic
amide,
19´:
Yield
after 34.5 (d, JPC 4.2 Hz, C3), 55.0 (d, JPC 1.8 Hz, C2), 126.7 (d, JPC
3
3
chromatography (20% AcOEt:Hexanes): 4%. White solid. Mp: 111- 10.8 Hz, C9), 128.2 (d, JPC 13.4 Hz, C13), 130.2 (d, JPC 7.8 Hz,
C7), 131.0 (d, 2JPC 11.0 Hz, C12), 131.6 (d, 4JPC 2.9 Hz, C14), 132.3
20
1
112 ºC. [α]D -58.3 (c 0.6, CH2Cl2). H NMR δ (CDCl3) 0.33 (d,
1
4
1
2
3
(d, JPC 124.4 Hz, C11), 132.8 (d, JPC 2.3 Hz, C8), 134.4 (d, JPC
9H, JSnH 55.8 Hz, H6´), 0.92 (s, 9H, H4), 1.16 (d, 3H, JHH 6.6 Hz,
H2´), 2.66 (dd, 1H, JHH 11.1 Hz, JPH 6.1 Hz, H1), 2.88 (ddc, JHH
2
2
3
2
3
131.6 Hz, C5), 135.3 (d, JPC 4.7 Hz, C6), 135.4 (d, JPC 6.9 Hz,
11.1, JPH 9.1, 1H, JHH 6.6 Hz, H2), 7.47 (m, 5H, C10) ppm. 31P NMR (CDCl3) δ 23.5 ppm. IR (ATR, υ cm-1): 3231
3
3
H8+H9+H13+H14), 7.80 (m, 1H, H7), 7.97 (m, 3H, H10+H12) (bs, NH), 1186 (s, P=O). HRMS (ESI) calcd for C18H24PNOCl:
336.1284 (MH)+, found: 336.1276.
4
1
ppm. 13C NMR δ (CDCl3) -4.8 (dd, JPC 0.9, JSn,C 380.5 Hz, C6´),
3
3
19.1 (d, JPC 2.5 Hz, C2´), 26.6 (s, C4), 34.8 (d, JPC 6.2 Hz, C3),
56.0 (d, JPC 2.7 Hz, C2), 127.8 (d, JPC 11.9 Hz, C9), 128.4 (d, JPC
11.9 Hz, C13), 130.6 (d, JPC 3.6 Hz, C8), 131.6 (d, JPC 2.7 Hz,
2
3
3
(S)-N-((S)-3,3-dimethylbutan-2-yl)-P-phenyl-P-(2-(trimethyl-
silyl)phenyl)phosphinic amide, 23: Yield after chromatography
4
4
20
2
2
(20% AcOEt:Hexanes): 54%. Colorless oil. [α]D +238.3 (c 0.9,
C14), 132.1 (d, JPC 12.8 Hz, C10), 132.3 (d, JPC 9.6 Hz, C12),
1
133.2 (d, 1JPC 127.4 Hz, C11), 137.1 (d, 3JPC 17.3 Hz, C7), 138.1 (d, CH2Cl2). H NMR (CDCl3) δ 0.45 (s, 9H, H6´), 0.90 (s, 9H, H4),
3
3
2
1JPC 133.5 Hz, C5), 151.2 (d, JPC 18.4 Hz, C6) ppm. 31P NMR δ
2
1.25 (d, 3H, JHH 6.6 Hz, H2´), 2.59 (dd, 1H, JHH 10.6 Hz, JPH 4.5
3
3
3
(CDCl3): 24.3 (d, JSnP 18.8 Hz) ppm. IR (ATR, υ cm-1): 3382 (d,
3
Hz, H1), 2.88 (ddc, 1H, JHH 10.6, JPH 8.3, JHH 6.6 Hz, H2), 7.41
(m, 4H, H9+H13+H14), 7.45 (m, 1H, H8), 7.78 (m, 1H, H7), 7.90
(m, 2H, H12), 7.92 (m, 1H, H10) ppm. 13C NMR (CDCl3) δ 2.1 (s,
NH), 1193 (bs, P=O. HRMS (ESI) calcd for C20H29NOPSn:
450.1012 (M-Me)+, found: 450.1012.
3
3
C6´), 19.0 (d, JPC 1.7 Hz, C2´), 26.5 (s, C4), 34.8 (d, JPC 7.2 Hz,
C3), 56.2 (d, 2JPC 2.8 Hz, C2), 128.0 (d, 3JPC 12.6 Hz, C9), 128.3 (d,
(S)-N-((S)-3,3-dimethylbutan-2-yl)-P-(2-iodophenyl)-P-phenyl-
phosphinic amide, 20: Yield after chromatography (50%
AcOEt:Hexanes): 80%. White solid. Mp: 121-122 ºC. [α]D +148.1
4
4
3JPC 12.2 Hz, C13), 130.4 (d, JPC 3.1 Hz, C14), 131.3 (d, JPC 2.8
2
2
20
Hz, C8), 131.8 (d, JPC 9.0 Hz, C12), 133.7 (d, JPC 12.3 Hz, C10),
135.1 (d, 1JPC 123.4 Hz, C11), 136.1 (d, 3JPC 16.3 Hz, C7), 137.3 (d,
1
(c 0.9, CH2Cl2). H NMR (CDCl3) δ 0.80 (s, 9H, H4), 1.30 (d, 3H,
2
1JPC 133.7 Hz, C5), 147.1 (d, JPC 18.0 Hz, C6) ppm. 31P NMR
2
3
3JHH = 6.6 Hz, H2´), 3.24 (dd, 1H, JPH = 14.3 Hz, JHH 10.3 Hz,
(CDCl3) δ 25.1 ppm. IR (ATR, υ cm-1): 3065 (d, NH), 1110 (s,
P=O). HRMS (ESI) calcd for C21H33PNOSi: 374.2069 (MH)+,
found: 374.2068.
3
3
3
H1), 3.41 (ddc, 1H, JPH 19.7 Hz, JHH 10.1Hz, JHH 6.6 Hz, H2),
7.17 (tdd, 1H, JHH 7.8, JPH 1.2, JHH 1.7 Hz, H8), 7.42 (m, 2H,
3
4
4
H13), 7.51 (m, 2H, H14+H9), 7.66 (m, 2H, H12), 7.91 (ddd, 1H,
3JHH 7.8, JPH 3.9, JHH 0.7 Hz, H7), 8.31 (ddd, 1H, JPH 12.1, 3JHH
4
4
3
7.6, JHH 1.7 Hz, H10) ppm. 13C NMR (CDCl3) δ 19.6 (d, JPC 3.0
Hz, C2´), 26.4 (s, C4), 34.7 (d, 3JPC 4.1 Hz, C3), 55.3 (d, 2JPC 1.8 Hz,
C2), 98.8 (d, 2JPC 7.8 Hz, C6), 127.8 (d, 3JPC 10.8 Hz, C9), 128.4 (d,
4
3
(S)-P-(2-azidophenyl)-N-((S)-3,3-dimethylbutan-2-yl)-P-phenyl-
phosphinic amide, 24: Yield after chromatography (50%
AcOEt:Hexanes): 89%. Brown oil. [α]D -45.1 (c 0.5, CH2Cl2). H
20
1
3JPC 13.2 Hz, C13), 131.5 (d, JPC 10.8 Hz, C12), 131.8 (d, JPC 3.0
2
4
NMR (CDCl3) δ 0.88 (s, 9H, H4), 1.21 (m, 3H, H2´), 3.22 (m, 2H,
3
4
H1+H2), 7.20 (ddd, 1H, JHH 8.1, 4JPH 5.1, JHH 1.0 Hz, H7), 7.27
4
1
Hz, C14), 132.6 (d, JPC 2.4 Hz, C8), 133.6 (d, JPC 129.3 Hz, C11),
136.0 (d, JPC 7.8 Hz, C10), 137.2 (d, JPC 126.7 Hz, C5), 140.9 (d,
3
3
4
2
1
(tdd, 1H, JHH 7.6 Hz, JPH 2.0 Hz, JHH 1.0 Hz, H9), 7.44 (m, 3H,
10 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 11 of 15
Journal Name
Dalton Transactions
ARTICLE
3
4
4
3
ppm. 13C NMR (CDCl3) δ 18.8 (d, JPC 2.8 Hz, C2´), 26.5 (s, C4),
H13+H14), 7.53 (tdd, 1H, JHH 7.5 Hz, JHH 1.6 Hz, JPH 1.0 Hz,
H8), 7.79 (m, 2H, H12), 8.07 (ddd, 1H, JPH 13.2, 3JHH 7.6, JHH 1.6
3
4
34.8 (d, 3JPC 5.5 Hz, C3), 38.2 (d, 3JPC 3.8 Hz, C15), 56.0 (d, 2JPC 2.4
Hz, H10) ppm. 13C NMR (CDCl3) δ 19.2 (d, JPC 2.4 Hz, C2´), 26.3 Hz, C2), 116.0 (s, C17), 125.6 (d, JPC 12.5 Hz, C9), 128.3 (d, JPC
3
3
3
View Article Online
(s, C4), 34.6 (d, 3JPC 4.8 Hz, C3), 55.1 (d, 2JPC 1.6 Hz, C2), 118.3 (d, 12.5 Hz, C13), 131.1 (d, JPC 11.6 Hz, C7),D1O31I:.120.(1d0,3 JPC 125.8 Hz,
3
1
9/C5DT02860D
3
1
4
4
3JPC 7.9 Hz, C7), 124.9 (d, JPC 11.4 Hz, C9), 125.0 (d, JPC 121.5 C5), 131.5 (d, JPC 2.8 Hz, C14), 131.6 (d, JPC 2.7 Hz, C8), 132.2
3
2
2
2
1
Hz, C5), 128.2 (d, JPC 13.1 Hz, C13), 131.4 (d, JPC 10.6 Hz, C12), (d, JPC 9.7 Hz, C12), 133.0 (d, JPC 10.6 Hz, C10), 134.2 (d, JPC
131.5 (d, 4JPC 3.0 Hz, C14), 133.0 (d, 4JPC 2.4 Hz, C8), 134.8 (d, 2JPC 126.1 Hz, C11), 137.6 (d, JPC 0.7 Hz, C16), 144.1 (d, JPC 9.8 Hz,
4
2
1
2
C6) ppm. 31P NMR (CDCl3) δ 25.6 ppm. IR (ATR, υ cm-1): 3261
6.5 Hz, C10), 135.0 (d, JPC 130.0 Hz, C11), 140.5 (d, JPC 4.1 Hz,
C6) ppm. 31P NMR (CDCl3) δ 23.00 ppm. IR (ATR, υ cm-1): 3246 (bs, NH),, 1182 (s, P=O). HRMS (ESI) calcd for C21H29PNO:
(bs, NH), 2126 (s, N=N), 2094 (s, N=N), 1189 (s, P=O). HRMS 342.1987 (MH)+, found: 342.1986.
(ESI) calcd for C18H24PN4O: 343.1688 (MH)+, found: 343.1684.
tert-butyl
2-((S)-(((S)-3,3-dimethylbutan-2-yl)amino)(phenyl)-
phosphoryl)benzoate, 28: Yield after chromatography (20%
(S)-N-((S)-3,3-dimethylbutan-2-yl)-P-(2-hydroxyphenyl)-P-
phenylphosphinic amide, 25: Yield after chromatography (50% AcOEt:Hexanes): 60%. White solid. Mp: 126-127 ºC. [α]D20 -37.5 (c
20
1
AcOEt:Hexanes): 66%. White solid. Mp: 139-141 ºC. [α]D +38.1
0.3, CH2Cl2). H NMR (CDCl3) δ 0.77 (s, 9H, H17), 1.24 (s, 9H,
1
3
3
3
(c 0.5, CH2Cl2). H NMR δ (CDCl3) 0.92 (s, 9H, H4), 1.31 (m, 3H, H4), 1.34 (d, 3H, JHH 6.7 Hz, H2´), 3.53 (tc, 1H, JPH = JHH 10.7,
H2´), 2.94 (m, 2H, H1+H2), 6.83 (dddd, 1H, JHH 7.7, 3JHH 7.3, 4JPH 3JHH 6.8 Hz, H2), 4.11 (dd, 1H, JPH 12.1, JHH 10.7 Hz, H1), 7.33
2.9, 4JHH 1.0 Hz, H9), 6.91 (ddd, 1H, 3JHH 8.4, 4JPH 5.3, 4JHH 1.2 Hz, (m, 2H, H13), 7.39 (m, 1H, H14), 7.56 (m, 1H, H8), 7.59 (m, 2H,
H7), 7.36 (dddd, 1H, 3JHH 8.5, 3JHH 7.3, 4JHH 1.8, 4JPH 1.3, H8), 7.41 H12), 7.69 (ddt, 1H, 3JHH 7.7 Hz, 4JPH 1.6 Hz, 4JHH 1.6 Hz, H9), 7.83
(m, 1H, H10), 7.50 (m, 2H, H13), 7.55 (m, 1H, H14), 7.96 (m, 2H, (ddd, 1H, 3JHH 7.9 Hz, 4JPH 4.6 Hz, 4JHH 1.2 Hz, H7), 8.55 (ddd, 1H,
3
2
3
3JPH 12.6 Hz, JHH 7.6 Hz, JHH 1.2 Hz, H10) ppm. 13C NMR
3
4
3
H12) ppm. 13C NMR δ (CDCl3) 19.4 (d, JPC 1.4 Hz, C2´), 26.4 (s,
C4), 34.8 (d, JPC 7.8 Hz, C3), 56.6 (d, JPC 2.7 Hz, C2), 110.9 (d, (CDCl3) δ 19.9 (d, 3JPC 3.3 Hz, C2´), 26.4 (s, C17), 27.6 (s, C4), 34.6
3
2
1JPC 131.6 Hz, C5), 118.0 (d, JPC 9.5 Hz, C7), 118.8 (d, JPC 12.1 (d, JPC 3.6 Hz, C3), 54.0 (d, JPC 1.6 Hz, C2), 82.0 (s, C16), 127.8
3
3
3
2
Hz, C9), 128.7 (d, JPC 12.6 Hz, C13), 131.7 (d, JPC 9.6 Hz, C12), (d, 3JPC 13.6 Hz, C13), 130.1 (d, 3JPC 9.1 Hz, C7), 130.3 (d, 2JPC 11.3
3
2
132.3 (d, 4JPC 2.9 Hz, C14), 132.4 (d, 1JPC 130.9 Hz, C11), 132.5 (d, Hz, C12), 130.6 (d, JPC 2.0 Hz, C8/C14), 130.7 (d, JPC 2.5 Hz,
4
4
2JPC 7.7 Hz, C10), 134.4 (d, JPC 2.4 Hz, C8), 164.0 (d, JPC 5.4 Hz, C14/C8), 131.4 (d, JPC 10.9 Hz, C9), 134.0 (d, JPC 7.2 Hz, C6),
4
2
3
2
2
1
C6) ppm. 31P NMR δ (CDCl3): 32.2 ppm. IR (ATR, υ cm-1): 3358
(bs, NH) 1158 (bs, P=O). HRMS (ESI) calcd for C18H25NO2P:
318.1623 (MH)+, found: 318.1626.
134.3 (d, JPC 6.2 Hz, C10), 136.1 (d, JPC 113.6 Hz, C5), 136.9 (d,
1JPC 132.8 Hz, C11), 166.6 (d, JPC 3.0 Hz, C15) ppm. 31P NMR
3
(CDCl3) δ 27.6 ppm. IR (ATR, υ cm-1): 3403 (bs, NH), 1703 (s,
C=O), 1169 (s, P=O). HRMS (ESI) calcd for C23H33PNO3: 402.2198
(MH)+, found: 402.2195.
(S)-N-((S)-3,3-dimethylbutan-2-yl)-P-(2-(diphenylphosphoryl)-
phenyl)-P-phenylphosphinic
amide,
26:
Yield
after
chromatography (80% AcOEt:Hexanes): 93%. White solid. Mp: (S)-Methyl (2-iodophenyl)(phenyl)phosphinate, 29: Phosphinic
20
1
amide 20 (70 mg; 0.16 mmol) was dissolved into a solution of HCl
in methanol (0.64 mL; 1.25 M, 0.8 mmol). The reaction was stirred
for 48 h at room temperature. Then, methylene chloride (5 mL) was
added and the reaction mixture was washed with 1 M NaOH (3x5
mL). The organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuo. See ESI for the numbering scheme used.
Yield after chromatography (50% AcOEt:Hexanes): 75%. Colorless
oil. [α]D20 +3.8 (c 0.4, CH2Cl2). 1H NMR δ (CDCl3) 3.81 (d, 3H, 3JPH
189-191 ºC. [α]D -118.8 (c 0.6, CH2Cl2). H NMR δ (CDCl3) 0.83
(s, 9H, H4), 1.34 (d, 3H, 3JHH 6.7 Hz, H2´), 3.51 (tc, 1H, 3JPH = 3JHH
10.7, JHH 6.7 Hz, H2), 5.83 (dd, 1H, 2JPH 12.2, JHH 10.7 Hz, H1),
3
3
7.00 (m, 5HAr), 7.21 (m, 3HAr), 7.44 (m, 9HAr), 7.72 (m, 1H, H8),
8.84 (m, 1H, H7) ppm. 13C NMR δ (CDCl3) 19.8 (d, JPC 3.2 Hz,
3
3
2
C2´), 26.6 (s, C4), 34.8 (d, JPC 4.0 Hz, C3), 54.2 (d, JPC 1.8 Hz,
C2), 127.1 (d, 3JPC 13.5 Hz, CH), 128.2 (d, 3JPC 12.4 Hz, CH), 128.5
3
3
4
(d, JPC 12.3 Hz, CH), 129.6 (dd, JPC 12.7, JPC 2.6 Hz, CH), 130.4
3
4
5
1
4
2
11.3 Hz, H1), 7.22 (tdd, 1H, JHH 7.6, JHH 1.8, JPH 1.2 Hz, H8),
(d, JPC 105.8 Hz, C), 130.7 (d, JPC 2.9 Hz, CH), 131.0 (d, JPC 9.6
Hz, CH), 131.0 (d, 2JPC 11.3 Hz, CH), 131.3 (dd, 3JPC 10.3, 4JPC 3.1
Hz, CH), 131.3 (d, 4JPC 3.0 Hz, CH), 131.6 (dd, 1JPC 100.3, 2JPC 10.8
Hz, C), 131.7 (d, 2JPC 9.9 Hz, CH), 132.0 (d, 4JPC 2.7 Hz, CH), 133.9
3
4
4
7.47 (m, 2H, H13), 7.51 (tdd, 1H, JHH 7.6, JPH 2.5, JHH 1.2 Hz,
H9), 7.57 (m, 1H, H14), 7.82 (m, 2H, H12), 7.99 (ddd, 1H, 3JHH 7.6,
4JPH 4.1, 4JHH 1.2 Hz, H7), 8.10 (ddd, 1H, 3JPH 12.1 Hz, 3JHH 7.6 Hz,
(d, 1JPC 106.0 Hz, C), 134.6 (dd, 2JPC 13.9, 3JPC 10.5 Hz, CH), 135.2 4JHH 1.2 Hz, H10) ppm. 13C NMR δ (CDCl3) 51.6 (d, JPC 6.0 Hz,
2
(dd, JPC 10.8, JPC 6.7 Hz, CH), 136.3 (d, JPC 130.0 Hz, C), 141.7 C1), 98.0 (d, 2JPC 8.3 Hz, C6), 127.7 (d, 3JPC 11.3 Hz, C9), 128.4 (d,
2
3
1
3JPC 13.7 Hz, C13), 129.9 (d, 1JPC 141.9 Hz, C11), 132.3 (d, 4JPC 4.2
(dd, JPC 111.5 Hz, JPC 9.5 Hz, C) ppm. 31P NMR δ (CDCl3): 26.5
1
2
2
4
3
3
Hz, C14), 132.4 (d, JPC 10.7 Hz, C12), 133.5 (d, JPC 3.0 Hz, C8),
(d, JPP 11.2 Hz, PON), 33.2 (d, JPP 11.2 Hz, P=O) ppm. IR (ATR,
υ cm-1): 3283 (bs, NH), 1185 (bs, NP=O), 1118 (w, P=O). HRMS
(ESI) calcd for C30H34NO2P2: 502.2065 (MH)+, found: 502.2068.
1
2
134.5 (d, JPC 138.3 Hz, C5), 135.9 (d, JPC 8.3 Hz, C10), 141.8 (d,
3JPC 11.3 Hz, C7) ppm. 31P NMR δ (CDCl3): 33.2 ppm. IR (ATR, υ
cm-1): 1225 (bs, P=O), 1033 (bs, C-O). HRMS (ESI) calcd for
C13H13IO2P: 358.9698 (MH)+, found: 358.9699.
(S)-P-(2-allylphenyl)-N-((S)-3,3-dimethylbutan-2-yl)-P-phenyl-
phosphinic amide, 27: Yield after chromatography (50%
20
(R)-(2-chlorophenyl)(2-(((S)-3,3-dimethylbutan-2-yl)amino)-
phenyl)(phenyl)phosphine oxide, 32: To a cooled mixture at -78 ºC
of potassium floride (30 mg, 0.6 mmol), 18-crown-6 (133 mg, 0.6
AcOEt:Hexanes): 70%. White solid. Mp: 128-129 ºC. [α]D +108.9
1
(c 1.1, CH2Cl2). H NMR (CDCl3) δ 0.91 (s, 9H, H4), 1.12 (d, 3H,
JHH 6.6 Hz, H2´), 2.66 (dd, 1H, JHH 10.2 Hz, JPH 9.4 Hz, H1), 3.03
(ddc, 1H, JPH 9.2, JHH 10.2, JHH 6.5 Hz, H2), 3.84 (m, 2H, H15),
n
3
3
3
mmol) and 22 (40 mg, 0.12 mmol) in THF, a solution of BuLi (1.6
3
2
4
M in hexanes, 0.11 mL, 0.144 mmol) was added and the reaction
was allowed to reach room temperature. Then, 2-
(trimethylsilyl)phenyl trifluoromethanesulfonate (0.09 mL, 0.42
mmol) was added and the solution was heated to reflux and stirred
for 16 h. After this time, the reaction was cooled to room
temperature, poured into water, extracted with methylene dichloride
4.91 (dc, 1H, JHH 17.0, JHH = JHH 1.6 Hz, H17trans), 4.99 (dc, 1H,
3JHH 10.3, 2JHH = 4JHH 1.7 Hz, H17cis), 5.88 (ddt, 1H, 3JHH 17.0, 3JHH
3
3
4
10.3, JHH 6.4 Hz, H16), 7.23 (tdd, 1H, JHH 7.6 Hz, JPH 2.6 Hz,
4JHH 1.4 Hz, H9), 7.28 (m, 1H, H7), 7.44 (tt, JHH 7.6 Hz, JPH =,
4JHH 1.4 Hz, H8), 7.46 (m, 2H, H13), 7.52 (m, 1H, H14), 7.73 (ddd,
1H, 4JPH 13.5 Hz, 3JHH 7.6 Hz, 4JHH 1.4 Hz, H10), 7.83 (m, 2H, H12)
3
5
This journal is © The Royal Society of Chemistry 2012
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Dalton Transactions
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Journal Name
ARTICLE
(3x5 mL), dried over anhydrous sodium sulfate and concentrated in
vacuo. See ESI for the numbering scheme used. Yield after
Notes and references
20
View Article Online
DOI: 10.1039/C5DT02860D
chromatography (50% AcOEt:Hexanes): 48%. Colorless oil. [α]D
1
a
+22.89 (c 0.8, CH2Cl2). H NMR (CDCl3) δ 0.82 (s, 9H, H4), 1.05
Área de Química Orgánica, Universidad de Almería, Carretera de
3
3
3
(d, 3H, JHH 6.6 Hz, H2´), 3.24 (dc, 1H, JHH 8.8, JHH 6.6 Hz, H2),
Sacramento s/n, 04120 Almería, Spain.
6.49 (dddd, 1H, JH4H 7.8, JHH 7.3, 4JPH 2.8, 4JHH 1.0 Hz, H8), 6.72
(dd, 1H, 3JHH 8.4, JPH 5.4 Hz, H10), 6.85 (m, 1H, H7), 6.87 (d, 1H,
4JPH 8.7 Hz, H1), 7.27 (m, 1H, H15), 7.33 (m, 1H, H9), 7.40 (m, 1H,
H16), 7.49 (m, 4H, H13+H14+H19), 7.56 (m, 1H, H20), 7.71 (m,
2H, H18) ppm. 13C NMR (CDCl3) δ 15.2 (d, C2´), 26.3 (s, C4), 34.7
(d, C3), 56.5 (d, C2), 110.0 (d, 1JPC 110.3 Hz, C6), 111.0 (d, 3JPC 8.3
3
3
b
Instituto de Ciências Exatas, Departamento de Química, Universidade
Federal Rural do Rio de Janeiro, 23870-000 Seropédica, RJ, Brazil.
†
Electronic Supplementary Information (ESI) available: NMR spectra
of the reported compounds, computed pathway for the reaction between
benzyne and
intermediate
N
-lithiated 22, IRC analysis of the conversion of TS1 into
3
3
Hz, C10), 114.0 (d, JPC 13.7 Hz, C8), 126.4 (d, JPC 10.7 Hz, C15),
128.4 (d, JPC 12.5 Hz, C19), 131.2 (d, JPC 103.1 Hz, C11/C17),
E
, Cartesian coordinates of all computed structures and
3
1
ORTEP diagrams of 19, 19’, 20 and 34 are available in the ESI. CCDCs
3
4
131.3 (d, JPC 6.6 Hz, C13), 131.9 (d, JPC 3.0 Hz, C20), 132.0 (d,
1406955-1406957 and 1409186. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/b000000x/
1JPC 107.3 Hz, C17/C11), 132.2 (d, JPC 9.5 Hz, C18), 133.2 (d, 4JPC
2
2.4 Hz, C14), 133.5 (d, 2JPC 11.9 Hz, C7), 133.7 (d, 4JPC 1.8 Hz, C9),
2
2
135.2 (d, JPC 10.1 Hz, C16), 138.4 (d, JPC 3.6 Hz, C12), 153.2 (d,
2JPC 4.8 Hz, C5) ppm. 31P NMR (CDCl3) δ 36.1 ppm. IR (ATR, υ
cm-1): 3314 (bs, NH), 1175 (m, P=O), HRMS (ESI) calcd for
C24H28ClNOP: 412.1597 (MH)+, found: 412.1599.
Procedure for the synthesis of complex 34. To a solution of
26 (0.10 mmol, 50 mg) in
5
mL of
a
mixture
methylenedichloride:acetonitrile (1:1), 0.10 mmol of ZnCl2 (0.1
mL of a 1.0 M solution in diethyl ether) were added and the
reaction was stirred at room temperature overnight. Then,
methylenedichloride was added to dissolve the precipitate
formed completely and the solution was filtered. Crystals
suitable for X-ray analysis were obtained through slow vapour
diffusion of diethyl ether into a solution containing the complex
in methylenedichloride:acetonitrile. See ESI for the numbering
scheme used.
1
(a) S. E. Denmark and J. Fu, Chem. Rev., 2003, 103, 2763-2793; (b)
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2264; (k) Z. Yang, C. Xia, D. Liu, Y. Liu, M. Sugiya, T. Imamoto and
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Yield after recrystallization: 85%. White solid. Mp: 278-280
ºC (dec.). [α]D20 -2.32 (c 0.6, CH2Cl2). 1H NMR
δ
(CDCl3) 0.91
3
4
(s, 9H, H4), 1.08 (dd, 3H, JHH 6.7, JHH 0.8 Hz, H2´), 2.46 (tc,
3
1H, 3JPH
=
3JHH 11.0, JHH 6.7 Hz, H2), 3.76 (d, 1H, 3JHH 11.0
Hz, H1), 7.07 (m, 2HAr), 7.15 (m, 2HAr), 7.22 (m, 2HAr), 7.30
(m, 1H, H7), 7.33 (m, 3HAr), 7.45 (m, 1HAr), 7.50 (m, 2HAr),
3
4
7.61 (m, 2H, H8), 7.67 (m, 2HAr), 7.88 (tc, 1H, JHH 7.6, JHH
2
1.8 Hz, H9), 8.46 (m, 1H, H10) ppm. 13C NMR
δ
(CDCl3) 18.9
3
3
(d, JPC 7.5 Hz, C2´), 26.5 (s, C4), 34.7 (d, JPC 1.8 Hz, C3),
59.0 (d, 2JPC 2.7 Hz, C2), 126.6 (d, 1JPC 139.0 Hz, C), 128.3 (d,
3
1
3JPC 13.4 Hz, Cm), 128.6 (d, JPC 13.4 Hz, Cm), 128.7 (d, JPC
3
1
117.0 Hz, C), 128.9 (d, JPC 12.3 Hz, Cm), 129.0 (d, JPC 107.2
2
2
Hz, C), 131.0 (d, JPC 10.9 Hz, Co), 131.6 (d, JPC 9.8 Hz, Co),
132.1 (d, JPC 3.1 Hz, Cp), 132.2 (m, C9/C8) 132.3 (d, JPC 3.0
4
4
Hz, Cp), 132.8 (m, C8/C9), 132.9 (d, 2JPC 9.8 Hz, Co), 132.9 (d,
4JPC 2.8 Hz, Cp), 134.4 (dd, JPC 98.6, JPC 12.4 Hz, C), 136.4
1
2
(dd, 1JPC 132.8, 2JPC 8.6 Hz, C), 137.0 (m, C10/C7), 137.1 (m,
C7/C10) ppm. 31P NMR
δ
(CDCl3): 32.6 (d, 3
J
PP 7.5 Hz, PON),
3
42.5 (d, JPP 7.5 Hz, P=O) ppm. IR (KBr,
υ
cm-1): 3558 (bs,
NH), 1166 (bs, P=O). HRMS (ESI) calcd for
C30H34NO2P2ZnCl2: 636,0733 (MH)+, found: 502.2059,
corresponds to [MH]+ of the ligand 26
.
3
4
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Acknowledgements
We thank the MICINN and FEDER program for financial
support (projects: CTQ2011-27705 and CTQ2014-5715P).
The authors would like to thank the Centro de
Supercomputación of the University of Granada (UGRGRID,
Spain) for allocating computational time.
Recent examples: (a) K. Nikitin, K. V. Rajendran, H. Müller-Bunz and
D. G. Gilheany, Angew. Chem., Int. Ed., 2014, 53, 1906−1909; (b) S.
12 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C5DT02860D
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Graphical abstracts
Manuscript ID DT-ART-07-2015-002860R1
DOI: 10.1039/C5DT02860D
Synthesis of P-stereogenic diarylphosphinic amides by
directed lithiation. Stereospecific transformation into tertiary
phosphine oxides via methanolysis, aryne chemistry and
complexation behaviour toward zinc(II)
Miguel A. del Águila-Sánchez,a Yolanda Navarro,a Jesús García López,a Guilherme P. Guedesb
and Fernando López Ortiz*a
aÁrea de Química Orgánica, Universidad de Almería, Carretera de Sacramento s/n, 04120, Almería, Spain.
E-mail: flortiz@ual.es
b Instituto de Ciências Exatas, Departamento de Química, Universidade Federal Rural do Rio de Janeiro, 23870-000
Seropédica, RJ, Brazil
Submitted for publication in Dalton Transactions themed issue: Phosphorus Chemistry:
Discoveries and Advances as an article.
Graphical Content Entry
A general synthesis of P-stereogenic compounds via directed ortho lithiation-electrophilic quench of phosphinic
amides and subsequent derivatizations is reported