Derivatization of (quinolin-8-yl)phosphinimidic amides via ortho-lithiation revisited

Article abstract of DOI:10.1039/c5dt01392e

The direct ortho-lithiation of N-H containing (quinolin-8-yl)phosphinimidic amides by reaction with 1 equiv. of n-BuLi described by Wang and co-workers has been re-examined. The multinuclear magnetic resonance (¹H, ²H, ⁷Li

Full text of DOI:10.1039/c5dt01392e

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Derivatization of (quinolinꢀ8ꢀyl)phosphinimidic
amides via orthoꢀlithiation revisited†
Cite this: DOI: 10.1039/x0xx00000x
Nerea Fernández Sáez,a Jesús García López,a María José Iglesiasa and Fernando
López Ortiz*a
Received 00th January 2015,
Accepted 00th xxxxxxx 2015
The direct orthoꢀlithiation of NꢀH containing (quinolinꢀ8ꢀyl)phosphinimidic amides by reaction
with 1 equiv of
examined. The multinuclear magnetic resonance (1H, H, Li, 13C, 15N and 31P) study of the
species formed in the monolithiation of ꢀ(tertꢀbutyl)ꢀP,PꢀdiphenylꢀN'ꢀ(quinolinꢀ8ꢀ
yl)phosphinimidic amide with ꢀBuLi in THF showed that proton abstraction occurred
exclusively and quantitatively at the NH. The combination of the NMR results with a DFT
study made it possible to describe the structure of the Nꢀlithiated species as a dimer
nꢀBuLi described by Wang and coꢀworkers (see reference 12) has been reꢀ
2
7
DOI: 10.1039/x0xx00000x
N
www.rsc.org/
5
n
9
consisting of an eightꢀmembered ring showing two lithium ions triply coordinated to nitrogen
atoms corresponding to the deprotonated amine and aminoquinoline moieties of different
monomers. The formation of a polymer featuring the same coordination mode coudn’t be
excluded. In addition, optimized conditions for the efficient derivatization of
lithiation were found. The reaction of with 2.4 equiv of ꢀBuLi in THF in the temperature
range ˗80 ºC to 25 ºC for 3 h afforded a N,Corthoꢀdilithiated species that was trapped with a
series of electrophiles leading to new functionalized ortho derivatives of in good yields.
5 via orthoꢀ
5
t
5
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characterized based on its elemental analysis and NMR
Introduction
spectroscopy data. Apparently, the C/H/N analyses of
6 are in
agreement with its expected elemental composition. Moreover,
Directed orthoꢀlithiation (DoLi) is a valuable synthetic method
for the derivatization of aromatic rings. It is based on the ability
of a polar group, commonly known as the directing metallation
group (DMG), for increasing the acidity of the ortho protons
and approaching an organolithium base to that position
facilitating thus the selective deprotonation. Subsequent
electrophilic quench provides the orthoꢀsubstituted products
generally in high yields.1 A large variety of Cꢀbased and
heteroatomꢀbased DMGs have been reported.1,2 The application
of this strategy to phosphorusꢀcontaining systems represents a
very efficient route to the synthesis of orthoꢀfunctionalized
derivatives.3 In addition, the orthoꢀlithiated species can be used
as chelating ligands for the construction of complexes of other
mainꢀgroup, transition metals and fꢀblock elements via
metathetical reactions with metal halides.4
the 1H NMR spectrum measured in benzeneꢀd6 showed a
doublet at
δ
3.56 ppm (2JPH 6.3 Hz) assigned to the NH signal.
Surprisingly, the 13C NMR spectrum did not show any of the
characteristic signals found in orthoꢀlithiated Ph2P=X (X= O,
N) moieties.13 Particularly striking are the apparent absence of
the doublets corresponding to the two ipso carbons linked to
1
phosphorus of JPC > 80 Hz and the signal for the lithiated
carbon for which one would expect a chemical shift of ca 200
ppm.4d,13,14 In contrast to these foreseeable structural features,
the 13C NMR spectrum of
6 contains only two doublets of 2.2
Hz and 8.3 Hz that are appropriate for 31P, 13C scalar couplings
transmitted through 4 and 2 bonds, respectively, and the most
deshielded signal appears as a singlet at
Due to the discrepancies between the ortho deprotonation of
the structurally similar phosphinimidic amides and we
decided to reinvestigate the DoLi reaction of . The results of
this study are reported here. They showed that orthoꢀlithiation
of proceeds in a similar manner to phosphinimidic amide
δ 144.17 ppm.
1
5
Functional groups bearing acidic protons may also act as
efficient DMGs.5,6 These include phosphinic acids7 and
phosphinic amides.8 As can be expected, in these cases the first
step of the process is the deprotonation of the DMG, i.e., the
orthoꢀlithiation is directed by a lithiated functional group.
5
5
1,
that is, NꢀH abstraction by one equivalent of the organolithium
base originates a Nꢀlithiated species that is subsequently
lithiated at the ortho position with respect to the phosphorus by
a second equivalent of base. The structure of the Nꢀlithium
derivative has been elucidated using multinuclear magnetic
resonance spectroscopic methods and DFT calculations. In
Recently, we have shown that phosphinimidic amides
undergo orthoꢀlithiation with excellent diastereoselectivity by
treatment with 3 equivalents of ꢀBuLi at ˗90 ºC in THF for 15
h (Scheme 1).9 After electrophilic quench Pꢀchiral orthoꢀ
functionalized derivatives are obtained in high yield and
1
t
4
addition, a procedure for the orthoꢀlithiation of
5 similar to that
optical purity. These primary products can be readily converted
into a variety of Pꢀstereogenic compounds via functional group
transformations.10 The study of the mechanism of this lithiation
reported for ( )ꢀ is described. Electrophilic trapping of the
R
1
orthoꢀanion furnished orthoꢀfunctionalized products in high
yield via carbonꢀcarbon and carbonꢀheteroatom bond forming
reactions.
revealed that monoꢀ deprotonation of
intermediate which exist in a conformation that favours the
almost exclusive DoLi reaction of the proꢀS Pꢀphenyl ring to
give the N,Cortho dianion 3 11
1 afforded the Nꢀlithiated
2
.
Me
Me
4
O
O
CO2Me
N
(THF)m
3
1) tBuLi,
THF
N
P
2) tBuLi,
THF
2 N
O
Li
O
Ph2P
Ph
NH
Ph
Ph
Li
(THF)n
P
1
Li
(THF)2
5
N
N
ꢀ90 ºC
ꢀ90 ºC,
15 h
Me
7
Ph
Me
(R)ꢀ1
6
Ph
Me
H
H
Scheme 2 Cortho lithiation of phosphinimidic amide 5.
(R)ꢀ2
(SP,RC)ꢀ3
3) E+
CO2Me
Results and discussion
N
E
Ph
P
NH
Ph
E = Me, Allyl, Ph2P(O), I,
Br, N3, Me3Sn,Me3Si,
Monolithiation of (quinolinꢀ8ꢀyl)phosphinimidic amide 5
Phosphinimidic amide was prepared according to the the
(SP,RC)ꢀ4
dr 95:5
Me
5
method of Wang et al.12 through the Staudinger reaction
between and 8ꢀ
tertꢀbutylꢀ1,1ꢀdiphenylphosphanamine15
azidoquinoline16
in CH2Cl2 at room temperature for 4 hours
(Scheme 3). Solvent evaporation followed by precipitation from
Scheme 1 Cortho lithiation of phosphinimidic amide (R)ꢀ1.
N
ꢀ
7
8
These results are in sharp contrast with those reported by
Wang and coꢀworkers on the monolithiation of (quinolinꢀ8ꢀ
a mixture of CH2Cl2:hexane in a ratio of 1:2 afforded
yield of 82%.
5 in a
yl)phosphinimidic amide 5 12
.
According to these authors, the
with one equivalent of ꢀBuLi in THF provides
exclusively the orthoꢀlithiated derivative (Scheme 2).
Compound was described as a yellow solid that was
reaction of
5
n
Once available, compound
5 was monodeprotonated under
6
the reaction conditions described by Wang and coꢀworkers.
6
Thus, a solution of
5
in THF at ˗80 ºC was treated with 1.1
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DOI: 10.1039/C5DT01392E
equiv of nꢀBuLi, and the reaction mixture was allowed to reach
room temperature and stirred overnight. In order to identify the
site of the deprotonation, the reaction was quenched with
1
CD3OD. After aqueous workup, the H NMR spectrum of the
crude mixture proved to be identical to that of the starting
material. The recovery of nonꢀdeuterated
5 implies that orthoꢀ
deprotonation has not taken place. The aqueous workup of the
reaction would not affect a carbonꢀdeuterium bond. However,
D/H exchange could restore the NꢀH bond of
5. Rapid D/H
exchange in
5
was confirmed by measuring the 1H NMR
Scheme 4 Nꢀlithiation of phosphinimidic amide
numbering scheme used.
5 to give 9 and
spectrum of a sample of the compound in CDCl3 after the
addition of a drop of CD3OD. As expected, the NH signal
disappeared in agreement with the results of the lithiationꢀ
deuteration reaction.
The unequivocal demonstration of the Nꢀlithiated structure
of
9
was obtained through the analysis of the 15N data of
1
compounds
5
and
9
arising from their H,15N HMQC spectra
(Fig. 1). The nitrogen atoms of the [N˗P˗NH] backbone of
5
were identified based on the correlations observed for the NH
and the methyl protons with a signal at δ ˗297.1 ppm (N11) and
the correlation detected at δ ˗289.5 ppm between N18 and the
neighboring proton H8 of the quinoline heterocycle. The
nitrogen N1 showed three correlations with H2, H3 and H8 at δ
ꢀ70.2 ppm (Fig. 1a). The analogous spectrum of species
revealed that N1 (δ ˗96.1 ppm) underwent a significant
9
Scheme 3 Synthesis of phosphinimidic amide 5.
shielding of ꢀδ5 – 9 = ˗25.9 ppm, whereas N11 (δ ˗300 ppm) is
shielded by only ˗2.9 ppm. The apparent insensitivity of the 15
N
In order to ascertain unequivocally the site of
monodeprotonation of we carried out a NMR study of two
monolithiated samples of concentration 0.42 M and 75 mM
prepared by treating a solution of in THFꢀd6 with 1.1
equivalents of ꢀbutyllithium (1.6 M solution in hexanes) at ˗60
5
chemical shift of N11 to the deprotonation is in agreement with
the analogous observation for the lithiated nitrogen of complex
(R . Unfortunately, no correlations were found for N18
)ꢀ2 11
1
5
neither in the H,15Nꢀ nor the 31P,15N{1H} HMQC spectra of
9 18
n
ºC. The 1H, 7Li and 31P{1H} NMR spectra acquired in the
temperature range of ˗110 ºC to 25 ºC showed that the anion
was quite stable (Figs S12). The sample remained unaltered
when stored in the refrigerator at ca. 4 ºC for 20 h and only a
2% of the neutral compound was detected when the sample was
left standing at room temperature for 5 h (Fig S13).
.
These results, together with the fact that the known Xꢀray
crystal structures of monolithiated phosphinimidic amides19
consist of a fourꢀmembered metallacycle formed by N,N
chelation of the lithium cation, suggest that the anionic system
of is acting as a N,N,Nꢀtridentate ligand toward the lithium
ꢀ
9
The lithiated species
analysis of the NMR spectra measured at ˗40 ºC. The 31P{1H}
NMR of the freshly prepared sample consisted of a singlet at
˗6.7 ppm together with a 3% of a byꢀproduct at 8.5 ppm (Fig
9 was characterized through the
ion. The NMR study indicates that this coordination mode is
7
highly favored. A single species is observed in the Liꢀ and 31P
δ
NMR spectra measured in the temperature range of 0 ºC to ˗100
ºC for both the concentrated and the highly diluted NMR
δ
S5). In this solvent, the 31P signal of
5 appears at δ 0.2 ppm. samples (Fig. S12).
Analogously, the 7Li NMR spectrum was dominated by a
singlet at δ 2.5 ppm (Fig S7). The H and 13C NMR spectra
1
revealed significant changes in the chemical shift of the
aromatic signals, especially those of the quinoline ring, as
compared with
5 (Figs S4, S6). The important point is that both
spectra showed that neither the heterocyclic system nor the
Ph2P moiety had been deprotonated. These data, together with
1
the absence of the NH signal in the H NMR spectrum of
9
indicate that the deprotonation of
5 occurred at the NH (Scheme
4).17 The 1H and 13C signals were assigned based on the
standard combination of 1D and 2D NMR spectra (Figs S8ꢀ
S10). The protons most affected by the Nꢀdeprotonation are H2
(
ꢀδ5 – 9 = ˗0.3 ppm), H6 (ꢀδ5 – 9 = 0.3 ppm) and H7 (ꢀδ5 – 9
0.36 ppm), whereas the largest changes in δC
nJPC occurred for
C6 (ꢀδ5 – 9 = 4.5 ppm), C8 (ꢀδ5 – 9 = 3.8 ppm/˗14.3 Hz) and C14
ꢀδ5 – 9 = ˗4.6 ppm/17.8 Hz). The deshielding of C14 promoted
by the abstraction of the NH proton of together with the
notable decrease of JPC are in agreement with those observed
for the Nꢀlithiation of (
)ꢀ1 11
=
/
(
5
1
R
.
Figure 1 1H,15N HMQC NMR spectra of a 75 mM sample in
THFꢀd8 of (a) compound measured at 25 ºC and (b) the Nꢀ
lithiated derivative measured at ˗40 ºC.
5
9
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