Ambident reactivity of P CH N heterocycles: Lithiation and substitution sites

Article abstract of DOI:10.1080/10426507.2010.514486

Benzofused 1H-1,3-azaphospholes are lithiated at the N-atom by tBuLi but phosphinylation takes place at either the N- or the P-atom. Smaller chlorophosphines react at nitrogen, bulkier react at phosphorus. Substituents at C2 promote the latter mode. N-Substituted 2H-1,3-benzazaphospholes undergo CH-metalation or addition at the P C bond, depending on the conditions, and allow access to 2-functionally substituted benzazaphospholes or their 2,3-dihydro derivatives, new σ²P,X or σ³P,X hybrid ligands (X=O,P). Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.514486

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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Ambident Reactivity of
P˭CH‒N‒Heterocycles: Lithiation and
Substitution Sites
Joachim Heinicke a , Bhaskar R. Aluri a , Basit Niaz a , Sebastian
Burck b , Dietrich Gudat b , Mark Niemeyer c , Oldamur Holloczki d
Laszlo Nyulaszi d & Peter G. Jones e
,
a Institut für Biochemie–Anorganische Chemie , Universität
Greifswald , Germany
b Institut für Anorganische Chemie , Universität Stuttgart , Germany
c Institut für Anorganische und Analytische Chemie , Universität
Mainz , Germany
d Department of Inorganic Chemistry , Technical University
Budapest , Hungary
e Institut für Anorganische und Analytische Chemie , Technische
Universität Braunschweig , Germany
Published online: 25 Apr 2011.
To cite this article: Joachim Heinicke , Bhaskar R. Aluri , Basit Niaz , Sebastian Burck , Dietrich
Gudat , Mark Niemeyer , Oldamur Holloczki , Laszlo Nyulaszi & Peter G. Jones (2011) Ambident
Reactivity of P˭CH‒N‒Heterocycles: Lithiation and Substitution Sites, Phosphorus, Sulfur, and Silicon
and the Related Elements, 186:4, 683-687, DOI: 10.1080/10426507.2010.514486
To link to this article: http://dx.doi.org/10.1080/10426507.2010.514486
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Phosphorus, Sulfur, and Silicon, 186:683–687, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.514486
AMBIDENT REACTIVITY OF P CH N HETEROCYCLES:
LITHIATION AND SUBSTITUTION SITES
Joachim Heinicke,1 Bhaskar R. Aluri,1 Basit Niaz,1
Sebastian Burck,2 Dietrich Gudat,2 Mark Niemeyer,3
Oldamur Holloczki,4 Laszlo Nyulaszi,4 and Peter G. Jones5
1Institut fu¨r Biochemie–Anorganische Chemie, Universita¨t Greifswald, Germany
2Institut fu¨r Anorganische Chemie, Universita¨t Stuttgart, Germany
3Institut fu¨r Anorganische und Analytische Chemie, Universita¨t Mainz, Germany
4Department of Inorganic Chemistry, Technical University Budapest, Hungary
5Institut fu¨r Anorganische und Analytische Chemie, Technische Universita¨t
Braunschweig, Germany
Abstract Benzofused 1H-1,3-azaphospholes are lithiated at the N-atom by tBuLi but phos-
phinylation takes place at either the N- or the P-atom. Smaller chlorophosphines react at ni-
trogen, bulkier react at phosphorus. Substituents at C2 promote the latter mode. N-Substituted
2H-1,3-benzazaphospholes undergo CH-metalation or addition at the P C bond, depending
on the conditions, and allow access to 2-functionally substituted benzazaphospholes or their
2,3-dihydro derivatives, new σ2P,X or σ3P,X hybrid ligands (X=O,P).
Keywords Ambident reactivity; hybrid ligands; lithiation; phosphinylation; phosphenes; phos-
phorus heterocycles
INTRODUCTION
Lithium 1,3-azaphospholides1 are cyclodelocalized five-membered anions that are
electronically related to cyclopentadienides,2 but the structure and reactivity, studied in par-
ticular with the easily accessible benzazaphospholides 13,4 or 2-lithiobenzazaphospholes
2,5 are modified and controlled by the heteroatoms. Lithiation of non- or benzo-anellated
1H-1,3-azaphospholes and arsenic analogues was achieved with LDA,1a,3 but later tBuLi
was preferred4,5 to avoid the formation of diisopropylamine, which may interfere in con-
secutive substitution reactions with electrophiles. It was found that the bulky tBuLi in
polar solvents at low temperature favors NH or (for N-alkyl or N-aryl derivatives) 2-CH-
lithiation to addition at the P C bond of benzazaphospholes, yielding the lithium reagent
1 or 2, respectively (Scheme 1). Recent work showed that bulky N-substituents hinder CH-
lithiation at the 2-position and cause competing addition at the P C bond. Polar systems
such as tetrahydrofuran (THF)/KOtBu were found to favor 2-CH lithiation and to suppress
Received 10 July 2010; accepted 3 August 2010.
Address correspondence to Professor Dr. J. Heinicke, Institut fu¨r Biochemie–Anorganische Chemie, Uni-
versita¨t Greifswald, Felix-Hausdorff-Str. 4, D-17487 Greifswald, Germany. E-mail: heinicke@uni-greifswald.de
683

684
J. HEINICKE ET AL.
(R = H)
tBuLi
(R = alkyl, aryl)
P
Li
N
tBuLi
R
THF
(–78 °C)
2
P
P
But
THF (KOtBu)
(–78 °C)
N
N
Li
.
.
R
tBuLi
pentane
P
H
1
(–78 °C)
Li
N
R
Li
3
.
.
P
But
+
H
N
R
4 (by-product)
Scheme 1 Lithiation of benzazaphospholes by tBuLi at N, C2, and P.
addition completely in the case of N-neopentyl groups, whereas less polar solvents such
as diethyl ether and in particular nonpolar solvents such as hexane were found to support
the addition. The “normal” addition product 3 with tert-butyl attached at phosphorus is
strongly preferred, but for N-neopentyl substitution small amounts of the “inverse” addi-
tion product 4 were also detected. For the bulkier N-adamantyl group inverse addition is
sterically prevented and only normal addition is observed (in hexane).5a,b
PHOSPHINYLATION OF AMBIDENT BENZAZAPHOSPHOLIDE 1
In the THF solvate of lithium 2,5-dimethyl-1,3-benzazaphospholide 1a the metal
is bonded to nitrogen but substitution reactions with alkyl halides, pivaloyl chloride, or
cyclopentadienylcarbonyl transition metal halides (CpW(CO)3Cl, CpFe(CO)2Cl) occur at
phosphorus. Chlorotrimethylsilane undergoes N- or P-substitution, depending on the 2-
substituent.4 Phosphinylation of benzazaphospholides had not been studied in the earlier
investigations. However, it was of interest with respect to the relative stabilities of N- and
P-substituted isomers and in view of the unusual properties of the P-P bonded 2-phospholyl-
1,3,2-diazaphospholes.6 The latter display bond lengthening and increased P-P bond ionic-
ity, implying a diazaphospholium phospholide resonance structure, and possess high reac-
tivity for insertion reactions into polar single and multiple bonds.7 The reaction of 1a with
2-chloro-1,3-dimesityl-1,3,2-diazaphosphole leads, however, to the N-substitution product
5. The same is observed in the reaction with chlorodicyclohexyl phosphine to 6, whereas
chloro-di-tert-butyl and chlorodiadamantyl phosphine react at phosphorus, yielding diphos-
phines 7 and 8 (Scheme 2). Quantum chemical calculations show that N-phosphinylation
for 2-unsubstituted benzazaphospholes is generally preferred.8 The aromaticity is main-
tained for N-substituted benzazaphospholes.9 However, substituents in the 2-position, even
when small (methyl), favor P-substitution in the case of bulkier phosphino groups by steric
reasons. Thus, the formation of aromatic N-(5,6) or nonaromatic P-substituted phosphino-
benzazaphospholes (7,8) depends on the size of the substituents in 2-position and at the

P
CH
N
HETEROCYCLES
685
PtBu2
Mes
N
PCl
P
P
N
N
P
Mes
tBu2PCl
N
Mes
N
7
N
Mes
P
_
5
N
1-Ada2PCl
Cy2PCl
Li+(solv)
1a
P(1-Ada)2
P
P
P
N
N
N
P
THF Li
Cy
Cy
Cy
Cy
P
Cl
(major)
(minor)
2
8
6
Scheme 2 Ambident reactivity in the phosphinylation of lithium dimethyl-1,3-benzazaphospholide 1a.
phosphino group. The barrier for rotation around the N-P bond is quite high for 6, which
displays sharp signals for two rotamers at 25◦C in the NMR spectra, confirmed by the
respective cross peaks in a 2D-EXSY spectrum. The two phosphorus resonances of the
diphosphines are broadened and indicate flexible molecules in solution. VT-NMR stud-
ies of 7 revealed two dynamic processes, low-temperature inversion at ring phosphorus
(ꢀH# = 22 kJ/mol, ꢀS# = 2 J/(K mol)) and very low-temperature rotation of the tBu2P
group.8
REACTIVITY OF 2-LITHIO-(DIHYDRO)-1,3-BENZAZAPHOSPHOLES 2 AND 3
2-Lithio-1,3-benzazaphospholes are relatively stable and could be crystallized for 2a
(R = Me) as Li(THF)2-solvates.5c 2-Lithio-3-tert-butyl-dihydro-1,3-benzazaphospholes 3
are highly reactive cyclic α-phosphino, α-amino sp3C-lithium reagents that rapidly depro-
tonate THF, and slowly deprotonate diethyl ether, but use of hexane allows substitution
reactions with electrophiles to give functionally substituted dihydrobenzazaphospholes; for
example, with CO2 the corresponding heterocyclic α-phosphinocarboxylic acids. Like 1,
the lithium reagents 2 and 3 possess each two nucleophilic sites, at carbon and phosphorus,
but electrophiles show a strong preference for reaction at carbon, as is typical for α-lithiated
phosphines. The introduction of functional groups such as COOH or R2P in 9–12 or of
SiMe3 groups in 13 and 14 illustrates the variety of new σ2P and σ3P hybrid ligands acces-
sible in this way, whereas the formation of 12 in THF shows limitations in the case of 3 by
rapid solvent deprotonation (Scheme 3).10
For RLi 2, reactions at phosphorus would result in cyclic phosphino-aminocarbenes
(PNHC) which, because of the threefold coordinated P-atom, would be incapable of cy-
clodelocalization and be much less stable than the isomeric, aromatically stabilized benza-
zaphospholes. Therefore, apart from the much lower nucleophilicity at σ2P, C-substitution
by electrophiles is also favored thermodynamically. However, because of the π-donor

686
J. HEINICKE ET AL.
But
.
.
P
P
COOH
H
COOH
N
N
R
R
CO2/Me3SiCl
MeOH
CO2/Me3SiCl
MeOH
(9a,b, R = Me, Np)
(10a,b, R = Np, 1-Ada)
But
But
P
.
.
P
R2PCl
P
P
THF
H
Li
PR'2
Li
CH2
N
R
N
R
N
R
N
R
Me3SiCl
(12a,b, R = Np, Ada)
(11a, R = Me, R′ = PPh2)
(11b, R = Np, R′ = PtBu2)
2
Me3SiCl
3
But
.
.
P
P
SiMe3
H
SiMe3
N
N
R
R
(13a,b, R = Me, Np)
(14, R = Np)
Scheme 3 Reactivity of 2 and 3 to some electrophiles.
properties of nitrogen, P-alkylation and even catalytic P-arylation are possible for non-
metalated benzazaphospholes and distinguishes these π-excess P C aromatics from phos-
phinines.11 The handling of the benzazaphospholium salts 15 and particularly 18 proved
difficult because they are extremely sensitive to hydrolysis and furnish P,N-disubstituted
benzazaphospholine-P-oxides 17 and 19, respectively, with any trace of moisture (Scheme
4). The nature of the phosphine oxides is confirmed by conclusive multinuclear NMR
data and by crystal structure analyses for 19 (aryl = 2-thienyl and 2-dimethylamino-5-
methylphenyl). Attempts to detect PNHC by 2-CH deprotonation or trapping have failed
so far.
Et
Et
O
BF3
Et
O
H2O
H2O
P
P
N
P
H
H
H
H
H
N
N
Et3OBF4
CH2Cl2
BF4
Np
Np
Np
(15, δ31P 18.9 ppm)
(16, δ31P 71.5 ppm;
q, 3JPF = 6.9 Hz)
(17, δ31P 52.4 ppm)
P
Aryl-X
N
Aryl
P
X
Aryl
O
Np
PdCl2
K2CO3
H2O
P
H
H
H
N
N
Np
Np
(18, Aryl = Ph: δ31P _17.8 ppm)
(19, Aryl = Ph: δ31P 38.1 ppm)
Scheme 4 P-Alkylation and arylation of benzazaphospholes.

P
CH
N
HETEROCYCLES
687
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