σ2-P Ligands: Convenient syntheses of N-methyl-1,3- benzazaphospholes

Article abstract of DOI:10.1016/j.tetlet.2012.07.037

A convenient three-step route to 1,5-dimethyl-1,3-benzazaphosphole via Cu- or Pd-catalyzed phosphonylation of 2-iodo-4-methylaniline, reduction to 2-phosphino-4-methylaniline, and disproportionative cyclization with excess formaldehyde is reported. N-Methylbenzazaphospholes can be functionalized in the 2-position via α-CH-lithiation with tBuLi and are π-acidic σ²P-ligands.

Full text of DOI:10.1016/j.tetlet.2012.07.037

Tetrahedron Letters 53 (2012) 5012–5014
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Tetrahedron Letters
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r
2-P Ligands: convenient syntheses of N-methyl-1,3-benzazaphospholes
Mohammed Ghalib a, Basit Niaz a,b, , Peter G. Jones c, Joachim W. Heinicke a,
⇑
a Institut für Biochemie, Ernst-Moritz-Arndt-Universität Greifswald, 17487 Greifswald, Germany
b Department of Chemistry, Hazara University Mansehra, Pakistan
c Institut für Anorganische und Analytische Chemie der Technischen Universität Braunschweig, 38023 Braunschweig, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient three-step route to 1,5-dimethyl-1,3-benzazaphosphole via Cu- or Pd-catalyzed phospho-
nylation of 2-iodo-4-methylaniline, reduction to 2-phosphino-4-methylaniline, and disproportionative
cyclization with excess formaldehyde is reported. N-Methylbenzazaphospholes can be functionalized
Received 15 June 2012
Accepted 9 July 2012
Available online 16 July 2012
in the 2-position via
a
-CH-lithiation with tBuLi and are
p-acidic
r
2P-ligands.
Ó 2012 Elsevier Ltd. All rights reserved.
Dedicated to Prof. Dr. Klaus Jurkschat on the
occasion of his 60th birthday
Keywords:
Phosphonylation
Phosphinoaniline
Aromatic phosphorus heterocycles
Lithiation
P ligand
Trivalent phosphorus compounds play a key role as ligands in
homogenous late-transition-metal catalyzed organic reactions.
The broad spectrum of electronic and steric properties of R3P1 spe-
cies provides for tailor-made catalysts for many applications.2
However, investigations on the use of neutral dicoordinated phos-
phorus compounds as catalyst ligands are more or less restricted to
phosphabenzene and phosphaalkene derivatives, recently with
emphasis on hybrid ligands with an additional donor site.3,4 To ex-
tend the variety of such catalyst ligands to 1,3-benzazaphospholes,
originally synthesized in a multistep procedure,5 we studied new
tential of this compound by two examples for introduction of
substituents in 2-position and by forming an LW(CO)5 complex.
The novel route, with disproportionative formaldehyde conden-
sation as the key step, is depicted in Scheme 1 and started with
phosphonylation of the easily accessible 2-iodo-4-methylaniline11
by diethyl phosphite. This P–C coupling was catalyzed either by
CuI/N,N0-dimethylethylenediamine in the presence of K2CO3, using
a protocol reported by Gelman, Jiang, and Buchwald for coupling of
p-iodoaniline and dibutylphosphite,12 or by Pd(PPh3)4 in the pres-
ence of triethylamine. The resulting phosphonotoluidine 1 was re-
duced with LiAlH4 to the crude phosphinotoluidine 2, which was
cyclized in toluene with excess aqueous formaldehyde or parafor-
maldehyde in the presence of catalytic amounts of p-toluenesul-
fonic acid. Under mild conditions benzazaphospholine 3 was
detected by its characteristic NMR data (d31P ꢀ42.8 ppm). During
heating under reflux in a Dean–Stark apparatus it was transformed
strategies for the access to these p-excess, aromatically stabilized,
dicoordinated phosphorus heterocycles6–9 and ways to introduce
an additional donor group.8–10 Bulky N-substituted benzazaphosp-
holes are conveniently accessible via bulk-dependent Pd-catalyzed
amination and phosphonylation steps but in the subsequent func-
tionalization procedure tend to add tBuLi at the P@C bond instead
of undergoing
is easily functionalized at the 2-position via
a
-CH lithiation.9,10 N-Methyl-1,3-benzazaphosphole
-CH lithiation, but
into the 1H- and 1-methyl-benzazaphospholes 4 (minor, d
a
71.8 ppm) and 5 (major, d 69.8 ppm). Subsequent introduction of
an N-methyl group into 4 by heating with excess formaldehyde
did not take place. Clean formation of 5 was achieved by heating
with excess paraformaldehyde.
It should be mentioned here that the analogous unsubstituted
benzazaphospholine was found to be stable and distillable when
prepared from 2-phosphinoaniline and paraformaldehyde in the
absence of an acidic catalyst.5a Thus, the acid catalyst plays a key
role in the aromatization of the benzazaphospholines. The forma-
tion of 4 may be caused by partial transfer of the hydrogen atoms
at P and C2 to formaldehyde, activated by O-protonation. The
has so far been available only by a time-consuming multistep
route.10 We present here a novel three-step route to N-methyl-
1,3-benzazaphospholes, illustrated by the synthesis of 1,5-di-
methyl-1,3-benzazaphosphole, and demonstrate the synthetic po-
⇑
Corresponding author. Fax: +49 3834864377.
E-mail address: heinicke@uni-greifswald.de (J.W. Heinicke).
Present address: Department of Chemistry, Hazara University Mansehra,
Pakistan.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.037

M. Ghalib et al. / Tetrahedron Letters 53 (2012) 5012–5014
5013
Scheme 1. Route to 1,5-dimethylbenzazaphosphole via disproportionative formaldehyde condensation.
Scheme 2. Synthesis of compounds 6–8.
formation of the major product 5 is formally attributable to an
acid-catalyzed disproportionation of an unstable bis(condensation)
product into a P@C bond and an N-methyl group. No intermediate
was observed that would shed light on the mechanism. In three-
component condensations of Ph2PH and RNH2 with glyoxylic acid
hydrate, the reaction of P–H was faster than the reaction of N–H
with the hydrated aldehyde group,13 and thus the initial step of
the N-methylation might be an attack of excess (H2CO)n at the P–
H function of the interim compound 3. Subsequent condensation
to an unstable bicyclic product with 1,3-azaphosphetane ring,
which then undergoes P–C bond cleavage within the four-mem-
bered ring, coupled with saturation of the carbon by hydrogen
transfer and formation of the P@C bond, appears as a plausible
mechanism. An alternative route to 5 might be the reduction of
an immonium intermediate without the usual addition of P–H at
C@N, for example, because of steric effects.
(along with the yields) in Table 1. Compound 7 crystallized by slow
concentration of the d8-THF solution, thus permitting more de-
tailed structural information (Fig. 1).14 It forms monoclinic crystals,
space group P21/c, with typical carboxylic acid dimers (O–H
0.85(2), Hꢁ ꢁ ꢁO 1.79(2), Oꢁ ꢁ ꢁO 2.64(12) Å, O–Hꢁ ꢁ ꢁO 178(2)°); the
COOH group is almost coplanar with the benzazaphosphole ring
(P3–C2–C9–O1 ꢀ176.86(10), P3–C2–C9–O2 2.50(15), N1–C2–C9–
O1 3.1(2)°). Bond lengths and angles are similar to those in 1-
neopentylbenzazaphosphole-2-carboxylic acid9b and show a smal-
ler difference between the P@C2 and P-C3A bonds than does the
unsubstituted 1H-1,3-benzazaphosphole (1.695(9), 1.807(7) Å15).
In conclusion, the synthesis of 5 from 2 by disproportionative
cyclocondensation with excess paraformaldehyde as a key step
represents a new convenient three-step route to N-methyl-1,3-
benzazaphospholes. This paves the way for easier access to func-
As mentioned above, N-methyl-1,3-benzazaphosphole was
found to be particularly suitable as a starting material for the syn-
Table 1
Yields (%) and characteristic 31P and
a
-
13C NMR data, d [ppm], J [Hz] of compounds 1–
thesis of various benzazaphosphole-based
an additional classical donor site, via -CH lithiation and coupling
r
2P-hybrid ligands with
8a
a
Compd Yield 31P NMR: d
13C{1H} NMR: d
(1JPC) (3a)
13C{1H} NMR: d
(1JPC) (C2)
of the 2-lithiobenzazaphosphole with the corresponding electro-
philic reagents.10 These reactions are also applicable to compound
5, as demonstrated by trimethylsilylation and carboxylation at the
2-position yielding 6 and 7, respectively (Scheme 2). Reaction of 5
1
65/
76
75
n.d.
n.d.
62
21.5
107.80 (183.1)
—
2b
3
4
5
6
ꢀ150.3b
ꢀ41.2
72.6
110.85 (9.3)
n.d.
—
n.d.
with W(CO)5(THF) provided the corresponding
phosphole W(CO)5 complex 8, which displays strong upfield 31P
coordination chemical shift,
d = ꢀ38.3 ppm, characteristic of the
-acidic properties of
2P-ligands.
The new compounds were identified by conclusive NMR and
HRMS data. Characteristic 31P and 13C NMR data are presented
g
1-P benzaza-
n.d.
n.d.
D
69.8
142.55 (39.8)
144.12 (43.8)
143.13 (37.2)
161.94 (54.4)
180.22 (74.3)
162.02 (51.8)
156.64 (29.2)
75
72
114.7
115.0
p
r
7
8
65
31.5 (241.0)c 138.82 (22.6)
a-

5014
M. Ghalib et al. / Tetrahedron Letters 53 (2012) 5012–5014
References and notes
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Figure 1. Structure of 7 in the crystal (ellipsoids with 50% probability). Selected
bond lengths (Å) and angles (°): P3–C2 1.7299(12), P3–C3A 1.7610(12), N1–C2
1.3766(15), N1–C7A 1.3802(16); C2–C13 1.4705(16); C2–P3–C3A 88.59(6), N1–C2–
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r
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Acknowledgments
Support of this study by Deutsche Akademische Austauschd-
ienst (B.N., project ID 54387192) and Deutsche Forschungsgeme-
inschaft (HE 1997/14-1) is kindly acknowledged. We thank Dr.
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spectra, Dr. H. Frauendorf and G. Sommer-Udvarnoki (Georg-Au-
gust-Universität Göttingen, Institut für Organische und Biomoleku-
lare Chemie), and Professor. Dr. H.-C. Böttcher and B. Breitenstein
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for HRMS measurements.
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6.73331(10), b = 19.2709(3), c = 7.3381(2) A°, b = 92.859(2)°, V = 950.98(3) Å3,
Z = 4, Dc = 1.447 mg/m3,
T = 100(2) K, Oxford Diffraction Nova diffractometer, k(Cu K ) = 1.54184 Å,
l
= 2.341 mmꢀ1, specimen 0.40 ꢂ 0.15 ꢂ 0.15 mm3,
a
2hmax 152°, 25219 reflections collected, independent reflections 1979
[R(int) = 0.0221]. Refinement (SHELXL-97) by full-matrix least squares on F2
Supplementary data
proceeded to wR2 = 0.0824, conventional
R
1 = 0.0291 for 133 parameters.
Crystallographic data for
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Supplementary data (experimental procedures as well as char-
acterization of new compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.07.037.