Mannich-based condensation reactions as a practical route to new aminocarboxylic acid tertiary phosphines

Article abstract of DOI:10.1016/S0040-4039(01)02361-9

The facile syntheses of a range of aminocarboxylic acid tertiary phosphines are reported including the X-ray crystal structure of 2-{Ph₂PCH₂N(H)}-4,5-(MeO)₂C₆H ₂CO₂H.

Full text of DOI:10.1016/S0040-4039(01)02361-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1299–1301
Mannich-based condensation reactions as a practical route to
new aminocarboxylic acid tertiary phosphines
Martin B. Smith* and Mark R. J. Elsegood
Department of Chemistry, Loughborough University, Loughborough, Leics LE11 3TU, UK
Received 12 September 2001; accepted 13 December 2001
Abstract—The facile syntheses of a range of aminocarboxylic acid tertiary phosphines are reported including the X-ray crystal
structure of 2-{Ph2PCH2N(H)}-4,5-(MeO)2C6H2CO2H. © 2002 Published by Elsevier Science Ltd.
The synthesis of new carboxylic acid functionalised
tertiary phosphines has attracted recent interest for
their various uses, e.g. as precursors to phosphine
amides,1 in catalysis,2 as P,O-hemilabile ligands and for
their water-solubilising properties.3–6 Some examples of
known tertiary phosphines modified with carboxylic
acid groups are illustrated in Chart 1.1,2,7,8 To the best
of our knowledge very few examples contain an addi-
tional nitrogen donor atom between both ‘soft’ and
‘hard’ donor centres.9 In the course of our studies we
have employed a phosphorus-based Mannich reaction
as an extremely efficient method for generating new
‘hybrid’ ligands.10 We, and others, have found this
procedure reaps many advantages over more classical
routes (nucleophilic substitutions using primary/sec-
ondary phosphides, palladium–catalysed PꢀC couplings
and free-radical addition reactions) including short
reaction times and no requirement for prior generation
of reactive intermediates. Accordingly we describe here
a facile one-step method for the synthesis of new car-
boxylic acid functionalised tertiary phosphines from
cheap, commercially available starting materials.
Results and discussion
Using a similar procedure to that recently developed for
preparing novel pyridylphosphines,10 reaction of 1
equiv. of Ph2PCH2OH [readily preformed from
equimolar amounts of Ph2PH and (CH2O)n or gener-
ated in situ] with the appropriate stoichiometry of
2-aminobenzoic acid in methanol gave the condensed
ligand 2-{Ph2PCH2N(H)}C6H4CO2H 1a in 88% yield.†,‡
Furthermore, as demonstrated by the synthesis of 1b–j
(Eq. (1)), this method is extremely reliable and tolerant
to a range of functional groups with no significant
variation in yield. Various functional groups (F, Cl, Br,
I, OH, OMe, CO2H) substituted either in the 5- or
4-position (CO2H) or both (OMe, 1j) can be incorpo-
rated. The procedure also works well when the CO2H/
PPh2
PPh2
PPh2
PPh2
CO2H
CO2H
CO2H
Fe
CO2H
I
II
III
IV
Chart 1.
Keywords: amines; carboxylic acids and derivatives; Mannich reactions; phosphines.
* Corresponding author. Tel.: +44 (0)1509 222553; fax: +44 (0)1509 223925; e-mail: m.b.smith@lboro.ac.uk
†
Typical synthesis for 1a: To the solids Ph2PCH2OH (1.001 g, 4.63 mmol) and 2-H2NC6H4CO2H (0.632 g, 4.61 mmol) was added methanol (10
ml) to afford a deep yellow solution. After stirring for 30 min, solid 1a was filtered off in air, washed with MeOH (5 ml) and dried in vacuo.
Further crops could be obtained upon allowing the filtrate to stand. Yield: 1.367 g, 88%.
All new compounds gave satisfactory microanalytical and spectroscopic results.
‡
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(01)02361-9

1300
M. B. Smith, M. R. J. Elsegood / Tetrahedron Letters 43 (2002) 1299–1301
Table 1. Selected data for compounds 1–3
aminobenzoic acid and 2 equiv. of Ph2PCH2OH
(MeOH, 31 h) gave 1a in 64%. Compounds 1–3 are
soluble in methanol but thus far show little evidence for
solubility in water or weakly basic media.
Compound
Yield (%)
31P NMR
Solvent
l(P) (ppm)
CO2H
NH2
CO2H
H
N
1a
1b
1c
1d
1e
1f
1g
1h
1j
2a
2b
2c
3
88
55
76
90
81
77
66
80
94
63
n.r.a
96
93
−20.0
−19.4
−20.2
−19.4
−20.2
−20.3
−20.2
−19.7
−18.5
−21.5
−19.8
−18.9
−18.6
CDCl3/(CH3)2SO
CDCl3
PPh2
Ph2PCH2OH
MeOH, r.t.
CDCl3/(CH3)2SO
CDCl3/CH3OH
CDCl3/CH3OH
CDCl3/CH3OH
CDCl3/CH3OH
CDCl3/(CH3)2SO
CDCl3
CDCl3/(CH3)2SO
CDCl3/CH3OHb
CDCl3
X
X
Y
Y
X = Y = H
1a
1b
1c
1d
1e
1f
1g
1h
1j
X = F, Y = H
X = Cl, Y = H
X = H, Y = Cl
X = Br, Y = H
X = I, Y = H
X = OH, Y = H
X = CO2H, Y = H
X = Y = OMe
CDCl3
(1)
a n.r.=not recorded.
b In addition to small amounts of 2-(OH)-4-{(Ph2PCH2)2N}-
C6H3CO2H.
CO2H
CO2H
X
X
Ph2PCH2OH
MeOH, r.t.
Y
Y
NH2 substituents are either para or meta (Eqs. (2) and
(3)) to each other with the highest yield obtained for 2c.
The yields for 1–3 are unoptimised and in the range of
55–96% with seven examples exceeding 80% (Table 1).
For 2b, the predominant species observed was the
singly substituted 2-(OH)-4-{Ph2PCH2N(H)}C6H3-
CO2H although small amounts of the bis-substituted
species was also observed (NMR evidence). The
31P{1H} NMR data (Table 1) confirm single phospho-
rus species at l(P) −20 ppm indicating, in all cases,
substituents have negligible effect on the 31P chemical
shift and some 10 ppm upfield with respect to that of
Ph2PCH2OH [l(P) −9.9 ppm (CDCl3)].10 Attempts to
NH2
HN
PPh2
X = Y = H
X = OH, Y = H
X = H, Y = OMe
2a
2b
2c
(2)
(3)
prepare
2-{(Ph2PCH2)2N}C6H4-CO2H
from
2-
Figure 1. X-Ray structure of compound 1j showing (i) the molecular structure (ii) the intramolecular N(1)ꢀH(1)···O(1) H-bonded
cyclisation and (iii) the intermolecular carboxylate head-to-tail H-bonding motif giving rise to dimer pairs.

M. B. Smith, M. R. J. Elsegood / Tetrahedron Letters 43 (2002) 1299–1301
1301
An X-ray structure (Fig. 1)§ of 1j confirms that the
overall geometry comprises ortho-substituted
References
1. (a) Mino, T.; Kashihara, K.; Yamashita, M. Tetrahedron:
Asymmetry 2001, 12, 287; (b) Lange, P.; Schier, A.;
Schmidbauer, H. Inorg. Chem. 1996, 35, 637.
2. Komon, Z. J. A.; Bu, X.; Bazan, G. C. J. Am. Chem. Soc.
2000, 122, 12379.
3. Brauer, D. J.; Schenk, S.; Robenbach, S.; Tepper, M.;
Stelzer, O.; Hausler, T.; Sheldrick, W. S. J. Organomet.
Chem. 2000, 598, 116.
-N(H)CH2PPh2 and -CO2H groups (in addition to the
two methoxy groups).¶ Hydrogen bonding is also evi-
dent and links molecules into head-to-tail dimer pairs
through hydrogen bonding [O(2)···O(1A) 2.646(1),
,
H(2)···O(1A) 1.81(3) A; O(2)ꢀH(2)···O(1A) 169(2)°].
There is also an intramolecular NꢀH···O hydrogen
,
bond [N(1)···O(1) 2.713(2), H(1)···O(1) 2.04(2)A;
N(1)ꢀH(1)···O(1) 137(2)°].
4. Hingst, M.; Tepper, M.; Stelzer, O. Eur. J. Inorg. Chem.
1998, 73.
In conclusion, we have developed a facile procedure for
the synthesis of new functionalised tertiary phosphines
bearing carboxylic acid groups. This synthetic route is
extremely practical with reactions generally complete
within a few hours. In addition to the short reaction
times this method obviates the preparation of reactive
intermediates, uses cheap and commercially available
starting materials, requires no purification steps nor
any stringent need for performing reactions under an
oxygen free atmosphere. Current efforts are directed
towards understanding their co-ordination behaviour
and potential utility in catalysis.
5. Herd, O.; Hebler, A.; Hingst, M.; Tepper, M.; Stelzer, O.
J. Organomet. Chem. 1996, 522, 69.
6. Heesche-Wagner, K.; Mitchell, T. N. J. Organomet.
Chem. 1994, 468, 99.
7. Brauer, D. J.; Kottsieper, K. W.; Nickel, T.; Stelzer, O.;
Sheldrick, W. S. Eur. J. Inorg. Chem. 2001, 1251.
8. Podlaha, J.; Stepnicka, P.; Ludvik, J.; Cisarova, I.
Organometallics 1996, 15, 543.
9. Karasik, A. A.; Georgier, I. O.; Sinyashin, O. G.; Hey-
Hawkins, E. Polyhedron 2000, 19, 1455.
10. Durran, S. E.; Smith, M. B.; Slawin, A. M. Z.; Steed, J.
W. J. Chem. Soc., Dalton Trans. 2000, 2771.
§ Crystal data for 1j: C22H22NO4P, Mw=395.38; monoclinic, space
,
group P21/c, a=10.0587(8), b=19.0185(15), c=11.1660(9) A, i=
3
113.342(2)°; U=1961.2(3) A , Dcalcd=1.339 g cm−3, u(Mo Ka)=
,
0.71073 A, Z=4, v=0.169 mm−1, T=150(2) K, wR2=0.1153 for all
,
4698 unique data, R1=0.044 for 3473 reflections with F2>2|(F2).
The -PPh2 unit is disordered over two sets of positions; ratio of
major:minor components 84:16(1). Crystallographic data (excluding
structure factors) for the structure in this paper has been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 177016. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44(0)-1223-336033 or e-mail:
deposit@ccdc.ac.uk].
¶
,
Selected bond lengths (A) and angles (°): P(1)ꢀC(1) 1.8208(19),
P(1)ꢀC(11) 1.830(2), P(1)ꢀC(17) 1.838(2), C(1)ꢀN(1) 1.456(2),
N(1)ꢀC(2) 1.367(2), C(8)ꢀO(1) 1.246(2), C(8)ꢀO(2) 1.329(2).
C(1)ꢀP(1)ꢀC(11)
100.60(10),
C(1)ꢀP(1)ꢀC(17)
101.07(10),
C(11)ꢀP(1)ꢀC(17) 100.84(12), P(1)ꢀC(1)ꢀN(1) 111.56(13).