Synthesis and characterisation of β-aminophosphine ligands on a solid support

Article abstract of DOI:10.1039/b009640g

Synthesis and characterization of β-aminophosphine ligands on a solid support was described. An assessment strategy combining complementary on-resin characterization techniques demonstrated the yield and purity of the support-bound ligands. The combination of the applied synthetic and analytical methods represented an innovative and general approach to the solid-phase synthesis of phosphorus ligands.

Full text of DOI:10.1039/b009640g

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Synthesis and characterisation of ꢀ-aminophosphine ligands on a
solid support†
Amal Mansour and Moshe Portnoy*
1
School of Chemistry, Tel-Aviv University, Ramat Aviv 69978, Israel
Received (in Cambridge, UK) 1st December 2000, Accepted 19th March 2001
First published as an Advance Article on the web 30th March 2001
6
A highly efficient and expeditious synthesis of mono-N-
substituted ꢀ-aminophosphine ligands on a polystyrene
support accompanied by thorough characterisation,
utilising a combination of NMR techniques, was demon-
strated for the first time.
significantly lower than the reported one. The substitution of
the OH group by chloro afforded highly variable yields (30–
60%) of colourless salt 1. This rather disappointing result was
attributed to side reactions forming di- and oligo-mers of the C
unit. It was presumed that the observed side reactions would
not affect the solid-phase synthesis due to the pseudodilution
principle. Deprotonation of 1 to give 2 proceeded smoothly.
However, some difficulties were encountered while attempting
to perform the phosphination of 2 with diphenylphosphide.
2
7
8
Polymer-immobilised catalysts combine useful properties of
both homogeneous and heterogeneous systems. As such, they
continue to be the focus of the research efforts and interest of
1
catalytic chemists. Catalysis based on solid matrix-bound
While there is no doubt that the reaction of HPPh with NaH
2
t
structures represents a potentially fruitful field for the combin-
atorial approach and high throughput screening techniques.
or with BuLi formed in situ the required metal diphenyl-
phosphides, both phosphides were completely unreactive
2
One possible way toward a successful preparation of a polymer-
immobilised catalytic library proceeds through an efficient and
expeditious assembly of ligands on a solid support. While an
attachment of phosphine ligands presynthesised in solution to
a reactive polymer through a remote functionality is well
towards 2. Finally, the phosphination was successfully per-
9
formed utilising LiPPh , generated in situ from Ph P and Li.
2
3
Interestingly, while such an approach usually requires quench-
t
ing of the byproduct PhLi with BuCl, omission of the quench-
ing had no detrimental effect on the reaction outcome. Similar
results regarding the nucleophilic reactivity of the in situ gener-
ated phosphides, as well as the tolerance of PhLi in the reaction
1d–f
known, a multistep assembly of such ligands on resin utilis-
ing a number of building blocks has hardly been investigated at
3
10
all.
mixture, were recently observed. The phosphination step
Due to our interest in catalytic systems with hemilabile
ligands, we recently launched a research project aimed at
the solid-phase synthesis of phosphorus–nitrogen ligands of
exhibited very high sensitivity to oxygen and therefore requires
rigorous anaerobic conditions.
The success of the synthesis was confirmed by NMR meas-
urements and comparison of product 3a with an authentic
4
type I.
11
sample obtained by an alternative method.
After the model study in solution was completed, the syn-
thesis on a solid support was targeted. Since the goal is a set of
resin-bound ligands, a compatible cleavage procedure at the
end of the synthetic sequence is not compulsory. Thus, the
Merrifield resin, as one of the most robust supports for organic
synthesis, was utilised. A synthetic scheme similar to the one
established for the solution chemistry was exercised (Scheme 2).
For the synthesis of ligands I on a support, the approach
based on anchoring through the nitrogen substituent was
chosen due to its synthetic simplicity as well as the diversity of
the available building blocks. Our solid-phase synthesis of
ligands I was preceded by an examination of the synthetic
scheme in solution for a model compound. Remarkably, while
the solution synthesis is characterised by a medium yield and a
low reproducibility, an excellent, high yielding synthesis on a
solid support was observed.
The synthesis in solution was based on a literature pro-
5
cedure. Although the modified synthesis (Scheme 1) formed
the model ligand 3a, the overall yield never exceeded 45%,
Scheme 2 Reagents and conditions: i, ethanolamine, DMF, 50 ЊC, 17 h;
i
ii, SOCl , CHCl , 60 ЊC, 2 h; iii, Pr EtN, THF; iv, LiPPh , THF, r.t.,
2
3
2
2
2
4 h, 91% (4 steps).
According to the scheme, ethanolamine (2-aminoethanol)
immobilisation on the Merrifield resin was followed by chlo-
rodehydroxylation with SOCl (to give resin 5a). Deprotonation
2
of the (chloroethyl)ammonium salt 5a was followed by phos-
phination using the earlier established procedure to yield a pale
yellow target resin 6.‡ While the chlorodehydroxylation and
Scheme 1 Reagents and conditions: i, SOCl , CHCl , 60 ЊC, 2 h, 35%;
2
3
phosphination steps closely followed the procedures in solution,
ii, NaOH, H O, 70%; iii, LiPAr , THF, r.t., 18 h, quant.
2
2
i
an organic base ( Pr EtN) rather than hydroxide was used for
2
the deprotonation step in order to better suit the solid-phase
synthesis.
Major emphasis was placed on the determination of the
purity and the yields of the product and the intermediates along
†
Electronic supplementary information (ESI) available: details of the
preparation of compounds 1–3, 7–10. http://www.rsc.org/suppdata/p1/
b0/b009640g/
9
52
J. Chem. Soc., Perkin Trans. 1, 2001, 952–954
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b009640g

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1
3
Table 1
C NMR chemical shifts of the aliphatic carbons for resins 4,
5
b and 6 (from monitoring resin 6 synthesis)
1
2
3
3
1
Fig. 1 Gel-phase P NMR of 6 (a) and 10 (b).
Merrifield resin
—
—
46.1
53.4
52.9
57.7
4
60.9
44.7
29.7
50.9
50.4
53.6
the synthetic pathway. The efficiency and integrity of the syn-
thesis were established by a combination of complementary
techniques.
5
6
b
As expected, direct assessment of yields and selectivities
through cleavage of the derivatised amine from resin 6 was not
possible. Thus, a series of direct measurements of resin-bound
31
13
compounds was undertaken. First, gel-phase P and C NMR
were applied to the model resin 6 as well as to resins 7–10
prepared by analogous procedures.
1
3
13
Fig. 2 Comparison between gel-phase C NMR of 10 (a) and
NMR of 3b (b). * denotes signals of an impurity in solution.
C
existence of a resin-bound diarylphosphine moiety. These
observations, as well as similar data obtained for resin 6,
demonstrate with a high degree of confidence that the target
compounds are cleanly formed on the support.
3
1
The P NMR of resins 6–9 exhibited clean spectra with a
broad peak at ca. Ϫ20 ppm (Fig. 1(a)).§ In most cases, a very
small broad peak (2–5% of the total) was observed at ca. Ϫ10
ppm. The main signal belongs to the target ligands (as
evidenced by comparison to their soluble analogue 3a). The
smaller signal is attributed to the product of the diphenyl-
phosphide reaction with unsubstituted chlorobenzyl sites on
the resin. This assignment was confirmed by the direct reaction
A continuous step-by-step monitoring of the synthesis of
resin 6 followed the on-resin characterisation of the product
ligands. The chemical shifts of the three aliphatic carbons are
summarised in Table 1. The shifts are in full agreement with
those of the soluble analogues of compounds 4, 5b and 6.
Moreover, each transformation results, according to the moni-
toring, in clean and practically quantitative conversion of the
starting material into product. No byproducts or remaining
starting materials were detected for any step. This observation is
supported by the elemental analysis data.‡
of Ph PLi with Merrifield resin, forming resin 11, which
exhibited a single broad peak at Ϫ10.6 ppm.
The formation of 11 as a very minor byproduct could be
explained by incomplete substitution of the chloromethyl sites
of the Merrifield resin by ethanolamines in the first step of the
sequence. An alternative explanation is a minor degree of cleav-
age of the resin-bound ethanolamine during the SOCl -induced
substitution step.
For resin 10, a similar spectrum was observed: a major
peak at Ϫ41 ppm and a minor peak (∼4%) at Ϫ30 ppm
Fig. 1(b)). The P NMR clearly showed that the product resins
2
31
Finally, a P NMR-based quantification experiment was per-
formed with resins 6 and 10. Each resin was mixed with a com-
mercial polystyrene-immobilised triphenylphosphine reference
2
31
resin.¶ After recording of the P gel-phase NMR spectra, the
yields of resins 6 and 10 were determined using the mixing
ratio, the integral ratio and the known reference loading. Yields
of 91% and 95% were determined for resins 6 and 10
respectively.
31
(
do not contain more than 5% of phosphorus-containing
impurities.
The absence of impurities that do not contain phosphorus
The comparison of the solid-phase synthesis to that in solu-
tion reveals that all the three common steps proceed in a much
more satisfactory fashion on a solid support. In contrast to
solution chemistry, the dehydroxychlorination is practically
quantitative. The absence of di- or oligo-merisation due to the
pseudodilution principle is clearly responsible for this differ-
ence. The deprotonation step proceeds better on a solid support
as well, probably because of milder conditions and a simpler
purification technique. Finally, the significantly lower suscepti-
bility to oxidation of the resin-bound phosphines, as compared
13
12
was proven by gel-phase C NMR of resins 6 and 10. For
13
13
example, the gel-phase C NMR of 10 was compared to the
C
NMR of its soluble analogue 3b (Fig. 2). Four aliphatic signals
only were observed for 10 (as expected). These signals closely
resemble the analogous peaks in the spectrum of 3b. (Slight
differences of up to 4 ppm are attributed to the differences in
the environment polarity and steric crowding.) Although the
polymer obscures some of the aromatic signals of 10, broad
signals near the polymer peak are clearly visible, disclosing the
J. Chem. Soc., Perkin Trans. 1, 2001, 952–954
953

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to soluble analogues, contributes markedly to the higher yield
of phosphination on a solid support.
(125 MHz, C
6
D
6
): δ 133.0, 57.7, 53.6, 29.7. IR (KBr): 3417, 3022, 2922,
Ϫ1
1
0
668, 1599, 1488, 1445, 1180, 1025 cm . Anal. calcd. (for loading of
.56 mmol g of C H NP on PS-DVB, prepared from Merrifield resin
Ϫ1
In conclusion, an expeditious and efficient method for the
synthesis of β-aminophosphines on a solid support was estab-
lished. This is a remarkable achievement, since the analogous
synthesis in solution is far from satisfactory. An assessment
strategy combining complementary on-resin characterisation
techniques demonstrated the excellent yield and purity of the
support-bound ligands. The combination of the applied syn-
thetic and analytical methods represents an innovative and
general approach to the solid-phase synthesis of phosphorus
ligands.
15 17
Ϫ1
with a loading of 0.63 mmol g ) C 86.70, H 7.39, N 0.79. Found
C 87.59, H 7.47, N 0.90%.
31
§
The P NMR chemical shifts are reported with reference to an
external 85% H PO standard.
3
4
¶
Purchased from Fluka, crosslinked with 1% divinylbenzene, particle
Ϫ1
size 100–200 mesh, 1.6 mmol g
.
1 (a) See for example A. C. Comely, S. E. Gibson and N. J. Hales,
Chem. Commun., 1999, 2075; (b) M. Bao, H. Nakamura and
Y. Yamamoto, Tetrahedron Lett., 2000, 41, 131; (c) I. Fenger and
C. Le Drian, Tetrahedron Lett., 1998, 39, 4287; (d) Y. Uozumi,
H. Danjo and T. Hayashi, Tetrahedron Lett., 1997, 38, 3557; (e) Y.
Uozumi, H. Danjo and T. Hayashi, Tetrahedron Lett., 1998, 39,
Acknowledgements
8
303; ( f ) Y. Uozumi, H. Danjo and T. Hayashi, J. Org. Chem., 1999,
This research was supported by the Israel Science
Foundation founded by the Israel Academy of Sciences and
Humanities.
2
Notes and references
‡
Typical procedures. 4: Ethanolamine (3.6 mmol, 10 eq.) was added to
Liebigs Ann., 1997, 637.
a suspension of the Merrifield resin (0.5 g, 0.36 mmol) in a minimal
volume of dry DMF. The suspension was stirred for 17 h at 50 ЊC,
filtered, the resin washed with ethanol (×2) and DCM (×2) and dried
in vacuo. Yield 95% to quantitative. Partial gel-phase C NMR (125
MHz, C D ): δ 60.9, 53.4, 50.9. IR (KBr): 3366, 3020, 2905, 1600, 1493,
3 (a) W. Dumont, J.-C. Poulin, T.-P. Dang and H. B. Kagan, J. Am.
Chem. Soc., 1973, 95, 8295; (b) J. M. Brown and H. Molinari, Tetra-
hedron Lett., 1979, 31, 2933; (c) phosphine-containing peptides were
assembled on a solid support using a phosphine-containing amino
acid: S. R. Gilbertson and X. Wang, Tetrahedron Lett., 1996, 37,
6475.
1
3
6
6
Ϫ1
Ϫ1
1
451, 1027 cm . Anal. calcd. (for loading of 0.71 mmol g of
C H NO on PS-DVB, prepared from Merrifield resin with a loading
of 0.72 mmol g ) C 89.96, H 7.90, N 0.99. Found C 89.20, H 7.86,
N 0.96%.
4 Hemilabile phosphine-containing chelates were successfully used
in a number of catalytic cycles; for representative examples see
(a) M. Nandi, J. Jin and T. V. RajanBabu, J. Am. Chem. Soc., 1999,
121, 9899; (b) S. Mecking and W. Keim, Organometallics, 1996,
15, 2650; (c) E. K. van den Beuken, W. J. J. Smeets, A. L. Spek
and B. L. Feringa, Chem. Commun., 1998, 223; (d) T. Kamikawa
and T. Hayashi, Tetrahedron, 1999, 55, 3455; (e) M. McCarthy and
P. J. Guiry, Tetrahedron, 1999, 55, 3061; ( f ) S. R. Gilbertson
and D. Xie, Angew. Chem., Int. Ed., 1999, 38, 2750.
3
8
Ϫ1
5
b: Thionyl chloride (0.37 ml, 5.04 mmol, 16 eq.) was added dropwise
to a suspension of 4 (ca. 0.32 mmol) in a minimal amount of chloro-
form at 0 ЊC. After 30 min of stirring, the temperature was raised to
6
0 ЊC and the suspension stirred for 2 hours. After cooling, the resin
was filtered, washed with DCM (×3), ethanol, DCM and dried in vacuo
(
5a). The deprotonation was performed by stirring the resin in a solu-
i
tion of 20 eq. of Pr EtN in a minimal amount of THF for one hour,
5 M. M. T. Khan and A. P. Reddy, Polyhedron, 1987, 6, 2009.
6 A possible explanation may be connected to an apprehension
expressed in ref. 11 which states that in ref. 5 a dibenzylated eth-
anolamine, rather than the monobenzylated one, was utilised.
7 BnNHCH CH OCH CH NHBn was identified as one of the side
2
filtering the resin and resuming the stirring with the base for another
hour. Finally, the resin was filtered, washed with THF (×3) and dried
1
3
in vacuo. Yield 95% to quantitative. Partial gel-phase C NMR (125
MHz, C D ): δ 52.9, 50.4, 44.7. IR (KBr): 3410, 3020, 2926, 1600, 1493,
6
6
2
2
2
2
Ϫ1
Ϫ1
1
453, 1026 cm . Anal. calcd. (for loading of 0.61 mmol g of
products. Other oligomeric byproducts were observed, but not fully
characterized.
8 J. S. Fruchtel and G. Jung, Angew. Chem., Int. Ed. Engl., 1996, 35, 17.
9 M. D. Fryzuk and B. Bosnich, J. Am. Chem. Soc., 1977, 99, 6262.
10 J.-O. Durand, Synthesis, 1999, 835.
C H ClN on PS-DVB, prepared from Merrifield resin with a loading
of 0.63 mmol g ) C 89.22, H 7.73, N 0.86, Cl 2.18. Found C 88.67,
H 7.67, N 0.65, Cl 1.88%.
3
7
Ϫ1
6
: Under argon. Freshly cut Li wire (0.11 g, 15.3 mmol, 48 eq.) was
added to a solution of triphenylphosphine (0.84 g, 3.2 mmol, 10 eq.) in
ml of THF. After stirring for 3 h, the residual lithium was filtered off
11 M. Bassett, D. L. Davies, J. Nield, L. J. S. Prouse and D. R. Russell,
Polyhedron, 1991, 10, 501.
8
1
3
and the filtrate was added to a suspension of resin 5b (ca. 0.32 mmol) in
a minimal volume of THF. The suspension was stirred for 24 h. The
resin was filtered off and washed with water, acetone, chloroform,
benzene and ether and dried in vacuo. Quantitative yield. Gel-phase
12 For gel-phase C measurement, conditions reported by F. Lorge,
A. Wagner and C. Mioskowski, J. Comb. Chem., 1999, 1, 25 were
slightly altered (P1 = 10 µs, D1 = 175 ms). From numerous gel-phase
1
3
C NMR measurements we assume that the upper limit for
undetected impurities is 10%.
31
13
P NMR (202 MHz, C D ): δ Ϫ19.9(s). Partial gel-phase C NMR
6
6
9
54
J. Chem. Soc., Perkin Trans. 1, 2001, 952–954