A simple solid phase diversity linker strategy using enol phosphonates.

Article abstract of DOI:10.1039/b411111g

Polymer bound lactam enol phosphonates can be easily generated using simple phenol on polystyrene resin. These stable, storable compounds can be released in a diversity cleavage strategy, using Suzuki cross coupling conditions, to provide 2-arylenamides in moderate to good overall yields. Copyright 2004 The Royal Society of Chemistry

Full text of DOI:10.1039/b411111g

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C O M M U N I C A T I O N
A simple solid phase diversity linker strategy using enol
phosphonates†
Ian B. Campbell,a Jun Guo,b Edward Jonesb and Patrick. G. Steel*b
a
GlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts., UK SG1 2NY
Department of Chemistry, University of Durham, Science Laboratories, South Road,
b
Durham, UK DH1 3LE. E-mail: p.g.steel@durham.ac.uk
Received 22nd July 2004, Accepted 16th August 2004
First published as an Advance Article on the web 1st September 2004
mono and bis phospho-esters. Without purification, the mono
Polymer bound lactam enol phosphonates can be easily
generated using simple phenol on polystyrene resin. These
stable, storable compounds can be released in a diversity
cleavage strategy, using Suzuki cross coupling conditions, to
provide 2-arylenamides in moderate to good overall yields.
substituted product was directly combined with p-cresol to
afford the desired phenyl phosphonate 2a in an overall yield
of 70–80%, Scheme 1. In a similar fashion p-cresol could be
loaded onto Tentagel® resin using 4-hydroxymethylbenzoic acid
as a simple spacer group. Although both systems underwent
the desired Suzuki cross coupling reaction [Pd(PPh3)4, Na2CO3,
DME, 80 °C] this was accompanied by significant amounts of
the biaryl 4 derived from homo coupling of the boronic acid.
Attempts to circumvent this problem through screening of alter-
native catalysts (metal sources and ligands), bases and solvents
were not successful with the homo-coupling pathway always
occurring more readily. Suspecting that the low reactivity of the
Ar–OP bond to oxidative addition towards the metal centre was
contributing to this problem we explored alternative substrates.
Owing to the developments stimulated by combinatorial
(medicinal) chemistry, solid phase organic synthesis (SPOS)
now has an accepted place in the armoury of the synthetic and
medicinal chemist.1 A key component of a SPOS procedure is
the linker unit which must be stable under the reaction condi-
tions and also provide a mild method for the release of the
desired product at the end of the synthesis. Traditionally, SPOS
linkers resemble protecting groups with the product to linker
connection being, most commonly, an ester or amide.2 Draw-
backs to this approach exist in that, following cleavage, the
target library structure contains a common auxiliary polar
functionality which can adversely affect the functional (pharma-
cological) profile and that the process of attachment and
cleavage represent non-productive chemical steps. To address
the first of these issues ‘traceless’ linkers, in which cleavage pro-
duces a hydrogen atom at the site of resin attachment, have been
developed.3–5 An enhanced version of the ‘traceless’ approach
is to use the linker as a means to introduce additional diversity
into the product library. In these cases the additional steps are
compensated by increased product complexity in the library.
One particularly attractive approach to generate diversity in
the cleavage step is to use transition metal mediated cross coup-
ling strategies.6 In this, both the nucleophilic (organometallic)4
and electrophilic components5 have been polymer supported
with the latter generally providing greater scope for substrate
stability during the reaction sequence. Despite this, relatively few
electrophilic tethers have been reported.
Enol phosphates have long been known to be effective cross
couplingpartnersfororganocopperreagents7 and, morerecently,
in various palladium or nickel catalysed strategies.8,9,10 Impor-
tantly these are reported to exhibit higher stability than many
other enol derivatives but have not been used in the context of a
solid phase synthetic strategy. Recognising that enhanced stabil-
ity of the linker and a reduction in the potential for competing
reactions would be achieved by replacement of the spectator
P(OR) units in a phosphate linker with alkyl or aryl substitu-
ents we opted to explore the use of alternative phosphorus ester
derived activating groups, i.e. phosphinites and phosphonates.
In this communication we report our preliminary results that
demonstrate that simple effective diversity cleavage strategies
are feasible with readily accessible phosphonate based linker
groups.11
Scheme 1
In contrast to the low reactivity of aryl phosphates, vinyl
phosphates have been reported as being viable substrates for
various cross coupling reactions although other phosphorus
activating groups have not been explored. In particular,
Nicolaou and Coudert have demonstrated the potential of
lactam enol phosphates in both the Stille and Suzuki reactions.8,9
Consequently, following these precedents, N-Boc caprolactam
5 was treated with LDA and TMEDA to generate the corres-
ponding enolate and then combined with the model support 1a
to afford phosphonate 6 in modest yield. Although acid labile,
decomposing in chloroform overnight, 6 underwent efficient
cross coupling reactions, Scheme 2. In the hope that immobili-
sation on a polymer support would provide enhanced stability
we then explored the preparation of the analogous supported
phosphonates. However, analysis of the resins by 31P NMR
showed no evidence for the presence of the phosphonate.
Suspecting that this instability was due to the benzylic nature of
the linkage, preparation of the alkyl derivative 9 was attempted
albeit with no success.
Initial studies commenced with benzyl alcohol 1a as a
simple solution phase model of a hydroxyl functionalised resin.
Reaction with 1.25 equivalents of phenylphosphonic dichloride
(PPDC; PhP(O)Cl2) in the presence of Et3N gave a mixture of
† Electronic supplementary information (ESI) available: characterisa-
tion data for Suzuki products 15 from diversity cleavage of resin 14.
See http://www.rsc.org/suppdata/ob/b4/b411111g/
During these solution phase studies it had proved possible to
prepare the bis enol phosphonate 10. Surprisingly, this proved
T h i s j o u r n a l i s
©
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 2 5 – 2 7 2 7
2 7 2 5

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Table 1 Suzuki reaction results
Entry
i
ArB(OH)2
Yielda
49%
46%
57%
ii
iii
iv
v
53%
48%
vi
35%
32%
Scheme 2
vii
to be considerably more stable than the benzylic derivative 6.
Moreover, preliminary studies reveal this to be a viable substrate
for cross coupling reactions – providing an atom economical
method for activation of two equivalents of an enol with a single
equivalent of the phosphorus reagent, Scheme 3.
viii
ix
72%
42%
21%
x
xi
34%
0%
xii
a Yield of purified, isolated product based on initial resin 12 used.
Scheme 3
These results and the earlier work using phenyl phosphates
suggested that an sp2C–O–P linkage would be stable and
attention turned to the use of a phenolic linker unit. Initial
attempts to sequentially treat polystyrene bound phenol resin
12 with PPDC and the lactam enolate 13 failed to produce a
resin exhibiting a significant response in the 31P NMR spectrum.
However, simply reversing the order of addition, combining the
enolate with PPDC at −78 °C and then transferring this solution
to a slurry of the resin in THF afforded the desired immobilised
enolate, Scheme 4. Analysis by 31P NMR spectra revealed a
major broad peak at d = 12 for the desired enol phosphonate
14 accompanied by a minor component corresponding to a
cross-linked bis phenyl phosphonate at d = 16. Importantly,
this resin is stable, giving identical analysis and performance
in cross coupling reactions (vide infra) even after storage for
several months. Treatment of the resin with a range of boronic
acids under the standard Suzuki reaction conditions afforded
the desired 2-substituted enamides 15 in modest to good yields,
Table 1.12 The quoted yields refer to the overall process of resin
activation, loading and cross coupling cleavage. Whilst the 2-
aryl and styryl products derived from caprolactam are stable
compounds attempts to isolate the vinyl derivative derived from
pent-1-enylboronic acid failed (entry xii). Similarly the more
electron rich aryl derivatives hydrolyse in mild acidic conditions
(CDCl3) to afford the corresponding keto amine and this may
Scheme 4
account for some of the lower yields for these derivatives under
these standard reaction conditions.
In summary, we have demonstrated that resin bound phos-
phonates can provide a simple catch-and-release strategy for
lactam enolates. These supported enolates are amenable to
prolonged storage and can be employed in a diversity cleavage
strategy in solid phase synthesis. Applications of this new metho-
dology and studies to further enhance the use of phosphorus
based linkers to permit the use of aryl substrates are in progress
and results will be reported in due course.
2 7 2 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 2 5 – 2 7 2 7

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(University of Southampton) for details of the preparation of
phenol-on polystyrene resin; Neil Edwards for some preliminary
experiments and Dr. A. M. Kenwright for assistance with NMR
experiments.
Experimental
Enol phosphonate resin 14
To a cold (−78 °C) solution of lactam 5 (14 mmol, 4 eq) and
TMEDA (16.8 mmol, 4.8 eq) in dry THF (50 ml) was added a
solution of LDA (16.8 mmol, 4.8 eq). This mixture was stirred
at −78 °C for 40 minutes and phenylphosphonic dichloride
(12.6 mmol, 3.6 eq) was added dropwise. The reaction mixture
was stirred for 0.5 h at −78 °C and then at room temperature for
1 h. It was then transferred via a cannula into a suspension of
phenol on polystyrene resin 12 (3.5 mmol g−1, 1.0 g, 3.5 mmol)
and dry TEA (7 mmol, 2 eq) in THF (10 ml). The suspension
was stirred at room temperature for 18 h. The reaction mix-
ture was then filtered. The beads were washed with MeOH
(3 × 20 ml), DMF (3 × 20 ml), THF (3 × 20 ml), and dry ether
(3 × 20 ml), and then dried to give the title resin. dP (121 MHz,
CDCl3) 11.96, 15.93.
Notes and references
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Typical Suzuki reaction with resin 14. Preparation of 7-(4-
methylphenyl)-2,3,4,5-tetrahydro-azepine-1-carboxylic acid
tert-butyl ester (15ii)
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Chem., 1999, 64, 8557; F. Stieber, U. Grether and H. Waldmann,
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A suspension of resin 14 (1 g, 1.61 mmol), tolylboronic acid
(4.83 mmol, 3 eq) and Na2CO3 (6.44 mmol, 4 eq) in DME
(20 ml), H2O (8 ml), EtOH (8 ml) was degassed with Ar for
30 minutes. Pd(PPh3)4 (0.16 mmol, 0.1 eq) was added and the
reaction mixture was refluxed for 1 h and then cooled to room
temperature. The resin was filtered and washed with THF and
ether. The combined filtrate was concentrated and extracted
with EtOAc/brine. The organic phase was dried (MgSO4),
filtered and evaporated. Flash chromatography on silica gel
(1%–3% EtOAc/petrol ether) gave the title compound as a white
solid as a 4:1 mixture of two rotomers (56%). mp. 94–95 °C.
Found C 75.17%, H 8.78%, N 4.86%. C18H25NO2 requires C
75.26%, H 8.71%, N 4.88%. mmax 2963 (C–H), 1690 (O–CO),
1385, 1363, 1333, 1156, 1115, 810, 770 cm−1. dH (400 MHz,
CDCl3) 1.11 (9H, s, (CH3)3C), 1.47 (2H, m, 4-H2), 1.84 (2H, m,
3-H2), 2.28 (4H, m, 5-H2 + 2-H2), 2.34 (3H, s, CH3), 5.84 (0.8H,
t, J1 = 6.4 Hz, 6-H), 6.02 (0.2H, t, J1 = 6.4 Hz, 6-H), 7.10 (2H,
m, Ar-H), 7.26 (2H, m, Ar-H). dC (125 MHz, CDCl3) Rotamer 1:
21.10 (CH3), 27.42 (C4), 27.93 ((CH3)3C), 28.39 (C5) 29.70 (C3),
47.86 (C2), 79.60 ((CH3)3C), 121.65 (C6), 124.78 (2 × Ph C–H),
128.69 (2 × Ph C–H), 136.73 (C4), 136.90 (C1), 144.35 (C7),
154.12 (O–CO). Rotamer 2: 21.11 (CH3), 27.46 (C4), 28.93
((CH3)3C), 28.39 (C5), 29.98 (C3), 49.02 (C2), 79.60 ((CH3)3C),
123.11 (C6), 124.78 (2 × Ph C–H), 128.69 (2 × Ph C–H), 136.73
(C4), 136.90 (C1), 144.39 (C7), 154.12 (O–CO). m/z (ES+)
310.2 (MNa+), 597.4 (M2Na+).
8 K. C. Nicolaou, G. Q. Shi, J. L. Gunzner, P. Gartner and Z. Yang,
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11 Phosphonate linkers have been reported for use in other
cleavage strategies. See for example C. R. Johnson and
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Acknowledgements
We thank the EPSRC (GR/M75990/01) and GlaxoSmithKline
for financial support of this work (JG); Dr Richard Brown
12 In all cases the 2-arylenamide products 15 are isolated as rotomeric
mixtures interconvertable at 60 °C as ascertained by simple VT
NMR studies.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 2 7 2 5 – 2 7 2 7
2 7 2 7