A novel route to functionalized PFP esters via rapid intermolecular radical addition to PFP acrylate mediated by ethylpiperidinium hypophosphite (EPHP)

Article abstract of DOI:10.1016/j.tetlet.2004.01.082

Pentafluorophenyl (PFP) acrylate, a stable compact bifunctional scaffold undergoes rapid N-ethylpiperidinium hypophosphite (EPHP) mediated conjugate radical addition to yield a variety of active esters susceptible to further functionalization by aminolysis.

Full text of DOI:10.1016/j.tetlet.2004.01.082

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2363–2366
A novel route to functionalized PFP esters via rapid intermolecular
radical addition to PFP acrylate mediated by ethylpiperidinium
hypophosphite (EPHP)
Stephen Caddick,a,* Daniel Hamza,a Duncan B. Judd,b Melanie T. Reich,c
Sjoerd N. Wadmand and Jonathan D. Wildena
aDepartment of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK
bGlaxoSmithKline, New Frontiers Science Park (SC1), Third Avenue, Harlow, Essex CM19 5AW, UK
cCentre for Biomolecular Design and Drug Development, University of Sussex, Brighton BN1 9QJ, UK
dHigh Throughput Chemistry, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, UK
Received 24 November 2003; revised 5 January 2004; accepted 19 January 2004
Abstract—Pentafluorophenyl (PFP) acrylate, a stable compact bifunctional scaffold undergoes rapid N-ethylpiperidinium hypo-
phosphite (EPHP) mediated conjugate radical addition to yield a variety of active esters susceptible to further functionalization by
aminolysis.
Ó 2004 Published by Elsevier Ltd.
Intermolecular radical reactions provide an attractive
means of carbon–carbon bond formation due to their
mild conditions and functional group tolerance. How-
ever, while the functional group compatibility of these
transformations is good, unwanted side reactions such
as dimerization and polymerization, can severely limit
the scope of the process. In recent years tri-n-butyltin
hydride (TBTH), a toxic and expensive but highly
effective chain carrier, has been employed by a number
of groups to develop efficient radical mediated chain
processes.1 Although there have been numerous reports
of alternative reagents to TBTH it is the case that no
single reagent or protocol has been sufficiently general to
replace this toxic reagent. In particular the difficulty in
defining a reagent system that can be used for both inter-
and intramolecular radical addition reactions has yet to
be found.
wished to develop a complimentary solution phase
variant, but were uncertain whether a polyfluorinated
acrylate or the resulting addition products would be
sufficiently stable to make such an approach practical.
Moreover we wanted to develop a tin-free methodology.
We here report such a protocol employing pentafluoro-
phenyl (PFP) acrylate 3,3 an air and moisture stable
electron deficient olefin, which could easily be prepared
in a single step and on large scale (0.1 mol) (Scheme 1).4
It should be noted that this bifunctional acrylate could
be stored for long periods of time (>2 years) at low
temperatures ()20 °C) without a stabilizer.5
In a previous report we described a TBTH protocol for
radical additions to PFP-sulfonate derivatives,6 and we
found that such reactions could be effected on the
present PFP-acrylate species 3. However we were keen
to test a variety of non-tin alternatives.7 We found the
commercially available hypophosphite reagent EPHP
We have previously established TBTH-mediated radical
additions to an activated tetrafluorophenyl (TFP)-
acrylate acceptor on solid support.2 However, the suc-
cess of that system we felt relied in part on the stability
of the solid-supported substrates and products. We
OH
F
F
F
F
F
F
F
F
F
O
Et3N, Et2O, 0 ºC, 30 min
O
+
Cl
O
1
2
Keywords: EPHP; Radical; Addition; Amides; PFP esters.
* Corresponding author. Tel.: +44-20-7679-4694; fax: +44-1273-678-
734; e-mail: s.caddick@ucl.ac.uk
F
3, 88 - 95 %
Scheme 1. Preparation of PFP acrylate.
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.01.082

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S. Caddick et al. / Tetrahedron Letters 45 (2004) 2363–2366
(1-ethylpiperidine hypophosphite 95% available from
Aldrich, UK) to be the most suitable reagent for radical
mediated C–C bond formation with PFP acrylate 3.8
impurities can be removed by a simple aqueous work-
up). In addition to this, no large excess of either iodide
or acceptor is required (or indeed improves the yields),
but rather they can be employed in a near 1:1 ratio,
illustrating the efficiency of the transformation.
Dichloromethane was chosen as the solvent for solu-
bility reasons as well as to limit solvent–radical inter-
actions.
In the case of PFP acrylate, we found that to avoid
decomposition,9;10 5 equiv of the chain carrier were
required to effect intermolecular radical addition at 0 °C.
The most suitable initiator for the chain process was a
combination of triethylborane and oxygen, which can be
employed at such temperatures. Abstraction of hydride
from hypophosphite we envisaged would lead to a
phosphorus centred radical, which could then abstract a
halide atom in a similar manner to TBTH-mediated
processes.11 These reactions are particularly facile,
involving short reaction times (<5 min) and efficient
work-up procedure (ca. 95% of hypophosphite derived
Having established optimum reaction conditions we
wished to demonstrate the effectiveness of this EPHP
mediated radical addition to PFP acrylate 3 with a
selected number of functionalized alkyl iodides (Table
1).12 Yields are mostly good, although in some cases,
such as alcohol 4e (entry 5) and amino acid derivative 4j
(entry 10) lower yields were observed. In such cases the
Table 1. EPHP mediated functionalization of PFP
O
O
RI, EPHP, Et3B,
air, 0 ºC, 5 min
DCM
PFPO
R
PFPO
4
5
Entry
1
Iodide (4a–k)
Product (5a–k)
Isolated yield, %
85
O
PFPO
O
I
2
3
4
78
78
57
I
PFPO
O
PFPO
O
Cl
I
Cl
I
TBSO
HO
PFPO
OTBS
O
5
6
7
8
9
41
72
67
68
66
I
OH
O
PFPO
O
O
I
MeO
PFPO
O
OMe
O
OH
O
PFPO
HO
O
I
O
O
O
I
PFPO
O
O
Cl
I
Cl
PFPO
O
I
BnO
O
O
H
N
10
11
39
80
Boc
OBn
NH
Boc
PFPO
OAc
O
OAc
OAc
OAc
AcO
AcO
O
O
AcO
AcO
PFPO
I

S. Caddick et al. / Tetrahedron Letters 45 (2004) 2363–2366
2365
halides were more susceptible to reduction and
O
NH2R', Et3N,
O
substantial quantities of the reduced products were
observed (47% and 50%, respectively). Residual iodide
(28%) was observed only in the case of TBS ether 2d
(entry 4). Most noteworthy is the very good yield
achieved in the stereoselective formation of anomeric
C-glycoside 5k (entry 11).13 Such acid-stable species,
found in a variety of bio-active natural products, are
most often prepared via free-radical methods.14;15 In this
case the anomeric radical undergoes stereocontrolled
addition to the more electrophilic methylene of the
acrylate 3.16 Such C-glycosidations are generally stereo-
selective due to the strong stereoelectronic influences
that govern radical reactions at anomeric centres.17
However, in the case of glucose derivatives, mixtures are
often observed when TBTH is employed as the chain
carrier and so the good yield and selectivity is note-
worthy.18 Also noteworthy is the good yield achieved for
the carboxylic acid derivative 4g (entry 7).19
PFPO
R
R'HN
R
CH2Cl2, 0 o
C
6
5
OAc
O
OAc
O
AcO
AcO
AcO
AcO
O
O
O
AcO
AcO
N
N
OH
6b,86 %a
S
H
6a,92 %
OAc
O
OAc
O
AcO
AcO
AcO
NH
AcO
O
AcO
AcO
N
N
CO2Me
CO2Et
6c,98 %
6d,97 %
H
H
Figure 1. Examples of aminolysis products of 5k.
Although these EPHP mediated additions work well
with alkyl iodides, we have found that the analogous
reactions with alkyl bromides usually proceed relatively
poorly.20 Similarly inefficient in our experience are
reactions using electrophilic radicals generated from
iodoacetamide and iodoacetonitrile.
Acknowledgements
We gratefully acknowledge the financial support of
EPSRC and GlaxoSmithKline (GSK). We also grate-
fully acknowledge AstraZeneca, Novartis, Pfizer,
EPSRC, BBSRC and AICR for support of our pro-
gramme. We also thank the EPSRC Mass Spectrometry
Service at Swansea and Drs. Abdul-Sada, Avent and
Hitchcock at the University of Sussex for their contri-
bution to this work.
Having established easy access to a large variety of alkyl
PFP esters 5 the opportunity for further functionaliza-
tion by the well-documented aminolysis of such species
could be explored. PFP esters have been widely used in
peptide chemistry since the 1970s, especially on solid
support,21 but have recently also found application in
solution phase chemistry.22 Their popularity is partly
due to their stability and ease of handling. The use of the
PFP group as an activating and protecting group is an
advantage.23 While unstable acid chlorides and carbo-
diimide reagents were important milestones in peptide
chemistry, the need for harsh conditions and the po-
tential racemization associated with such protocols has
led to the development of a variety of active esters.24
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