Palladium-catalysed nucleophilic release of allylic amines from a phenolic resin

Article abstract of DOI:10.1016/S0040-4039(01)01739-7

2° Allylic alcohols were coupled to phenolic polystyrene resin under Mitsunobu conditions to provide substituted allyl ethers, which underwent efficient nucleophilic cleavage by 1° and 2° amines in the presence of catalytic palladium to afford allylic amines.

Full text of DOI:10.1016/S0040-4039(01)01739-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8227–8230
Palladium-catalysed nucleophilic release of allylic amines from a
phenolic resin
Martyn Fisher and Richard C. D. Brown*
Department of Chemistry, The University of Southampton, Highfield, Southampton SO17 1BJ, UK
Received 7 August 2001; accepted 14 September 2001
Abstract—2° Allylic alcohols were coupled to phenolic polystyrene resin under Mitsunobu conditions to provide substituted allyl
ethers, which underwent efficient nucleophilic cleavage by 1° and 2° amines in the presence of catalytic palladium to afford allylic
amines. © 2001 Elsevier Science Ltd. All rights reserved.
Solid-phase combinatorial and multiple parallel synthe-
sis methods have become significant in many areas,
including the synthesis of small organic molecules.1–5
As a result, new linkers and cleavage strategies are
constantly under investigation.6–9 Linkers which enable
release of the target molecule from the solid support
under mild conditions or are robust towards a variety
of reaction conditions are particularly desirable, as are
those which allow the introduction of structural vari-
ability in the cleavage step.
vided phenolic polystyrene resin 4. The loading of resin
4 was established to be 2.5 mmol/g by coupling with
3-phenylpropionyl chloride and reductive cleavage
(LiBH4) of dihydrocinnamyl alcohol, which was
quantified by GC.
The allylic alcohol 8a,18 prepared by treating benzalde-
hyde with vinyl magnesium bromide, was coupled to
the resin 4 under Mitsunobu conditions.14–16 The pres-
ence of the 2° allylic ether 3a was supported by signals
at 138.4 (CH), 116.4 (CH2) and 81.1 (CH) ppm in the
gel-phase 13C NMR spectrum.
We have previously reported the cyclisation cleavage of
allylic carboxylates 1 under mild conditions to afford
pyrrolidines 2 (Scheme 1).10 Although the ester linkage
contained in 1 proved compatible with acidic conditions
(Boc-deprotection with TFA), it was cleaved under
nucleophilic conditions such as hydride reduction. Here
we report the development of a complementary strategy
based on the cleavage of allyl phenyl ethers 3 (Scheme
2),11–13 which are stable to nucleophiles in the absence
of palladium, but readily cleaved by amines in the
presence of catalytic Pd(0).
Nucleophilic cleavage of allyl ether 3a was first investi-
gated with piperidine in the presence of Pd(acac)2 and
dppe (Scheme 4). The effect of changing various reac-
Pd(acac)2
dppe
Ar
R
H
N
R
N
O
O
Ar
Our approach to the allyl ethers 3 would employ a
Mitsunobu coupling reaction to form the ether bond
(Scheme 3).14–16 The starting phenolic resin 4 was pre-
pared in three steps from polystyrene resin, commenc-
ing with a Friedel–Crafts acylation to afford the resin
bound acetophenone 6,17 which was transformed to
acetate 7 upon treatment with mCPBA. No evidence
was found to support the presence of the regioisomeric
methylbenzoate resin. Hydrolysis of the acetate 7 pro-
1
2
Scheme 1. Palladium-catalysed cyclisation cleavage of pyrro-
lidines.
O
OH
Pd(0)
Nu-H
Nu
+
Ar
Ar
4
3
5
Scheme 2. Palladium-catalysed nucleophilic cleavage of allyl
* Corresponding author. Tel.: +(0)23 80594108; fax: +(0)23 80596805;
e-mail: rcb1@soton.ac.uk
ethers.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01739-7

8228
M. Fisher, R. C. D. Brown / Tetrahedron Letters 42 (2001) 8227–8230
different amines (Table 1). With the exception of the
O
2-furyl-substituted allylic ether 3d (entry 13, Table 1),
all reactions afforded the desired products in acceptable
yield. For the unsuccessful reaction, it is unclear
whether the failure of the overall process originated in
the initial immobilisation of 8d or at the cleavage step
as no conclusive analytical data could be obtained on
resin 3d.
b
a
c
6
polystyrene resin
2% crosslinked
OAc
OH
d
A by-product 23, arising from attack by the acetylacet-
onate ligand, was observed in varying quantities in all
reactions using Pd(acac)2 (Fig. 2). This problem was
avoided in later experiments by simply swapping the
catalyst to Pd(PPh3)4 (entries 2, 4, 6 and 9, Table 1).
OH
7
4
Ar
8a-d
O
a Ar = Ph
b Ar = p-Cl(C6H4)
c Ar = 3-pyridyl
d Ar = 2-furyl
The intermolecular substitution reactions of allylic
acetates with 1° amines has been reported not to be a
useful process due to the formation of by-products
arising from diallylation and direct nucleophilic attack
on the ester.12 In our case the latter side reaction was
not an issue, although unsurprisingly, reactions with 1
equiv. of BnNH2 in the solid-phase led to a certain
amount of diallylated material 24 (Fig. 2). Formation
of 24 was significantly reduced, but not eliminated, by
using four equivalents of the 1° amine.
Ar
3a-d
Scheme 3. Synthesis of immobilised allyl ethers. Reagents and
conditions: (a) AlCl3, AcCl, CS2, D; (b) mCPBA, CH2Cl2; (c)
Me3SiOK, MeOH, CH2Cl2; (d) PPh3, DEAD, THF.
O
a
Ph
N
Ph
Purification of the crude products was required due to
the presence of some unreacted 1° or 2° amines in the
crude product. The 2° amines were conveniently scav-
enged from the reaction mixtures using an isocyanate
resin (Fig. 3).21 For the removal of excess 1° amine
from 2° amine products, acetoacetoxy ethyl methacryl-
ate (AAEM) resin was employed.22 Further purifica-
tion of the products involved simple chromatography
to remove non-polar catalyst-derived components.
NH
3a
9
Scheme 4. Nucleophilic cleavage of resin 3a with piperidine.
Reagents and conditions: (a) Pd(acac)2, dppe, THF, D.
tion parameters, including reaction time, amount of
catalyst, amount of ligand, amount of piperidine and
temperature, was investigated. The palladium-catalysed
nucleophilic cleavage reaction did not proceed at room
temperature, whereas prolonged reaction times (3–8 h)
at reflux led to slow degradation of the product. Moni-
toring of the release of product 9 over time by GC
revealed that a maximum yield (70% by GC, 52%
isolated after flash chromatography) was achieved after
1 to 2 h at reflux with 5 mol%† Pd(acac)2 and 10 mol%
dppe. The catalyst loading could be reduced further (2
mol%) with a modest decrease in the yield of 9,
although 5 mol% catalyst was routinely used. Efficient
cleavage required only 1 equivalent of piperidine and
resubmitting the recovered resin to the cleavage condi-
tions failed to afford any additional amine 9. Only a
trace amount of the regioisomeric 2° allylic amine was
In summary, a facile synthesis of immobilised allylic
ethers has been described from aldehyde starting mate-
rials. The allylic ethers are resistant to a variety of basic
and nucleophilic conditions until activated with cata-
lytic palladium, allowing incorporation of amine nucle-
ophiles to produce allylic amines. The allylic amine
structural motif is present in a large number of biolog-
ically active molecules, and the methodology described
may present a means of preparing arrays of allylic
amines for screening. Our future studies will focus on
Ns
N
H
1
NH
NH
NH2
N
present in the crude product (determined from the H
Et
NMR spectrum).
22
To investigate the scope of the palladium-catalysed
nucleophilic cleavage process further, the reactions of
four different amines (Fig. 1) with four resin-bound
allylic ethers were investigated (Scheme 5).19 Allylic
alcohols 8a–d18,20 were immobilised on hydroxy
polystyrene (4), and the resulting resins 3a–d were
subjected to the cleavage conditions in the presence of
Figure 1. Amines used in cleavage reactions.
O
a or b
R1
Ar
N
R2
(see
table 1)
Ar
3a-d
9-21
Scheme 5. Palladium-catalysed nucleophilic cleavage with
amines. Reagents and conditions: (a) R1R2NH, 5 mol% Pd-
(acac)2, 10 mol% dppe, THF, D; (b) R1R2NH, 5 mol%
Pd(PPh3)4, THF, D.
† Yields and amounts of reagents are all based on the initial loading
of the resin 4, assuming quantitative conversions for solid-phase
reactions.

M. Fisher, R. C. D. Brown / Tetrahedron Letters 42 (2001) 8227–8230
8229
Table 1. Palladium-catalysed nucleophilic cleavage of allylic amines (Scheme 5)19
Entry
Ar
Amine
Catalyst
Product
Yield (%)a
1
2
3
4
5
6
7
8
Phenyl
Phenyl
Phenyl
Piperidine
BnNH2
Pd(acac)2/dppe
Pd(PPh3)4
Pd(acac)2/dppe
Pd(PPh3)4
Pd(acac)2/dppe
Pd(PPh3)4
Pd(acac)2/dppe
Pd(acac)2/dppe
Pd(PPh3)4
Pd(acac)2/dppe
Pd(acac)2/dppe
Pd(acac)2/dppe
Pd(acac)2/dppe
9
10
11
12
13
14
15
16
17
18
19
20
21
52
76
49
69
72
77
67
49
30
53
51
61
b
EtNHBn
b
p-Cl(C6H4)
p-Cl(C6H4)
p-Cl(C6H4)
p-Cl(C6H4)
p-Cl(C6H4)
3-Pyridyl
3-Pyridyl
3-Pyridyl
3-Pyridyl
2-Furyl
BnNH2
Piperidine
Piperidine
EtNHBn
22
b
9
BnNH2
10
11
12
13
Piperidine
EtNHBn
22c
22
Trace
a Isolated yield of purified product based on the loading of the phenoxy polystyrene (4).
b 4 equivalents of benzylamine were used.
c 2 equivalents of 22 were used.
MeOC COMe
Bn
N
6. Gordon, K.; Balasubramanian, S. J. Chem. Technol. Bio-
technol. 1999, 74, 835–851.
Ar
Ar
Ar
Ar
7. Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000,
100, 2091–2157.
23
24
8. James, I. W. Tetrahedron 1999, 55, 4855–4946.
9. Eggenweiler, H. M. Drug Discov. Today 1998, 3, 552–560.
10. Brown, R. C. D.; Fisher, M. Chem. Commun. 1999,
1547–1548.
Figure 2. By-products obtained in Pd-catalysed cleavage reac-
tions.
O
O
11. Inoue, Y.; Taguchi, M.; Toyofuku, M.; Hashimoto, H.
Bull. Chem. Soc. Jpn. 1984, 57, 3021–3022.
NCO
O
Isocyanate resin
12. Tsuji, J. Organic Synthesis with Palladium Compounds;
Springer-Verlag: Berlin, 1980.
AAEM resin
13. Bergbreiter, D. E.; Chen, B.; Lynch, T. J. J. Org. Chem.
1983, 48, 4179–4186.
Figure 3. Isocyanate and acetoacetoxy scavenger resins.
14. Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63,
864–866.
15. Mitsunobu, O.; Yamada, M.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1967, 40, 935–939.
the elaboration of the resin-bound allylic ethers and
cleavage in the presence of other nucleophiles.23
16. Typical procedure for Mitsunobu coupling. THF (25 mL)
was added to a mixture of phenoxypolystyrene resin (4)
(2.04 g, 3.06 mmol), triphenylphosphine (5.24 g, 20.0
mmol) and allylic alcohol 8b (3.36 g, 20.0 mmol) under
an inert atmosphere. The suspension was cooled to 0°C
and stirred for 10 min. DEAD (3.2 mL, 3.48 g, 20.0
mmol) was added dropwise and the reaction was allowed
to warm to rt, and the resulting orange suspension was
stirred at rt for 12 h. The resin was collected by filtration,
washed with CH2Cl2, DMF, MeOH, DMF and CH2Cl2
(100 mL each) and dried under vacuum (0.7 mmHg,
50°C) for 2 h. This afforded the product 3b as a beige
solid (2.62 g).
Acknowledgements
We acknowledge the EPSRC for a QUOTA stu-
dentship (M.F.) and the Royal Society for a University
Research Fellowship (R.C.D.B.). We also thank Profes-
sor Mark Bradley for the kind donation of AAEM
resin. Syngenta and Merck Sharp and Dohme are also
gratefully acknowledged for unrestricted grants.
17. Frechet, J. M.; Nuyens, L. Can. J. Chem. 1976, 54,
926–934.
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19. Typical procedure for palladium-catalysed nucleophilic
cleavage. THF (3 mL) was added to a mixture of resin 3b
(149.6 mg, 0.19 mmol), Pd(acac)2 (2.8 mg, 9.3 mmol),
dppe (7.4 mg, 18.6 mmol) and piperidine (15.8 mg, 0.19
mmol) under an inert atmosphere. The reaction was
heated at reflux with gentle stirring for 1.5 h. After
cooling to rt, the resin was collected by filtration, washed
2. Franzen, R. G. J. Comb. Chem. 2000, 2, 195–214.
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17–42.

8230
M. Fisher, R. C. D. Brown / Tetrahedron Letters 42 (2001) 8227–8230
with CH2Cl2 (50 mL) and the filtrate concentrated under
20. Iwasaki, M.; Kobayashi, Y.; Li, J.-P.; Matsuzaka, H.;
Ishii, Y.; Hidai, M. J. Org. Chem. 1991, 56, 1922–1927.
21. For the preparation and use of isocyanate resin, see:
Booth, R. J.; Hodges, J. C. J. Am. Chem. Soc. 1997, 119,
4882–4886.
22. Yu, Z.; Alesso, S.; Pears, D.; Worthington, P. A.; Luke,
R. W. A.; Bradley, M. Tetrahedron Lett. 2000, 41, 8963–
8967.
23. For related studies on the palladium-catalysed cleavage
of resin-bound allyl sulfones with C-nucleophiles, see:
Cheng, W. C.; Halm, C.; Evarts, J. B.; Olmstead, M. M.;
Kurth, M. J. J. Org. Chem. 1999, 64, 8557–8562.
vacuum to give the crude product as an orange oil (45
mg). Purification by column chromatography (6×1.5 cm
SiO2) eluting with CH2Cl2/MeOH (19:1) afforded the
allylic amine 13 as a colourless oil (31.5 mg, 0.13 mmol,
1
72%). H NMR (400 MHz, CDCl3): 7.29 (2H, d, J=8.5
Hz), 7.27 (2H, d, J=8.5 Hz), 6.46 (1H, d, J=15.6 Hz),
6.29 (1H, dt, J=15.6, 7.0 Hz), 3.13 (2H, dd, J=6.5, 1.5
Hz), 2.45 (4H, br s), 1.65–1.60 (4H, m) and 1.46 (2H, br
s); 13C NMR (100 MHz, CDCl3): 135.67, 133.16, 131.73,
128.85, 127.88, 127.66, 61.87, 54.77, 26.04 and 24.41;
LRMS (EI) m/z (rel. intensity): 235.9 (100), 238.0 (29).