Direct release of nitriles from solid phase

Article abstract of DOI:10.1016/S0040-4039(00)01988-2

Cleavage conditions are described which allow resin bound secondary amides to be liberated from Sieber or Rink resin as nitriles. The method has been applied to the synthesis of a series of cyanobiaryls. Published by 2001 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01988-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1115–1118
Direct release of nitriles from solid phase
Neal D. Hone,a,* Lloyd J. Paynea and Colin M. Ticeb
aCambridge Discovery Chemistry, The Merrifield Centre, Rosemary Lane, Cambridge CB1 3LQ, UK
bRohm and Haas Company, 727 Norristown Road, Spring House, PA 19477-0904, USA
Received 15 August 2000; revised 27 October 2000; accepted 8 November 2000
Abstract—Cleavage conditions are described which allow resin bound secondary amides to be liberated from Sieber or Rink resin
as nitriles. The method has been applied to the synthesis of a series of cyanobiaryls. © 2001 Published by Elsevier Science Ltd.
Solid phase organic synthesis (SPOS) has its roots in
peptide chemistry.1 The widespread adoption of SPOS
for the generation of libraries of small molecules for
drug and agrochemical discovery has led to the devel-
opment of a variety of linkers that allow the release of
a range of functional groups beyond that typical of
peptides.2 The traceless linkers developed by several
groups are particularly noteworthy in this context.3 In
this letter we report conditions that allow the direct
release of nitriles from Sieber and Rink resins4 in
excellent yields. Nitriles are found in a number of
biologically active molecules ranging from pyrethroid
insecticides, e.g. fenvalerate to the cardiotonic milri-
none. Thus, this method adds a significant new method
to the SPOS toolbox.5 As a demonstration of its utility
we have prepared a series of cyanobiaryls.
bound amide 3a (Scheme 1). Amide 3a was treated with
trifluoroacetic anhydride (TFAA, 5 equiv.) and pyri-
dine (10 equiv.) in dichloromethane at room tempera-
ture overnight to furnish a crude product containing
the desired 2-cyanobiphenyl 4a in addition to by-prod-
ucts derived from TFAA and pyridine (Method A).7 A
simple aqueous work up afforded 4a in 82% yield
(Table 1, Entry 1). Treatment of seven additional resin
bound amides 3b–h with TFAA/pyridine afforded the
expected nitriles 4b–h in 51–98% yield (Table 1, Entries
2–8).
Further exploration of this chemistry revealed that
cleavage of 3a to 4a can also be effected using
trichloroacetyl chloride and triethylamine (Method B)
or with Burgess reagent (methoxycarbonyl sulfamoyl)
triethylammonium hydroxide, inner salt (Method C)
albeit in lower yields (Table 1: Entry 1 versus 2 and 3;
Entry 5 versus 6 and 7). In addition, Rink resin can
also be employed in place of Sieber resin with equal or
Fmoc Sieber resin 1 was deprotected under standard
conditions to give 2 and biphenyl-2-carboxylic acid was
coupled under standard conditions6 to afford resin
Scheme 1. (i) 20% piperidine in DMF, rt, 30 min; (ii) TBTU, HOBt, DIEA, DMF, rt, 2 h; (iii) TFAA (5 equiv.), pyridine (10
equiv.), DCM, rt, 12 h.
Keywords: solid phase synthesis; combinatorial chemistry; libraries; nitriles; biphenyls.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01988-2

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N. D. Hone et al. / Tetrahedron Letters 42 (2001) 1115–1118
better product yields but slightly reduced purities.
(Table 1: Entry 1 versus 4; Entry 5 versus 8).
allowing synthesis of a series of cyanobiaryls (Scheme
2). Several groups have recognised the utility of the
biphenyl scaffold and employed it in library synthesis.9
Bromoarylcarboxylic acids 5a–h were coupled to Sieber
resin 2 using standard conditions to afford resin bound
amides 6a–h.5 Bromine analyses of 6a–h indicated that
the loading reaction had been successful. Suzuki cou-
plings with various benzeneboronic acids 7 (Table 2)
were carried out under the conditions of Frenette and
Friesen8b to afford resin bound biarylamides 8. Cleav-
age from the resin using TFAA/pyridine (Method A)
afforded the crude cyanobiaryls 9. By-products from
the cleavage cocktail could be removed either by
aqueous workup (ether/saturated aqueous sodium
bicarbonate) or by solid supported liquid extraction
(SLE)10 to provide the expected cyanobiaryls 9, gener-
ally in good yield and purity (Table 2).
The facile dehydration of Sieber and Rink amides is in
contrast to the more forcing conditions usually required
for secondary amides. The electron rich nature of these
benzylamides presumably enhances both the nucleo-
philicity of the amide during O-trifluoroacetylation as
well as benzylic cleavage prior to TFA elimination. The
corresponding amides formed from aminomethyl
polystyrene are stable to the cleavage/dehydration con-
ditions. Certain functional groups such as primary and
secondary amines, primary amides and alcohols are
expected to be incompatible with these conditions.
As a demonstration of the utility of the method, we
combined it with the solid phase Suzuki reaction8
Table 1. Nitriles synthesised on solid phase
Scheme 2. (i) TBTU, HOBt, DIEA, DMF, rt, 18 h; (ii) Ar%B(OH)2 (7), Pd(PPh3)4, Na2CO3, DME, D, 48 h; (iii) TFAA (5 equiv.),
pyridine (10 equiv.), DCM, rt, 16 h.

N. D. Hone et al. / Tetrahedron Letters 42 (2001) 1115–1118
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Table 2. Cyanobiaryls synthesised
In conclusion, we have developed a practical solid
phase synthesis of nitriles and demonstrated its utility
by preparing a number of cyanobiaryls.
Showalter, H. D. H. J. Org. Chem. 1996, 61, 6498–6499.
(c) Hughes, I. Tetrahedron Lett. 1996, 37, 7595–7598. (d)
Hone, N. D.; Davies, S. G.; Devereux, N. J.; Taylor, S.
L.; Baxter, A. D. Tetrahedron Lett. 1998, 39, 897–900.
4. Novabiochem Rink Amide MBHA (1% DVB
crosslinked, 0.59 mmol/g) and Sieber Amide (1% DVB
crosslinked, 0.6 mmol/g) resins were employed.
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