Solid-phase synthesis of tertiary methylamines via reductive alkylation-fragmentation using a hydroxylamine linker

Article abstract of DOI:10.1016/S0040-4039(00)01103-5

The solid-phase synthesis of tertiary methylamines via reductive alkylation-fragmentation employing a hydroxylamine linker is described. The hydroxylamine linker is traceless, robust and versatile, allowing strong organometallic reagents to be used in the synthesis of diverse tertiary methylamines. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01103-5

Tetrahedron Letters 41 (2000) 6635±6638
Solid-phase synthesis of tertiary methylamines via reductive
alkylation±fragmentation using a hydroxylamine linker
Paul Blaney,a Ronald Grigg,a,* Zoran Rankovicb and Matthew Thoroughgooda
aMolecular Innovation, Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry,
Leeds University, Leeds LS2 9JT, UK
bMedicinal Chemistry Department, Organon Laboratories Ltd., Newhouse ML1 5SH, Scotland, UK
Received 5 June 2000; accepted 29 June 2000
Abstract
The solid-phase synthesis of tertiary methylamines via reductive alkylation±fragmentation employing a
hydroxylamine linker is described. The hydroxylamine linker is traceless, robust and versatile, allowing
strong organometallic reagents to be used in the synthesis of diverse tertiary methylamines. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: solid-phase synthesis; tertiary methylamines; traceless hydroxylamine linker.
Solid-phase synthesis has evolved into a powerful tool for the rapid construction of combinatorial
libraries of small, drug-like compounds.1 There is a perceived lack of suitable linkers that are
stable to a wide range of reagents required during synthesis, which can be cleaved under mild
conditions and which are traceless.2
Tertiary amines are an attractive target from a drug discovery perspective, due to their good
intestinal absorption, CNS penetration and the potential for involvement of the tertiary nitrogen
in ligand binding.3 REM resin has been used successfully for the synthesis of tertiary amine
libraries.4 However, the ester linkage of the REM resin precludes the use of certain desirable but
aggressive reagents, which the more stable vinyl sulfone linker partially addresses.5
This letter describes a novel solid-phase strategy for the synthesis of tertiary methylamines
utilising resin-bound hydroxylamine as a linker. This linker is inert to a range of aggressive
reagents, including Grignard reagents, metal hydride reducing agents and strong acids or bases.
The hydroxylamine linker employed in these studies is attached directly to hydroxymethyl
polystyrene resin6 (Scheme 1).
The hydroxylamine linker 1 was Boc-protected and the protected resin 2 alkylated (20 mol
equiv. NaH/DMF/RT/16 h) with alkyl halides (40 mol equiv.), giving 3. The Boc group was
* Corresponding author. E-mail: grigg@chemistry.leeds.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01103-5

6636
Scheme 1.
removed and the unprotected resin 4 reductively alkylated7 with a variety of aldehydes (10 mol
equiv. R2CHO/5 mol equiv. NaBH(OAc)3/THF/RT/16 h) to give the resin-bound tertiary
hydroxylamines 5. Extensive solution-phase studies of the quaternisation of tertiary hydroxyl-
amines showed that methyl tri¯ate was the only alkylating agent that gave excellent yields of
quaternary salts. Although other tri¯ates prepared in situ via silver tri¯ate/alkyl halide exchange
gave quaternary salts in solution (unpublished observations), this methodology proved unsuitable
for the solid-phase sequence due to interference from the silver halide precipitate. The possibility
that the a-e€ect might facilitate the quaternisation was not realized and this accords with related
observations by other workers.8
Alkylation of 5 with methyl tri¯ate (5 mol equiv./CH2Cl2/RT/16 h) gave the quaternised resin 6
and base-induced cleavage (5 mol equiv. Et3N/CH2Cl2/RT/16 h) furnished the resin-bound
aldehyde 7 and tertiary amines 8 (Table 1). The tertiary amines released from the resin were
separated from the excess triethylamine and salts by a simple aqueous sodium bicarbonate wash.
The yields for the six-step reaction sequence are mostly excellent. The purity of the amine
released from the resin is high (>99%, Table 1), because only the quaternised material 6 is
susceptible to the base-induced cleavage. The reaction sequence was followed by FTIR analysis of
the resins 1±7, i.e. the alkylation step 2!3 was characterised by Boc carbamate CˆO str. shifting
from ꢀ1740 to ꢀ1700 cm^1 after alkylation. The resin-bound aldehyde 7 was characterised by the
appearance of a strong absorption band at 1702 cm^1.
To establish whether the hydroxylamine linker was more robust than REM resin4 with respect
to strong reducing agents, we synthesised 9 by alkylation of 2 with ethyl bromide (Scheme 1) and

6637
Table 1
Solid-phase synthesis of tertiary amines 8 (Scheme 1)
subsequent Boc deprotection. Acylation of 9 (Scheme 2) with phenylacetyl chloride gave resin-
bound hydroxymate 10. Solution-phase studies indicated that the best conditions for the
reduction were a 1:1 mixture of aluminium trichloride and lithium aluminium hydride11 in THF
at 45ꢁC. Using lithium aluminium hydride alone resulted in partial N±O bond cleavage.
Scheme 2.
Applying these conditions to the solid-phase synthesis (20 mol equiv. AlCl3/20 mol equiv.
LiAlH4/45ꢁC/45 min; followed by addition of resin 10/45ꢁC/4 h) gave tertiary hydroxylamine
resin 11, which was quaternised and cleaved, yielding the resin-bound aldehyde 7, plus the
tertiary amine 12 in a yield of 56%. A direct comparison of the two routes for the synthesis of 12
is shown in Table 2. The somewhat lower yield in the hydroxymate reduction pathway is the
result of Hunig base-induced fragmentation during the conversion of 9 to 10 (Scheme 2),
releasing the secondary amide and resin-bound aldehyde 7. This was observed in solution-phase

6638
Table 2
Comparison of yields for synthesis of 12
experiments, and the FTIR spectrum of 11 indicated the presence of a small amount of aldehyde
carbonyl (1702 cm^1) in addition to the expected hydroxymate carbonyl (1670 cm^1). The N±O
bond remained intact during the reduction, according to solution-phase experiments.
In order to establish the stability of the hydroxylamine towards strong acids, resin 11 was
agitated overnight in a 95% TFA/dichloromethane solution and, after a base wash, subjected to
quaternisation and cleavage. The tertiary amine 12 was obtained with no drop in yield, indicating
the linker's stability to strong acidic conditions.
Acknowledgements
We thank Leeds University and Organon Laboratories for support.
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