One-pot Hofmann elimination-transesterification/amidation reactions on REM resin using perfluorous solvents

Article abstract of DOI:10.1016/S0040-4039(02)01388-6

The incorporation of 2,2,2-trifluoroethanol esters into substrates for the REM resin synthesis of 3° amines allows a one-pot Hofmann elimination/transesterification protocol to be performed. In this way α-amino acid esters and amides were synthesised by a

Full text of DOI:10.1016/S0040-4039(02)01388-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6413–6415
One-pot Hofmann elimination–transesterification/amidation
reactions on REM resin using perfluorous solvents
J. Richard Morphy,* Zoran Rankovic and Mark York
Medicinal Chemistry Department, Organon Laboratories Ltd., Newhouse ML1 5SH, Scotland, UK
Received 16 May 2002; revised 24 June 2002; accepted 4 July 2002
Abstract—The incorporation of 2,2,2-trifluoroethanol esters into substrates for the REM resin synthesis of 3° amines allows a
one-pot Hofmann elimination/transesterification protocol to be performed. In this way a-amino acid esters and amides were
synthesised by adding alcohols or 1° amines to the Hofmann elimination mixture. The excess of nucleophile required to drive the
transesterification or amidation to completion was found to be considerably lower when perfluorous solvents were used to
accelerate the reaction (FAST effect). © 2002 Elsevier Science Ltd. All rights reserved.
The use of solid-phase organic synthesis (SPOS) as a
tool for the synthesis of chemical libraries is an area of
great importance, both in academia and in the pharma-
ceutical industry.1 REM resin methodology is an
efficient approach for the solid phase synthesis of 3°
amines.2 In its simplest form the REM resin, 1 under-
goes Michael addition with a 2° amine to give a poly-
mer bound 3° amine, 2. Quaternisation of 2 with an
alkyl halide then gives a quaternary ammonium salt 3,
which on exposure to a mild base releases the 3° amine
product 4 from the resin (Hofmann elimination) whilst
regenerating starting material 1 (Scheme 1).
6 (20 equiv., DMSO, 20°C, 1 h) and subjected to
Hofmann elimination conditions (DIPEA 2 equiv.,
K2CO3 2 equiv., DCM) in the presence of methanol
(Scheme 2, X=O, R=CH3).5 The results are shown in
Table 1.
For reactions in DCM, although transesterification did
occur, the process did not proceed to completion with
less than 30 equiv. of methanol (Table 1, entries 1–5).
In order to reduce this prohibitive excess, reaction was
attempted in perfluorohexane. We have recently
reported large increases in yield for solid-phase Michael
reactions with this solvent due to its immiscibility with
common reagents and a consequent reagent concentra-
The use of 2,2,2-trifluoroethanol esters as activating
groups in peptide coupling and transesterification reac-
tions has been previously reported.3,4 It was thought
that by incorporating such a moiety into the alkyl
halide used for quaternisation, a resin bound activated
ester would be obtained that could be cleaved from the
resin and transesterified in one-pot. In this way a large
batch of polymer bound quaternary ammonium salt 3
could be prepared and then split into numerous smaller
batches for the synthesis of an array of esters and
amides by transesterification with alcohols and amines,
respectively.
In order to test this hypothesis REM resin bound
N-methylphenethylamine 5 was quaternised with halide
Keywords: tertiary amines; perfluorous solvents; polymer support;
reagent concentration; solid-phase synthesis; REM resin; transesterifi-
cation.
* Corresponding author. E-mail: r.morphy@organon.co.uk
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01388-6

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J. R. Morphy et al. / Tetrahedron Letters 43 (2002) 6413–6415
Scheme 2.
Table 1.a
Table 2.a
Entry
Solvent
Equiv. MeOH
Conversion (%)b
1
2
3
4
5
6
7
DCM
DCM
DCM
DCM
DCM
Perfluorohexane
Perfluorohexane
2
5
10
20
30
2
18
49
76
86
\95
\95
\95
5
a Quaternisation (0.05 mmol resin, 1 mmol 6) performed for 1 h in
DMSO. Transesterification performed for 18 h (0.05 mmol resin,
DIPEA 2 equiv., K2CO3 4 equiv., MeOH, solvent 1 mL). For
procedure see Ref. 6.
b Conversion determined by 1H NMR (CDCl3).
tion effect.2c Use of this solvent did indeed result in
improvements with only traces of trifluoroester 7 seen
with 2 equiv. of methanol and only product 8 observed
when 5 equiv. were used (Table 1 entries 6–7). No
transesterification was observed under any conditions
when the 2,2,2-trifluoroethanol ester was replaced with
an ethyl ester.
It was conceivable that the increases in conversion seen
with perfluorohexane were simply due to the miscibility
of the liberated 2,2,2-trifluoroethanol with the
perfluorous solvent and the favourable effects this
would have on the transesterification equilibrium. How-
ever, this was shown not to be the case since the two
species are in fact immiscible. Having established the
feasibility of the one-pot Hofmann elimination/transes-
terification protocol the reaction was performed on a
number of different alcohols (Table 2). All of the 1°
alcohols studied gave complete transesterification when
reaction was performed in perfluorohexane with gener-
ally less than 50% conversion in DCM. With 2° alco-
hols the reaction did not proceed to completion with
either solvent (Table 2, entry 7) although once again
conversions in perfluorohexane were considerably
higher than in DCM.
Although 1° amines reacted efficiently to give the corre-
sponding amide 9, no product could be detected when
2° amines were used as the nucleophile (Table 3, entry
6). This interesting reactivity could perhaps be
exploited in a selective scavenger reagent for primary
amines and studies to investigate this possibility are
currently underway. Hydroxylamines and a-amino
acids were also suitable nucleophiles for the transester-
ification process (Table 3, entries 7 and 8).
When volatile amines/alcohols were used as nucleophile
any excess was simply removed at the end of the
procedure by evaporation. Excesses of nucleophile for
which this treatment was not amenable were removed
by the use of a polymer-supported isocyanate (for
amines),7 or sulphonyl chloride (for alcohols)8 scav-
enger reagent.
The use of 1° amines to give, after Hofmann elimina-
tion, a-amino acid amides (Scheme 2, X=NH) was also
successful (Table 3). Once again the use of perfluoro-
hexane as solvent gave greater conversions than DCM.
In summary, the incorporation of
a
2,2,2-tri-
fluoroethanol ester into substrates for REM resin

J. R. Morphy et al. / Tetrahedron Letters 43 (2002) 6413–6415
6415
Table 3.a
and 1° amines. The extent of transesterification/amida-
tion was found to be greatest when perfluorohexane was
used as the solvent. These results represent another
manifestation of the so-called FAST (fluorocarbon accel-
erated supported transformation) effect which we have
previously reported for Michael additions.2c Hence this
technique is potentially useful for accelerating a broad
range of solid supported transformations.
References
1. Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96,
555–600.
2. (a) Morphy, J. R.; Rankovic, Z.; Rees, D. C. Tetrahedron
Lett. 1996, 37, 3209–3212; (b) Brown, A. R.; Rees, D. C.;
Rankovic, Z.; Morphy, J. R. J. Am. Chem. Soc. 1997, 119,
3288–3295; (c) Morphy, J. R.; Rankovic, Z.; York, M.
Tetrahedron Lett. 2001, 42, 7509–7511.
3. Miyazawa, T.; Nakajo, S.; Nishikawa, M.; Imagawa, K.;
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1 1996, 2867–2868.
4. Raghavan, R.; Ishida, M.; Shinozaki, H.; Nakanishi, K.;
Ohfune, Y. Tetrahedron Lett. 1993, 34, 5765–5768.
5. REM resin was prepared according to the published pro-
cedure,2b with a 1% PS-DVB resin matrix. REM resin
loading was 1.23 mmol/g.
6. Typical reaction conditions: REM resin bound N-
methylphenethylamine (0.05 mmol) was suspended in
DMSO (1 mL) and treated with 6 (1 mmol). The mixture
was shaken at 20°C for 1 h, filtered, washed (3×1 mL
DMF, DCM) and dried in vacuo. The resin was then
treated with the nucleophile (0.125–1 mmol), K2CO3 (0.2
mmol), DIPEA (0.1 mmol) and the appropriate solvent
and shaken at 20°C for 18 h. The product was then
isolated by filtration and resin washing (1×1 mL DCM,
3×1 mL 1:1 v/v toluene/hexane, DCM).
chemistry allows a one-pot Hofmann elimination–trans-
esterification process to be performed as the last step in
the reaction cycle. This would allow the synthesis of a
wide variety of amino acid esters and amides from a single
batch of quaternised resin by splitting at the Hofmann
elimination stage and treating with a variety of alcohols
7. Kaldor, S. W.; Siegel, M. G.; Fritz, J. E.; Dressman, B. A.;
Hahn, P. J. Tetrahedron Lett. 1996, 37, 7193–7196.
8. Rueter, J. K.; Nortey, S. O.; Baxter, E. W.; Leo, G. C.;
Reitz, A. B. Tetrahedron Lett. 1998, 39, 975–978.