Oxidation-Cope elimination: A REM-resin cleavage protocol for the solid-phase synthesis of hydroxylamines

Article abstract of DOI:10.1016/S0040-4039(01)00477-4

We have established that using an oxidation-Cope elimination cleavage protocol allows for the synthesis of N,N-disubstituted hydroxylamines from REM resin (polymer-bound benzyl acrylate). Michael addition of a secondary amine or addition of a primary amine followed by reductive alkylation provides polymer-bound tertiary amines. Oxidation of these resin-bound tertiary amines with MCPBA is followed by concomitant Cope elimination to regenerate the polymer-bound acrylate and provide the cleaved hydroxylamines.

Full text of DOI:10.1016/S0040-4039(01)00477-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3419–3422
Oxidation–Cope elimination: a REM-resin cleavage protocol for
the solid-phase synthesis of hydroxylamines
Robert E. Sammelson and Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis, CA 95616-5295, USA
Received 14 March 2001; revised 19 March 2001; accepted 21 March 2001
Abstract—We have established that using an oxidation-Cope elimination cleavage protocol allows for the synthesis of N,N-disub-
stituted hydroxylamines from REM resin (polymer-bound benzyl acrylate). Michael addition of a secondary amine or addition of
a primary amine followed by reductive alkylation provides polymer-bound tertiary amines. Oxidation of these resin-bound tertiary
amines with MCPBA is followed by concomitant Cope elimination to regenerate the polymer-bound acrylate and provide the
cleaved hydroxylamines. © 2001 Elsevier Science Ltd. All rights reserved.
Solid-phase organic synthesis1 (SPOS) is, at this time, a
well respected tool for the production of combinatorial
libraries.2 Linkers, which connect resin and synthetic
scaffold, together with cleavage protocols for removing
synthetic compounds from the resin are important fac-
tors in solid-phase synthesis.3 Traceless linkers have
emerged as useful tools in SPOS; one such traceless
linker is polymer-supported benzyl acrylate A (Fig. 1),
commonly known as REM resin as coined by Morphy
et al. (since it’s regenerated upon cleavage of the sub-
strate and the first reaction is a Michael addition to the
acrylate).4 To date, Wang and JANDAJEL™ resin-
bound acrylates B and C,5 polystyrene-bound benzyl
and phenyl vinyl sulfones D and E,6 and polystyrene-
bound acrylamides F7 have all been developed for
SPOS.
Some of these resins have been applied to the synthesis
of tertiary amines libraries8 and, to our knowledge,
Hofmann elimination9 (quaternization followed by
elimination to give tertiary amines) is the only reported
cleavage protocol for REM resins. We now demon-
strate that employing the Cope elimination10 efficiently
produces N,N-disubstituted hydroxylamines. It is
important to note both that many hydroxylamines
exhibit biological activity11 and that many hydroxy-
lamine derivatives possess biological activities similar to
their corresponding amines (indeed, amine“hydroxy-
lamines conversion can increase potency).12 N,N-Disub-
stituted hydroxylamines have previously been prepared
in solution-phase by either direct oxidation of the sec-
ondary amine using dimethyldioxirane or dibenzoyl
peroxide,13 addition of Grignard reagents to nitroalka-
O
O
O
O
JJ
O
O
O
O
A
B
C
R
O
O
S
O
O
N
S
O
O
D
E
F
Figure 1. REM resins.
Keywords: solid-phase synthesis; hydroxylamines; Cope elimination; N-oxide.
* Corresponding author. E-mail: mjkurth@ucdavis.edu
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00477-4

3420
R. E. Sammelson, M. J. Kurth / Tetrahedron Letters 42 (2001) 3419–3422
nes,14 or reduction of oximes with sodium borohydride
in the presence of carboxylic acids.15
Following literature protocols,4 Michael addition of a
primary amine to the REM resin followed by reductive
amination with a pyridine–borane complex22 in DMF/
EtOH gave tertiary amines (Scheme 2). This allows for
a more effective combinatorial approach where several
amines and aldehydes can be utilized in library produc-
tion and thus increase the advantages of SPOS. FT-IR
shows the typical shift for the acrylate and the unconju-
gated ester (1721 and 1732 cm−1, respectively) and these
were used to monitor Michael addition and Cope elim-
ination reactions. The REM resin was also recycled up
to three times without noticeable change in the IR
spectrum or dramatic decrease in hydroxylamine yield.
Our solid-phase route to hydroxylamines began by
attachment of acryloyl chloride to hydroxymethyl
polystyrene to deliver the REM resin (Scheme 1).16
Michael addition of secondary amines produced the
corresponding tertiary b-amino ester. After washing the
resin, this tertiary amine was reacted with MCPBA in
chloroform for 1–2 h to deliver the N-oxide. Normally,
the Cope elimination of the amine oxide is carried out
at high temperatures (pyrolysis).17 It has also been
reported that solution-phase Cope eliminations can be
effected by passing a chloroform solution of the N-
oxide through a column of basic alumina.18 For solid-
phase organic synthesis with combinatorial potential,
where numerous functional groups would be repre-
sented, we required milder conditions. Cram et al.
reported that the solution-phase Cope elimination can
be carried out at room temperature in either THF or
DMSO.19 In light of their work, we attempted several
trial oxidations in chloroform followed by filtration. An
additional volume of chloroform was added and the
swollen resin was shaken briefly and filtered. THF was
added to the resin, mixed briefly, and again filtered. A
second volume of THF was added and the resin was
shaken overnight to complete the elimination. In our
hands, we found that premature elimination occurred
prior to addition of THF which lead to MCPBA and
MCBA contamination of the cleaved hydroxylamine.20
In light of this, the organic layers were combined and
concentrated to give a white solid. Extraction or chro-
matography of this residue provided pure hydroxy-
lamine.21 Using chloroform for the entire process
proved more effective.21b
We have also examined other oxidation protocols
(hydrogen peroxide in THF, peracetic acid in various
solvents, and dimethyldioxirane in acetone/CH2Cl2).
Unfortunately, these procedures were not as effective as
MCPBA/CHCl3.
A solid-phase Cope elimination method to prepare
N,N-disubstituted hydroxylamines from tertiary b-
amino esters has been developed. Thus, both Cope and
Hofmann elimination strategies can be used to deliver
product from REM resin.
Experimental
Melting points were determined using an Electrother-
mal 9100 apparatus and are uncorrected. Infrared spec-
tra were taken on the neat samples or dried beads with
1
the use of a refractive spectrophotometer. H and 13C
NMR were measured in CDCl3 at 300 and 75 MHz,
with tetramethylsilane and CDCl3 as internal standards,
O
O
OH
O
O
i
ii
N R
R'
1
2
3a
O
O
OH
O
O
iii
+
N
R
R
R'
4a-e
N
O
+
H
2
R'
-
Scheme 1. (i) Acryloyl chloride, DIPEA, DCM, rt; (ii) RR%NH, DMF, rt; (iii) MCPBA, CHCl3, rt. Product, yield; piperidinol 4a,
67%; morphin-4-ol 4b, 70%; 1,2,3,4-tetrahydroisoquinolin-2-ol 4c, 61%; methylbenzylhydroxylamine 4d, 47%; 2,6-dimethylmor-
pholin-4-ol 4e, 64%.
OH
N
O
O
iii
i
ii
+
O
O
R
CH2R'
O
O
O
O
4f-g
3b
3a
H
N
R
R'CH2
N
R
2
2
Scheme 2. (i) RNH2, DMF, rt; (ii) R%CHO, borane–pyridine complex, DMF/EtOH (4:1), rt; (iii) MCPBA, CHCl3, rt. Product,
yield; hexylpropylhydroxylamine 4f, 60%; (4-nitrobenzyl)propylhydroxylamine 4g, 56%.

R. E. Sammelson, M. J. Kurth / Tetrahedron Letters 42 (2001) 3419–3422
3421
1
Compound 4b13b IR 3193, 2937, 2830, 1455 cm−1; H
NMR: l 2.76 (td, J=11.1, 2.9 Hz, 2H), 3.14 (dd,
J=10.3, 1.5 Hz, 2H), 3.59 (td, J=11.7, 1.7 Hz, 2H),
3.93 (dd, J=10.0, 1.8 Hz, 2H), 7.20 (br s, 1H); 13C
NMR: l 58.2, 65.9.
respectively. Elemental analyses were preformed by
Midwest Microlabs, Indianapolis, IN. MCPBA (80–
90%) had been purchased from Aldrich; hydroxymethyl
polystyrene (100–200 mesh), 1% DVB, substitution:
1.10 mmol g−1 was purchased from Novabiochem; sol-
vents were purchased from either Fischer Scientific or
EM Science and used as received. All reactions and
work-ups were carried out using the Eyela CCS-600 V
Personal Organic Synthesizer.
Compound 4c23 mp 76–78°C, IR 3196, 3022, 2899,
1
2830, 1476, 751 cm−1; H NMR: l 3.00 (br, 3H), 3.43
(br, 1H), 3.92 (br, 1H), 4.26 (br, 1H), 8.41 (br s, 1H);
13C NMR: l 28.2, 55.5, 60.0, 126.0, 126.6, 126.8, 128.2,
132.9, 133.1.
Preparation of the REM resin 2
Compound 4d15 IR 3298, 3027, 2936, 2790,1495, 1447
Hydroxymethyl polystyrene resin 1 (0.750 g, 0.825
mmol) was added to the reaction vessel and suspended
in DCM. Diisopropylethylamine (1.00 mL, 5.7 mmol)
followed by acryloyl chloride (0.50 mL, 5.9 mmol) were
added. The reaction was shook for 10 h at rt followed
by filtering, washing (2×5 mL DCM, 2×5 mL MeOH,
2×5 mL DCM, 2×5 mL MeOH), and drying in vacuo.
1
cm−1; H NMR: l 3.95 (s, 3H), 5.43 (s, 2H), 7.39 (m,
3H), 7.49 (m, 2H); 13C NMR: l 47.7, 62.6,127.0, 128.8,
129.2, 129.8.
Compound 4e mp 78–79.5°C, IR 3207, 2970, 2893,
2839,1461, 1381,1078 cm−1; 1H NMR: l 1.21 (d, 6.6 Hz,
6H), 2.28 (t, 10.3 Hz, 2H), 3.14 (d, 10.1 Hz, 2H), 3.63
(m, 2H), 8.02 (br s, 1H); 13C NMR: l 19.0, 63.9, 71.0.
Anal. calcd for C6H13NO2: C, 54.93; H, 9.99; N, 10.68.
Found: C, 54.61; H, 9.60; N, 10.35.
General procedure for the Michael addition
REM resin 2 was swollen in DMF and primary or
secondary amine (6.6 mmol, 8 equiv.) was added. The
resin was agitated for 20 h at rt, then washed (2×5 mL
DMF, 2×5 mL MeOH, 2×5 mL DCM, 2×5 mL
MeOH) and dried.
Compound 4f14 IR 3250, 2956, 2928, 2857,1495, 1465
1
cm−1; H NMR: l 0.91 (m, 6H), 1.30 (br, 6H), 1.59 (m,
4H), 2.62 (m, 4H); 13C NMR: l 11.8, 14.1, 20.5, 22.6,
27.0, 27.2, 31.8, 60.8, 62.6.
General procedure for the reductive alkylation
Compound 4g mp 60–61°C, IR 3219, 3094, 2963, 2870,
1605, 1513, 1346 cm−1; 1H NMR: l 0.88 (t, 7.3 Hz, 3H),
1.53 (sx, 7.5 Hz, 2H), 2.62 (t, 7.6 Hz, 2H), 3.83 (s, 2H),
6.75 (br s, 1H), 7.49 (d, 8.8 Hz, 2H), 8.15 (d, 8.8 Hz,
2H); 13C NMR: l 11.5, 20.1, 62.0, 63.6, 123.3, 130.4,
144.7, 147.1. Anal. calcd for C6H13NO2: C, 57.13; H,
6.71; N, 13.33. Found: C, 56.99; H, 6.69; N, 13.19.
Resin containing secondary amine was swollen in
DMF:EtOH (4:1) and followed by addition of aldehyde
(6.6 mmol, 8 equiv.) and borane–pyridine complex (6.6
mmol, 8 equiv.). After the reaction was shook for 4
days at rt, it was filtered, washed (5 mL DMF: EtOH
(4:1), 5 mL MeOH, 2×5 mL DCM, 3×5 mL MeOH),
and dried.
Acknowledgements
General procedure for the oxidation and Cope
elimination
We are grateful to the National Science Foundation for
financial support of this research and the Eyela corpo-
ration for donation of a CCS-600 V Personal Organic
Synthesizer. The 300 and 400 MHz NMR spectrome-
ters used in this study were funded in part by a grant
from NSF (CHE-9808183).
Polymer-supported tertiary amine (3a) was swollen in
chloroform and treated with MCPBA (0.40 g, ꢀ2.0
mmol) and the reaction was agitated at rt for 12 h. The
resin was filtered and washed (5 mL DCM, 5 mL ether,
2×5 mL DCM, 2×5 mL MeOH). The combined wash-
ings were evaporated to afford a white solid. Method
A: this solid was dissolved in ether and extracted three
to four times with 5% HCl, the combined aqueous
layers were basified with sodium bicarbonate and
extracted with DCM three to four times. Method B: the
crude white solid was dissolved in ether and extracted
three times with saturated sodium bicarbonate. In both
cases the final organic extracts were dried with sodium
sulfate, filtered, and evaporated to give the desired N,
N-dialkylhydroxylamines.
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1
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