General combinatorial synthesis of tertiary amines on solid support. A novel conditional release strategy based on traceless linking at nitrogen

Article abstract of DOI:10.1016/S0040-4039(00)01902-X

A novel solid phase synthesis of tertiary amines involving iodide-induced cleavage of the N-O bond of resin bound alkoxyammonium intermediates is described. The quaternary intermediates were assembled via sequential reductive aminations followed by alkylation. Cleavage from the solid support was induced by iodide ion or base, to afford the target tertiary amines in excellent purity.

Full text of DOI:10.1016/S0040-4039(00)01902-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 133–136
General combinatorial synthesis of tertiary amines on solid
support. A novel conditional release strategy based on traceless
linking at nitrogen
Magnus Gustafsson, Roger Olsson and Carl-Magnus Andersson*
Synthetic Chemistry, ACADIA Pharmaceuticals A/S, Fabriksparken 58, DK-2600 Glostrup, Denmark
Received 15 September 2000; revised 18 September 2000; accepted 26 October 2000
Abstract—A novel solid phase synthesis of tertiary amines involving iodide-induced cleavage of the NꢀO bond of resin bound
alkoxyammonium intermediates is described. The quaternary intermediates were assembled via sequential reductive aminations
followed by alkylation. Cleavage from the solid support was induced by iodide ion or base, to afford the target tertiary amines
in excellent purity. © 2000 Elsevier Science Ltd. All rights reserved.
Solid phase organic synthesis (SPOS) offers certain
advantages compared to traditional solution phase re-
actions.1 Solid phase reactions are particularly attrac-
tive for combinatorial parallel synthetic work because
of the relative ease of isolation and automated purifica-
tion of the resin bound material after each reaction
step. As part of a major effort to identify novel ligands
for G-protein coupled receptors via R-SAT™ ultra high
throughput screening2 we needed to develop a general
combinatorial approach to tertiary amines. Although
amine-containing building blocks may be introduced
using a variety of the traditional coupling reactions,
greater diversity in the target library requires the com-
binatorial construction of carbonꢀnitrogen bonds. Ele-
gant approaches utilising resin bound Michael
acceptors for this purpose have been described by
Brown et al. and Heinonen et al.3,4 Unfortunately, the
limited availability of secondary amine building blocks
as well as potential lability of the linkers and a require-
ment for basic cleavage conditions present potential
drawbacks with these methods.
which, under mild cleavage conditions, would release
only fully functionalised material.
Upon surveying the literature for suitable nitro-
genꢀheteroatom linking chemistries, we were particu-
larly intrigued by two papers by Liguori et al.,5,6 who
investigated ring opening reactions of isoxazolidinium
salts by a variety of reagents, including bases and,
notably, lithium iodide. These reports invited the use of
alkoxyammonium intermediates in a solid phase syn-
thesis of amines involving very mild conditional release
from the resin. A suitable aminoxy-functionalised resin,
allowing extremely robust linking during the sequence,
was recently prepared for other purposes by Floyd et
al. and Salvino et al.7,8 We envisaged to introduce
building blocks at nitrogen via either alkylation with
alkyl halides, or a reductive amination sequence em-
ploying carbonyl compounds. Quaternisation of the
trisubstituted hydroxylamines with a suitable elec-
trophile would labilise the linking bond in the final step.
Since only the quaternised material would be suscepti-
ble to iodide-induced release, tertiary amines of high
purity should result. Grigg et al. very recently disclosed
a related sequence, relying upon base induced cleavage
to afford tertiary amines from resin bound alkoxyam-
monium precursors.9 This prompted us to report on
our preliminary results10 concerning the solid phase
synthesis of tertiary amines.
Important provisos for our approach were (i) to use the
nitrogen of the target tertiary amine as the point of
attachment to the solid support, (ii) to construct all
three carbonꢀnitrogen bonds via reliable reactions in-
volving readily available building blocks, and, impor-
tantly, and (iii) to use a highly robust linking chemistry
Keywords: tertiary amines; NꢀO cleavage; LiI; SmI2; conditional
release; solid phase.
* Corresponding author. Tel.: +4543293015; fax: +4543293030; e-
mail: cma@acadia-pharm.com
Preliminary experiments were carried out in solution,
but under reaction conditions suitable for immediate
adaption to the solid phase.
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01902-X

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M. Gustafsson et al. / Tetrahedron Letters 42 (2001) 133–136
NH2
H
N
R
O
N
R
O
a
b
O
III
I
II
R'
R'
N
R
N
R
R'
O
O
c
e
d
OTf
N
R
IV
V
VI
Scheme 1. Solution phase synthesis of tertiary amines via a hydroxylamine anchor. (a) RCHO, HOAc, MeOH, rt, 15 h. (b)
BH3·pyridine, HCl (4 M in dioxane), MeOH, rt, 12 h. (c) R%CHO, PPTS, BH3·pyridine, THF:MeOH 1:3, rt, 12 h. (d) MeOTf,
CH2Cl2, rt, 15 h. (e) Cleavage reagent.
Thus, reaction of O-benzylhydroxylamine I with alde-
hydes, RCHO (R=Ph, C6H11 or Bn), in methanol
containing 5% acetic acid for 15 h uneventfully re-
turned the corresponding oximes II in over 80% yield
(Scheme 1). Reduction of the oximes II proved some-
what difficult. After optimisation, we found that the use
of borane–pyridine complex under acidic conditions
(HCl, 4 M in dioxane, 12 h) afforded an approximately
70% yield of the N-alkylated products III. The com-
monly used reducing agent NaCNBH3 in acetic acid
gave considerably lower yields.11 Subsequent reaction
with an aldehyde, R%CHO (R%=Ph, CH(CH3)2 or
C6H11), under reductive alkylation conditions (PPTS,
BH3·pyridine, MeOH:THF 3:1, rt, 12 h), gave the
corresponding alkoxydialkylamines IV in over 60%
yield.12 Importantly, preliminary results from exhaus-
tive alkylation of several alkoxyamine intermediates
have indicated that the second alkylation may be
achieved equally selectively using an excess of an alkyl
halide. Unfortunately, attempted quaternisation under
a variety of different alkylation conditions (Table 1)
turned out to be very sluggish, and failed to return the
desired product with most alkylating agents.
The reaction conditions which were developed during
the successful solution phase sequence turned out to be
readily transferred to the solid phase matrix (Scheme
2). In order to facilitate analysis of the efficiency of the
individual steps in the polymer bound version of the
protocol, building blocks carrying fluorine atoms were
favoured initially.14
The aminoxy resin VII was synthesised from
chloromethylated polystyrene (200–400 mesh, 1.19
mequiv. Cl per gram) via O-alkylation (K2CO3, N-hy-
droxyphthalimide, DMF, 60°C, 15 h), followed by de-
protection with methylamine (H2O:THF 4:6, 12 h, rt).
Similarly, applying Mitsunobu conditions on Wang-OH
or Argogel-OH resins afforded the desired aminoxy
resin after deprotection of the phthalimido moiety.7,8
Resin VII was treated with p-fluorobenzaldehyde (5
Table 1. Attempts to quaternise BnONiPrBn (A) and
BnONiPr(C6H11) (B) under various methylation conditions
Entry
Substrate
Conditions
Yield (%)
1
2
3
A
A
A
CH3I, CH2Cl2, rt–50°C
CH3I, DMF, 70°C
CH3OSO2CH3, CH2Cl2,
rt–50°C
nr
nr
nr
However, the use of an excess of methyl triflate resulted
in a good yield of quaternisation product at room
temperature (entry 5).9,13 In addition, activation of
methyl iodide using silver triflate gave a similar yield
(entry 6). We also noted that the introduction of
K2CO3 as a base sometimes promoted the methylation
reaction, probably by removing any trace of acid. An
interesting observation was that combining methyl io-
dide and K2CO3 in DMF (entry 7) returned the product
iBuC6H11N+Me2I− despite the fact that methyl iodide
alone was not a strong enough electrophile to quater-
nise the alkoxyamines under similar reaction condi-
tions.
4
A
CH3OSO2C6H4CH3,
CH2Cl2, rt–50°C
nr
5
6
A
A
CH3OSO2CF3, CH2Cl2, rt \80
CH3I, AgSO3CF3,
CH2Cl2, rt
80
a
7
B
CH3I, K2CO3, DMF,
70°C
–
i
a NꢀO cleavage occurred to produce BuC6H11N+Me2I− in \80%
yield.
Table 2. Release of amine VI from V (R=Ph, R%=iBu)
using various reagents
Entry
Conditions
Purity (%)a
As expected, cleavage of the quaternised alkoxy amines
could be induced by treatment with base (Table 2,
entries 3 and 4). Encouragingly, exposure of the
alkoxyammonium intermediate to the much milder
reagents lithium iodide (in dioxane or acetonitrile) or
samarium diiodide (in THF) also resulted in highly
efficient cleavage, delivering tertiary amines of high
purity (Table 2, entries 1, 2 and 5).
1
2
3
4
5
LiI, dioxane, 70°C
LiI, acetonitrile, 70°C
K2CO3, DMF, 70°C
Et3N, CH2Cl2, rt
\99
\99
\90
\99
89
SmI2, THF, 70°C
a After ion-exchange chromatography.

M. Gustafsson et al. / Tetrahedron Letters 42 (2001) 133–136
135
F
F
H
N
NH2
N
O
O
O
a
b
c
VII
VIII
IX
F3C
F3C
F
F3C
N
F
N
O
O
d
e
N
OTf
F
X
XI
XII
Purity (UV crude): LiI/MeCN >99%
LiI/dioxane 91%
SmI2/THF >99%
Scheme 2. Solid phase synthesis of tertiary amines using a polystyrene based resin with a hydroxylamine linker.7,8 (a)
p-F-C6H4CHO, HOAc, THF:MeOH 2:1, rt. (b) BH3·pyridine, HCl (4 M in dioxane), THF:MeOH 1:1, rt. (c) p-CF3-C6H4CHO,
PPTS, BH3·pyridine, THF:MeOH 3:1, rt. (d) MeOTf, CH2Cl2, rt. (e) LiI in dioxane or acetonitrile, 70°C or SmI2 in THF, rt.
equiv., THF:MeOH 2:1, 5% HOAc, 15 h) to give resin
VIII. The oxime was smoothly reduced (BH3·pyridine,
4 M HCl in dioxane, rt) to give the monoalkylated resin
IX. A second reductive alkylation with p-trifluoro-
methylbenzaldehyde (PPTS, BH3·pyridine, MeOH:
THF 1:3, rt, 12 h) gave the dialkylated alkoxyamine
resin X. This resin was treated with an excess of
methyl triflate for 15 h at room temperature to give
the quaternary salt ready for cleavage. As expected,
both LiI and SmI2 released the desired tertiary
amine XII with very high purity (Scheme 2). Generally,
100 mg of resin afforded 5–10 mg of amine in a purity
of over 90%. Purification by ion-exchange chromatog-
raphy increased the purity to over 99%. In agreement
with the solution phase behaviour, cleavage could be
effected also with bases such as triethylamine.
The above reaction sequence could be monitored using
gel-phase or solid phase IR spectroscopy or, more
conveniently, 19F NMR spectroscopy. Resin VIII dis-
played two signals (−109 and −110 ppm, respectively)
in the 19F NMR spectrum, assigned as a mixture of E-
and Z-stereoisomers of the oxime (Fig. 1).
After reduction (Scheme 2, step b) a single new reso-
nance appeared at −115 ppm. A trace amount of
unreacted oxime could be observed. The second reduc-
tive amination (Scheme 2, step c) resulted in the ex-
pected two signals (−63 and −115 ppm, respectively)
integrating at a ratio of 4:1.
We have prepared a variety of tertiary amines following
the general procedure detailed above. For example,
Figure 1. 19F NMR spectra obtained at 376.8 MHz using CCl3F as an internal standard.

136
M. Gustafsson et al. / Tetrahedron Letters 42 (2001) 133–136
aliphatic aldehydes as well as hindered aryl ketones
(e.g. indanone, methylpropanal, etc.) were introduced
as building blocks without complications. In our experi-
ence, cleavage from 30–50 mg of resin releases appro-
priate amounts of tertiary amines for HTS purposes.
Furthermore, although basic cleavage remains an op-
tion, we have observed that the use of lithium iodide in
acetonitrile, which is generally preferred because of the
neutral reaction medium, tends to deliver products of
superior purity. Product isolation can be conveniently
performed via simple aqueous extraction and
concentration.
NMR spectra, and Dr. Nicholas Kelly for valuable
comments on the manuscript.
References
1. Obrecht, D.; Villalgordo, J. M. Solid-Supported Combi-
natorial and Parallel Synthesis of Small-Molecular-Weight
Compound Libraries; Pergamon: New York, 1998.
2. Brann, M. R. US Patent 5,707,798, 1998; Chem Abstr.
1998, 128, 111548.
3. Brown, A. R.; Rees, D. C.; Rankovic, Z.; Morphy, J. R.
J. Am. Chem. Soc. 1997, 119, 3288.
In summary, we have developed a general solid phase
sequence for the synthesis of quaternary alkoxy amines,
and shown that tertiary amines of high purity may be
released from the resin using several reagents, including
lithium iodide or samarium iodide. We believe that this
methodology will provide a useful addition to existing
combinatorial strategies for the synthesis of tertiary
amines, especially where very mild cleavage conditions
are desired. A drawback of the current procedure is the
requirement for a very strong alkylating reagent for
quaternisation, and further investigations aimed at ex-
tending the scope of this step as well as the application
of our protocol to the synthesis of focused libraries will
be reported in due course.
4. Heinonen, P.; Lo¨nnberg, H. Tetrahedron Lett. 1997, 38,
8569–8572.
5. Liguori, A.; Giovanni, R.; Giovanni, S.; Uccella, N.
Chem. Ber. 1988, 121, 105–109.
6. Liguori, A.; Giovanni, S.; Uccella, N. Tetrahedron 1984,
40, 1901–1906.
7. Floyd, C. D.; Lewis, C. N.; Patel, S. R.; Whittaker, M.
Tetrahedron Lett. 1996, 37, 8045–8048.
8. Salvino, J. M.; Mervic, M.; Mason, H. J.; Kiesow, T.;
Teager, D.; Airey, J.; Labaudiniere, R. J. Org. Chem.
1999, 64, 1823–1830.
9. Blaney, P.; Grigg, R.; Rankovic, Z.; Thoroughgood, M.
Tetrahedron Lett. 2000, 41, 6635–6638.
10. US Patent Application 60/146,978, 1999.
11. Robinson, D. E.; Holladay, M. W. Org. Lett. 2000, 2,
2777–2779.
Acknowledgements
12. Swayze, E. E.; Yogesh, S. Synlett 1997, 859–861.
13. Kelly, D. R.; Harrison, S. J.; Jones, S.; Masood, M. A.;
Morgan, J. J. G. Tetrahedron Lett. 1993, 34, 2689–2690.
14. Svensson, A.; Fex, T.; Kihlberg, J. Tetrahedron Lett.
1996, 37, 7649–7652.
We thank Tina Jensen and Monica Jørgensen for
HPLC analyses, May-Britt Nielsen for recording 19F
.
.