Expedient protocol for solid-phase synthesis of secondary and tertiary amines

Article abstract of DOI:10.1021/ol049575h

Equation presented. An expedient solid-phase synthetic approach to secondary and tertiary amines was developed. The protocol employs conversion of resin-bound amino alcohols to the corresponding iodides, followed by iodide displacement with primary or sec

Full text of DOI:10.1021/ol049575h

ORGANIC
LETTERS
2004
Vol. 6, No. 12
1935-1938
Expedient Protocol for Solid-Phase
Synthesis of Secondary and Tertiary
Amines
,†
Christian A. Olsen,† Matthias Witt,‡ Jerzy W. Jaroszewski,† and Henrik Franzyk*
Department of Medicinal Chemistry, The Danish UniVersity of Pharmaceutical
Sciences, UniVersitetsparken 2, DK-2100 Copenhagen, Denmark, and Bruker Daltonik
GmbH, Fahrenheitstrasse 4, D-28359 Bremen, Germany
hf@dfuni.dk
Received March 8, 2004
ABSTRACT
An expedient solid-phase synthetic approach to secondary and tertiary amines was developed. The protocol employs conversion of resin-
bound amino alcohols to the corresponding iodides, followed by iodide displacement with primary or secondary amines or with unprotected
amino alcohols. This two-step procedure, affording products in good to excellent yields, is suitable for solid-phase synthesis of polyamines.
Di- and polyamines such as putrescine (1), spermidine (2),
and spermine (3) are ubiquitous in eukariotic cells.1 Simple
N-alkylated analogues of 3 have been investigated as
potential chemotherapeutic leads.2 Furthermore, polyamine
derivatives, including wasp and spider toxins, have been
shown to interact with ion channels in the central and
peripheral nervous systems.3 Therefore, synthetic analogues
of these toxins are of considerable interest as potential
therapeutic lead compounds4 and as probes for receptor
specificity studies.5
tropic glutamate receptors and nicotinic acetylcholine recep-
tors,3 several methods for their solid-phase organic synthesis
(SPOS) have been investigated. Introduction of secondary
and tertiary amino functionalities is obviously a crucial step
in the construction of polyamines on solid phase,6 but also
in the SPOS of small molecule libraries.7
Previously, construction of polyamine chains on solid
phase has been achieved by reduction of resin-bound imines8
(1) For reviews, see: (a) Bienz, S.; Detterbeck, R.; Ensch, C.; Guggisberg,
A.; Hausermann, U.; Meisterhans, C.; Wendt, B.; Werner, C.; Hesse, M.
Alkaloids (Academic Press) 2002, 58, 83-338. (b) Cohen, S. S. A Guide
to Polyamines; Oxford University Press: New York, 1998.
(2) For a review, see: Casero, R. A.; Woster, P. M. J. Med. Chem. 2001,
44, 1-26.
(3) For a review, see: Mueller, A. L.; Roeloffs, R.; Jackson, H. Alkaloids
(Academic Press) 1995, 46, 63-94.
(4) For examples, see: (a) Blagbrough, I. S.; Carrington, S.; Geall, A.
J. Pharm. Sci. 1997, 3, 223-233. (b) Klenke, B.; Stewart, M.; Barrett, M.
P.; Brun, R.; Gilbert, I. H. J. Med. Chem. 2001, 44, 3440-3452.
(5) For examples, see: (a) Bixel, M. G.; Weise, C.; Bolognesi, M. L.;
Rosini, M.; Brierley, M. J.; Mellor, I. R.; Usherwood, P. N. R.; Melchiorre,
C.; Hucho, F. J. Biol. Chem. 2001, 276, 6151-6160. (b) Brier, T. J.; Mellor,
I. R.; Tikhonov, D.; Neagoe, I.; Shao, Z.; Brierley, M. J.; Strømgaard, K.;
Jaroszewski, J. W.; Krogsgaard-Larsen, P.; Usherwood, P. N. R. Mol.
Pharmacol. 2003, 64, 954-964.
To obtain chemically diverse libraries of polyamine toxins
for structure-activity relationship (SAR) studies on iono-
(6) For reviews on polyamine synthesis, see: (a) Strømgaard, K.;
Andersen, K.; Krogsgaard-Larsen, P.; Jaroszewski, J. W. Mini ReV. Med.
Chem. 2001, 1, 317-338. (b) Karigiannis, G.; Papaioannou, D. Eur. J. Org.
Chem. 2000, 1841-1863. (c) Kuksa, V.; Buchan, R.; Lin, P. K. T. Synthesis
2000, 1189-1207.
* To whom correspondence should be addressed. Phone: +45-35306255.
Fax: +45-35306040.
† The Danish University of Pharmaceutical Sciences.
‡ Bruker Daltonik GmbH.
10.1021/ol049575h CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/08/2004

or polyamides.9 Recently, Fukuyama-Mitsunobu N-alkyla-
tion has emerged as a versatile method for sequential SPOS
of polyamines,10 and also the formation of tertiary amines
mediated by (cyanomethyl)trialkylphosphonium iodide has
been reported.11 Furthermore, alkylation of resin-bound
sulfonamides with alkyl bromides,12 as well as SN2 reactions
employing amines together with halides,13 methanesulfonates,14
p-toluenesulfonates,15 or nitrobenzenesulfonates16 have been
described.
performance of these reagents was judged from the purity
of the isolated 3-bromo-1-propaneamine (Table 1). Bromine
Table 1. Test of Reagents for the Preparation of Resin-Bound
Bromidesa
Preliminary alkylation experiments with resin-bound meth-
anesulfonate, 2- and 4-nitrobenzenesulfonates, or imida-
zolylsulfonate17 led to low yields and purities in our hands.
This was possibly due to a competing transsulfonation, as
previously observed in N-alkylation of resin-bound piperazine
with 2-nitrobenzenesulfonates.16b
Accordingly, further exploration of the halogen displace-
ment strategy seemed an attractive alternative. The present
paper describes the development of a new, efficient, and
versatile protocol consisting of conversion of resin-bound
aliphatic alcohols into iodides and subsequent displacement
by primary or secondary amines as well as unprotected amino
alcohols.
entry
phosphine
reagent
purity of 4,b %
1
2
3
4
5
6
PBu3
PPh3
PBu3
PPh3
PBu3
PPh3
Br2
Br2
CBr4
CBr4
NBS
NBS
>95
>95
∼75
∼5
∼35
∼55
a Reagents and conditions: (a) Br2, CBr4 or NBS (3 equiv), PBu3 or
PPh3 (3 equiv), CH2Cl2, N2, 16 h; (b) TFA/CDCl3 (1:1), 1 h. b Estimated
1
from H NMR spectra (CDCl3/TFA 4:1).
was superior to the other reagents and led to the desired
product, 4, in high yield. By contrast, the use of carbon
tetrabromide or NBS resulted in recovery of large amounts
of 3-amino-1-propanol along with the formation of 4. In the
case of NBS-PBu3 the formation of ∼10% of N-(3-
aminopropyl)succinimide was observed. The reagent pairs
Br2-PPh3 and Br2-PBu3 performed equally well. Thus, PPh3
was chosen for subsequent investigations due to its higher
stability toward air.
Treatment of the resin-bound 3-bromo-1-propaneamine
with 3-amino-1-propanol resulted in pronounced cross-
linking, as shown by the concomitant isolation of 6 after
cleavage with TFA (Table 2). It was assumed that the use
of a resin with a lower loading would result in diminished
cross-linking, due to the statistically larger distance between
Initially, various reagents for the on-resin conversion of
N-trityl-linked 3-amino-1-propanol to the corresponding
bromide were investigated. The selected reagent combina-
tions were CBr4-PPh3,18 Br2-PPh3,19 and NBS-PPh3,20 as
well as the corresponding reagent pairs containing PBu3. The
(7) For a review, see: Thompson, L. A.; Ellman, J. A. Chem. ReV. 1996,
96, 555-600.
(8) (a) Chhabra, S. R.; Khan, A. N.; Bycroft, B. W. Tetrahedron Lett.
2000, 41, 1095-1098. (b) Jo¨nsson, D. Tetrahedron Lett. 2002, 43, 4793-
4796.
(9) For examples with different resins, see: (a) Paikoff, S. J.; Wilson,
T. E.; Cho, C. Y.; Schultz, P. G. Tetrahedron Lett. 1996, 37, 5653-5656.
(b) Nefzi, A.; Ostresh, J. M.; Meyer, J.-P.; Houghten, R. A. Tetrahedron
Lett. 1997, 38, 931-934. (c) Hall, D. G.; Laplante, C.; Manku, S.;
Nagendran, J. J. Org. Chem. 1999, 64, 698-699.
(10) For a few selected examples, see: (a) Miller, S. C.; Scanlan, T. S.
J. Am. Chem. Soc. 1997, 119, 2301-2302. (b) Chhabra, S. R.; Khan, A.
N.; Bycroft, B. W. Tetrahedron Lett. 2000, 41, 1099-1102. (c) Strømgaard,
K.; Andersen, K.; Ruhland, T.; Krogsgaard-Larsen, P.; Jaroszewski, J. W.
Synthesis 2001, 877-884. (d) Olsen, C. A.; Witt, M.; Jaroszewski, J. W.;
Franzyk, H. Synlett 2004, 473-476.
Table 2. Alkylation of Trityl Resins with Different Degrees of
Loadinga
(11) Zaragoza, F.; Stephensen, H. J. Org. Chem. 2001, 66, 2518-2521.
(12) (a) Tomasi, S.; Le Roch, M.; Renault, J.; Corbel, J. C.; Uriac, P.
Pharm. Pharmacol. Commun. 2000, 6, 155-160. (b) Kan, T.; Kobayashi,
H.; Fukuyama, T. Synlett 2002, 1338-1340.
(13) (a) Barn, D. R.; Morphy, J. R.; Rees, D. C. Tetrahedron Lett. 1995,
37, 3213-3216. (b) Vojkovsky, T.; Weichsel, A.; Pa´tek, M. J. Org. Chem.
1998, 63, 3162-3163. (c) Burkoth, T. S.; Fafarman, A. T.; Charych, D.
H.; Connolly, M. D.; Zuckermann, R. N. J. Am. Chem. Soc. 2003, 125,
8841-8845.
(14) (a) Virgilio, A. A.; Schu¨rer, S. C.; Ellman, J. A. Tetrahedron Lett.
1996, 37, 6961-6964. (b) Renault, J.; Lebranchu, M.; Lecat, A.; Uriac, P.
Tetrahedron Lett. 2001, 42, 6655-6658.
resin loading,
(15) (a) Kick, E. K.; Ellmann, J. A. J. Med. Chem. 1995, 38, 1427-
1430. (b) Zhou, J.; Termin, A.; Wayland, M.; Tarby, C. M. Tetrahedron
Lett. 1999, 40, 2729-2732.
entry
mmol/g
solvent
DMF
NMP
DMF
NMP
THF/PhMe
ratio 6:5b
(16) (a) Lee, E. K.; Kick, E. K.; Ellmann, J. A. J. Am. Chem. Soc. 1998,
120, 9735-9747. (b) Olsen, C. A.; Witt, M.; Jaroszewski, J. W.; Franzyk,
H. Org. Lett. 2003, 5, 4183-4185.
(17) Hanessian, S.; Vate`le, J.-M. Tetrahedron Lett. 1981, 22, 3579-
3582.
1
2
3
4
5
1.28
1.28
0.52
0.52
0.52
0.19
0.29
0.05
0.27
N.D.c
(18) (a) Wang, B.; Chen, L.; Kim, K. Tetrahedron Lett. 2001, 42, 1463-
1466. (b) Ryoo, S.-J.; Kim, J.; Kim, J.-S.; Lee, Y.-S. J. Comb. Chem. 2002,
4, 187-190.
a Reagents and conditions: (a) Br2 (5 equiv), PPh3 (5 equiv), CH2Cl2,
N2, 16 h; (b) 3-aminopropanol (1.0 M), DMF, NMP or THF/PhMe (1:1),
50 °C, 6 h. b Estimated from 1H NMR. c Not determined due to low
conversion.
(19) Katritzky, A. R.; Cai, X.; Rogovoy, B. V. J. Comb. Chem. 2003, 5,
392-399.
(20) Howarth, N. M.; Wakelin, L. P. G. J. Org. Chem. 1997, 62, 5441-
5450.
1936
Org. Lett., Vol. 6, No. 12, 2004

adjacent alkyl bromides on the solid support. To test this
hypothesis, a resin with ∼40% (0.52 mmol/g)21 of the
original loading was prepared. This was achieved by
performing a partial loading of O-trimethylsilyl (TMS)
protected 3-amino-1-propanol (0.5 equiv) onto the polysty-
rene trityl chloride resin. The residual chlorine functionalities
were end-capped by treatment with 10% diisopropylethyl-
amine (DIPEA) in methanol, and finally the TMS group was
removed with tetrabutylammonium fluoride (TBAF). After
bromination of this trityl resin with Br2-PPh3, and subse-
quent alkylation with 3-amino-1-propanol in selected sol-
vents, the product was cleaved from the resin with TFA.
Only 5% of the tertiary amine 6 was obtained when the
alkylation step was performed in DMF, whereas the alkyl-
ation in N-methylpyrrolidinone (NMP) resulted in 27% of 6
(Table 2).
were displaced with different types of amines, and post-
cleavage examination of the products showed that the method
is efficient for the preparation of secondary as well as tertiary
amines in high purities (7 and 9-12, Table 4). Noticeably,
Table 4. Solid-Phase Synthesis of Amines by Displacement of
Iodides on Argopore Wang Resina
The degree of cross-linking (5% in DMF) was found
acceptable, and additional experiments were performed on
this trityl resin (0.52 mmol/g). Displacement of a bromide,
and also an iodide prepared under previously described
conditions (I2-PPh3 and imidazole),22 resulted in impure
crude products, and only 20-30% yields (Table 3) were
a Compounds 7 and 9-12 were synthesized by using general procedure
B.23 Reagents and conditions: (a) I2 (5 equiv), PPh3 (5 equiv), imidazole
(5 equiv), CH2Cl2, N2, 16 h; (b) amine (1.0 M, 10 equiv), DMF, 50 °C, 6
h; (c) TFA/CH2Cl2 (1:1), 1 h. b Yields are based on the weight of crude
Table 3. Solid-Phase Synthesis of Amines by Displacement of
Halides on a Polystyrene Trityl Resina
1
material relative to the initial loading. c Estimated from H NMR.
unprotected amino alcohols were employed without any
detectable ether formation. Compounds 11 and 12 were
prepared in somewhat lower yield but still with a high purity.
The products 13 and 14 were prepared on larger scale, as
purification by reversed-phase VLC was necessary. The
isolated yields were 55% and 43%, respectively, which
showed that acceptable yields could be obtained in alkyl-
ations of relatively hindered alcohols by using this protocol
(Scheme 1).
a All compounds were synthesized by using general procedure A.23
b Iodide displacement. c Bromine displacement. d Yield of the corresponding
bis(TFA) salts after reversed-phase VLC.
Scheme 1. Synthesis of 13 and 14 on Argopore Resin
obtained after reversed-phase vacuum liquid chromatography
(VLC). Since neither the bromides nor the iodides performed
satisfactorily on the trityl resins, a macroporous Argopore
Wang resin in combination with a carbamate linker was
considered. When performing the iodide displacement se-
quence with this resin, close to quantitative conversions were
observed.23
To test the scope of this SPOS protocol, portions of
p-nitrophenylcarbonate-activated Argopore Wang resin were
loaded with 3-amino-1-propanol, 6-amino-1-hexanol, phe-
nylalaninol, or 4-hydroxymethylpiperidine, and the hydroxy
groups were converted into iodides. Subsequently, the iodides
In summary, an expedient SPOS protocol for the prepara-
tion of amines has been developed. The scope of this strategy
was shown to include formation of secondary and tertiary
amines in good yields and high purities. Also, the use of
protecting groups could be omitted when employing amino
alcohols as the nucleophile. We envisage that this synthetic
(21) The loading was calculated from 1H NMR spectra of cleaved amino
alcohol with DMSO added as internal quantitative standard.
(22) Nicolaou, K. C.; Winssinger, N.; Pastor, J. A.; Ninkovic, S.; Sarabia,
F.; Fe, Y.; Vourloumis, D.; Yang, Z.; Li, T.; Giannakakou, P.; Hamel, E.
Nature 1997, 387, 268-272.
(23) Consult the Supporting Information for details.
Org. Lett., Vol. 6, No. 12, 2004
1937

scheme may be exceedingly useful for the introduction of
amino functionalities in SPOS of compound libraries, as it
is a both cheap and efficient method for conversion of
hydroxy groups into amino functionalities. In this protocol
the Argopore Wang resin proved superior to the polystyrene
trityl resin. Whether this difference observed between the
two types of resin is due to the polymer properties and/or
the linker remains to be investigated in detail.
Foundation (Grant ANS-0372/30) for financial support. We
also thank Ms. Uraiwan Ngamrabiab Adamsen for technical
assistance.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 7 and 9-14.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Danish Technical
Research Council (Grant No. 26-00-0312) and the Carlsberg
OL049575H
1938
Org. Lett., Vol. 6, No. 12, 2004