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