LETTER
Photochemical Release of Amines
503
55, 4855. (c) Guillier, F.; Orain, D.; Bradley, M. Chem. Rev.
2
000, 100, 2091.
NR R2
1
NR R
1
2
(
3) (a) Sarker, A. M.; Kaneko, Y.; Nikolaitchik, A. V.; Neckers,
D. C. J. Phys. Chem. A 1998, 102, 5375. (b) Sarker, A. M.;
Kaneko, Y.; Neckers, D. C. J. Photochem. Photobiol. A
hν
1
998, 117, 67.
4) Peng, L.; Wirz, J.; Goeldner, M. Tetrahedron Lett. 1997, 38,
961.
(
(
MeO
O
O
MeO
O
O
2
1
13
5) For a general review on photochemical cleavage reactions of
arylmethyl-heteroatom sigma bonds, see: Fleming, S. A.;
Pincock, J. A. In Organic Molecular Photochemistry, Vol.
3; Ramamurthy, V.; Schanze, K. S., Eds.; Marcel Dekker:
New York, 1999, 211.
CH2
(
6) For reviews on photolabile protecting groups, see:
(a) Pelliccioli, A. P.; Wirz, J. J. Photochem. Photobiol. Sci.
2002, 1, 441. (b) Bochet, C. G. J. Chem. Soc., Perkin Trans.
1 2002, 125. (c) McCray, J. A.; Trentham, D. R. Ann. Rev.
Biophys. Biophys. Chem. 1989, 18, 239. (d) Givens, R. S.;
Kueper, L. W. III Chem. Rev. 1993, 93, 55. (e) Corrie, J. E.
T.; Trentham, D. R. In Bioorganic Photochemistry, Vol. 2;
Morrison H., Wiley: New York, 1993, 243. (f) Pillai, V. N.
R. Synthesis 1980, 1.
1
2
R R N
+
MeO
O
O
1
4
15
H-Donor
H-Donor
2
5
Scheme 4
(7) The aminomethyl coumarins 1a–d were synthesized from
the commercially available 4-bromomethyl-7-methoxy-
coumarin in a substitution reaction with the corresponding
amines in the presence of Hünig’s base. The yields are nearly
quantitative. Aminomethyl coumarin 1a was irradiated at
NHR R2
1
20 °C for 30–90 min in methanol with a 500 W Hg high-
RS
RS
pressure lamp and a 360 nm cutoff filter. The yields of the
cleaved off amine 2a and the coumarin derivatives 5 and 6
3
hν
– 2
MeO
1
RSH
were determined by RP-HPLC. The influence of H-donors
was checked by adding 50 equiv 1,4-cyclohexadiene or
n-decanethiol before irradiation.
MeO
O
O
O
O
16
15
(
8) Experimental conditions for the photocleavage of 1a:
A solution of aminomethyl coumarin 1a (47.0 mg, 0.145
mmol), n-decanethiol (3.10 mL, 14.5 mmol) and 1 M HCl
SR
(
2
233 L, 0.218 mmol) in methanol (120 mL) was purged for
0 min with argon and irradiated with a 150 W Hg middle-
SR
O
+
pressure lamp with a pyrex coating for 30 min under
continuous cooling with water (15 °C). For the separation of
MeO
O
O
MeO
O
the amine 2a, 3 M aqueous NH Cl solution (50 mL) was
added, methanol was evaporated and the residue was washed
4
17
18
Scheme 5
with CH Cl (3 × 50 mL). The aqueous solution was
2 2
basified, extracted with diethyl ether (5 × 50 mL), dried over
MgSO and concentrated under reduced pressure, yielding
4
In conclusion, our experiments show that, for the first
time, C,N-photocleavage of tertiary and secondary
amines can be carried out in solution and on solid support.
16.6 mg (0.123 mmol, 85%) of amine 2a.
(
9) Synthesis of 12: Umbeliferon 7 was alkylated under basic
conditions with tert-butyl protected 5-bromovaleric acid
yielding 7-alkoxy-substituted coumarin 8. The oxidation of
1
7
8
with selenium dioxide gave aldehyde 9 after deprotection
1
8
Acknowledgment
of the tert-butyl ester with trifluoroacetic acid. Coupling of
with commercially available amino support (TentaGel S-
NH ) was performed with diisopropylcarbodiimide (DIC),
9
This work was supported by the Swiss National Science Foundation
and by Novartis Pharma AG; R. O. S. is grateful for a grant from the
Amt für Ausbildungsbeiträge des Kantons Basel-Landschaft.
2
1
-hydroxybenzotriazole (HOBT) in CH Cl /DMF, yielding
2 2
the aldehyde linker 10. The anchoring proceeded with
1
9
complete conversion as determined by the Kaiser test. The
amine coupling, forming 12, was conducted on solid phase
after reduction of 10 with tetrabutylammonium boro-
References
2
0
21
(1) (a) Peukert, S.; Giese, B. J. Org. Chem. 1998, 63, 9045.
hydride, subsequent Appel bromination (CBr , PPh ),
4 3
(b) Glatthar, R.; Giese, B. Org. Lett. 2000, 2, 2315.
and nucleophilic substitution of the bromide 11 with the
amine 2a in the presence of Hünig’s base. An alternative
way of coupling the amine to the solid support is the
reductive amination of aldehyde 10 with amine 2a in the
(
c) Schoenleber, R. O.; Bendig, J.; Hagen, V.; Giese, B.
Bioorg. Med. Chem. 2002, 10, 97. (d) Kessler, M.; Glatthar,
R.; Giese, B.; Bochet, C. G. Org. Lett. 2003, in press.
2) For recent reviews of the use of photolabile linkers, see:
2
2
(
presence of NaBH(OAc) and acetic acid. All reaction
3
1
3
23
(
a) Bunin, B. A. In The Combinatorial Index; Academic
steps were checked by gel-phase C NMR. Picric acid
Press: New York, 1998. (b) James, I. W. Tetrahedron 1999,
monitoring showed that resin 12 was obtained with 0.112
2
4
mmol/g loading of amine 2a.
Synlett 2003, No. 4, 501–504 ISSN 0936-5214 © Thieme Stuttgart · New York