LETTER
Solid Phase Synthesis of 2-Oxo-1,4-piperazines
1087
Table Yields of 2-Oxo-1,4-piperazines
In order to test the efficacy of this method for library pro-
duction we made an array of 384 compounds using the 96-
well FlexChem block technique, where one resin bound -
amino acid, eight -amino alcohols and twelve different
N-substitutions in the four different ways described above
Sub- Pathb Purity Yield M
+e
Ketopiperazineb
a
c
d
strate
%
%
6
A
B
A
96
98
31
69
80
353
297
438
1
1
were used. LC-MS analysis showed that the success rate
1
1
7
12
was 76%, the average purity was 89% and the average
yield 61%.
In conclusion, we have described a convenient route for
the combinatorial solid-phase synthesis of 2-oxo-1,4-pip-
erazines. The procedure utilizes commercially available
building blocks thus allowing high diversity at three dif-
ferent positions. The mild cyclization conditions allow the
selective cleavage of the desired product from the resin,
resulting in very high purity of the target compounds.
1
2
B
97
65
70
382
8
3
A
B
41
95
425
369
1
1
Acknowledgement
This work was supported by Bayer AG Central Research. J.C.G.G.
thanks Bayer AG, for a three month stipendium and the University
of Santiago de Compostela for a doctoral fellowship. The authors
thank Dr. Daniel Auriel and Daniel Meibom for the revision of this
manuscript.
9
4
A
B
38
90
464
408
339
65
50
1
0
5
A
B
34
88
References
1
(1) Balkenhohl, F.; von dem Bussche-Hünnefeld, C.; Lansky,
a
b
c
A.; Zechel, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2288.
See Scheme 1.
See Scheme 2.
(2) Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324.
(3) For excellent reviews see: (a) Krch ák, V.; Holladay, M.
Chem. Rev. 2002, 102, 61. (b) James, I. V. Tetrahedron
The purity of crude products was defined as the relative area of the
compound peak in a C-18 RP-HPLC-MS, using a linear gradient of 0–
0% acetonitrile in 20 min with H O containing 1mL/L TFA, UV ab-
1999, 55, 4855. (c) Guillier, F.; Orain, D.; Bradley, M.
8
2
Chem. Rev 2000, 100, 2091.
sorption was monitored at 214 nm.
d
(4) Mohamed, N.; Bhatt, U.; Just, G. Tetrahedron Lett. 1998,
Yields of crude product based on experimentally determined loading
39, 8213.
of resin bound amino acid.
e
(5) (a) Hulme, C.; Ma, L.; Kumar, V.; Krolikowski, P. H.; Allen,
Observed protonated parent ion in positive electrospray mass spec-
A. C.; Labaudiniere, R. Tetrahedron Lett. 2000, 41, 1509.
trometry.
(
5
b) Hulme, C.; Cherrier, M. P. Tetrahedron Lett. 1999, 40,
295. (c) Kung, P. P.; Swayze, E. Tetrahedron Lett. 1999,
Indeed, the reductive amination of tBuO-tyrosine on
Merrifield resin with the -N-Boc-phenylalaninal (3b)
proceeds as well as with the Fmoc analog. The secondary
amine 11 was then further transformed to the intermedi-
ates 12–15 as indicated in Scheme 1. N-Boc (and at the
same time tBuO)-deprotection using 50% TFA
40, 5651. (d) Goff, D. A. Tetrahedron Lett. 1998, 39, 1473.
6) The preparation of reagent 1 was achieved following the
procedure published in: Menenschein, H.; Sourkouni-
Argirusi, G.; Schubotte, K. M.; O’Hare, T.; Kirsching, A.
Org. Lett. 1999, 1, 2101; using a polymer-bound bromide
purchased from Fluka which was previously vacuum dried
over anhydrous P O for 2 days.
(
2
5
(
Scheme 2, path B) was followed by washings with
(7) Sourkouni-Argirusi, G.; Kirschning, A. Org. Lett. 2000, 2,
CH Cl and 1% Et N in CH Cl . No cyclic product was
3781.
2
2
3
2
2
(
8) This aldehydes have been shown to be prone to undergo
racemization under several oxidation conditions and by
storage: Rittle, K. E.; Homnick, C. F.; Ponciello, G. S.;
Evans, B. E. J. Org. Chem. 1982, 47, 3016.
detected either in the TFA solution or in the washings.
Treatment of the resulting solid supported free amines (in
brackets) with a 4% triethylamine solution in CH Cl2
2
overnight at room temperature induced cyclization with
concomitant cleavage of 2-oxo-1,4-piperazines 21–25 in
good yields (50-80%) and very high purity (Table).
(
9) Look, G. C.; Murphy, M. M.; Campbell, D. A.; Gallop, M.
A. Tetrahedron Lett. 1995, 17, 2937.
1
(10) Data for 12: H NMR (CDCl ) 0.54 (d, J = 6.5 Hz, 3 H),
3
0
2
.82 (d, J = 6.5 Hz, 3 H), 2.39 (dd, J = 13.6, 10.3 Hz, 1 H),
.73–2.96 (m, 3 H), 3.19 (d, J = 7.1 Hz, 1 H exch.), 3.29 (dd,
The diastereomeric purity was confirmed by RP-HPLC
1
0
and NMR. The NMR spectrum of crude compound 12
revealed the presence of only one diastereoisomer show-
ing two clean doublets at 4.05 ppm, for the proton at car-
bon 3, with J = 9.35 Hz and at 4.50 ppm, for one of the
methylene protons at carbon 5, with a geminal coupling
constant of 10.2 Hz.
J = 13.7, 2.7 Hz, 1 H), 3.45 (q, J = 6.6 Hz, 1 H), 3.72–3.82
m, 1 H), 4.05 (d, J = 9.3 Hz, 1 H), 4.50 (d, J = 10.2 Hz, 1
(
H), 5.74 (s, 1 H exch.), 6.70 (d, J = 8.4 Hz, 2 H), 7.05 (d, J =
8.4 Hz, 2 H), 7.11–7.31 (m, 5 H), 7.82 (s, 1 H exch.).
(
11) General procedure for the synthesis of 2-oxo-1,4-piperazine
library: Eight -N-Boc-amino alcohols (18 mmol) were
dissolved in CH Cl (160 mL) and treated with polymer
2
2
Synlett 2002, No. 7, 1085–1088 ISSN 0936-5214 © Thieme Stuttgart · New York