Introduction of substituents on the 2-oxo-piperazine skeleton by [3+2] cycloaddition and subsequent transformation

Article abstract of DOI:10.1515/znb-2006-0410

The 3,4-substituted 2-oxo-piperazines 5-9 are obtained by [3+2] cycloaddition from nitrone 1 and a variety of alkenes. Subsequent functionalization of the bicyclic adducts involves reductive N-O bond cleavage. A route towards libraries of immobilized 1,3-aminoalcohols with a 3,4-substituted 2-oxo-piperazine scaffold is briefly discussed for adducts derived from N-substituted maleic imides.

Full text of DOI:10.1515/znb-2006-0410

Introduction of Substituents on the 2-Oxo-piperazine Skeleton by
[3+2] Cycloaddition and Subsequent Transformation*
Frank Wierschem and Karola Ru¨ck-Braun
Institut fu¨r Chemie, Technische Universita¨t Berlin, Sekr. C 3, Straße des 17. Juni 135,
D-10623 Berlin
Reprint requests to Prof. Dr. K. Ru¨ck-Braun. Fax: (+49) 30-314-79651.
E-mail: krueck@chem.tu-berlin.de
Z. Naturforsch. 61b, 431 – 436 (2006); received January 17, 2006
The 3,4-substituted 2-oxo-piperazines 5 – 9 are obtained by [3+2] cycloaddition from nitrone 1
and a variety of alkenes. Subsequent functionalization of the bicyclic adducts involves reductive N-O
bond cleavage. A route towards libraries of immobilized 1,3-aminoalcohols with a 3,4-substituted
2-oxo-piperazine scaffold is briefly discussed for adducts derived from N-substituted maleic imides.
Key words: 2-Oxo-piperazine, Scaffold, [3+2] Cycloaddition, Nitrone, N-O Bond Cleavage
Introduction
In this paper we describe exemplarily details for
the preparation of 3,4-disubstituted 2-oxo-piperazines
in solution. In addition, we present key steps for
the preparation of libraries of functionalized 1,3-
aminoalcohols from maleic imide-based cycloadducts
by reductive N-O bond cleavage on solid support using
Mo(CO)6.
In medicinal and agricultural chemistry hetero-
cycles are among the target molecules for synthesiz-
ing libraries of compounds for finding lead structures.
This is also the case for 2-oxo-piperazines and deriva-
tives, which are privileged biologically active scaffolds
and promising pharmaceutical target molecules [1].
From a medicinal standpoint the fields of applications
are numerous, e. g. 2-oxo-piperazines were success-
fully investigated as farnesyl-protein transferase in-
hibitors, fXa inhibitors or non-peptide GPII antago-
nists [2]. Members of this class of compounds were in-
vestigated as nucleoside analogs [3]. They were found
to display antiviral activity against a mammalian retro-
virus [4]. Furthermore, 2-oxo-piperazines are promis-
ing scaffolds in the treatment of asthma and bronchi-
tis [5].
Recently, we have reported [3+2] cycloaddition re-
actions of a polymer-bound 2-oxo-piperazine-derived
nitrone with alkenes and alkynes furnishing libraries
of 3,4-disubstituted and 3,4,5-trisubstituted 2-oxo-
piperazines [1, 6]. The bicyclic (2-oxo-piperazine)-
based isoxazolidines and isoxazolines are well suited
for additional functionalization steps starting with
N-O bond cleavage furnishing versatile libraries of
2-oxo-piperazines.
Results and Discussion
For the [3+2] cycloadditions in solution described
here the nitrone 1 was synthesized starting from 2-
oxo-piperazine 2 by alkylation of the amide with
bromoacetic acid methyl ester followed by deprotec-
tion of the Boc-protecting group using trifluoroacetic
acid in anisole. The secondary amine was generated
prior to oxidation by adjusting a pH-value of 7.5
using triethylamine. Subsequent treatment with 30%
aqueous H2O2 (2.2 equiv.) using Na2WO4 × 2H2O in
methanol as catalyst gave nitrone 1 in 73% isolated
yield (Scheme 1) [7]. This proved to be the method
of choice, since oxidation with Davis’ Reagent [7] (2.0
equiv.) in either CH2Cl2 or CHCl3 yielded nitrone 1
only in 32 and 34% yield, respectively.
Starting from 5H-furan-2-one and crotonic acid
methyl ester the expected cycloadducts 5 and 6
(Scheme 2) were isolated in thermal reactions in good
yields, although long reaction times were required
(5: 56 h, 6: 42 h). Notably, Yb(OTf)3 ×H2O-catalyzed
reactions (20 mol%) could be successfully applied to
* Presented in part at the 7th Conference on Iminium Salts
(ImSaT-7), Bartholoma¨/Ostalbkreis, September 6 – 8, 2005.
c
0932–0776 / 06 / 0400–0431 $ 06.00 ꢀ 2006 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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F. Wierschem – K. Ru¨ck-Braun · Introduction of Substituents on the 2-Oxo-piperazine Skeleton
Scheme 1. Synthe-
sis of the nitrone 1.
Scheme 3. Conditions: (a) N-Phenylmaleic imide (3 equiv.),
THF, 65 ◦C, (b) Mo(CO)6 (3 equiv.), MeCN/H2O, 85 ◦C.
Scheme 4. Automated synthesis of 1,3-aminoalcohols 12:
R = Me (56%), Et (62%), Pr (75%), C6H11 (81%), CH2C6H5
(70%), C6H5 (65%), 12a: 3-Cl,5-Cl-C6H3 (90%).
◦
trile at 85 C [9]. The aminoalcohol 10 was obtained
Scheme 2. [3+2]
Cycloadditions of
nitrone 1 with al-
kenes.
in 38% yield (Scheme 3). Unfortunately, the purifica-
tion proceeded sluggishly. Generally, only after several
manipulations, including separation of the impurities
R
derived from Mo(CO)6 by hyflowꢀ filtrations, precip-
shorten the reaction times (5: 4 h, 6: 14 h). The endo- itation with ether and a flash-column chromatography
adducts were obtained regioselectively, as confirmed prior to a preparative RP-HPLC, pure product was iso-
by NOE experiments.
lated [1, 9]. However, solid phase synthesis can result
in an easier purification of intermediates, by remov-
ing the excess of reagents applied by simple wash-
ing procedures prior to cleavage from the solid. Con-
sequently, we turned our attention next to automated
solid phase synthesis without further optimization of
solution phase studies.
The endo-preference is also very high for [3+2]
cycloaddition reactions using 2-vinylpyridine and 4-
vinylpyridine (Scheme 2). Only a small amount of
exo-8 was detected and structurally assigned. In test
reactions we also examined N-phenylmaleic imide as
dipolarophile (Scheme 3). The reaction proceeded re-
gioselectively, the resulting adduct 9 was isolated in
The polymer-bound nitrone 11 was prepared as pre-
66% yield and was treated with Mo(CO)6 for cleav- viously described [1]. The compound immobilized on
age of the N-O bond to obtain the 1,3-aminoalcohol 10 Wang resin is stable at r. t. and can be stored on
(Scheme 3).
the bench for several months without decomposition.
For the synthesis of a library we employed seven N-
substituted maleic imides. The reactions were carried
out in a m◦yriad core system (Mettler Toledo) in diox-
ane at 65 C. All cycloadditions proceeded smoothly,
as well as the subsequent reductive N-O bond cleav-
age with 4 equivalents of Mo(CO)6 followed by cleav-
age of the 1,3-aminoalcohols from Wang resin using
NaOMe.
Usually Pd/C, Pd(OH)2/C or Raney nickel in the
presence of H2, or zinc in acetic acid are used for N-O
bond cleavage in solution phase studies [8]. However,
for the preparation of libraries of compounds on solid
support using polystyrene resins these methods are not
suitable, because of the heterogeneous reaction condi-
tions or insufficient swelling of the resins. For auto-
mated solid phase synthesis we also needed to avoid re-
action conditions under pressure. Therefore, we turned
The products were isolated in good to excellent
our attention to a Mo(CO)6-mediated (0.7– 6 equiv.) yields (Scheme 4) compared with solution phase stud-
reductive cleavage of the N-O bond in wet acetoni- ies. During workup we observed the elimination of
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433
water by treatment with NaOMe in MeOH/THF and (C=O), 153.7 (C=O), 80.8 (C(CH3)3), 52.2 (C=O-OCH3),
48.0 (CH2), 47.5 (CH2), 40.0 (br, CH2), 28.2 (C(CH3)3). –
IR (KBr): ν = 2988, 2954, 2874, 1758 (C=O, ester), 1692
(C=O, Boc), 1654 (C=O, 2-oxo-piperazine), 1493, 1480,
1422, 1367, 1337, 1322, 1293, 1239, 1133, 1099, 1073,
1011, 990, 979, 965, 868, 771 cm−1. – MS (EI, 90 ◦C): m/z
(%) = 272 (1) [M+], 216 (12), 172 (20), 157 (8), 113 (16),
85 (8), 57 (100). – HR-MS (EI): calcd. 272.1372; found
272.1377. – C12H20N2O5 (272.3): calcd. C 52.93, H 7.40,
N 10.29; found C 52.90, H 7.34, N 10.15.
subsequent evaporation of the solvent with a speed
vac concentrator at 60 ◦C. Thus, we obtained the
corresponding unsaturated maleic imides as the only
byproducts in minor amounts (analytical RP-HPLC/
MS). Byproduct formation can be avoided by evapo-
◦
ration of the solvent at lower temperature (20 C). Pure
aminoalcohols were isolated after cleavage from the
resin by a single purification step using preparative RP-
HPLC.
Compound 4: Trifluoroacetic acid (48.2 ml, 0.626 mol,
16.50 equiv.) was added to a stirred solution of 3 (10.42 g,
38 mmol, 1.0 equiv.) in anisole (86 ml). After 90 min (TLC
monitoring) toluene (85 ml) was added and the solvent was
removed in vacuo. The crude product 4 was used in the next
step without further purification (14.77 g, quant.), pale yel-
low solid. – M. p. 112 ◦C. – Rf = 0.01 (methanol). – 1H NMR
(200 MHz, CD3CN): δ = 4.12 (s, 2H; NCH2COOCH3), 3.81
(s, 2H; O=C-CH2-N), 3.68 (s, 3H; CH3), 3.63 – 3.58 (m, 2H;
CH2), 3.48 – 3.43 (m, 2H; CH2). – 13C NMR (50.3 MHz,
CD3CN): δ = 169.9 (C=O), 163.1 (C=O), 161.3 (q, 2J =
36.1 Hz; F3CCOO−), 52.9 (C=O-OCH3), 48.7, 45.6, 45.1,
41.6 (CH2). The signals of the C-atom of the CF3-group are
not detectable. – IR (KBr): ν = 3017, 2965, 2828, 2767,
2676, 2594, 2491, 1752 (C=O, ester), 1672 (F3CC=O), 1659
(C=O, 2-oxo-piperazine), 1504, 1483, 1472, 1428, 1402,
1354, 1296, 1261, 1230, 1203, 1193, 1169, 1143, 1080,
1021, 837, 799, 723, 685, 515 cm−1. – MS (EI, 120 ◦C): m/z
(%) = 172 (92) [M+-F3CCOOH], 113 (12) [F3CCOO−],
102 (40), 85 (100), 69 (40), 56 (88), 57 (32), 51 (24). – HR-
MS (EI): calcd. for C7H12N2O3 172.0847; found 172.0844.
In conclusion, we have demonstrated a preparatively
useful access to 3,4-disubstituted 2-oxo-piperazine
templates and successfully proven the use of Mo(CO)6
for N-O bond cleavage in automated solid phase syn-
thesis. This route has already been developed further
beneficially as a starting point for more complex trans-
formations for library generation [1, 6].
Experimental Section
General information
Solvents for the automated synthesis on solid support
were used in p. a. quality without further purification. All
products were characterized with RP-HPLC/LC-MS after
cleavage from the resin. NMR spectra were measured on
Bruker spectrometers AC200, AC400, AM400 and DRX500
at 200, 400 and 500 MHz for 1H and 50.3, 100.6 and
125.7 MHz for 13C at room temperature. Starting materials,
reagents and compound 10 were prepared by following the
literature procedure [1], and products were purified and ana-
lyzed by RP-HPLC as previously described by us.
Nitrone 1: Triethylamine (5.37 ml, 14.20 mmol, 1.1
equiv.) was added dropwise to a suspension of 4 (5.0 g,
12.95 mmol, 1.0 equiv.) in methanol (50 ml), until pH 7.5
was adjusted. Then the reaction mixture was stirred at r. t.
(1 h) before Na2WO4 × 2 H2O (0.29 g, 0.65 mmol, 0.05
equiv.) was added in one portion. After cooling the reaction
mixture to 0 ◦C, 30% aqueous H2O2 (3.92 ml, 28.50 mmol,
2.2 equiv.) was added (10 min). The reaction mixture was
1-Methoxycarbonylmethyl-4-tert-butyloxycarbonyl-2-
oxo-piperazine (3): Sodium hydride (1.73 g, 73.0 mmol,
◦
1.15 equiv.) was added in one portion at 0 C to a stirred
solution of 2 (12.70 g, 63.0 mmol, 1.0 equiv.) in 280 ml of
DMF. The reaction mixture was maintained at this temper-
ature for 1 h until bromoacetic acid methylester (6.60 ml,
◦
69.0 mmol, 1.10 equiv.) was added. After 20 min at 0 C
◦
the solution was allowed to warm to r. t. and stirring was
continued (18 h, TLC monitoring). Then methanol (10 ml),
water (10 ml) and brine (180 ml) were added. The organic
layer was separated and the aqueous layer was extracted
with diethyl ether (1 × 250 ml, 3 × 140 ml). The combined
organic phase was dried (MgSO4), filtered and concentrated
in vacuo. Purification by flash chromatography on silica
(pentane/acetone 4 : 1 → 2 : 1) afforded 3 (14.16 g, 82%,
stirred at 0 C (15 min) and after warming to r. t. stirring
was continued until TLC monitoring indicated complete con-
sumption of the starting material (2 h 45 min). The solvent
was removed in vacuo and the remaining residue was dis-
solved in dichloromethane (40 ml). The organic layer was
washed with brine (2 × 40 ml) and then the aqueous layer
extracted with dichloromethane. The combined organic layer
was dried (MgSO4) and the solvent removed in vacuo yield-
ing 5.78 g of 1 as a pale yellow oil. Purification by flash chro-
◦
52.0 mmol) as a white solid. – M. p. 57 C. – Rf = 0.60
(pentane/acetone 1:1). – 1H NMR (400 MHz, CDCl3): matography on silica (ethyl acetate/methanol 80 : 1) afforded
δ = 4.15 (s, 2H; NCH2COOCH3), 4.11 (s, 2H; O=C-CH2- 1 (1.76 g, 73%, 9.45 mmol) as a white solid. – M. p. 78 ◦C. –
N), 3.72 (s, 3H; CH3), 3.69 – 3.66 (t, 2H, 3J = 5.5 Hz; CH2), Rf = 0.68 (methanol). – 1H NMR (200 MHz, CDCl3): δ =
3.42 – 3.39 (t, 2H, 3J = 5.5 Hz; CH2), 1.44 (s, 9H; CH3). – 7.17 (s, 1H; N=CH), 4.23 (s, 2H; CH2), 4.19 – 4.13 (t, 2H,
13C NMR (50.3 MHz, CDCl3): δ = 169.0 (C=O), 166.3 3J = 6.35 Hz; CH2), 3.78 – 3.72 (t, 2H, 3J = 6.35 Hz; CH2),
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F. Wierschem – K. Ru¨ck-Braun · Introduction of Substituents on the 2-Oxo-piperazine Skeleton
3.75 (s, 3H; CH3). – 13C NMR (50.3 MHz, CDCl3): δ = (C=O), 166.2 (C=O), 76.7 (C-8), 67.6 (C-3), 58.5 (C-7),
168.6 (C=O), 159.3 (C=O), 128.4 (C=N), 58.7 (CH2), 52.3 52.2 (COOCH3), 52.0 (COOCH3), 47.6 (NCH2COOCH3),
(CH3), 46.9, 43.8 (CH2). – IR (KBr): ν = 3059, 2991, 1758 47.1 (C-6), 44.9 (C-5), 18.4 (C-9). For the signal assign-
1
(C=O, ester), 1652 (C=O, 2-oxo-piperazine), 1574 (C=N), ments H, 1H-COSY and HMQC spectra were recorded. –
1488, 1457, 1432, 1399, 1365, 1349, 1339, 1305, 1282, IR (ATR): ν = 2955, 1735 (C=O), 1655 (C=O), 1640 (C=O),
1250, 1214, 1171, 1131, 1085, 1023, 986, 970, 932, 884, 1491, 1436, 1404, 1373, 1344, 1292, 1277, 1201, 1179,
◦
845, 722, 694 cm−1. – MS (EI, 60 ◦C): m/z (%) = 186 (78) 1103, 1078, 1037, 998, 974, 938 cm−1. – MS (EI, 120 C):
[M+], 127 (100) [M+-CO2CH3], 116 (14), 69 (86), 56 (40), m/z (%) = 286 (24) [M+], 255 (20) [M+-OCH3], 211 (58),
51 (42). – HR-MS (EI): calcd. 186.0640; found 186.0639. – 199 (26), 183 (50), 158 (100), 127 (16), 123 (30), 69 (30),
C7H10N2O4 (186.17): calcd. C 45.16, H 5.41, N 15.04; 56 (66). – HR-MS (EI): calcd. for C12H18N2O6 286.1164;
found C 45.09, H 5.48, N 15.17.
found 286.1165.
Cycloadduct 7: By following the general procedure, ni-
trone 1 (200 mg, 1.07 mmol) dissolved in THF (5.0 ml)
was treated with 4-vinylpyridine (0.35 ml, 3.22 mmol, 3.0
equiv.) for 22 h. Purification by flash column chromatog-
raphy (pentane/acetone 4:1) afforded endo-7 [(3S, 8R) and
(3R, 8S)], (233 mg, 75%, 0.80 mmol) as a yellow oil. – Rf =
[3+2] Cycloaddition reactions of nitrone 1 with alkenes in
solution
General procedure: Nitrone 1 was dissolved in THF and
the alkene (3.0 equiv.) was added. Then the reaction mixture
was heated to reflux until TLC monitoring indicated com-
plete consumption of the starting material. The solvent was
removed in vacuo and the resulting crude product was puri-
fied by flash chromatography on silica or by preparative RP-
HPLC.
1
0.24 (acetone). – H NMR (200 MHz, CDCl3): δ = 8.79 –
3
4
8.76 (dd, 2H, J = 6.82 Hz, J = 1.54 Hz; ortho-H), 7.79
(d, 2H, 3J = 6.82 Hz; meta-H), 5.41 – 5.33 (dd, 1H, 3J =
3
2
5.86 Hz, J = 4.40 Hz; 8-H), 4.36 (d, 1H, J = 17.56 Hz;
NCH2COOCH3), 4.16 – 4.10 (dd, 1H, 3J = 2.92 Hz, 3J =
8.30 Hz; 3-H), 4.05 – 3.93 (m, 1H; 5-H), 4.04 – 3.95 (d,
1H, 2J = 17.56 Hz; NCH2COOCH3), 3.76 (s, 3H; CH3),
3.67 – 3.46 (m, 2H; 6-H, 6’-H), 3.35 – 3.21 (m, 2H; 7-H,
5’-H), 2.66 – 2.52 (ddd, 1H, 3J = 5.86 Hz, 3J = 8.30 Hz,
2J = 14.10 Hz; 7’-H). – 13C NMR (125 MHz, CDCl3):
δ = 168.9 (C=O; NCH2COOCH3), 168.6 (C=O; C-2), 160.5
(C-quart), 143.3 (ortho-C), 123.0 (meta-C), 75.8 (C-8), 63.1
(C-3), 52.4 (COOCH3), 48.5 (NCH2COOCH3), 47.4 (C-6),
Cycloadduct (5): yellow solid. – M. p. 160 ◦C. – 1H NMR
(200 MHz, CDCl3): δ = 4.97 – 4.89 (dddd, 1H, 3J =
7.28 Hz, 3J = 5.5 Hz, 3J = 1.9 Hz, 4J = 1.2 Hz; 8-H), 4.53 –
4.39 (m, 2H, 3J = 5.5 Hz, 3J = 1.9 Hz; 9-H, 9’-H), 4.29
(d, 1H, 2J = 17.08 Hz; NCH2COOCH3), 4.25 (d, 1H, 3J =
2.44 Hz; 3-H), 4.07 – 3.93 (m, 2H; 6-H, 7-H), 3.96 (d, 1H,
2J = 17.08 Hz; NCH2COOCH3), 3.73 (s, 3H; CH3), 3.52 –
3.43 (m, 2H; 5-H, 5’-H), 3.16 – 3.07 (ddd, 1H, J = 1.96,
4.40, 5.36 Hz; 6’-H). – 13C NMR (50.3 MHz, CDCl3): δ =
175.5 (C=O; C-11), 168.5 (C=O; NCH2COOCH3), 166.7
(C=O; C-2), 75.4 (C-8), 74.2 (C-9), 66.6 (C-3), 52.2 (CH3),
51.6 (C-7), 48.5 (NCH2COOCH3), 46.2 (C-5), 43.3 (C-6).
For the signal assignments 1H,1H-COSY, HMBC, NOE and
HMQC spectra were recorded. – IR (KBr): ν = 2982, 2969,
2949, 1774 (C=O, C-11), 1742 (C=O, ester), 1652 (C=O,
2-oxo-piperazine), 1502, 1461, 1399, 1389, 1380, 1359,
1338, 1295, 1219, 1207, 1189, 1149, 1075, 1054, 987, 944,
934, ◦902, 836, 731, 724, 575, 530, 491 cm−1. – MS (EI,
120 C): m/z (%) = 270 (60) [M+ + 1], 211 (100) [M+-
COOCH3], 183 (24), 158 (44), 125 (20), 123 (16), 56 (66),
1
1
43.6 (C-5), 41.8 (C-7). For the signal assignments H, H-
COSY, HMBC, NOE and HMQC spectra were recorded. –
IR (ATR): ν = 2954, 2855, 1748 (C=O, ester), 1655 (C=O, 2-
oxo-piperazine), 1600, 1560, 1491, 1438, 1412, 1364, 1345,
1290, 1214, 1182, 1067, 994, 815 cm−1. – MS (EI, 120 ◦C):
m/z (%) = 292 (12) [M++1], 291 (100) [M+], 274 (44), 204
(28), 158 (68), 125 (76), 106 (40), 69 (44), 56 (92). – HR-
MS(EI): calcd. 291.1219; found 291.1221. – C14H17N3O4
(291.31): calcd. C 57.72, H 5.88, N 14.42; found C 57.81,
H 6.01, N 14.25.
Cycloadduct 8: By following the general procedure, ni-
55 (26). – HR-MS (EI): calcd. 270.0851; found 270.0853. – trone 1 (250 mg, 1.34 mmol) dissolved in THF (5.0 ml)
C11H14N2O6 (270.24): calcd. C 48.89, H 5.22, N 10.36; was treated with 2-vinylpyridine (0.43 ml, 4.03 mmol, 3.0
found C 48.70, H 5.43, N 9.92.
equiv.) for 23 h. Purification by flash column chromatog-
raphy (pentane/acetone 4 : 1 → acetone) afforded endo-8
[(3S, 8R) and (3R, 8S)], and exo-8 [(3R, 8R) and (3S, 8S)]:
Cycloadduct 6: yellow oil, 98%. – 1H NMR (500 MHz,
CDCl3): δ = 4.54 – 4.52 (m, 1H; 8-H), 4.39 (d, 1H,
3J = 10.05 Hz; 3-H), 4.22 (d, 1H, 2J = 17.30 Hz;
endo-8 (285 mg, 73%, 0.98 mmol), yellow oil. – Rf
=
NCH2COOCH3), 3.97 (d, 1H, 2J = 17.30 Hz; NCH2 0.57 (acetone). – 1H NMR (200 MHz, CDCl3): δ = 8.53
COOCH3) 3.69 (s, 3H; COOCH3), 3.65 (s, 3H; COOCH3), (d, 1H, 3J = 4.88 Hz; ortho-H), 7.73 – 7.64 (m, 1H; para-
3.63 – 3.58 (m, 1H; 6-H), 3.56 – 3.53 (m, 1H; 5-H), 3.38 – H), 7.48 (d, 1H, 3J = 7.80 Hz; meta-H), 7.23 – 7.16 (m,
3
3.35 (m, 1H; 5’-H), 3.32 (d, 1H, 3J = 10.05 Hz; 7-H), 3.21 – 1H; meta-H), 5.21 – 5.12 (m, 1H, J = 8.30 Hz; 8-H), 4.28
3.18 (m, 1H; 6’-H), 1.34 (d, 3H, 3J = 6.00 Hz; 9-H). – (d, 1H, 2J = 17.56 Hz; NCH2COOCH3), 4.26 – 4.18 (dd,
13C NMR (50.3 MHz, CDCl3): δ = 171.5 (C=O), 168.5 1H, 3J = 6.34 Hz, 3J = 6.80 Hz; 3-H), 4.01 (d, 1H, 2J =
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17.56 Hz; NCH2COOCH3), 3.90 – 3.78 (m, 1H; 5-H), 3.71 3.45 (ddd, 1H, 2J = 11.3 Hz, 3J = 4.9 Hz, 3J = 4.7 Hz;
(s, 3H; COOCH3), 3.60 – 3.39 (m, 2H; 6-H, 6’-H), 3.35 – 6’-H), 3.18 – 3.15 (dd, 1H, 2J = 11.7 Hz, 3J = 4.7 Hz;
3.09 (m, 2H; 7-H, 5’-H), 2.76 – 2.62 (ddd, 1H, 3J = 6.80 Hz, 5’-H). – 13C NMR (125 MHz, CDCl3): δ = 174.0 (C=O),
3J = 8.30 Hz, 2J = 13.3 Hz; 7’-H). – 13C NMR (125 MHz, 173.6 (C=O), 168.8 (C=O, NCH2COOCH3), 166.7 (C=O,
CDCl3): δ = 169.3 (C=O, NCH2COOCH3), 169.0 (C=O, 2-oxo-piperazine), 131.2 (q; C-aromat), 129.3 (ortho-C),
2-oxo-piperazine), 159.1 (q; C-aromat), 149.1 (ortho-C), 129.1 (para-C), 126.4 (meta-C), 75.2 (C-8), 66.3 (C-3), 52.6
137.0 (para-C), 122.9 (meta-C), 121.2 (meta-C), 80.6 (C-8), (COOCH3), 52.1 (C-7), 48.7 (NCH2COOCH3), 46.1 (C-6),
63.9 (C-3), 52.3 (COOCH3), 48.6 (NCH2COOCH3), 48.2 43.2 (C-5). For the signal assignments 1H, 1H-COSY and
(C-6), 44.2 (C-5), 40.4 (C-7). – IR (ATR): ν = 2955, 1746 HMQC spectra were recorded. – IR (KBr): ν = 2953, 1721
(C=O, ester), 1646 (C=O, 2-oxo-piperazine), 1592, 1489, (br, C=O, ester, imide), 1656 (C=O, 2-oxo-piperazine), 1597,
1437, 1405, 1345, 1210, 1182, 994, 947, 779, 750 cm−1. – 1495, 1438, 1389, 1350, 1250, 1206, 1069, 1024, 939, 869,
MS (EI, 130 ◦C): m/z (%) = 291 (18) [M+], 184 (28), 769, 733, 710, 693, 602 cm−1. – MS (EI, 180 ◦C): m/z
170 (20), 125 (24), 122 (56), 108 (100), 97 (28), 69 (24), (%) = 360 (20) [M++1], 359 (100) [M+], 300 (16), 272 (12),
56 (56). – HR-MS (EI): calcd. 291.1219; found 291.1221. – 211 (50), 184 (17), 173 (29), 158 (44), 125 (32), 119 (26),
C14H17N3O4 (291.31): calcd. C 57.72, H 5.88, N 14.42; 56 (38). – HR-MS (EI): calcd. 359.1116; found 359.1118. –
found C 57.93, H 6.07, N 14.09; exo-8 (54 mg, 14%, C17H17N3O6 (359.34): calcd. C 56.82, H 4.77, N 11.60;
0.19 mmol), yellow oil. – Rf = 0.27 (acetone). – 1H NMR found C 57.01, H 4.61, N 11.43.
(200 MHz, CDCl3): δ = 8.44 (d, 1H, 3J = 4.88 Hz; ortho-H),
General procedure for automated solid phase synthesis
3
3
7.63 – 7.54 (dd, 1H, J = 7.80 Hz, J = 7.82 Hz; para-H),
7.39 (d, 1H, 3J = 7.82 Hz; meta-H), 7.12 – 7.05 (m, 1H;
meta-H), 5.27 – 5.20 (m, 1H, 3J = 4.88 Hz; 8-H), 4.23
(d, 1H, 2J = 17.56 Hz; NCH2COOCH3), 4.21 – 4.14 (m,
1H; 3-H), 4.13 (d, 1H, 2J = 17.56 Hz; NCH2COOCH3),
3.83 – 3.72 (m, 1H; 5-H), 3.75 (s, 3H; COOCH3), 3.52 –
3.33 (m, 3H; 5’-H, 6-H, 6’-H), 3.21 – 3.07 (m, 1H; 7-H),
2.98 – 2.85 (m, 1H; 7’-H). – 13C NMR (125 MHz, CDCl3):
δ = 169.0 (C=O, NCH2COOCH3), 168.8 (C=O, 2-oxo-
piperazine), 160.3 (q; C-aromat), 147.7 (ortho-C), 138.5
(para-C), 123.1 (meta-C), 121.1 (meta-C), 77.8 (C-8), 63.4
(C-3), 52.4 (COOCH3), 48.2 (NCH2COOCH3), 48.1 (C-6),
44.2 (C-5), 40.5 (C-7). – IR (ATR): ν = 2954, 1747 (C=O,
ester), 1654 (C=O, 2-oxo-piperazine), 1591, 1570, 1491,
1473, 1437, 1404, 1364, 1344, 1291, 1213, 1182, 1152,
1046, 994, 835, 780, 751 cm−1. – MS (EI, 140 ◦C): m/z
(%) = 292 (8) [M+ +1], 291 (24) [M+], 274 (12), 273 (20),
260 (12), 185 (92), 184 (56), 125 (30), 117 (32), 108 (100),
56 (26). – HR-MS (EI): calcd. for C14H17N3O4: 291.1219;
found 291.1223.
according to Scheme 4: Resin 11 (200 mg, 0.16 mmol,
0.78 mmol/g) was swollen in dioxane (3 ml, 1 min, 1×),
the solvent removed in vacuo and the resin dried (0.5 min).
After the addition of dioxane (1.0 ml), a 0.85 M solu-
tion of the N-substituted maleic imide in dioxane (2.75 ml,
2.34 mmol, 15.0◦equiv.) was added. The reaction mixture
has heated to 65 C for 2 h. Then the solvent was removed
in vacuo and dried in vacuo (0.5 min), washed twice with
THF (3 ml, 1 min, 1×) and dried (0.33 min). For reductive
N-O bond cleavage the resins were swollen in acetonitrile
(3 ml, 1 min, 1×). Then the solvent was removed in vacuo
and the resin was dried (0.5 min). After the addition of ace-
tonitrile (3.30 ml), water (0.20 ml) and Mo(CO)6 (164 mg,
0.62 mmol, 4.0 equiv.) the reaction mixture was heated to
85 ◦C for 3 h. Afterwards the solvent was removed in vacuo,
and the resin was dried (1.0 min) prior to three times wash-
ing with acetonitrile (3 ml, 1 min, 2×) and drying (0.5 min),
followed by washing with THF (3 ml, 1 min, 2×) and drying
(0.5 min) and washing with methanol (3 ml, 1 min, 2×) and
drying (0.5 min).
For the cleavage of the 1,3-aminoalcohols the resins
(50 mg, 0.03 – 0.04 mmol, 0.65 – 0.72 mmol/g) were swollen
in 4 ml of THF and 0.5 ml of methanol (5 min). After the
addition of neat NaOMe (6.3 mg, 0.12 mmol, 3.33 – 3.64
equiv.) the reaction mixture was stirred at room temperature
for 22 h. Afterwards the solvent was removed in vacuo and
the resin was washed with methanol (1.0 ml, 4 min, 1×).
The combined filtrates were dried in a speed vac concen-
trator. The crude products were analyzed by analytical RP-
HPLC/MS eluting with acetonitrile/water 5 : 95+0.1% TFA
→ acetonitrile/water 100 : 0+0.1% TFA within 5 min.
Cycloadduct 9: By following the general procedure, ni-
trone 1 (250 mg, 1.34 mmol) dissolved in THF (4.0 ml)
was treated with N-phenylmaleic imide (0.70 g, 4.02 mmol,
3.0 equiv.) dissolved in THF (1 ml) for 2 h. Purification by
flash chromatography (pentane/ethyl acetate 2 : 1 → 1 : 1) af-
forded 9 (320 mg, 66%, 0.89 mmol) as a yellow amorphous
solid. – M. p. 85 ◦C. – Rf = 0.54 (ethyl acetate). – 1H NMR
(500 MHz, CDCl3): δ = 7.49 – 7.46 (m, 2H; H-aromat),
7.42 – 7.39 (m, 1H; H-aromat), 7.31 (d, 2H, 3J = 7.5 Hz;
H-aromat), 4.95 (d, 1H, 3J = 7.5 Hz; 8-H), 4.35 (br d,
1H; 3-H), 4.26 (d, 1H, 3J = 7.5 Hz; 7-H), 4.19 (d, 1H,
2J = 17.3 Hz; NCH2COOCH3), 4.13 (d, 1H, 2J = 17.3 Hz;
Spectroscopic data of compound 12a: yellow oil. – Rf =
NCH2COOCH3), 4.10 – 4.04 (ddd, 1H, 2J = 11.7 Hz, 3J = 0.13 (ethyl acetate). – 1H NMR (200 MHz, CDCl3): δ = 7.57
4.0 Hz, J = 4.9 Hz; 5-H), 3.75 (s, 3H; COOCH3), 3.67 – (d, 2H, 4J = 1.96 Hz; H-aromat), 7.09 (m, 1H; H-aromat),
3
3.64 (dd, 1H, 2J = 11.3 Hz, 3J = 4.0 Hz; 6-H), 3.51 – 4.98 (d, 1H, 3J = 8.78 Hz; CH), 4.30 (d, 1H, 3J = 8.78 Hz;
Unauthenticated
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436
F. Wierschem – K. Ru¨ck-Braun · Introduction of Substituents on the 2-Oxo-piperazine Skeleton
CH), 4.22 (br m, 3H; CH, CH2), 3.81 (s, 3H; CH3), 3.77 – [M+ + 1], 429 (96) [M+], 415 (14), 413 (38), 251 (56),
3.61 (m, 3H; CH2), 3.47 – 3.24 (m, 1H, CH2). The sig- 240 (28), 223 (66), 211 (26), 180 (32), 163 (62), 161 (100),
nals of the secondary amine and the hydroxy group were 125 (24), 83 (26), 71 (32), 57 (56). – HR-MS (EI): calcd. for
not detectable. – IR (ATR): ν = 3455 (OH), 3315 (NH), C17H17N3O6Cl2: 429.0494; found 429.0491.
3185, 3082, 2954, 1747 (C=O, ester), 1690 (br, 2 C=O,
Acknowledgements
imide), 1652 (C=O, 2-oxo-piperazine), 1588, 1544, 1487,
1443, 1412, 1366, 1306, 1209, 1182, 1136, 1114, 994, 985,
This work was supported by the BASF AG, the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen In-
dustrie.
◦
927, 844, 801, 763, 723, 670 cm−1. – MS (EI, 230 C) m/z
(%) = 433 (10) [M+ + 4], 431 (64) [M+ + 2], 430 (20)
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