Microwave-assisted stereoselective one-pot synthesis of symmetrical and unsymmetrical 2,5-diketopiperazines from unprotected amino acids

Article abstract of DOI:10.1002/ejoc.200800605

The facile condensation of unprotected amino acids by a phosphite-promoted one-step coupling reaction is a highly efficient synthesis to generate stereoselective and optically pure symmetrical and unsymmetrical functionalized diketopiperazines. The use of microwaves enhanced by small amounts of ionic liquid is accompanied by significant improvement in reaction times and yields. Simple filtration through a pad of silica provides the pure compounds in very good to excellent yields. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800605

FULL PAPER
DOI: 10.1002/ejoc.200800605
Microwave-Assisted Stereoselective One-Pot Synthesis of Symmetrical and
Unsymmetrical 2,5-Diketopiperazines from Unprotected Amino Acids
Manuel Jainta,[a] Martin Nieger,[b] and Stefan Bräse*[a]
In memory of Professor Ivar K. Ugi (1930–2005)
Keywords: Amino acids / Diketopiperazines / Heterocycles / Natural products / One-pot reactions / Microwave-assisted
organic synthesis (MAOS) / Ionic liquids
The facile condensation of unprotected amino acids by a
phosphite-promoted one-step coupling reaction is a highly
efficient synthesis to generate stereoselective and optically
pure symmetrical and unsymmetrical functionalized diketo-
piperazines. The use of microwaves enhanced by small
amounts of ionic liquid is accompanied by significant im-
provement in reaction times and yields. Simple filtration
through a pad of silica provides the pure compounds in very
good to excellent yields.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
In nature, amino acids can be found in a great variety.
Their role for life existence is indisputable. Therefore, the
smallest cyclic peptides, the diketopiperazines and their
higher-functionalized analogues, the epithiodiketopiperaz-
ines, are common motifs that can be found in several natu-
ral products (Figure 1).[1–4]
In recent research, the 2,5-diketopiperazines have be-
come more attractive due to their diverse biological proper-
ties,[5] such as antitumor,[6,7] antiviral,[8] antifungal,[9,10] an-
tibacterial[11,12] or antifouling[13] activities. They are also
used as organic catalysts for the hydrocyanation of im-
ines.[14] Diketopiperazines are also jointly responsible for
the bitter taste in some food like coffee, beer, cacao and
chocolate.[15]
Figure 1. Natural 2,5-diketo- and epithiodiketopiperazines.
In the past few years, using microwave energy for chemi-
cal reactions has become increasingly popular in organic
chemistry.[16] Since the first reports of microwave-assisted
synthesis in 1986,[17,18] microwave technology has matured
to an established technique, and the efficiency of microwave
flash heating, with often dramatically reduced reaction
times, is just one of the many advantages. Both mechan-
ismsϪdipolar polarization and conductionϪare responsible
for the heating effect. To solve problems in heating with
apolar solvents like hexane or toluene, power modulators
such as charcoal, silicon carbide,[19] palladium salts or ionic
liquids can be added. Ionic liquids are thermally stable salts
with melting points below 100 °C. They consist of a bulky
organic cation and an inorganic or organic anion. These
compounds can be used as catalysts (including chiral cata-
lysts) or solvents for many organic reactions. Ionic liquids
as solvents are nontoxic, inflammable and many times recy-
clable. Ionic liquids combined with microwave irradiation
form a new synergy in organic chemistry and have potential
in a huge variety of applications. One example of these new
applications is presented in this article.
[a] Institut für Organische Chemie, Universität Karlsruhe (TH),
Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax: +49-721-608-8581
E-mail: braese@ioc.uka.de
[b] Laboratory of Inorganic Chemistry, University of Helsinki,
00014 Helsinki, Finland
On our way towards the cytotoxic compound Rostratin
C (3), we were faced with two challenges. The first challenge
was the synthesis of the necessary monomer, the bicyclic
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One-Pot Synthesis of Diketopiperazines
amino acid, whose skeleton was accessible via intramolecu- very good purity. The compatibility of protected functional
lar Diels–Alder reaction.[20] The second challenge was an groups was proven by the coupling of protected 4-trans-
efficient method for the condensation of amino acids.
hydroxyprolines. We decided to use the well-established and
To avoid the often-published multi-step synthesis con- base-stable silyl, benzyl and alkyl ethers 9b–d. In all cases,
taining standard peptide chemistry, with its protecting reaction occurred without noteworthy difficulties in good
group, activation and coupling strategies,[21] we used a yields (Scheme 2). These results show the applicability of
phosphorus-promoted coupling method with microwave ir- this method in the total synthesis of natural products.
radiation-induced heating (Scheme 1).[22] Of course, there
exist a lot of other synthetic pathways for a brief access to
2,5-diketopierazines, e.g. thermal cycloamidation[23] or
vaporous condensation[24] of sublimated amino acids under
reduced pressure in the presence of silica. The yields of di-
ketopiperazines prepared in this manner are comparable,
but the substrate scope is limited to the thermal stability
of the used α-amino acids and the stereoselectivity is not
consistent. In contrast to these methods, the procedure de-
scribed herein is gentler and uses fraction of the time, en-
ergy and physical complexity of previous methods. In pre-
liminary experiments, we tried to condense protected amino
acids using boronic acids[25] with limited success. Thus, we
Scheme 2. Synthesis of cyclo(Pro-Pro) and substituted derivatives.
switched to the phosphorus-promoted coupling of unpro-
tected amino acids.
This method is also applicable in condensing the well-
known primary natural amino acids, which has already
been shown by Ugi and Scheeser.[22] To avoid the additional
step of protecting the free amide functionalities in following
reactions, we used sarcosine (10), the naturally occurring N-
methylglycine, to generate a derivative of the smallest pos-
sible cyclic dipeptide 11, in excellent yield (Scheme 3).
Furthermore, the +I-effect of the additional methyl group
increases the nucleophilic character of the nitrogen atom,
and so has a positive influence on the coupling.
Scheme 1. PIII-promoted coupling of amino acids.
Results and Discussion
The condensation occurs by prolonged heating of amino
acids together with methyldichlorophosphite in the pres-
ence of excess triethylamine. The reaction takes place be-
tween 70 and 150 °C; thus toluene, having a boiling point
Scheme 3. Dimerization of sarcosine (10).
With these optimized reaction conditions, we tried to
of about 111 °C, was chosen as the solvent. However, due find out what happens to amino acids with sp2-hybridiza-
to its low loss factor [tanδ = 0.040 (2.45 GHz; 20 °C)],[26] tion or quaternary stereogenic centers. Thus, we coupled 2-
toluene is more or less transparent to microwave irradia- pyrrolecarboxylic acid, 2-indolecarboxylic acid and (S)-2-
tion. To enhance the efficiency of absorption, along with a methylproline to form their corresponding 2,5-diketopiper-
rapid heating of the solvent, small amounts of ionic liquid azines 12–14, in satisfactory yields (Figure 2).
were added.[27] The ionic liquid should be very similar to
other reactants used in order to avoid difficulties with these
high-boiling substances. Thus, we chose 1,3-dimethylimid-
azolium dimethyl phosphate, because the imidazolium cat-
ion is similar to the nitrogen base, and the phosphate anion
is very close to the coupling promoter. The ionic liquid was
easily and quantitatively removed by filtration together with
the accumulated ammonium salts. During the optimization
ids.
of this method, charcoal was also used as a power modula-
Figure 2. 2,5-Diketopiperazines from sterically hindered amino ac-
tor, with comparable yields, but with more difficulty in the
work-up.
With regard to the target molecules Rostratin C (3) and
Aranotin (4), our main interest is in polycyclic ring systems
Starting with the cyclization of proline (8a), we could like the structure of 13. Condensation of the partially satu-
directly isolate the tricyclic product 9a in good yield and rated indole derivatives indoline- and octahydroindolecar-
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M. Jainta, M. Nieger, S. Bräse
FULL PAPER
boxylic acid, afforded the corresponding pentacyclic 2,5-di- respect to the order of the used amino acids, no significant
ketopiperazines 15 and 16 in 93% and 97% yield, respec- differences in yields could be detected in initial cross-coup-
tively (Figure 3).
ling experiments.
Due to the mild reaction conditions, racemization or in-
version of the stereogenic centres of the amino acids was
neither expected nor ascertained. In all cases, complete re-
tention of the stereochemistry was observed by NMR spec-
troscopy. Furthermore, this issue could be unequivocally
proven by X-ray crystallography of 11, 12 and 14 (Fig-
ures 5, 6 and 7).
Figure 3. Pentacyclic diketopiperazines 15 and 16.
Due to the importance of this structural motif in natural
product synthesis, we were also interested in an extension
of this one-pot reaction to unsymmetrical 2,5-diketopiper-
azines. There are few other methods which afford such de-
fined heterodiketopiperazines in a single step, with excellent
yields.[28] To comply with this challenge, we synthesized all
possible cross-coupled permutations 17–22 using the highly
reactive proline (8a), sarcosine (10), indoline- and octahy-
droindolecarboxylic acids, in overall good yields (Figure 4).
Figure 6. Molecular structure of 12. Displacement parameters are
drawn at 50% probability level. The molecule possesses crystallo-
graphic Ci symmetry.
Figure 4. Unsymmetrical 2,5-diketopiperazines 17–22.
To obtain the heterodiketopiperazines without any by-
products, especially not the corresponding homodiketopip-
erazines, a small excess of about 1.2 equiv. of one amino
acid was necessary. In contrast to the C2-symmetrical
homodiketopiperazines, the unsymmetrical heterocycles
have an increased solubility in most organic solvents. With
Figure 7. Molecular structure of 14. Displacement parameters are
drawn at 50% probability level. The molecule possesses crystallo-
graphic C2 symmetry.
Conclusions
Within this article we describe a convenient route to ob-
tain highly functionalized symmetrical and unsymmetrical
2,5-diketopiperazines in a single-step, one-pot reaction.
This method is characterized by overall good yields, scal-
ability and tolerance to most popular base-stable protecting
groups. Another advantage of this reaction is its very simple
work-up, consisting in a facile filtration step that removes
the ammonium salts and the ionic liquid quantitatively.
Furthermore, it was shown that the reaction is free of race-
mization or inversion, and leads reliably and successfully to
the expected 2,5-diketopiperazines without any byproducts.
Figure 5. Molecular structure of 11. Displacement parameters are
drawn at 50% probability level. The molecule possesses crystallo-
graphic Ci symmetry.
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One-Pot Synthesis of Diketopiperazines
2.04 (m, 4 H, 2ϫCH2), 2.06–2.20 (m, 2 H, CH2), 2.22–2.34 (m, 2
H, CH2), 3.45–3.53 (m, 4 H, 3-CH2, 8-CH2), 4.14 (t, J = 8.11 Hz,
2 H, 5a-H, 10a-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.2
(s, 2 C, C-2, C-7), 27.6 (s, 2 C, C-1, C-6), 45.1 (s, 2 C, C-3, C-8),
60.4 (t, 2 C, C-5a, C-10a), 166.3 (q, 2 C, C-5, C-10) ppm. IR (neat):
Experimental Section
General Remarks: Solvents and chemicals used for reactions were
purchased from commercial suppliers. Solvents were dried under
standard conditions; chemicals were used without further purifica-
tion. All reactions were carried out under Ar in flame-dried glass-
ware. Evaporation of solvents and concentration of reaction mix-
tures were performed in vacuo at 40 °C on a Büchi rotary evapora-
ν = 3851 (vw), 3310 (w), 3089 (w), 2974 (m), 2848 (m), 2775 (vw),
˜
2369 (vw), 2224 (vw), 2119 (vw), 1985 (vw), 1938 (vw), 1802 (w),
1667 (m), 1670 (w), 1487 (w), 1434 (m), 1337 (m), 1318 (w), 1292
(m), 1237 (m), 1211 (m), 1164 (m), 1070 (w), 1052 (w), 1028 (w),
1003 (w), 970 (w), 919 (w), 881 (w), 844 (w), 795 (vw), 773 (w), 633
(w), 598 (w), 555 (w), 487 (w), 472 (w) cm–1. EI–MS (70 eV): m/z
(%) = 194 (97) [M+], 138 (25), 110 (17), 96 (23), 70 (91), 55 (15),
41 (100). HRMS (C10H14N2O2): calcd. 194.1055; found 194.1059.
C10H14N2O2 (194.1): calcd. C 61.84, H 7.27, N 14.42; found C
61.42, H 7.24; N 14.43.
tor. TLC was performed on silica gel plates (Kieselgel 60, F254
,
Merck) with detection by UV and visualization by spraying with
the Seebach solution.[29] Normal-phase silica gel (silica gel 60, 230–
400 mesh, Merck) was used for preparative chromatography. Sol-
vents used were hexane and ethyl acetate (EE). Melting points
(m.p.) were determined with a Laboratory Devices Inc. Mel-Temp
II and are uncorrected. IR spectra were recorded with a Bruker
IFS88. Absorption is reported as ν values in cm–1. H NMR and
1
(2R,4S,7R,9S)-2,7-Bis(tert-butyldimethylsilanyloxy)octahydrodipyr-
rolo[1,2-a:1Ј,2Ј-d]pyrazine-5,10-dione (9b): 16 mg, 86 % (scale
13C NMR spectra were recorded with a Bruker AC-250, AM-400
or DRX 500. Chemical shifts are reported as δ values (ppm) down-
field from internal TMS in the indicated solvent. Coupling con-
0.1 mmol). [α]2D0 = –58.3 (MeOH, c = 1.01). H NMR (400 MHz,
1
CDCl3): δ = 0.06 [s, 12 H, 2ϫ(CH3)2], 0.87 (s, 18 H, tBu), 2.05–
2.13 (m, 2 H, 2ϫCH2N), 2.25–2.32 (m, 2 H, 2ϫCH2N), 3.49 (d,
J = 12.6 Hz, 2 H, CH2CH), 3.58–3.64 (m, 2 H, CH2CH), 4.48 (t,
J = 3.7 Hz, 2 H, CH2CH), 4.53–4.58 (m, 2 H, CHOSi) ppm. 13C
NMR (100 MHz, CDCl3): δ = –4.7 (p, 4 C, 4ϫCH3), 18.1 (q, 2
C), 25.8 (p, 6 C, tBu), 37.8 (s, 2 C, 2 ϫ CHCH2), 54.6 (s, 2 C,
2ϫCH2N), 59.2 (s, 2 C, 2ϫCHCH2), 69.7 (t, 2 C, 2ϫCHOSi),
1
stants (J) are given in Hz; H: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br = broad, 13C: p = primary C, s =
secondary C, t = tertiary C, q = quaternary C. High-resolution
mass spectra (HRMS) were determined on a Finnigan MAT90 in-
strument. Elemental analysis was performed with Heraeus CHN-
O-Rapid and Elementar vario   instruments. Optical ro-
tations were determined with a Perkin–Elmer 241 polarimeter (Na,
589 nm).
166.8 (q, 2 C, 2ϫCO) ppm. IR (neat): ν = 3321 (w), 2962 (m),
˜
2859 (m), 1669 (m), 1435 (m), 1362 (w), 1305 (w), 1262 (m), 1221
(w), 1096 (m), 1020 (m), 921 (w), 881 (w), 803 (w), 700 (w), 622
(w) cm–1. EI–MS (70 eV): m/z (%) = 397 (100), 369 (14) [M+], 253
(4). HRMS (C22H41N2O4Si2): calcd. 453.2605; found 453.2611.
Crystal Structure Studies 11, 12, and 14: Single-crystal X-ray dif-
fraction studies were carried out with a Bruker-Nonius APEXII
diffractometer at 123(2) K using Mo-Kα radiation (λ = 0.71073 Å).
The structures were solved by direct methods (SHELXS-97[30]), and
refinement was carried out using SHELXL-97[30] (full-matrix least-
squares refinement on F2). The hydrogen atoms were localized by
difference electron density determination and refined using a “ri-
ding” model. The absolute structure of 14 could not be determined
reliably [refinement of Flack’s x-parameter x = –0.7(12)[31]], and 11
is a redetermination of N,N-dimethyldiketopiperazine at 123 K.[32]
Important data from the data collection, structure solution and
refinement are listed in Table 1.
(2R,4S,7R,9S)-2,7-Bis(benzyloxy)octahydrodipyrrolo[1,2-a:1Ј,2Ј-d]-
pyrazine-5,10-dione (9c): 38 mg, 96% (scale 0.2 mmol). [α]2D0 = –4.02
(MeOH, c = 1.02). 1H NMR (400 MHz, CDCl3): δ = 2.08–2.16 (m,
2 H, 2ϫCH2), 2.57 (dd, J = 13.8 Hz, 2 H, 2ϫCH2), 3.28–3.42 (m,
2 H, CH2CH), 3.62 (dd, J = 13.4, 4.6 Hz, 2 H, 2ϫNCH2), 3.68–
3.80 (m, 2 H, 2ϫNCH2), 4.15–4.32 (m, 2 H, 2ϫCHOBn), 4.54
(s, 4 H, 2ϫCH2Ph), 7.23–7.39 (m, 10 H, Ar-H), ppm. 13C NMR
(100 MHz, CDCl3): δ = 33.8 (s, 2 C, CH2), 50.9 (s, 2 C, NCH2),
58.8 (p, 2 C, 2 ϫ CH), 70.7 (p, 2 C, 2 ϫ CHBn), 75.4 (s, 2 C,
2ϫCH2Ph), 127.5 (t, 4 C, Ar-C), 127.8 (t, 2 C, C-Ar), 128.4 (t, 4
C, C-Ar), 137.2 (q, 2 C, Ar-C), 166.2 (q, 2 C, CO) ppm. IR (neat):
CCDC-687884 (for 11), -687885 (for 12) and -687886 (for 14) con-
tain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
ν = 2942 (w), 2739 (w), 2678 (w), 2492 (m), 1669 (m), 1578 (w),
˜
1454 (m), 1399 (w), 1362 (w), 1263 (m), 1201 (m), 1099 (m), 800
(w), 741 (w), 720 (w), 701 (w), 632 (w) cm–1. EI–MS (70 eV): m/z
(%) = 406 (7) [M+ ], 315 (3), 300 (10), 90 (100). HRMS
(C24H26N2O4): calcd. 406.1892; found 406.1896.
Microwave Irradiation Experiments: All microwave experiments
were performed using the CEM Discover Synthesizer possessing a
single-mode microwave cavity producing controlled irradiation at
2.45 GHz.[33] Experiments were carried out in standard microwave
process Pyrex vials (capacity 10 mL) using the high absorbance
level. Reaction time reflects irradiation times at the set reaction
temperature (fixed hold times).
(2R,5aS,7R,10aR)-2,7-Di-tert-butoxyoctahydrodipyrrolo[1,2-a:1Ј,2Ј-
d]pyrazine-5,10-dione (9d): 86 mg, 97% (scale 0.5 mmol). Rf = 0.05
(hexane/EE, 3:1). [α]2D0 = –48.73 (CHCl3, c = 0.87). M.p. 119–
1
123 °C. H NMR (400 MHz, CDCl3): δ = 1.16 (s, 18 H, 6ϫCH3),
2.12–2.26 (m, 4 H, 1-H, 6-H), 3.31–3.40 (m, 2 H, 3-H, 8-H), 3.62–
3.72 (m, 2 H, 3-H, 8-H), 4.18–4.25 (m, 2 H, 5a-H, 10a-H), 4.38–
4.47 (m, 2 H, 2-H, 7-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
28.1 (p, 6 C, 6ϫCH3), 36.4 (s, 2 C, C-1, C-6), 53.4 (s, 2 C, C-3, C-
8), 58.9 (t, 2 C, C-5a, C-10a), 68.1 [q, 2 C, 2ϫC(CH3)3], 74.3 (t, 2
General Procedure for the Dimerization of α-Amino Acids: The
amino acid (1 mmol) was suspended in toluene (3 mL) with few
drops of 1,3-dimethylimidazolium dimethylphosphate. Triethyl-
amine (4 mmol) and methyl dichlorophosphite (1 mmol) were
added via cannula. After irradiation under closed-vessel microwave
conditions at 145 °C for 1 h, the solution was filtered, and the pre-
cipitate was washed with hot toluene. The filtrate was evaporated,
and the resulting crude product was purified by flash column
chromatography, if necessary.
C, C-2, C-7), 166.5 (q, 2 C, C-5, C-10) ppm. IR (neat): ν = 3314
˜
(w), 2968 (s), 2870 (m), 1744 (m), 1657 (s), 1437 (s), 1390 (s), 1363
(s), 1313 (m), 1292 (m), 1263 (m), 1194 (s), 1147 (m), 1127 (m),
1096 (s), 1079 (s), 1045 (m), 1014 (s), 973 (w), 902 (m), 883 (m),
850 (w), 760 (w), 727 (w), 650 (w), 632 (w), 587 (w), 482 (w), 412
(w) cm–1. EI–MS (70 eV): m/z (%) = 338 (21) [M+], 282 (10), 226
(31), 140 (9), 86 (9), 58 (48), 43 (100). HRMS (C18H30N2O4): calcd.
338.2206; found. 338.2204.
(S,S)-Octahydrodipyrrolo[1,2-a:1Ј,2Ј-d]pyrazine-5,10-dione (9a): 151
mg, 91% (scale 1.7 mmol). Rf = 0.27 (EE). [α]2D0 = 130.3 (CHCl3, c
= 1.00). M.p. 138–145 °C. 1H NMR (400 MHz, CDCl3): δ = 1.80–
Eur. J. Org. Chem. 2008, 5418–5424
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M. Jainta, M. Nieger, S. Bräse
FULL PAPER
Table 1. Crystallographic data, structure solution and refinement of 11, 12, 14.
11
12
14
Empirical formula
Formula weight
C6H10N2O2
142.16
C10H6N2O2
186.17
C12H18N2O2
222.28
Temperature [K]
Crystal system
Space group
a [Å]
b [Å]
c [Å]
α [°]
123(2)
123(2)
123(2)
monoclinic
P21/n (No. 14)
6.9079(5)
6.0733(5)
18.0337(5)
90
monoclinic
P21/n (No. 14)
5.410(1)
5.701(1)
12.938(2)
90
monoclinic
C2 (No. 5)
11.410(2)
6.413(1)
7.911(1)
90
β [°]
102.706(5)
90
328.79(4)
2
1.436
0.109
100.34(1)
90
392.56(12)
2
1.575
0.114
102.62(2)
90
564.88(15)
2
1.307
0.090
γ [°]
V [Å3]
Z
Dcalcd. [gcm–3]
Absorption coefficient [mm–1]
F(000)
152
192
240
Crystal size [mm]
2θmax. [°]
Limiting indices
0.25ϫ0.15ϫ0.10
50
–7 Յ h Յ 8
–6 Յ k Յ 7
–7 Յ l Յ 9
1612
0.50ϫ0.40ϫ0.30
55
–7 Յ h Յ 6
–7 Յ k Յ 7
–16 Յ l Յ 16
4766
0.45ϫ0.35ϫ0.25
55
–14 Յ h Յ 14
–8 Յ k Յ 8
–10 Յ l Յ 10
5580
Reflections collected
Unique reflections
Rint
574
0.0346
891
0.0140
1298
0.0544
Data/restraints/parameters
574/0/47
1.089
891/0/64
1.123
1298/1/73
1.078
GOF on F2
R1 [IϾ2σ(I)]
0.0366
0.0844
0.141/–0.230
0.0418
0.1144
0.393/–0.312
0.0348
0.0855
0.312/–0.201
wR2 (all data)
Largest diff. map peak/hole [eA–3]
1,4-Dimethylpiperazine-2,5-dione (11): 38 mg, 97 % (scale
11-H), 7.15 (dd, J = 1.0, 8.5 Hz, 2 H, 3-H, 10-H), 7.25 (ddd, J =
0.6 mmol). Rf = 0.42 (hexane/EE, 3:1). M.p. 136–139 °C. 1H NMR 1.0, 7.0, 8.5 Hz, 2 H, 2-H, 9-H), 7.43 (dd, J = 0.9, 8.2 Hz, 2 H, 7-
(250 MHz, CDCl3): δ = 2.90 (s, 6 H, 2 ϫ CH3), 3.91 (s, 4 H,
2ϫCH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 33.0 (p, 2 C,
2ϫCH3), 51.3 (s, 2ϫCH2), 162.8 (q, 2 C, C-2, C-5) ppm. IR (neat):
H, 14-H), 7.63 (dd, J = 0.9, 8.2 Hz, 1-H, 8-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 109.3 (t, 2 C, C-7, C-14), 113.3 (t, 2 C, C-
4, C-11), 121.4 (t, 2 C, C-3, C-10), 123.2 (t, 2 C, C-1, C-8), 126.0
(t, 2 C, C-2, C-9), 128.5 (q, 2 C, C-7a, C-14a), 128.7 (q, 2 C, C-6a,
C-13a), 139.1 (q, 2 C, C-4a, C-11a), 164.0 (q, 2 C, C-6, C-13) ppm.
ν = 3919 (vw), 3293 (w), 3153 (w), 2967 (m), 2936 (m), 2784 (w),
˜
2676 (w), 2492 (w), 2421 (w), 2374 (w), 2275 (vw), 2056 (vw), 1971
(vw), 1739 (w), 1657 (m), 1555 (w), 1501 (m), 1446 (m), 1399 (m), IR (neat): ν = 3335 (m), 3122 (m), 3057 (m), 2953 (m), 2489 (w),
˜
1340 (m), 1297 (w), 1254 (m), 1164 (m), 1135 (w), 1016 (m), 991
2035 (w), 1949 (w), 1917 (w), 1882 (w), 1696 (s), 1561 (m), 1530
(w), 838 (w), 806 (w), 738 (m), 604 (m), 486 (vw), 411 (m) cm–1. (m), 1478 (m), 1449 (m), 1365 (m), 1344 (m), 1314 (m), 1259 (m),
EI–MS (70 eV): m/z (%) = 142 (100) [M+], 113 (9), 86 (9), 57 (31), 1230 (m), 1199 (m), 1156 (m), 1120 (m), 1079 (m), 1008 (m), 992
42 (24). HRMS (C6H10N2O2): calcd. 142.0742; found 142.0740.
(m), 938 (m), 880 (m), 853 (m), 825 (m), 772 (m), 747 (m), 701 (m),
662 (m), 607 (w), 579 (w), 565 (w), 539 (m), 478 (w), 435 (m) cm–1.
EI–MS (70 eV): m/z (%) = 286 (100) [M+], 143 (33), 115 (38), 57
(11), 43 (19). HRMS (C18H10N2O2): calcd. 286.0742; found
286.0745.
Dipyrrolo[1,2-a;1Ј,2Ј-d]pyrazine-5,10-dione (12): 70 mg, 84% (scale
0.9 mmol). Rf = 0.66 (hexane/EE, 3:1). M.p. 272–276 °C. 1H NMR
(400 MHz, CDCl3): δ = 6.48 (t, J = 3.4 Hz, 2 H, 2-H, 7-H), 7.37
(dd, J = 3.4, 1.5 Hz, 2 H, 3-H, 8-H), 7.72 (dd, J = 3.4, 1.5 Hz, 2
H, 1-H, 6-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 114.7 (t, 2 (5aS,10aS)-5a,10a-Dimethyloctahydrodipyrrolo[1,2-a:1Ј,2Ј-d]pyraz-
C, C-2, C-7), 123.4 (t, 2 C, C-3, C-8), 123.7 (t, 2 C, C-1, C-6), 124.3 ine-5,10-dione (14): 58 mg, 86% (scale 0.6 mmol). M.p. 178–180 °C.
(q, 2 C, C-5a, C-10a), 150.9 (q, 2 C, C-5, C-10) ppm. IR (neat): ν
1H NMR (400 MHz, CDCl3): δ = 1.50 (s, 6 H, 2ϫCH3), 1.80–2.13
(m, 8 H, 4ϫCH2), 3.44–3.51 (m, 2 H, 2ϫNCH2), 3.73–3.80 (m, 2
H, 2ϫNCH2) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.2 (s, 2
C, C-2, C-7), 24.8 (p, 2 C, 2ϫCH3), 36.4 (s, 2 C, C-1, C-6), 44.4
(s, 2 C, C-3, C-8), 66.1 (q, 2 C, C-5a, C-10a), 168.9 (q, 2 C, 2ϫCO)
˜
= 3978 (w), 3390 (m), 3260 (w), 3127 (m), 3011 (w), 2954 (w), 2883
(w), 2850 (w), 2725 (w), 2604 (w), 2542 (w), 2476 (w), 2426 (w),
2359 (w), 2288 (w), 2252 (w), 2225 (w), 2141 (w), 2089 (w), 2036
(w), 1964 (w), 1937 (w), 1881 (w), 1816 (m), 1771 (m), 1701 (s),
1627 (m), 1558 (s), 1479 (m), 1458 (s), 1414 (s), 1324 (s), 1256 (m), ppm. IR (neat): ν = 3274 (m), 2963 (m), 2605 (m), 2497 (m), 1960
˜
1221 (m), 1182 (m), 1149 (m), 1069 (s), 1022 (m), 997 (m), 910 (m), (w), 1654 (m), 1504 (m), 1459 (m), 1429 (m), 1376 (m), 1364 (m),
857 (m), 778 (m), 738 (s), 704 (m), 618 (m), 588 (m), 439 (w) cm–1.
1332 (m), 1312 (m), 1261 (m), 1209 (m), 1166 (m), 1093 (m), 1018
EI–MS (70 eV): m/z (%) = 186 (100) [M+], 155 (15), 130 (16), 93 (m), 946 (m), 904 (m), 868 (m), 802 (m), 752 (m), 699 (w), 651 (m),
(33), 77 (10), 65 (11), 58 (11), 43 (23). HRMS (C10H6N2O2): calcd. 623 (w) cm–1. EI–MS (70 eV): m/z (%) = 222 (73) [M+], 207 (10),
186.0429; found 186.0430.
194 (39), 151 (19), 84 (100), 83 (33), 43 (11). HRMS (C12H18N2O2):
calcd. 222.1368; found 222.1371.
Pyrazino[1,2-a;4,5-aЈ]diindole-6,13-dione (13): 78 mg, 90% (scale
0.6 mmol). Rf = 0.58 (hexane/EE, 1:1). M.p. 249–254 °C. 1H NMR (S,S)-(6a,7,13a,14)-Tetrahydropyrazino[1,2-a:4,5-aЈ]diindol-6,13-di-
(400 MHz, CDCl3): δ = 7.06 (ddd, J = 1.0, 7.0, 8.5 Hz, 2 H, 4-H,
one (15): 162 mg, 93% (scale 1.2 mmol). Rf = 0.38 (hexane/EE, 3:1).
5422
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5418–5424

One-Pot Synthesis of Diketopiperazines
[α]2D0 = –2.21 (CHCl3, c = 1.00). M.p. 263–268 °C. 1H NMR
(m), 2623 (w), 1968 (w), 1666 (s), 1600 (m), 1487 (m), 1454 (m),
(400 MHz, CDCl3): δ = 3.46 (dd, J = 9.6, 16.8 Hz, 2 H, 7,14-H), 1413 (m), 1344 (m), 1307 (m), 1289 (m), 1250 (m), 1210 (m), 1162
3.82 (dd, J = 9.6, 16.8 Hz, 2 H, 7,14-H), 4.99 (dd, J = 9.6, 16.8 Hz,
2 H, 6a,13a-H), 7.13 (dt, J = 1.0, 8.0 Hz, 2 H, 1,8-H), 7.29 (t, J =
(m), 1132 (m), 1091 (w), 1033 (w), 1001 (m), 956 (w), 919 (m), 868
(w), 846 (w), 793 (w), 768 (m), 711 (w), 644 (m), 599 (w), 555 (w),
8.0 Hz, 4 H, 3,4,10,11-H), 8.13 (d, J = 8.0 Hz, 2 H, 2,9-H) ppm. 531 (w), 498 (w), 478 (vw), 430 (m) cm–1. EI–MS (70 eV): m/z (%)
13C NMR (100 MHz, CDCl3): δ = 30.0 (s, 2 C, C-7,14), 61.6 (t, 2
= 242 (100) [M+], 214 (25), 194 (38), 186 (11), 174 (17), 144 (16),
C, C-6a,13a), 115.7 (t, 2 C, C-4,11), 125.0 (t, 4 C, C-2,3,9,10), 127.9 131 (35), 117 (75), 89 (17), 83 (11), 77 (14), 70 (51), 58 (18), 43 (80),
(t, 2 C, C-1,8), 129.7 (t, 2 C, C-7a,14a), 140.5 (q, 2 C, C-4a,11a),
41 (11). HRMS (C14H14N2O2): calcd. 242.1054; found 242.1050.
164.2 (q, 2 C, CO) ppm. IR (neat): ν = 3344 (vw), 3069 (w), 3050
˜
(5aS,6aS,10aS,12aS)-Dodecahydropyrrolo[1Ј,2Ј:4,5]pyrazino[1,2-a]-
indole-5,12-dione (18): 188 mg, 88% (scale 0.9 mmol). Rf = 0.16
(hexane/EE, 3:1). [α]2D0 = –1.00 (CHCl3, c = 1.10). M.p. 68–72 °C.
1H NMR (400 MHz, CDCl3): δ = 0.83–0.98 (m, 1 H, CH2), 1.0–
1.05 (m, 1 H, CH2), 1.19–1.33 (m, 1 H, CH2), 1.36–1.47 (m, 1 H,
CH2), 1.47–1.65 (m, 4 H, CH2), 1.66–1.76 (m, 1 H, CH2), 1.89–
1.99 (m, 2 H, CH2), 2.25–2.37 (m, 6 H, CH2), 3.37 (m, 1 H, 10a-
H), 3.87 (dd, Jtrans = 11.9, Jcis = 6.2 Hz, 1 H, 12a-H), 3.99–4.09
(m, 1 H, 5a-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.5 (s, C-
9), 23.3 (s, C-2), 25.6 (s, C-8), 27.2 (s, C-7), 28.2 (s, C-10), 28.4 (s,
(w), 2898 (w), 2863 (m), 1793 (vw), 1681 (m), 1603 (w), 1483 (m),
1462 (m), 1446 (w), 1410 (m), 1343 (w), 1315 (w), 1245 (w), 1213
(w), 1182 (w), 1156 (w), 1131 (w), 1086 (w), 1018 (w), 996 (w), 928
(w), 867 (w), 849 (w), 776 (w), 756 (m), 713 (w), 647 (w), 563 (w),
528 (w) cm– 1 . EI–MS (70 eV): m/z = 290 [M+ ]. HRMS
(C18H14N2O2): calcd. 290.1055; found 290.1051. C18H14N2O2
(290.1): calcd. C 74.47, H 4.86, N 9.65; found C 74.45, H 5.08, N
9.65.
(4aS,6aS,7aS,11aS,13aS,14aS)-Hexadecahydropyrazino[1,2-a:4,5-
aЈ]diindole-6,13-dione (16): 82 mg, 97% (scale 0.6 mmol). Rf = 0.50 C-1), 35.8 (s, C-6), 35.9 (t, C-6a), 44.8 (s, C-3), 55.6 (t, C-5a), 60.2
(hexane/EE, 3:1). [α]2D0 = 12.60 (MeOH, c = 0.50). M.p. 204–208 °C.
1H NMR (400 MHz, CDCl3): δ = 0.91–1.04 (m, 2 H, CH2), 1.09–
1.25 (m, 2 H, CH2), 1.26–1.40 (m, 2 H, CH2), 1.44–1.53 (m, 2 H,
CH2), 1.55–1.72 (m, 4 H, 2ϫCH2), 1.73–1.82 (m, 2 H, CH2), 1.92–
2.50 (m, 2 H, CH2), 2.23–2.43 (m, 6 H, 2ϫCH2, 2ϫCH), 3.92–
4.00 (m, 2 H, 4a-H, 11a-H), 4.11 (t, 2 H, 6a-H, 13a-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 20.7 (s, 2 C, C-3, C-10), 23.3 (s, 2
C, C-2, C-9), 25.9 (s, 2 C, C-1, C-8), 27.3 (s, 2 C, C-4, C-11), 28.5
(s, 2 C, C-7, C-14), 36.2 (t, 2 C, C-7a, C-14a), 55.9 (t, 2 C, C-6a,
C-13a), 60.5 (t, 2 C, C-4a, C-11a), 167.4 (q, 2 C, C-6, C-13) ppm.
(t, C-12a), 60.3 (t, C-10a), 166.4 (q, C-5), 166.9 (q, C-12) ppm. IR
(neat): ν = 3309 (w), 2929 (m), 2858 (m), 1661 (s), 1413 (s), 1371
˜
(m), 1347 (m), 1295 (m), 1262 (m), 1175 (m), 1134 (w), 1115 (w),
1077 (w), 1022 (w), 952 (w), 919 (w), 891 (w), 854 (w), 822 (w), 787
(w), 729 (w), 666 (w), 641 (w), 610 (w), 577 (w), 556 (w), 501 (vw),
464 (vw), 449 (w), 424 (w) cm–1. EI–MS (70 eV): m/z (%) = 248
(100) [M+], 220 (11), 194 (11), 178 (10), 154 (13), 124 (35), 96 (12),
70 (46). HRMS (C14H20N2O2): calcd. 248.1525; found 248.1522.
(4aS,6aS,13aS,14aS)-1,2,3,4,4a,6a,7,13a,14,14a-Decahydropyraz-
ino[1,2-a:4,5-aЈ]diindole-6,13-dione (19): 145 mg, 81 % (scale
0.6 mmol). Rf = 0.04 (hexane/EE, 3:1). [α]2D0 = 5.08 (CHCl3, c =
1.23). M.p. 198–203 °C. 1H NMR (400 MHz, CDCl3): δ = 0.86–
1.04 (m, 1 H, CH2), 1.05–1.19 (m, 1 H, CH2), 1.20–1.35 (m, 1 H,
CH2), 1.38–1.82 (m, 4 H, CH2), 1.90–2.11 (m, 1 H, CH2), 2.15–
2.44 (m, 3 H, CH2), 3.24 (dd, Jtrans = 16.9, Jcis = 10.7 Hz, 1 H, 7-
H), 3.62 (dd, Jtrans = 16.9, Jcis = 10.7 Hz, 1 H, 7-H), 3.85–3.94 (m,
1 H, 4a-H), 4.29 (t, J = 8.3 Hz, 1 H, 13a-H), 4.66–4.74 (m, 1 H,
6a-H), 6.98–7.05 (m, 1 H, Ar-H), 7.13–7.23 (m, 2 H, Ar-H), 7.97–
8.03 (m, 1 H, Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.5
(s, C-3), 23.1 (s, C-2), 25.6 (s, C-1), 27.3 (s, C-4), 28.3 (s, C-7), 29.7
(s, C-14), 35.9 (t, C-14a), 55.7 (t, C-13a), 56.1 (t, C-6a), 60.7 (t, C-
4a), 115.2 (t, C-11), 124.4 (t, C-10), 124.8 (t, C-9), 127.5 (t, C-8),
129.9 (q, C-7a), 140.4 (q, C-11a), 165.4 (q, C-6), 167.2 (q, C-13)
IR (neat): ν = 3307 (w), 2979 (m), 2928 (m), 2858 (m), 2670 (vw),
˜
1660 (m), 1466 (m), 1411 (m), 1370 (m), 1347 (m), 1295 (w), 1262
(w), 1192 (w), 1175 (w), 1159 (w), 1134 (w), 1114 (w), 1077 (w),
1062 (w), 1022 (w), 950 (w), 933 (w), 910 (vw), 891 (w), 878 (w),
855 (w), 823 (w), 789 (w), 766 (vw), 677 (w), 667 (w), 610 (w), 577
(w), 555 (w), 526 (vw), 498 (w), 463 (w), 448 (m), 421 (m), 413 (m)
cm–1. EI–MS (70 eV): m/z (%) = 302 (100) [M+], 274 (8), 208 (13),
178 (20), 151 (4), 124 (53), 81 (8). HRMS (C18H26N2O2): calcd.
302.1994; found 302.1997. C18H26N2O2 (302.2): calcd. C 71.49, H
8.67, N 9.26; found C 71.81, H 8.42, N 9.05.
General Procedure for the Synthesis of Cross-coupled 2,5-Diketopip-
erazines: The first amino acid (1 mmol) was suspended in toluene
(4 mL) plus a few drops of 1,3-dimethylimidazolium dimethylphos-
phate. Triethylamine (4 mmol), methyldichlorophosphite (1 mmol)
and the second amino acid (1.2 mmol) were added subsequently.
After irradiation under closed vessel microwave conditions at
145 °C for 1 h, the solution was filtered and the precipitate was
washed with hot toluene. The filtrate was evaporated, and the re-
sulting crude product was purified by flash column chromatog-
raphy, if necessary.
ppm. IR (neat): ν = 3331 (w), 3116 (w), 3069 (w), 2924 (m), 2859
˜
(m), 1674 (s), 1601 (m), 1483 (m), 1461 (m), 1410 (m), 1348 (w),
1307 (w), 1247 (m), 1196 (w), 1164 (w), 1133 (w), 1086 (w), 1065
(w), 1008 (w), 978 (w), 955 (w), 932 (w), 907 (w), 891 (w), 971 (w),
858 (w), 787 (w), 757 (m), 676 (w), 654 (w), 609 (w), 557 (w), 528
(w), 501 (w), 448 (w), 422 (w) cm–1. (EI, 70 eV) m/z (%): 302 (100),
296 (27) [M+], 274 (11), 208 (15), 178 (20), 124 (63), 117 (13), 81
(19). HRMS (C18H20N2O2): calcd. 296.1525; found 296.1522.
(5aS,12aS)-1,2,3,5a,6,12a-Hexahydropyrrolo[1Ј,2Ј:4,5]pyrazino[1,2-a]-
indole-5,12-dione (17): 172 mg, 83% (scale 0.9 mmol). Rf = 0.04 (S)-2-Methyl-2,3,10,10a-tetrahydropyrazino[1,2-a]indole-1,4-dione
(hexane/EE, 3:1). [α]2D0 = –2.93 (CHCl3, c = 13.3). M.p. 159–163 °C.
1H NMR (400 MHz, CDCl3): δ = 1.87–2.08 (m, 2 H, CH2), 2.24–
2.42 (m, 2 H, CH2), 3.30 (dd, J = 10.5, 16.8 Hz, 1 H, NCH2), 3.54–
3.60 (m, 2 H, 6-H) 3.64 (dd, J = 10.5, 16.8 Hz, 1 H, NCH2), 4.29
(t, J = 7.8 Hz, 1 H, 12a-H), 4.81 (t, J = 9.8 Hz, 1 H, 5a-H), 7.03–
7.08 (m, 1 H, Ar-H), 7.17–7.23 (m, 2 H, Ar-H), 8.01–8.05 (m, 1 H,
Ar-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.4 (s, C-2), 27.5
(20): 121 mg, 93% (scale 0.6 mmol). Rf = 0.48 (hexane/EE, 3:1).
[α]2D0 = –6.44 (CHCl3, c = 0.51). M.p. 248–252 °C. 1H NMR
(400 MHz, CDCl3): δ = 3.07 (s, 3 H, CH3), 3.44 (dd, Jgem = 16.8,
J = 10.3 Hz, 1 H, 10-H), 3.79 (dd, Jgem = 16.8, J = 9.0 Hz, 1 H,
10-H), 3.88–3.98 (m, 1 H, 3-H), 4.30–4.41 (m, 1 H, 3-H), 4.97 (dd,
J = 10.3, 9.0 Hz, 1 H, 10a-H), 7.07–7.14 (m, 1 H, Ar-H), 7.21–7.30
(m, 2 H, Ar-H), 8.02–8.12 (m, 1 H, Ar-H) ppm. 13C NMR
(s, C-1), 30.0 (s, C-6), 45.4 (s, C-3), 60.7 (t, C-5a), 61.2 (t, C-12a), (100 MHz, CDCl3): δ = 30.1 (p, CH3), 33.8 (s, C-10), 54.2 (s, C-3),
115.5 (t, C-10), 124.7 (t, C-8), 149.9 (t, C-9), 127.6 (t, C-7), 129.9 61.6 (t, C-10a), 115.7 (t, C-6), 125.0 (t, C-8), 127.9 (t, C-7), 129.7
(q, C-6a), 140.5 (q, C-10a), 165.1 (q, C-5), 165.5 (q, C-12) ppm. IR (t, C-9), 140.4 (q, C-9a), 140.7 (q, C-5a), 164.2 (q, C-4), 166.9 (q,
(neat): ν = 3318 (w), 3114 (w), 3080 (w), 2987 (m), 2960 (m), 2874 C-1) ppm. IR (neat): ν = 3344 (w), 3051 (m), 2898 (m), 2863 (w),
˜
˜
Eur. J. Org. Chem. 2008, 5418–5424
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5423

M. Jainta, M. Nieger, S. Bräse
FULL PAPER
[7] B. Nicholson, G. K. Lloyd, B. R. Miller, M. A. Palladino, Y.
Kiso, Y. Hayashi, S. T. C. Neuteboom, Anti-Cancer Drugs
2006, 17, 25–31.
[8] S. Sinha, R. Srivastava, E. De Clercq, R. K. Singh, Nucleosides
Nucleotides Nucleic Acids 2004, 23, 1815–1824.
[9] D. R. Houston, B. Synstad, V. G. H. Eijsink, M. J. R. Stark,
I. M. Eggleston, D. M. F. Van Aalten, J. Med. Chem. 2004, 47,
5713–5720.
1681 (s), 1603 (m), 1483 (s), 1462 (m), 1410 (m), 1343 (m), 1315
(m), 1246 (m), 1213 (m), 1183 (w), 1155 (w), 1132 (m), 1086 (m),
1058 (w), 1018 (m), 996 (m), 930 (w), 867 (w), 849 (w), 777 (m),
755 (m), 712 (w), 647 (w), 599 (w), 564 (w), 528 (m), 421 (m) cm–1.
EI–MS (70 eV): m/z (%) = 216 (100) [M+], 199 (12), 142 (27), 131
(12), 117 (40), 90 (10). HRMS (C12H12N2O2): calcd. 216.0899;
found 216.0896.
[10] H.-G. Byun, H. Zhang, M. Mochizuki, K. Adachi, Y. Shizuri,
W.-J. Lee, S.-K. Kim, J. Antibiot. 2003, 56, 102–106.
[11] F. Fdhila, V. Vázquez, J. L. Sánchez, R. Riguera, J. Nat. Prod.
2003, 66, 1299–1301.
[12] W.-R. Abraham, Drug Des. Rev. 2005, 2, 13–33.
[13] X. Li, S. Dobretsov, Y. Xu, X. Xiao, O. S. Hung, P.-Y. Qian,
Biofouling 2006, 22, 187–194.
(5aS,9aS,10aS)-2-Methyldecahydropyrazino[1,2-a]indole-1,4-dione
(21): 113 mg, 91% (scale 0.6 mmol). Rf = 0.14 (hexane/EE, 3:1).
[α]2D0 = –0.82 (CHCl3, c = 1.83). M.p. 129–133 °C. 1H NMR
(400 MHz, CDCl3): δ = 0.74–1.04 (m, 1 H, CH2), 1.04–1.38 (m, 2
H, CH2), 1.40–1.52 (m, 1 H, CH2), 1.52–1.70 (m, 2 H, CH2), 1.70–
1.82 (m, 1 H, CH2), 1.92–2.14 (m, 1 H, CH2), 2.14–2.46 (m, 3 H,
9a-H, 10-H), 2.95 (s, 3 H, CH3), 3.65–3.69 (m, 1 H, 5a-H), 3.69–
3.73 (m, 1 H, 10a-H), 3.87–4.03 (m, 1 H, 3-H), 4.04–4.15 (m, 1 H,
3-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 20.5 (s, C-7), 23.3 (s,
C-8), 25.7 (s, C-9), 27.2 (s, C-6), 33.5 (s, C-10), 35.6 (p, CH3), 36.1
(t, C-9a), 55.8 (s, C-3), 59.1 (t, C-10a), 60.4 (t, C-5a), 163.7 (q, C-
[14] C. Becker, C. Hoben, D. Schollmeyer, G. Scherr, H. Kunz, Eur.
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7231.
[16] a) N. E. Leadbeater, H. M. Torenius, H. Tye, Comb. Chem.
High Throughput Screening 2004, 7, 511–528; b) J.-M. Lévêque,
G. Cravotto, Chimia 2006, 60, 313–320.
4), 168.3 (q, C-1) ppm. IR (neat): ν = 2930 (m), 2859 (m), 1663
˜
(m), 1448 (m), 1411 (m), 1370 (w), 1347 (w), 1294 (w), 1263 (w),
1195 (w), 1175 (w), 1114 (w), 1042 (w), 951 (w), 892 (w), 854 (w),
822 (w), 788 (w), 677 (w), 642 (w), 611 (w), 577 (w), 555 (w), 449
(w), 424 (w) cm–1. EI–MS (70 eV): m/z (%) = 222 (2) [M+], 128 (1),
58 (32), 43 (100), 39 (3). HRMS (C12H18N2O2): calcd. 222.1368;
found 222.1370.
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Laberge, L. Roussell, Tetrahedron Lett. 1986, 27, 279–282.
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J = 8.6, 5.5 Hz, 2 H, 6-H), 3.81 (s, 2 H, 3-H), 4.02 (t, J = 8.1 Hz,
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27.2 (s, C-8), 32.7 (p, CH3), 44.7 (s, C-6), 51.1 (s, C-3), 60.0 (t, C-
8a), 162.7 (q, C-4), 165.9 (q, C-1) ppm. IR (neat): ν = 3917 (w),
˜
3304 (m), 3152 (m), 2973 (m), 2884 (m), 2420 (w), 2372 (w), 1739
(w), 1668 (m), 1440 (m), 1338 (m), 1259 (m), 1163 (m), 1070 (m),
1015 (m), 969 (w), 919 (m), 880 (w), 839 (m), 739 (m), 631 (m), 601
(m), 505 (w), 487 (w), 476 (w), 412 (w) cm–1. EI–MS (70 eV): m/z
(%) = 168 (69) [M+], 142 (100), 140 (13), 112 (16), 83 (16). HRMS
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Received: June 20, 2008
Published Online: September 30, 2008
5424
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Eur. J. Org. Chem. 2008, 5418–5424