Diastereoselective Diels-Alder additions of ethene to substituted homochiral 2(1H)-pyrazinones

Article abstract of DOI:10.1002/ejoc.200600805

Diels-Alder reactions of ethene with 2(1H)-pyrazinones bearing a homochiral auxiliary group are presented. The cycloaddition products form with diasteromeric excesses of up to 50%. To the best of our knowledge, these are the first Diels-Alder reactions wi

Full text of DOI:10.1002/ejoc.200600805

FULL PAPER
DOI: 10.1002/ejoc.200600805
Diastereoselective Diels–Alder Additions of Ethene to Substituted Homochiral
2(1H)-Pyrazinones
Jo Alen,[a] Wim J. Smets,[a] Liliana Dobrzan´ska,[b] Wim M. De Borggraeve,*[a]
Frans Compernolle,[a] and Georges J. Hoornaert[a]
Keywords: Cycloaddition / Diastereoselectivity / Chiral auxiliaries / Pyrazinone / Ethene
Diels–Alder reactions of ethene with 2(1H)-pyrazinones
bearing a homochiral auxiliary group are presented. The cy-
cloaddition products form with diasteromeric excesses of up
to 50%. To the best of our knowledge, these are the first
Diels–Alder reactions with ethene showing some degree of
diastereoselectivity.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
iary, the 1-, the 3- and the 6-position. Since the substituents
at position 3 and 6 cannot be chosen freely in the design of
the dipeptide mimics (they represent side chains of amino
acids in the turn mimics), the 1-position was the only viable
option left.
Introduction
The short and highly versatile synthesis of 3,5-dichloro-
2(1H)-pyrazinones[1] is the starting point for many of the
synthetic methods developed in our group.[2] One important
research area is the application of Diels–Alder reactions
with alkene dienophiles to the cyclic azadiene contained in
these compounds. In these reactions, bicyclic adducts are
formed as racemic mixtures which in turn are precursors
for scaffolds with beta turn inducing properties.[3] So far,
we were unsuccessful in modifying this reaction in an enan-
tioselective fashion using homochiral catalysts.[4] For incor-
poration of the beta turn mimicking scaffolds in biomole-
cules it is important to obtain the 5-aminopiperidinone-2-
carboxylate (APC) systems in their optically pure forms.[5]
In this paper, we describe a modification of our original
strategy with a homochiral auxiliary group in the system to
produce diastereomeric reaction products.
Scheme 1. Possible products from reaction of 2(1H)-pyrazinones
with optically active dienophiles.
We therefore attached an (R)-α-methylbenzyl group to
the lactam-nitrogen atom of the pyrazinone.[6] Since Diels–
Alder reactions proceed at elevated temperature and the di-
enophile (ethene) is relatively small (and therefore hardly
subject to steric interactions in the transition state), only
minor diastereoselectivity was expected and our primary fo-
cus was on the purification and separation of the diastereo-
isomers of the products.
The pyrazinones bearing the homochiral α-methylbenzyl
group were synthesized from an α-aminonitrile and oxalyl
chloride (Scheme 2).[1] Synthesis of the aminonitrile by
Strecker reaction did not pose any problems. In the cyclis-
ation, rather low yields were obtained with increasing size
of R6. Bringing the substituents R1 and R6 close to each
other in a planar system causes a lower yield because of
steric hindrance. NMR spectra of the pyrazinones 1b and
1c show broad benzyl H signals, whereas for 1a well-re-
solved quartets appear. This suggests the absence of free
Results and Discussion
Synthesis of Functionalized (α-Methylbenzyl)pyrazinones
In theory, a chiral auxiliary can be introduced either by
the diene or the dienophile. However, because of the poten-
tial complexity of reaction mixtures resulting from Diels–
Alder reactions with substituted dienophiles (Scheme 1), we
prefer the method in which the auxiliary is introduced by
the diene system. In the pyrazinones, used in our methodol-
ogy, there are 3 potential attachment points for the auxil-
[a] Moleculair Design & Synthese, Departement Chemie, Katho-
lieke Universiteit Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax: +32-16-327990
E-mail: Wim.DeBorggraeve@chem.kuleuven.be
[b] Department of Chemistry, University of Stellenbosch,
Matieland 7602, South Africa
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rotation of the α-methylbenzyl group in 1b and 1c, probably learn more about the energy barriers of the α-methylbenzyl
also due to steric hindrance by the substituent at the 6- rotation, we conducted a molecular modeling experiment
position. Hindered rotation of a 6-substituent in pyraz- on compound 4b.[8]
inones has previously been reported to give rise to atropo-
isomeric compounds.[7]
Table 1. Functionalisation of the 3-position of (α-methylbenzyl)-
pyrazinones.
In this experiment the torsion angle between the homo-
chiral auxiliary group and the pyrazinone was set to certain
fixed values (Figure 1), while all the other parameters were
allowed to change freely.[8] The calculated energy profile
Scheme 2. Strecker synthesis of α-aminonitrile and direct conver-
suggests that indeed two energetically favoured conforma-
tions exist. The energy difference between these two low-
energy conformations is 2.7 kJ/mol and the rotation barrier
is about 43 kJ/mol. At room temperature, the structures are
equilibrating. Otherwise it would be possible, at least in
principle, to separate them as diastereoisomers, considering
they contain a chiral centre as well as a chiral axis.
sion to dichloropyrazinones 1 bearing a homochiral α-methylben-
zyl group.
Pyrazinones 1a and 1b were further functionalised at the
3-position using Stille chemistry, leading to compounds 3
(via intermediate 2) and 4 (Scheme 3/Table 1).[2] Because of
the low yield for compound 1c, we did not further use it in
this program. For product 4b, again a broadened signal was
observed in the proton NMR spectrum (suggesting the exis-
tence of atropoisomers at low temperature). In order to
Figure 1. Energy profile of 4b.
Synthesis of Stereochemically Pure Diels–Alder Adducts
The subsequent cycloaddition with ethene and following
hydrolysis step (Scheme 4) showed some interesting fea-
tures. In spite of the previous (pertinent) remarks concern-
ing the high temperature necessary to drive the reaction to
completion (135 °C) and ethene being a small dienophile, a
certain degree of diastereoselectivity could be observed in
these Diels–Alder reactions (Table 2). As far as we know,
these are the first diastereoselective Diels–Alder reactions
Scheme 3. Functionalisation of the 3-position of the (α-methylben-
zyl)pyrazinones.
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Diastereoselective Diels–Alder Additions with Ethene
FULL PAPER
with ethene. The degree of diastereoselectivity parallels the in the transition state energies as calculated are extremely
degree of steric hindrance possibly exerted by the substitu- small and cannot explain the diastereoselectivity we ob-
ents at the 3- and 6-position of the pyrazinone. These steric served in this case.
effects will determine the most stable transition state for
The stereochemistry of 5aI was undoubtedly established
the adducts. The diastereomeric excess in the compounds by single-crystal X-ray analysis. An ORTEP representation
formed (de) was deduced from NMR spectra of the concen- of the solid-state structure, given in Figure 2, identifies this
trated crude reaction mixtures of the different isomers.
compound as the (1S,4S) isomer (5aI, Scheme 4, B). How-
ever, as long as there are no X-ray data of 5d, we make no
attempt to draw any conclusion regarding preferential at-
tack of ethene on either side.
Scheme 4. Diels–Alder reaction/hydrolysis of functionalized (α-
methylbenzyl)pyrazinones.
Table 2. Diels–Alder reaction/hydrolysis of functionalized (α-meth-
ylbenzyl)pyrazinones.
Figure 2. The molecular structure of 5a I, with atom labels and
50% probability displacement ellipsoids for non-H atoms.
Conversion of the Diels–Alder Adducts to the APC Systems
Some closing tests were conducted to investigate whether
these adducts experience the same selectivity in the meth-
anolysis reaction as reported earlier for analogous sys-
tems.[13] The optically pure 5aI and the diastereomeric mix-
ture 5b were submitted to the methanolysis procedure
(Scheme 5). We observed selective methanolysis of the sec-
ondary amide function, leading to the APC systems 6aI
and 6b, after capping of the amine with acetic anhydride.
The diastereomers 6bI and 6bII could be separated by me-
ans of column chromatography.
[a] The diastereoisomeric mixtures 5a and 5d could be separated in
diastereoisomers by ways of column chromatography on silica gel.
We labelled the isomers as I and II, with I being the compound
eluting first from column on purification.
Compounds 5a and 5d could be separated in their dif-
ferent diastereomers by means of column chromatography
on silica gel. At the current stage 5b and 5c were not re-
solved in the separate diastereomers after chromatography.
In an attempt to quantify the effect substituents on the
pyrazinone have on the transition state energy of the ad-
ducts, a molecular modeling study has been performed on
5a and 5b. The energy and structure of the transition states
of 4 Diels–Alder (2 pairs of diastereoisomers) adducts were
calculated by using the standard features of the Spartan
software (PM3 level). These calculations revealed small en-
ergy differences in the transition states of the different iso-
mer pairs (data not shown).[9] The energy differences in-
creased in parallel with the observed diastereoselectivities
Scheme 5. Selective methanolysis reaction of the (α-methylbenzyl)-
in the compounds. We do note however that the differences pyrazinones.
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overlap of the signals, mainly caused by peak broadening, renders
exact peak assessment impossible in the region 137.0–125.4 ppm of
the 13C NMR spectrum. Yield: 3.5 g, Ͻ 10%; m.p. 139 °C (EtOH).
Conclusions
We have developed a new and useful method to prepare
diastereomeric Diels–Alder adducts of 2(1H)-pyrazinones
IR (KBr): ν = 1659 (s, C=O), 1559 (s, C=N) cm–1. 1H NMR
˜
through introduction of a homochiral α-methylbenzyl (300 MHz, CDCl3, 25 °C): δ = 7.49–7.06 (m, 10 H, Ph-H), 5.62 [br.
s (q), 1 H, NCHPh], 4.41 (br. d, J = 15 Hz, 1 H, CHPh), 4.24 (br.
d, J = 15 Hz, 1 H, CHPh), 1.61 (d, J = 7 Hz, 3 H, CH3). 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 152.1 (C-2), 146.6 (C-3), 137.4 (2ϫ
group. The diastereoisomers can be separated by column
chromatography. Moreover, we report, to the best of our
knowledge, on the first Diels–Alder reaction with ethene
showing diastereoselectivity.
PhC-ipso), 137.0–125.4 (C-Ar, C-5, C-6), 58.9 (CH broad), 36.3
(CH2Bn), 15.3 (CH3). EIMS: m/z (%) 358 [M+, 4], 105 (C8H9
,
+
100). HRMS: calcd. for C19H16Cl2N2O: 358.0639; found: 358.0632.
Experimental Section
5-Chloro-1-[(1R)-1-phenylethyl]-3-(tributylstannyl)-2(1H)-pyrazin-
one (2): A mixture of 1a (0.02 mol), hexabutylditin (0.024 mol) and
Pd(PPh3)4 (0.1 mmol) in toluene (50 mL) is stirred at 110 °C under
inert atmosphere for 1 d. Upon completion of the reaction and
removal of the solvent under vacuum, the residue is dissolved in
EtOAc (60 mL) and stirred at room temp. for 4 h with excess KF.
After filtration of the mixture, the filtrate is evaporated and puri-
fied by column chromatography (silica gel, 20:80 hexane/CH2Cl2
General Methods: Melting points were taken using an Electrother-
mal IA 9000 digital melting point apparatus and are uncorrected.
Infrared spectra were recorded on a Perkin–Elmer 1600 Fourier
transform spectrometer. Mass spectra were recorded on a Hewlett–
Packard MS-Engine 5989A apparatus for EI and CI spectra, and
a Kratos MS50TC instrument for exact mass measurements per-
formed in the EI mode. For the NMR spectra (δ, ppm) a Bruker
AMX 400 and a Bruker Avance 300 spectrometer were used. Ana-
lytical and preparative thin layer chromatography was carried out
using Merck silica gel 60 PF-224, for column chromatography 70–
230 mesh silica gel 60 (E.M. Merck) was used as the stationary
phase.
Ǟ 95:5 hexane/CH Cl ). Yield: 8.0 g, 76%. IR (NaCl): ν = 1632
˜
2
2
(s, C=O), 1575 (s, C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C):
δ = 7.41–7.26 (m, 5 H, Ph-H), 6.77 (s, 1 H, 6-H), 6.12 (q, J = 7 Hz,
1 H, NCHPh), 1.71 (d, J = 7 Hz, 3 H, CH3), 1.58 (quintet, J =
7.5 Hz, 6 H, SnCH2CH2), 1.31 (quintet, J = 7.5 Hz, 6 H, CH3CH2),
1.18 (t, J = 7.5 Hz, 6 H, SnCH2), 0.90 (t, J = 7.5 Hz, 9 H, CH3).
3,5-Dichloro-1-[(1R)-1-phenylethyl]-2(1H)-pyrazinone (1a): (R)-
Methylbenzylamine (0.1 mol) is added dropwise to a solution of
sodium formaldehyde metabisulfite adduct (0.1 mol) in water
(300 mL). After stirring for 4 h at ambient temperature, potassium
cyanide (0.1 mol) is added and the reaction mixture is stirred over-
night at 60 °C. The resulting amino nitrile is extracted with dichlo-
romethane (3ϫ200 mL), dried with MgSO4 and concentrated un-
der vacuum. The hydrochloric salt of this aminonitrile is prepared
by passing gaseous HCl through the cooled solution of the amino-
nitrile in diethyl ether (300 mL) and filtration of the precipitated
salt. Oxalyl chloride (0.2 mol) is added dropwise to a suspension
of the hydrochloride of the amino nitrile (0.1 mol) in chlorobenzene
(300 mL). After stirring for 30 min, triethylammonium chloride
(10 g) is added and the resulting mixture is stirred at room tempera-
ture for 2 d under inert atmosphere. After evaporation of the sol-
vent, the residue is purified by column chromatography (silica gel,
CH2Cl2 Ǟ EtOAC/CH2Cl2) and subsequent crystallization (etha-
3-Benzyl-5-chloro-1-[(1R)1-phenylethyl]-2(1H)-pyrazinone (3a): A
suspension of 5-chloro-1-[(1R)-1-phenylethyl]-3-(tributylstannyl)-
2(1H)-pyrazinone 2 (1 mmol), benzyl bromide (1.1 mmol) and
Pd(PPh3)4 (0.005 mmol) in toluene (15 mL) is stirred at 110 °C un-
der inert atmosphere for 1 d. After solvent removal under reduced
pressure, the residue is dissolved in EtOAc (75 mL) and stirred at
ambient temperature for 4 h with excess KF. After filtration of the
mixture, the filtrate is evaporated and purified by column
chromatography (silica gel, CH2Cl2 Ǟ EtOAc). Yield: 0.211 g,
65%. IR (NaCl): ν = 1650 (s, C=O), 1588 (s, C=N) cm–1. 1H NMR
˜
(300 MHz, CDCl3, 25 °C): δ = 7.46–7.24 (m, 10 H, Ph-H), 6.91 (s,
1 H, 6-H), 6.20 (q, J = 7 Hz, 1 H, NCHPh), 4.18 (d, J = 14 Hz, 1
H, CH2Ph), 4.10 (d, J = 14 Hz, 1 H, CH2Ph), 1.68 (d, J = 7 Hz, 3
H, CH3). 13C NMR (75 MHz, CDCl3, 25 °C): δ = 158.6 (C-2),
154.2 (C-3), 138.0 (C-ipso), 136.5 (C-ipso), 129.4, 129.0, 128.7,
128.4, 127.3, 126.6 (all CH-Ar), 126.0 (C-5), 121.9 (C-6), 54.2
(NCHPh), 39.9 (CH2Ph), 18.5 (CH3). EIMS: m/z (%) 324 [M+, 6],
105 (C8H9+, 100). HRMS: calcd. for C19H17ClN2O: 324.1029;
found: 324.1029.
nol). Yield: 23.0 g, 86%; m.p. 88 °C (EtOH). IR (KBr): ν = 1654
˜
(s, C=O), 1581 (s, C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C):
δ = 7.45–7.31 (m, 5 H, Ar-H), 7.02 (s, 1 H, 6-H), 6.23 (q, J = 7 Hz,
1 H, NCHPh), 1.75 (d, J = 7 Hz, 3 H, CH3). 13C NMR (75 MHz,
CDCl3, 25 °C): δ = 151.6 (C-2), 147.2 (C-3), 137.3 (C-ipso), 129.4
(C-Ar), 129.2 (C-Ar), 127.0 (CH-Ar), 124.3 (C-5), 123.5 (C-6), 56.0
(CH), 18.5 (CH3). EIMS: m/z (%) 268 [M+, 6], 105 (C8H9+, 100).
HRMS: calcd. for C12H10Cl2N2O: 268.0170; found: 268.0162.
tert-Butyl 3-({6-Chloro-3-oxo-4-[(1R)-1-phenylethyl]-3,4-dihydro-2-
pyrazinyl}methyl)-1H-indole-1-carboxylate (3b): Prepared according
1
to the procedure given for compound 3a. Yield: 0.264 g, 57%. H
NMR (300 MHz, CDCl3, 25 °C): δ = 8.13 (d, J = 8 Hz, 1 H, indole-
H), 7.72 (d, J = 7 Hz, 1 H, indole-H), 7.61 (s, 1 H, indole-H), 7.42–
7.21 (m, 7 H, Ph-H, indole-H), 6.93 (s, 1 H, 6-H), 6.23 (q, J =
7 Hz, 1 H, NCHPh), 4.27 (d, J = 15 Hz, 1 H, indole-CH2), 4.19
(d, J = 15 Hz, 1 H, indole-CH2), 1.70 (d, J = 7 Hz, 3 H, CH3),
1.66 (s, 9 H, tert-butyl CH3). EIMS: m/z (%) 463 [M+, 4], 407 (M+ –
C4H8, 5), 105 (C8H9+, 100). HRMS: calcd. for C26H26ClN3O3:
463.1663; found: 463.1655.
3,5-Dichloro-6-methyl-1-[(1R)-1-phenylethyl]-2(1H)-pyrazinone (1b):
Prepared according to the procedure given for compound 1a. Yield:
16.6 g, 59%; m.p. 101 °C (EtOH). IR (KBr): ν = 1657 (s, C=O),
˜
1561 (s, C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.40–
7.17 (m, 5 H, Ph-H), 6.50 [br. s (q), 1 H, NCHPh], 2.20 (s, 3 H,
CH3), 1.99 (d, J = 7 Hz, 3 H, CH3). 13C NMR (75 MHz, CDCl3,
25 °C): δ = 153.1 (C-2), 144.1 (C-3), 138.1 (PhC-ipso), 135.9 (C-6),
129.0 (CH-Ar), 127.9 (CH-Ar), 126.0 (CH-Ar), 124.7 (C-5), 56.2
(CH), 17.6 (CH3), 16.6 (CH3). EIMS: m/z (%) 282 [M+, 3], 105
(C8H9+, 100). HRMS: calcd. for C13H12Cl2N2O: 282.0326; found:
282.0364.
5-Chloro-3-methyl-1-[(1R)-1-phenylethyl]-2(1H)-pyrazinone (4a): A
mixture of pyrazinone 1a (7 mmol), tetramethyltin (8.4 mmol) and
Pd(PPh3)4 (1 mol-%) in toluene (10 mL) is heated at 110 °C for
24 h. Upon completion of the reaction and removal of the solvent
under vacuum, the residue is dissolved in EtOAc and stirred with
an excess KF for 1/2 d at room temp. After filtration of the mixture,
the filtrate is evaporated and purified by column chromatography
6-Benzyl-3,5-dichloro-1-[(1R)-1-phenylethyl]-2(1H)-pyrazinone (1c):
Prepared according to the procedure given for compound 1a. The
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Diastereoselective Diels–Alder Additions with Ethene
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(silica gel, 10 % EtOAc/CH2Cl2). Yield: 1.5 g, 86 %; m.p. 84 °C
chromatography [EtOAc Ǟ EtOAc/EtOH (95:5)]. The diastereoiso-
(EtOH). IR (KBr): ν = 1663 (s, C=O), 1594 (s, C=N) cm–1. 1H
mers however could not be separated and therefore 2 signal sets
˜
1
NMR (300 MHz, CDCl3, 25 °C): δ = 7.59–7.20 (m, 5 H, Ph-H),
6.96 (s, 1 H, 6-H), 6.23 (q, J = 7 Hz, 1 H, NCHPh), 2.48 (s, 3 H,
are observed in the H NMR spectrum (ratio of diastereoisomers
55:45). The1H NMR spectrum (integration normalised to 20 pro-
CH3), 1.72 (d, J = 7 Hz, 3 H, CH3). 13C NMR (75 MHz, CDCl3, tons per product) shows that several signals are broadened due to
25 °C): δ = 157.8 (C-2), 154.5 (C-3), 137 (PhC-ipso), 128.9 (CH-
hindered rotation The 1-methyl signal and C-1 signal are not ob-
Ar), 128.5 (CH-Ar), 127.3 (CH-Ar), 125.7 (C-5), 121.2 (C-6), 53.9 served in the 13C-NMR due to this signal broadening. Total yield:
(CH), 20.8 (CH3), 18.3 (CH3). EIMS: m/z (%) 248 [M+, 4], 105
(C8H9+, 100). HRMS: calcd. for C13H13ClN2O: 248.0716; found:
248.0716.
1.1 g, 79%; m.p. unrelevant (diastereoisomeric mixture). IR (KBr):
1
ν = 1696 (br. s, CO) cm–1. H NMR (300 MHz, CDCl , 25 °C): δ
˜
3
= 7.35–7.22 (m, 5 H + 5 H, Ar-H), 6.93 (br. s, 1 H, NH minor
isomer), 6.48 (br. s, 1 H, NH major isomer), 5.40 and 5.29 (br. s,
1 H, NCHPh major and minor isomer), 2.07–1.79 (m, 2ϫ 4 H, 7-
H and 8-H), 1.75 (d, J = 7 Hz, 3 H, CH3 major isomer), 1.72 (d,
J = 7 Hz, 3 H, CH3 minor isomer), 1.48 (s, 3 H, CH3), 1.46 (s, 3
H, CH3), 1.44 (br. s, 3 H, CH3), 1.43 (br. s, 3 H, CH3). 13C NMR
(75 MHz, CDCl3, 25 °C), major isomer: δ = 173.9 (C=O), 172.8
(C=O), 141.8 (PhC-ipso), 128.9 (CH-Ar), 127.4 (CH-Ar), 126.6
(CH-Ar), 62.8 (C-4), 57.9 (NCH), 34.4 (CH2), 32.3 (CH2), 19.0
(CH3), 18.3 (CH3). 13C NMR (75 MHz, CDCl3, 25 °C), minor iso-
mer: δ = 173.9 (C=O), 172.8 (C=O), 142.4 (PhC-ipso), 128.8 (CH-
Ar), 127.3 (CH-Ar), 126.8 (CH-Ar), 62.8 (C-4), 57.8 (NCH), 34.3
(CH2), 32.2 (CH2), 19.1 (CH3), 17.9 (CH3). EIMS: m/z (%) 272
[M+, 54], 167 (M+ – C8H9, 6), 139 (M+ – C8H9 – CO, 23), 124
(M+ – C8H9 – HNCO, 100), 105 (C8H9+, 68). HRMS: calcd. for
C16H20N2O2: 272.1525; found: 272.1525.
5-Chloro-3,6-dimethyl-1-[(1R)-1-phenylethyl]-2(1H)-pyrazinone (4b):
Prepared according to the procedure given for compound 4a. Yield:
1.5 g, 82%; m.p. 135 °C (EtOH). IR (KBr): ν = 1643 (s, C=O),
˜
1568 (s, C=N) cm–1. 1H NMR (300 MHz, CDCl3, 25 °C): δ = 7.41–
7.17 (m, 5 H, Ar-H), 6.56 [br. s (q), 1 H, NCH], 2.46 (s, 3 H, CH3),
2.18 (br. s, 3 H, CH3), 1.88 (d, J = 7 Hz, 3 H, CH3). 13C NMR
(75 MHz, CDCl3, 25 °C): δ = 156.3 (C-2), 154.4 (C-3), 139.0 (PhC-
ipso), 133.0 (C-6), 128.8 (CH), 127.5 (CH), 126.5 (C-5), 125.8 (CH),
54.1 (broad) (CH), 20.8 (CH3), 17.4 (CH3), 16.7 (CH3). EIMS: m/z
(%) 262 [M+ , 3], 105 (C8 H9 + , 100). HRMS: calcd. for
C14H15ClN2O: 262.0873; found: 262.0868.
(1R/S,4R/S)-1-Methyl-5-[(1R)-1-phenylethyl]-2,5-diazabicyclo-
[2.2.2]octane-3,6-dione (5a I/II): The substituted pyrazinone 4a
(5 mmol) is dissolved in toluene and heated at 145 °C in a stainless
steel bomb under ethene pressure (35 atm) for 4 h. The progress of
the cycloaddition is monitored on TLC, by the disappearance of
the starting pyrazinone. The resulting mixture is stirred for one
night at room temperature open to the air to hydrolyse the imidoyl
chloride. After evaporation of the solvent, the diastereoisomers can
be separated by column chromatography (silica gel, Et2O/EtOAc,
95:5), ratio of diastereoisomers 50:50; total yield: 1.0 g, 77%.
(1R*,4S*)-1-Benzyl-5-[(1R)-1-phenylethyl]-2,5-diazabicyclo[2.2.2]-
octane-3,6-dione (5c): Prepared according to the procedure given
for compound 5a. The diastereoisomers however could not be sepa-
rated and therefore 2 signal sets are observed in the 1H NMR spec-
trum (ratio of diastereoisomers 65:35). Some signals in the 13C
NMR spectrum cannot be assigned to the major or minor isomer
(indicated with *). Yield: 1.4 g, 81%; m.p. unrelevant (diastereoiso-
meric mixture). IR (KBr): ν = 1704 (br. s, CO) cm–1. 1H NMR
(1S,4S)-1-Methyl-5-[(1R)-1-phenylethyl]-2,5-diazabicyclo[2.2.2]-
˜
octane-3,6-dione (5aI): M.p. 174 °C (CH Cl /hexane). IR (KBr): ν
˜
2
2
(300 MHz, CDCl3, 25 °C): δ = 7.50–7.20 (m, 10 H + 10 H, Ar-H),
6.90–6.50 (m, 2 H + 2 H, NH and NCHPh), 3.86 (dd, J = 4 Hz, J
= 2 Hz, 1 H, 4-H major isomer), 3.82 (dd, J = 4 Hz, J = 2 Hz, 1
H, 6-H major isomer), 3.48 (d, J = 15 Hz, 1 H, Bn-H major iso-
mer), 3.45 (d, J = 15 Hz, 1 H, Bn-H minor isomer), 3.13 (d, J =
15 Hz, 1 H, Bn-H minor isomer), 3.09 (d, J = 15 Hz, 1 H, Bn-H
major isomer), 2.15–1.20 (m, 4 H + 4 H, 2ϫ CH2 major and minor
isomer), 1.88 (d, J = 7 Hz, 3 H, CH3 major isomer), 1.58 (d, J =
8 Hz, 3 H, CH3 minor isomer). 13C NMR (75 MHz, CDCl3, 25 °C),
major isomer: δ = 172.0 (C=O), 170.7 (C=O), 139.7 (PhC-ipso),
135.2 (PhC-ipso), 130.8 (CH-Ar), 129.5 (CH-Ar), 129.1 (CH-Ar),
128.5 (CH-Ar), 127.7 (CH-Ar), 127.2 (CH-Ar), 60.9 (C-3), 55.1
(NCH), 50.8 (CH), 37.7 (C-8)*, 30.7 (C-7)*, 25.0 (CH3)*, 16.9
(CH2Ph)*. 13C NMR (75 MHz, CDCl3, 25 °C), minor isomer: δ =
171.5 (C=O), 170.7 (C=O), 140.0 (PhC-ipso), 135.2 (PhC-ipso),
130.8 (CH-Ar), 129.5 (CH-Ar), 129.2 (CH-Ar), 128.4 (CH-Ar),
127.9 (CH-Ar), 127.2 (CH-Ar), 60.7 (C-3), 55.7 (NCH), 51.5 (CH),
37.6 (C-8)*, 30.9 (C-7)*, 26.4 (CH3)*, 17.5 (CH2Ph)*. EIMS: m/z
(%) 334 (100) [M+], 229 (M+ – C8H9, 71), 201 (M+ – C8H9 – CO,
47), 105 (C8H9+, 61). HRMS: calcd. for C21H22N2O2: 334.1681;
found: 334.1681.
= 1714 (s, C=O), 1655 (s, C=O) cm–1. 1H NMR (400 MHz, CDCl3,
25 °C): δ = 7.35–7.26 (m, 5 H, Ar-H), 6.74 (s, 1 H, NH), 5.72 (q,
J = 7 Hz, 1 H, NCHPh), 3.82 (dd, J = 4 Hz, J = 2 Hz, 1 H, 4-H),
1.82 (ddd, J = 13 Hz, 1 H, 11 Hz, 4 Hz, 7-H), 1.72 (ddd, J = 13
Hz, J = 10 Hz, J = 4 Hz, 1 H, 7-H), 1.65 (dddd, J = 13 Hz, J =
11 Hz, J = 4 Hz, J = 2 Hz, 1 H, 8-H), 1.30 (dddd, J = 13 Hz, J =
10 Hz, J = 4 Hz, J = 4 Hz, 1 H, 8-H), 1.54 (d, J = 7 Hz, 3 H,
CH3), 1.52 (s, 3 H, CH3). 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 172.5 (C=O), 17.7 (C=O), 139.4 (PhC-ipso), 128.7 (CH-Ar),
128.0 (CH-Ar), 127.3 (CH-Ar), 58.3 (C-1), 54.7 (CH-Bn), 50.2
(CH), 32.0 [CH2 (C-7)]; 24.6 [CH2 (C-8)]; 18.3 [CH3 (α-MeBn)];
16.5 (CH3). EIMS: m/z (%) 258 (100) [M+], 153 (M+ – C8H9, 80),
125 (M+ – C8H9 – CO, 70), 105 (C8H9+, 78). HRMS: calcd. for
C15H18N2O2: 258.1368; found: 258.1369.
(1R,4R)-1-Methyl-5-[(1R)-1-phenylethyl]-2,5-diazabicyclo[2.2.2]-
octane-3,6-dione (5aII): M.p. 182 °C (CH Cl /hexane). IR (KBr): ν
˜
2
2
1
= 1681 (br. s, C=O) cm–1. H NMR (300 MHz, CDCl3, 25 °C): δ
= 7.34–7.24 (m, 5 H, Ph-H), 6.38 (s, 1 H, NH), 5.67 (q, J = 7 Hz,
1 H, NCHPh), 3.88 (dd, J = 4 Hz, J = 2 Hz, 1 H, 4-H), 2.01–1.86
(m, 4 H, 7-H, 8-H), 1.56 (d, J = 7 Hz, 3 H, CH3), 1.50 (s, 3 H,
CH3). 13C NMR (75 MHz, CDCl3, 25 °C): δ = 171.7 (C=O), 170.7
(C=O), 139.8 (PhC-ipso), 128.8 (CH-Ar), 128.0 (CH-Ar), 126.8
(CH-Ar), 58.1 (C-1), 55.3 (C-Bn), 50.9 (CH), 32.5 [CH2 (C-7)]; 25.8
tert-Butyl 3-({(1R*,4S*)-5-[(1R)-3,6-Dioxo-1-phenylethyl]-2,5-di-
azabicyclo[2.2.2]oct-1-yl}methyl)-1H-indole-1-carboxylate (5dI/II):
Prepared according to the procedure given for compound 5a. The
diastereoisomers can be separated via column chromatography (sil-
ica gel, EtOAc/CH2Cl2, 10:90). The CO signal of the Boc group is
unresolved in the 13C NMR spectrum. Ratio of diastereoisomers
75:25; total yield: 1.3 g, 54%.
[CH2 (C-8)]; 18.3 (CH3), 17.0 (CH3). EIMS: m/z (%) 258 (100)
+
[M+], 153 (M+ – C8H9, 67), 125 (M+ – C8H9 – CO, 66), 105 (C8H9
,
74). HRMS: calcd. for C15H18N2O2: 258.1368; found: 258.1369.
(1R*,4R*)-1,4-Dimethyl-2-[(1R)-1-phenylethyl]-2,5-diazabicyclo-
[2.2.2]octane-3,6-dione (5b): 5b was synthesized according to the
procedure given for compound 5a I/II, and purified by column
5d I: Minor isomer; m.p. 100 °C (hexane/CH2Cl2). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 8.16 (d, J = 8 Hz, 1 H, indole-H),
Eur. J. Org. Chem. 2007, 965–971
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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969

W. M. De Borggraeve et al.
FULL PAPER
7.54 (d, J = 7 H, 1 H, indole-H), 7.53 (s, 1 H, indole-H), 7.36–7.24
14 Hz, J = 14 Hz, J = 5 Hz, 1 H, bridgeax-H), 2.10–1.50 (m, 2 H,
(m, 7 H, Ar-H + indole-H), 5.74 (s, 1 H, NH), 5.72 (q, J = 7 Hz, bridge-H), 1.97 (s, 3 H,CH3), 1.68 (s, 3 H, CH3), 1.65 (d, J = 7 Hz,
1 H, CHPh), 3.86 (m, 1 H, 4-H), 3.51 (d, J = 15 Hz, 1 H, indole-
3 H, CH3), 1.41 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3, 25 °C):
CH), 3.24 (d, J = 7 Hz, 1 H, indole-CH), 2.09–1.85 (m, 4 H, 2ϫ δ = 174.6 (C=O), 173.9 (C=O), 169.7 (C=O), 142.2 (PhC-ipso),
CH2), 1.68 (s, 9 H, CH3), 1.59 (d, J = 7 Hz, 3 H, CH3). 13C NMR 128.1 (CH-Ar), 126.8 (CH-Ar), 126.7 (CH-Ar), 64.1–57.2 (C-2, C-
(100 MHz, CDCl3, 25 °C): δ = 171.1 (C=O), 170.3 (C=O), 139.7
(C-ipso), 130.8–113.6 (CH-Ar + indole CH), 84.1 (indole C), 60.5
(C-1), 55.3 (NCH), 51.2 (C-4), 30.9 (CH2), 28.2 (CH3 BOC), 26.4
5), 52.6 (OMe), 33.4 (CH3), 28.9 (CH2), 25.6–24.6–24.4–19.3
(3ϫCH3, CH2). EIMS: m/z (%) 346 [M+, 15], 287 (M+
CO2CH3,16), 259 (M+ – NH2COCH3 – CO, 3), 120 (C8H10N+,
–
(CH2), 25.9 (CH2), 17.2 (CH3). EIMS: m/z (%) 473 [M+, 40], 417 100), 105 (C8H9+, 55). HRMS: calcd. for C19H26N2O4: 346.1893;
(M+ – C4H8, 63), 374 (M+ – BOC, 94), 268 (M+ – BOC – indolyl, found: 346.1895.
40), 224 (268 – H2NCO, 100), 105 (C8H9+, 92). HRMS: calcd. for
C28H31N3O4: 473.2315; found: 473.2317.
6bII: Major isomer; m.p. 125 °C (hexane/CH Cl ). IR (KBr): ν =
˜
2
2
1727 (s, C=O), 1647 (br. s, C=O) cm–1. 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 7.35–7.10 (m, 5 H, Ar-H), 6.65 (s, 1 H, NH),
4.39 (q, J = 7 Hz, 1 H, NCHPh), 2.80–2.70 (m, 1 H, bridge-H),
2.23 (m, 3 H, 3ϫ bridge-H), 1.94 (s, 3 H, CH3), 1.84 (d, J = 7 Hz,
3 H, CH3), 1.61 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3, 25 °C):
δ = 173.8 (C=O), 173.2 (C=O), 169.7 (C=O), 142.4 (PhC-ipso),
128.2 (CH-Ar), 126.5 (CH-Ar), 125.9 (CH-Ar), 65.5–57.7 (C-2, C-
5), 56.9 (CH-Bn), 52.8 (OMe), 32.9 (CH3), 28.8 (CH2) 25.6–24.3–
5d II: Major isomer; m.p. 172 °C (hexane/CH2Cl2). 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 8.15 (d, J = 8 Hz, 1 H, indole-H),
7.55 (m, 2 H, indole-H), 7.31 (m, 9 H, Ar-H, indole-H), 5.80 (s, 1
H, NH), 5.79 (q, J = 7 Hz, 1 H, NCHPh), 3.81 (dd, J = 4 Hz, J =
2 Hz, 1 H, J = 2 Hz, 4-H), 3.52 (d, J = 15 Hz, 1 H, indole-CH2),
3.23 (d, J = 15 Hz, 1 H, indole 2-H), 2.01 (ddd, J = 13 Hz, J = 11
Hz, J = 4 Hz, 1 H, 7-H), 1.80 (ddd, J = 13 Hz, J = 10 Hz, J =
4 Hz, 1 H, 7-H), 1.69 (s, 9 H, CH3), 1.60 (dddd, J = 13 Hz, J = 11
Hz, J = 4 Hz, J = 2 Hz, 1 H, 8-H), 1.56 (d, J = 7 Hz, 3 H, CH3),
1.31 (dddd, J = 13 Hz, J = 10 Hz, J = 4 Hz, J = 4 Hz, 1 H, 8-H).
13C NMR (100 MHz, CDCl3, 25 °C): δ = 171.6 (C=O), 170.3
(C=O), 139.4 (C-ipso), 130.8–113.6 (CH-Ar, indole-CH), 84.1 (in-
dole-C), 60.7 (C-1), 54.6 (NCH), 50.5 (C-4), 30.5 (CH2), 28.2 (CH3
BOC), 26.4 (CH2), 24.7 (CH2), 16.6 (CH3). EIMS: m/z (%) 473
23.9–19.3 (3ϫ CH3, CH2). EIMS: m/z (%) 346 [M+, 23], 287 (M+
–
CO2CH3,47), 259 (M+ – NH2COCH3 – CO, 4), 120 (C8H10N+,
100), 105 (C8H9+, 78). HRMS: calcd. for C19H26N2O4: 346.1893;
found: 346.1893.
Crystal Data for 5aI: C15H18N2O2, M = 258.31, colorless block,
0.42ϫ0.22ϫ0.18 mm3, orthorhombic, space group P212121 (No.
19), a = 6.9623(18), b = 11.418(3), c = 16.932(4) Å, V =
1346.1(6) Å3, Z = 4, Dc = 1.275 g/cm3, F(000) = 552, Bruker APEX
CCD area detector, Mo-Kα radiation, λ = 0.71073 Å, T = 100(2)
[M+, 40], 417 (M+ – C4H8, 63), 374 (M+ – BOC, 94), 268 (M+
–
BOC – indolyl, 40), 224 (268 – H2NCO, 100), 105 (C8H9+, 92).
HRMS: calcd. for C28H31N3O4: 473.2315; found: 473.2317.
K, 2θmax = 56.7°, 8211 reflections collected, 1835 unique (Rint
=
Methyl (2S,5S)-5-(Acetylamino)-1-[(1R)-1-phenylethyl]-5-methyl-6-
oxo-2-piperidinecarboxylate (6aI): A cooled solution of adduct 5a
I (1 mmol) in methanol is flushed with gaseous HCl for 10 min.
After stirring the acidified solution for 2 d at 50 °C, the solvent is
removed under reduced pressure. The oily residue is dissolved in
acetic anhydride and triethylamine is added till precipitate forma-
tion is observed. After additional stirring for 1 h at ambient tem-
perature, the ammonium salts are filtered off. The filtrate is evapo-
rated and purified by column chromatography (silica gel, EtOAc).
0.0706). Final GooF = 1.034, R1 = 0.0501, wR2 = 0.0931, R indices
based on 1463 reflections with IϾ2σ(I) (refinement on F2), 174
parameters, 0 restraints. Lp and absorption corrections applied, µ
= 0.086 mm–1. The structure was solved and refined using the
SHELX-97 suite of programs[10] and the X-Seed[11] interface. Frie-
del pairs (1289) were merged before final refinement. Figure 2 was
prepared using X-SEED[11] and POV-Ray.[12]
CCDC-620133 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Yield: 0.279 g, 84%; m.p. 99 °C (hexane/CH Cl ). IR (KBr): ν =
˜
2
2
1739 (s, C=O), 1682, (s, C=O), 1641 (s, C=O) cm–1 1H NMR
.
(300 MHz, CDCl3, 25 °C): δ = 7.42–7.21 (m, 5 H, Ar-H), 6.75 (s,
1 H, NH), 5.89 (q, J = 7 Hz, 1 H, NCHPh), 3.75 (m, 4 H, OCH3,
2-H), 2.78 (ddd, J = 14 Hz, J = 6 Hz, J = 3 Hz, 1 H, bridge-H),
2.13–2.00 (m, 2 H, bridge-H), 1.99 (s, 3 H, CH3), 1.89 (m, 1 H,
bridge-H), 1.63 (s, 3 H, CH3), 1.40 (d, J = 7 Hz, 3 H, CH3). 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 173.9 (C=O), 173.0 (C=O),
170.0 (C=O), 139.9 (PhC-ipso), 129.0 (CH-Ar), 127.8 (CH-Ar),
127.0 (CH-Ar), 57.6 (C), 54.7 (CH), 52.7 (C-Bn), 52.5 (OCH3), 30.0
(CH2), 25.2 (CH3), 24.3 (CH3), 23.7 (CH2), 15.3 (CH3). EIMS: m/z
Acknowledgments
The authors thank the Fonds Wetenschappelijk Onderzoek –
Vlaanderen (FWO) for financial support. We are grateful to R. De
Boer for HR-MS measurements and to K. Duerinckx for assisting
with the NMR measurements. J. A. (Research Assistant of the
FWO) and W. M. D. B. (postdoctoral fellow of the FWO) thank
the FWO, W. S. thanks Katholieke Universiteit Leuven for the fel-
lowships received.
(%) 332 [M+ , 16], 273 (M+ – CO2 CH3 , 26), 245 (M+
NH2COCH3 – CO, 100), 185 (45), 120 (C8H10N+, 29), 105 (C8H9
74). HRMS: calcd. for C18H24N2O4: 332.1736; found: 332.1738.
–
,
+
Methyl (2R*,5R*)-5-(Acetylamino)-1-[(1R)-1-phenylethyl]-2,5-di-
methyl-6-oxo-2-piperidinecarboxylate (6bI/II): Prepared according
to the procedure given for compound 6a I. The absolute configura-
tions on C-2 and C-5 are unknown (relative configuration of amine
and carboxylate unambiguously cis). Total yield: 0.298 g, 86%
[1] J. Vekemans, C. Pollers-Wieërs, G. J. Hoornaert, Heterocycl.
Chem. 1983, 20, 919–923.
[2] a) R. Azzam, W. M. De Borggraeve, F. Compernolle, G. J.
Hoornaert, Tetrahedron Lett. 2004, 45, 1885–1888; b) W. M.
De Borggraeve, F. J. R. Rombouts, B. M. P. Verbist, E. V.
Van der Eycken, G. J. Hoornaert, Tetrahedron Lett. 2002, 43,
447–449; c) F. J. R. Rombouts, W. M. De Borggraeve, S. M.
Toppet, F. Compernolle, G. J. Hoornaert, Tetrahedron Lett.
2001, 42, 7397–7399; d) F. J. R. Rombouts, J. Van den Bossche,
S. M. Toppet, F. Compernolle, G. J. Hoornaert, Tetrahedron
2003, 59, 4721–4731; e) T. C. Govaerts, I. A. Vogels, F. Com-
6bI: Minor isomer; m.p. 91 °C (hexane/CH Cl ). IR (KBr): ν =
˜
2
2
1733 (s, C=O), 1644 (s, C=O), 1636 (s,C=O) cm–1. 1H NMR
(300 MHz, CDCl3, 25 °C): δ = 7.30–7.50 (m, 5 H, Ar-H), 6.79 (s,
1 H, NH), 5.41 (br. s, 1 H, NCHPh), 3.58 (s, 3 H, OMe), 2.77 (ddd,
J = 14 Hz, J = 4 Hz, J = 4 Hz, 1 H, bridgeeq-H), 2.20 (ddd, J =
970
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 965–971

Diastereoselective Diels–Alder Additions with Ethene
FULL PAPER
pernolle, G. J. Hoornaert, Tetrahedron 2003, 59, 5481–5494; f)
A. Tahri, K. J. Buysens, E. V. Van der Eycken, D. M. Vanden-
berghe, G. J. Hoornaert, Tetrahedron 1998, 54, 13211–13226; g)
K. J. Buysens, D. M. Vandenberghe, S. M. Toppet, G. J. Hoor-
naert, Tetrahedron 1995, 51, 12463–12478; h) K. J. Buysens,
D. M. Vandenberghe, S. M. Toppet, G. J. Hoornaert, J. Chem.
[6] T. W. Greene, P. G. M. Wuts,“Protective Groups in Organic Syn-
thesis, 3rd Ed., Wiley, p. 638–639.
[7] J. Tulinsky, B. V. Cheney, S. A. Mizsak, W. Watt, F. Han, L. A.
Dolak, T. Judge, R. B. Gammill, J. Org. Chem. 1999, 64, 93–
100.
[8] The calculations were performed using the density functional
B3LYP model with a 6-31G* basis set. All calculations were
done with the Spartan’04 molcular modeling package (Spart-
an’04 Wavefunction, Inc. Irvine, CA).
[9] The calculations reveal a difference of 0.2661 kJ/mol in the case
of 5a and 0.4867 kJ/mol in the case of 5b on an average transi-
tion state energy of respectively 217.7309 and 199.2635 kJ/mol
and point towards a preferred tendency for attack of ethene
from the “top side”. However, the reliability of these results is
questionable, due to the small energy differences.
[10] G. M. Sheldrick, SHELX-97: Structure solution and refine-
ment programs, University of Göttingen, 1997.
[11] a) L. J. Barbour, J. Supramol. Chem. 2001; 1, 189–191; b) J. L.
Atwood, L. J. Barbour, Cryst. Growth Des. 2003, 3, 3–8.
[12] http://www.povray.org.
Soc., Perkin Trans.
1 1996, 231–237; i) N. Kaval, J.
Van der Eycken, J. Caroen, W. Dehaen, G. A. Strohmeier, C. O.
Kappe, E. V. Van der Eycken, J. Comb. Chem. 2003, 5, 560–
568; j) N. Kaval, K. Bisztray, W. Dehaen, C. O. Kappe, E. V.
Van der Eycken, Mol. Diversity 2003, 7, 125–133; k) For a re-
view see: V. G. Pawar, W. M. De Borggraeve, Synthesis 2006,
17, 2799–2814.
[3] a) W. M. De Borggraeve, B. M. P. Verbist, F. J. R. Rombouts,
V. G. Pawar, W. J. Smets, L. Kamoune, J. Alen, E. V.
Van der Eycken, F. Compernolle, G. J. Hoornaert, Tetrahedron
2004, 60, 11597–11612; b) W. M. De Borggraeve, F. J. R. Rom-
bouts, E. V. Van der Eycken, S. M. Toppet, G. J. Hoornaert,
Tetrahedron Lett. 2001; 42, 5693–5695.
[4] W. M. De Borggraeve, Ph. D. Thesis, K. U. Leuven 2002.
[5] a) APC systems (on analytical scale) can be separated in their
enantiomers by means of HPLC using a chiral stationary phase
(Daicel Chiralpack series). This method implies some disad-
vantages: e.g. only minor amounts of product can be purified
with each injection; b) P. Franco, A. Senso, C. Minguillón, L.
Oliveros, J. Chromatogr. A 1998, 796, 265–272.
[13] B. M. P. Verbist, W. J. Smets, W. M. De Borggraeve, F. Com-
pernolle, G. J. Hoornaert, Tetrahedron Lett. 2004, 45, 4371–
4374.
Received: September 15, 2006
Published Online: December 19, 2006
Eur. J. Org. Chem. 2007, 965–971
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
971