Acid catalysed methanolysis of 2,5-diazabicyclo[2.2.2]octane-3,6-diones: Scope and limitations

Article abstract of DOI:10.1016/j.tetlet.2004.03.186

The selective methanolysis of 2,5-diazabicyclo[2.2.2]octane-3,6-dione systems is a key step in a synthetic procedure leading to 4-amino-6-oxo-2- piperidinecarboxylate systems. This reaction seems to be primarily governed by steric hindrance caused by the substituents at the 1- and 4-bridgehead positions of the dione. In absence of bulky substituents the methanolysis is directed by the secondary or tertiary nature of the two lactam moieties.

Full text of DOI:10.1016/j.tetlet.2004.03.186

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4371–4374
Acid catalysed methanolysis of 2,5-diazabicyclo[2.2.2]octane-3,6-
diones: scope and limitations
Bie M. P. Verbist, Wim J. Smets, Wim M. De Borggraeve, Frans Compernolle
and Georges J. Hoornaert*
Laboratorium voor Organische Synthese, K.U. Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
Received 11 March 2004; revised 29 March 2004; accepted 30 March 2004
Abstract—The selective methanolysis of 2,5-diazabicyclo[2.2.2]octane-3,6-dione systems is a key step in a synthetic procedure
leading to 4-amino-6-oxo-2-piperidinecarboxylate systems. This reaction seems to be primarily governed by steric hindrance caused
by the substituents at the 1- and 4-bridgehead positions of the dione. In absence of bulky substituents the methanolysis is directed by
the secondary or tertiary nature of the two lactam moieties.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In order to check the generality of our approach we
performed a more profound study of the factors gov-
erning the feasibility and the selectivity of the methano-
lysis of 2,5-diazabicyclo[2.2.2]octane-3,6-dione systems.
The role of bulky substituents at the bridgehead positions
1 and 4 of the dione on the selectivity of the methanolysis
as well as the effect of the secondary or tertiary nature
of the lactam moiety is disclosed by using 2D NMR
analysis, which is found to be a most helpful tool for the
structural assignment of the reaction products.
In our previous work a syntheticstrategy has been
developed, which led to 4-amino-6-oxo-2-piperidine-
carboxylate (APC) systems that can be used as b-turn
mimics.1 A key step in this procedure is the selective acid
catalysed methanolysis of a secondary lactam function
in the presence of a tertiary one.2 This behaviour is in
agreement with the general observation that the rate-
controlling step during acid hydrolysis of amides is the
attack of water on the O-protonated amide to form a
tetrahedral intermediate: indeed, stericretardation of
the latter process appears to be the governing factor in
many cases.3
2. Preparation of starting materials
Our approach to the 2,5-diazabicyclo[2.2.2]octane-3,6-
dione bicyclic system is based on the pyrazinone chem-
istry previously developed in our laboratory (Scheme
1).6 Pyrazinones 1 were synthesised starting from the
appropriate aminonitriles and oxalyl chloride. The
chlorine atom at the 3-position was substituted by an
alkyl group by reacting 1 with 1.2 equiv of the corre-
sponding alkylMgBr in THF at )78 ꢁC. After workup at
low temperature and extraction with dichloromethane,
products 2 were purified by column chromatography
(silica gel, gradient CH2Cl2 fi EtOAc/CH2Cl2 2/98). The
bicyclic system was generated by a Diels–Alder reaction
of ethene on substituted pyrazinones 2 in toluene (steel
bomb, 33 atm, 135 ꢁC, 18 h). The crude imidoyl chlorides
3 were converted into 4 by exposure to air moisture
(stirring in CHCl3 in an open flask). Evaporation of this
reaction mixture and column chromatography yielded
the pure diazabicyclooctanediones 4 to be studied.
However, an anomalous behaviour was observed for
simple secondary and tertiary N-methylamides since the
latter react slightly faster upon acid hydrolysis.3 This
result is probably due to nonstericfactors, for example,
r-donation by the N-alkyl substituents and/or solvation
effects. Some other examples of the selective acidic
cleavage of a tertiary lactam over a secondary one have
been reported for nonrelated bislactam systems, that is a
strained bridged bislactam,4 and a 7/5 ring-fused struc-
ture.5
Keywords: Pyrazinone; Bislactam; Methanolysis; Steric hindrance.
* Corresponding author. Tel.: +32-16-327409; fax: +32-16-327990;
e-mail: Georges.Hoornaert@chem.kuleuven.ac.be
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.186

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B. M. P. Verbist et al. / Tetrahedron Letters 45 (2004) 4371–4374
Scheme 1. Synthesis of 2,5-diazabicyclo[2.2.2]octane-3,6-diones.
Reagents and conditions: (a) R3MgBr, THF, )78 ꢁC; (b) ethene,
33 atm, toluene, 135 ꢁC; (c) CHCl3, air moisture, rt.
3. Effect of bulky groups on methanolysis process
Scheme 2. Effect of bulky substituents on the methanolysis. Reagents
and conditions: (a) MeOH, HCl, rt; (b) Ac2O, Et3N, rt; (c) NaH,
DMF, MeI, rt; (d) CAN, H2O, 0 ꢁC.
Firstly we studied the effect of bulky substituents on the
bridgehead positions 1 and 4 of the diones (Scheme 2).
Thus
treatment
of
4-isopropyl-2,5-diazabyclo-
[2.2.2]octane-3,6-dione 5 with a HCl-saturated methanol
solution overnight resulted in a selective cleavage of the
secondary lactam moiety. In order to prevent recycli-
sation upon neutralisation of the reaction mixture, the
newly formed primary amine was trapped as the N-
substituted acetamide by addition of triethylamine and
acetic anhydride. The ammonium salts were removed by
filtration and the reaction mixture was evaporated to
yield product 6, which was further purified by column
chromatography (silica gel, MeOH/CH2Cl2 5/95).
2,3-amide linkage. When precursor 9 is subjected to acid
methanolysis compound 11 is also readily formed. In
our experience the p-methoxybenzyl group is not easily
removed from a lactam nitrogen; hence the less hindered
tertiary lactam probably is cleaved first followed by
removal of the benzylicgroup from the amine formed
after cleavage.
4. Effect of secondary or tertiary lactam group on the
methanolysis
In a second experiment the secondary and tertiary amide
functions were interchanged. To this end the secondary
amide of bislactam 5 was methylated (NaH, DMF, MeI)
and the para-methoxybenzyl group was removed by
treatment of the purified product (silica gel, CH2Cl2/
EtOAc60/40), dissolved in acetonitrile, with 3 equiv of
cerium ammonium nitrate (CAN, dissolved in water);
this resulted in precipitation of the 2-N-deprotected
bislactam 7. The latter was subjected to the acid meth-
anolysis/N-acetylation sequence, which now led to
selective cleavage of the tertiary amide affording the
APC system 8. The 4-isopropyl group appears to shield
the ‘top’ (2,3) lactam function irrespective of its sec-
ondary or tertiary nature. Hence, relief of the bicyclic
strain can be attained only by attack of methanol at the
sterically more accessible lactam carbonyl group.
In a second part we studied the selectivity for methano-
lysis in the presence of two equal nonbulky substituents
in-position, that is two methyl groups (Scheme 3).
Acidic methanolysis of the bicyclic system 12 resulted in
selective cleavage of the secondary amide to afford the
monocyclic lactam 13.
A comparable behaviour
was observed for 2-benzyl-1,4-diphenyl-2,5-diazabi-
cyclo[2.2.2]octane-3.6-dione.2 When the secondary and
tertiary amides were interchanged as in compound 14,
again the secondary amide was cleaved selectively to
afford 15. Removal of the p-methoxybenzyl group from
12 provided compound 16 containing two secondary
lactam functions. Subsequent treatment of 16 with HCl-
saturated methanol solution for 48 h and trapping of the
intermediate amine as the N-acetyl derivative furnished
the monocyclic secondary lactam 17. However, when the
methanolysis was continued for one week, a mixture of
singly cleaved product 17 and doubly cleaved compound
18 was obtained. The absence of bicyclic strain accounts
for the much slower second cleavage. These results
This statement also holds for the methanolysis of pre-
cursor 10, obtained after removal of the p-methoxy-
benzyl group by the CAN procedure. In this case the
6-carbonyl function is shielded by the isopropyl group in
positon 1 resulting in selective cleavage of the ‘upper’

B. M. P. Verbist et al. / Tetrahedron Letters 45 (2004) 4371–4374
4373
Figure 1. Eclipsing interactions in gem-diol intermediates corre-
sponding to hydrolysis at CONMe and CONH groups of 14.
Figure 2. Two possible structures obtained upon methanolysis of
compound 7 and structure assignment of 8a by HMBC.
bouring protons (HMBC). The principle is explained for
compound 8. A coupling is noticed between the car-
bonyl of the methyl ester and the 2-methyl protons as
well as a coupling between the N-methyl protons and the
acetyl carbonyl group as seen in 8a. These two couplings
are not consistent with structure 8b, formed by cleavage
of the other lactam group (Fig. 2).
Scheme 3. Effect of the secondary and tertiary nature of the lactam
moiety. Reagents and conditions: (a) MeOH, HCl, rt; (b) Ac2O, Et3N,
rt; (c) NaH, DMF, MeI, rt; (d) CAN, H2O, 0 ꢁC.
5. Conclusion
indicate that a secondary lactam is cleaved preferentially
without risk for a tertiary lactam cleavage if bulky
substituents are absent. If a secondary lactam remains a
second cleavage might occur if the reaction is left for a
longer period of time.7
The selective methanolysis of 2,5-diazabicyclo-
[2.2.2]octane-3,6-dione systems is a key step in the syn-
thesis of APC type b-turn mimics. A systematic analysis
of the factors governing the feasibility and the selectivity
of this methanolysis reaction was performed. The main
driving force of the reaction is alleviation of the bicyclic
strain, which enhances the rate of acid hydrolysis of the
bicyclic lactam relative to subsequent cleavage of the
monocyclic lactam formed. The selectivity of the meth-
anolysis reaction further depends on the steric factors
involving the N-alkyl and bridgehead substituents. An
isopropyl group at the a-position of the lactam carbonyl
seems to prevent completely its sensitivity to methano-
lysis. In this case, the bicyclic strain will be relieved by
cleaving the other lactam function, irrespective of its
secondary or tertiary lactam nature. In the absence of
bulky a-substituents, secondary lactam functions cleave
more readily than tertiary ones. When after the first
methanolysis a secondary lactam is still present, a sec-
ond slow cleavage can occur but tertiary lactams seem to
be stable.
To unravel the reasons for the preferential acidic
cleavage of the secondary lactam group in the bridged
bislactam compounds, we performed a molecular
mechanics model study of the two tetrahedral geminal
diol intermediates corresponding to attack of water on
either one of the two lactam functions of compound 14.
This study clearly revealed a much higher energy (dif-
ference ca. 6–7 kcal/mol) for the geminal diol formed
next to the N-methyl group as compared to the one
formed next to NH. Indeed, since the methyl group is
now located on an sp3 N-atom in a tight boat confor-
mation it experiences a severe eclipsing interaction with
one neighbouring OH group (Fig. 1).
From our combined results it appears that the prefer-
ential cleavages observed for the bislactams studied here
can be ascribed to two interrelated effects, that is relief
of the bicyclic strain which is modulated by the steric
retardation caused by the N-alkyl and bridgehead sub-
stituents. While the first effect enhances the rate of acid
hydrolysis of the bicyclic versus the monocyclic lactams,
the latter apparently directs the attack of the nucleophile
to the less sterically hindered lactam carbonyl group.
Based on these observations on the feasibility and out-
come of methanolysis, we are currently designing a
number of specific APC-systems for peptide incorpora-
tion.
Acknowledgements
The site of cleavage in the APC systems was determined
by 2D NMR spectroscopy using the long range 13C–1H
couplings between the carbonyl groups and the neigh-
The authors wish to thank the Institute for the promo-
tion of Innovation through Science and Technology in

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Compernolle, F.; Hoornaert, G. J. Tetrahedron 2003, 59,
5047–5054.
Flanders (IWT-Vlaanderen) and the FWO (Fund for
Scientific Research Flanders, Belgium) for financial
support. We are grateful to R. De Boer for HRMS
measurements and to S. Toppet for 2D NMR. BV
thanks the IWT and WDB thanks the FWO for the
fellowship received.
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