A tandem amination/lactamisation route to 2-Azabicyclo[2.2.2]octanones

Article abstract of DOI:10.1055/s-0030-1258811

An efficient one-pot amination/lactamisation sequence for the preparation of 2-azabicyclo[2.2.2]octanones from 6-carboalkoxycyclohex-2-enones and aqueous ammonia is described. Scope and limitation studies are reported for this tandem procedure and a range of bicyclic compounds have been prepared, two of which were characterised by X-ray crystallography.

Full text of DOI:10.1055/s-0030-1258811

LETTER
2805
A Tandem Amination/Lactamisation Route to 2-Azabicyclo[2.2.2]octanones
T
andem
A
a
mination/L
m
actamisationRoute
e
to 2-Azabi
s
cyclo[2.2.2]octa
D
nones . Cuthbertson,a Andrew A. Godfrey,b Richard J. K. Taylor*a
a
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt1@york.ac.uk
AstraZeneca, Pharmaceutical Development, Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA, UK
b
Received 31 August 2010
In order to establish the viability of this approach, we ini-
tially decided to examine the cyclisation of the known6
methyl-substituted cyclohexenone 3a (Scheme 2 and
Table 1).
Abstract: An efficient one-pot amination/lactamisation sequence
for the preparation of 2-azabicyclo[2.2.2]octanones from 6-car-
boalkoxycyclohex-2-enones and aqueous ammonia is described.
Scope and limitation studies are reported for this tandem procedure
and a range of bicyclic compounds have been prepared, two of
which were characterised by X-ray crystallography.
Key words: amination, lactamisation, azabicyclo[2.2.2]octanones,
bicyclic compounds, 6-carboalkoxycyclohex-2-enones
O
O
O
O
NH
"NH3"
NH
OEt
solvent, r.t.
O
O
6
3a
Functionalised 2-azabicyclo[2.2.2]octan-3-ones occur in
a number of natural products such as 3-oxocoronaridine
(1)1 and brevianamide A (2; Scheme 1).2 The best-
described procedures for the preparation simple 2-azabi-
cyclo[2.2.2]octan-3-ones involve the use of either Diels–
Alder cycloaddition routes3 or the thermal cyclisation of
aminocyclohexane carboxylic acids.4 We recently de-
scribed an efficient method for preparing isoquinuclidino-
nes from 6-acylcyclohex-2-enones using a tandem
amination/imination sequence.5 Herein we describe the
application of a similar tandem procedure to prepare func-
tionalised 2-azabicyclo[2.2.2]octane-3,5-diones 5 from 6-
carboalkoxycyclohex-2-enones 3 as shown in Scheme 1.
Thus, we envisaged that conjugate addition of ammonia
into enones 3 would generate intermediate amino esters 4
which we expected to undergo intramolecular lactamisa-
tion to give the desired lactams 5, possibly in a one-pot
process.
5a
Scheme 2
Table 1 Conversion of Enone 3a into 8b-Methyl-2-azabicyclo-
[2.2.2]octane-3,5-dione (5a)a
Entry
NH3 source
2.0 M in IPA
35% aq
Co-solvent
–
Time (h) Conv.b
1
2
3
4
5
24
24
6
<5%
100%
100%
100%
100%
THFc
MeCN
MeOH
–
35% aq
35% aq
2
35% aq
1
a All reactions were performed on a 0.1 mmol scale; entries 2–5 were
carried out using 35% aq NH3 (0.25 mL) and solvent (0.5 mL).
b Conversion estimated by 1H NMR spectroscopy.
c A similar result was observed using CH2Cl2 as solvent.
O
N
H
The first attempt was carried out using ammonia in iso-
propanol (IPA) but only a trace amount of 8b-methyl-2-
azabicyclo[2.2.2]octane-3,5-dione (5a)7 was observed,
even after extended reaction times. On changing to 35%
aqueous ammonia, success was achieved under a range of
conditions (entries 2–5). When THF or dichloromethane
were employed as co-solvents (entry 2), quantitative con-
versions were observed with a reaction time of 24 hours
but the use of acetonitrile or methanol as co-solvent gave
full conversion in just a few hours (entries 3 and 4). The
optimum procedure, however, used 35% aqueous ammo-
nia without a co-solvent and under these conditions the
conversion was complete after one hour at room tempera-
ture (entry 5). All of the aqueous ammonia examples re-
sulted in the formation of a single diastereomeric product
which was confirmed as the desired methylated 2-azabi-
N
N
O
HN
N
H
MeO
O
O
O
1
2
O
O
O
O
R2
OR1
NH2
NH
O
R2
NH3
O
R2
OR1
4
3
5
Scheme 1
SYNLETT 2010, No. 18, pp 2805–2807
x
x
.x
x
.2
0
1
0
1
cyclo[2.2.2]octane-3,5-dione 5a by H NMR/13C NMR
Advanced online publication: 12.10.2010
DOI: 10.1055/s-0030-1258811; Art ID: D23610ST
spectroscopy [characteristic bridgehead proton signals at
© Georg Thieme Verlag Stuttgart · New York

2806
J. D. Cuthbertson et al.
LETTER
d = 4.0 and 3.1 ppm; 13C NMR signals at d = 205.1 ppm Table 2 Scope of Amination/Cyclisation Sequencea
(bridging ketone) and d = 171.8 ppm (amide)]. This dia-
6
5
O
O
O
stereomer was confirmed as the 8b-methyl isomer by
NMR analysis and by X-ray crystallography of a crystal-
line derivative (see later), and the isomeric 8a-methyl iso-
mer 6 was not observed; we assume that the 1,4-addition
of ammonia occurs preferentially anti to the methyl sub-
stituent and that this is followed by in situ lactamisation.
35% aq
NH3
O
1
LDA
7
NH2
O
OEt
THF, DMPU, –78 °C
R
8
4
3
then EtOC(O)CN
R
R
5
3
7
Entry Substrate 3
Product 5
Time (h) Yieldb (%)
Having confirmed the viability of the one-pot amination/
lactamisation sequence, the scope of the transformation
was investigated using a range of substrates (Table 2).
First the required b-ketoesters 3 were prepared; substrate
3b was prepared using a literature8 procedure and the re-
maining substrates were obtained from cyclohexenones 7
by treatment with LDA in THF–DMPU followed by trap-
ping with ethyl cyanoformate.
O
O
O
NH
OEt
OEt
1
2
3
2
2
93%9
O
5a
3a
O
O
O
NH
Ph
76
As can be seen, the tandem amination/lactamisation se-
quence was applicable to a range of substituted b-keto es-
ters. The reactions generally proceeded rapidly to give the
expected 2-azabicyclo[2.2.2]octane-3,5-diones 5 in good
to excellent yields. The initial example giving the 8b-me-
thyl product 5a proceeded in 93% isolated yield (entry 1)
and the corresponding process with a phenyl substituent
(3b → 5b) also proceeded smoothly and stereoselectively
(entry 2). However, cyclisation was not observed when 3-
methyl-6-carboethoxycyclohexenone (3c) was employed
as starting material (entry 3), presumably substitution at
the b-position of the enone disfavours the initial 1,4-addi-
tion of ammonia. Moving on to disubstituted enones (en-
tries 4–6), 2-azabicyclo[2.2.2]octane-3,5-diones 5d–5f
were obtained bearing 7,7-, 6,8- and 4,8- substitution pat-
terns in good to excellent yields. The successful cyclisa-
tion of the carvone-derived cyclohexenone (3e → 5e;
entry 5) indicated that the tandem amination/lactamisa-
tion sequence is compatible with substitution at the a-
position of the cyclohexenone. Similarly, the successful
formation of azabicyclo[2.2.2]octane 5f (entry 6; struc-
ture confirmed by X-ray crystallography, Figure 1) illus-
trates that ammonia addition/cyclisation can occur on
same face as methyl substituent (cyclisation is not possi-
ble from the anti-addition product due to the presence of
the a-methyl substituent preventing ester epimerisation).
In both of the latter examples (entries 5 and 6) longer re-
action times were required for cyclisation to go to comple-
tion. Finally, in this part of the study, we investigated
cyclisation of the parent unsubstituted cyclohexenone 3g
(entry 7); in this case the unpurified reaction mixture was
O
Ph
5b
3b
O
O
O
NH
OEt
24
0
O
3c
5c
O
O
O
OEt
O
NH
4
5
2
83
O
5d
3d
O
OEt
O
HN
24
98c
O
5e
3e
3f
O
O
O
O
O
NH
6
7
6
4
83
60
OEt
OEt
O
5f
O
NH
O
3g
5g
a All reactions were performed on a 0.25 mmol scale using 35% aq
NH3 (1.0 mL) at r.t.
b Isolated yields.
c Diastereomeric ratio ca. 4:1
slightly more complex but the required 2-azabicyclo-
[2.2.2]octane-3,5-dione 5g was isolated by column chro-
matography in 60% yield.
Finally, we briefly explored the use of substituted amines
in this process in order to directly prepare N-substituted 2-
azabicyclo[2.2.2]octane-3,5-diones 8 (Scheme 3). First,
the readily available enone 3a was treated with excess
aqueous methylamine. This procedure generated the ex-
Figure 1 X-ray structure of compound 5f depicted using ORTEP-3
(CCDC 789903)
Synlett 2010, No. 18, 2805–2807 © Thieme Stuttgart · New York

LETTER
Tandem Amination/Lactamisation Route to 2-Azabicyclo[2.2.2]octanones
2807
O
O
MeN
O
10% aq HCl
OEt
40% aq MeNH2 (excess)
NMe
NMe
H2O, r.t.
r.t., 24 h
ca. 98%
53% over 2 steps
O
O
3a
9
8a
O
O
O
R
8a; R = Me, 62%
8b; R = allyl, 43%
8c; R = Pr, 49%
RNH2
N
OEt
H2O, r.t.
24–48 h
O
3a
Scheme 3
pected bicyclic product but, somewhat surprisingly in
view of the ammonia reactions, led to the formation of the
unstable imine 9 (characterised by NMR spectroscopy
only). However, imine 9 could be readily hydrolysed with
10% aqueous HCl to afford the desired 2-azabicyclo-
[2.2.2]octane 8a in 53% overall yield.
Acknowledgment
We are grateful to the EPSRC and AstraZeneca for studentship sup-
port (J.D.C.).
References and Notes
(1) Perera, P.; Sandberg, F.; van Beek, T. A.; Verpoorte, R.
Phytochemistry 1985, 24, 2097.
(2) Bringmann, G.; Lang, G.; Steffens, S.; Schaumann, K.
J. Nat. Prod. 2004, 67, 311.
(3) (a) Brooke, G. M.; Matthews, R. S.; Robson, N. S. J. Chem.
Soc., Perkin Trans. 1 1980, 102. (b) McClure, C. K.; Link,
J. S. J. Org. Chem. 2003, 68, 8256.
(4) (a) Quirante, J.; Diaba, F.; Vila, X.; Bonjoch, J. Magn.
Reson. Chem. 2005, 43, 599. (b) Gong, L.; Hogg, J. H.;
Collier, J.; Wilhelm, R. S.; Soderberg, C. Bioorg. Med.
Chem. Lett. 2003, 13, 3597.
Subsequently, it was found that the unwanted imine for-
mation could be precluded by the use of a stoichiometric
amount of methylamine giving adduct 8a directly in 62%
yield (Scheme 3). Similar reactions using allylamine and
propylamine gave the corresponding N-alkyl-2-azabicyclo-
[2.2.2]octane-3,5-diones 8b and 8c in fair yields. This
process is susceptible to steric effects, however, and no
cyclisation was observed when cyclohexenone 3a was
treated with tert-butylamine, anisidine or benzylamine.
The structure of N-methyl 8b-methyl-2-azabicyclo-
[2.2.2]octane-3,5-dione (8a) was confirmed by X-ray
crystallography (Figure 2).
(5) Cuthbertson, J. D.; Godfrey, A. A.; Taylor, R. J. K.
Tetrahedron Lett. 2010, in press (http://dx.doi.org/10.1016/
j.tetlet.2010.08.052).
(6) Hamada, Y.; Hara, O.; Kawai, A.; Kohno, Y.; Shioiri, T.
Tetrahedron 1991, 47, 8635.
(7) All novel compounds were fully characterised by 1H NMR,
13C NMR, IR spectroscopies and by HRMS.
(8) Pietrusiewicz, K. M.; Monkiewicz, J. J. Org. Chem. 1983,
48, 788.
(9) Typical Procedure for the Synthesis of 8b-Methyl-2-
azabicyclo[2.2.2]octane-3,5-dione (5a): A solution of b-
keto ester 3a (46 mg, 0.25 mmol) in 35% aq NH3 (1 mL) was
stirred at r.t. until consumption of starting material was
observed by TLC analysis (CH2Cl2–MeOH, 9:1), ca. 2 h.
The reaction mixture was then concentrated in vacuo and
purified by column chromatography (SiO2, CH2Cl2–MeOH,
98:2) to give the title compound 5a as a colourless
crystalline sold (36 mg, 93%); mp 135–137 °C; Rf 0.40
(CH2Cl2–MeOH, 9:1). IR (thin film): 3244, 2961, 1730,
1681, 1335, 1105 cm–1. 1H NMR (400 MHz, CDCl3): d =
7.92 (br s, 1 H, NH), 3.93–3.98 (m, 1 H), 3.03–3.11 (m, 1 H),
2.40–2.49 (m, 2 H), 2.28–2.37 (m, 1 H), 2.20 (dd, J = 18.5,
1.9 Hz, 1 H), 1.31 (ddd, J = 13.0, 4.6, 1.0 Hz, 1 H), 1.06 (d,
J = 7.1 Hz, 3 H). 13C NMR (100 MHz, CDCl3): d = 205.1
(CO), 171.8 (CO), 64.4 (CH), 47.0 (CH), 43.8 (CH2), 35.4
(CH2), 29.4 (CH), 20.8 (Me). MS: m/z (ESI) = 154 [MH]+.
HRMS (ESI): m/z [M + H+] calcd for C8H12NO2: 154.0863;
found: 154.0864 (0.6 ppm error).
Figure 2 X-ray structure of compound 8a depicted using ORTEP-3
(CCDC 789904)
In summary, an efficient tandem amination/lactamisation
sequence has been developed for the preparation of 2-
azabicyclo[2.2.2]octane-3,5-diones from 6-carboalkoxy-
cyclohex-2-enones and aqueous ammonia. The scope and
limitations of this methodology have been investigated
and it has been extended to the direct preparation of some
N-substituted 2-azabicyclo[2.2.2]octane-3,5-diones. Ap-
plications of the amination/lactamisation sequence in the
synthesis of polycyclic alkaloids are currently under in-
vestigation.
Synlett 2010, No. 18, 2805–2807 © Thieme Stuttgart · New York

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