Neighbouring group participation in N-methoxymethyl 7-azanorbornanes 1: The synthesis of N,N′-methano-bridged diazasesquinorbornanes, N3-[3]polynorbornanes and CN3-[4]Polynorbornanes

Article abstract of DOI:10.1055/s-2001-10789

A new tandem route to N,N′-methano-bridged diazasesquinorbornanes is reported in which 7-azabenzonorbornadienes are reacted with ester-activated N-(methoxymethyl)aziridinocyclobutanes to form adducts which immediately undergo N,N′-methano-bridge formation by nucleophilic attack of the nitrogen lone pair of one N-bridge onto the methoxymethyl group attached to the adjacent N-bridge. Alternative routes to N,N′-methano-bridged structures of this type are discussed.

Full text of DOI:10.1055/s-2001-10789

202
LETTER
Neighbouring Group Participation in N-Methoxymethyl 7-Azanorbornanes 1:
The Synthesis of N,N’-Methano-bridged Diazasesquinorbornanes,
N3-[3]Polynorbornanes and CN3-[4]Polynorbornanes
Ronald N. Warrener,* Davor Margetic, Douglas N. Butler, Guangxing Sun
Centre for Molecular Architecture, Central Queensland University, Rockhampton, Queensland, 4702, Australia
Fax 61 7 4930 9917; E-mail: r.warrener@cqu.edu.au
Received 16 November 2000
work. In practice, bis-alkene 2 resisted almost all attempts
Abstract: A new tandem route to N,N’-methano-bridged diazases-
to achieve Diels-Alder, 1,3-dipolar or ruthenium-cata-
lysed [2+2] addition at one or both -bonds. The excep-
tion was the photochemically-induced 1,3-dipolar addi-
quinorbornanes is reported in which 7-azabenzonorbornadienes are
reacted with ester-activated N-(methoxymethyl)aziridinocyclobu-
tanes to form adducts which immediately undergo N,N’-methano-
bridge formation by nucleophilic attack of the nitrogen lone pair of tion of epoxide 4 to 2 (R = CF3) which produced the
mono-adduct 5 and the bis-adduct 6.4 Attempts to build
one N-bridge onto the methoxymethyl group attached to the adja-
cent N-bridge. Alternative routes to N,N’-methano-bridged struc-
tures of this type are discussed.
onto the -bonds of mono-adduct 5 or the domino adduct
3 were equally unrewarding. Accordingly, we have devel-
oped a new approach to the synthesis of N,N’-methano-
bridged diazasesquinorbornanes in which the methano-
Key words: neighbouring-group, cycloadditions, bicyclic com-
pounds, stereoselectivity
bridge is formed as the second part of a tandem sequence
in concert with the [n]polynorbornane construction re-
gime,3a and this is the subject of the present communica-
tion.
N,N’-Methano-bridged diazasesquinorbornanes are a rare
class of aza-alicyclic compounds which were first de-
scribed in 1985 by Visnik and Battiste who reported that
addition of perfluorobut-2-yne or dimethyl acetylenedi-
carboxylate (DMAD) to bis-(N-pyrrolyl) methane 1
(Scheme 1) produced exclusively the pincer adducts 2 and
that these could be isomerised to domino-adducts 3 upon
heating.1
a) Stepwise assembly process and b) origin of 1,3-dipolar cyclo-
addition stereoselectivitiy
Scheme 2
The reaction leading to the formation of the intermediate
N-(methoxymethyl) diazasesquinorbornane 13 was envis-
aged to occur by 1,3-dipolar cycloaddition of an appropri-
ate 7-azanorbornene acting as the dipolarphile with an N-
(methoxymethyl)aziridine. In practice, intramolecular
displacement of methoxide occurred spontaneously by
participation of the neighbouring bridge-nitrogen lone
pair to form the N,N’-methano bridged products (Scheme
2a). As outlined in the reaction pathway shown in Scheme
3, the participating N-bridge component could be intro-
duced into the [3]polynorbornane 13 either from the
aziridine reagent, i.e. 10a or as part of the dipolarophile,
i.e. 12 (Y = NR). In both cases, 1,3-dipolar cycloadditions
were anticipated to occur with exo,exo-stereoselectivity
by underface attack on the dipole (Scheme 2b) to afford
the syn-facial XNY-[3]polynorbornane adducts 13a,b, in
which the central N-bridge bears the methoxymethyl
Previous work in the field of N,N’-methano-bridged diazasesquinor-
bornane synthesis
Scheme 1
As part of our block building program for scaffold con-
struction,2,3 we examined 2 (R = CF3) as a bis-alkene
block to incorporate the N,N’-methano-bridged diazases-
quinorbornane subunit into a [n]polynorbornane frame-
Synlett 2001, No. 2, 202–205 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Neighbouring Group Participation in N-Methoxymethyl 7-Azanorbornanes
203
substituent and is set up for intramolecular cyclisation norbornadiene 18 with 10b produced, somewhat surpris-
(X = NR or Y = NR) to furnish the desired N,N-methano- ingly, the N,N’-methano-bridged product 2112 directly.
bridged diazasesquinorbornane subunit.
Clearly, the Z-group is lost in the course of the methano-
bridge formation from the initially-formed adduct 19
(Scheme 5). The mechanism proposed in Scheme 4 for
this process has some interesting features since it involves
nucleophilic attack by the nitrogen of the N-Z bridge in
adduct 19 and requires that it has non-planar geometry.6
There is evidence for the terminal N-Z bridge of N3-
[3]polynorbornanes being able the adopt the non-planar
geometry depicted in 19 based on X-ray data for the cor-
responding N-benzyl system.7,8 A consequence of the
non-planar geometry is the attendant loss of resonance
stabilisation typical of the planar system and so the bridge
nitrogen should become more nucleophilic. This should
favour attack by the N-bridge lone pair onto the adjacent
N-methoxymethyl to form the N,N’-methano-bridge (19 to
20, arrows a). In a second step, attack by the concommi-
tantly generated methoxide ion onto the Z-group of 20
would effect removal of that group.
Preparation of aziridino cyclobutanes and reaction with norborna-
dienes. Series a) X = CH2: b) X = NZ.
Scheme 3
Preparation of the required N-(methoxymethyl)aziridines
10a,b12 was achieved by addition of methoxymethyl azide
8 to the appropriate cyclobutene-1,2-diesters 7a,b fol-
lowed by deazetisation of the resultant triazolines by ul-
traviolet irradiation.3a,5 The first route was illustrated by
reaction of 7-azabenzonorbornadiene 14 (Scheme 4) with
the methano-bridged N-(methoxymethyl)aziridino cy-
clobutane 10a (benzene at reflux for 3 hours) to afford the
N,N’-methano-bridged CN2-[3]polynorbornane 1712 in
59% yield. The 1:1-adduct 15 is the presumed intermedi-
ate and cyclisation (arrows on 15) requires the N-inver-
tomer to be proximate to the NH-bridge. Significantly,
this is the preferred invertomer geometry in the related N-
benzyl CN2-[3]polynorbornane.3a
Synthesis of N,N-methano-linked N3-[3]polynorbornadiene 21 and
deprotected byproduct 23
Scheme 5
It has been established in the N-benzyl series that signifi-
cant flattening of central N-bridge occurs when flanking
bridges are present in XNY-[3]polynorbornanes and that
when X = Y, dynamic invertomerisation of the N-substit-
uent occurs at room temperature.3a,3b It is reasonable to ex-
pect a similar situation can exist in 19 and that the N-
methoxymethyl substituent is rapidly interconverting be-
tween the two invertomers. This compression towards
planar nitrogen would lower the transition state energy
(ground state effect) for vicinal elimination of methoxide
from 19 (arrows b) to form iminium ion 22. While we do
not consider that 22 is an intermediate in the formation of
20, it does present itself as a plausible intermediate in the
formation of NH compound 2312, which is isolated as a
Preparation of N,N’-methano-bridged CN3-[3]polynorbornadiene 17
Scheme 4
The second method is demonstrated using the aza-bridged
N-(methoxymethyl)aziridinocyclobutane 10b (Scheme
5). In this case, reaction of the Z-protected benzo-7-aza-
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204
R. N. Warrener et al.
LETTER
minor byproduct in this reaction. Formation of 23 in-
volves a hydrolysis step and preliminary evidence indi-
cates that this probably occurred in the course of
chromatographic workup.9 Interestingly, the de(meth-
oxymethylation) step becomes the major pathway in N-
methoxymethyl XNY[3]polynorbornanes where intramo-
lecular cyclisation is no longer available and has been
used to prepare CN-bridged compounds where X or
Y = isopropylidene (see also formation of 27, Scheme 6).8
Acknowledgement
We thank Mr Malcolm Hammond for conducting some of the
developmental work on the synthesis of N-(methoxymethyl)aziri-
dines. GS and MH thank Central Queensland University for the
award of a CQU PhD scholarship.
References and Notes
(1) a) Visnick, M.; Battiste, M. A. J. Chem. Soc., Chem. Commun
1985, 1621-1622. We have found difficulty in reproducing the
results for the addition of DMAD with bis-(N-pyrrolyl)-
methane 1. b) For theoretical treatments of this reaction, see
Domingo, L. R.; Picher, M. T.; Arno, M.; Andres, J.; Safont,
V. S. Theochem. 1998, 426, 257-262. c) Domingo, L. R.;
Arno, M.; Andres, J. J. Am. Chem. Soc. 1998, 120, 1617-1618.
(2) Warrener, R. N.; Schultz, A. C.; Butler, D. N.; Wang, S.;
Mahadevan, I. B.; Russell, R. A. Chem. Commun. 1997,
1023-1024.
(3) Applications of 1,3-dipolar coupling to form [n]polynor-
bornane scaffolds: a) Butler, D. N.; Hammond, M. L. A.;
Johnston, M. R.; Sun, G.; Malpass, J. R.; Fawcett, J.;
Warrener, R. N. Org. Lett. 2000, 2, 721-724. b) Malpass, J. R.;
Butler, D. N.; Johnston, M. R.; Hammond, M. L. A.;
Warrener, R. N. Org. Lett. 2000, 2, 725-728. c) Schultz, A. C.;
Kelso, L. S.; Johnston, M. R.; Warrener, R. N.; Keene, F. R.
Inorg. Chem. 1999, 38, 4906. d) Warrener, R. N.; Schultz, A.
C.; Johnston, M. R.; Gunter, M. J. J. Org. Chem. 1999, 64,
4218. e) Warrener, R. N.; Margetic, D.; Amarasekara, A. S.;
Russell, R. A. Org. Lett. 1999, 1, 203. f) Warrener, R. N.;
Butler, D. N.; Russell, R. A. Synlett 1998, 556. g) Warrener,
R. N.; Margetic, D.; Amarasekara, A. S.; Foley, P. J.; Butler,
D. N.; Russell, R. A. Tetrahedron Lett. 1999, 40, 4111-4114.
h) Warrener, R. N.; Margetic, D.; Russell, R. A. Article 014,
Electronic Conference on Heterocyclic Chemistry ’98 1998,
H. S. Rzepa and O. Kappe (Eds), Imperial College Press.
i) Warrener, R. N.; Butler, D. N.; Russell, R. A. Synlett 1998,
566. j) Butler, D. N.; Malpass, J. R.; Margetic, D.; Russell, R.
A.; Sun, G.; Warrener, R. N. Synlett 1998, 588. k) Sun, G.;
Butler, D. N.; Warrener, R. N.; Margetic, D.; Malpass, J. R.
Article 062, Electronic Conference on Heterocyclic
Chemistry ’98 1998, H. S. Rzepa and O. Kappe (Eds), Imperial
College Press.
As mentioned in the introduction, direct addition to the -
bond of alkene 2 has not proved to be a fruitful route to
functionalised N,N’-methano-bridged [n]polynorbor-
nanes. Limited success was forthcoming from the reaction
of the aziridine 24 with the pincer adduct 2, however, the
1:1-adduct (m/z = 813.2475) that is formed lacks the ole-
finic protons expected for a product derived directly from
2. The 1H and 13C NMR spectral data support structure 25
(Scheme 6) which is considered to be derived from addi-
tion to the domino adduct 3, generated from 2 under the
thermal reaction conditions. A similar reaction of the N-
(methoxymethyl)aziridine 10a with 2 also follows this
path and leads to the formation of 27 (m/z = 607.1882), a
deprotected form of the initially-formed adduct 26. Disap-
pointingly, attempts to form a product with four N-bridges
by reaction of aziridine 10b with 2 were not rewarding.10
(4) Margetic, D.; Russell, R. A.; Warrener, R. N., unpublished.
(5) Butler, D. N.; Malpass, J. R.; Margetic, D.; Russell, R. A.;
Sun, G.; Warrener, R. N. Synlett 1998, 588-589.
(6) Ohwada, T.; Achiwa, T.; Okamoto, I.; Shudo, K. Tetrahedron
Lett. 1998, 39, 865-869.
Rare example of pincer diene 3 acting as a dipolarophile in CN3-
[4]polynorbornane formation
(7) Malpass, J. R.; Fawcett, J., unpublished.
(8) G. Sun PhD Thesis, Central Queensland University, Sept
2000.
Scheme 6
(9) Bohme, H; Viehe, H. G. "Iminium Salts in Organic
Chemistry" Adv. Org. Chem. 1976, Vol 9.
In conclusion, this ability to prepare N,N’-methano-
bridged compounds either by direct cycloaddition or by
neighbouring group participation opens up entry to a ver-
satile range of entirely new hetero-bridged [n]polynorbor-
nane frames. Such scaffolds can be used to modify
topology since molecular modelling shows that they are
less curved than the compounds lacking the N,N-methano-
bridge.11 The N-bridges are locked into a geometry corre-
sponding to the highly disfavoured syn,syn-invertomer
geometry of diazasesquinorbornanes, a feature which can
be exploited in the molecular design of polarofacial scaf-
folds. The neighbouring group participation route is not
restricted to N-C-N bridges and other examples will be re-
ported in due course.
(10) Reactions involving aziridines containing the N-Z-bridge as in
10b often fail with less-reactive dipolarophiles owing to the
competing fragmentation of the dipolar intermediate, e.g. 11b
to form N-Z isoindole and the related N-substituted pyrrole.
(11) Warrener, R. N. Eur J. Org. Chem. 2000, 3363-3380.
(12) Representative spectral details of new compounds: 10b 1H
NMR (CDCl3 at 60 °C) 2.36 (2H, s, H9,13), 3.50 (3H, s,
OMe), 3.77 (6H, s, CO2Me 2), 4.20 (2H, s, NCH2O), 5.03
(2H, s, CH2Ph), 5.76 (2H, s, H1,8), 7.16-7.44 (9H, m,
aromatic). 13C (CDCl3 at 60 °C) : 52.9, 57.7, 61.3, 62.1, 67.6,
80.8, 112.9, 121.3, 127.3, 128.2, 136.9, 156.4, 167.2, 183.6.
HRMS m/z calcd for C26H27N2O7: 478.1740, found 478.1721.
17: mp 207-208 °C 1H NMR (CDCl3) (ppm): 1.45 (1H, d,
J = 8.9 Hz), 1.87 (2H, s), 2.07 (2H, s), 3.10 (2H, s), 3.20 (1H,
Synlett 2001, No. 2, 202–205 ISSN 0936-5214 © Thieme Stuttgart · New York

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Neighbouring Group Participation in N-Methoxymethyl 7-Azanorbornanes
205
d, J = 8.9 Hz), 4.02 (6H, s), 4.20 (2H, s), 4.27 (2H, s), 7.03-
C21), 75.32, 75.38 (C1,12), 120.22, 120.68 (C5,8, C16,19),
127.40, 127.47 (C6,7, C18,19), 128.33, 128.48, 128.90,
C2',3',4' of Bn, 137.76 (C1' of Bn), 145.29, 145.32, 145.60,
145.78 (C4,C9,C15,C20), 153.21 (CO2Bn), 171.75, 171.80
(CO2Me, CO2Me). HRMS C35H31N3O6 requires 589.2213,
found 589.2219.
7.25 (8H, m), 13C NMR (CDCl3) (ppm): 44.5, 47.1, 50.6,
52.7, 54.4, 63.5, 67.5, 75.9, 120.4, 121.8, 126.2, 127.0, 145.2,
149.1, 171.7. HRMS m/z calcd for C28H26N4O2: 454.1893,
found 454.1901.
21 mp 135-137 °C. 1H NMR (CDCl3) 2.20 (2H, s, H2,11),
2.14 (2H, s, H13,22), 3.80 (3H, s, E), 4.07 (3H,s, E), 4.18 (1H,
s, H21), 4.23 (1H, s, H14), 4.39 (1H, d, J = 14.7 Hz,
NCHaHbN), 4.50 (1H, d, J = 14.7 Hz, NCHaHbN), 5.00 (1H,
d, J = 12.5 Hz, CHaHbPh), 5.04 (1H, s, H3/10), 5.14 (1H, d,
J = 12.5 Hz, CHaHbPh), 5.14 (1H, s, H10/3), 7.08-7.32 (13H,
m, aromatic). 13C NMR (CDCl3) 451.01, 51.05 (C13, C22),
52.81, 53.17 (CO2Me, CO2Me), 54.13, 54.59 (C2,C11), 62.29,
62.57 (C3,10), 63.74 (C26), 67.20 (Bn), 67.35, 67.41 (C14,
23 mp 160-161 °C. 1H NMR (CDCl3) 2.03 (4H, s, H2,11,
13,22), 3.83 (6H, s, 2 CO2Me), 5.04 (4H, s, 2 CH2Ph),
5.15 (4H, s, H3,10,14,21), 7.06-7.35 (18H, m, aromatic)
Article Identifier:
1437-2096,E;2001,0,02,0202,0205,ftx,en;Y18600ST.pdf
Synlett 2001, No. 2, 202–205 ISSN 0936-5214 © Thieme Stuttgart · New York